Cancer Treatment - Haskell, Charles M., 1939

UNIVERSITY OF CALIFORNIA
SAN FRANCISCO LIBRARY

-v- 1
c
^.ancer
Treatment
Edited by
CHARLES M. HASKELL, M.D.

Associate Professor of Medicine and Surgery,
UCLA School of Medicine
Director, Veterans Administration
Wadsworth Cancer Center and
Chief, Hematology-Oncology Section,
Medical and Research Services,
Veterans Administration Wadsworth
Medical Center,
Los Angeles, California 90073
Director for Clinical Programs,
GCLA Jonsson Comprehensive Cancer Center
QXlo.%
With 53 collaborators and a Foreword by

Sherman M. Mellinkoff,M.D.
Dean, UCLA School of Medicine
1980
W.B. SAUNDERS COMPANY
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Library of Congress Cataloging in Publication Data
Main entry under title:
Cancer treatment.
1. Cancer. I. Haskell, Charles M. [DNLM: 1. Neoplasms-

Therapy. QZ266C219]
RC270.8.C38 616.9'94'06 79-3926
ISBN 0-7216-4566-6
Cancer Treatment ISBN 0-7216-4566-6
© 1980 by W. B. Saunders Company. Copyright under the International Copyright Union.

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CONTRIBUTORS
All Faculty Appointments Are With the UCLA School of Medicine Unless Otherwise
Listed.
SAMUEL C. BALLON, M.D. JOSEPH W. CULLEN, Ph.D.

Assistant Professor of Gynecology and Professor, UCLA School of Public Health
Obstetrics, Stanford University School Physical Rehabilitation
of Medicine, Stanford, California
Gynecologic Neoplasms MAYER B. DAVIDSON, M.D.
Professor of Medicine
Endocrine Pancreas
ULRICH BATZDORF, M.D.
Professor of Surgery/Neurosurgery RICHARD M. DAVIS, M.D.
Neoplasms of the Nervous System; Pain Assistant Clinical Professor of Surgery
Syndromes Ph ys ica I Reh a b Hi tatio
MICHAEL BERMAN, M.D. JEAN B. deKERNION, M.D.

Assistant Professor of Obstetrics and Gyn- Associate Professor of Urology, Tulane
ecology, University of Pittsburgh. Ma- University School of Medicine, New
gee Women's Hospital, Forbes and Orleans, Louisiana
Halkett Streets, Pittsburgh, Pennsyl- Prostate; Rladder; Kidney
vania
Gynecologic Neoplasms FREDERICK R. EILBER, M.D-
Professor of Surgery
Principles of Cancer Surgery; Osteosar-
JOHN BEUMER, III, D.D.S.
coma, Ewing's Sarcoma, Soft Tissue
Associate Professor, UCLA School of
Sarcomas; Melanoma
Dentistry
Physical Rehabilitation
PETER M. FALK, M.D.
Assistant Clinical Professor of Pediatrics
WILLIAM H. BLAHD, M.D. Retinoblastoma
Thyroid Gland HENRY FEE, M.D.
Assistant Clinical Professor of Surgery,
University of Utah School of Medicine,
THOMAS C. CALCATERRA, M.D.
Salt Lake City, Utah
Professor of Surgery/Head and Neck
Mediastinal Tumors
Oral Cavity and Oropharynx; Nasal Cav-
ity and Paranasal Sinuses; Naso- STEPHEN A. FEIG, M.D.
pharynx; Salivary Glands; Larynx and
Associate Professor of Pediatrics
Hypopharynx
Childhood Solid Tumors
MARTIN J. CLINE, M.D. ERIC W. FONKALSRUD, M.D.

Bowyer Professor of Medical Oncology Professor of Surgery
The Histiocytic Malignancies Childhood Solid Tumors
in
It Contributors
ROBERT P. GALE, M.D. H. PHILLIP KOEFFLER

Associate Professor of Medicine Assistant Professor of Medicine
Acute Leukemia Chronic Leukemia; B Lymphocyte Neo-
plasms Capable of Immunoglobulin
HARVEY A. GILBERT, M.D. Synthesis
Assistant Clinical Professor of Radiation
Oncology
LEO D. LAGASSE, M.D.
Professor of Obstetrics and Gynecology
Mediastinal Tumors
Gynecologic Neoplasms
DAVID W. GOLDE, M.D. BARRY B. LOVVITZ, M.D.
Assistant Professor of Medicine
Chronic Leukemia; B Lymphocyte Neo-
Paraneoplastic Syndromes
plasms Capable of Immunoglobulin
Synthesis
HERBERT I. MACHLEDER, M.D.
Associate Professor of Surgery
H. EARL GORDON, M.D.
Vascular Tumors
Thyroid
LAWRENCE S. MILLER. M.D.
Assistant Clinical Professor of Medicine
PETER R. GRAZE, M.D.
Physical Rehabilitation
Associate Professor of Medicine, Uni-
versity of Nevada School of Medical
Sciences, Las Vegas, Nevada
DONALD L. MORTON, M.D.
Bone Marrow Failure
Principles of Cancer Immunology and
Immunotherapy; Melanoma
CHARLES M. HASKELL
Associate Piofessor of Medicine and
Surgery
H. STEPHENS MOSELEY, M.D.
Assistant Professor of Surgery, University
Introduction; Principles of Cancer Che-
of Oregon School of Medicine, Port-
motherapy; Drugs Used in Cancer Che- land, Oregon
motherapy; Breast Cancer; Gastroin-
Melanoma
testinal Tract Neoplasms; Multiple
Endocrine Neoplasia; Carcinoid Tu- DONALD G. MULDER, M.D.
mors; Adrenal Cortex Neoplasms; Professor of Surgery
Hodgkin's Disease
Mediastinal Tumors
JEROME M. HERSHMAN, M.D. ROBERT G. PARKER, M.D.

Professor of Medicine Professor of Radiation Oncology
Thyroid Principles of Radiation Oncology; Retino-
blastoma; Hodgkin's Disease; Pituitary
E. CARMACK HOLMES, M.D.
Professor of Surgery ZBIGMEW PETROVICH, M.D.
Lung Cancer; Parathyroid Carcinoma; Associate Professor of Radiation Oncology
Malignant Effusions Lung Cancer
GUY J. F. JUILLARD, M.D. KENNETH P. RAMMING, M.D.

Professor of Radiation Oncology Associate Professor of Surgery
Gynecologic Neoplasms; Oral Cavity and Gastrointestinal Neoplasms
Oropharynx; Nasal Cavity and Para-
nasal Sinuses; Nasopharynx; Larynx ROBERT W. RAND, M.D
and Hypopharynx Professor of Surgery
Pituitary
A. ROBERT KAGAN, M.D.
Associate Clinical Professor of Radiation ARTHUR L. ROSENBAUM, M.D.
Oncology Associate Professor of Ophthalmology
Non-Hodgkin's Lymphomas Retinoblastoma
Contributors
GREGORY P SARNA. M.D. RONALD K. TOMPKINS. M.D.

Medicine
\>sistant Professor of Professor of Surgery
Lung Cancer; Son-Hodgkin's Lympho- Endocrine Pancreas; Carcinoid Tumors;
mas Pheochromocijtoma; Adrenal Cortex
DONALD G SKINNER, M.D. WATSON WATRING. M.D.

Professor of Surgery. University of Associate Professor of Obstetrics and
Southern California School of Medi- Gynecology, Tufts University School of
cine, Los Angeles, California Medicine. Boston. Massachusetts
Testis Gynecologic Xeoplasms
ROBERT B. SMITH. M.D. THOMAS H. WEISENBURGER. M.D.

Associate Professor of Surgery Assistant Professor of Radiation
Oncology
Testis Osteosarcoma; Ewing's Sarcoma; Soft-
Tissue Sarcomas; Seoplasms of the
FRANK C. SPARKS. M.D. Nervous System; Childhood Solid
Professor of Surgery. University of Con- Tumors; Superior Vena Cava Syndrome
necticut School of Medicine. Farming-
ton. Connecticut DAVID K WELLISCH. Ph.D.
Breast Cancer Assistant Professor of Biobehavioral Sci-
ences
RICHARD A. STRICK. M.D. Psychosocial Problems of Cancer
Assistant Professor of Medicine in Derm-
atology JOHN H WITTIG. M.D
Skin Cancer Chief Resident in Thoracic Surgery
Malignant Effusions
HECTOR L. SULIT. M.D.
Assistant Clinical Professor of Ophthal- ROY T. YOUNG
mology \ >ociate Professor of Medicine
Ocular Malignant Melanoma Pheochromocijtoma
ALAN S. TESLER. M.D JACOB ZIGHELBOIM. M.D.

Assistant Professor of Radiation Oncology Assistant Professor of Medicine and Mi-
Gastrointestinal Neoplastics crobiology and Immunology
Acute Leukemia
RONALD \V THOMPSON. M.D.
Associate Professor of Radiation Oncology
Breast Cancer
FOREWORD
According to Professor Lynn White, Jr, the great medievalist, "The essence
of C. P. Snow's 'two cultures' (science and the humanities) is to be found in
Europe 600 years ago." Grammar, rhetoric, and logic were the "trivium."
Arithmetic, geometry, astronomy, and music (the study of acoustic propor-
tions) constituted the "quadrivium." For a time both the "trivium" and the
"quadrivium" were highly regarded by the same scholars. In this dichotomy
were the seeds of bitter fruit. As quadrivial studies burgeoned, the modern
meaning of "trivial" took shape. Quadrivial pursuits have been immensely
rewarding and productive, but they do not address the inescapable human
needs relating to ethics, beauty, courage, and the place of humans in the
cosmos. Human concerns are anything but trivial.
Innumerable discoveries in the "quadrivial" disciplines and their progeny
have subdivided science. Dr. Eugene Stead reminds us that relatively
recently the medical "school" has become in fact a "university." Even a
single topic like the treatment of cancer is the proper concern of a wide range
of doctors — from surgeons to psychiatrists.
Although it is of enormous importance to all, bridging the gap between the
"two cultures" is a particularly poignant need in medicine. Every patient
encompasses both scientific and human problems. Similarly, although in-
creasing specialization is a necessary accompaniment of rapidly increasing
knowledge, an effective faculty must somehow learn to avoid "gaps" among
the disciplines.
There seems to be no simple formula for bridging "gaps" — or better still
avoiding them — for ensuring that the patient does not suffer from the lack of
specialized information or from the lack of communication among the
specialists and with the patient. In the dean's office, where one feels in a
sense like an obligate general practitioner, it appears that interdisciplinary
cooperation and understanding are products of individual faculty characters
and interests. It is therefore with deep appreciation that I have observed
Dr. Charles M Haskell and his colleagues from disparate specialties working
harmoniously in the best interests of their patients, and hence in the best
interests of medical education.
This book is a valuable by-product of those harmonious labors. In the best
sense it is an artful blend of "trivium" and "quadrivium."
Sherman M Mellinkoff, MD
vii
PREFACE
Cancer Treatment was written as a succinct "state of the art" book for
physicians who are responsible for the overall care of patients with cancer.
The multidisciplinary nature of modern therapy is emphasized, as is the
critical importance of staging and the development of newer, experimental
approaches to treatment. This book is committed to exploring and defining
the current interfaces of the disciplines relevant to cancer therapy, including
surgery, radiation therapy, chemotherapy, and immunotherapy. To this end,
the text contains 5079 references, of which 399 are identified as key references
or reviews.
I selected the contributors for this book from my colleagues at UCLA,
including the School of Medicine, the Jonsson Comprehensive Cancer

Center, and the Veterans Administration Wadsworth Cancer Center. Although
some of these people have subsequently changed their institutional affiliation
and some of the topics reviewed are approached very differently by different
members of the UCLA community, this book is best thought of as a UCLA
effort. Indeed, the writing of this book served to define more clearly those
areas of agreement and disagreement as we continue to evolve improved
strategies of treatment for our cancer patients.
I wish to thank the following individuals for reviewing selected chapters
or providing general comments and advice on the development of this book:
Martin J Cline, MD, Robert G Parker, MD, Donald L Morton, MD, Robert
Lehrer, MD, Gregory P Sarna, MD, Peter R Graze, MD, Dennis Casciato,
MD, John H Fitchen, MD, Kenneth Melmon, MD, Michael Belzer, MD,
Susan Taylor, MD, Bradley R Straatsma, MD, Ronald Reisner, MD, Victor
Newcomer, MD, Harold Carlson, MD, and Christine Haskell. Linda Olt
provided invaluable editorial assistance throughout the process of writing
and preparing the manuscript, and final editorial review at WBSaunders
Company was provided by Jodi Kaye. Secretarial help was provided by
Patricia Gwyn, Susan Tucker, and Gwen Dangerfield, and the accuracy of
the references was verified by Roger Ianuzzi. Partial financial support was
generously provided by the Wald Foundation.
Charles M Haskell
June, 1979
IX
CONTENTS
PART I GENERAL PRINCIPLES
Chapter 1
INTRODUCTION 3
Charles M. Haskell
Chapter 2
PRINCIPLES OF CANCER SURGERY 8
Frederick R. Eilber
Chapter 3
PRINCIPLES OF RADIATION ONCOLOGY 19
Robert G. Parker
Chapter 4
PRINCIPLES OF CANCER CHEMOTHERAPY 37
Charles M. Haskell
Chapter 5
DRUGS USED IN CANCER
CHEMOTHERAPY 53
Charles M. Haskell
Chapter 6
CANCER IMMUNOLOGY AND
IMMUNOTHERAPY 124
Donald L. Morton James Goodnight
PART II TREATMENT OF SPECIFIC

NEOPLASMS
Chapter 7
BREAST CANCER 159
Charles M. Haskell Frank C. Sparks
Ronald W. Thompson
Chapter 8
LUNG CANCER 197
Gregory P. Sarna E. Carmack Holmes
Zbigniew Petrovich
xt
xii Contents
Chapter 9
GASTROINTESTINAL TRACT NEOPLASMS 231
Kenneth P. Ramming Charles M. Haskell
Alan S. Tesler
Section 1. ESOPHAGUS 233

Section 2. STOMACH 246
Section 3. SMALL BOWEL 262
Section 4. COLORECTAL MALIGNANCIES 265
Section 5. ANAL CANCER 304
Section 6. CANCER OF THE EXOCRINE
PANCREAS 308
Section 7. CANCER OF THE LIVER 319
Section 8. MANAGEMENT OF LESIONS
METASTATIC TO THE LIVER 325
Section 9. CARCINOMA OF THE
GALLBLADDER 334
Section 10. EXTRAHEPATIC BILE DUCTS 336
Section 11. AMPULLA OF VATER 342
Chapter 10
GENITOURINARY NEOPLASMS 358
Section 1. CANCER OF THE PROSTATE 358

Jean B. deKernion
Section 2. BLADDER CANCER 374
Jean B. deKernion
Section 3. RENAL CELL CARCINOMA 392
Jean B. deKernion
Section 4. TESTICULAR CARCINOMA 406
Donald G. Skinner Robert B. Smith
Chapter 11
GYNECOLOGIC NEOPLASMS 434
Samuel C. Ballon Leo D. Lagasse
Michael L. Berman Watson G. Watring
Guy J. F. Juillard
Section 1. GESTATIONAL TROPHOBLASTIC

DISEASE 434
Section 2. CARCINOMA OF THE
ENDOMETRIUM 442
Section 3. CANCER OF THE VULVA 457
Section 4. CANCER OF THE VAGINA 468
Section 5. CERVICAL CARCINOMA 476
Section 6. OVARIAN CANCER 492
Section 7. SARCOMAS OF THE UTERUS 515
Contents xiii
Chapter 12
HEAD AND NECK NEOPLASMS 522
Section 1. CANCER OF THE ORAL CAVITY

AND OROPHARYNX 522
T. C. Calcaterra Guy J. F. Juillard
Section 2. NASAL CAVITY AND PARANASAL

SINUSES 531
Section 3. NASOPHARYNX 535

Section 4. TUMORS OF THE SALIVARY
GLANDS 538
T. C. Calcaterra
Section 5. CANCER OF THE LARYNX AND
HYPOPHARYNX 547
Section 6. CHEMOTHERAPY OF HEAD AND

NECK CANCER 558
Jacob Zighelboim
Chapter 13
NEOPLASMS OF THE EYE 569
Section 1. RETINOBLASTOMA 569

Arthur Rosenbaum Peter Falk
Robert G. Parker
Section 2. OCULAR MALIGNANT MELANOMA 577
Hector L. Sulit
Chapter 14
ENDOCRINE TUMORS 586
Section 1. MULTIPLE ENDOCRINE

NEOPLASIA 586
Charles M. Haskell
Section 2. PARATHYROID CARCINOMA 588
E. Carmack Holmes
Section 3. THYROID GLAND 591
Jerome M. Hershman William H. Blahd
H. Earl Gordon
Section 4. ENDOCRINE PANCREAS 603
Ronald K. Tompkins Mayer B. Davidson
Section 5. CARCINOID TUMORS 609
Charles M. Haskell Ronald K. Tompkins
Section 6. PHEOCHROMOCYTOMA 620
Ronald K. Tompkins Roy T. Young
Section 7. ADRENAL CORTEX NEOPLASMS 627
Ronald K. Tompkins Charles M. Haskell
Section 8. PITUITARY TUMORS 633
Robert W. Rand Robert G. Parker
xiv Contents
Chapter 15
NEOPLASMS OF THE MUSCULOSKELETAL
SYSTEM 655
Section 1. OSTEOSARCOMA 655

Frederick R. Eilber Thomas Weisenburger
Section 2. EWING'S SARCOMA 662
Thomas Weisenburger Frederick R. Eilber
Section 3. SOFT-TISSUE SARCOMAS 667
Frederick R. Eilber Thomas Weisenburger
Chapter 16
MELANOMA 678
H. Stephens Moseley Frederick R. Eilber
Donald L. Morton
Chapter 17
SKIN CANCER 695
Richard A. Strick
Chapter 18
NEOPLASMS OF THE NERVOUS SYSTEM 726
Ulrich Batzdorf Thomas H. Weisenburger
Section 1. BRAIN 726

Section 2. SPINAL CORD 747
Chapter 19
CHILDHOOD SOLID TUMORS 759
Eric W. Fonkalsrud Stephen A. Feig
Thomas H. Weisenburger
Section 1. NEUROBLASTOMA 759

Section 2. WILMS" TUMOR 767
Chapter 20
MISCELLANEOUS SOLID TUMORS 778
Section 1. MEDIASTINAL TUMORS 778

Donald G. Mulder Henry Fee
Harvey A. Gilbert
Section 2. VASCULAR* TUMORS 792
Herbert I. Machleder
Chapter 21
ACUTE LEUKEMIA 802
Jacob Zighelboim Robert P. Gale
Section 1. ACUTE LYMPHOBLASTIC

LEUKEMIA 805
Section 2. ACUTE MYELOGENOUS LEUKEMIA 820
Contents *«
Chapter 22
CHRONIC LEUKEMIA 832
H. Phillip Koeffler David W. Golde
Section 1. CHRONIC MYELOGENOUS LEUKEMIA... 832

Section 2. CHRONIC LYMPHOCYTIC LEUKEMIA 841
Chapter 23
B LYMPHOCYTE NEOPLASMS CAPABLE
OF IMMUNOGLOBULIN SYNTHESIS 853
David W. Golde H. Phillip Koeffler
Chapter 24
HODGKIN'S DISEASE 866
Charles M. Haskell Robert Parker
Chapter 25
NON-HODGKIN'S LYMPHOMAS 905
Gregory P. Sarna A. Robert Kagan
Chapter 26
THE HISTIOCYTIC MALIGNANCIES 952
Martin J. Cline
PART III MANAGEMENT OF SELECTED

COMPLICATIONS OF CANCER AND
CANCER TREATMENT
Chapter 27
BONE MARROW FAILURE: MANAGEMENT
OF ANEMIA, INFECTIONS, AND BLEEDING
IN THE CANCER PATIENT 961
Peter R. Graze
Chapter 28
COMPLICATIONS CAUSED BY ORGAN
COMPRESSION 984
Section 1. MANAGEMENT OF MALIGNANT

PLEURAL EFFUSIONS 984
John H. Wittig E. Carmack Holmes
Section 2. SUPERIOR VENA CAVAL
SYNDROME 990
Thomas H. Weisenburger
Chapter 29
PARANEOPLASTIC SYNDROMES 994
Barry B. Lowitz
xvi Contents
Chapter 30
PAIN SYNDROMES IN MALIGNANT
DISEASE 1009
Ulrich Batzdorf
Chapter 31
PHYSICAL REHABILITATION 1021
Lawrence S. Miller Richard M. Davis
John Beumer, 111 Joseph W. Cullen
Chapter 32
PSYCHOSOCIAL PROBLEMS OF CANCER 1036
David K. Wellisch
Appendix A
NOMOGRAPH FOR CALCULATING THE BODY
SURFACE AREA OF ADULTS 1046
Appendix B
PER CENT OF NORMAL BONE MARROW
IRRADIATED USING STANDARD
RADIATION PORTS 1048
Appendix C
SELECTED ABBREVIATIONS 1049

Selected Organizations, Societies and
Proceedings 1049
Selected Drug Abbreviations 1050
Selected Drug Combinations (Acronyms) 1051
Miscellaneous Abbreviations 1051
INDEX 1053
Part I
GENERAL
PRINCIPLES
CHAPTER 1
INTRODUCTION
Charles M Haskell
The scope of clinical oncology has expanded dramatically during the past
decade. Special services that contribute to cancer patient care can be provid-
1
ed by a variety of professionals: surgeons, radiation therapists, medical on-

cologists, nurses, psychologists, psychiatrists, nutritionists, pharmacists, so-
cial workers, and rehabilitation specialists. The magnitude of the cancer
problem warrants such a broadly based clinical commitment (Fig. l-l). 2
The expanded and diversified attack on cancer has achieved some success. 3
The application of basic research findings in clinical trials of new treatments
and preventive measures can provide urgently needed progress. 4 Advances in
clinical oncology will be possible only if such basic and applied research is
accompanied by adequate economic support and a willingness of patients and
physicians to participate. Without this cooperation, we run the risk of perpet-
uating the use of marginally effective methods, procedures, and drugs.
This book represents the authors' attempt to define contemporary multidis-
ciplinary cancer treatment. Part I consists of this introductory chapter, which
provides a synopsis of cancer, followed by the principles of surgery, radiation
therapy, chemotherapy, and immunology as they relate to cancer treatment.
Chemotherapy is extensively covered, since all cancer specialists need ready
access to this information. The disease-oriented chapters that follow in Part II
discuss the contemporary role of each of the oncologic specialties in cancer
treatment, and Part III deals with selected complications of cancer and their
treatment.
NATURAL HISTORY OF CANCER

Most neoplasms appear to arise from a single cell that undergoes malignant
transformation. 5 The subsequent growth of this cell as a clone can lead to
additional sublines whose acquired genetic variability allows more aggres-
sive behavior. Tumor cells may be less genetically stable than normal cells —
possibly from the activation of specific gene loci, continued presence of
carcinogens, the development of abnormal DNA repair mechanisms, or even
nutritional deficiencies within the tumor. The inherent genetic instability of
I / General Principles
1979 ESTIMATED CANCER INCIDENCE BY SITE AND SEXt

2% SKIN
SKIN 2%
2% ORAL
ORAL 5% 27% BREAST
8% LUNG
LUNG 22%
COLON &
COLON & 15% RECTUM
RECTUM 3% PANCREAS
PANCREAS 4% OVARY
13% UTERUS
PROSTATE
4% URINARY
URINARY
LEUKEMIA &
LEUKEMIA & 7% LYMPHOMAS
LYMPHOMAS 8%
15% ALL OTHER
ALL OTHER 19%
tExcluding non-melanoma skin cancer and carcinoma in situ.
1979 ESTIMATED CANCER DEATHS BY SITE AND SEX

y 1% SKIN
SKIN 1% — y/\ 1% ORAL
ORAL 3% — ^y\./ u% 19% BREAST
LUNG
LUNG 34%
COLON &
COLON & y 15% RECTUM
RECTUM 12%
-«,
\^ /^ 5% PANCREAS
PANCREAS . 6% OVARY
^~ 6% UTERUS
PROSTATE 10% ^\/ ^^
URINARY 5%' / 3% URINARY
LEUKEMIA &
LEUKEMIA & 9% LYMPHOMAS
LYMPHOMAS 9% 21% ALL OTHER
ALL OTHER 21%
FIGURE 1-1. Cancer incidence and deaths by anatomic site and sex for
1979. It has been estimated that more than 700,000 people in the United
States will develop one of these forms of cancer in 1979 and that more than
half of these cases will result in death. 2 (Reproduced with the permission of
the author and the American Cancer Society.)
these cells, accompanied by variable processes of cell loss and selection, can
result in advanced neoplasms Wrth unique biologic and cytogenetic
"
characteristics. 5These changes may be further accentuated by cancer treat-
7
ment, as seen in the development of drug-resistant cancer cells. It is possible

that the use of multiagent or multimodality therapy, as discussed in sub-
sequent chapters, may minimize this risk.
Cancer may remain a localized invasive process or it may spread to noncon-
tiguous sites. Some neoplasms
exhibit a relatively orderly pattern of progres-
sion. these tumors grow locally, and as they grow, tumor cells
Initially,
spread to and colonize the regional nodes. Finally, and only with very ad-
vanced size, distant metastases occur. However, it is also clear that other
1 / Introduction
tumors nun metastasize to distant organs prior to or coincident with their

spread to regional lymph nodes. These disparate patterns of tumor spread
underline the importance of defining the extent of disease in a patient with
cancer. By understanding the natural history of the cancer in question and the
individual characteristics of the patient, an optimal, yet reasonable, diagnostic
strategy for assessing the extent of tumor spread can be applied.
ASSESSMENT OF PROGNOSIS
Anatomic Staging
For most types of malignant neoplasms the extent or stage of disease is a

8 10
"
critical determinant of prognosis and treatment. Thus, throughout this book

specific recommendations for a staging work-up are given, based on the
natural history of each cancer type, and treatment recommendations for pa-
tients with various neoplasms are presented as a function of the stage of the
tumor. Although we have generally used the 1978 American Joint Committee
\JC) recommendations for clinical and postsurgical staging, in some in-
8
stances we retained well-established and widely employed alternative stag-

ing systems as preferable guides to management.
Miscellaneous Factors
A variety of other factors have been proposed as important prognostic

variables for patients with cancer. 11 Examples include the patient's immun-
ologic function 12 (see Chapter6), the performance status of the patient (dis-
cussed in Chapter 4), the presence of complicating non-neoplastic diseases, 13
the duration of symptoms, 14 and even the site of dominant metastases in
patients with more advanced tumors. 15 When appropriate, these factors will
be discussed in the disease-oriented chapters of this book.
CHOICE OF THERAPY
Treatment Goals
The concern in establishing a treatment plan should be the quality of

first
the patient's life. This involves a careful assessment of the projected impact of
the tumor and its treatment on the individual patient. There is no simple
formula for dealing with this question, but it must be given careful consider-
ation as soon as possible after diagnosis and be re-evaluated as events dic-
tate.
The second major concern is the potential impact of the tumor and its
treatment on the duration of the patient's life. Traditionally, treatment of
I / General Principles
curative intent has been distinguished from that of palliative intent. "Cure"
has been achieved when group
a. of treated cancer patients has the same death
rate as an age- and sex-matched population of individuals without cancer. 16
Cure is not simply equivalent to surviving with no evidence of disease (NED)
for some arbitrary period, such as three, five, or even ten years. For example,
patients with primary breast cancer are at risk of recurrence for life. 17 At no
time does this group of patients have a normal life expectancy, although many
individuals within it may attain a "normal" cancer-free survival. Strictly
speaking, breast cancer cannot be cured, but it may be inappropriate and
psychologically devastating for a patient to be labeled incurable. The patient
may grossly misinterpret incurable as meaning untreatable or uncontrollable
or even terminal. Indeed, the chances of living for five or ten years with no
evidence of disease may be substantial, and treatment may be associated with
a major improvement in both the quality- and duration of life.
Since the majority of cancer patients are not curable by the definition used
here, it follows that most of our treatment efforts are palliative. It is widely
held that some treatment- related morbidity and even the risk of mortality may-
be justified for patients with potentially curable tumors, whereas such risks
are less acceptable for patients for whom the treatment goal is palliation.
To summarize, one must consider the quality and expected duration of life
in both relative and absolute terms when establishing a treatment plan. The
potential for true cure should be assessed, but one should be alert to the
dangers of misusing the term in dealing with individual patients. It is also
important to remember that life itself is a terminal condition: It is not a
question of whether an individual will die, it is a question of how and
when.
Integrated Cancer Treatment

(Multimodality Therapy)
The importance of integrating the cancer treatment modalities is generally

recognized. The local control of cancer is commonly attempted with surgery
or radiation therapy. However, local therapy is not capable of controlling
systemic disease, and the proper timing of systemic treatment is controversial.
In childhood tumors, such as Wilms' tumor or Ewing's sarcoma, it is used
immediately after local therapy. In adults with cancer, the value of such early
systemic treatment is less well established but is under active investigation. 18
The theoretic basis for such adjuvant or combined modality- treatment is
presented in Figure 1-2.
The task of appropriately integrating cancer treatment may be difficult and
complex. In some hospitals tumor boards contribute to this function, but their
practical value is limited. In many instances the patient's welfare depends on
the ongoing services of a flexible and sophisticated treatment team. For such
patients a team leader should be identified. Modern cancer treatment is too
dynamic and complex to succeed without good communication as well as the
requisite technical competence of individual physicians.
1 / Introduction
Death
\
Pol Hat ion
AA /
/ ' /
/
V
/ /
V /C/ 2
t
TIME
FIGURE 1-2.Schematic diagram of the natural history and treatment of a
tumor. A cancer cell population of 10 10 cells corresponds to 10 gm of tumor,
and 10 n cells correspond to 1 kg of tumor. Curve A ( ) shows the growth
curve for an untreated cancer. The tumor doubles about 30 times by cell
division before becoming clinically evident. Line B ( ) shows the result
of successful local treatment undertaken prior to metastatic spread. Lines C,

and C 2 illustrate two ways of adding systemic chemotherapy to local treat-
ment, depicted as vertical arrows. In C 2 ( ) systemic chemotherapy used
for clinically evident cancer is palliative; it fails because of cancer cell

resistance or patient intolerance to chemotherapy. In Ci ( ) systemic
chemotherapy is used immediately after local treatment in a patient with a

high risk of recurrence from clinically occult "micrometastases." The goal of
this "adjuvant" treatment is to eradicate the occult cancer before it becomes
resistant to chemotherapy or the patient develops unacceptable toxic reac-
tions.
PROSPECTS FOR THE FUTURE

We are midst of a scientific revolution with important implications for
in the
cancer treatment. 19,20 The biochemical basis of gene action is being dis-
covered by molecular biologists using recombinant DNA techniques. This
may reveal totally new approaches to cancer prevention and treatment.
The study of cancer etiology and epidemiology has identified a variety of
potential environmental carcinogens, and the probable mechanisms of viral
"
and radiation carcinogenesis are being clarified. 20 22 Hopefully, these studies
will permit us to identify individuals with increased risks of cancer so that
earlier diagnoses and more effective treatment modalities may be offered.
This work may also provide the tools to prevent cancer by averting expo- —
sure to carcinogens or, possibly, by providing preventive therapy with drugs
or vaccines.
Meanwhile, we are faced with the tremendous problems posed by the
patient with clinically apparent cancer. This book is intended to serve as a
guide for those involved with the care of such patients.
8 I / General Principles
References (Asterisk indicates key reference)
1. National Cancer Program: The Strategic- 12. HarrisJE and Sinkovics JG: The Im-
Plan DHEW Publ No (NIH) 74^569, munology of Malignant Disease. 2nd
Washington DC, Government Printing ed, St. Louis, The CV Mosbv Co,
Office, 1973. 1976.
2. SilverbergE :CA 29:6, 1979. 13. Lowitz BB and Benjamin RS: West J Med
3. Cutler SJ, etal.: N Engl J Med 293:122, 127:5, 1977.
1975. 14. Feinstein AR: N Engl J Med 279:747,
4. Carbone PP: Ann Intern Med 88:703, 1968.
1978. 15. Slack NH, Bross IDJ: Br J Cancer 32:78,
5. Nowell PC: Science 194:23, 1976. 1975.
6. Medawar P: Ann Intern Med 87:100, 16. Easson E: Cancer 19:345, 1966.
1977. 17. Mueller CB and Jeffries W: Ann Surg
7. Fidler IJ and Kripke ML: Science 182:334, 1975.
197:893, 1977. 18. Salmon SE and Jones SE (eds): Adjuvant
*8. American Joint Committee for Cancer Therapy of Cancer. New York,
Staging and End-Results Reporting: Elsevier-North Holland Pub Co,
Manual fur Staging of Cancer 1978. 1977.
(Address: 55 E. Erie St., Chicago, 19. Shimkin MB: Contrary to Nature. Wash-
111.) ington DC, US DHEW
Publ No (NIH)
9. TNM Classification of Malignant Tu- 76-720, 1977.
mours. 3rd ed, Geneva, International 20. Fortieth Anniversary Issue: J Natl Can-
Union Against Cancer, 1978. cer Inst 59 (suppl):545, 1977.
10. Carbone PP, et al.: Cancer Res 31: 1860, 21. Wynder EL and Rauscher FS Jr (eds):
1971. Semin Oncol 3:1, 1976.
11. Staquet MJ (ed): Cancer Therapy: Prog- 22. Proceedings of the Conference on Can-
nostic Factors and Criteria of Re- cer Epidemiology and the Clinician:
sponse. New York, Raven Press, 1975. Cancer 39:1769, 1977.
CHAPTER 2
PRINCIPLES OF
CANCER SURGERY
Frederick R Eilber
INTRODUCTION
the oldest and most tested therapeutic modality- for the
Surgical excision is
treatment of cancer. Early surgical attempts, however, often resulted in the

death of the patient or rapid local recurrence of the malignant neoplasm.
Outcomes such as these were largely due to operative and immediate postop-
erative problems, such as excessive blood loss, difficult anesthesia, and res-
piratory insufficiency, all of which required a hurried, suboptimal operation.
With advances such as blood transfusions, the use of antibiotics, tracheostomy
2 / Principles of Cancer Surgery
toprevent airway obstruction, and nasogastric decompression of the stomach,

the surgical treatment of cancer became safe and effective. Operative deaths
were greatly reduced, and therapeutic results improved.
Despite these major advances in the surgical pre- and postoperative care of
patients, soon became clear that surgical treatment of malignant neoplasms
it
was a "limited" type of cancer therapy. We now realize that surgical tech-
niques are effective only in the area of the primary tumor or regional lymphat-
ics and do nothing for the neoplasm outside the operative field. There have
been numerous attempts to extend the operative procedure to encompass
additional contiguous anatomic structures —
for example, the supraradical
operations for carcinoma of the stomach and breast; these attempts, by and
large, have not proven efficacious. The surgical excision is not at fault, since
tumor spread is already well beyond the confines of the operative field.
In order to understand the principles of cancer surgery, it is helpful to
divide its application into four basic topics: (1) diagnostic biopsy, (2) the
surgical treatment of the primary tumor, (3) the treatment of regional lymphat-
ics and metastases, and (4) the combination of various modes of therapy. A
discussion of these principles will be followed by guidelines for integrating
surgery into a treatment plan for the individual patient.
DIAGNOSTIC BIOPSY
Since different types of neoplasms have their own responses to the various
modalities of therapy, a histologic diagnosis is imperative in planning the
appropriate management of malignant disease. For example, cancer of the
parotid gland is not a single disease, since there are at least ten different
histologic types of cancer of this gland, each with a different response and
cure rate. An accurate histopathologic diagnosis may therefore be critical in
tailoring the surgical procedure to the needs of the patient.
Biopsy is a crucial procedure in the diagnosis of malignant disease in that it
provides the pathologist with adequate samples of tumor. Adequate, in this
instance, means a fragment of tissue that is representative of the tumor —
neither crushed nor contaminated. Careful handling of the tissues is mandato-
ry. Noncrushing techniques to preserve nodal architecture, electron microsco-
py for sarcomas, and immediate touch preparations for lymphomas may be

needed for histopathologic diagnosis.
Several biopsy techniques are available to the practicing physician, which
include exfoliative cytology, punch biopsy, incisional biopsy, excisional biop-
sy, shave biopsy, and needle aspiration biopsy.
In planning the type of biopsy to be used and the site to be sampled it is
very important to consider the eventual methods of treatment. If surgery is
contemplated, the biopsy should be performed by an individual familiar with
the various surgical procedures. Tumors have a propensity for seeding and
contaminating biopsy incisions; therefore, when en bloc surgical procedures
are performed, it is essential to include the biopsy site or incision in the
subsequent operation. A biopsy site that is far removed from the potential
operative incision can severely jeopardize later attempts for surgical control of
will result in a compromised operation or in severe wound healing

tumor and
problems.
Since the core of many neoplasms is necrotic and sometimes infected, it is
usually preferable to perform the biopsy at the periphery of the tumor, specifi-
cally at the interface of the advancing tumor margin. In addition to providing
less necrotic tissue, a biopsy at the tumor margin affords the pathologist an
opportunity to evaluate the invasion of normal tissue. Many tumors have a
very low mitotic rate, and, therefore, their cytologic features (e.g., of the
parathyroid gland) are insufficient for determining malignancy; thus, their
invasive characteristics may be the only clue to tumor type.
Lymph node biopsy deserves further comment. Before this technique is
employed in the head and neck area, the primary tumor needs to be iden-
tified. Examination should include palpation and direct or indirect visualiza-
tion of the oral cavity, oropharynx, hypopharynx, and larynx. If the primary
1
tumor site is found, a biopsy of it should be performed. Such a biopsy may be

more meaningful, and it may spare the neck a scar, which itself could make
subsequent evaluation and surgical procedures more difficult.
Needle biopsy has several advantages over incisional or excisional biopsies.
It is easier to perform, has fewer complications, and causes little tissue
reaction. The primary prerequisite for this method is the pathologist's famil-
iarity with the interpretation of needle biopsy specimens. Second, an ade-
quate quantity and quality of tissue must be obtained. The major drawback of
needle biopsy is a false-negative result if the malignant tumor is missed by the
needle.
In summary, biopsy for histologic diagnosis is a crucial technique in the
management of the cancer patient. All too often, the biopsy procedure has
been performed by an inexperienced surgeon who does not appreciate the
importance of the procedure and its role in subsequent treatment. Inappro-
priate biopsy by the wrong person often results in a pathology report stating
"tissue inadequate for diagnosis; suggest rebiopsy." Biopsy should be per-
formed only by a surgeon trained and prepared to undertake definitive
surgical treatment.
TREATMENT
Primary Tumor
The primary goal of all cancer surgery is the complete eradication of the
localand regional tumor. The biology and natural history of each neoplasm
must be taken into consideration before any surgical procedure is undertaken.
Knowledge of the most common avenues of spread for the various histologic
types of neoplasm is essential for ultimate success in primary tumor therapy.
This involves obtaining adequate margins of normal tissue surrounding the
neoplasm.
The techniques of cancer surgery are nearly identical to those of general
surgery except for the following: (1) A bloodless surgical field is necessary
during a cancer operation because the appearance of the tissue is very impor-
I Principles of Cancer Surgery 11
tumor spread. 2 In order to achieve a

tant in terms of gross visualization of
wide surgical margin of normal uninvolved tissue, the line of incision should
not contain visible or palpable tumor. This differs from other types of general
surgery in that liberal frozen sections of the operating margins are a neces-
sity. These margins must include any suspicious areas, the limits of the
surgical excision in depth and length, and the margins of the adjacent nerves
in neoplasms that have the potential for perineural spread. If the tumor is
visualized, the wide normal tissue margin required has not been achieved.
Finally, and most important, in order to accomplish adequate removal of the
neoplasm, the cancer surgeon must employ a three-dimensional approach to
the tumor, including its length, width, and depth. This should be carefully
planned before the operation, so that the margins of the procedure will be
adequate and assure normal tissue planes.
Table 2-1 gives examples of the most common neoplasms encountered and
the essential adequate tissue margin required for complete surgical therapy.
The rationale for an "adequate" tissue margin is based on the fact that surgical
excisions that do not include a given amount of normal tissue result in a high
recurrence rate, even though the tumors appear to be grossly excised
eared"). Obviously, this reasoning must take into account the biology of
the particular neoplasm in terms of its ability to spread through the organ.
whether mucosally or submucosallv along fascial planes or along nerves.
,
A problem that is not uncommon for the cancer surgeon is to find that the
final report from the pathologist shows a less than adequate margin. At this
juncture his option is to operate, to do nothing but careful follow-up, or to
employ adjuvant chemotherapy or radiotherapy. In this setting, the word
"adjuvant" often is used to cover an inadequate surgical procedure. The
surgeon should assess the potential morbidity and mortality of reoperation,
which must encompass not onlv the positive margin but the entire operated
field.
The final area of consideration concerns the reconstruction of the primary
tumor site. The goals of surgical treatment for cancer patients should include
eradication of the cancer, associated with satisfactory physiologic function
and acceptable cosmetic results. All too often, the large, extensive surgical
TABLE 2-1. Adequate Normal Tissue Margins for

Primary Malignancy Treated by Surgery Alone
Histology Normal Tissue Margin
Melanoma 5 ~n — fasc _ 5 face)
Sarcoma Origin to insertion of involved muscle! s) and fascia or one

joint above for bone
Breast Entire breast
Colon 5 cm
Squamous cell carcinoma of 2 cm minimum

head and neck
procedures are time consuming, and very important decisions or procedures

for subsequent functional or cosmetic results may occur at the end of the
procedure when the surgeon is fatigued. Many authors suggest that the prima-
ry excision be followed by a tumor-free period before any reconstructive
procedures are initiated. This principle, although sound, imposes multiple
operations and severe cosmetic deformities on many patients. An alternative
approach to this problem is the surgical team method, in which one member
of the team is responsible for ablating the tumor without concern for preserva-
tion of adjacent tissues for reconstruction, while the second member performs
the reconstruction without concern for the tumor excision. This team ap-
proach enables the first surgeon to be somewhat more aggressive than if he
had to be concerned with the ability to reconstruct.
Local Wound Seeding
Although the most efficacious method for preventing local recurrence is

wide excision, several additional principles are worthy of discussion. A key
consideration is to widely encompass any biopsy incision or needle track into
the en bloc excision.
Numerous techniques have been attempted to prevent seeding of tumors
into the operative field or transplanting tumor cells from the primary tumor to
another site. These include irrigation of the wound with tumoricidal solu-
tions, such as V2 per cent formaldehyde or sterile water, to lyse any residual
cells that may be present, or the use of various "no-touch" techniques, which
include minimal palpation of the tumor and early ligation of the blood supply
to prevent any dislodgement of the tumor cells into the venous circulation
during the time of the operation. 2 These techniques have been extended in
some cases to the application of a tourniquet to the extremities prior to
performing a biopsy to prevent dissemination of the tumor.
Early ligation of the blood supply, wide normal tissue margins, and never
seeing the tumor necessitate a much more radical surgical procedure in order
to achieve wound healing than does a lesser excision. Although these various
techniques to reduce local recurrence are controversial, their theoretic value
has led to their widespread acceptance.
If a second area of the body requires operation at the time of tumor excision,
all gloves and instruments must be changed. This principle further prevents
any wound seeding or transplantation of tumor cells from the primary tumor to
a distant site. These precautions should be routinely employed when a skin
graft is required to cover defects, since there have been numerous instances of
seeding various solid neoplasms to the distant skin graft donor site. Thus, the
same principles that prevail for operating on infectious processes must be em-
ployed to prevent seeding to a distant wound.
Regional Lymphatics
In addition to contiguous spread, most solid tumors have a propensity for

dissemination via local lymphatics to the regional lymph nodes. Therefore,
2 Principles of Cancer Scrgery 13
careful surgical consideration must be given to the regional lymphatics and

the possibility of regional node dissection.
Attempts to sample one regional lymph node in order to determine nodal
spread have not been of value because examination of a single node does not
ensure the absence of occult metastases in adjacent nonexcised nodes. Fur-
thermore, in patients with palpable disease in the neck, it has been found that
once the size of a lymph node exceeds 3 cm, the tumor is extranodal and
involves the perinodal fat and the lymphatic channels. Local excision of the
area is inadequate for treatment of the perinodal spread. Therefore, surgical
techniques for en bloc excision of regional lymph nodes have been devised
for the neck, axillae, and pelvic and inguinal areas.
If a regional lymphadenectomy is contemplated for the treatment of clini-
cally evident regional metastases or as a means of histologic determination of
the stage of disease, the appropriate regional lymph nodes must be dissected.
Two nodal areas deserve emphasis because they tend to be overlooked. The
first is the parotid group of lymph nodes. Squamous carcinomas, basal cell
cell
carcinomas, and melanomas of the forehead, cheek, and scalp region drain
primarily to this area. 3 Since these lymph nodes are within the capsule of the
parotid gland, it is obvious that in order to remove them, a superficial parot-
idectomy is required. Failure to perform such a procedure leav es potentially
malignant nodes in the intervening parotid lymphatic-
The second group of nodes is associated with carcinoma of the central or
inner quadrants of the breast. Tumors in these locations have a great propen-
sity for metastases to the internal mammary group of lymph nodes.
4
An
operation such as the standard radical mastectomy neither removes the inter-
nal mammary nodes nor prov ides accurate staging information. In response to
this. Urban devised an operation to remove these nodes along with the chest
wall. However, this procedure is not widely used because of its magnitude,
the possibility of complications, and the lack of proof that it prolongs survival.
As an alternative, the "trap door" procedure of Yonemoto et al. 3 may be used
to sample these nodes for use in establishing the patient's prognosis and the
potential need for adjunctive treatment.
Distant Metastases
All too often the patient with disseminated disease is treated for terminal
disease and not a candidate for surgical procedures. It must be emphasized

is
that there is a certain percentage of these patients, albeit a small one, with
truly isolated metastases that are amenable to a complete surgical excision.
Such metastatic sites include the solitary cerebral or hepatic metastasis; pul-
monary metastases; either an isolated metastasis after a long, disease-free
interval or those metastases that are multiple but have a prolonged doubling
time associated with a controlled primary; multiple subcutaneous metastases
that present cosmetic problems; and bowel metastases that cause life-threat-
ening obstruction or bleeding. Surgical treatment for these metastatic le-
sions may result in long-term tumor control or even cure. Significant pallia-
tion has been achieved in most patients, and a small percentage (less than 10
per cent) has been ultimately cured. 6 To deny these patients the potential
benefit of surgical treatment is inappropriate.
Additional surgical treatment for patients with distant metastases should
include the placement of intrahepatic catheters for infusion chemotherapy.
Attempts at dearterialization of the liver and hepatic artery ligation, combined
with infusion, have been numerous and are, by and large, experimental.
However, the results obtained from the placement of an intra-arterial catheter
for 5-fluorouracil (5-FU) infusion for inoperable hepatoma have provided
significant long-term palliation. Although catheters can be placed percutan-
eously via the brachial or femoral route, their placement directly into the
hepatic artery at laparotomy provides problem-free, long-term function and
less impairment of normal activity.
Radiation Therapy
Much has been written about the combination of surgery and radiation
therapy for the management of cancer, and this topic is discussed in detail in
Chapter 3. In general, two settings for combining these modalities can be
identified: (1) preplanned combined modality treatment, as discussed in
many chapters in this book, and (2) radiation therapy, which may be employed
as a "rescue" technique when the surgical procedure has proven incomplete
or inadequate. In the latter setting, high-dosage radiation may be required for
control, the major difficulty being local complications, including difficult
wound healing. This should be anticipated if possible, and techniques should
be employed that will minimize this problem. Specifically, single incisions, as
opposed to multibranched ones, should be performed, and every effort should
be made to cover major blood vessels. This is especially important in the groin
and the neck, where carotid and femoral ruptures are often fatal. In these
areas, covering an exposed artery with skin or muscular flaps has proven to be
of great value. As a final concern, preoperative radiation therapy in some areas
may predispose the patient to the formation of a fistula. In some cases, a
controlled fistula may be preferred, such as the use of a pharyngoscope to
prevent leakage of saliva into an irradiated field. 7
Chemotherapy
Surgical procedures for patients who are receiving chemotherapy require

any, alteration. In most instances, local tissue healing has not been a
little, if
significant problem. The major difficulties involve hemostasis in patients who

are pancytopenic or thrombocytopenic. In these instances, platelet transfu-
sions may be necessary. Considering the necessary normal fibroblastic repair
process that must take place for surgical healing, one must consider the
duration of fibroblast suppression by the various chemotherapeutic drugs.
There are very few quantitative data on this question, but certain guidelines
appear reasonable. For methotrexate (MTX) and the alkylating agents, the
maximum usually about a week, and, if possible, the surgical proce-
effect is
dure should be delayed until after this period. Doxorubicin (Adriamycin),

2 / Principles of Cancer Surgery 15
dimethyltriazenoimidazolecarboxamide (dacarbazine) (DTIC), and the nitro-

soureas affect fibroblasts for 10 to 16 days, and operative procedures should
therefore be postponed longer if possible. Obviously, in emergency situa-
tions, operations can and have been performed on patients under less than
ideal circumstances, and wound healing has not been significantly delayed.
The use of stay sutures in abdominal incisions for patients on large doses of
chemotherapy has been useful.
Because many patients require long-term chemotherapy, there may be a
problem with collapse of the accessible venous system after prolonged drug
infusion. This may be severe enough to warrant the creation of an arterioven-
ous (AV) shunt by anastomosis of an artery and vein in the forearm or leg of
these patients. The principle is similar to that employed in hemodialysis
patients for vascular access. Early creation of an AV fistula is often worth-
while.
A recent concept has to do with debulking or removing the major part of the
tumor. Rationale for this came from observations that the bulk of the tumor, in
terms of the total number of cells in the leukemias and lymphomas, was
reduced by sequential courses of chemotherapy. This result can be achieved
with radiation therapy to some extent in that the percentage of cells killed
correlates with increased doses of radiation. Those who would transfer this
concept to surgical procedures suggest that one can remove a portion of a
tumor and then return to remove another portion of the tumor or that one can
remove 80 per cent of a tumor and rely on radiation and chemotherapy to
destroy the residual. However, in practice, incomplete excision of a tumor
often results in excessive blood loss and carries a high risk. Furthermore, such
a procedure can seed tumor cells into areas that would otherwise not be at
risk. Finally, as after any surgical procedure, the blood supply to the area is
compromised, making radiation or chemotherapy more difficult. Therefore,
unless the primary tumor can be removed in toto, it would seem prudent to
perform a biopsy of the site, visualize the extent of the tumor and cease the
operation in order to reconsider the treatment options.
TIMING OF DEFINITIVE SURGERY

Once a diagnosis of operable cancer is established, most patients want
immediate surgery. However, this is not always possible or appropriate. The
immediate surgical excision of a primary tumor is based on the premise that
the tumor is excised before dissemination of tumor cells, yet we know that any
clinically evident tumor has been present in the patient for a prolonged
period. Furthermore, the exact time that it takes for a tumor to metastasize is
unclear, since it is obvious that some tumors metastasize very early in the
preclinical stage, whereas others achieve enormous proportions before any
metastases are evident. Clearly, some immediate surgical procedures, such as
amputation for osteogenic sarcoma or immediate resection for Wilms' tumor,
have not provided increased cures or a reduction of disease recurrence.
Since the time interval for metastasis is unknown in almost all tumors, it
becomes apparent that an accurate diagnosis by histologic means and a thor-
ough search by various diagnostic procedures to determine the stage of the

tumor should be done as expeditiously as possible. The advantages of the
knowledge gained by this delay far outweigh the disadvantages of inappro-
priate treatment. To proceed with treatment with inadequate knowledge of
the tumor is more harmful for the patient than the one or two week delay
required for adequate preoperative evaluation.
NUTRITION
A significant advance in the surgical therapy of patients with malignant
disease has been a better understanding of nutritional support. The use of
intravenous hyperalimentation or the administration of various high-caloric
materials given via the alimentary tract has proved extremely useful in the
surgical management of patients. The result is clear in patients with cachexia
from carcinoma of the esophagus or with severe disability following radiation
therapy. Nasogastric feeding of high-caloric solutions or intravenous hyperali-
mentation prior to operation has markedly reduced the mortality and morbidi-
ty rates of the surgical procedures for carcinomas of the esophagus and for
patients who have undergone radiation therapy. Earlier fears that alimenta-
tion or calories or bothwould cause rapid tumor growth have not been borne
out by experience. Therefore, a period of alimentation before the surgical
procedure is essential for the patient who is undernourished.
GUIDELINES FOR INTEGRATING

SURGERY INTO A TREATMENT PLAN
When considering surgery for the cancer patient, the physician must be
concerned with four major topics: (1) tumor factors, (2) patient factors, (3) the
treatment team, and (4) the treatment goals.
Tumor Factors
The anatomic location constitutes an important tumor factor. Some tumors,

such as those located in the nasopharynx, cannot be treated by surgical
resection because an adequate margin of normal tissue cannot be achieved.
Those that intimately involve major blood vessels (cancer of the lung involv-
ing the aorta) or bilaterally involve an essential organ (such as the liver)
clearly do not benefit from surgical treatment.
Certain histologic types of tumor are not treated by surgical resection. For
example, lymphomas, leukemias, and oat cell carcinoma of the lung are not
treated by surgical resection because these tumors are disseminated at the
outset, and local control is not the major consideration.
Another major tumor factor is stage. Clearly, if a patient has a widespread
2 / Principles of Cancer Surgery 11
metastatic disease, long-term local control is not as important as it is in

patients who have localized disease. When examination reveals fixed regional
lymph nodes, nodes that are greater than 3 cm in diameter, or multiple
palpable lymph nodes, surgical resection alone usually will result in a proba-
bility of local recurrence that is greater than 50 per cent. A patient with such
findings may therefore require more treatment than simple surgical exci-
sion.
A mostimportant tumor factor concerns the size of the primary tumor. In
general, larger tumors respond more favorably to surgical therapy than to
other modalities of treatment. Chemotherapy and radiation therapy require an
excellent blood and oxygen supply in order to cause destruction, whereas
surgical resection does not. Thus, large localized tumors that tend to have
necrotic centers and poor blood supplies are best treated with surgical resec-
tion.
Patient Factors
Age and general health are important patient factors. Older patients fre-
quendy tolerate surgical procedures better than radiation or chemotherapy.
Although this seems somewhat paradoxical, the physiologic insult from surgi-
cal resection is relatively brief (four to five days), whereas
from radiation
that
or chemotherapy tends to be much more prolonged. Certainly, important
consideration must be given to the patient's medical history, because those
who have had recent cerebral vascular accidents or cardiovascular catas-
trophes or who have uncontrolled diabetes tend to be very poor surgical
candidates because of the high postoperative mortality rate. The social history
of the patient must be considered, and any concurrent diseases should be
evaluated. Finally, and probably most important, the patient's desire for
treatment must be assessed. Surgical resection in a patient who does not want
an operation, even though it may be the most effective means for tumor
control, is not appropriate.
Treatment Team
The experience and expertise of the treatment team must be closely
matched each patient's needs. In many cases the sophisticated resources of
to
a cancer center or a major medical center are not required for optimal treat-
ment of the individual patient. However, for some tumors, treatment in a
community setting may seriously jeopardize the patient's welfare. In making
such an assessment, the primary physician should carefully consider the
adequacy of local resources for the patient —
in surgery, radiation therapy,
and chemotherapy. For example, a patient with a primary bone tumor may
require the close cooperation of specialists in orthopedic surgery, head and
neck surgery, plastic surgery, radiation therapy, and chemotherapy. Such a
combination of talents may be very difficult to assemble away from a cancer
center.
Treatment Goals
Just as the considerations for surgical resection are important, so too are
those of the goals of the treatment. Different surgical procedures are per-
formed to achieve specific treatment goals, for example, palliation versus
complete tumor eradication. Certainly, total eradication of all viable tumor
cells requires a much more extensive surgical procedure than does a palliative
resection; either may be justified depending on the situation.
CONCLUSIONS
A dogmatic statement of when surgical resection, radiation therapy, or
chemotherapy should be applied is not possible, because each or all may have
a place in treatment of the cancer patient. The judicious integration of each of
these modalities is currently being tested with some very exciting results.
These studies are designed to search for a realistic appreciation of each type
of therapy, examining its advantages, limitations, and complications in order
to achieve the optimal effect and to provide the best chance for long-term
survival of the patient with cancer.
Tumor factors, patient factors, treatment team availability, and treatment
goals must be considered prior to any therapy. Considerations of the primary
tumor, the regional lymphatics, and the distant metastases are very important
from the standpoint of effective tumor control. However, from a social and
emotional point of view, patients need to have one doctor who directs the
treatment course, even though multiple treatment modalities may be re-
quired.
References
1. JesseRH, et al: Cancer 31 :854, 1973. 5. Yonemoto RH, et al.: Surg Gynecol
2. Tumbull RB Jr, et al: Ann Surg 166A2Q, Obstet 736:417, 1973.
1967. 6. Holmes EC and Morton DL: Orthop Clin
3. Storm FK, et al: Am J Surg 134:115, N Am 8:805, 1977.
1977. 7. Ballantyne AJ: In Neoplasia of Head and
4. Haagensen CD: In The Lymphatics in Neck. Chicago, Year Book Medical Pub-
Cancer. Haagenson CD, et al. (eds), lishers, Inc, p. 85, 1974.
Philadelphia, WB Saunders Co, 1972.
3 / Principles of Radiation Oncology 19
CHAPTER 3
PRINCIPLES OF
RADIATION
ONCOLOGY
Robert G Parker
INTRODUCTION
Radiation oncology is a clinical medical specialty in which ionizing radia-
tions are used in the treatment of cancer patients. The objective, with rare
exception, is eradication of cancer. Proper patient management includes pre-
treatment evaluation and long-term post-treatment observation as well as the
actual treatment application.
Ionizing radiations can be very effective in controlling a variety of malig-
nant tumors in the human and consequently are used in the management of
one half to two thirds of all patients with cancer. 1- 2 Like surgery, the effective-
ness of irradiation must be judged by the frequency of local and regional
tumor control in relation to treatment-induced morbidity. Such local control of
tumor can result in cure or palliation, depending on tumor distribution at the
time of treatment. The importance of local tumor control will increase as the
effectiveness of the treatment of widespread cancer improves.
The local disposition of radiations that are sufficiently energetic to cause
ionization of atoms in an absorber, such as tissue, results in the formation of
highly reactive radicals. Thus, radiation therapy should be considered as a
form of localized chemotherapy that is capable of highly accurate delivery to a
body without direct dependence on blood supply or diffusion through
part,
tissues and without
restriction based on anatomic factors, such as the location
of vessels, nerves, or bone. This relative freedom from anatomic restriction
permits the destruction of tumors with the preservation of structure, function,
and cosmesis. Consequently, not only is radiation therapy most effective
against small cancers with limited numbers of tumor cells, but it is also best
used in situations in which these small cancers have not destroyed normal
tissues, thus allowing their preservation.
Another advantage of radiation therapy, as compared with surgery, is that
the application is less influenced by concurrent medical problems of the
patient.Treatment infrequently requires hospitalization or anesthesia. The
prolonged time of application, often six to eight weeks, provides an important
opportunity for support of the patient.
However, the long overall treatment time can be an inherent disadvantage

if the patient must be displaced from familiar surroundings and family support
to be near facilities with sophisticated equipment and trained personnel.

Other disadvantages of radiation therapy include chronic sequelae, which
may develop months to years after irradiation and become more severe with
the passage of time.
PHYSICAL BASIS
Ionizing radiations are characterized by the mechanism of energy dissipa-
tion,namely ionization (and excitation) of atoms and molecules of the absorb-
ing material (i.e., tissue). These radiations may be electromagnetic (x-rays,
gamma rays) or corpuscular (electrons, protons, neutrons, alpha particles,
mesons) of natural origin (gamma rays from radium) or artificial origin (x-rays,
gamma rays from cobalt-60 or cesium-137). The basic physical mechanisms of
action of all types of ionizing radiations are the same, and differences in
observed effects of equal physical doses are secondary to differences in their
spatial or temporal distribution, or both.
Current conventional clinical use is limited to high-energy x-rays, high-
energy electrons, gamma rays, and beta rays. Other types of ionizing radia-
tions, such as protons, neutrons, pi-mesons, and heavy ions, are being stud-
ied.
Ionizing radiations can be measured more accurately than can other medi-
cations. This provides an opportunity and a responsibility for precise and
careful clinical use.
For decades radiation doses in patients were extrapolated from measured
exposure doses, i.e., the roentgen. Current clinical use requires a measure-
ment of radiations that are actually absorbed at the point of interest as implied
by the dose unit, the rad (radiation absorbed dose). In many circumstances
this measurement can be made directly in the patient through the use of
small volume receptors, i.e., thermoluminescent capsules.
For proper clinical use, accurately measured physical doses must then be
related to dose rate, overall time and pattern of application, anatomic part and
tissue volume and other host factors.
irradiated,
Modern been made possible by the development of
radiation therapy has
sophisticated equipment that is capable of generating and precisely deliver-
ing very high-energy radiations. The physical characteristics of ionizing radia-
tions graduallychange over the spectrum of energies practical for clinical use.
Although the penetration of a teletherapy beam in an absorber — i.e., tis-
sue —
continually increases in direct proportion to increasing energy, other
changes, such as reduced absorption in bone, skin-sparing, and reduced
lateral scattering, occur after the peak energies exceed 400 to 800 kVp.*
Radiations with peak energies over 1 to 2 MeVf are arbitrarily labeled mega-
voltage or supervoltage.
*kVp = peak kilovoltage on the x-ray tube

tMeV = million electron volts potential on the x-ray tube
The widespread modern radiation therapy in the United

availability of
States has been by the distribution of cobalt-60 teletherapy units.
facilitated
Currently, linear accelerators are popular because of higher peak energies,
greater dose rates, and less lateral scattering than possible with cobalt-60
teletherapy.
A revival of interest in the use of radiation sources introduced into tissues
(interstitial) or body been generated, in part, by the
cavities (intracavitary) has
development of radioactive isotopes, i.e., iridium-192 and iodine-125, which
can be used in highly adaptable, flexible, custom-made applicators. Such
clinical use, which requires an operative procedure, can deliver radiation
doses to the points of interest that are relatively high when compared with the
doses inadvertently received by the surrounding normal tissues.
Systemically introduced radiation sources —
e.g., phosphorus-32 —are of
limited use. Interest in total body irradiation from an external source is being
revived both as a systemic treatment of lymphomas and leukemias and as a
method of eradicating abnormal bone marrow prior to the transplantation of
healthy bone marrow.
Although the importance of technologic developments should not be min-
imized, the critically important component of clinical radiation therapy is the
trained physician. In practice, excellent facilities and good radiation on-
cologists can be found together.
BIOLOGIC BASIS
In contrast to the well-established physical basis of radiation therapy, labo-
ratory-generated biologic support for clinical application is only beginning to
develop. To date, most of the clinical applications have been empirical, with
little confirmation in the research laboratory. In his 1970 Failla Memorial
Lecture, Kaplan 3 acknowledged that "fundamental studies of the mechanism

by which radiation acts on mammalian cell systems have, to date, contributed
not one well-documented example of a significant improvement in the cure-
rate of a human cancer
However, current conventional applications of ionizing radiations in multi-
ple (usually daily) increments over a protracted period (weeks), which am-
plify the destructive effects on tumor cells in relation to normal tissues, are
based on early observations by Regaud 4 in his attempts to sterilize the ram's
testicle. Soon thereafter, protracted application by dose fractionation was
developed clinically by Coutard, 5 and the method remains in use today. Al-
though the basic physical and chemical changes that are incited in matter by
ionizing radiations of any type are the same and occur almost instantaneously
(10~ 4 to 10~ 12 sec), 6 the observed wide spectrum of biologic effects may be
recognized from within seconds of the insult to 15 to 20 years later for carci-
nogenesis or even generations later for genetic changes. Based on current
knowledge, this chain of events, once initiated, is considered irreversible.
Vitally important cell structures may be damaged by radiation-activated
chemical products originating in the immediate environment (indirect effect)
22 I / Ceneral Principles
or by direct intracellular energy transfer with consequent ionization and

excitation (direct effect).
The biologic effects of ionizing radiation, ranging from the barely detect-
able to cell death, are directly proportional to the amount of energy absorbed
(dose).
Radiosensitivity is a measure of susceptibility to injury by ionizing radia-
tions. This injury may be through interruption of the capacity
lethal to the cell
to replicate indefinitely (reproductive death) or through metabolic incapacita-
tion or structural degeneration that is independent of progression through the
reproductive cycle (interphase death). A conventional measurement of this
cellular susceptibility to damage is the dose required to reduce a replicating
cell population to 37 per cent of its initial value on the exponential portion of
the cell survival curve. This D 37 or D value for most aerobic mammalian cells
ranges between 110 and 240 rad. 7
Recovery from radiation-induced injury ranges from partial to complete. In
addition to repair of sublethal damage in the cell, functional recovery of
collections of cells may result from repopulation, redistribution within the
replication cycle, and reoxygenation of remaining viable cells.
Radioresistance is the reciprocal reaction to radiosensitivity and therefore is
relative rather than absolute. These terms are frequently misused in clinical
oncology because of the misconception that the rate of gross reduction in the
size of a tumor is a meaningful measure of the effectiveness of irradiation.
Such gross response depends not only on cellular susceptibility to damage but
also on other factors, such as the rate of clearance of dead cells and the
proportion of intercellular components.
Another misconception is that there is a specific radiation dose that will kill
all cells of a certain type or all cells in a tumor mass. A repeated specific
radiation dose kills a constant fraction, not an absolute number of cells of a
particular type. Thus, initial radiation doses kill the largest absolute number
of cells. Further reduction of cells to a number incapable of causing a clinical
recurrence is a fractional process governed in part by statistical rules of proba-
bility.
Lingering incorrect concepts of radiosensitivity may result in incorrect
clinical use.Tumor location and extent, rather than a potential for rapid gross
response to ionizing radiations, usually dictate whether or not radiation thera-
py is applicable. Thus, adenocarcinomas arising in and confined to the breast
or uterus may be curable by irradiation, whereas adenocarcinomas arising in
the stomach and metastasizing to the regional lymph nodes and liver are not.
Actually, the most radiocurable cancers (with the exception of a few, e.g.,
seminoma arising in the testis) usually are not the most responsive to irradia-
tion as measured by rate of gross tumor disappearance. Thus, epidermoid
carcinomas arising in the skin, uterine cervix, or oral cavity are only moderate-
ly radioresponsive but are highly radiocurable.
If the response of tumor and normal cells to ionizing radiations could be
modified to increase the therapeutic ratio (response of the tumor compared
with the response of normal tissues), the effectiveness and applicability of the
method could be usefully extended. Radiosensitivity might be modified by (1)
increasing the yield of irreversible radiochemical lesions by using chemicals
such as oxygen, nitric oxide, metronidazole, or the nitrofurans or by using

high linear energy transfer (LET)* particle radiations; or (2) increasing the
intrinsic sensitivity of target DNA through the use of halogenated pyrimidine
analogues or purine starvation; or (3) inhibiting repair through the use of
chemical inhibitors, hyperthermia, or high LET particle radiations; or (4)
synchronizing cells in sensitive phases through the use of drugs such as mi-
totic spindle poisons or fractionated irradiation in sequence with mitotic
8
delay; or (5) selectively protecting normal tissues.
CLINICAL BASIS
Like other legitimate therapeutic methods, radiation therapy has definite
indications and contraindications for clinical application. The use of this
powerful modality —
which often eradicates cancer and sometimes creates
substantial morbidity —
for ill-defined reasons, such as inoperability per se or
psychologic support of the patient and family (and involved physicians), is
ill-considered and is a disservice to both the patient and the method. In
evaluating a patient to determine whether or not radiation therapy might be
helpful, there are factors to be considered that are related to the tumor itself
and others that are related to the host.
Inasmuch as all therapeutic methods for cancer in the human may produce
serious morbidity, or even occasional mortality, and such treatment legit-
imizes the diagnosis, it is essential that the diagnosis be established prior to
the institution of treatment. Initial diagnostic proof should be based on the
study of a specimen obtained by biopsy. Exceptions (when therapy can be
licensed without documenting histology) are rare and are related to unreason-
able threats posed by the biopsy itself, such as in patients with tumors of the
midbrain, brain stem, or optic tract. Although histologic documentation of the
reappearance of tumor after initial treatment may also be basic to further
management, evidence obtained by other means, such as roentgenograms or
isotope scans or even clinical findings, is often adequate. For example, al-
though an initial pulmonary lesion requires biopsy identification, post-
treatment regrowth or the identification of a second lesion on chest roentgeno-
gram may be adequate evidence for treatment.
Histologic identification of tumor type and an assessment of tumor cell
activity within a particular tumor type (grading) are useful pretherapeutic
predictors of biologic behavior. However, such evidence is a poor predictor of
radioresponsiveness or radiocurability. For example, epidermoid carcinomas
and adenocarcinomas are equally radioresponsive, and the advisability of
treatment and outcome are related to other factors, such as tumor site and
extent. Likewise, the advisability of radiation therapy for epidermoid carcino-
ma arising in the floor of the mouth is related not to histologic differentiation
but to other factors.
*LET = linear energy transfer. It is the measure of the average rate of energy loss along the track
of an ionizing particle expressed as energy units per unit track length.
The anatomic and the extent of a cancer are often more

site of origin
important than tumor type in deciding whether or not irradiation is appro-
priate. Thus, whereas an epidermoid carcinoma that is limited to a freely
movable vocal cord should be irradiated, local extension of such a tumor from
the true cord to adjacent structures or the subglottic region makes surgery
preferable. In contrast, although a pulmonary epidermoid carcinoma without
spread to the mediastinum should usually be resected, extension of such a
tumor to the mediastinum might make local irradiation preferable. Identifica-
tion of intracranial metastases might make any treatment of this primary lesion
or regional spread unnecessary.
At times, when radiation therapyseems indicated for the cancer, it may be
inappropriate because of host factors. For example, even in some palliative
situations, radiation therapy may be unacceptably vigorous. Thus, the rela-
tively high radiation doses needed to open an esophageal lumen obstructed
by epidermoid carcinoma may not be tolerated by a frail, chronically ill,
elderly patient. Irradiation of a potentially responsive cancer may be deterred
because of an adjacent growth center in a youngster. As with surgery and
chemotherapy, treatment application may be prevented by irrational fears of
the patient. For example, radiation therapy of a radiocurable cancer threaten-
ing the life of the host may be refused because of a fear of carcinogenesis.
After evaluation, the objective of radiation therapy must be defined. If the
cancer is potentially radiocurable, patient inconvenience, high cost, and a
reasonable risk of serious treatment-related morbidity are acceptable. If pal-
liation of bothersome cancer-induced symptoms or signs in the incurable
patient is the objective, these consequences of treatment usually are not ac-
ceptable.
In planning the actual treatment, not only identifiable gross tumor but also
sites of high risk of spread must be delineated. Irradiation of clinically nonde-
tectable tumor, such as in the abdominal para-aortic nodes in patients with
seminomas of the testis or the cervical nodes with epidermoid
in patients
carcinomas of the oral tongue, can be very effective with modest doses that are
unlikely to cause morbidity. 9
When radiation therapy is directed to a limited tissue volume that is es-
timated to contain identified tumor or sites of high risk for spread, or both,
doses to different sites in the same patient may vary, and actual delivery may
require an integration of different types of radiations from several radiation
sources. Thus, in cancers of the prostate gland, uterine cervix, or oral cavity,
the primary site with the largest tumor volume may be locally treated with
radioactive materials to deliver a very high dose to a small tissue volume,
whereas regional structures containing metastases, such as in the pelvis or
neck, may be homogeneously irradiated from an external source. The integra-
tion of the various components of the planned treatment is likely to take place
only if it is directed by a single, responsible physician.
Like any medication, the total dose of ionizing radiations must be related to
the size and number of increments and the pattern and overall time of applica-
tion. For example, a total dose of 6000 rad delivered in 5 equal increments per
week for six consecutive weeks is not biologically equal to the same total dose
delivered in 6 equal increments at weekly intervals or 30 equal increments
split into two sessions separated by a rest period. The difficulty in comparing
the biologic effectiveness of varying treatment programs has prompted at-

tempts to normalize all factors into a single numeric value. The best known of
10
these attempts is the nominal single dose (NSD) concept of Ellis. Unfortu-
nately, these simplifying concepts, which are often based on estimated aver-
age normal tissue tolerances rather than on tumor responses, have proved
more an intellectual exercise than a useful clinical tool.
SIDE EFFECTS
Every effective therapeutic procedure has undesirable, and at times dan-
gerous, side effects. Inasmuch as accurate dosimetry, megavoltage equip-
ment, basic understanding of normal tissue tolerances, and availability- of
trained radiation oncologists are relatively recent developments, some physi-
cians today still recall treatment sequelae (and therapeutic ineffectiveness)
that remain monuments to former ignorance. In addition, injuries continue to

be produced under experimental conditions. It is important to differentiate
these unfortunate events from the risk of injury that is present from conven-
tional therapy that is considered competent by current standards. Also, even
today, the incidence of treatment- related side effects varies with the philoso-
phy of the radiation oncologist, for there must be a balancing of risks. Are the
risks of serious damage in many worth possible tumor control in a few more
patients?
Early reactions occur during or immediately following radiation therapy
and include constitutional and local effects, which, although uncomfortable,
are self-limiting. These include anorexia, nausea, and vomiting (which almost
always are avoidable by reducing the size of the daily dose increment or the
tissuevolume irradiated), diarrhea, esophagitis, skin reactions (which are
most marked in body folds), mucosal reactions, epilation, and hematopoietic
suppression (which is manifested by a reduction of circulating white blood
cells or platelets, or both).
The clinically important, severe sequelae of radiation therapy, which be-
come manifest months or even years after treatment, should be minimized by
good treatment and are not dissimilar to those incident to cancer surgery, i.e.,
colostomy and laryngectomy. Serious injury, such as radiation myelopathy,
bowel stenosis, or necrosis of bone, should be rare. Such long-term injuries, if
unavoidable, need to be viewed in the perspective of tumor-related accom-
plishment. Is a colostomy that is made necessary by bowel stenosis produced
in curing a patient with stage III cancer of the cervix less acceptable than a
colostomy produced as part of a planned abdominal perineal resection for
cancer of the colon?
COMBINATION THERAPY
As will be evidenced throughout the remainder of this book, radiation
therapy is increasingly being combined with surgery, chemotherapy, or im-
munotherapy, or any combination thereof. Interactions with surgery date to

many years ago. The objective of such combined use must be improvement of
localand regional control of tumor, which is likely to occur only from planned
treatment, not from grudging attempts to rescue the failures of one modality
by the other. Both surgery and radiation therapy must be directed to the same
anatomic site, with the intent of improving local tumor control, such as in
patients with malignant tumors of the paranasal sinuses. Alternatively, the
modalities may be
directed to adjacent, but different, anatomic sites in an
attempt to extend tumor control locally and regionally, such as in patients
with cancers arising in the oral tongue or testis.
Radiation therapy may precede or follow surgery, depending on the dif-
ferent objectives of treatment and the prejudices of the involved physicians.
The between the application of each treatment method should be
interval
planned to minimize the additive complications without dissipating any ad-
vantage in tumor control. This interval will vary with the quality of radiations,
radiation dose, irradiated volume, anatomic structures involved, and extent of
the surgery, but it usually ranges from four to six weeks.
Interactions of radiation therapy and chemotherapy have increased strik-
ingly over the past few years. Usually the objectives of each are
complementa-
ry, with irradiation of large tumor masses, often at the primary site, and
systemic treatment of widespread metastases, either documented or imper-
ceptible. Chemotherapeutic agents may also modify the response of tumor
and normal tissues to irradiation, whether this be incidental or by intent. For
example, dactinomycin (DACT) (actinomycin D), an active antitumor agent in
itself, augments acute normal tissue reactions to ionizing radiations, whereas
metronidazole is used specifically to increase the radiation damage to hypoxic

cancer cells.
Planned interactions of agents that stimulate the human immune system
and ionizing radiations, which are immunosuppressive, are the subject of
current research.
From this discussion of the necessity of correlating cancer biology in the
human, basic radiobiology and physics, radiation responses of cancers and
normal tissue, and continuing evaluation of performance, it should be evident
that the selection of patients for radiation therapy is beyond the capabilities of
the referring physician, regardless of competence chosen medical
in his or her
specialty. Thus, the selection of patients for radiation therapy must be made
1
by the radiation oncologist, just as the selection for surgery or chemotherapy

must be the decision of the surgeon or medical oncologist.

The clinical use of ionizing radiations dates to the discovery of x-rays in
1895 and the recognition of natural radioactivity in 1896. However, the physi-
cal foundations of therapeutic application, the development and distribution
of megavoltage generators, the training of substantial numbers of physicians
and support personnel, and an even cursory knowledge of radiobiology began
only a few years ago.
The prospects for better therapeutic use of ionizing radiations in the future
4 / Principles of Cancer Chemotherapy 27
are very good —

through both research developments and education. Re-
search objectives include a better understanding of cancer biology through
modification of the radiosensitivity of both tumors and normal tissues, better
application of ionizing radiations by improving the definition of targets and
delivery systems, development of particle irradiation, improved use of ad-
juvants, and more effective interaction with other modalities.
A great improvement in the use of currently available radiation therapy
could result immediately from education, since the potentials of this method
are presently unknown to a large number of physicians.
References
1. Buschke F and Parker RG: Radiation 7. Suit HD: In Textbook of Radiotherapy,

Therapy in Cancer Management. New 2nd ed. Fletcher GH(ed), Philadel-
York, Grune & Stratton, 1972. phia, Lea & Febiger, 1973.
2. Kramer S and Herring DF: Int J Radial 8. Kaplan HS: Cancer 39:689, 1977.
Oncol Biol Phys 1:1231, 1976. 9. Fletcher GH: Cancer 29:1450, 1972.
3. Kaplan HS: Radiat Res 43:460, 1970. 10. Ellis F: In Modern Trends in Radiother-
4. Regaud C. C R Soc Biol (Paris) 86:787, apy, Vol 1. Deeley TJ and Woodcap
1922. CAP (eds), Woburn, Mass, Butter-
5. Coutard H: Am J Roentgenol 28:313, worths Pub Inc. p. 34, 1967.
1932.
6. Boag JW: Am J Roentgenol 90:896,
1963.
CHAPTER 4
PRINCIPLES OF
CANCER
CHEMOTHERAPY
Charles M Haskell
Although Lissauer demonstrated the anticancer effect of potassium arsenite

(Fowler's solution) in 1865, 1 the modern age of cancer chemotherapy more
properly dates from the early 1940s, when Huggins and Hodges 2 showed that
patients with prostatic cancer benefited from the administration of estrogen.
By 1950 the rate of the introduction of useful new agents began to accelerate,
and during the 1960s research in tumor cell biology and pharmacology led to
TABLE 4-1. Development of Chemotherapeutic Agents
Approximate
Date Agent Diseases Treated
1865 Potassium arsenite Leukemias, various malignancies

1893 Coley's toxins Various malignancies
1941 Estrogens Carcinoma of prostate and breast
Androgens Carcinoma of breast
1945 Nitrogen mustard Lymphomas, solid tumors
1948-1950 Adrenocorticosteroids Leukemias, lymphomas, multiple myeloma
Antifolates Acute leukemia, choriocarcinoma
1950-1955 Busulfan Chronic granulocytic leukemia
6-Mercaptopurine Acute leukemia
Actinomyein D Wilms tumor, testicular tumors, choriocarcinoma
1955-1960 5-Fluorouracil Carcinoma of breast and gastrointestinal tract
Progestins Endometrial carcinoma
Cyclophosphamide Lymphomas, solid tumors
Mitotane Adrenal carcinoma
Vinca alkaloids Lymphomas, acute leukemia, reticuloendothelial
malignancies of childhood, choriocarcinoma
1960-1965 Hydroxyurea Chronic granulocytic leukemia
Procarbazine Hodgkin's disease
Cytosine arabinoside Acute leukemia
Nitrosoureas Lymphomas, brain tumors, solid tumors
Daunorubicin" Acute leukemia
1965-1970 L-Asparaginase Acute leukemia
DTIC Melanoma
os-Dichloro-
diammineplatinum 1 Testicular and ovarian tumors
1970-present Doxorubicin Sarcomas and a wide spectrum of other tumors
Bleomycin Lymphomas, head and neck cancer
Antiestrogens Breast cancer
"Experiment; il.
more rational drug therapy. The principal historic developments in cancer

chemotherapy are summarized in Table 4-1. 3>4
It is apparent that the complex field of chemotherapy is new and that its
growth has been rapid. Fortunately, there are certain unifying concepts that
aid in the selection and rational use of chemotherapeutic agents. This chapter
summarizes these concepts, whereas Chapter 5 provides more detailed infor-
mation about each of the clinically useful cancer chemotherapeutic agents.
SELECTIVE TOXICITY
The clinically useful anticancer agents have a greater toxicity for sensitive
malignant cells than for normal tumor-bearing host. They are
cells of the
therefore said to exhibit selective toxicity. 5 The most useful chemotherapeutic
agents appear to work by affecting enzymes or substrates that are acted upon
by enzyme systems. 6 For most agents, the target is an enzyme or substrate that
is related to DNA
synthesis or function, and, consequently, these drugs
appear to exert their major toxic and antitumor effects by inhibiting cells that
undergo DNA synthesis at some time in their life cycle. A schematic summary
of the mechanisms and sites of action of selected drugs that are useful in the
treatment of neoplastic diseases is given in Figure 4-1.
Malignant tissues are largely composed of dividing cells that synthesize

DNA at some point in their life cycle. use large amounts of
Cancer cells
glucose as a source of energy to permit the exaggerated utilization of amino
acids and nucleosides in the synthesis of DNA. 6 This pattern of metabolism is
nonspecific, since it is also seen in fetal or regenerating tissue. What appears
to be unique with neoplastic tissues, however, is a basic difference in gene
expression, namely, the failure of the cancer cell to cease some gene expres-
sion and stop cell division. Unfortunately, the mechanisms of this unique
feature are not understood, and this difference has not been exploited for
treatment.
Selective toxicity of chemotherapeutic agents is possible because of quanti-
tative differences between malignant and normal cells; that is, there are no
unique biochemical pathways or molecules in the cancer cell, but there are
differences in the amounts of certain chemicals or in the rates of various
chemical reactions. Indeed, the fact that these differences are quantitative
rather than qualitative results in at least some degree of injury to normal
tissues during treatment. It important to emphasize that the differences
is
between normal tissue and malignant tissue may be slight. Many normal
tissues have a high proliferative capacity rivaling and in some instances
exceeding that of malignant tissues. Such normal tissues, including bone
marrow elements, gastrointestinal epithelium, and hair follicles, bear the
brunt of the toxic effects of certain anticancer drugs. Fortunately, the rapidly
proliferating normal cells and cancer cells are not always equally vulnerable.
It is apparent, however, that the margin of safety is often very narrow.
There are myriad factors contributing to selective toxicity, some of which

have been the subject of intense scrutiny. 5,6 The interactions of these factors
Drug Receptor: Drug Receptor:

ENZYMES SUBSTRATES
PURINE PYRIMIDINE
SYNTHESIS SYNTHESIS
ALKYLATING
AGENTS
cross-link ONA
DOXORUBICIN
DAUNORUBICIN
ACTINOMYCIN D
MITHRAMYCIN
FIGURE 4-1. Summary of the intercalate with DNA
mechanisms and sites of action of
selected drugs used in cancer che-
BLEOMYCIN
motherapy. damages DNA and
prevents repoir
PROCARBAZINE
depolymerizes DNA
RNA
(Transfer-Messenger-Ribosomal)
L-ASPARAGINASE
deaminates
L-osparagine
PROTEINS VINCA ALKALOIDS
ENZYMES
/ V
MICRO-
TUBULES
inhibits
MODIFYING FACTORS
• TUMOR TYPE
DRUG • CELL KINETICS RECEPTOR

• COMORBID CONDITIONS
|
• SCHEDULE AND DOSE

OF A DRUG OR DRUG
COMBINATION
T
• DRUG INTERACTIONS
ABSORPTION
• IMMUNE COMPETENCE
FIGURE 4-2. Factors contributing to
1 / DRUG- \ selective toxicity.
DISTRIBUTION RECEPTOR
*• V COMPLEX
J
W
METABOLISM |^
DRUG EFFECT ON NORMAL
EXCRETION & NEOPLASTIC CELLS
NET EFFECT ON HOST

(Therapeutic Index)
are summarized schematically Figure 4-2. The cancer cell is a variable and
in
fluctuating target that contains a variety of receptor molecules. 6 The cell and
its constituent receptor molecules will vary depending on the type of tumor,
the status of that cell's growth cycle, and other factors as listed in the figure.
Ultimately, drug action depends upon a direct interaction of the drug or its
metabolite or metabolites with a specific receptor or receptors. The ability
of a given drug or drug combination to reach cellular receptors is affected
by variations in drug absorption, distribution, metabolism, and excretion. 7,8
The formation of a drug-receptor complex, with its ultimate impact on the cell,
is markedly influenced by biologic factors, at both the cellular level and the
molecular level. Thus, successful chemotherapy depends upon pharmacolo-

gic and biologic factors. For any given antineoplastic drug, the net effect on
the host is often referred to as the drug's therapeutic index, that is, a ratio of
the doses at which therapeutic effect and toxicity occur.
PHARMACOLOGIC FACTORS
Factors that alter the concentration over time of a critical drug or its active
metabolite at the primary site of action must be considered in the use of
"
cancer chemotherapeutic drugs. 6 8 This relationship is sometimes expressed
as the product of drug concentration multiplied by drug exposure time, or the
C x T function. 9 The important factors relating to this function are known for
some drugs and are being explored for others; drug absorption, transport and
distribution, biotransformation, excretion, and drug interactions appear to be
particularly important. 10 These factors, plusthose of drug resistance and drug
toxicity,are discussed briefly in this chapter. More detailed information
about these pharmacologic factors as they relate to specific drugs is found in
Chapter 5.
Route of Administration and Absorption
Differences in drug absorption at different sites have resulted in the use of

diverse routes of administration in cancer chemotherapy in order to optimize
drug availability. 11 For example, one may administer drugs intravenously,
intramuscularly, or intra-arterially. One also may choose to instill a drug
locally, such as into the pleural space or the cerebrospinal fluid. Careful
selection of the route of administrationmay improve the antitumor effect of a
given drug by allowing it to reach high concentrations in the areas of greatest
clinical need. One very specialized example of this approach involves iso-
lation-perfusion of an extremity with large doses of alkylating agents for
regional melanoma. 12 Although this technique is experimental, it appears to
have been useful in some situations, and it is certainly capable of providing a
sustained level of drug to a regional area without leading to dangerous sys-
temic toxicity.
Distribution
The and transport of drugs may profoundly influence drug

distribution
is absorbed it may be bound to serum albumin or other
therapy. 13 After a drug
blood components. It may then enter or pass through various body compart-
14
ments, including vascular spaces and extracellular spaces, and into cells. 7 In
some cases drugs may accumulate in certain areas as a result of binding, active
transport, or high solubility in fat.
15
The converse of this is that some drugs
may be excluded from certain areas because of factors influencing distribu-
tion, including the blood supply of the tumor. 16
Since most anticancer drugs exert their effects by interacting with intra-
cellular target molecules, the ability of a particular drug or its active me-
tabolites to get to the cancer cell becomes a vital concern. If tumor cells are in
an area of the body that is inaccessible to anticancer drugs, the drug concen-
tration over time for those drugs will be negligible, and the cancer cells will
survive. This phenomenon is sometimes referred to as the "sanctuary"
effect. 1719 An example of such a sanctuary is the brain, where tumor cells
appear to be relatively inaccessible to most anticancer drugs by virtue of the
so-called blood-brain barrier. 18, 19 Factors influencing the ability of a drug to
cross the blood-brain barrier include its relative ionization at physiologic pH
values, its molecular size, and its lipid solubility. 19
Biotransformation
The metabolism of a given drug may be an important consideration. 20 22 "
Some drugs are inactive prior to administration, requiring biotransformation

to achieve an active form. One example of this is cyclophosphamide (CYC),
which is metabolized in the liver from an inactive to an active form. This
biotransformation is clinically important; for example, patients with malig-
nant pleural effusions are frequently treated by the instillation of drugs into
the pleural space, and success usually depends on a direct local drug effect.
Consequently, cyclophosphamide, which requires hepatic biotransformation,

should not be used for such local therapy.
A variety of drugs can modify cyclophosphamide biotransformation, but
clinical problems have not been identified from these drug interactions,
primarily because of the rapidity with which the activation process occurs. 23 A
possible exception to this is the combination of cyclophosphamide with allo-
purinol, which has been associated with more toxicity than would be expect-
ed of cyclophosphamide treatment alone. 24
Excretion
The kidney and liver are the most common routes of excretion for chemo-
therapeutic drugs. Their function may be critical to the success of therapy,
and great care is often needed in the use of drugs when either of these organs
isfunctioning abnormally.
Excellent guidelines are available for modifying many kinds of drug treat-
ment for patients with renal disease. 25 Of particular note are those that modify
doses of methotrexate for patients with renal dysfunction, since this drug is
excreted almost entirely by the kidney. 25 Also, it is not unusual for a brisk
response to chemotherapy to result in the elaboration of large amounts of uric
acid from the breakdown of the nucleic acids of destroyed cancer cells. Uric-
acid nephropathy may ensue, leading to altered renal function and even more
severe reactions to drugs that require clearance by this route. 26
Dosage modification may also be required for some drugs when given to
patients with liver disease. Doxorubicin (Adriamycin; ADR) and vincristine
(VCR) are primarily excreted in bile, and their respective toxicities of bone
marrow suppression and severe neuropathy may be increased markedly in
27, 28
patients with liver dysfunction.
Drug Interactions
"
A variety of drug interactionsoccur in clinical medicine. 29 31 Since a

may
hospitalized patient commonly receives as many as nine or more drugs at the
same time, 32 and since there are many opportunities for the development of
clinically important drug interactions in the care of the cancer patient, this
subject warrants a brief review. Drug interactions may occur by a variety of
mechanisms, some of which are listed here.
1. Direct chemical or physical interaction.

2. Interaction during intestinal absorption.
3. Interaction at plasma or blood transport sites.
4. Interaction at the cellular receptor site.
5. Interaction by accelerated or inhibited metabolism.
6. Altered acid-base balance, leading to changes in drug distribution and
renal clearance.
7. Alterations of renal function that influence rates of renal excretion.
8. Alterations in cellular transport mechanisms.
9. Alterations in cellular biochemical pathways and drug resistance.
Specific examples of drug interactions as they relate to cancer chemothera-

py may be cited. Nitrogen mustard and many of its derivatives are highly
reactive compounds. Thus, direct chemical inactivation in physical mixtures
of drugs in infusion solutions is a likely problem. 33 Oral absorption of metho-
trexate may be profoundly altered by concomitant use of antibiotics that
suppress gastrointestinal microbial flora. 34 Methotrexate is bound and trans-
ported on serum albumin, and both aspirin and sulfonamides are known to
displace this drug, thereby altering free drug levels with resultant drug
toxicity.
35, 3K
Cellular transport of specific drugs may be altered by other drugs.
One example of this appears to be inhibition of methotrexate transport across
37
cell membranes by L-asparaginase (L-ASP).
Interactions may occur by accelerated or inhibited metabolism, such as
suppression of pseudocholinesterase by some alkylating agents, potentially
leading to prolonged apnea if succinylcholine is used during general anesthe-
38
sia. Finally, it is important to emphasize the possibility- that allopurinol, a
potent xanthine oxidase inhibitor, can profoundly affect the metabolism of
6-mercaptopurine (6-MP), a purine analogue. Clinically, this effect results in
markedly augmented toxicity when the two drugs are used in combination,
and therefore it is necessary to decrease the dose of 6-mercaptopurine to 25
per cent of the usual amount. 33
Drug Resistance
The chemotherapeutic agent may be severely limit-

clinical usefulness of a
ed by the emergence of a line of malignant cells resistant to that drug. 39 42 It is
"
common clinical experience to find that the first trial of a given drug adminis-
tered to a cancer patient is successful and that often subsequent trials are
progressively less successful, until no apparent beneficial effect is
achieved.
A number of cellular mechanisms are probably involved in drug resistance.
For example, altered metabolism of the drugs (decreased activation or in-
creased deactivation), impermeability of the cell to the active compound,
altered specificity of an inhibited enzyme, increased production of a target
molecule, increased repair of cytotoxic lesions, and, in some cases, the
bypassing of an inhibited reaction by alternative biochemical pathways.
There is obviously an analogy between the development of resistance to
drugs in cancer therapy and the appearance of antibiotic-resistant strains of
bacteria during the course of an infection. Both situations may be approached
in the same manner by changing drugs or, less often, by using larger doses of
the same drug. The use of drug combinations is also a way of attempting to
avert the development of drug resistance.
Drug Toxicity
The usefulness of cancer chemotherapy is often limited by toxic reactions in

normal cells. Ideally, one would prefer to use drugs with a high therapeutic
index, that is, maximum therapeutic benefit with virtually no toxicity. Howev-
er, this situation is rarely realized in clinical practice. One must therefore be
thoroughly familiar with the spectra of toxicities seen with antineoplastic

drugs. 4, 33,43 In the sections that follow, the major classes of drug toxicity will
be given with selected illustrative examples. Details of toxicity for individual
drugs are described in Chapter 5.
Gastrointestinal Toxicity. Anorexia, nausea, and vomiting are among
the most common and distressing acute reactions to a wide variety' of cancer
chemotherapeutic agents. The pathophysiology and treatment of this problem
has been nicely reviewed. 44 Suppression with antiemetics, such as prochlor-
perazine (Compazine) or trimethobenzamide hydrochloride (Tigan), is only
variably effective. Experimentally, suppression of this problem with delta-9-
tetrahydrocannabinol (THC) has appeared to be superior to placebo treat-
ment, 443 but this observation requires confirmation and major changes in
legislation before it would be likely to have much impact on clinical practice.
Other forms of gastrointestinal toxicity that are seen with some drugs include
stomatitis, esophagitis, peptic ulcer disease, and diarrhea.
Bone Marrow TOXICITY. This is the most important form of toxicity for
many of the antineoplastic drugs used in clinical practice. Its most serious
form is leukopenia with an attendant high risk of infection, although thrombo-
cytopenia and bleeding may also occur and be life-threatening. Because of the
critical importance of this problem in cancer chemotherapy, a classification of
drugs according to their myelosuppressive potential and the time course of
recovery from granulocytopenia is given in Table 4-2. Several schemes for
TABLE 4-2. Drug-Induced Myelosuppression
Nadir of
Granulocytes Recovery
Category t Drug (Days) (Days)
I Mechlorethamine 7-15 28
Melphalan 10-12 —
Busulfan 11-30 24-54
Carmustine 26-30 35-49
Lomustine 40-50 60
Semustinel 28-63 82-89
Cytarabine 12-14 22-24
Vinblastine 5-9 14-21
II Cyclophosphamide 8-14 18-25

5-Fluorouracil 7-14 20-30
6-Mercaptopurine 7 14-21
Methotrexate 7-14 14-21
Actinomycin D 15 22-25
Procarbazine 25-36+ 35-50+
III Vincristine 4-5 7

Bleomycin - -
L-Asparaginase — —
cis-Dichlorodiammine- — —
platinum II
Hormones — —
"Modified from Henderson ES: In Drugs and Hematologic Reactions. Dimitrov NV and Nodine JH (eds).
New York. Grime 6c Stratton, 1974 and Creaven P.I and Mihic-h E: Sciuiu Oncol 4147. 1977.
f Categories: I, primarily myelosuppressive toxicity; II, myelosuppressive but other toxicities equally im-
portant; III, rarely cause granulocytopenia.

I Experimental drug.
TABLE 4-3. Grades of Myelosuppression
Toxicity White Blood Cell Granulocyte! Platelet

Grade Count per ml Count per ml Count per ml
Normal Values 4500-10,000 2000-7000 150,000-350,000

5*4000 2*1500 2*100,000
1 3000-3999 1000-1499 75,000-99,000
2000-2999 500-999 50,000-74,999
3 1000-1999 250-499 25.000-49,999
4 <1000 <250 < 25.000
°As used in the Division of Hematology-Oncology, Dept. of Medicine, UCLA School of Medicine,
t Granulocytes include both segmented and juvenile neutrophils.
grading the severity of myelosuppression exist, and clinicians vary in their

willingness to continue class I and class II drugs during periods of myelosup-
pression. As a point of reference, Table 4-3 gives the system that is used for
grading myelosuppression in the Division of Hematology-Oncology of the
Department of Medicine, UCLA School of Medicine.
Patients who develop grade 4 toxicity from chemotherapy usually require
hospitalization for observation and, frequently, treatment for infection or
bleeding. 47 Courses of chemotherapy are generally postponed until myelo-
suppression abates. Patients who develop grade 3 or grade 4 toxicity are
usually given reduced doses of class I and class II agents (25 to 50 per cent)
once myelosuppression has resolved. Exceptions to these general guidelines
may be found in the disease-oriented chapters of this book.
Some drugs cause cumulative, delayed myelosuppression, which may rare-
48 50 "
ly lead to prolonged, severe pancytopenia. This is particularly true of
certain alkylating agents, including the nitrosoureas and mitomycin-C
(MMC). Therefore, great care must attend their use, including careful atten-
tion to the platelet count.
Immunosuppression. Most of the commonly used antineoplastic agents
are capable of suppressing both cellular and humoral immunity. 51 53 However,
"
immunosuppression varies tremendously, depending upon the precise dose

and schedule of drug administration and whether the drug is used alone or as
part of a multidrug combination. In view of evidence implicating host immun-
ologic factors in the control of certain tumors (see Chapter 6), the potential
effect of cancer chemotherapeutic drugs on the immune system becomes
increasingly important. Because of this, the immunosuppressive effects in
humans of the commonly used anticancer drugs are given in Chapter 5.
The immunosuppressive cancer chemotherapy
effects of most drugs used in
do not extend for prolonged periods beyond the time of active drug adminis-
tration. Hersh has studied this problem in patients receiving five-day courses
of intensive combination chemotherapy. 54 The immunologic factors studied
included macrophage entry into experimental inflammatory sites (the skin
window), response to primary antigenic stimulation, and lymphocyte blas-
togenic response to phytohemagglutinin (Fig. 4-3). There is a marked de-
crease in all these host defenses during treatment; however, within two or
three days there is complete or nearly complete recovery of immune function.
Indeed, in some patients an "immunologic overshoot" may occur during the
FIGURE 4-3. Effects of intensive in-

termittent chemotherapy on host de-
fense mechanisms. (From Hersh EM:
In Cancer Medicine. Holland JF and
Frei E III (eds), Philadelphia, Lea i*
Fehiger, 1973.)
-2 12 4 6 6
f | DAYS
A N T I 6 E N
I 2
recovery period. Thus, when such five-day courses of combination chemo-

therapy are given every two to four weeks, the patient's immunologic function
is normal most of the time.
Immunologic theories of cancer etiology and pathogenesis are in ferment,

and time and research are needed to resolve many conflicts (see Chapter 6). In
terms of cancer chemotherapy, the practical result of almost all contemporary
thought on the immune system is that we should strive for programs of cancer
treatment that are minimally immunosuppressive whenever possible. Even if
one believes that the immune system does not play an important role in the
pathogenesis of cancer, it is clearly an important host defense mechanism for
many of the complications that occur during treatment. Specifically, infections
commonly lead to the death of patients with advanced cancer, and impaired
immunity may contribute to such deaths. Therefore, we should carefully
consider the effect of treatment on the immune system of our patients.
Skin Reactions. With the exception of local tissue necrosis, which may
occur when some drugs extravasate from an infusion site, skin reactions are
rarely dangerous. 4 Examples of other skin reactions include hyperpigmenta-
tion, hyperkeratosis, dermatitis, urticaria, vasculitis, flushing, and nail
changes, including transverse banding and, rarely, nail loss. 55
ALOPECIA. Doxorubicin and cyclophosphamide are the two drugs most
frequently associated with alopecia, but many other agents can cause this
problem. 4 It is almost always a reversible process. Attempts to prevent alope-
cia through low-dose radiation therapy to the scalp 56 or through the use of
scalp tourniquets 57 have not been generally accepted.
Hepatic Toxicity. This is an uncommon problem in cancer chemothera-
py, but when it occurs it may be very serious. The range of toxicity includes
transient elevation of transaminases seen with cytarabine (ara-C), cirrhotic

changes seen with methotrexate, and even liver necrosis seen with 6-
mercaptopurine. 43 Guidelines for the management of hepatic toxicity vary
with each drug. However, in the face of abnormal liver function in a patient
receiving cancer chemotherapy, it is prudent to avoid the severely hepatotox-
ic drugs, such as the 6-thiopurines and mithramycin, unless their use is
unequivocally indicated.
Pulmonary Toxicity. Although this is an unusual form of toxicity, a
58
variety of drugs may cause profound pulmonary disturbances. Methotrexate
and some alkylating agents occasionally cause pulmonary dysfunction, but the
most important and common cause of this complication is bleomycin (BLEO).
Although the fibrosis caused by bleomycin is somewhat dose related, occur-
ring most frequently at doses greater than 400 mg, the range of doses associat-
ed with this complication is immense. In addition, there is neither a known
predictive test for its occurrence nor an effective treatment.
Cardiac Toxicity. Doxorubicin, daunomycin (D), and very high doses of
cyclophosphamide may all cause cardiac damage. 445 This represents the
major dose-limiting toxicity of doxorubicin and daunomycin, as discussed in
detail in Chapter 5.
Genitourinary Toxicity. Hemorrhagic cystitis occurs in about 10 per
cent of patients treated with cyclophosphamide, but it rarely occurs with other
agents. The kidney can be damaged by a variety of drugs but most prominent-
ly by high doses of methotrexate or 6-mercaptopurine and by standard
doses of mithramycin, streptozotocin (STZ), L-asparaginase, and cis-
dichlorodiammineplatinum II (DDP). 43 Uric acid nephropathy may also be a
problem for some patients, although this can generally be prevented by the
use of allopurinol and hydration.
CNS TOXICITY. A wide variety of drugs can cause mild to moderate
reversible neurologic problems. 59 Severe neurotoxicity is commonly seen
with excessive doses of vincristine. 60
Sterility and Congenital Malformations. A variety of drugs, but
most prominently the alkylating agents, can cause sterility. 61 63 Sperm storage
"
prior to the initiation of chemotherapy may be of social and psychologic value

in selected patients. Lesser degrees of male and female gonadal dysfunction
may also be seen. 64 The reversibility of these problems in adults is in ques-
tion, but recovery of reproductive function is generally seen when such
treatment is given to children with acute leukemia. 65 Congenital malforma-
tions are also possible. 61,66 Such malformations appear to be particularly
common when a pregnant patient receives treatment with methotrexate or an
alkylating agent during her first trimester.
Second Malignancies. Many of the commonly employed antineoplastic
drugs are mutagenic as well as teratogenic. Some, including procarbazine
(PROC) and the alkylating agents, are clearly carcinogenic in animals. 61 67 '
Thus, an apparent increase in the frequency of second malignancies in suc-

cessfully treated patients with Hodgkin's disease (HD), multiple myeloma,
"
and possibly some solid tumors is of particular concern. 68 70 It is clear that this
risk, which is commonly delayed many years after successful chemotherapy,
will require careful consideration in assessing the therapeutic index of any
new therapy. For now, however, the initial benefits of chemotherapy appear
to strongly outweigh the potential risk of this delayed complication for most
patients.
Miscellaneous Complications. A wide variety of other complications
may occur.43 Coagulation problems, the syndrome of inappropriate antidiuret-
ic hormone action (SIADH), other electrolyte problems, pancreatitis, diabe-
tes mellitus, pituitary insufficiency, adrenal insufficiency, fever, anaphylaxis,
aseptic necrosis of the femoral heads, pathologic fractures, hemolytic anemia,
cataracts,and suppression of growth are examples of rare complications seen
with some drugs, as detailed in Chapter 5. Indeed, the prudent physician
should be alert to both the known complications of cancer chemotherapy and
the currently unrecognized complications of this emerging discipline.
BIOLOGIC FACTORS
The Cell Cycle
The concept of differential drug efficacy during specific phases of the life
cycle of proliferating malignant cells appears to be important to both the
theoretic and the practical aspects of cancer therapy. 71, 72 The life cycle of
normal and neoplastic cells starts with mitosis, or cell division (Fig. 4—4). After
the cell has completed its division, it enters the G phase, or the first "gap"
x
phase, which for a long time was considered by cell biologists to be relatively
quiescent. When cells stop proliferating and come to rest, they usually do so
in the G, phase. For example, after partial hepatectomy and subsequent
hepatic proliferation, the liver cells stop dividing and are arrested in the Gj
phase. Occasionally, cells rest for prolonged periods of time; this phenome-
non is sometimes referred to as G Emerging from G l5 the cell begins a phase
.
of active DNA
synthesis, which has been termed the S phase. In this phase,
the cellular content of DNA
is doubled. After the completion of syn- DNA
thesis, the cell again enters a phase of apparent rest before the initiation of
mitosis; this phase is called G2 or the second "gap" phase.
,
CELL
DIFFERENTIATION
FIGURE 4-4. The cell cycle: D, cell

division; G,, the phase preceding ac-
tive DNA synthesis; S, the phase of
DNA synthesis; G the premitotic rest-
2)
ing phase.
4, 71
Certain interesting features of this cycle are worth reviewing. Tradition-
ally, morphologists had concentrated on the rather dramatic events of mitosis,
with its formation of the spindle, separation of the chromosomes, and related
events. Subsequently, other aspects of the cycle have received attention. In
most dividing cells the periods of DNA
synthesis, the G 2 phase, and division
are relatively fixed in timeand are of nearly constant duration. However, the
length of the Gi phase in the cell cycle generally varies. The G phase is not at
x
all the inactive period it was once thought to be. Active RNA synthesis and
protein synthesis occur during this interval. The duration of this phase is often
related to the proliferation activity of the tissues. When proliferative activity is
high, the G, phase tends to be short. When proliferative activity is low, the Gi
phase usually long. In very rapidly proliferating protozoa, as well as in the
is
early embryo and in certain malignant tissues, the G! phase may be so short
that it is essentially obscured.
It is not clear how a differentiated mammalian cell receives instruction to
leave the Gj phase and begin DNA

synthesis. Although most of our informa-
tion on comes from the study of microorganisms, in higher life
this subject
forms there is evidence that the control mechanism requires interaction be-
tween the nucleus and the cytoplasm of the replicating cell. Once the S phase
begins, several things happen in rapid succession. The enzymes necessary for
DNA synthesis, including those of purine and pyrimidine biosynthesis, and
the enzymes necessary for the formation of macromolecular nucleic acids,
increase in specific activity. After the DNA content of the cell has doubled,
the phase of DNA synthesis is complete, and the cell enters the G 2 phase. This
phase was once thought to be a quiescent period also, but it is now quite clear
that RNA synthesis and protein synthesis are required before the cell can con-
struct a mitotic apparatus and begin division.
These considerations appear to be critical to the action of some chemothera-
peutic agents. Agents that are effective only during a particular phase of the
cell cycle, such as the S phase of cellular DNA synthesis, are called phase-
specific. Those agents in which action is prolonged and independent of any
specific cell cycle phase are called phase-nonspecific. This distinction be-
tween specific and nonspecific agents is relative rather than absolute. Some
experts in cell kinetics make additional distinctions, separating the phase-
nonspecific drugs into those that demonstrate increased killing of proliferating
tissue as opposed to nonproliferating tissue (cycle-specific drugs) versus those
thatshow no such specificity (cycle-nonspecific). 73 Another distinction that is
sometimes made is that of "self-limited cell killing." 74-75 Drugs of this type
methotrexate), which kill cells in
(e.g., DNA
synthesis, simultaneously inhibit
other cells from starting DNA
synthesis and thus prevent these cells from
entering the sensitive phase of the cycle.
Although the nomenclature of cell kinetics appears confusing, and its true
role in developing improved programs of treatment is controversial, 75 cytokin-
etic concepts have proved useful in understanding and interpreting some
aspects of tumor cell biology. Agents that are most effective during the S
phase are usually ineffective inhibitors of cell populations with a slow turn-
over and a high percentage of dormant cells. Conversely, alkylating agents
and other drugs that interact primarily with macromolecular DNA (e.g., dox-
orubicin) seem
be largely independent of the cell replication cycle and are
to
effective against tumors with relatively low proliferative activity. Excellent
reviews of this complex subject are available for the reader interested in the
history, 76 methodology, 77, 78 and applications of this interesting area of contem-
78, 79
porary research. 75,
Gompertz and Cell Population Growth
Although pass through the same sequence of phases, differences

all cells
exist between populations of normal cells and populations of cancer cells in

their number and distribution in the replication cycle. Both normal and
neoplastic cells may be influenced by certain growth factors, and populations
of both appear to contain more dividing cells when the population size is
small and fewer dividing cells when it is large. Thus, the young fetus grows
rapidly, and the postnatal child grows more slowly. This relationship between
size and growth rate may be expressed quantitatively in two ways:
1. As a function of population doubling times (time for any given number of

cells to double in number).
2. As a function of the growth fraction (that fraction of cells undergoing
division at any one time).
Figure 4-5 presents a logarithmic plot of human fetal and childhood growth
versus time, 80 and includes specific data on the cell population doubling times
during growth. Early growth is clearly exponential, with a high growth frac-
tion and very short doubling times. As time passes, the doubling time in-
creases, and the growth fraction decreases. The specific equation describing
this relationship was originally derived by the nineteenth century mathemati-
cian Benjamin Gompertz, and biologic growth that conforms to this pattern is
therefore referred to as Gompertzian growth. 81 Evidence that normal and
neoplastic cell growth follows a Gompertzian pattern is increasing. At least 18
different animal tumors conform to a Gompertzian growth curve, 82 and prelim-
inary evidence suggests that human multiple myeloma follows this pat-
84
tern. 83,
A major implication of these concepts is that the choice of a drug or combi-
nation of drugs should probably be different for large tumors than for micro-
scopic tumors. When the tumor is small and growing rapidly, a relatively high
proportion of its cells are synthesizing DNA
(in its S phase) at any given time.
At this point in the life history of the cancer, one should use phase-specific
drugs that are effective against dividing cells. In contrast, an advanced tumor
with a very low growth fraction and a slow increase in size may respond better
to a phase-nonspecific drug.
The Log Cell Kill Hypothesis
At any given exposure, antineoplastic drugs kill a variable fraction of

cells, from very few to a maximum of 99.99 per cent. 85 For convenience, the
fractional cell kill observed in experimental studies with chemotherapy is
Age of Males (in years)

Birth
05 1 2 3 4 5 6 7 8 9 10 II 12 13 14 15 16 17 18 19
i to to to to to to to to to to to to to to to to to to to to
100,000 ;
—
10 2
"i r~
3
T
4
1II1TTIIIIITII
5 6 7 8 9 10 II 12 13 14 15 16 17 18
1
19
1
20
1
Pic toou, co 70 kg
!
CM-JO-*^ " "~"

—
ca 7 Year Doubling Tim*
10,000
r 1
co 6 Year Doubling Timt
(ovorall for first y«or
'
1,000 - -^-- 51
xnsr^
79 05
l46
ft"
10
63 «*i
JLlSV^Z™
100 ,10'
~:
f
4 doy-/ yC Human Fttu» (wot Might),
Ayr Gompvrtnan E itrapolation

• II
10 10'
Bolow Data Points (<0. Ig) ~z
^ A/9 1
:
o
^^ 6 4/> 7
» 10 r 1
•
* >Y<
/
y
/ 1
1 :
1 10
1
/
** 8 / — Thooroticol Conxquoncot
Accumulation
of
/ Loukomia Coll
/ '
at Oifftront RaUt Over ;
/ Difforont Population Sui Rang*!

01 / ~ 10'
r 4.
-1
/
/
1 /
1
f-2 Day Doubling
Tim* - &
6
001 * io I
r
/
/
1
/ J
/
0001 F /
-.
1
K0
x- 2 9 Day /
Doubling
Tim* /
/
00001 i i 1 i 1 1 1 1 1 1 1
• 1 10
20 40 60 80 100 120 140 160 180 200 220 240
Age of Human Fetus (days)
FIGURE 4^5. Human fetal and childhood growth as a Gompertzian process and
the theoretic consequence* of accumulation of leukemic cells at different rates over
varying population ranges. (From Skipper and Perry S: Cancer Res 30:1883, HE
1970.)
often expressed in logarithmic terms. Since the body burden of tumor cells in
humans with advanced malignancies may be greater than 10 cells (1 kg), and 12
since the best one can hope for with a single maximal exposure of tumor cells
to a drug is somewhere between 2 and 5 logs of cell kill, it is apparent that
treatment must be repeated many times in order to achieve control. Theoreti-
cally, this hypothesis suggests that chemotherapeutic drugs may not be cap-
able of totally eradicating any given population of tumor cells. However,
numerous studies with experimental animal tumors have proven the curative
potential of cancer chemotherapy. There is evidence that immunologic ap-
proaches to therapy may be more effective than chemotherapy when the
tumor cell mass is small; however, it may be totally ineffective against large
tumor cell masses. 86 The order
of magnitude for this latter effect is approxi-
mately 0.1 mg of tumor in most model systems, or about 10 5 cells. 87
DRUG SCHEDULES AND

COMBINATION CHEMOTHERAPY
Studies with experimental animal tumors have conclusively demonstrated
the critical importance of drug scheduling in therapy. 85, 88 One factor related to
drug scheduling is the phase specificity or nonspecificity of the drug to be
administered. Cytarabine, an antimetabolite that is rapidly catabolized and

kills cells only in their S phase, must be given frequently in order to as-
sure contact with cancer cells during this critical period. When this drug is
so employed, it is possible to "cure" some forms of murine leukemia, whereas
maximally tolerated doses of the drug given at less frequent intervals fail to
prolong survival. In contrast, cyclophosphamide, which is phase-nonspecific,
achieves optimal suppression of most experimental neoplasms when given on
a high-dosage, intermittent schedule.
A second factor related to drug scheduling is the growth status of any given
tumor. 80 85 In general, solid tumors with a large tumor mass grow slowly, have
'
a small growth fraction (less than 10 per cent), and a prolonged tumor dou-
bling time (TDT). Since relatively few of their cells are dividing, it should not
be surprising that such tumors are generally insensitive to phase-specific
drugs. Thus, the usual treatment for advanced nonhematologic tumors has
been with phase-nonspecific drugs, such as alkylating agents. Successful
treatment with such drugs, however, may render the tumor more susceptible
to phase-specific drugs, by converting it from a tumor with a low growth
fraction with few cells in its S phase to a tumor with a high growth fraction with
many cells in its S phase. Experimental data support this concept. Schabel has
shown that a hamster plasmacytoma, which grows with Gompertzian kinetics,
can be "cured" with cyclophosphamide therapy when followed by cytarabine
therapy. 82 When either drug is used alone or in the reverse sequence, "cures"
are not observed. These results are consistent with the conversion of the
tumor from cytarabine insensitivity to cytarabine sensitivity. Presumably this
occurs by a cyclophosphamide-induced decrease in tumor size, with a con-
sequent increase in the growth fraction. The phase-specific drug cytarabine
then eliminates the dividing cells.
In recent years it has become obvious that combinations of drugs provide
the optimal treatment for many kinds of tumors. 89 90 Several theoretic and
'
practical advantages to combination therapy have emerged. At the risk of

oversimplification, to illustrate the principle of combination chemotherapy it
is useful to think of a population of malignant cells as resembling a culture of

bacteria. 4 In both, combinations of agents can delay or suppress the emer-
gence of drug-resistant cells and prolong the time necessary for the popula-
tion of malignant cells or bacteria to reach a density that produces clinically
apparent disease. Addition of an anticancer drug to malignant cells results in
the killing of the drug-sensitive cells, just as the addition of an antibiotic to
bacteria results in the killing of bacteria. If the drug is not completely effec-
tive, a portion of the cancer (or bacterial population) survives. The surviving
population may contain drug-resistant cells. If the drug-resistant cells are
capable of replication, they give rise to a drug-resistant tumor — or bacterial
population. The administered drug thus has a selective mode of action, lead-
ing to the emergence of a resistant cell line.
The frequency of the emergence of an antibiotic-resistant bacterium can be
determined precisely, whereas the frequency of the occurrence of drug-
resistant cancer cells is not as easy to determine. It is obvious, however, that
the chances for the development of a drug-resistant line will be less if two or
more drugs of dissimilar modes of action can be used in a treatment combina-

tion. The terms sequential, concurrent, and complementary inhibition have
been coined to categorize biochemical approaches to combination chemo-
therapy. 37 91 93 These categories were initially derived from studies in animal
~
'
tumor models, but their conceptual utility recommends them for serious study
by clinicians. Because of their heuristic value, they are schematically depict-
ed in Figure 4-6, as modified from the review of this subject by Capizzi,
Keiser, and Sartorelli. 37
The first form of inhibition, sequential blockade, was described by Potter91
to indicate the simultaneous action of two inhibitors acting on different en-
zymes of a linear metabolic pathway. A successful example of this concept is
the combined use of an inhibitor of ribonucleotide reductase, such as hydrox-
yurea (OH-urea), and an inhibitor of DNA polymerase, such as cytarabine
(Fig. 4-1). In the L1210 mouse leukemia, this combination has produced
synergistic tumor cell destruction with subadditive toxicity to the normal host
tissues. 94,95
Concurrent inhibition, as depicted in Figure 4-6, is primarily of theoretic
interest, since no examples in human cancer are known at present. Converse-
93
ly, complementary inhibition has distinct clinical utility. In this case, one of
the inhibitors affects the function of an end product (a given substrate, such as
DNA). The other inhibitor or inhibitors affect the synthesis or utilization of
precursors along the biosynthetic pathway leading to the formation of that end
product (enzyme-active agents). Inspection of Figure 4-1 suggests a variety of
ways in which complementary inhibition might be achieved. In humans, one
such complementary combination would be cytarabine and daunomycin; in-
deed, the therapeutic index of these two drugs in human adult acute nonlym-
phocytic leukemia appears to exceed the expected benefit of either drug used
alone. 96 In mice, this combination has shown true synergism. 97
I. Sequential Blockade
© ©
E E
i 2
II. Concurrent Inhibition
FIGURE 4-6. Biochemical categories of combina-

tion chemotherapy: £, and E 2 are enzymes catalyz-
ing the change of A to B to C or of A and B to C; Ii
and I 2 are inhibitors of the respective reactions.
This figure is discussed further in the text. (Modi-
fied from Capizzi RL, et ah: Semin Oncol 4:227,
1977.)
III. Complementary Inhibition

nhibition ^~.
©— f
SYNTHESIS *~+* BIOPOLYMER
^[biopoly
DNA
RNA
PROTEIN
Although the potential benefit of combination chemotherapy is great, not all

combinations are beneficial. Some combinations of drugs or sequences of
multiple drug administration may prove to be antagonistic. In some cases, the
same drugs combined in different sequences may yield a spectrum of effects
from antagonistic to synergistic. This is sometimes referred to as schedule
dependency 37 Multiple examples exist, including the schedule dependency
.
of the combination of L-asparaginase and methotrexate. In tumor cells that are

sensitive to L-asparaginase, protein synthesis is inhibited; shortly thereafter
DNA synthesis stops. This inhibition of DNA synthesis, as well as an L-
asparaginase-induced inhibition of methotrexate transport, greatly attenuates
the effectiveness of methotrexate. However, a marked delay in the administra-
tion of methotrexate until the post-L-asparaginase recovery of DNA synthesis
results in augmented neoplastic cell killing in both leukemic mice and
humans without an increase in host toxicity. 37
Another important, but controversial, example of schedule dependency is
seen with the combination of methotrexate and 5-fluorouracil. These two
drugs are very frequently combined in the treatment of several solid tumors,
most prominently breast cancer (with the added use of cyclophosphamide). In
treating breast cancer, 5-fluorouracil and methotrexate are commonly given
simultaneously as an intravenous injection. However, laboratory studies uti-
lizing this combination in various schedules have produced results ranging
from frank antagonism to synergism. The details of these studies have been
summarized, 37 but the disparate and occasionally conflicting results have
raised serious question about the most appropriate use of this combination in
human patients with neoplastic diseases. 98 For the moment, the empirical
success of the combination outweighs the theoretic concern; however, the
possibility clearly exists that this commonly employed combination may be
suboptimal.
How should the treating physician approach combination chemotherapy
while these theoretic principles are being sorted out? Fortunately, the
successful programs of combination chemotherapy now in use all share cer-
tain common features. These criteria can be summarized as follows:
1. Only drugs that are active against the tumor in question are included in
the combination, with the exception of certain drugs that are inactive against
tumors but that appear to minimize dangerous toxicity to normal tissues (so-
called "rescue" agents). 37, "
2. Drugs that are included have different mechanisms of action in order to
minimize the possibility of drug resistance.
3. Drugs that are chosen generally have different spectra of clinical toxic-
ities, thus allowing the administration of full or nearly full doses of each of the
active agents.
An additional factor, which is generally but not universally employed,

relates to the preference of most investigators to utilize intermittent courses of
intensive combination chemotherapy rather than continuous programs of drug
administration. This approach tends to maximize tumor cell killing, is usually
53, 89
better tolerated by patients and appears to minimize immunosuppression.
Hopefully, as knowledge of schedule dependency becomes more complete
for human
tumors, one will be able to add a consideration of the cell cycle
specificity of drugs to this list of established principles for combination che-
motherapy. However, it is worth re-emphasizing that the use of cytokinetic
data as a guide to drug use is worthwhile only if it improves the therapeutic
index of a drug or drug combination. 75 The ultimate concern of chemotherapy
is selective toxicity.
GUIDELINES FOR THE USE OF

CHEMOTHERAPY
important to establish and observe certain basic tenets for the
It is critically
use of cancer chemotherapeutic agents in a clinical setting. 4 In general, the

following guidelines have proved useful.
1. Use chemotherapeutic agents only when a diagnosis of malignancy has

been established histologically.
2. Do not use chemotherapeutic agents unless there are adequate facilities
to monitor the potential toxicity of the agent to the patient's normal tissues.
3. Follow objective markers of the tumor if at all possible in order to
determine the response of the tumor to chemotherapy.
4. Determine whether the malignancy is known to respond to the treatment
in a reasonable percentage of cases in a manner that is beneficial to the
patient or if the treatment is a useful adjunct to surgery or radiation therapy in
the management or cure of malignancy.
These points are worthy of elaboration. The difficulties in treating a patient

"blindly," without a tissue diagnosis, may be so terrible that one experience is
enough to drive the lesson home that anticancer drugs are never given with-
out a histopathologic diagnosis of malignancy. An example of a situation when
one might be tempted to initiate a "blind therapeutic trial" is that of the
patient who is suspected of having lymphoma because of fever, weight loss,
constitutional symptoms, and a downhill course. 4 When such patients are
subsequently proved to have tuberculosis, occult fungal infection, or carcino-
ma such as hypernephroma, the prior use of chemotherapeutic agents is often
an embarrassment to the physician and a disservice to the patient. An exten-
sion of this basic tenet of chemotherapy is that these agents are rarely, if ever,
used in a diagnostic trial to determine the extent or type of malignancy.
Because of their narrow margins of safety, chemotherapeutic agents should
not be used unless die physician is prepared to monitor potential toxicities to
normal tissues, as previously detailed in this chapter. This means close and
frequent follow-up visits (including history-taking for symptoms of toxicity,
e.g., nausea, vomiting, and dysuria), a physical examination with particular
attention to the skin and mucous membranes, a white blood cell count, and a
platelet count. A good look at a blood smear may substitute for a platelet count
in the hands of an experienced observer.
The choice of a specific dose of chemotherapy warrants particular attention.
The age, nutritional status, prior chemotherapy or radiation therapy, blood
count, bone marrow reserve, renal and hepatic function, and condition of the
patient must be considered. Not infrequently, reduced doses of drugs are

all
required high risk of toxicity, as defined by such factors.

for patients at
Since chemotherapeutic agents are potentially toxic, one should strive,
whenever possible, to follow objective markers of response. For example,
objective markers may include a decrease in the size of the tumor, disappear-
ance of hypercalcemia, disappearance of paraprotein in the serum, return of
an infiltrated bone marrow to normal, or disappearance of a tumor marker such
as human chorionic gonadotropin (HCG) or carcinoembryonic antigen (CEA).
Subjective improvement, such as a decrease in pain, is a less satisfactory
indication of drug action, although an objective assessment of performance
status may provide very important information about a patient's overall condi-
tion.
Unfortunately, the response to treatment for the various tumors considered
in thisbook cannot be evaluated by a single set of criteria. The criteria for an
objective response for some of these diseases are considered in more detail in
subsequent disease-oriented chapters. As a guideline, however, a complete
response generally implies the complete disappearance of all signs and symp-
toms of cancer. A partial response generally means a 50 per cent or greater
reduction in the sum of the products of the greater and lesser diameters of all
measured lesions and the absence of new lesions during treatment. Usually, a
partial response is accompanied by subjective improvement. A summary of
possible markers used in following a patient's response to chemotherapy and
the commonly employed Karnofsky performance scale 100 appear in Tables
4-4 and 4-5, respectively.
The ultimate criterion for the clinical use of chemotherapy is that of an-
ticipated benefit. If the malignancy is known to respond to chemotherapy in a
reasonable percentage of cases in a manner that is beneficial to the patient, or
if chemotherapy is known to be a useful adjunct to other treatment modalities,
one is usually justified in recommending the treatment. Like many aspects of

medicine, established criteria for drug use are relative. Some neoplasms
TABLE 4-4. Tumor Response
Types of Tumor Response
Tumor Palpation, radiologic measurement, radioisotope scans

size:
Serum and urinary
paraproteins: Myeloma, macroglobulinemia
Peripheral white blood cell count: Leukemia
Gonadotropin titer: Choriocarcinoma, certain testicular tumors
Disappearance of effusions: Tumors involving pleural or peritoneal surfaces or obstructing
lymphatics
Organ function: For example, improved renal function after obstructive uropathy
Carcinoembryonic antigen: Gastrointestinal tumors
Response Criteria Used in Cancer Chemotherapy
Complete response (CR): Complete disappearance of all signs and symptoms of cancer
Partial response (PR): A 50% or greater reduction in the sum of the products of the greater
and lesser diameters of all measured lesions and an absence of any
new lesions during treatment
4 Principles of Cancer Chemotherapy 41
TABLE 4-5. The Karnofsky Performance Status Scale 100
Per-
Condition centage Comments
Able to carry on normal activity 100 Normal, no complaints, no evidence of disease.

and to work. No special care 90 Able to carry on normal activity, minor signs or
is needed. symptoms of disease.
80 Normal activity with effort, some signs or symp-
toms of disease.
Unable to work. Able to live at 70 Cares for self. Unable to carry on normal activ-
home, care for most personal ity or to do active work.

needs. A varying degree of 60 Requires occasional assistance but is able to
assistance is needed. care for most personal needs.
50 Requires considerable assistance and frequent
medical care.
Unable to care for self. Requires 40 Disabled, requires special care and assistance.
equivalent of institutional or 30 Severely disabled, hospitalization is indicated,
hospital care. Disease may be although death not imminent.
progressing rapidly. 20 Hospitalization necessary, very sick, active sup-
portive treatment necessary.
10 Moribund, fatal processes progressing rapidly.
Dead.
respond favorably to drugs in nearly all patients treated. Other types of

malignant disease respond only a small fraction of the time. The indications
for treatment in the latter situation are influenced by many variables, includ-
ing the toxicity of treatment, performance status, extent of disease, rapidity of
tumor growth, and social and financial factors. Table 4—6 lists the types of
malignancy in which the patient is usually, occasionally, or seldom benefited
by cancer chemotherapy. This list must be considered only a general guide.
Criteria for Experimental Trials
The experimental use of chemotherapeutic agents

within the province
falls
of the clinical investigator. Basic requirements for experimental trials are that
useful information be obtained that is applicable to the care of the treated
patient or of other patients with similar disease and that, insofar as possible,
no harmful effects result from the experimental approach. The experimental
administration of new or old drugs is not to be undertaken casually. Experi-
mental drugs that are administered to a single patient almost never yield
useful information and often do harm. Therefore, new drugs and procedures
are usually restricted to medical centers, where large numbers of patients are
treated and where experimental procedures are rigidly controlled. In this
book we are concerned principally with established criteria for cancer treat-
ment, and experimental therapy is cited only when it provides insight into
treatment of malignant disease or when such therapy holds great promise for
the future. Nevertheless, every clinician should be familiar with the types of
clinical trials commonly employed (Table 4-7).
TABLE 4-6. Role of Antineoplastic Drugs

in the Treatment of Cancer
Chemotherapy Very Useful (Patient Benefit > 50%)"

Trophoblastic tumors
Burkitt's lymphoma
Acute lymphoblastic leukemia
Hodgkin's disease
Histiocytic lymphoma
Lymphocytic lymphoma
Testicular tumors
Wilms' tumor
E wing's sarcoma
Osteosarcoma (adjuvant chemotherapy only)
Embryonal rhabdomyosarcoma of childhood
Carcinoma of breast
Chemotherapy Moderately Useful (Patient Benefit 20-50%)

Acute non lymphocytic leukemia
Carcinoma of ovary
Chronic myelogenous and lymphocytic leukemia
Multiple myeloma
Carcinoma of prostate
Carcinoma of endometrium
Adrenal carcinoma
Adult sarcomas
Oat-cell carcinoma of lung
Islet cell carcinomas
Chemotherapy Rarely Useful (Patient Benefit < 20%)

Carcinoma of bowel and stomach
Bronchogenic carcinoma other than oat cell
Head and neck carcinoma
Carcinoma of cervix
Melanoma
Neuroblastoma
Brain tumors
Bladder carcinomas
Benal carcinomas
Pancreatic, liver, and bile duct carcinomas
Carcinoid tumors
"An objective partial or complete response with subjective benefit lasting six months or longer as defined in
the text is required for "patient benefit." The approximate percentage of patients who benefit is given for
each group.
- 103
TABLE 4-7. Types of Clinical Trials 101
Phase Goal Comment
I Determine the maximum safely The mechanism of action, likely toxici-

tolerated dose for a given schedule ties, and prohable useful schedule are
ofadrugin humans (\ITD). generally available from preclinical
animal studies. Patients do not have to
have measurable disease for study
entry.
II Define the spectrum of antitumor The MTD of a drug is used in patients

action of a drug. with different kinds of measurable
cancer. The response rate is determined
and rare side effects are looked for.
Ill To compare two or more drugs, drug This is usually conducted as a randomized
schedules, or drug doses to more clinical trial, with the control group re-
precisely define the clinical value ceiving "standard" treatment,
of a new therapy.
The reader who is interested in a more thorough discussion of the princi-

ples and implementation of clinical trials is referred to several excellent

Will it ever be possible to cure more than just a few malignancies by drug
therapy? The answer to this question is unknown, but there is certainly reason
for hope. New drugs continue to be developed, and new concepts of drug
104 106 "
5, 107, 108
development may further improve this outlook. Hopefully, further
maturation of the field of cell kinetics may allow us to more precisely tailor
chemotherapy to the biology of the tumor in the individual patient. 109 Like-
wise, better definitions of the pharmacologic characteristics of drug action
may allow us to develop better programs of single or combination agent
chemotherapy, and perhaps clinicians will be better able to individualize
regimens further by measuring the blood levels or tissue levels, or both, of the
respective agents, with subsequent rigorous pharmacokinetic analysis to as-
sure optimal treatment.
Other promising areas include the development of predictive tests to allow
us more selectivity in choosing drug therapy 110111 and the development of
some newer physical methods that may augment the action of chemotherapeu-
112
tic drugs. Examples of the latter include the use of drugs with ultrasound or
hyperthermia. 113,114
We need better ways of detecting malignant cells when
they are too few in number to produce clinical manifestations. 115 We must
learn to identify and manipulate host defense mechanisms in order to combat
the malignant process and perhaps even learn how to prevent the develop-
ment of neoplasms in susceptible people. 116 When these goals are achieved,
perhaps we shall be able to add a number of additional malignant diseases to
the list of those curable by chemotherapy. Moreover, as we learn to combine
drug therapy with other modalities of cancer treatment, including immuno-

therapy, it is likely that still greater improvements in survival will be possible
for the cancer patient. 117
Unfortunately, it is unlikely that major improvements in therapy will result
merely from a more aggressive and intensive use of currently available
drugs. 118 Unless such aggressive treatment is combined with maneuvers that
reduce toxicity and help maintain an acceptable therapeutic index, 119 more
intensive therapy is not likely to be of benefit to the patient.
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5 / Drugs Used in Cancer Chemotherapy 53
CHAPTER 5
DRUGS USED IN
CANCER
CHEMOTHERAPY
Charles M Haskell
This chapter summarizes the mechanisms of action, pharmacologic charac-

teristics,standard doses, side effects, and clinical uses of the major drugs used
in cancer chemotherapy. Most of these drugs are in common use; some are
experimental but are nevertheless described here, either because they are
likely to become commercially available or because they play some other
unique role in oncology. Table 5-1 gives selected aspects of the pharmacol-
ogy of certain key drugs discussed in this chapter. Appendix C lists some of
the abbreviations that are used for these drugs.
ALKYLATING AGENTS
The alkylating agents are highly reactive compounds that have the ability to
substitute alkyl groups (for example, R — —
CH 2 CH 2 ) for the hydrogen
+
atoms of certain organic compounds. Although many cellular substances can

be alkylated in this way, the alkylation of nucleic acids, primarily DNA, is
1-4
the critical cytotoxic action for most of these compounds. Alkylation pro-
duces breaks in the DNA molecule and cross-linking of its twin strands, thus
interfering with DNA replication and the transcription of RNA. Similar effects
are produced by certain kinds of ionizing radiations, so that the alkylators are
said to be "radiomimetic." The effects of alkylators, like the corresponding
ones of x-rays, are often visible microscopically as abnormalities of chromo-
some structure. This appears to correlate with the carcinogenic potential of
this group of drugs, as described in Chapter 4.
There are five chemical classes of alkylating agents: (1) the nitrogen mus-
tard derivatives (mechloretliamine [HN2], cyclophosphamide, chlorambucil
[CHL], and melphalan [L-PAM]); (2) ethylenimine derivatives (Thiotepa); (3)
alkyl sulfonates (busulfan); (4) triazene derivatives (dacarbazine); and (5)
nitrosoureas (Cannustine [BCNU], Lomustine [CCNU], and Semustine
[MeCCNU]). Most of these drugs are considered to be polyfunctional alkylat-
ing agents, since they contain more than one alkylating group. Moreover, the
nitrosoureas and dacarbazine appear to have additional mechanisms of cyto-
toxicity that are separate from their ability to alkylate nucleic acids.
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56 I / General Principi
As a class, the various alkylating agents are considered to be cell cycle

phase-nonspecific. 5* * There are marked differences in their pharmacologies
and clinical uses; nevertheless, the nitrogen mustard derivatives that are
administered to the same level of toxicity produce similar antitumor effects,
and. with rare exception, 7,8 tumor cell resistance to one nitrogen mustard
derivative indicates resistance to others. 9 It also tends to predict resistance to
other alkylating agents, with the exception of dacarbazine and the nitro-
soureas. The varied mechanisms that are responsible for this resistance are
under active study; a likely explanation is the development of D\A repair
enzymes, but other changes, including modified drug transport, may also be
responsible. 10, "
The choice of an alkylator. therefore, reflects certain clinical consider-
ations, such as the preferred route of administration; the desired rapidity of
effect; the presence of bowel, hepatic, or genitourinary disease; and the
experience of the therapist. For a detailed consideration of the mode of action
of alkylating agents, the reader is referred to the excellent reviews of
Wheeler2 and Calabresi and Parks. 4 A guide to the commercially available
alkylating agents is given in Table .5-2.
Mechlorethamine (Mustargen)
During World War I it was noted that mustard gas poisoning caused bone
marrow aplasia, dissolution of lymphoid tissue, and gastrointestinal ulcer-
ation. These effects prompted Gilman 12 to study the effects of nitrogen mus-
tard, initially on a mouse lymphosarcoma and subsequently on human lym-
phoma. The transitory clinical benefit induced by that agent helped to launch
the field of cancer chemotherapy, and thousands of variants of the nitrogen
mustard molecule have since been tested. 4, 13 Mechlorethamine is the proto-
type for three other useful alkylating agents, namely, cyclophosphamide,
chlorambucil, and melphalan. Their chemical structures are given in Figure
5-1.
Because mechlorethamine is a vesicant, gloves are worn during its prepara-
tion. It isgiven intravenously, with care being taken to avoid infiltration into
the soft tissues or splashing on the exposed skin or conjunctivae of the patient
or physician. It is commonly injected directly into intravenous tubing through
which physiologic saline solution is running. Mechlorethamine is also useful
for direct intracavitary injection in treating recalcitrant malignant effusions.
When used in this manner, its absorption from the cavity may produce system-
ic effects. Since this compound reacts rapidly with water and undergoes
chemical transformation, it is prepared immediately before use. If there are
any delays in its administration after preparation, it is likely that it will be-
come inactivated.
Less than 0.01 per cent of mechlorethamine can be recovered in the urine;
since it is altered so rapidly , there no opportunity for excretion. 4 The drug
is
rapidly interacts with cells in vivo, and it appears that its primary effects occur
within a few seconds or minutes; therefore, the only control the physician has
over it is at the time of administration. One can van the dose but cannot
Drugs Used in Cancer Chemotherapy 57
:
: .
d
- I
- - i
— -r ./-
r = — > > > -

z r •J -r
~2 ~5 ~~ =
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HN2 CHLORAMBUCIL
CH 2 CH
2
CI / \ .CH^HjCI
CHjN' HOOCHjCHjCHjC N
N
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Methyl-bis (B chloroethyl) amine 4-(p-[Bis(^-chloroefhyl)aminoJ phenyl) butyric acid
MELPHALAN CYCLOPHOSPHAMIDE
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I I
/C H 2 CH 2 CI
H C
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2
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/ ch 2 ch 2 ci
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Oxazaphosphorinane, 2-oxide
FIGURE 5-1. Chemical structure of alkylating agents I: mechlorethamine (HN2) and

its derivatives.
otherwise titrate the drug, as is possible with the slower acting alkylating
agents.
The dosage of mechlorethamine varies with the previous chemotherapeutic
history and the related marrow reserve of the patient. In a previously untreat-
ed patient, a dose of 0.4 mg/kg given once or in divided doses of 0.2 mg/kg on
each of two successive days is usually sufficient. Doses in excess of 0.6 mg/kg
are dangerous; doses as low as 0.2 mg/kg may suffice for chronic lymphocytic
leukemia (CLL). For intracavitary administration, the dose is 0.2 to 0.4 mg/kg.
If the patient has inadequate bone marrow reserves reflected in a low white
blood cell count (WBC) or platelet count, or marrow hypoplasia, a lower dose
of mechlorethamine is given.
The nadir of the fall in the white blood cell and platelet counts usually
occurs within 7 to 15 days of injection of the drug. The patient should be
followed closely during this time. The fall may be greater in a patient whose
bone marrow has been damaged by previous chemotherapy, radiation thera-
py, or malignant infiltration. The white blood cell and platelet counts usually
begin to increase by the second to fourth weeks following drug administra-
tion, and it is generally advisable to delay administration of a second course of
the drug for at least four weeks.
The infection and bleeding associated with bone marrow depression are the
most serious toxic side effects of mechlorethamine, although the acute gastro-
intestinal symptoms may be more annoying to the patient. Because of the
severe nausea and vomiting that invariably accompany the administration of
this drug, the patient is often given an antiemetic such as prochlorperazine (10
mg) before the alkylator is given. A sedative such as secobarbital sodium (100
to 200 mg) may also be useful in reducing untoward symptoms.
Other side effects are less common but may include menstrual irregular-
ities, sterility, a poorly understood skin rash, alopecia, and, rarely, a toxic
encephalopathy. 4, 14 When given topically, it frequently causes a delayed

cutaneous hypersensitivity reaction. 15 The drug should be used only if abso-
lutely necessary in a pregnant patient, and the possibility of delayed carcin-
ogenesis should be kept in mind. 16 It does not appear to have clinically
important immunosuppressive effects. 17 A final caution relates to a toxic reac-
tion seen in seven patients with Hodgkin's disease who were treated at
Stanford University. 18 These patients had all received mediastinal radiation
therapy followed by combination chemotherapy with mechlorethamine, vin-
cristine, procarbazine, and prednisone (PRED). In each case, either radiation
pneumonitis or radiation pericarditis was apparently activated during sub-
sequent withdrawal from prednisone. Successful treatment of this complica-
tion involved the prolonged use of corticosteroids.
Mechlorethamine has a time-honored place in the treatment of disseminat-
ed Hodgkin's disease and other lymphomas, including mycosis fungoides. It
is particularly useful in Hodgkin's disease when it is combined with vincris-
tine, procarbazine, and prednisone (MOPP) (see Chapter 24). When it is

employed in the treatment of mycosis fungoides, it is commonly applied
topically. 15 It may also be useful in occasional patients with carcinoma of the
prostate, stomach, breast, ovary, and lung. 19,20 In general, it is not useful in
treating the acute leukemias or multiple myeloma. Mechlorethamine is some-
times used in conjunction with radiation therapy in the treatment of spinal
cord compression secondary to lymphoma, although other alkylators that
cause less emesis are usually preferable.
Cyclophosphamide (Cytoxan)
This widely used alkylating agent was originally synthesized in 1958 as a

potential inert transport form of mechlorethamine. 21 It was postulated then
that cancer cells may preferentially activate the drug; however, it is known
now that the major site of biotransformation for cyclophosphamide occurs in
the liver, as depicted in Figure 5-2. 22, 23
CHjCHjCI
R-N
/ M
\,
11/
0- •CH,
\ NON-
—
ACTIVE METABOLITES
r~~~~
ENZYME Hr-p.
CH
NON- NH, OHC OHC / I
ENZYME
O ,0—CH, O O-CHj IV. V
l_
R— V
11/ ^ Microsomal \
R—P CH,- = . . - P, CH. LIVER
ALDEHYDE
\ NH-CH,/ '
Function N
NH-CH OXIDASE
OxidaM
I
OH r CARBOXYPHOSPHAMIDE
II.
-KETOCYCLOPHOSPHAMIDE
_l
INACTIVE METABOLITES
FIGURE 5-2. Cyclophosphamide and its biotransformation products. (From Chabner BA, et
al.: Semin Oncol 4: 165, 1977.)
60 I / General Principi
The details of biotransformation that are given in Figure 5-2 are probably
correct, although they remain somewhat controversial." It is likely that al-
dophosphamide represents a major transport metabolite that undergoes sub-
sequent breakdown within cells into acrolein and phosphoramide mustard.
There are some data suggesting that acrolein or its degradative product may
be the major moiety responsible for hemorrhagic cystitis, whereas phosphora-
mide mustard may be more responsible for the antitumor effect of cyclophos-
phamide. The experimental prevention of hemorrhagic cystitis by acetylcys-
teine, without abrogation of the antitumor effectiveness of cyclophosphamide
in animals, lends indirect support to this hypothesis
Cyclophosphamide is effective by both the oral and intravenous routes of
administration. It probably is not directly effective by intracavitary adminis-
tration, since it requires activation in the liver prior to exerting its systemic
effect. Cyclophosphamide itself is not bound to albumin, whereas its me-
tabolites are —50 per cent).- 5 Owing to moderate lipid and water solubility,
I
the drug and its metabolites are widely distributed to the extracellular water
spaces of the body, and a small amount may reach the cerebrospinal fluid,
milk, sweat, saliva, and synovial fluid. The disappearance of injected cyclo-
phosphamide from plasma is biexponential. with an average longer half-life of
4 to 6.5 hours; however, after a large intravenous dose, the drug and its
metabolites may remain measurable in the plasma for several days. Excretion
takes place primarily via the kidney, where alkylating metabolites constitute
90 per cent of the total drug excreted by that route.
The usual oral dose for continuous therapy with cyclophosphamide is 1 to
2.5 mg/kg/day in divided doses. The best guides to regulating the oral dosage
are the response of the disease and the level of the white blood cell count.
which should be maintained at approximately 3500 to 400 /xL. When a more
rapid drug effect is desired, or for those clinical situations in which intermit-
tent high-dose treatment is preferred, cyclophosphamide may be given intra-
venously in a dose of 30 to 40 mg/kg. Again, the use of repeated courses is
guided by the response of the tumor and the levels of the leukocyte and
platelet counts. It is usually advisable to wait at least three weeks after a large
intravenous dose before giving additional drugs.
Cyclophosphamide, like all of the clinically useful alkylating agents, pro-
duces toxicities in rapidly proliferating normal tissues. 2H It has been stated
that cyclophosphamide has a platelet-sparing effect, but this is not well sub-
stantiated. It may simply be easier to control this orally effective, slowly
acting alkylator, making it possible to avoid significant depression of thrombo-
cytopoiesis. Large doses of cyclophosphamide produce thrombocytopenia
comparable to that produced by mechlorethamine. In addition to marrow
suppression, cyclophosphamide has some other clinically important toxic-
ities. Nausea and vomiting are common with higher dose treatment. Alopecia
is a frequent side effect; it is advisable to warn patients of this complication
beforehand, so that they may prepare for the possibility by obtaining a wig if
necessary.
As described earlier, the metabolites of cyclophosphamide can produce
severe hemorrhagic cystitis; however, this is almost always avoidable when a
high fluid output is maintained. Dehydration must be avoided if this drug is
used, since hemorrhagic cystitis may prove lethal, and its treatment may
27 28
require such maneuvers as instillation of formalin into the bladder or*
urinary diversion. 29 Even in the absence of hemorrhagic cystitis, the drug can
cause urinary bladder fibrosis, 29 and there are reports of patients who have
developed carcinoma of the bladder after cyclophosphamide exposure. 30 It
has been postulated by some workers that low-dose oral cyclophosphamide
therapy may lead to fewer genitourinary problems, 29 although other workers
dispute this. 31 Because of the important role of renal excretion, patients with
severe renal failure who require ongoing low-dose oral cyclophosphamide
treatment should probably have the interval between doses doubled. 32
Other noteworthy side effects include moderate to severe immunosuppres-
33-35
sion, water intoxication when the drug is given in large doses with large
16,40
fluid loads, 36,37 sterility, 38,39 fetal damage, and, potentially, delayed car-
16,41,42
cinogenesis. There is also a theoretic danger that patients may tolerate
anesthesia poorly while on therapy. 43,44 Cardiac damage has been associated
with very high doses (^180 mg/kg over -^4 days), 45,46 and, rarely, pulmonary
47
fibrosis may occur. Extremely rare side effects include fever or anaphylaxis
after IV doses, 26, 48
skin and nail hyperpigmentation, 26, 49 mucosal ulceration, 26
26
urticaria, 50 and immediate oropharyngeal sensations
51
liver damage, or tran-
sient cerebral symptoms 52 after rapid intravenous injection of the drug.
In general, intravenously administered cyclophosphamide is used in oncol-
ogy in the same situations as is mechlorethamine. 26 It may occasionally be
curative in Burkitt's lymphoma, and it is often effective in treating other
lymphomas and certain carcinomas and sarcomas. In addition, clinical experi-
ence has indicated that it may be effective in multiple myeloma and acute
leukemia, especially acute lymphoblastic leukemia that is refractory to more
usual therapy. The drug is usually given by the oral route in patients with
these diseases. As a rule, cyclophosphamide is not effective in patients with
lymphoma when the disease has proved resistant to adequate doses of other
alkylating agents.
Cyclophosphamide widely known and used as an immunosuppressant as
is
well as an antineoplastic drug. It has been mentioned in over 10,000 publica-

tions, and it is known in various countries by at least 28 names. 53 Good
reviews are available on its pharmacology 23, 53 and clinical use in both neo-
plastic 26 and non-neoplastic conditions. 33, 54
Chlorambucil (Leukeran)
Chlorambucil is an aromatic derivative of mechlorethamine that is effective

by the oral route of administration (Fig. 5-1). It is the slowest acting and
generally least toxic of the alkylating agents in common use.
The initial dose is usually 0.1 mg/kg/day in either single or divided doses.
Once the desired effect is achieved, usually in three to four weeks, mainte-
nance therapy with 2 to 4 mg/day may be considered. It is important for the
maintenance dosage not to exceed these levels and for a complete blood count
to be obtained weekly, since it is far more difficult to treat aplastic anemia
than the usual case of chronic lymphocytic leukemia. An alternative program
of treatment in chronic lymphocytic leukemia involves the administration of

chlorambucil every two weeks in a single dose of 0.4 mg/kg, or more. Re-
sponses are excellent with this schedule, and toxicity is minimal. 55
If chlorambucil is given for prolonged periods, it may produce immunosup-
pression, 56 myelosuppression, gastrointestinal symptoms, and rarely, hepato-
toxicity, dermatitis, or a peculiarwasting syndrome. 4 57 These toxic side ef-
-
fects are usually avoidable if proper attention is paid to the patient and to the
laboratory studies. A potentially unavoidable complication of prolonged use,
however, may be carcinogenesis. 16,58
Not only is chlorambucil frequently used in chronic lymphocytic leukemia
to reduce the mass of abnormal lymphoid tissue, but it is also occasionally-
used in lymphomas to maintain a remission. Like other alkylators, it has been
used in the treatment of malignancies of the breast 61 and ovary. 62 Although it
has also been used in treating patients with multiple myeloma, macroglobu-
linemia, choriocarcinoma, testicular tumors, and some other tumors, the gen-
eral experience with this agent when used alone is less extensive than with
20
other alkylators. 19 *
Melphalan (Alkeran)
Melphalan is a phenylalanine derivative of mechlorethamine that is given

orally. When it is given on a daily basis, severe and somewhat unpredictable
myelosuppression may occur. Since the time of onset and the severity of
myelosuppression are more predictable with an intermittent schedule, it is
generally preferable to use the drug as an intermittent "pulse" of treatment, as
described by Alexanian and coworkers. 63 This intermittent program uses a
dose of 0.25 mg/kg/day for four days, with courses repeated at four- to six-
week intervals. Alternatively, melphalan may be given in a dose of 0.05 to 0.1
mg/kg/day in divided doses until the white blood cell count is less than
4000//i.L or until thrombocytopenia is observed. The drug is stopped until
there is evidence of hematologic recovery and is then resumed at a mainte-
nance level of 1 to 4 mg/day.
Therapy is usually continued intermittently for several months. The initial
fall in white blood cell count generally takes place two to three weeks after
the initiation of therapy, but in some patients it may occur as early as day five;
therefore, patients receiving this drug must be watched extremely closely. It
is of interest that in animals, bone marrow toxicity varies greatly depending
on the time of day of melphalan administration. Although it may be premature

to judge its relevance for patients with cancer, this observation, plus some
incomplete observations in humans, suggests that it may be wiser to admin-
ister melphalan with breakfast rather than at bedtime. 64
The toxicity of the drug is similar to that of other alkylating agents (bone
marrow suppression, nausea with high doses, immunosuppression, sterility,
potential carcinogenesis); however, the very low incidence of alopecia with
melphalan makes it particularly useful in treating women with responsive
tumors.
Melphalan has been used most extensively in the treatment of multiple
myeloma, in which its effectiveness is roughly comparable to that of cyclo-
5 Drugs Used e\" Cancer Chemotherapy 63
phosphamide. 19 0,65 '

It also appears to be the equal of cyclophosphamide in
the treatment of ovarian carcinoma, but it is probably less effective in the
treatment of breast cancer.*6 An intermittent schedule has generally been
superior for both these diseases.
Busulfan (Myleran
This alkylating agent is an alkyl sulfonate and is not chemically related to

mechlorethamine predominant effect is against cells of the
iFig. 5-3 Its
granulocytic series. Detailed pharmacokinetic studies of this compound have

been performed in humans. 67 After intravenous or oral administration of 3 H-
labeled busulfan, the drug rapidly disappears from the circulation. Sub-
quently. repeated doses lead to a gradual accumulation of radioactivity in
plasma and a urinary excretion of less than 50 per cent of the total dose given.
This suggests a slow elimination of the metabolic products.
Busulfan is effective by the oral route. Adult patients with chronic myelo-
cytic leukemia are generally given doses of 4 to 10 mg day. until the white
blood cell count falls to within the range of 10,000 to 15.000 /zL, at which
;- :
II
:
N f \
<x u
N = N- N
\
FIGURE 5-3. Chemical structure of alkylating -- z'l'--

agents 11: and triazene
alkyl sulfonate? ethylenimine,
deritati: ":' — '":
HjC^ I
* N
Triilfcjli«*hinr»-i--v
: o
ii ii
CH,- S-0-(CH2-CH2te- - S-O^

II II
o o
time the drug is discontinued. Maintenance therapy is begun when the white
blood cell count shows a tendency to rise above this range; the maintenance
dose is usually 2 to 4 mg/day.
The proper use of busulfan requires a blood cell count at least once weekly,
since it occasionally produces abrupt drops in the white blood cell and
platelet counts that may be irreversible. The acute toxicities of the drug are
almost exclusively hematopoietic, the major ones being the suppression of
platelet and granulocyte production. The appearance of these toxicities may
be delayed, which makes the determination of dosage difficult. With pro-
longed administration, complex side effects can occur, including hyperpig-
mentation that resembles Addison's disease or porphyria cutanea tarda,
pulmonary fibrosis, ocular cataracts, gynecomastia, and, possibly, new primary
tumors. 16,68-72
Busulfan widely used to treat patients with chronic myelocytic leukemia
is
and is occasionally used to treat patients with polycythemia and other myelo-
proliferative disorders. In the latter cases, the drug is usually restricted to
those patients with myeloid metaplasia, whose disease picture resembles
chronic myelocytic leukemia, or to those patients with symptomatic or aggres-
sive essential thrombocytosis.
Triethylenethiophosphoramide (Thiotepa)
The initial chemical reaction that mechlorethamine undergoes before al-

kylation involves the formation of an ethylenimonium ion. For this reason,
compounds with were screened for antitumor activity, and
this structure
several were foundbe active. 2, One of these, a relatively stable sulfur-
to
containing compound commercially known as Thiotepa, has remained avail-
able (Fig. 5-3). 73
The dose of Thiotepa generally double that of mechlorethamine when
is
used in a comparable situation —

namely, 0.6 to 0.8 mg/kg intravenously
every three to four weeks. This polyfunctional alkylating agent has a spectrum
of toxicity and clinical use that is nearly identical to that of mechlorethamine.
However, it is more mechlorethamine and need not be prepared at
stable than
the bedside. In addition, not a vesicant and seldom causes nausea.
it is
Although the use of Thiotepa has been largely supplanted by cyclophospha-

mide, it remains a potentially useful agent for intracavitary administration in
selected patients with malignant pleural or pericardial effusion (see Chapter
28).
Dacarbazine (DTIC-Dome)
Dacarbazine is one of several imidazolecarboxamide derivatives developed

under NCI contract by scientists at the Southern Research Institute (Fig. 5-3).
Although it is a structural analogue of certain purines, its major mode of action
appears to be alkylation. Interestingly, the target substrate does not appear to
be DNA, since its use primarily leads to inhibition of RNA and protein synthe-
sis.
As with cyclophosphamide, dacarbazine itself is inactive and must undergo

biotransformation before exerting its cytotoxic effects. 25, 74 Two forms of bio-
transformation have clinical importance. The major metabolic pathway in vivo
appears to be oxidative N-demethylation by liver enzymes. This forms alkylat-
ing metabolites that are cytotoxic for neoplastic cells; however, this process
may also form products that are carcinogenic in animals. The other major
pathway of biotransformation by photodegradation to active and inactive
is
metabolites. This fact should be borne in mind, since prolonged exposure of

dacarbazine to light prior to its administration may modify its effectiveness.
Dacarbazine is cell cycle phase-nonspecific, 74 and in human studies it is
only minimally immunosuppressive. 75 Detailed reviews of the pharmacology
of dacarbazine are available, and a summary of the more important features of
this drug is given in Tables 5-1 and 5-2. 8, 74,
7,i
Dacarbazine may be given intravenously in doses ranging from 2.4 to 4.5

mg/kg/day for five to ten days. 74 Much higher single doses have also been
used, 77 and in selected patients with regional melanoma, dacarbazine has
been used experimentally by the intra-arteria] route. 78 Perhaps the most con-
venient of the available programs of drug use is the IV use of 250 mg/m 2 /day
for five days, repeated every three weeks. 79
Toxicity generally includes anorexia, nausea, and moderate to severe vomit-
ing in most patients. 79 This often abates after two or three doses despite
continued therapy, and it may be reduced by the use of prochlorperazine.
Toxicity may also include mild to moderate bone marrow suppression. Very
rare forms of toxicity include a flu-like syndrome, as well as chills, malaise,
dizziness, facial flushing or paresthesias, alopecia, hepatic dysfunction, and
possibly cerebral dysfunction. 23 74, 80 The teratogenic and carcinogenic poten-
'
1H 74, 79
tial of this drug must also be considered. -
Dacarbazine is used in the treatment of malignant melanoma; it may also be

useful in sarcomas and in some lymphomas.
Nitrosoureas: Carmustine (BCNU),

Lomustine (CCNU), Semustine
(MeCCNU)
The nitrosoureas are made upof a group of lipophilic alkylating agents that
were originally developed by scientists at the Southern Research Institute. 81
Two drugs from this class are commercially available (BCNU and CCNU) and
a third is available from the National Cancer Institute on an experimental
basis (MeCCNU). The chemical structures of these agents appear in Figure
5-4, and Table 5-2 summarizes selected clinical aspects of BCNU and CCNU.
This group of drugs undergoes extensive biotransformation in vivo, leading to
a variety of biologic effects, including alkylation, 81, K carbamoylation, 81, 83 and
inhibition of DNA repair. 81 Multiple mechanisms of action may explain why
the nitrosoureas generally lack cross resistance with other alkylating agents.
Such mechanisms may also explain a variety of unusual effects on the cell
cycles of normal and neoplastic cells, including the possible induction of
greater damage to resting cells than to cells in cycle. 81,84
BCNU: 1,3Bis(2chloroethyl)1 nitrosourea
CI-CH 2 -CH 2 -N-C-NH-CH 2 -CH 2 -CI
NO
CCNU: 1(2-chloroethyl)-3-cyclohexyl-1 -nitrosourea
FIGURE 5-4. Chemical structure of alkyl-

I
-N-C-NH-/ -AA )
ating agents III: nitrosoureas.
MeCCNU: 1-(2-Chloroethyl)-3-(4-methyl cyclohexyl)-1 -nitrosourea
-CH,
I
NO
The nitrosoureas are very lipid soluble, and they cross the blood-brain
barrier with ease. 23,81 They and disappear rapidly from
are well absorbed
plasma, but their metabolites may persist for several days. Peak levels of
metabolites are seen after one to six hours of an oral dose; excretion occurs
primarily via the kidney, although the liver assists in excretion and an en-
terohepatic recirculation of the drug has been demonstrated. Other aspects of
the pharmacology of these drugs have been published, and a summary of
some of the details for CCNU
appears in Table 5-1.
The usual dose of BCNU is 200 to 250 mg/m 2 as a single intravenous
injection every six to eight weeks. CCNU and MeCCNU are generally given
as single oral doses every six to eight weeks. The dose of CCNU is 100 to 130
mg/m 2 and the dose of MeCCNU is 200 to 225 mg/m 2 81 Other programs of
, .
administration have been tried with interesting results but have not been
widely accepted. 85,86 Patients with bone marrow depression or extensive
previous bone marrow suppressive therapy require the lower dose, and pro-
longed treatment with the nitrosoureas commonly necessitates further dose
reductions.
The major toxicities of the nitrosoureas include nausea and vomiting, which
start three to six hours after the dose is given and last less than one day of each
may be reduced by antiemetics and by drug administration at
cycle. 81 This
bedtime on an empty stomach. The other major toxic reaction is delayed bone
marrow depression, commonly occurring four to six weeks after a given dose
of drug. Weekly blood counts, including a platelet count, are needed between
doses in order to identify patients who are at risk of serious infection or
bleeding. Interestingly, the immunosuppressive activity of the nitrosoureas
has not been defined, so the potential contribution of this to infection is
unknown. Very rarely, these drugs may be associated with stomatitis, 81 alope-
cia,
81
renal dysfunction, 87 hepatic dysfunction, 81,88 pulmonary fibrosis, 89 hy-
pe rpigm en tation in areas of skin that come in contact with BCNU, 90 optic
neuritis, 81 and neurologic problems (disorientation, lethargy, ataxia, and dys-
arthria). As with other alleviators, the nitrosoureas may be mutagenic, tera-

81
togenic, and carcinogenic. BCXU has the unique toxicity of local pain upon
16
injection. This may be difficult to control despite alterations in the rate of drug
administration or the concentration of the solution being injected. MeCCNU
has the unique characteristic of being very unstable at room temperature; the
practical consequence of this is that bottles of MeCCXU stored at room
temperature may explode. 91
The nitrosoureas differ from each other in the inhibition of experimental
animal tumors. 81 Despite these differences in animals the available nitro-
soureas share a common spectrum of activity in human cancer. 819 - The most
noteworthy effects in humans (with the nitrosourea of apparent choice indi-
cated in parentheses) have been against brain tumors (BCXU) and lymphomas
(CCXU), with lesser activity seen in lung cancer (CCXU), melanoma (BCNU),
myeloma (BCXU), and cancer of the colon (MeCCXU and BCXU). Less com-
monly, responses may be seen in other solid tumors as well.-" M 90 *
ANTIBIOTICS
Theclinically useful antibiotics are natural products of various strains of the
soil fungus Streptomyces. They produce their antibiotic and tumoricidal ef-
fects by directly damaging DXA, either through a process termed intercala-
tion or through other forms of binding. 93, m As a consequence, their major
inhibitory effects are on DXA synthesis or RXA synthesis, or both. As a class,
these drugs have a variety of effects on different phases of the cell cycle 5 6 -
;
nevertheless, the kinetics of their killing action is that of cell cycle phase-
nonspecific agents.
Drugs of this class include doxorubicin, daunomycin, dactinomycin, bleo-
mycin sulfate, mithromycin, and mitomycin-C. The chemical structures of
the useful members of this class of drugs are given in Figure 5-5, and a guide
to their clinical uses is summarized in the following discussion and in Table
5-3.
Doxorubicin (Adriamycin) and

Daunomycin
Doxorubicin and daunomycin (XSC-82151) are closely related anthracy-

cline antibiotics derived from Streptomyces peucetius varcaesius. Both drugs
bind to DNA by intercalation, thereby disrupting the synthesis of RNA by
template disordering and steric obstruction. 93-95 Chemically, they differ by
only a single hydroxy] group on carbon-14 (see Figure 5-5).
The pharmacologic characteristics and toxicities of doxorubicin and daun-
omycin are very similar. 96-98 After intravenous injections, both drugs undergo
extensive biotransformation in the liver to active and inactive metabolites. In
addition, both are extensively bound to tissues, both are excreted primarily in
the bile, and both persist in plasma for prolonged periods. Xeither drug
crosses the blood-brain barrier to any appreciable extent. Table 5-1 gives
specific information on the pharmacology of doxorubicin. 97
DACTINOMYCIN ANTHRACYCLINES
R-CM,OH
MITHRAMYCIN
FIGURE 5-5. Chemical structure of selected antibiotics.
TABLE 5-3. Antibiotics
Route of
Adminis- Available
Compound Orig in- Clinical Considerations tration Preparations
Doxorubicin Streptomyces Hematopoietic and GI toxicities; IV Powder;

(Adriamycin) alopecia; cardiac damage; locally 10 mg/vial
irritating 50 mg/vial
Dactinomycin Streptomyces Hematopoietic and GI toxicities; IV Powder;
(Cosmegen) locally irritating 500 ugl vial
Bleomycin Streptomyces Pulmonary fibrosis; skin and mucous IV or IM Powder;
(Blenoxane) membrane toxicity 15 units/vial
Mithramycin Streptomyces Hemorrhagic diathesis; hematopoietic IV Powder;
(Mithracin) and GI toxicities 2500 M g vial
Mitomycin-C Streptomyces Delayed, severe hematopoietic IV Powder;
(Mutamycin) toxicity; locally irritating 5 mg/vial
20 mg/vial
These pharmacologic data have clinical relevance. The prolonged plasma

clearance time of doxorubicin has led to the widespread adoption of an
intermittent single high-dosage schedule of drug administration." Although a
variety of routes, doses, and schedules of doxorubicin administration have
been used, 95, 100_102 in most cases a single intravenous dose of 60 mg/nr
infused slowly over about four to five minutes and repeated even three weeks
is recommended." Reduced doses should be used for patients with extensive
previous chemotherapy or radiation therapy and for patients with liver dys-
function. The recommended dosage reduction for patients with bilirubin
levels of 1.2 to 3.0 mg/dL is 50 per cent, and for bilirubin levels greater than
3.0 mg/dL, it is 75 per cent." The extensive biotransformation of doxorubicin
by hepatic microsomal enzymes, with its subsequent biliary excretion, alerted
clinicians to the need for dosage modifications in patients with liver dysfunc-
tion." In addition, it is of interest that the effectiveness of doxorubicin may
be reduced in animals by stimulating hepatic microsomal enzymes with
phenobarbital. 103 Given the wide variety of drugs commonly administered to
patients with cancer, this potential drug interaction requires additional
study.
The maximum recommended lifetime total dose of doxorubicin is 550
mg/nr, but in patients previously treated with mediastinal irradiation or
recommended maximum dose is 450 mg/m 2 For daun-
alkylating agents, the .
omycin, the recommended maximum dose in 600 mg/nr.

Both doxorubicin and daunomyein are highly toxic drugs. 9> 10° Both may
-
cause severe bone marrow suppression, severe alopecia, stomatitis, vomiting,

severe irritation of tissues if allowed to extravasate at the site of injection, 104
and cardiac toxicity. Very rarely, doxorubicin may cause other problems,
including renal failure, 105 hyperpigmentation, 106, 107 skin rashes, ,08 109 and on-
-
ycholysis with epidermolysis. 110 Patients should be informed that their urine
may turn red after treatment, owing to the red color of doxorubicin, but that
this is harmless.
The anthracyclin.es are minimally immunosuppressive, 111112 and they are
potentially mutagenic, teratogenic, and carcinogenic. 16 Doxorubicin may also
sensitize tissue to radiation therapy; therefore, great care must be exercised in
combining these two modalities. 113-115 This has been manifested clinically as
increased immediate toxicity (e.g., esophagitis from radiation therapy at lower
doses than usual) or as a "recall phenomenon" when doxorubicin is given
after previous radiation therapy. Although it is difficult to predict these reac-
tions quantitatively in even patient, it has been suggested that one guideline
to combining these treatments is to equate a full course of doxorubicin to
approximately 1000 rad of radiation. 115
Although most of these reactions may be severe, the major limiting toxicity
23116-119
is cardiac damage. Two forms of cardiac damage occur: (1) arrhyth-
mias, which occur early in the course of treatment and are commonly associat-
ed with pre-existing cardiac disease, and (2) delayed moderate to severe
congestive heart failure, which not infrequently leads to death. Pathologic-
findings include fragmentation and dropout of myofibrils, mitochondrial
swelling, and intracellular inclusions. 23, 116 120 The underlying mechanism of
*
cardiac toxicity is unknown, although studies in mice suggest that it may be

associated with peroxidation of cardiac lipids. 121 Both the lipid peroxidation
and cardiac toxicity of doxorubicin may be reduced in mice by prior treatment
with the free radical scavenger tocopherol. This treatment does not inhibit the
antitumor effectiveness of doxorubicin, thus raising the possibility that the
mechanism of cardiac damage may be qualitatively different from the mech-
anism of tumor cell toxicity. This work has encouraged pharmaceutical chem-
ists to modify the doxorubicin molecule further in the hope of developing a
new anthracycline antibiotic that is effective without causing cardiac damage.

It has also led to efforts to prevent cardiac damage with tocopherol in larger
animals, although the high doses required for the effect make it unlikely that
this can be used clinically.
At present, the most reliable way to avoid cardiac toxicity is to limit the
maximum total dose of anthracycline drug given to the patient. 116, 118, 119 Pa-
tients should have an electrocardiogram at least every two months but prefera-
bly each month before treatment. The risk of cardiomyopathy appears to
increase in patients who develop a ^ 30 per cent decrease in limb-lead QRS
voltage. 119 Other attempts to predict cardiac toxicity, including measurements
of the systolic time interval, 122 "sphygmo-recording" of the pulse wave delay
(QKd interval), 123 and echocardiography studies, 124 have proved somewhat
cumbersome and have not been widely adopted. They may, however, have
value in selected cases.
Both doxorubicin and daunomycin have undergone extensive international
testing, but the latter is considered to be an experimental drug in the United
States, and its use has been largely restricted to the treatment of acute leu-
kemia. In contrast, doxorubicin has demonstrated one of the widest spec-
trums of antitumor activity ever observed, including lymphomas, leukemias,
95, 10 °
soft tissue sarcomas, and a wide variety of carcinomas. It is of great inter-
est that in many of these cases, the patients responded despite the presence
of advanced disease and extensive prior therapy. This suggests that doxorubi-
cin may lack cross resistance with most of the commonly used anticancer
drugs. 100 As befits such a key drug, doxorubicin has been intensively studied
and its use widely reviewed. 23,95, 10 °
Dactinomycin (Cosmegen)
The actinomycins were discovered in 1940 and first given to patients in

1952. 125
Most have been derived from Streptomyces parvulus, and more than
100 analogues have been extracted or synthesized.
Dactinomycin is the most clinically useful member of this group. Its mech-
anism of action at a molecular level has been well defined. 125 At low concen-
trations in mammalian tissues, dactinomycin inhibits DNA-primed RNA syn-
thesis by intercalating with the guanine residues of DNA. At higher
concentrations, it also inhibits DNA
synthesis. This combination of effects
causes a variety of concentration-dependent changes in the life cycle of
126
cells; 5, the net effect, however, is best described as being phase-
nonspecific. Tumor resistance to dactinomycin appears to be related, at least
in part, to changes in membrane permeability. 127 Other mechanisms of resis-
tance are under investigation, and a variety of other topics related to this
interestingand important drug have been reviewed. 125
Dactinomycin must be administered intravenously because of its erratic
absorption if given orally. Although in the past, animal studies showed that
dactinomycin is initially removed rapidly from the circulation, 1 it is now
known important longer plasma half-life is, in fact, very long (approxi-
that its
mately 36 hours), and the drug is extensively bound to tissues. 128 It appears to
be preferentially retained by nucleated cells, and only about 30 per cent of an
injected dose of radioactive dactinomycin can be recovered from the urine
and feces after nine days. There is evidence that the drug is concentrated in
bone marrow and tumor cells but that a partial blood-testis barrier exists, as
well as a nearly complete blood-brain barrier. Indeed, for most normal tissue,
the factor that limits the ultimate concentration of dactinomycin in the tissue
is the blood supply to that tissue, rather than the tissue's cell membrane
permeability to the drug. 129

A number of dosage regimens have been used, and the optimal program is
still not known. The most common regimen is to give 15 ^g/kg IV (maximum
single dose, 0.5 nig) on each of five successive days. 125 Such a course may be
repeated every three or four weeks. Lesser doses may be used in treating
adults with impaired bone marrow function, and extra care is needed in
treating small infants. An alternative, but at present incompletely tested,
regimen has been devised by Benjamin and coworkers. 130 It is based on the
newer understanding of dactinomycin's pharmacology described earlier. In
this regimen, a single dose of 2.0 mg/m is given intravenously every four
2
weeks.
The major toxic reactions of dactinomycin include bone marrow depression,
vomiting, alopecia, glossitis, stomatitis, and diarrhea. 125 It can also cause skin
rashes, including a moderately severe folliculitis, 131 which appears to be a
somewhat greater problem in patients who are treated with higher dosage
intermittent schedules. 130 As with doxorubicin, dactinomycin is a radiosensi-
tizing drug, and it can cause delayed radiation reactions ("recall phenome-
non"), 125 teratogenesis, mutagenesis, and, potentially, delayed carcinogene-
sis.
16
The drug is weakly immunosuppressive. 35
also A final caution relates to
the severe tissue inflammation and necrosis that may result from local extrava-
sation. For this reason, it is usually preferable to administer the drug via the
tubing of a smoothly running intravenous infusion.
Dactinomycin is widely used in the treatment of Wilms' tumor, rhabdomyo-
sarcomas, gestational choriocarcinoma, and testicular carcinomas. 19
Bleomycin Sulfate (Blenoxane)
Bleomycin is an antibiotic complex that was isolated in 1962 from a strain of

Streptomyces verticillus that was obtained from a soil sample taken from a
Japanese coal mine. 132-134 It can be separated into at least 13 fractions desig-
nated as A, to A 6 A' 2 and Bj to B 6 Although fraction A, is probably the most
, .
active, the proportion of the various fractions has varied slightly from batch to
batch without any apparent impact on the potency of the clinically used mix-
ture.
Bleomycin appears to affect cells by directly binding to DNA, resulting in

reduced syntheses of DNA, RNA, and proteins. 133, 134 It can also lead to single
strand breaks in DNA through scission of thymine by a process referred to by
one research group as "partial intercalation." 135 Drugs acting by intercalation
appear to augment the cytotoxic effects of bleomycin, 136 as do radiation and
chemicals that generate superoxide radicals. 137 Bleomycin should be consid-
ered cell cycle phase-nonspecific. It is more damaging to nonproliferating
cells than to most proliferating cells, although in some cell culture systems it
has G 2 specificity, and it is capable of partially synchronizing the population
of cells. 5, 6> 134, 138 This may become a more important consideration in future
programs of combination chemotherapy. 134,139
Mechanisms of resistance to bleomycin have been defined only for animal
tumors. The bleomycins are subject to degradation by the action of an amino-
peptidase found only in tumor cells, liver, and kidney. 133 The degradative
enzyme is notably absent from skin and lung — two body parts that are
particularly vulnerable to the drug. It appears, based on animal studies, that
tumor cell resistance to bleomycin is also related to an increased ability to
degrade the drug. 140
After intravenous injection, bleomycin is rapidly cleared from plasma with a
TV2 of about two hours. 141 It reaches high concentrations in the skin, lung,
kidney, peritoneum, and lymphatics, but it appears to lack an affinity for
hematopoietic tissues. 142, 143 It is cleared primarily by the kidney, and clear-
ance is markedly reduced in renal failure. 144 It has been recommended that
the dose of bleomycin be reduced as much as 50 per cent in patients with
severe renal failure (creatinine clearance < 10 ml/min). 32
The regular dosage schedule is 10 to 20 units/m 2 given IV, IM, or subcutan-
eously weekly or twice weekly. It has also been administered by the intra-
arterial 145 and intracavitary 146 routes, although such treatment has not been
widely accepted.
Toxicities of bleomycin are distinctly different from those of most other
antineoplastic drugs. 143, 147 It rarely causes bone marrow depression, but it
causes pulmonary dysfunction in about 10 per cent of treated patients. This
reaction usually begins as dyspnea with fine rales, but in approximately 1 per
cent of cases, it may progress to fatal pulmonary fibrosis. Although these
pulmonary changes may occur in young patients who have received a low
total dose, they are much more common in patients receiving more than 400
units total dose, in patients receiving single doses greater than 26 units/m 2 in
,
patients with underlying pulmonary disease, and in patients past the age of 70
years. 143, 147 Unfortunately, pulmonary function tests have not been particular-
148
ly helpful in predicting this complication. The manufacturer recommends
taking a chest x-ray every one to two weeks during treatment to aid in early
diagnosis; 143 however, changes on x-ray usually occur later than the develop-
ment of symptomatic dyspnea and rales, so careful attention to the patient is of
the utmost importance. At present, one must rely primarily on clinical find-
ings to make an early diagnosis, with the chest x-ray being considered a useful
adjunct that may be of additional value in excluding other causes of pulmona-
ry dysfunction, such as infection, radiation pneumonitis, drug reaction, or
progressive tumor. Rarely, problematic cases may require open lung biopsy to
establish the diagnosis. In such cases, the lung shows interstitial edema,
intra-alveolar hyaline membrane formation, hyperplasia of type II alveolar
macrophages, and, in advanced stages, collagen deposition. 149 The treatment
of bleomycin-induced pulmonary dysfunction is cessation of bleomycin treat-
ment. There is no other specific treatment, although occasional benefit may be
seen from the administration of corticosteroids. 150
Other toxic reactions with bleomycin may include severe skin reactions
(erythema, hyperpigmentation, systemic sclerosis, loss of fingernails, ulcer-
ation), mucositis, alopecia, nausea, hyperpyrexia, and soft-tissue calcifica-
143-152
tions. The drug is not clinically immunosuppressive, 153 although it is
mutagenic and probably teratogenic. 16 It can also cause cataracts in rats. 154
Finally, bleomycin can cause a rare fulminant reaction that is characterized by
high fever, hypotension, cardiorespiratory collapse, and death. 143, 147 Although
this reaction is assumed to be a form of anaphylaxis, its etiology is not clear. It
has been seen only in patients with lymphomas that were treated with large
single doses. For this reason, the manufacturer recommends that lymphoma
patients be treated with 2 units or less of bleomycin for the first two doses. 143 If
no reaction occurs, the regular dosage schedule may be used. In lymphoma
patients who respond, reduced maintenance doses of 1 unit daily or 5 units
weekly may be employed.
When bleomycin is used produces partial remissions in
as a single agent, it
a minority of patients for a short time. Responsive tumors include squamous

cell carcinomas of the head and neck, testicular neoplasms, and lympho-
mas. 147 The absence of bone marrow suppression in most patients has led to
the widespread use of bleomycin in a variety of drug combinations. When
used in this way, it appears to make a particularly substantial contribution to
the treatment of lymphomas and testicular tumors, as described in Chapters
10, 24, and 25. However, the use of bleomycin in combination regimens may
intensify the skin and pulmonary toxicity- of the drug; therefore, the treating
physician must remain especially alert to toxic reactions during its use in drug
156
combinations. 155,
Mithramycin (Mithracin)
Mithramycin is an antibiotic that is derived as a natural product of Strep-

tomyces plicatus. As with other antibiotics, it binds to DNA and inhibits RNA
synthesis. 157 Relatively little is known about the pharmacology of mithramy-
cin, although limited studies in mice have been published. 158
Mithramycin is used in the treatment of testicular tumors, especially em-
bryonal cell carcinoma of the testis. 19,20 It can also inhibit bone resorption,
and it has been widely used in the treatment of many forms of hypercal-
cemia. 159
Early clinical studies demonstrated severe toxicity when daily treatment
was employed. Kennedy 160 has developed an alternate-day program of drug
administration that appears to be effective and relatively safe. He recom-
mends mithramycin in a dose of 50 /ag/kg/day, administered as a rapid in-
travenous injection three days a week on alternate days. On the morning of
each day of treatment, the serum lactic dehydrogenase (LDH), blood urea
nitrogen (BUN), prothrombin time, and platelet count are determined. The
upper limit of safety set by Kennedy for the LDH is 2000 IU/liter, for the BUN
it is 25 mg/dL, and for the prothrombin time it is 15 seconds (normal, 11
seconds). Any clear-cut decline in the platelet count is regarded as an early

sign of toxicity. A course of therapy consists of alternate-day mithramycin
administration until toxicity occurs, as defined by these tests. Treatment is
then discontinued. It is resumed as another course not more than four weeks
after the initial injection but at least two weeks after the last injection of the
previous course. Using this program of treatment, Kennedy has reported a 47
per cent response rate in embryonal cell carcinoma of the testis, with no drug-
related mortality.
When mithramycin is used in the treatment of hypercalcemia, a different
dose and schedule of drug administration is generally used. 161, 162 When the
hypercalcemia is due to bone destruction by metastatic malignancy, a dose of
25 Mg/kg may be given daily for up to three or four days. If this is successful,
intermittent weekly doses may serve to maintain the response. Other regi-
mens have been used in the treatment of Paget' s disease of bone 163, 164 and in
the intractable hypercalcemia associated with parathyroid carcinoma. 165
Toxicities resulting from mithramycin include severe hemorrhagic diathe-
sis, arterial occlusions, malaise, fever, vomiting, skin eruptions, central ner-
vous system reactions (headache, apprehension, lethargy), stomatitis, hypo-
calcemia, and hepatorenal dysfunction. 19, 166_168 These reactions may be
severe, unpredictable, and life-threatening, leading many clinicians to aban-
don the drug. Because of these problems, the manufacturer of mithramycin
recommends that the drug be given only to hospitalized patients. 161
Mitomycin-C (Mutamycin)
Mitomycin-C is an extremely toxic antitumor antibiotic, which was initially

isolated from Streptomyces caespitosus in 1958. 169 Unlike most other antibiot-
ics, it is activated in vivo to a bifunctional or trifunctional alkylating agent. 170
After activation,it binds preferentially to the guanine and cytosine moieties of
DNA, leading to cross-linking of DXA and inhibited DXA synthesis and

function. The drug may also be degraded in vivo, and resistant cells appear to
have an enhanced ability to perform this degradation. Mitomycin-C-resistant
cells are often resistant to other alkylating agents, but the converse is only
rarely true. Thus, prior treatment with alkylating agents is not a contraindica-
tion to its use. Mitomycin-C is cell cycle phase-nonspecific, and it is only
minimally immunosuppressive.
Mitomycin-C is almost always given intravenously, although many other
routes of administration have been studied. 169 It is rapidly cleared from plas-
ma (TV2, 10 to 15 minutes), primarily by metabolism in the liver. Renal
clearance also occurs, although this is a minor route of excretion. The drug
does not appear to cross the blood-brain barrier.
Two different schedules of drug administration have generally been em-
ployed. 169, 1T1 The schedule preferred by most investigators is a single IV dose
of 20 mg/m 2 given through a smoothly running intravenous line. As an

,
alter-
native, 20 mg/m 2 may be divided into ten separate doses of 2 mg/m
2
each,
given over 12 days. 172
Either schedule may be repeated every six to eight
weeks, by the patient.
as tolerated
The major toxicity of mitomycin-C is myelosuppression. This reaction is
usually delayed, cumulative, and occasionally fatal. Patients who have had
extensive prior chemotherapy or radiation therapy may be especially suscep-
tible to this problem, and patients responding to mitomycin-C who experi-
ence severe bone marrow suppression require reduced doses of the drug.
Indeed, the nadir of leukocytes and platelets after a course of mitomycin-C
should be determined, and subsequent doses reduced as follows (see Table
A-A for details of toxicity grading): grade to 1 toxicity, give 100 per cent of
the previous dose; grade 2 toxicity, give 70 per cent of the previous dose;
grade 3 or 4 toxicity, give 50 per cent of the previous dose (modified from
Crooke and Bradner 189 ). In any case, mitomycin-C should not be repeated if
the toxicity grade at the time of treatment is worse than or 1 (WBC < 3000 or
platelets < 75,000, or both).
Reactions other than myelosuppression are less common. 189 Gastrointesti-
nal disturbances are usually mild, and alopecia, stomatitis, and rashes are
uncommon. Pulmonary, 173 hepatic, and renal dysfunction are rare. Delayed
renal failure is due to a sclerotic reaction of the glomerulus that is manifested
clinically as a rising serum creatinine level. 189 The drug can also cause local
tissue necrosis if extravasation occurs, and it is mutagenic, teratogenic, and
carcinogenic in animals. "- 17 °
1
Mitomycin-C appears to be active against a variety of adenocarcinomas

(stomach, pancreas, colon, breast) as well as certain head and neck tumors and
chronic myelogenous leukemia (CML). 169 Rarely, it may be useful in lympho-
mas and in carcinomas of the cervix, ovary, and lung. It has also been reported
to be useful as intravesicular treatment for transitional cell carcinoma of the
bladder. Unfortunately, the short duration of response, which is usually meas-
ured as one to three months, plus the potentially severe myelosuppression,
has limited the use of this agent. It is therefore not a first-line treatment for
any tumor, although it may provide useful palliation for occasional patients
who have not responded to previous treatment.
VINCA ALKALOIDS
Through folklore, random screening, and chance observation, plants have
provided some of our most useful antineoplastic agents. 174 175 Two of them are
'
vincristine and vinblastine (VBL). 175 These two drugs are alkaloids extracted
from the common periwinkle plant (Vinca rosea Linn, more properly known
as Catharanthus roseus). They were originally screened by pharmaceutic
chemists because of their use as hypoglycemic agents by natives in several
parts of the world. Their hypoglycemic properties were not impressive; how-
ever, their marrow suppressive and other cytotoxic effects were readily appar-
ent, and both drugs have well-established roles in the contemporary treat-
ment of cancer.
VINCA ALKALOIDS
VINCRISTINE
VINBLASTINE
o=c-o-ch
0=C-0-CH,
Vincristine Vinblastine
I
R is 0=C-H R is CH-
FIGURE 5-6. Chemical structure of vinca alkaloids.
The vinca alkaloids are large and complex molecules (Fig. 5-6). Vincristine
and vinblastine differ only in methyl (vinblastine) or formyl (vincristine) side
chains on a larger parent molecule. They both appear to exert their major
antitumor effect by binding to critical microtubular proteins within cells. 175
Since these proteins are essential contractile proteins of the mitotic spindle of
dividing cells, this binding leads to mitotic arrest. Similar proteins make up an
important part of nervous tissue. In addition, at high concentrations, the vinca
alkaloids can kill nonproliferating cells and exert complex effects on RXA and
protein synthesis. Because of these varied effects in different cell systems, the
vinca alkaloids are difficult to classify as being either cell cycle phase-specific
or phase-nonspecific. 5, Nevertheless, most clinicians consider these drugs to
be cell cycle phase-specific. They are also minimally immunosuppres-
34, 35
sive
Despite the many similarities in chemical structure and action shared by
vincristine and vinblastine, and toxic spectra are different,
their antitumor
and they are not cross resistant. 175 Their individual characteristics are sum-
marized in the discussion that follows and in Table 5—4.
At present, there are no other commercially available plant products used in
cancer chemotherapy, but several are under active investigation. Examples
include the semisynthetic May apple derivatives (epipodophyllotoxins:
VM-26 and VP-16-213) and maytansine. 175, 176 The reader who is interested in
175
these experimental drugs is referred to available reviews. 174 '
TABLE 5-4. Vinca Alkaloids
Route of
Adminis- Available
Compound Origin Clinical Considerations tration Preparations
Vincristine Periwinkle plant Neurotoxicity; severe IV Powder;

(Oncovin) alkaloid constipation; alopecia 1 mg/vial
5 mg/vial
Vinblastine Periwinkle plant Bone marrow toxicit\ In- Powder;
(Velban) alkaloid 10 mg/vial
5 Drugs Used en Cancer Chemotherapy 77
Vinblastine (Velban)
Using [ 3 H] vinblastine and a radioimmunoassay for vinblastine, Owellen

and colleagues 177 have greatly clarified the pharmacology of this drug (see
Table 5-1). Plasma clearance follows a triphasic pattern, with TV2 a — 4
minutes, TM> /3 — 53 minutes, and the terminal TV2 — 19.5 hours. There is
extensive binding of vinblastine to blood and other cellular elements, with
the tissue affinities being in the order of plasma > platelets > red blood cells
> leukocytes. The drug is metabolized in part in the liver to another active
compound, deacetylvinblastine. It is excreted primarily in bile as biodegrad-
ed products, but about 20 per cent of an injected dose is excreted in the urine
as unchanged drug. These findings help explain how vinblastine may play a
role in the development of neuropathy, despite its apparent lack of access to
the nervous system. As vinblastine slowly redistributes out of various tissues,
a slow but constant passage across the blood-brain barrier probably occurs,
with subsequent avid binding to the microtubules of the nervous system. The
pharmacology of this drug, with its primary excretion via the liver, also
explains the added toxicity that occurs when it is given to patients with liver
disease.
Vinblastine is administered intravenously, with extreme care being taken to
avoid extravasation because of its ability to cause local tissue damage. The
usual intravenous dosage is 0.1 to 0.15 mg/kg, given once weekly until the
desired effect is achieved or until bone marrow depression precludes further
treatment. This dose may be titrated upward to as high as 0.5 mg/kg/wk in
some patients. 178
Bone marrow suppression, manifested most commonly as granulocytopen-
ia, is the most frequent and dangerous toxicity. This dose related; the nadir
is
of granulocytopenia occurs 5 to 9 days after a given dose, with resolution by 14

to 21 days. Other less common forms of toxicity include temporary gastrointes-
tinal symptoms (nausea, vomiting, constipation, abdominal pain, pharyngitis),
alopecia, malaise, weakness, skin vesiculation and, rarely neurologic prob-
lems. The latter toxicities are qualitatively similar to those that will be de-
scribed for vincristine, although they are rarely as severe. Finally, based on
animal studies, 16 there is a theoretic risk of mutagenesis and teratogenesis
with vinblastine, although they have not been noted as problems in
humans.
Vinblastine is used primarily in the treatment of Hodgkin's disease and as a
part of combination therapy for some testicular tumors. It has sometimes been
used in pregnant patients with Hodgkin's disease as a palliative therapy
pending delivery of the infant. 179180 It is also used in the treatment of non-
Hodgkin's lymphomas, histiocytosis X, and breast cancer. Rare benefit may
attend its use for brain tumors, renal carcinoma, and carcinomas of the head
19,2 °
and neck. 1 -
Vincristine (Oncovin)
For all practical purposes, the pharmacology of vincristine

probably
is
identical to that of vinblastine, with the exception that vincristine has never
been shown to form active metabolites. 181 It is clear that both of the vinca
alkaloids are extensively bound to tissues and slowly eliminated from the
body by the liver and kidney; these facts probably help to explain the appear-
ance of cumulative neurotoxicity, particularly when vincristine is given on a
weekly schedule.
Vincristine isadministered intravenously because of erratic oral absorption.
As with vinblastine, this must be done carefully owing to the severe local
tissue destruction that results from extravasation. It is usually administered in
weekly doses of 1.4 mg/m 2 (the maximum dose in adults is usually 2 mg). This
therapy may be given for prolonged periods in some patients, whereas others
develop severe neurotoxicity after 10 to 12 doses or less. Much higher doses
have been given accidentally, and although they are not generally fatal, there
is no important improvement of antitumor response.
182, 183
The most important toxic reaction from vincristine is a mixed motor-sensory

and autonomic neuropathy. 184, 185 Its earliest manifestation is depression of the
Achilles tendon reflex, followed by paresthesias of the fingers and toes. If the
drug is continued, weakness, muscle pain, and sensory impairment may
develop. Further treatment may produce severe, generalized motor weakness
and, rarely, quadriparesis. Very rarely, convulsions may occur. Autonomic
neuropathy is manifested by constipation, ileus, or, rarely, bowel obstruction.
Recovery from most of these changes is possible by withdrawing the drug, but
motor weakness may be irreversible. Although neuropathy is bothersome to
the patient, mild to moderate dysfunction appears to be necessary for an
antitumor effect by this drug. 186 One guide to therapy is to discontinue vincris-
tine if the patient develops paresthesias proximal to the distal interphalangeal
joints of the hands or if any motor weakness occurs. This may easily be tested
by having the patient attempt to walk on his or her heels. The bowel prob- 1
lems from vincristine can usually be avoided by the use of stool softeners and
cathartics. If these are insufficient, vigorous cleansing enemas and discontin-
uation of vincristine may be necessary.
Other side effects of vincristine include occasional alopecia and rare bone
marrow suppression, stomatitis, nausea, and the syndrome of inappropriate
antidiuretic hormone secretion. 176 185, 187 Rare observations that vincristine
'
may precipitate myocardial infarction are of uncertain relevance. 188, 189 Never-
theless, it is probably wise to be alert to this potential problem and to obtain a
baseline electrocardiogram in patients treated with this medication. In an-
imals, vincristine has inhibited spermatogenesis; 190 the importance of this in
humans is unresolved. There have been sporadic reports of other rare toxic-
ities, but the documentation of their relationship to vincristine is inade-
quate. 185
Vincristine is component of programs of combina-
primarily used as a major
tion chemotherapy in acute lymphoblastic leukemia, Hodgkin's disease, and
the non-Hodgkin's lymphomas. It is less commonly used in the treatment of
breast cancer, some brain tumors, sarcomas, childhood tumors, cervical carci-
noma, and small cell carcinoma of the lung. 19, 20, 191, 192 It has been of equivo-
1 '
cal benefit in some nonmalignant conditions as well, most notably in some

194
forms of thrombocytopenia. 193,
ANTIMETABOLITES
The antimetabolites are structural analogues of normal metabolites that are
required for cell function and replication. As such, they work by interacting
with cellular enzymes. There are three ways in which antimetabolites or their
biotransformed active products may interact with enzymes and thereby dam-
age cells: 195 (1) by substituting for a metabolite that is normally incorporated
into a key molecule, making the key molecule function abnormally, (2) by
competing successfully with a normal metabolite for the occupation of the
catalytic site of a key enzyme, and (3) by competing with a normal metabolite
that acts at an enzyme regulatory site (the "allosteric' or noncatalytic site) to
alter the catalytic rate of a key enzyme.
Of the many antimetabolites that have been developed and tested in the last
30 years, only five are commercially available and widely used in oncology.
They are methotrexate, 5-fluorouracil, cytarabine, 6-mercaptopurine, and
6-thioguanine (6-TG). A sixth agent, azaribine (Triazure), is no longer avail-
able commercially and will not be discussed here.
With the exception of 5-fluorouracil, the clinically useful antimetabolites
are cell cycle phase-specific, as discussed in Chapter 4. 5,6 Their successful
use is often highly schedule dependent in animal systems, but the relevance
of this schedule dependency has been incompletely defined in programs of
single agent or combination agent chemotherapy in humans. 196
The use of these antimetabolites, as well as some comments on related
investigational compounds, is summarized in the following discussion and in
Table 5-5. Since schedule dependency may alter the success of therapy, this
problem will receive attention in this section, along with the pharmacology
and clinical use of these drugs.
Methotrexate (MTX)
introduction of folic acid antagonists by Farber and his colleagues 197 in

The
1948 marked the beginning of an important new phase in the history of cancer
chemotherapy. Many folic acid analogues have been developed and used
clinically, but an early compound, methotrexate, is the one currently used
(Fig. 5-7). Hopefully, other investigational folate antagonists will also prove
199
useful. 198 -
Methotrexate works by competing avidly for the folate binding site of the
enzyme dihydrofolate reductase (DHFR). 200 Tight but reversible binding of
MTX to DHFR leads to the blockage of tetrahydrofolate synthesis and the
depletion of reduced folate cofactors in the cell, resulting primarily in the
decreased synthesis of thymidine and purine nucleotides (Fig. 5-8). 23,201
There is evidence that some cells may have more than one kind of DHFR; the
more common type has a high affinity for MTX, whereas the other has a low
affinity.
202
Complete suppression of DNA synthesis by MTX commonly re-
quires an extracellular MTX concentration of 10~ 8 Mor higher, with the
resultant presence of unbound MTX within the cell. Indeed, the cytotoxicity
TABLE 5-5. Antimetabolites
Route of
Chemical Adminis- Available
Compound Characteristics Clinical Considerations tration Preparations
Methotrexate Folic acid Renal excretion; absorbed from Oral 2.5 mg tablets
(MTX) antagonist meningeal surfaces; toxicity for IV powder;
bone marrow, GI tract, and 5 mg/vial
buccal mucosa; renal toxicity at 50 mg/vial
high doses; hepatic, with
prolonged administration
Citrovorum factor Foli .id Antidote for methotrexate Oral" 3 mg/vial
(Leucovorin) IM 50 mg/vial
IV
5-Fluorouracil Fluoropyrimidine Hepatic metabolism; bone marrow IV 500 mg/vial
(Fluorouracil) and GI toxicities frequent
Cytarabine Pyrimidine nucleo- Rapidly excreted in urine; bone IV Powder;
(Cytosar) side analogue with marrow suppression 100 mg/vial
an altered sugar 500 mg/vial
moiety
5-Azacytidine Pyrimidine nucleo- Bone marrow suppression; GI and IV Powder;
(Investigational side analogue with liver toxicity; drug unstable 100 mg/vial
NSC-102816) an altered in solution
pyrimidine ring
6-Mercaptopurine Purine analogue Bone marrow and hepatic Oral 50 mg tablets
(Purinethol) reduce dose when
toxicity;
6-MP is given with allopurinol
Allopurinol Xanthine oxidase Inhibits purine catabolism and Oral Tablets;
(Zyloprim) inhibitor protects against uric acid 100 mg
nephropathy; causes allergic- 300 mg
skin reactions
6-Thioguanine Purine analogue Bone marrow and hepatic Oral 40 mg tablets
(Thioguanine, toxicity; no dose modification
Tabloid brand) needed with allopurinol
"As of June 1979, the Federal Drug Administration had not approved this route of administration.
of MTX is incomplete without a substantial concentration of free, unbound

intracellular MTX. 202 As will be discussed later, the duration of a cell's expo-
sure to free intracellular MTX is also critical. 23,201,203 Cellular resistance to
MTX may be related to the development of high levels of DHFR, altered
affinityof DHFR
for MTX, or alterations in cellular uptake of by a MTX
carrier-mediated process. 201, 204, 205
COOH
CH,
CH.
_CH 2 —N— / \—CONH—CH

CH 3 COOH
FIGURE 5-7. Chemical structure
METHOTREXATE of methotrexate and folic acid.
COOH
I
QCH, —CONH—CH
CH,
I
'
COOH
FOLIC ACID
Leucovorin Rescue
5
<N -formylFH 4 >
,u
^ N -formylFH 4
5
Purine
N "'°methenyl FH 4 Nucleotides
(JUMP + 5
N -'°methyleneFH 4 dTMP
Thymidylate Synthetase
5-FU FdUMP
FIGURE 5-8. Sites of action for methotrexate (MTX) and 5-fluorouracil
(5-FU). Abbreviations: DHFR, dihydrofolate reductase; FH^, dihydrofolic
acid; FH 4 ,tetrahydrofolic acid; dUMP, deoxyuridine monophosphate;
FdUMP, 5-fluorodeoxyuridine monophosphate; dTMP, deoxythymidine mon-
ophosphate.
It is well known that the cytotoxicity of MTX

can be reversed by leucovorin
(citrovorum factor, Leucovorin Calcium). 201,206-208 Leucovorin is readily con-
verted to other forms of reduced folate within the cell, which can then act as
methyl-donors for a variety of biochemical reactions (Fig. 5-8). In theory,
leucovorin should noncompetitively bypass the block of DHFR, but in prac-
ticehigh levels of MTX
may require large doses of leucovorin to prevent cell
death. This is assumed to be due to a competitively shared active transport
mechanism for MTX
and leucovorin. The use of leucovorin to overcome the
cytotoxic effect of MTXis commonly referred to as "leucovorin rescue."
208
Other forms of "rescue" have also been used experimentally, as reviewed by

Bertino. 208
With these basic facts in mind, most aspects of the clinical use and toxicity
of methotrexate can be understood as a function of the duration of time tissues
are exposed to critical threshold MTX concentrations. After intravenous ad-
ministration, MTX is widely distributed in body water, except for the nervous
system. 201 Clearance from plasma is triphasic: initially it is very rapid, but the
TV2 of the critical phase (which starts 12 to 36 hours after the IV dose) is 8 to 12
hours. The precise rate of clearance may be variable from patient to patient,
depending upon the dose and the route of drug administration, the adequacy
of renal function, and the presence or absence of so-called third space depots
(e.g.,an effusion in the chest or abdomen). 209
The delivery of MTX to tissues may be influenced by other factors as well.
MTX is 50 to 70 per cent bound by intravascular serum albumin, and hypoal-
buminemia or drugs that displace MTX from albumin (particularly aspirin or
sulfonamides) may cause augmented uptake of free MTX by cells. 210 The use
of gut-sterilizing antibiotics may cause increased MTX toxicity by eliminating
the gut bacteria, which, in part, degrade the MTX that is given orally or that
enters into the enterohepatic circulation phase of its distribution. 211,212 A
variety of drugs may affect the ability of MTX to enter or leave cells. For
example, cephalothin and hydrocortisone inhibit MTX accumulation by
human leukemia cells, whereas high concentrations of vincristine enhance

MTX uptake, apparently by inhibiting MTX efflux from the cell. 2"
It is worthy
of note, however, that the concentrations of vincristine that are achieved with
standard clinical doses do not increase the intracellular concentrations of
MTX. 214 Finally, the critical importance of renal clearance should be empha-
sized. MTX is very insoluble in acidic solutions, so alkalinization of the urine
leads to augmented renal clearance. Anything that reduces renal function will
increase MTX toxicity. 201, 206
Moreover, since the drug is secreted in part by
the kidney (and the liver via the bile), drugs (such as probenecid) that inhibit
the secretion of MTX may increase toxicity. 215
MTX currently used in one of three basic ways: in conventional oral or
is
parenteral doses (alone or in combination), experimentally as a very high dose

infusion followed by leucovorin, and as intrathecal treatment for meningeal
leukemia or carcinomatosis. 201 Conventionally, MTX
is given alone as a single
dose of 25 to 75 mg/m 2 intravenously, intramuscularly, or orally once or twice

weekly, depending upon the disease being treated. Doses of this magnitude
cause peak plasma concentrations of 1 x 10
-6
Mto 1 x 10
-5
M, clearance is
reasonably complete by one to two days, and in the absence of previous
marrow dysfunction or renal disease leucovorin is not required. 23 This dose
may be titrated up or down, depending upon patient tolerance. 216 In this
regard should be noted that plasma levels of MTX are comparable after low
it
oral or low intravenous doses of MTX, but they are predictable only at higher
doses when the intravenous route of administration is used. 201
The widespread, but experimental, use of very high dose MTX (s= 1 gm/m 2 )
with leucovorin rescue deserves special comment. 201, 206_208a Its use is based
on the pharmacologic principles just given, plus the likelihood that there may
be a quantitative (or qualitative?) difference between some tumor cells and
normal cells in their ability to transport MTX and folinic acid across the cell
membrane (Fig. 5-9). In one such regimen, a patient with a normal serum
creatinine determination and two unobstructed kidneys that appear normal on
intravenous pyelogram (IVP) is given 50 to 250 mg/kg of MTX intravenously
over six hours. This results in plasma concentrations of 10~ 4 M to 10~ 3 M. The
patient is given large amounts of intravenous fluids (3000 ml/m 2/day), receives
acetazolamide and NaHC0 3 to alkalinize the urine (pH > 6.5), and one hour
after the infusion of MTX, 15 mg/m 2 of folinic acid are given intramuscularly
MTX > 1000 mg/m 2
CANCER NORMAL
CELL CELL
FIGURE 5-9. Theoretic basis for

high-dose methotrexate administration
and leucovorin rescue therapy (see text
for discussion).
MTX 25-75 mg/m 2

Leucovorin 15 mg/m 2 q6 hr
-,-3
= 10"
FIGURE 5-10. tomogram for io~V

modifying Icucovoriti rescue as a
function of blood methotrexate Citrovorum dosage
levels at various times (see text 6
B IO"
Continue until
for discussion). (From BleyerWA: ""plosmo methotre-
Cancer Treat Rev 4: 87, 1977.) xate concentration
less than 5x :0" 8 m
iC
-e __ __
20 40 60 80 100 120
Time offer storting methotrexate { h )
and then repeated every six hours. A serum creatinine determination is ob-
tained at 20 to 24 hours after MTX administration; if it is more than 50 per cent
above the premethotrexate serum creatinine determination, the folinic acid
dose is increased to 100 mg/nr every six hours. The patient's plasma MTX
level is then determined, and the folinic acid dose is adjusted according to
Figure 5-10. Plasma MTX levels are then followed daily until they are below
5 x 10" 8 M, at which time folinic acid may be discontinued. In patients with
no change in the serum creatinine clearance at 24 hours, the leucovorin dose
need not be altered. However, the plasma MTX level should be measured at
48 hours and the results known by 72 hours. If the 48-hour level is elevated,
the plasma MTX determination should be repeated and leucovorin continued
until the plasma MTX level is less than 5 x 10~ M.
s 201
The concept of high-dose MTX administration with leucovorin rescue has

considerable appeal, and a number of variations of the basic regimen just
described have been tried. 201, 217 However, its efficacy is uncertain, and its safe
use requires diligent attention to all the specified details; it is particularly
crucial to measure and properly interpret the meaning of the plasma MTX
levels with time. This follows directly from the pharmacologic fact that tissue
damage and toxicity are related both to the threshold level of MTX, which
causes toxicity in any given tissue, and to the duration of tissue exposure to
that critical MTX concentration. 102 201 Indeed, for toxicity to occur, both the
'
concentration threshold and the time threshold for the tissue must be exceed-
ed, and the severity of the toxicity is particularly determined by the extent to
which the time threshold is exceeded. For bone marrow and gut epithelium,
the plasma concentration threshold and the time thresholds appear to be 2 x
10~ 8 M and about 42 hours, respectively. Estimated concentration thresholds
for toxicity in various tissues are 10
-3
M
for the kidney with alkaline urine,
10~ 4
M for the kidney witii acid urine, and 10~ 9 to 10~
7
for the lung and M
liver. 201
Unfortunately, the time threshold for many of these tissues is uncer-
tain.
Proliferating bone marrow cells, skin, and gastrointestinal epithelial cells
are the principal targets of toxicity. The buccal mucosa is particularly vulnera-
ble, and either stomatitis or diarrhea is a strong indication for interrupting

MTX treatment. Uncommon side effects include liver dysfunction, which may
result in cirrhosis or fibrosis, 218 pneumonitis, 219 osteoporotic fractures, 220 im-
munosuppression, 35 and congenital malformations. 16,221 Renal toxicity is rare
with standard doses, 222 but renal failure may result from higher doses. 23,201
Dialysis for the removal of MTX in these patients has been of equivocal
value, 23,32 but a variety of other "rescue" approaches are under study. 208
Unfortunately, leucovorin is incapable of "rescuing" patients from estab-
lished tissue damage; this underlines the need to anticipate its potential use
in high-risk patients.
It would appear we are close to a rational understanding of the use of
that
MTX. However, conventional use has largely been defined by empiricism.
its
This is particularly true with the use of combination chemotherapy programs,

in which the role of schedule dependency has been largely ignored. 196 Clear-
ly, a proper schedule of drug administration, taking into account the relative S
phase specificity of MTX, is important. 5, An example of this is the demonstra-

tion that the optimal utilization of MTX in maintaining remissions in child-
hood acute lymphoblastic leukemia is by twice weekly administration; other
schedules are clearly inferior. 223 As for the schedule of MTX that is used in
combination chemotherapy, suffice it to say that this is critical to success in
treating animal tumors. 196 The exact timing of MTX administration in relation
to 5-fluorouracil, cytarabine, and L-asparaginase is important, as discussed in
Chapter 4. Unfortunately, more data on these relationships in treating human
cancer are lacking. Thus, it is reasonable to hope that current guidelines for
the use of MTX in combination chemotherapy may be extensively modified in
coming years. With this caveat, it is fair to say that MTX is an important drug
in the treatment of acute leukemia, choriocarcinoma, mycosis fungoides, and
carcinomas of the head and neck, breast, testis, and lung. 19,20 Its high dosage
use with leucovorin rescue has been most successful in osteosarcomas —
primarily when used after surgery in patients with limited disease. 206,208
Conventional doses of MTX are also used in a variety of nonmalignant condi-
tions, most probably psoriasis. 224
A final comment relates to the use of MTX in the treatment of meningeal
leukemia and carcinomatosis. 201,225 MTX does not readily cross the blood-
brain barrier when given in conventional doses, and MTX-sensitive leukemic
cells may thus survive in the relative sanctuary of the cerebrospinal fluid.
Because of this, MTX may be given intrathecally as prophylactic or active
treatment for this complication. Usually, MTX is injected into the lumbar
subarachnoid space in a dose of 6 to 12 mg/m 2 up to a maximum of 15 mg of
,
MTX dissolved in 10 ml of saline or artificial cerebrospinal fluid (CSF). This

dose is given twice weekly until evidence of leukemic involvement disap-
pears. It is then administered monthly. In the case of prophylactic treatment, a
total of five doses is given in league with whole brain radiation therapy. The
normal TV2 for clearance from the cerebrospinal fluid is approximately 12
hours. 23 This is associated with a slow rise in the plasma MTX concentration,
with cytotoxic levels being maintained for as long as 48 hours. This curve
contrasts with the more rapid disappearance of MTX from plasma after IV
administration. For patients whose lives would be jeopardized by myelosup-
pression, several low doses of leucovorin (3 to 6 mg every six hours) should be

started 24 hours after intrathecal MTXis given.-"" This delay is necessary,
since a metabolite of leucovorin readily crosses the blood-brain barrier, and

its premature use would abrogate the effect of MTX
against the CSF leukemia
cells.
should be noted that intrathecal MTX may be associated with acute and
It
chronic forms of neurotoxicity, including arachnoiditis, nausea, vomiting, and

occasionally serious problems such as neuropathies, dementia, and even
death. 201,223 There is controversy about the causes of these toxicities, with
postulated mechanisms including toxicity from preservatives in the drug,
toxic inhibition of neurotransmitter synthesis, and possible pharmacologic
differences in drug clearance from the cerebrospinal fluid in patients exhibit-
ing toxicity. 2 " Fairly good data suggest that in acute toxicity, which usually
1
occurs after the second to fourth doses of MTX. the toxicity can be reduced by
using artificial CSF (Elliot's B solution, which can be obtained from Baxter
Travenal Laboratories. Morton Grove. Illin< IChronic forms of neurotox-
icity that are associated with the use of MTX are most commonly seen in
patients who have also received whole brain radiation therapy. The severity
of this reaction is variable, and it may be seen in patients who have received
parenteral as well as intrathecal methotrexate. 201
It cannot be emphasized too strongly that treatment with methotrexate is
potentially very dangerous. A mortality rate of 6 percent has been reported by

the National Cancer Institute, based on a survey taken of patients treated with
high-dose MTX administration and rescue techniques at many major medical
centers. 227 The risk of death from the high-dose MTX regimen described
herein should be much less than 6 per cent, and in most patients the treatment
is not only safe but also nontoxic. However, it is clearly therapy to be avoided
by the amateur, and its use must be restricted to centers where the facilities
and experience of the staff allow its safe use.
5-Fluorouracil (Fluorouracil)
5-Fluorouracil (5-FU was dev eloped by Heidelberger and his colleagut

in 1957 as a structural analogue of the important DNA
precursor thymine.
During the ensuing 20 years, numerous other fluorinated pyrimidines have
been synthesized, including floxuridine iFUDRj and ftorafur (XSC-148958,
an investigational drug developed in the Soviet Union .
The pharmacologic characteristics of these drugs differ, but their basic

mechanisms of action and chemical structures are similar (Fig. 5—1 1 ~ y They
]
all appear to work primarily as irreversible inhibitors of the enzyme thymidy-
late synthetase, but only after their intracellular conversion to the active
metabolite 5-fluorodeoxyuridylate (Fig. 5-8). A lesser, and probably undesir-
able, mechanism of action is by the formation of 5-fluorouridylate, which can
inhibit RXA synthesis. In addition to intracellular activation of 5-FU by sev eral
enzymes (most importandy thymidine kinase, uridine kinase, and phosphori-
bosyltransferase), these drugs are degraded in the liver and in some other
tissues. The degradative enzymes are found in high concentrations in the gut
FU
FTORAFUR
FIGURE 5-11. Chemical structure of fluoropyrimidine antimetabolites.

Abbreviations: FU, 5-fluorouracil; FUdR, floxuridine.
but not in colonic carcinomas; this finding may explain in part the susceptibility
of this tumor to 5-FU. Indeed, the balance between the degradative and
activating pathways of 5-FU may prove to have great clinical relevance. This
subject has been reviewed in detail, but, in brief, measurements of the
activating enzymes in tumor tissue may prove useful in predicting benefit to be
derived from subsequent treatment with 5-FU. 23, 229 More detailed measure-
ments of these metabolites in various tissues may also lead to an improved
understanding of 5-FU drug resistance and improved programs of drug treat-
ment.
Whereas their mechanisms of action are similar, the major differences among
FUDR, ftorafur, and the parent compound, 5-FU, stem from their pharma-
cologies. 229 FUDR is formed from 5-FU by an enzyme that appears to be nearly
ubiquitous, and the biologic effects of FUDR are nearly identical to those of
5-FU. The major difference is that FUDR is used in continuous infusions,
whereas 5-FU is commonly given as a rapid IV injection. Curiously, it is
possible to give a higher dose of 5-FU as a continuous infusion than as a single
rapid injection; exactly the opposite holds for FUDR. 230 Conversely, ftorafur
appears to act as a depot form of 5-FU. 229 Thus, a single dose of ftorafur leads to
prolonged levels of 5-FU in plasma, and its toxicity mimics that seen when
5-FU is given as a continuous infusion.
The clinical pharmacology of 5-FU is being re-examined with newer tech-
niques of drug and metabolite measurement. 23 229 After rapid IV injection,
'
5-FU rapidly diffuses into all body compartments, including the nervous
system and malignant effusions. 229 It is rapidly cleared from plasma with a TV2
of 10 to 20 minutes after a rapid intravenous injection of 15 mg/kg. Maximum
plasma levels with this dose reach 10" 4 to 10 _3 M, but by three hours 5-FU is
_8
not measurable in plasma (<10 M). In contrast to its rapid clearance from
plasma, 5-FU and its metabolites may persist for prolonged periods in some
tissues. In mice, the active metabolite of 5-FU has been shown to persist in
bone marrow and tumor cells for seven days after a single intravenous injec-
tion. This may explain the prolonged effect of intermittent single doses of
5-FU in humans. The injection of 5-FU into the lumen or wall of the colon has
also been studied. 231 The drug is primarily degraded by the liver (~ 80 per
cent), but renal excretion is also important.
The optimal dose, route of administration, and schedule for 5-FU have yet to
be determined. 229 Although it is used by some physicians as arterial infusion
5 / Drugs Used en Cancer Chemotherapy 87
therapy in the treatment of metastatic carcinomas involving the liver (see

Chapter 9), the benefit of this approach does not clearly outweigh its many
229
risks. 5-FU has also been given orally, but erratic absorption and variable
plasma concentrations have led to general abandonment of this route. 232 There-
fore, the drug is more commonly given by rapid intravenous injection. The
Roche Company has recommended 12 mg/kg as a rapid intravenous injection in
hospitalized patients (maximum of 800 mg) daily for four days. 233 If no toxicity is
observed, 6 mg/kg are given on the sixth, eighth, tenth, and twelfth days, unless
toxicity occurs during that period. They recommend that therapy be discontin-
ued at the end of the twelfth day, even if toxicity has not become apparent.
Maximal white blood cell count depression usually occurs within 7 to 14 days
of such a course, with resolution occurring by 20 to 30 days. Subsequent treat-
ment may be given either as weekly "maintenance" injections or as periodi-
cally repeated courses, as described in the previous discussion.
Because of the serious toxicity of this schedule, many clinicians prefer
238
modifications of this "standard" loading course. 234 One such modification
"
utilizes weekly rapid intravenous injections without a loading dose. 234 Doses
are titrated to avoid major toxicity and drug-related deaths, and patients can be
treated on an ambulatory basis. The dose for the first four weeks is 15 mg/kg/wk;
if possible, this is increased to 20 mg/kg/wk thereafter (maximum dose, 1 gm).
An adequate course is considered to be one that produces either an objective

antitumor response or mild toxicity. If toxicity supervenes, 5-FU is stopped
until the symptoms have subsided, and it is then resumed at a dose that is lower
by 5 mg/kg. This modification has been associated with much less drug toxicity
than encountered with the previously used standard course, but the response
237
rate for some tumors also appears to be somewhat less.
The principal signs of 5-FU toxicity are observed in the bone marrow and
gastrointestinal epithelium. Megaloblastic changes may be an early sign of
1
toxicity', and complete marrow aplasia may occur later. Ulceration of the buccal
mucosa, anorexia, nausea, and diarrhea are also common complaints. The usual
sequence of events visible to the physician is erythema of the buccal mucosa,
followed by a patchy white membrane and ulceration. When seen, stomatitis or
diarrhea is an indication for withholding 5-FU therapy. Less commonly, skin
problems may occur (reversible alopecia, maculopapular rash, photosensi-
tivity, hyperpigmentation, skin atrophy), and neuropathic problems (including
reversible somnolence, cerebellar ataxia, and pyramidal tract signs) may devel-
op in as many as 2 per cent of the patients treated with 5-FU. 184 229 The drug is *
immunosuppressive in humans. 238 There are also rare, isolated reports of

240
cardiac ischemia associated with 5-FU administration. 239, Topical 5-FU is
generally considered to be free of systemic toxicity, although a variety of skin

reactions may occur, including the very rare development of bullous pemphi-
241 242
goid. -
5-Fluorouracil may be difficult to use because of its propensity to produce

severe, life-threatening depression of the bone marrow. It should not be given
without extremely close supervision of the patient and his or her hematologic
status. This is particularly true in a patient with a limited bone marrow reserve,
either from previous therapy or from involvement of the marrow by tumor.
Fortunately, the dual role of the liver and kidney in removing 5-FU from the
body is so efficient that one need not modify the dose of 5-FU in patients with
liver or kidney dysfunction. 229
At the present time, 5-FU as a single agent is most useful in the treatment of
patients with carcinoma of the breast and gastrointestinal tract. 19, 20 It may also
be useful topically in the treatment of some malignant and premalignant skin
diseases. --'• 4ii - 44 5-FU has helped occasional patients with carcinoma of the
cervix or ovary, although objective antitumor responses, usually lasting less
than three months, are realized in only a minority of patients treated. Moreover,
itshould be noted that the systemic use of 5-FU alone rarely achieves response
rates greater than25 per cent in any tumor. Thus, its primary role in modern
therapy appears to be as part of combination chemotherapy regimens. 196 These
regimens have all been developed by trial and error, but hopefully an improved
understanding of the drug's pharmacology and a better appreciation of factors
such as schedule dependency (described in Chapter 4 and earlier in this
chapter) for MTX plus 5-FU will lead to improvements in treatment.
Nucleoside Analogues: Cytarabine

(Cytosar), 5-Azacytidine (NSC-102816)
A wide variety of nucleoside analogues have been synthesized and tested for
"
both antineoplastic and antiviral properties. 245 247 These analogues have the
potential advantages of being readily transported into rapidly dividing cells
and requiring only a single metabolic step (phosphorylation to a nucleotide) to
enter the de novo pathway of nucleotide triphosphate synthesis. 23 Adenine
nucleoside analogues are of great interest for their potential antiviral proper-
247
ties; analogues of cytosine have not been useful as antiviral compounds in
controlled trials, 248 251 but two analogues of cytosine are useful in cancer
"
chemotherapy (Fig. 5-12). Cytarabine is an analogue of deoxycytidine in which

the sugar moiety is altered. 252 5-Azacytidine (NSC-102816) is an experimental
NH, NH,
O^N o O^N
HOH,C
OH OH
Cytidine
NH,
HOH,C
a
OH
Deoxycytidine
FIGURE 5-12. Chemical structure of cy-
tarabine and 5-azacytidine. (From Myers,
CE, etal.: Cancer Treat Rev 3:175,1976.)
NH,
N^ ^N
kJ
o^\ N
HOH,C HOH,C
OH OH OH
5-Azacytidine Cytosine arabinotide
agent that contains a single nitrogen substitution in the pyrimidine ring of

cytidine. 253 Both drugs are cell cycle phase-specific and schedule dependent.
They are both immunosuppressive and useful primarily in the treatment of
acute granulocytic leukemia, and they undergo extensive metabolic transfor-
mations relevant to their clinical activity. 23 However, they differ in their
precise mode of action and are not cross resistant; they will therefore be
discussed separately.
Cytarabine. The active form of cytarabine is the triphosphate ara-CTP,
which functions as a competitive inhibitor of DNA polymerase. 23,252 The
activation of cytarabine to ara-CTP appears to be the crucial determinant of
drug cytotoxicity, and it is mediated by a series of nucleoside and nucleotide
kinases, the first of which is deoxycytidine kinase. 23 This is balanced by at least
one and possibly two degradative enzymes that are present in plasma and in
some cells (cytidine and deoxycytidylate deaminases). Resistance to cytara-
bine is probably related to the loss of critical kinase enzymes or to an overabun-
dance of deaminases. Other postulated mechanisms of resistance include an
altered affinity of DNA polymerase for ara-CTP or changes in the pool size of
the competitive natural substrate deoxyCTP. 23 Several groups of scientists are
exploring the quantitative roles of these enzymes in the hope of developing
better treatment schedules and identifying patients who are biochemically
resistant to ara-C, so that they can be spared its toxic effects. 23
The pharmacokinetics of cytarabine are largely determined by cytidine
deaminase, which is found in high concentrations in the gastrointestinal
mucosa, liver, and granulocytes. The terminal half-life of cytarabine disappear-
ance from plasma is 2 to 2.5 hours, and most of the drug is excreted in the urine
as the inactive metabolite uracil arabinoside. 254 Only moderate concentrations
of cytarabine cross the blood-brain barrier with standard treatment, but the
drug is reasonably well tolerated by the intrathecal route. When so given, ara-C
disappears more slowly from the CSF with aTVk of 2 to 11 hours, which relates
to the paucity of cytidine deaminase in the CSF. This makes intrathecal
cytarabine an alternative to MTX for the treatment of meningeal leukemia;
unfortunately, such treatment may also be associated with neurotoxicity, and it
is probably less effective than MTX. When ara-C is used intrathecally, doses
ranging between 4.5 and 73 mg/m 2 given every three to seven days are used.
Neurotoxicity can be minimized by using a dose below 27 mg/m 2 252 .
Because of the S phase specificity and short half-life in plasma of cytarabine,

great effort has been expended to develop rational schedules of drug adminis-
tration. 23, 252, 255, 256 The primary alternative to bolus therapy has been to give the
drug by continuous infusion for five days, aiming to achieve steady plasma
levels of 0.1 to 1 /z\I. 23 An experimental approach has been to prevent deami-
nation of the parent compound with tetrahydrouridine, a potent deaminase
inhibitor. A final experimental approach to achieving sustained levels of
cytarabine has been the use of depot forms of the drug. Cyclocytidine is an
example of this; however, its use has been limited by severe toxicity, including
hypotension and parotid gland pain.
Cytarabine toxicity primarily involves the rapidly proliferating tissues of
bone marrow and the gastrointestinal tract. In acute toxicity, gastrointestinal
symptoms, including nausea, vomiting, diarrhea, and abdominal pain, may
occur. Depression of normal leukopoiesis and thrombopoiesis will appear

later;the nadir of granulocytopenia usually occurs 12 to 14 days after starting
therapy, and recovery is usually complete by 3 weeks. However, intensive
supportive therapy may be needed during that interval. Cytarabine can induce
striking megaloblastic changes in bone marrow cells, sometimes leading to
difficulties in morphologic interpretation. This may be accompanied by multi-
ple chromosome breaks seen on cytogenetic analysis; 257 the drug is thus
potentially mutagenic, teratogenic, and carcinogenic. 16 Less common effects of
cytarabine include thrombophlebitis (8 per cent), hepatic dysfunction (7 per
cent), and stomatitis (9 per cent). 258 Cytarabine is a potent inhibitor of the
primary immune response, but it has minimal effects against established
immunity. 259,260 It is of interest that immunosuppression may vary markedly
with the dose of the drug. Specifically, low doses in animal systems may
preferentially suppress humoral immunity, whereas much larger doses of
cytarabine are required to suppress cell-mediated immunity.
In clinical practice, cytarabine is almost always used in combination with
other drugs in the treatment of acute granulocytic leukemia. 252 The first of the
commonly employed regimens was and coworkers, 261 in which 2.5
that of Gee
mg/kg of 6-thioguanine (6-TG) were given each morning, followed in the
afternoon by a rapid intravenous injection of cytarabine in a dose of 2.5 mg/kg.
This was given for 8 to 13 days until bone marrow hypoplasia occurred, and a 53
per cent complete remission rate was the result. A number of modifications of
this original combination have been developed, as described in Chapter 21. In
many of these subsequent programs, cytarabine and 6-TG are given at the same
time. It should be noted, however, that the administration of these two drugs
together may not be optimal. It is known from animal studies that 6-TG must be
incorporated into DNA to exert its cytotoxicity, but that cytarabine blocks 6-TG
incorporation into DNA. 262 This is only one of many examples of animal studies
illustrating the potential importance of schedule dependency; unfortunately,
there is a paucity of data relating this problem to the treatment of cancer in
humans. 196
5-AZACYTIDINE. This agent was initially synthesized in Czechoslovakia in
1964 and is now available in the United States as an experimental drug from the
National Cancer Institute (NCI). 253 It is thought to undergo a sequence of
biotransformations similar to that of cytarabine, with the ultimate formation of
an active triphosphate. 23 However, 5-azacytidine is a ribonucleoside, and its
initial phosphorylation is catalyzed by uridine-cytidine kinase; this is a dif-
ferent kinase from the one that initiates ara-C activation. The rest of its
metabolism appears to be identical to that of cytarabine. Unlike cytarabine,

however, the major biochemical effect of 5-azacytidine on the cell appears to
be inhibition of the sequential processing of large molecular weight-species
of RNA. Its effects on DNA and protein synthesis appear to be much less
important. Resistance to azacytidine is poorly understood, but it is probably
related to a deletion of the initial critical kinase enzyme that is responsible for
its activation in leukemic cells. 23
This drug may be given intravenously or subcutaneously. After intravenous
injection, the plasma clearance is moderately rapid with aT¥a of 3.5 hours; 90
263
per cent of an injected dose of the drug appears in the urine within 24 hours.
The drug distributes slowly into effusions but minimally into the cerebrospinal
fluid. Itappears to enter tumor cells by simple diffusion; no active transport
mechanism has been shown.
The optimal dose and schedule of 5-azacytidine administration appears to be
by a continuous 24-hour infusion of 150 mg/m 2 /day for 5 days. 253, 264, 265 The drug
should be reconstituted in sterile water and then further diluted with Ringer's
injection (USP). Since 5-azacytidine decomposes in solution, a fresh solution
must be prepared at least every three to four hours during treatment.
The major toxicities of 5-azacytidine are gastrointestinal, hematologic, and
hepatic. In the past, when the drug was given as intermittent bolus injections,
severe nausea, vomiting, and diarrhea were the rule. With the continuous
infusion regimen described in the previous discussion, nausea and vomiting
are markedly reduced in severity and frequency. Rare forms of toxicity include
two forms of neuromuscular reactions (rhabdomyolysis or lethargy, weakness,
and confusion), 266 fever, skin rashes, stomatitis, phlebitis, and hypotension.
This drug can be expected to achieve an overall response rate of 36 per cent,
with about 20 per cent complete remissions in patients with acute granulocytic
leukemia who have failed standard therapy. Further studies are in progress to
define its potential role as first-line treatment in programs of combination
chemotherapy. For a more detailed discussion of this interesting new drug, the
reader is referred to the review by von Hoff et a/. 253
Purine Analogues: 6-Thioguanine

(Thioguanine Tabloid Brand),
6-Mercaptopurine (Purinethol),
Allopurinol (Zyloprim)
Mammalian cellsuse preformed purines or those made de novo within the

cell as essential components of RNA, DNA, and coenzymes. Therefore, purine
antagonists were of early interest in the historic development of cancer chemo-
therapy, and two such antineoplastic agents that were developed by Hitchings
and Elion 267 in 1952 remain useful today. They are 6-thiopurine deriva-
tives: 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG). Closely related
compounds of clinical interest are azathioprine (Imuran) and allopurinol.
Azathioprine is a structural analogue of 6-MP that has important immunosup-
pressive properties; it will not be discussed further here. 268 Allopurinol is a
potent xanthine oxidase inhibitor with many uses in oncology. 269 Its chemical
relationship to 6-MP and its important effects on purine catabolism warrant
a summary of its use. The chemical structures of selected purines and their
analogues appear in Figure 5-13.
Botii 6-MP and 6-TG undergo extensive metabolic changes in vivo. 195, 270, 271
The relative importance of some of these changes is uncertain, but certain
features are of clinical interest; a simplified diagram is given in Figure 5-14.
For the interested reader, more detailed reviews, which include the myriad
types of resistance to 6-thiopurine treatment, are available. 270 271
'
Both of the 6-thiopurines require activation to their respective ribonucleo-

tides as a minimal requirement for cytotoxicity. 6-TG undergoes subsequent
6-TG
H,0 H2O
N N
6-Mercaptopurine 6-Thioguanine
FIGURE 5-13. Chemical structure of se-
lected purine analogues.
ALLOPURINOL
OH
changes, leading to its incorporation into DNA as a false purine base. This
appears to be its major mechanism of action, although recent data support an
additional cytotoxic effect that is related to its incorporation into RNA. 272 After
phosphorylation to its ribotide, 6-MP may be converted to 6-TG ribotide or one
of its products, and thus be incorporated into DNA. 273, 274 However, it may also
directly inhibit the conversion of aminoimidazolecarboxamide ribotide (AICR)
to inosine, or it may indirectly inhibit AICR synthesis after conversion to a
methylated form —
6-methylmercaptopurine ribotide (6-MMPR). 195 The latter
occurs by a novel mechanism: The 6-MMPR acts as a "pseudo-regulatory"
inhibitor of the allosteric, or controlling, site of the enzyme that catalyzes the
formation of AICR. The role of xanthine oxidase in degrading 6-MP and
6-MMPR is of particular interest in this schema. The clinical correlate of this is
is receiving allopurinol, the dose of 6-MP must be reduced to
that if the patient
one third or one quarter of that normally used. 275 Such a dose reduction is not
necessary with 6-TG, since its catabolism is not mediated by xanthine ox-
idase.
6-MP 6-TG
PRPP
6-MP ribotide 6-TG ribotide
DNA
6MMPR
False Feedback
NADH
Inhibition of an enzyme
degraded
allosteric site
products
Ribose-5-P \
+ glutamine
Normal
Feedback
FIGURE 5-14. Sites of action for 6-mercaptopurine (6-MP) and 6-thioguanine

(6-TG). Abbreviations: PRPP, phosphoribosylpyrophosphate; 6-MMPR, 6-
methylmercaptopurine ribotide; XO, xanthine oxidase; AICR, aminoimidazole-
carboxamide ribotide.
Both 6-MP and 6-TG are used almost solely in the treatment of acute
leukemia. They are both considered to be cell cycle phase-specific, 5, but data
relevant to their schedule dependency in humans are scant. The 6-thiopurines
are not cross resistant to other chemotherapeutic drugs used in clinical prac-
tice, but 6-MP and 6-TG are cross resistant to each other. Both are immunosup-
pressive and mutagenic, but they are probably not carcinogenic in
humans. 16,31,32 Their respective uses are summarized in the following discus-
sions and in Table 5-5; for additional discussions see Chapter 21.
6-THIOGUANINE. The pharmacokinetics of 6-TG has been studied in
humans. 276 After an IV dose, the plasma T h is about 80 minutes, and the urinary
l
excretion is about 75 per cent in 24 hours. 6-TG is given orally, but its
absorption is incomplete. 277 With oral therapy, the incorporation of 6-TG into
the D\A of bone marrow is usually very small after a single dose, but after five
daily doses, the guanine of DNA is largely replaced by 6-TG. As noted in the
previous discussion, the degradation of 6-TG is not influenced bv allopurin-
ol.
When used alone, the dose of 6-TG is 2 mg/kg/day;if no leukocyte depression
is noted by four weeks, one may cautiously increase the dose to 3 mg/kg/day.
More commonly, however, 6-TG is given in combination with other drugs in
the treatment of acute myeloid leukemia. Higher doses are then used, but for a
shorter time (see Chapter 21).
The main toxic side effect of 6-TG is myelosuppression. 277 This may be
delayed and profound, so careful monitoring of the patient's blood counts
during treatment is mandatory. Less common side effects include nausea,
vomiting, anorexia, stomatitis, and liver dysfunction. Patients with renal dys-
function should probably receive a lowered dose of 6-TG, since the kidney
represents a major route of excretion. A very rare complication that has been
seen in only two patients warrants an added comment. 278 Two adult males with
acute leukemia developed a fatal Budd-Chiari syndrome-like illness while re-
ceiving 6-TG. At autopsy, liver sections showed the typical findings of toxic
veno-occlusive disease. This, plus the known severe liver dysfunction that
will be described for 6-MP, 27 makes it very important to monitor liver func-
'
tion in these patients.

6-Mercaptopurine. The pharmacology-, toxic effects, and clinical use of
6-MP are very similar to those just described for 6-TG (Table 5-1). 271 27 279 The
"'
usual oral dose of 6-MP is 2.5 mg/kg/day; unlike 6-TG the dose of 6-MP must be
reduced to one third or one quarter of t fie usual dose in patients receiving
concurrent allopurinol therapy. An additional difference is that 6-MP is
employed in the treatment of both acute myelogenous leukemia and acute
lymphocytic leukemia (ALL). It is particularly useful in maintaining remis-
sions in ALL; in this situation a dose of 1.5 to 2.5 mg/kg/day is commonly
employed, since the patients will generally receive MTX as well.
The toxic reactions of 6-MP and 6-TG are similar, 275 although the greater use
of 6-MP in the past has revealed some additional, unusual problems. In
addition to myelosuppression and gastrointestinal distress, 6-MP may cause
moderate to severe liver dysfunction. 280,281 This is manifested primarily as
cholestatic jaundice. Although there is usually a response to withdrawal of
6-MP, it may progress to hepatic failure and death. Less common side effects
include the potential suppression of thyroid function 282 and an unconfirmed

increased dose requirement for the anticoagulant coumarin when given with
6-MP. 283 Dermatitis is a rare complication of 6-MP treatment, as are fever, 284
hematuria, and crystalluria after very large doses. 285
ALLOPURINOL. Allopurinol is an analogue of the purine base hypoxanth-
ine. It iswidely used in the treatment of both primary and secondary gout and is
particularly effective in preventing the uric acid nephropathy that may compli-
cate the vigorous treatment of acute leukemia, myeloma, and some lymphomas.
Certain features of its pharmacology are particularly relevant to its clinical
use. 286 Absorption of allopurinol is excellent by the oral route, and an intraven-
ous preparation is available only on an experimental basis. 287,288 It reaches a
peak plasma level two to six hours after administration and is rapidly cleared
from plasma with a TV2 of two to three hours. 269 Although renal excretion
contributes to this, most of allopurinol clearance is related to its conversion to
oxipurinol by xanthine oxidase. It appears that oxipurinol is in fact the active
compound that is responsible for lowering uric acid levels in humans. It is an
avid inhibitor of xanthine oxidase and has an extended plasma half-life 18 to 33
(
hours), which is apparently due to vigorous reabsorption by renal tubular

286
cells.
The inhibition of xanthine oxidase by allopurinol or its active metabolite
oxipurinol markedly reduces the conversion of xanthine and hypoxanthine to
uric acid. Since both xanthine and hypoxanthine are far more soluble than uric
acid, this largely eliminates the danger of uric acid nephropathy in most
patients with neoplasms. However, it should be noted that these xanthines are
not entirely soluble, and rare cases of urinary xanthine stone formation have
been reported. 289, 290
The usual dose of allopurinol is 300 mg once daily; cancer patients at great
risk of uric acid nephropathy may receive higher doses (up to 800 mg/day). 291, 292
In patients with acute leukemia, it is usually wise to start allopurinol and
hydration several days before initiating chemotherapy, if at all possible. The
optimal duration of allopurinol treatment in such patients is controversial;
some authorities have recommended continuous treatment for susceptible
patients with neoplastic diseases, whereas others recommend allopurinol use
only during the phase of vigorous treatment. Because of the toxicity of the drug
in some people, the latter recommendation is probably more prudent. 293
Most patients tolerate allopurinol without exhibiting any symptoms. 292 Non-
specific gastrointestinal complaints may occur, but they are rarely serious. The
most common serious adverse reactions involve hypersensitivity reactions of
the skin or blood. 294 296 Skin problems include a pruritic maculopapular rash,
"
which may rarely progress to exfoliation or toxic epidermal necrolysis. 297,298

Blood reactions include transient leukopenia or leukocytosis and eosinophilia.
Other rare forms of allopurinol toxicity include hepatic dysfunction, which may
progress to necrosis, 299,300 renal dysfunction, 301 fever, 296 lymphadenopathy, 296
and, possibly, hemosiderosis. 302 If a serious reaction to allopurinol occurs, the
drug should be discontinued immediately; if the reaction is severe, it should
not be resumed. 292
A final comment relates to the potential role of allopurinol in important drug
interactions. Its role in modifying 6-MP metabolism has already been dis-
cussed (see earlier discussion). In addition, the risk of bone marrow suppres-
5 / Drugs Used en Cancer CHENfOTHERAPY 95
sion may be increased when allopurinol is administered with cytotoxic

also
drugs that are not metabolized by xanthine oxidase, particularly cyclophospha-
mide. 303
HORMONES
Manipulation of the endocrine system is a well-established approach to the
treatment of some neoplastic diseases. Indeed, the empirical use of such
therapy long preceded any rational understanding of how it might work.
Fortunately, advances in endocrinology have greatly clarified the physiologic
roles of hormones and have provided working models of hormone action that
have relevance to treatment. 304 307
*
Two patterns of hormone-cell interaction have been recognized. In one, the

hormone reacts with membrane-bound nucleotide cyclase systems to stimulate
the conversion of a nucleoside triphosphate, such as adenosine triphosphate
ATP to the corresponding 3'5'-monophosphate. for example, cyclic adeno-
.
sine monophosphate (cAMP). This cyclic nucleotide then acts as a "second

messenger" to deliver and amplify the regulatory signal by interacting with
appropriate cellular sites. Examples of this mechanism, which include epi-
nephrine and a number of peptide hormones, have relevance to the para-
neoplastic syndromes seen in oncology (Chapter 29), and the modulation of it
has been a suggested mechanism of the prostaglandins. It has been proposed
that prostaglandin analogues, which could inhibit this mechanism of hormone
action, might have antineoplastic effects; however, at present this remains
unexplored territory. 307
A second pattern of hormone interaction appears to operate for steroid
hormones. 304 306 Certain features of this mechanism are given schematically in
"
Figure 5-15. In this model, a hormone (H,) enters the cell and binds to a
FIGURE 5-15. Mechanisms of hormone action (see text for discussion).

Abbreviations: H, and H% hormones 1 and 2; R and R*, receptor proteins for
x
H l and H*. respectively; mKSA, messenger RSA; tRSA, transfer RSA.

specific cytoplasmic "receptor" protein (R,), characteristic of the responsive or

"target" cell. With the estrogens, and probably with other steroid hormones as
well, the hormone-receptor complex (RiH,) undergoes a three-dimensional
structural rearrangement (called "receptor transformation" 304 or "activa-
305
tion" ), followed by translocation of the complex through the nuclear mem-
brane, with ultimate binding to DNA. Although the details of intranuclear
binding and effector function are incompletely understood, this binding leads
to the synthesis of messenger RNA (transcription), followed by the translation
of this information into new protein synthesis through the action of transfer
RNA and the polysomes. In some cases the new protein is a receptor for yet
another hormone (H 2 and pathway A in Figure 5-15), which must then repeat
the steps just described before the ultimate effect on cell function can be seen
(via pathway B in Figure 5-15). In other situations, a single hormone may be
sufficient to achieve the final biologic effect (pathway B in the figure).
There may be additional factors modulating this second model for the action
of steroid hormones, such as biotransformation of one hormone to another by
intracellular enzymes or cross reactivity between one hormone or its me-
tabolites with another class of receptors. 305 However, this model has greatly
clarified some elements of hormone action, and it has provided a useful tool in
predicting the response to endocrine treatment for some diseases. Specifically,
for breast cancer, endocrine manipulation is worthless in patients lacking
estrogen receptors (ER). 306 Moreover, it may be that for endocrine treatment to
work, the breast cancer cell must be capable of synthesizing a receptor
molecule for progesterone as well. 308 Thus, both pathways A and B in Figure
5-15 may be necessary for endocrine manipulation to be effective in the
treatment of breast cancer. These exciting observations require additional
study (see Chapter 7), but they provide added credence for the critical role of
hormone receptors in understanding the function of hormones in treating
cancer.
The reader who is interested in a more detailed discussion of these mechan-
306,308
referred to several excellent reviews. 304 The remainder of this
"
isms is
section will provide the chemical structures (Figure 5-16) and a brief summary
of the clinical uses (Table 5-6) of selected hormones that are commonly used in
oncology. Detailed guidelines to the choices of endocrine treatment are pro-
vided in the disease-oriented chapters of this book.
Estrogens
The only neoplastic diseases known to respond in a reproducible manner to

estrogen treatment are carcinoma of the prostate and carcinoma of the breast in
postmenopausal women. The pioneering work of Huggins and Hodges 309 and
Haddow et al. 310 in the 1940s established the usefulness of estrogen therapy.
However, estrogen has achieved some notoriety because of the development of
313
some women 311 "
uterine adenocarcinoma in treated with this hormone, and it
has been strongly implicated as a cause of rare vaginal adenomas in daughters

of estrogen-treated pregnant patients. 314,315 Other tumors have also been re-
ported, but only rarely. 316, 317
TESTOSTERONE PROPIONATE FLUOXYMESTERONE
A -Androit«nel7£ propionate 3 one 9a fVioro-Wfl hydroxyl7a •
metfiyrteKojferone
DIETHYLSTILBESTROL PREDNISONE
Ova' Diethyl 4,4' jlilbened.ol A '
- Pregnodiene 17a ,
21 diol 3, II, 20 Inone
17-HYDROXYPROGESTERONE CAPROATE 17-HYDROXY-^METHYlPROGESTERONE
0-C-|CH
2
l
r CH,
o
17a -Hydroxyprogesterone caproote I7a Hydroxy -6a merhylprogeiterone
TAMOXIFEN
CH 3
rH >N-C-C-0
CH 3 H H
2 2
FIGURE 5-16. Chemical structure of selected hormones.

TABLE 5-6. Antitumor Hormones
ROLTE OF
Chemical Clinical Adminis- Available
Compound Characteristics Considerations tration Preparations
Estrogen
Diethylstilbestrol Nonsteroidal Potent estrogen; active by Oral Tablets;
(DES) estrogen mouth; slow degradation; capsules;
fluid retention and GI dis- 0.1 mg
turbances; feminization; 0.25 mg
uterine bleeding; possibly 0.5 mg
carcinogenic 1 mg
5 mg
25 mg
Antiestrogen
Tamoxifen Nonsteroidal May cause thrombocyto- Oral Tablets;
(Nolvadex) estrogen analogue penia, nausea, breast en- 10 mg
gorgement, abnormal
uterine bleeding, hot
flashes
Progestins
Hydroxyprogesterone Progestin Minimal fluid retention IM In oil; 125 mg/ml
caproate in 2 and 10 ml
(Delalutin) vials; 250 mg/ml
in 1 and 5 ml
vials
Medroxyprogesterone Progestin Fluid retention IM Suspension
acetate (aqueous);
(Depo-Provera) 100 mg/ml in
5 ml vial;
400 mg/ml in
1, 2.5, and 10
ml vials
Medroxyprogesterone Progestin Fluid retention Oral Tablets; 2.5 mg
acetate and 10 mg
(Provera)
Megestrol acetate Progestin Side effects nil Oral Tablets; 20 mg
(Megace) and 40 mg
Androgens
Testosterone propionate Testosterone ester Virilization, fluid reten- IM In oil; 50 mg/ml
(Neo-Hombreol) tion, change in libido in 10 ml vial
Fluoxymesterone Halogenated Virilization plus oral ab- Oral Tablets;
(Halotestin) derivative sorption and hepatic 2 mg
toxicity 5mg
10 mg
Testolactone Androgen derivative Nonvirilizing and rarely IM Suspension;
(Teslac) associated with liver 100 mg/ml in
damage 5 ml vial
Oral Tablets;
50 mg
250 mg
Corticosteroids
Prednisone Synthetic analogue Short duration of action; Oral Tablets;
of adrenal cortical undesirable side effects — 1 mg
steroid potassium loss, sodium 2.5mg
and fluid retention, dia- 5 mg
betes mellitus, psychosis 20 mg
Dexamethasone Same as above Long duration of action; Oral Tablets;
(Decadron) side effects similar to 0.25 mg
prednisone 0.5 mg
1.5 mg
4 mg
IM Solution (as
IV phosphate);
4 mg/ml in 1.5
and 25 ml vials
Estrogen probably inhibits carcinoma of the prostate by abrogating the

effects of androgens. 4 In breast cancer, the effects of estrogen appear to be dose
dependent. 4, 318 At low physiologic doses, estrogen may stimulate the growth of
the tumor, whereas at higher pharmacologic doses, estrogen may suppress the
tumor's growth. It is presumed that high doses are preferentially concentrated
in the cell by binding to estrogen receptors, and these very high concentrations
7
prove to be toxic. Although this model of estrogen action is simplistic, it does

provide a conceptual model that accommodates the responsiveness of breast
cancer both to endocrine ablation and to high-dose estrogen therapy.
A novel approach to chemotherapy has emerged with the recognition that
estrogen binds to a specific intracellular receptor in its target tissue. The
hormone has been coupled with other drugs, most commonly alkylating agents,
with the hope that the estrogen would transport the other drug into the cell and
then release it upon binding to the estrogen receptor. 319 Early enthusiasm for
this approach was reflected in the experimental use of complexes such as
estradiol mustard (NSC-112259), 320 phenesterin (NSC-104469) 321 and estra-
mustine (Estracyt, NSC-89199). 319 Newer complexes are still being developed
322
for potential trials, although most clinicians feel that this approach has thus
319, ,21
far failed to improve the standard treatment.
Many estrogen analogues have been synthesized, but the most commonly
employed estrogenic compound used in oncology is diethylstilbestrol (DES)
(Fig. 5-16). 323 It is a nonsteroidal estrogen that is potent, inexpensive, effective
by oral administration, and relatively long-lasting in its effect, as compared
with natural estrogens. In addition to rapid and complete oral absorption, DES
may be absorbed through the skin. After absorption, the drug is metabolized by
the liver; however, the rate of inactivation is relatively slow, so small doses of
DES may be given once a day. Higher doses are generally better tolerated
when divided.
Tablets or capsules of DES are available in doses ranging from 0.1 to 25 mg
(Table 5-6). The usual dose of DES in carcinoma of the prostate is a single 1 mg
tablet given once daily. Although a higher dose may be needed for advanced
disease, 1 mg is usually given to stable patients because higher doses have
been associated with an increased risk of death from cardiovascular dis-
ease. 324, 325 The dose of DES in postmenopausal women with metastatic breast
cancer is usually 5 mg thrice daily. In a randomized, comparative study of 523
postmenopausal patients with breast cancer, dose levels of 1.5, 15, 150, or 1500
mg/day were given. 318 In general, this study demonstrated the superiority of
high-dose treatment over very low-dose treatment; 326 however, it did not cor-
relate the response with the estrogen-receptor status of the patient, and the
overall response rates seen in the study were somewhat low. Moreover,
higher-dose treatment was more toxic than the standard dose of 15 mg/day, so
these very high doses should probably be reserved for patients with slowly
growing estrogen receptor-containing tumors that have failed to respond to
standard-dose estrogen treatment.
The short-term undesirable side effects of estrogen treatment are to a major
degree dose related. They may include nausea and vomiting; salt and water
retention in patients with cardiac, liver, or renal disease; changes in libido in
women and impotence in men; aggravation of chronic cystic mastitis, uterine
fibroids, migraine, and endometriosis; a very low risk of thrombophlebitis,

embolism, and hypertension; liver dysfunction with very high doses; occasion-
al urinary stress incontinence in women; and hypercalcemia in women with
breast cancer. 315, 323 With the exception of hypercalcemia, which may rarely be
fatal, these side effects do not generally require the cessation of treat-
ment. 4, 315, 323 In men, gynecomastia may develop, but this is relatively easy to
prevent with a single 900 rad dose of radiation therapy to each breast prior to
estrogen administration. 327 Gynecomastia is very difficult to treat, however,
once it becomes symptomatic. Finally, the potential carcinogenicity of es-
trogen treatment is worth repeating, although this is a minimal risk for the
patient receiving estrogen for an established diagnosis of cancer. 315
Antiestrogens
Although any chemical that can impair the effect of estrogens can be called
antiestrogenic, the contemporary use of this term is limited to a well-defined
group of nonsteroidal estrogen antagonists that are unrelated to progesterone,
testosterone, or synthetic gestagens. 328 329 Three members of this class are of
'
interest: clomiphene (Clomid), nafoxidine, and tamoxifen (TAM) (Nolvadex)

(Fig. 5-16). Clomiphene is commercially available for the treatment of anovula-
tory sterility, but tamoxifen is the only member of this class of drugs that is
marketed in the United States for the treatment of cancer.

Clomiphene, nafoxidine, and tamoxifen appear to be weakly estrogenic
compounds that are capable of tight competitive binding to cytoplasmic es-
trogen receptors. 328 The antiestrogen-receptor complex may itself suppress the
genome of the breast cancer cell, although antiestrogens more commonly
appear to work by depleting the cell of available estrogen-receptor sites, both
by competitive binding and by a poorly understood inhibition of new receptor
synthesis. As a corollary of these facts, the antiestrogens are probably less
effective in premenopausal patients with breast cancer, and they may cause
mild estrogenic effects in postmenopausal patients, such as uterine bleeding
and vaginal cornification.
All three of the antiestrogens discussed here are given orally, and widely
varying doses have been effective: clomiphene, 100 to 300 mg/day in single or
divided doses; nafoxidine, 90 to 240 mg/day in divided doses; and tamoxifen,
10 to 80 mg/day in divided doses. As reviewed by Legha and Carter, 328 there is
no evidence for a dose-response relationship, and the optimal dose and sched-
ule of administration for these drugs have not been defined. Pharmacologically,
the antiestrogens are cleared very slowly from the body, and even a single dose
leads to estrogen antagonism that may last many weeks. Based on these facts, it
is likely that a single daily dose would be sufficient for most patients. Neverthe-
less, the recommended dose of tamoxifen is 10 mg twice daily.

The three antiestrogens discussed here have different spectra of toxicities.
Although they may all cause nausea or even vomiting, hot flashes occur only
with clomiphene and tamoxifen, skin reactions (dermatitis and ichthyosis) are
seen only with nafoxidine, visual blurring is seen only with clomiphene and
tamoxifen, 3293 and mild thrombocytopenia is seen only with tamoxifen. Clomi-
phene has also been associated with a severe, diffuse, reversible cerebral
dysfunction manifested by memory loss and intellectual deterioration. 330 As a

group, however, these drugs are remarkably nontoxic. 328 329 '
An antiestrogen such as tamoxifen may be considered the best available

primary endocrine treatment for postmenopausal patients with metastatic
breast cancer. 331 Antiestrogens are also being studied in the treatment of a
variety of tumors that are known to be occasionally responsive to hormones,
including carcinomas of the prostate, endometrium, and kidney. 332 There are
no clear-cut differences in clinical usefulness between the three antiestrogens
discussed here. They all achieve response rates in breast cancer of 28 to 35 per
cent (approximately 15 per cent are complete responses), with a median
duration of nine or more months. 328, 329, 333 In the United States, tamoxifen is the
agent of choice, since it is commercially available for the treatment of post-
menopausal patients with metastatic breast cancer, and it costs less than clomi-
phene.
Progestational Agents
The physiologic have been reviewed else-

effects of progestational agents
323
where, and the importance of estrogen interactions with progesterone was
mentioned earlier in this section. However, since the naturally occurring
progestins (e.g., progesterone) have no place in modern chemotherapy, and the
synthetic derivatives commonly employed demonstrate a wide spectrum of
antagonistic effects against estrogens, androgens, and gonadotropins, it is
difficult to relate the antitumor effects of any given progestin to the known
effects of the parent compound. Clearly, the use of this class of agents in
oncology has developed primarily by empirical trial and error.
Many progestins with primarily progestational activity and minimal an-
drogenic and fluid-retaining effects are available, including medroxyproges-
terone acetate (Provera), hydroxy progesterone caproate (Delalutin), and me-
gestrol acetate (MEG) (Megace). 323 Of these, injected hydroxyprogesterone
caproate and oral megestrol acetate appear to be the least toxic and most
widely useful progestins (Fig. 5-16). Hydroxyprogesterone caproate is usually
given intramuscularly in a dose of 1 gm twice weekly or as much as 5 gin
weekly. When megestrol acetate is used, the dose is 40 to 320 mg/day orally
for endometrial carcinoma and 160 mg/day orally for breast cancer. The total
dose is given in divided doses; for example, 40 mg four times daily for breast
cancer.
All the progestins in clinical useproduce the typical progestational changes
in the epithelium of the female genital tract and the acinar cells of the breast.
Their precise modes of metabolism are not known, although it is known that
progesterone is catabolized largely in the liver and its metabolites are excreted
in the urine. 323 As a class, progestins have virtually no toxic side effects.
In carcinoma of the uterus, progestins commonly yield a 30 to 35 per cent
response rate, with an average duration of 27 months. 334 Such treatment is
widely accepted as the primary therapy for patients with disease that is beyond
control by surgery or radiation therapy. In breast cancer the indications for the
use of progestins (principally megestrol acetate) are less clear. Few clinicians
have utilized progestins as primary hormonal therapy; their major use, in fact,
has been in patients who have failed all prior treatment, including combination
chemotherapy (see Chapter 7). 335 As simple, nontoxic, and moderately effective
treatment, they may be especially useful therapy for this group of patients. In
addition to the treatment of breast and endometrial carcinomas, progestins
have been used in the treatment of hypernephroma, with controversial re-
336
sults, and preliminary reports suggest that progestins may be active in the
treatment of prostatic carcinomas. 337 339 Finally, progestins alone or in combina-
"
tion with low doses of estrogens may be useful in the prevention of uterine
bleeding in thrombocytopenic females who are in the child-bearing years. This
is of particular concern in patients with acute leukemia. Since one should also
prevent conception in this group of patients, an oral contraceptive containing a

large amount of progestin (such as Ortho-Novum [northindrone with
mestranol], 10 mg) given daily without interruption should generally be
340
used
Androgens
Although many androgens are available, most of them are marketed for the
treatment of conditions other than cancer. They have been used for the
treatment of anemia in patients with renal dysfunction who are receiving
hemodialysis. 341,342 They have also been used for patients with aplastic ane-
mia, 342, 343 for patients with hereditary angioedema, 344 and, experimentally, for
patients with hypernephroma. 336 Androgens have also been used to improve
the blood counts of patients receiving cancer chemotherapy or radiation
therapy, 345, 346 and as "anabolic steroid treatment" for severely debilitated
patients with advanced cancer. 347 However, the clinical value of androgens for
these latter indications is controversial. The only well-established use for
androgens in the practice of oncology is for postmenopausal women with
metastatic breast cancer (see Chapter 7), although it is unclear how they exert
their beneficial effects. 347,348 One can see similar antitumor effects with an-
drogens of widely varying virilizing potency, and it is of interest that the
presence of estrogen receptors in the cytoplasm of the breast cancer cell
predicts a higher response rate from androgen therapy. 306 Moreover, at least
some androgens affect estradiol metabolism, leading to a net decrease in the
estrogenic potency of endogenous estrogen metabolites, 349 and androgens may
be converted into estrogens by some cells. 350
A detailed discussion of androgen biochemistry, pharmacology, and endo-
crine effects is beyond the scope of this chapter. 347 However, certain features
warrant comment. Testosterone and its esters are metabolized by the liver,
with the biotransformed products appearing in the urine. The esters are less
polar than is testosterone itself, and, when injected in oil, they are absorbed
more slowly and produce a more sustained effect. The halogenated testos-
terone derivatives are effectively absorbed from the gastrointestinal tract, but
they may cause hepatic dysfunction.
The androgen chosen by the Cooperative Breast Cancer Group as its stand-
ard is testosterone propionate (Neo-Hombreol), given in a dose of 100 mg three
times a week intramuscularly (Table 5-6). 348 When oral treatment is preferred,
one may choose between fluoxymesterone (Halotestin) and delta-1-
testolactone (Teslac). 331, A previously available oral androgen, calus-

348, 351, 352
terone (Methosarb), is no longer marketed. 351 353 The usual dose of fluoxymes-
'
terone is 10 to 40 mg/day in divided doses, whereas testolactone may be given

intramuscularly in a dose of 100 mg/day three times weekly, or orally in a dose
of 250 mg four times daily. The recommended doses result in blood levels of
androgens that are considerably above physiologic levels. Despite this, their
effects maynot be apparent for 6 to 12 weeks.
The most frequent undesirable effect of androgen therapy is virilization of
female patients. 347 This may include hirsutism, deepening of the voice, acne,
clitoral enlargement, and amenorrhea. The extent of virilization, however, is
related to the specific drug used, its dose, and the duration of treatment. 348 For
example, testolactone is devoid of virilizing effects, whereas virilization may
occur with fluoxymesterone. Androgens may also produce changes in libido
and personality, may cause fluid retention, and may worsen symptoms of
prostatic obstruction. The orally effective halogenated androgens rarely cause
cholestatic jaundice, which may require discontinuation of the drug. An-
drogens may precipitate acute, severe hypercalcemia in women with breast
cancer that is metastatic to bone; this occurs in as many as 10 per cent of such
patients, and it may represent an oncologic emergency. 4 In addition to with-
drawal of androgen treatment, these patients may require vigorous hydration
in the hospital as well as other measures for hypercalcemia from other causes
(as described in Chapter 29). Finally, androgens have been associated with
peliosis hepatis (a rare condition consisting of blood-filled cysts in the liver),
hepatic adenomas, and, very rarely, hepatomas. 354 357
"
Corticosteroids
Although cortisone and its synthetic derivatives are widely used, many
indications for their use are controversial, and we have an incomplete under-
358,359
standing of their mechanisms of action. As with other hormones, one
mechanism involves binding to intracellular receptors, followed by transloca-
tion to the nucleus, as shown in Figure 5-15 and as discussed previously. Other
mechanisms are involved as well, since at least some of the biochemical effects
of corticosteroids occur without entry into cells. As a result of these inter-
actions, corticosteroids cause a wide variety of biochemical and metabolic
changes, including stimulation of hepatic protein synthesis and gluconeo-
genesis, inhibition of protein synthesis by peripheral tissues, and either
inhibition or stimulation of lipogenesis, depending upon the location of fat in
the body.
A variety of anti-inflammatory and immunosuppressive effects may also be
seen with corticosteroid therapy. The basis for these effects is uncertain, but
certain general comments pertain. 358 The glucocorticosteroids cause neutro-
philic leukocytosis, together with a reduction in circulating eosinophils, mono-
cytes, and lymphocytes. A principal mechanism whereby these steroids inhibit
inflammation appears to be related to their ability to impede the access of
neutrophils and monocytes to an inflammatory site. Granulocyte function tests
remain normal with corticosteroid therapy, although monocyte-macrophage
function is suppressed by such treatment. The lymphocytopenia that is seen
with corticosteroid therapy is usually transient, and it involves all lymphocyte
subpopulations, but most prominently those derived from the thymus. The
mechanism of this action appears to be a redistribution of these cells from the
blood into other body compartments. Excellent reviews are available for the
reader who is interested in a more complete discussion of the mechanisms of
action and biochemical effects of corticosteroids. 358 360
"
Many synthethic analogues of the naturally occurring compound Cortisol are

available.The biologic potency of these analogues varies tremendously, and to
some extent these differences are compounded by differences in their pharma-
cologies (see Table 5-1). In general, one can separate the commonly used
two groups: those with a relatively short duration of action
corticosteroids into
and those with a prolonged duration of action and great relative potency.
Hydrocortisone (cortisol) and prednisone are relatively weak corticosteroids,
with a short duration of action. After oral administration, their respective
plasma half-lives are approximately 1.5 and 3.5 hours. Dexamethasone, a more
potent and longer acting synthetic derivative of Cortisol, has a plasma TVfc of 4.7
hours. The biologic half-lives of these three drugs are 1.5 to 2 times their
half-time of disappearance from plasma. These three compounds retain very
different potencies as they are cleared from plasma. In one study, the relative
potencies of hydrocortisone (cortisol), prednisone, and dexamethasone (Deca-
dron) at 0, 8, and 14 hours after oral administration were as follows: hydrocorti-
sone, 1, 1, 1; prednisone, 1.05, 3, 5.2; and dexamethasone, 17, 52, 154. 361 Such
studies indicate that the relative intrinsic biologic potency and relative rates of
disappearance from plasma are critical factors in determining the duration and
intensity of glucocorticoid action.
Prolonged daily high-dose corticosteroid therapy may be associated with a
host of complications and side effects. 359,360 Some complications may occur
with short-term treatment (e.g., sodium and water retention, potassium loss,
psychosis, exacerbation of diabetes mellitus), whereas other complications are
more commonly seen with prolonged treatment. Delayed side effects may
affect the musculoskeletal system (myopathy, osteoporosis, aseptic necrosis of
bone), gastrointestinal tract (pancreatitis, peptic ulceration), central nervous
system (pseudotumor cerebri), eye (glaucoma, cataracts), cardiovascular sys-
tem (hypertension), metabolism (centripetal obesity, hyperlipidemia, hyperos-
molar nonketotic coma), immune system (immunosuppression with superim-
posed infections of many kinds), skin (striae, impaired wound healing), and
endocrine system (growth failure, amenorrhea, and suppression of the
hypothalamic-pituitary-adrenal axis).
Several of these complications warrant special comment. Suppression of the
hypothalamic-pituitary-adrenal axis is variable, but with prolonged daily treat-
ment it may be severe and prolonged. 359, 362 As a consequence, patients with
malignant diseases are usually treated with very large doses for the minimal
period necessary to achieve the desired clinical response. If corticosteroid
treatment has been given for 48 hours or less, it can be discontinued abruptly.
Patients treated for longer periods should generally have steroid administra-
tion slowly withdrawn. If prolonged maintenance treatment is required, it is
usually preferable to administer the corticosteroids on alternate days or, if that
fails, as a single dose of a short-acting compound each morning.
There is some controversy about the importance of countermeasures direct-

ed against some of the other potential complications of corticosteroid treat-
ment. Although antacids have traditionally been prescribed for these patients,
the problem of peptic ulceration is in fact rare, and there is no good evidence
363
that such treatment prevents ulceration. Likewise, the use of prophylactic
potassium administration should be decided on an individual basis, since the
net potassium balance varies from patient to patient.
Corticosteroids are commonly employed as primary cytotoxic drugs in the
treatment of malignant hematopoietic diseases, such as acute lymphoblastic
leukemia, chronic lymphocytic leukemia, lymphomas, and multiple myelo-
ma. 364 Short, intensive courses of a short-acting corticosteroid such as predni-
sone are usually employed, although for some chronic conditions, alternate-
day prednisone treatment may be used to maintain a beneficial re-
sponse. 358, 359, 365 When corticosteroids are employed in the treatment of some of
the complications of cancer or when they are used in the treatment of breast
cancer or prostatic cancer, they are more commonly given for longer periods in
moderate doses. Alternate-day administration of prednisone may be very
appropriate for conditions of this type, as well as for patients with cortico-
steroid-responsive hemolytic anemia, thrombocytopenia, or hypercalcemia.
For patients with edema of the brain or spinal cord, the potent long-acting drug
dexamethasone is commonly employed in a dose of 4 mg four times daily. 366
However, it should be remembered that dexamethasone is not an appropriate
drug for programs of alternate-day steroid administration. 359 The recommended
dose and schedule of administration for corticosteroids varies with each of the
diseases just mentioned; therefore, details are provided elsewhere in this
book.
MISCELLANEOUS AND
EXPERIMENTAL AGENTS
Procarbazine (Matulane)
Procarbazine is was initially synthesized

a unique antineoplastic agent that
36T
as a potential monoamine oxidase inhibitor. 23, chemical structure is given
Its
in Figure 5-17, and selected clinical features are summarized in Table 5-7.
Procarbazine must undergo biotransformation prior to exerting its cytotoxic
effects on cells, and it may interfere with a wide variety of biochemical proc-
esses. Thus, its precise mechanism of cytotoxic action is controversial, al-
though it is well established that the metabolites of procarbazine can depoly-
merize DNA. 23, 367, 368 Candidate metabolites for this cytotoxic damage include
hydroxyl radicals that are formed by the auto-oxidation of procarbazine to azo-
procarbazine, as well as azoprocarbazine itself, or highly reactive X-methyl-
degradative products of procarbazine. The varied effects of these metabolites
share some resemblance to the effects of ionizing radiation; nevertheless,
procarbazine is not cross resistant to the alkylators or to other commonly
employed antineoplastic drugs. The mechanisms of resistance to procarbazine
are poorly understood, but resistance develops rapidly in most tumors when it
is used as a single antineoplastic agent. Procarbazine is cell cycle phase-
nonspecific.
PROCARBAZINE HYDROXYUREA
CH,J H O , ,
HO o
°l II / \ II \
N— C — NH,
l I II
HC -N-C-6v .VCHj-N-N-CH,
CH
I
H
/
DDP MITOTANE; o, p" - DDD

NH, .CI
Pt (II)
NH,
cisplatin
1, l-Dichloro-2-(o-chloroph«nyl>-2-
(p-chlorophenyl)-ethane
STREPTOZOTOCIN HEXAMETHYLMELAMINE
OH CH, CH-
J
I
CH3-N N-CH,
N>
° - C
/ VoOH
/
CH OH
2 N^N
N-CH,J N-CH,
I
NO CH,
Glucopyranose, 2-deoxy-2-
(3-methyl-3-nitrosoureidohD-
FIGURE 5-17. Chemical structure of selected miscellaneous drugs.
Procarbazine is well absorbed from the gastrointestinal tract and its use by
any other route of administration is experimental. Its half-time of clearance
from plasma is about ten minutes; this is closely related to rapid transformation
of the drug to azoprocarbazine by erythrocytes and hepatic microsomal en-
zymes. The drug freely crosses the blood-brain barrier, and its concentration in
the CSF is in equilibrium with plasma. The major route of excretion is the
kidney. In one study, 70 per cent of an injected dose of radioactive procarbazine
appeared in the urine by 24 hours as the inactive metabolite N-isopropyl-
terephthalamic acid. 23
In adults, when used alone procarbazine is generally given in a dose of 100 to
200 mg daily by mouth for the first week. 1, If this dose is tolerated, the daily-
dose is increased to 300 mg. Procarbazine is discontinued when grade 1
leukopenia or thrombocytopenia occurs and is reinstituted at a lower dose (50
to 100 mg/day) when hematologic recovery occurs. The dose of procarbazine
should be reduced in patients with impaired renal, liver, or bone marrow func-
tion.
TABLE 5-7. Selected Miscellaneous Agents
ROLTE OF
Chemical Adminis- Available
COMPOUND Characteristics Clinical Considerations tration Preparations
Procarbazine Methylhydrazine Bone marrow depression, nausea. Oral Capsules;

Matulane) derivative nervous system toxicity, 50 me
monoamine oxidase inhibitor
Hydroxyurea L'rea analogue Bone marrow depression Oral Capsules;
1 1 j drea) 500 mg
Mitotane o,p -DDD, an GI upset; central nervous system Oral Tablets.
Lysodren)
^ insecticide toxicity; skin rash 500 mg
L-A-.paraginase Enzyme from Anaphylaxis; depressed protein Paren- Vial; 10,000 IU
EKpar) E. coli synthesis; pancreatitis teral
367
A wide variety of toxic effects may result from the use of procarbazine.
Anorexia, nausea, and vomiting occur frequently, but these tend to subside
with continued treatment. Bone marrow suppression commonly occurs, as does
neurotoxicity. Up to one third of the patients treated with procarbazine develop
disorders of consciousness (somnolence, depression, agitation, psychosis), and
peripheral neuropathies have been reported to occur in 17 per cent of these
patients. The neurotoxic effects of procarbazine are rarely dose-limiting and
probably arise from a combination of its weak monoamine oxidase inhibitory
properties and decreased pyridoxal 5-phosphate levels. A wide variety of drugs
may potentiate the neurotoxic effects of procarbazine, including other mono-
amine oxidase inhibitors (such as imipramine hydrochloride), antihyperten-
sive and sympathomimetic agents, foods with a high tyramine content (such as
ripe cheese), phenothiazines, barbiturates, narcotics, and alcohol. With alco-
hol, a peculiar flushing syndrome may occur, not unlike that seen with disul-
firam (Antabuse).
pleuropulmonary reac-
Ataxia, orthostatic hypotension, allergic skin rashes,
tions with fever, and abnormal have also occasionally been
liver function tests
reported. As with other hydrazine derivatives, procarbazine may cause hemo-
lytic anemia, with hemoglobin denaturation and the formation of Heinz bodies
in erythrocytes. Procarbazine is also immunosuppressive, mutagenic, tera-
togenic, and a potent carcinogen. 16 367,369 -
Procarbazine is used primarily in the treatment of advanced Hodgkin's

disease. 367 As a single agent it yields a response rate of about 50 per cent;
however, these responses rarely last longer than two or three months, so it is
nearly always used in combination with other drugs. The most commonly
employed regimen is that of DeYita and colleagues, 370 in which mechloretha-
mine, vincristine, prednisone, and procarbazine (MOPP) are combined (see
Chapter 24). Procarbazine is less useful in the treatment of other kinds of
lymphoma, and it is of marginal value in the treatment of bronchogenic
carcinoma and brain tumors. 20,367
Hydroxyurea (Hydrea)
Although it was synthesized in 1869 and found to be bone marrow suppres-

sive in 1928, hydroxyurea was not used as a treatment for cancer until the early
1960s. 4 Hydroxyurea is a small, relatively simple chemical compound (Fig.

5-17), which acts as an inhibitor of ribonucleotide reductase an enzyme that —
is essential to DNA synthesis. 371
It is specifically cytotoxic to cells in the S phase
of the cell cycle. 5,6
Hydroxyurea is readily absorbed from the gastrointestinal tract. 872,87* Peak
plasma levels occur by 2 hours, and the half-time of plasma clearance is about
100 minutes. 373 Approximately 80 per cent of either an oral or an intravenous
dose of hydroxyurea can be converted to urea by the liver, and in the rat partial
hepatectomy leads to a substantial prolongation of the half-time for plasma
clearance. Despite these facts, there are no quantitative guidelines for modify-
ing the dose of hydroxyurea in patients with either kidney or liver dysfunction.
Nevertheless, the drug should be used cautiously, if at all, in such patients.
The most important adverse reaction from hydroxyurea is bone marrow
depression, involving leukopenia, megaloblastic anemia and, rarely, thrombo-
cytopenia. 4 If this develops, recovery may be delayed by previous bone marrow
suppressive therapy. Other adverse reactions include mild to moderate gastro-
intestinal symptoms (nausea, stomatitis), occasional skin reactions (alopecia,
hyperpigmentation, scaling, atrophy, nail changes, erythema of the hands and
face), and very rarely neurologic problems. 4, 374 The drug is teratogenic in
animals, so its use in pregnant women should be avoided. 375
Hydroxyurea is primarily used in the treatment of chronic granulocytic
leukemia that has become resistant to busulfan. 376 It may also be of occasional
use in carcinomas of the prostate, ovary, lung, kidney, and head and neck. 20, 377
For head and neck carcinomas it is usually given in combination with radiation
therapy. 378, 379 Its rapid onset of action has led to its use as emergency therapy
for patients with acute leukemia presenting with very high leukocyte counts. 380
Although hydroxyurea is marketed for the treatment of malignant melanoma, it
is probably not a useful drug for this disease. 381
Hydroxyurea is usually given as a single daily oral dose of 20 to 30 mg/kg to

patients with busulfan-resistant chronic granulocytic leukemia. When it is used
in the treatment of various solid tumors, or when it is combined with radiation
therapy, an intermittent dose of 80 mg/kg is generally given every three days. It
should not be given, however, to patients with pre-existing marked bone
marrow suppression (WBC < 2500/ /xL or platelets < 100,000/ /uL).
Mitotane (o, p'-DDD; Lysodren)
Mitotane is a derivative of the insecticide DDT

and causes necrosis and
atrophy of the adrenal cortex (Fig. 5-17). It is tightly and rapidly bound to the
mitochondria of the adrenal cortex, which leads to marked inhibition of the
conversion of cholesterol to adrenocorticotropic hormone (ACTH)-induced
steroids. 382 Mitotane leads to a direct destruction of adrenal cortical tissues and
to a peripheral extra-adrenal stimulation of Cortisol metabolism. 383 It may also
modify peripheral androgen metabolism. 384 Mitotane does not inhibit aldos-
terone synthesis, but spironolactone appears to abrogate the adrenal suppres-
sion seen with the drug. 3843 Because of this, the two should not be used togeth-
er.
Approximately 40 percent of an oral dose is absorbed. 4 Daily doses of 5 to 15

gm lead to plasma concentrations of 10 to 90 /ug/ml of unchanged drug and 30
4
to 50 /ig/ml of a metabolite. Its extensive deposition in fat results in measur-
383
able levels of mitotane in blood many months after its withdrawal. About
25 per cent of an oral dose ultimately appears in the urine as a water-soluble
metabolite.
Mitotane is given orally in divided doses (Table 5-7). The usual dose is 8 to
10 gm daily, although patient tolerance varies widely between 2 and 16 gm
daily. Treatment is usually initiated in the hospital with lower doses of 2 to 6
gm/day; the doses are gradually increased until a mildly toxic one is found. The
dose is then reduced, and the drug is continued as long as clinical benefits are
observed. Responses may occur as late as three months after starting treatment,
so it is important not to discontinue drug administration too soon. Plasma
Cortisol levels should be measured periodically to assess the effectiveness of
treatment in reducing elevated levels of Cortisol due to tumor and to assure
adequate residual adrenal function. Measurements of urinary 17-hydroxy cor-
ticosteroids or 17-ketosteroids are not useful owing to the extra-adrenal
383384
effects of the drug.
Adverse reactions commonly include gastrointestinal disturbances (80 per
cent of patients), central nervous system effects (40 per cent of patients), and
skin reactions (15 per cent of patients). In most cases these reactions can be
managed by the use of a lower dose of mitotane; it is rarely necessary to
discontinue treatment completely. A variety of rare reactions can occur, includ-
ing visual problems, proteinuria, hematuria, hypertension, flushing, and ortho-
static hypotension, and one must be alert to the possible development of
adrenal insufficiency. Exogenous steroids should be administered and mito-
tane discontinued if the patient sustains severe trauma or shock. Because of the
central nervous system problems, which may include depression, drowsiness,
lethargy, vertigo, and, rarely, permanent brain damage, the patient must be
warned to avoid tasks requiring mental alertness and he or she should be
carefully monitored for the development of behavioral or neurologic prob-
lems. 386
Mitotane is used in the treatment of inoperable adrenocortical carcinoma,
both the functional and nonfunctional types, and as treatment for selected
patients with Cushing's syndrome. 387 389 Clinical benefit has been reported in
"
about 50 per cent of cases of adrenocortical carcinoma treated with mitotane,

and in rare cases with residual tumor after operation, mitotane appears to have
been curative. 388
Aminoglutethimide*
(Elipten, Cytadren)
Aminoglutethimide an experimental analogue of the commercially

is
available hypnotic glutethimide (Doriden). 390 It was introduced as an

anticonvulsant in 1958 and was withdrawn by the Food and Drug Admin-
istration in 1966 because of toxicity associated with its prolonged use.
* Available from Ciba-Geigy Co, Summit, New Jersey.

Aminoglutethimide was found to block adrenal steroidogenesis by inhibit-

ing the enzymatic conversion of cholesterol to pregnenolone. Since it
caused clinically apparent adrenal insufficiency in humans, it was subse-
quently used in the treatment of Cushing's syndrome from adrenal tumors
or ectopic ACTH-secreting tumors and in the treatment of metastatic breast
cancer. In normal people, but not in patients with ACTH-independent car-
cinomas, aminoglutethimide therapy is accompanied by a markedly in-
creased level of ACTH (up to sevenfold), which can produce adrenocorti-
cal hypertrophy and a resumption of steroid synthesis. Thus, in patients
with breast cancer, one must also give a glucocorticosteroid to suppress the
reflex increase in ACTH output. This is usually done with hydrocorti-
sone. 391
The usual oral dose of aminoglutethimide is 250 mg four times daily.
Hydrocortisone is given three times daily in a dose that is sufficient to
suppress the blood level of dehydroepiandrosterone sulfate to less than 25
per cent of the control level. This usually involves a total dose of 100 mg
daily (divided into three doses of 20, 20, and 60 mg) for 2 weeks; the sub-
sequent maintenance dose is usually 40 mg daily (divided into three doses
of 10, 10, and 20 mg).
In addition to adrenal suppression, aminoglutethimide can cause a vari-
ety of reversible dose-dependent side effects. 390 391 A generalized macular,
'
pruritic skin rash, which is sometimes associated with fever, often occurs in
the first two to three weeks of treatment. Despite the continuation of treat-
ment, it generally disappears in four to seven days. If the rash continues or
worsens, aminoglutethimide is discontinued. Central nervous system reac-
tions may also occur, including somnolence, ataxia, nystagmus, or lethargy.
These reactions generally abate by lowering the dose of aminoglutethi-
mide. The drug is not usually marrow suppressive or immunosuppressive;
however, a single case of reversible marrow aplasia has been reported. 3913
In unselected patients with breast cancer a 25 per cent objective re-
sponse rate has been reported, 392 but a higher rate may be anticipated in
patients with tumors containing an estrogen receptor.
Streptozotocin*
Streptozotocin(NSC-85998) is an experimental antibiotic originally

derived from Streptomyces achromogenes. It has subsequently been syn-
thesized, and its structure consists of a nitrosourea moiety interposed be-
tween a methyl group and a glucosamine (Fig. 5-17). 393 The primary effect
is to inhibit DNA synthesis, but it can also inhibit nicotinamide adenine
dinucleotide) (NAD), reduced nicotinamide adenine dinucleotide (NADH)

and some key enzymes involved in gluconeogenesis. 394 These latter effects
may contribute to the damage sustained by pancreatic islet cells that are
exposed to this drug. As with the other nitrosoureas, streptozotocin is cell
cycle phase-nonspecific. However, despite structural similarities, streptozo-
tocin is not cross resistant with the other nitrosoureas discussed previously.
"Available from the Investigational Drug Branch of the National Cancer Institute.
Streptozotocin is administered parenterally, and it is rapidly distributed

395,396
into extracellular spaces. Its body is about 40
biologic half-life in the
minutes, whereas its half-time of plasma clearance approximately 13 min-
is
utes. The vast majority of the drug is excreted by the kidney. 396 The recom-
mended schedule of intravenous administration is 1 gm/m 2 weekly for four
394
weeks.
Streptozotocin frequently causes moderate nausea and vomiting and vari-
able hyperglycemia. Mild hematologic toxicity occurs in about 20 per cent
of treated patients. However, about two thirds of patients develop renal or
hepatic dysfunction. Although it is rarely serious by itself, the hepatic dys-
function may cause problems when streptozotocin is combined with drugs
that are metabolized by the liver. An example of such an adverse interac-
tion has been reported for doxorubicin. 397 Renal toxicity usually starts as
proteinuria with or without azotemia, and this can progress to renal tubular
acidosis and renal failure. In one early series, 5 out of 52 patients died of
renal failure. 394With newer dose schedules and alert attention to renal
function, this high mortality rate should be avoidable. Close monitoring of
renal function with urinalysis, blood urea nitrogen, and a weekly creatinine
clearance is recommended. The appearance of proteinuria or a deteriora-
tion of renal function is an indication for interrupting therapy. The drug is
mutagenic and potentially carcinogenic. 398
Streptozotocin is used in the treatment of pancreatic islet cell carcino-
mas. 394 A response rate of about 60 per cent can be expected, and a response is
associated with a doubling of the median survival. The drug has also been
useful in the treatment of some other endocrine tumors, including gastrin-
omas associated with the Zollinger-Ellison syndrome, 399,400 glucagon-
secreting pancreatic carcinoma, 401 and, very rarely, carcinoid
alpha-cell
tumors. 402,403 Preliminary results suggest that it may also be useful in treat-
ing some malignant lymphomas. 404,405
Hexamethylmelamine*
Hexamethylmelamine (HMM) (NSC 13875) was originally synthesized

as a derivative of melamine, a plastic widely used in the manufacture of
dishes, automobile parts, and other items of daily use (Fig. 5-17). It is struc-
turally related to the alkylating agent triethylenemelamine, but its lack of
cross resistance to alkylating agents and its failure to cause alkylation in
vitro makes alkylation an unlikely explanation for its cytotoxic effects. N-
demethylation appears to be the major metabolic pathway for hexamethyl-
melamine, and there is a correlation between demethylation and anti-
tumor activity. Nevertheless, the mechanism of action of this drug remains
unclear. 406
The drug is easily absorbed through the gastrointestinal tract. Peak plas-
ma by 1 hour and the half-time of plasma clearance is
levels are achieved
13 hours. extensively demethylated in the liver. The methyl
The drug is
groups are oxidized to C0 2 and the melamines are excreted in the urine. 406
,
*Available from the Investigational Drug Branch of the National Cancer Institute.
Hexamethylmelamine is available as 100 mg capsules. It may be given

in a high-dose regimen of 12 mg/kg/day (450 mg/m 2 for 21 days, with 4-
)
week rest periods between courses. An alternative is a prolonged low-dose

regimen of 8 mg/kg/day (300 mg/m 2 ) for 90 days, or indefinite use if the
drug is well tolerated. The high-dose regimen causes more nausea than the
low-dose program, but this can usually be minimized by giving the drug
after meals in four divided doses. Other forms of toxicity include low-grade
myelosuppression, very rarely skin rashes, pruritis, alopecia, and occasional
neurotoxicity. The neurotoxicity occurs only with prolonged therapy, and it
is readily reversed by discontinuing treatment or by reducing the dose and
giving the patient pyridoxine (100 mg twice daily). 406

Hexamethylmelamine has a wide spectrum of antitumor activity in
humans. 20,406 It appears to be particularly useful in patients with carcino-
mas of the ovary or lung and in patients with lymphomas. It has also shown
activity against carcinomas of the cervix, breast, colon, and head and neck.
HMM is a promising drug in programs of combination chemotherapy, and
it remains incompletely tested as a single agent in many other human solid
tumors.
Platinum Complexes (DDP)
In 1965 Rosenberg and coworkers discovered that the replication of E.

coli could be inhibited by passing an electric current between platinum
electrodes in nutrient broth containing ammonium and chloride ions. 407 It
was soon learned that this inhibition is caused by the release of platinum
complexes, and a wide variety of platinum compounds are now known to
inhibit animal and human tumors. One such complex, which has recently
become commercially available, is c/.s-dichlorodiammineplatinum (II) (cis-
platin; Platinol). It has received sufficient study to justify its discussion
here. 408 ' 409
Structurally, DDP
an inorganic complex formed by an atom of plati-
is
num (II) surrounded by chlorine and ammonia atoms in the cis position of
the horizontal plane (Fig. 5-17). The drug bears a resemblance to the bi-
functional alkylating agents derived from mechlorethamine (Fig. 5-1). It in-
hibits DNA synthesis to a much greater extent than RNA synthesis or pro-
tein synthesis, and it binds to DNA, causing both inter- and intrastrand
cross-linking with a predilection for binding to guanine residues.
It would appear that DDP functions as a new type of alkylating agent.
408
The fact that DDP is cell cycle phase-nonspecific and is not schedule de-
pendent supports this theory. 410 However, an alternative hypothesis ex-
plaining the cytotoxicity of DDP has been proposed by Rosenberg. 411 He
notes that platinum complexes are able to depress viral genome information
in tumor cells, that the inhibition of DNA synthesis by DDP occurs at lev-
els of the drug not frankly cytotoxic to cells, and that DDP inhibition of
animal tumors may be enhanced by immune stimulation (with zymosan) or
decreased by immunosuppression (with hydrocortisone). He and his
coworkers have also noted binding of platinum complexes to the DNA
5 Drugs Used in Cancer Chemotherapy 113
found on the membranes of sensitive tumor cells. Their conclusion has

cell
been that DDPmay work by enhancing the antigenicity of tumors, thus
improving the ability of the immune system to suppress tumor growth. The
discovery of cell membrane DXA on some tumor cells may have added
relevance as a new locus for drug action, and Rosenberg and his group are
pursuing the development of new anticancer agents that may selectively
inhibit the DXA found unexpected location.
in this
After intravenous administration, DDP is widely distributed in the body,
although it does not enter the brain tissue or the CSF to any appreciable
extent. 409, 412 Plasma clearance is triphasic, with an initial TV2 of 25 to 49
minutes and a terminal IV2 of 58 to 73 hours. It is extensively bound to
plasma proteins (90 per cent), and it reaches high concentrations in the
kidney, liver, and intestine. The principal route of excretion is the kidney,
although early studies showed only 27 to 45 per cent of an injected dose of
radioactive DDP Indeed, DDP has been shown
in the urine after five days.
to persist in tissues for as long as four months.
DDP is available in the form of a white powder in vials containing 10
m g 409 when reconstituted with sterile water it is stable for eight hours at
22° C. Although it has been used in many doses and schedules in the past,
one acceptable program involves the administration of 40 mg of furosemide
followed by DDP over six to eight hours in a dose of 20 mg/m 2 dissolved in
2000 ml of dextrose solution (D5-V3 XS) containing 37.5 gm of mannitol.
Prior to treatment, a serum creatinine determination, creatinine clearance,
and audiogram should be obtained. Patients with a creatinine clearance of
less than 65 ml/min or with pre-existing ototoxicity (decreased hearing in
the 1000 to 4000 cycle/sec range) are excluded from treatment. During a
course of therapy and for 12 hours preceding the start of DDP administra-
tion, the patient receives continuous intravenous hydration at the rate of
100 ml hr. The DDP infusion is given daily for four or five days, provided
the patient develops no signs of anaphylaxis or renal dysfunction (daily
serum creatinine determination < 1.5 mg/dL and not increased over base-
line by > 50 per cent). Courses of DDP may be repeated every four weeks
for three or four courses, provided that patient benefit is seen, subsequent
audiograms are normal, and any renal dysfunction or bone marrow suppres-
sion has cleared.
Early studies with DDP demonstrated a wide range of toxic reactions,
even with the use of a single dose of the drug. 409 These reactions included
nausea and vomiting in nearly all patients, renal dysfunction in about 25
per cent of patients, tinnitus or high-frequency hearing loss in 30 per cent
of patients, 413 transient and mild marrow suppression in occasional patients,
and, rarely, anaphylactic reactions, with wheezing, tachycardia, hypoten-
sion, and facial edema. 409 Very rarely, peripheral neuropathy, loss of taste,
and seizures have been reported (unpublished data on file with the Inves-
tigational Drug Branch of the Xational Cancer Institute). The drug is also
moderately immunosuppressive in animals. 414 However, nephrotoxicity' has
most commonly limited the effective use of this drug. 409 Indeed, the se-
verity and frequency of renal dysfunction led many physicians to abandon
the use of DDP until it was demonstrated that the kidney could be protect-
ed by mannitol diuresis. 409,415 As a result, studies on the use of DDP in

humans have been reactivated and one can now use the drug with relative
safety.
DDP is primarily useful in the treatment of nonseminomatous testicular
tumors. It is useful as a single agent but is even more useful as a major
component of combination chemotherapy regimens. 409 In a study reported
by Einhorn and Donohue, 416 DDP combined with vinblastine and bleomy-
cin achieved a 74 per cent complete remission (CR) rate in 50 patients with
advanced testicular tumors. Since good results have been reported by
others, it is likely that DDP will play an increasingly important role in the
treatment of this disease. 409 Other tumors known to respond to DDP in-
clude carcinomas of the ovary, bladder, prostate, and head and neck. How-
ever, the optimal role of DDP in the treatment of these and other tumors is
still under study. 409 ' 417
L-Asparaginase (Elspar)
In 1953 Kidd 418 discovered that guinea pig serum inhibited several ro-
dent neoplasms. The antitumor component of guinea pig serum was later
shown to be the enzyme L-asparaginase, 419 and related enzymes with anti-
tumor activity have since been extracted from a variety of bacteria. 420 Stud-
ies in patients with cancer subsequently confirmed the critical importance
of a specific enzyme, asparagine synthetase, in human cellular resistance to
L-asparaginase therapy. 421 Thus, the postulated mechanism of action for L-
asparaginase relates to its ability to destroy extracellular supplies of L-
asparagine, resulting in the death of cancer cells lacking the enzymatic
ability to make this amino acid. L-Asparaginase is usually considered to be
cell cycle phase-nonspecific, although it may block some cells in G, or S
phase. 5 6 '
After parenteral administration, L-asparaginase distributes into a body

space that is only 20 to 30 per cent greater than the plasma volume. 420 In
humans, plasma levels after intramuscular injection are about half those
seen with intravenous injection, although both routes are effective in re-
ducing the plasma level of L-asparagine. The drug is slowly cleared from
plasma with biexponential half-lives of 0.5 and 2.5 days. Very little L-
asparaginase reaches the CSF or urine, but appreciable concentrations ap-
pear in pleural effusions and lymph. Clearance from the body appears to be
accomplished primarily by the reticuloendothelial system.
The recommended dose of L-asparaginase is 6000 IU/m 2 intramuscularly
given three times weekly for a total of nine doses. 422 Generally, vincristine
and prednisone in standard doses will have been started four or five days
prior to starting L-asparaginase therapy (see Chapter 21).
Although L-asparaginase was originally thought to be free of serious tox-
icity, subsequent work has defined a variety of toxic reactions, including
allergic reactions, depression of clotting factors, liver dysfunction, central
nervous system dysfunction, nausea and vomiting, disordered glucose me-
tabolism (either with or without pancreatitis), and immunosuppres-
420 423
sion. -
The most dangerous reaction has been anaphylaxis, although pa-
tients who develop responding to L-asparaginase

allergic reactions after
from E. coli may be
treated relatively safely with another antigenic source
of the enzyme (such as L-asparaginase from Erwinia caratovora). Because
of the risk of anaphylaxis with L-asparaginase therapy, it is essential that
emergency supplies (including epinephrine) and a physician who is experi-
enced in resuscitation be readily available each time the patient is given
the drug.
The only current use of L-asparaginase is in the treatment of acute lym-
phoblastic leukemia, either in relapse or at initial diagnosis. It is not useful
in maintaining remissions in this disease, and
should not generally be
it
employed as a single agent. Selected clinical features of this drug appear in

Table 5-7.
Unproved Methods of Cancer Treatment
Thousands of unproved remedies for cancer have been sold in the Unit-
ed States during the last two centuries, and we are still faced with a public
that is highly susceptible to unproved remedies sold by disreputable or
misguided people. The space program and the highly publicized "war on
cancer" funded by the US Congress has conditioned people to expect mira-
cles of scientific progress.
As physicians we must exercise extreme care to evaluate each new treat-
ment before accepting it as standard practice, especially when the initial
announcement occurs outside the usual scientific forum. Reemtsma and
Maloney 424 have underlined this by developing what they consider to be a
new law of economics: "The public impact of instant medical reporting is
related inversely to the intrinsic merit of the observation." They concluded
that the unreliability of instant medical news was so reliable that large
profits could be made merely by betting against the value of medical break-
throughs reported by the lay press.
A complete guide to the currently fashionable unproved remedies is
beyond the scope of this book, but a few will be discussed briefly. Reviews
of this subject are available, 425,426 and one may also consult the American
Cancer Society for recent developments.
Laetrile. This is clearly the most controversial cancer treatment
known to date. 427 Amygdalin is the most common cyanogenic glycoside
found in laetrile samples, but numerous impurities and contaminants
abound in the most commonly used preparation manufactured by Cyto
Pharma of Mexico. 428 Because of these impurities and bacterial contamin-
ants in tablet and ampule forms, pharmacists in the United States consider
this source of amygdalin to be unfit for use in humans. Although widely touted
as "nontoxic" cancer treatment, laetrile commonly causes death from cyanide
poisoning when given to dogs, 429 and it has caused well-documented deaths
of this type in humans. 430,431 The United States National Cancer Institute has
tried to establish whether or not an anticancer effect of laetrile can be found
in humans, but the results of a retrospective analysis of submitted case re-
ports were equivocal. 432 The clamor and public outcry in support of lae-
trile has been unparalleled, and several states have legalized its use. As a
result, the United States National Cancer Institute is proceeding with plans to
subject the drug to a controlled clinical trial.
4 "
One can only speculate
whether or not this will settle the issue; we therefore recommend that physi-
cians be familiar with the diagnosis and treatment of cyanide poisoning. 4 - 7
Hydrazine Sulfate. Because of pilot studies conducted elsewhere
suggesting a salutary effect of this chemical in patients with cancer, 4 4 '
32 cancer patients at the Sloan-Kettering Institute (Memorial Center)

(SKMC) were carefully treated with this substance. 435 No subjective or ob-
jective benefit was noted in any patient. This drug has no established place
in contemporary cancer therapy.
Vitamin C. Cameron and Pauling 436, 437 have published a series of
papers summarizing their experiences with large doses of vitamin C as a
treatment for cancer. One patient with disseminated "reticulum cell sar-
coma" received high-dose vitamin C alone and had a "dramatic regres-
sion." 436 With lower doses, the disease progressed, but remission was ob-
served following reinstitution of high-dose vitamin C administration. They
have also compared the overall survival time of 100 "terminal" cancer pa-
tients treated with megadose vitamin C with 1000 historic control patients
and noted a threefold prolongation of life, which they ascribed to vitamin C
therapy. 437 Given the scientific eminence of Professor Pauling and the sim-
plicity of the treatment, many cancer patients are treating themselves with
up to 10 gm of vitamin C daily. Nevertheless, it is premature to consider
megadose vitamin C as accepted treatment. In guinea pigs, large doses of
vitamin C increase the rate of tumor growth, 438 the available trials in
humans are incompletely described and can be challenged on statistical
grounds, and the treatment may be harmful to some patients, such as those
with a tendency to form calcium oxalate urinary stones. 439 Further studies
are needed before the value of megadose vitamin C can be assessed.
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408. Leh FKV and Wolf W: J Pharm Sci 435. Ochoa M
Jr, et al: Cancer Treat Rep
65:315, 1976. 59:1151, 1975.
409. Bozencweig M, et al.: Ann Intern Med 436. Cameron E, et al: Chem Biol Interact
86:803, 1977. 11:387, 1975.
410. Drewinko B and Gottlieb JA: Cancer 437. Cameron E and Pauling L: Proc Natl
Chemother Rep Part 1, 59:665, 1975. Acad Sci USA 73:3685, 1976.
411. Bosenberg B: Cancer Chemother Rep 438. Migliozzi JA: Br J Cancer 35:448,
Part 1, 59:589, 1975. 1977.
412. DeConti BC, et al: Cancer Res 439. Smith LH: N
Engl J Med 298:856,
33:1310, 1973. 1978.
CHAPTER 6
CANCER
IMMUNOLOGY
AND
IMMUNOTHERAPY
Donald L Morton James Goodnight
INTRODUCTION
The concept that cancerpatients may develop an immune response against
their neoplasms not new. This view was very popular at the turn of the
is
century when it was observed that a strong immunity could be induced in

randomly bred laboratory rodents against transplantable neoplasms. A period
of intense laboratory and clinical investigation followed, in the hope that
tumor immunity might lead to the control of human cancer. Cancer patients
were treated with a variety of immunologic agents, including autogenous and
allogenic tumor vaccines, antitumor sera, and bacterial adjuvants, such as
Coley's toxins. Undoubtedly, there were occasional regressions but results
were inconsistent. Thus, clinical interest in cancer immunotherapy gradually
declined and was relegated to the background by the rapidly developing
fields of cancer surgery and radiation therapy.
Laboratory research in cancer immunology was also disappointing because
it soon became evident that the "tumor" immunity was, in reality, homograft
immunity not directed against tumor-specific antigens but against normal

histocompatibility antigens present on the tumor cells. Thereafter, interest in
tumor immunology rapidly declined because no antigens other than these
normal transplantation antigens could be demonstrated in neoplasms of labo-
ratory animals. During the long period of "dark ages'" that followed, most
immunologists and experimental oncologists doubted the existence of the
tumor-specific antigens that provide the very foundation of this discipline of
cancer research.
The modern era of tumor immunology began when in 1953 Foley, and then
1
in 1957 Prehn and Main, 2 conclusively demonstrated tumor-specific antigens

in methylcholanthrene-induced sarcomas of mice. Their work was aided by
the development of extensively inbred strains of laboratory rodents that had
the genetic homogeneity of monozygotic twins. In these animals, grafts of nor-
mal tissues could be permanently transplanted between members of the same
6 / Cancer Immunology and Immunotherapy 125
inbred This enabled the search for tumor-specific immunity to be

strain.
carried out in an environment free of histoincompatibility caused by genetic
differences. It was this important advance in immunogenetics, coupled with
the use of techniques derived from transplantation biology, that permitted the
first successful demonstration of tumor-specific antigens. Tumor-specific
transplantation resistance could be induced in inbred animals by presensi-

tization with a transplant of tumor tissue that was allowed to grow for a time
and was then excised. The immunized rodents were resistant to further
challenge with grafts of the same neoplasm. The antigens responsible for the
rejection of the tumor grafts were known as tumor-specific transplantation
antigens (TATA). Klein 3 demonstrated that the animal in which the neoplasm
had originated could be immunized against its own neoplasm by a vaccine
prepared from irradiated tumor cells.
The next major discovery in tumor immunology occurred when it was found
that oncogenic viruses (such as polyoma) produced tumors that contained
common transplantation antigens. These antigens rendered the virus-induced
tumors susceptible to rejection in immunized animals.
Cancer-specific antigens have been demonstrated in almost every ade-
quately studied neoplasm induced by viral or chemical carcinogens as well as
in certain spontaneous tumors of laboratory rodents.
CLINICAL EVIDENCE FOR HOST

IMMUNITY AGAINST CANCER
Until recently there was evidence for the existence of tumor-specific
little
antigens on human neoplasms. For obvious reasons, the tumor transplantation

techniques used to demonstrate tumor-specific antigens in animal neoplasms
were not applicable to the study of human tumors. Nevertheless, a number of
well-documented clinical observations suggest the existence of host immune
defenses against cancer in humans. Although other physiologic, endocrin-
ologic, and biologic explanations can be given for these observations, they are
most easily explained on an immunologic basis, as discussed in the following
paragraphs.
Spontaneous regression of established tumors is a rare but well-
documented phenomenon. Regressions have been observed after a minor
4
viral or bacterial infection. Although spontaneous regression has occurred in

many different tumor types, it is most frequently seen in neuroblastomas of
children, malignant melanoma, choricarcinoma, adenocarcinoma of the kid-
ney, and soft-tissue sarcomas. Except for neuroblastomas, the spontaneous
regression rate in these tumor types is less than 0.5 per cent. Small pulmonary
metastases have undergone spontaneous regression after surgical removal of a
primary hypernephroma5 — a phenomenon that may also account for pro-
longed survival or cure in patients who have had an incomplete surgical
excision of tumor.
The rapid recurrence of tumor ten or more years after the successful treat-
ment of the primary suggests an immunologic defense that successfully inhib-
its growth during the disease-free interval but is then lost, which results in
rapid growth of the tumor.
Evidence of tumor infiltration with histiocytes, plasmacytes, lymphocytes,
and eosinophils, resembling that seen in the rejection of an organ transplant,
suggests an anti-tumor immunologic mechanism in humans. This cellular
infiltration is often associated with an improved prognosis. In stomach cancer,
for example, the presence of this infiltration may predict a better survival rate
than does extensive surgical removal of the tumor. 6
The presence of many tumor cells in the peripheral blood, lymphatics,
pleural cavity, and operative wounds of patients who subsequently never
develop metastases suggests an immune mechanism that prevents these cells
from developing into clinical cancer. 7
There is a low incidence of successful autotransplants of tumor even in
patients with advanced disease. This resistance is relative rather than ab-
solute because challenge with larger numbers of cancer cells (greater than 100
million) usually results in tumor growth. When plasma or autologous leuko-
cytes are mixed with the tumor cells, the growth of the autotransplants is
stopped or slowed in approximately half of patients, 8 therefore suggesting the
immune nature of this resistance.
Evidence for Tumor-Associated Fetal

Antigens in Human Neoplasms
Numerous attempts have been made to detect tumor-associated antigens in
human neoplasms by a variety of in vitro serologic techniques. Initial studies
involved the analysis of antisera against human tumor tissues produced in a
foreign species such as the rabbit. After many failures, unique antigens were
detected in human hepatomas and colonic carcinomas. These antigens were
of a new class of substances known as fetal or carcinoembryonic antigens and
were quite different from the tumor-specific transplantation antigens of an-
imal neoplasms. Fetal antigens, produced by normal organs during embryonic
development, are usually repressed shortly after birth and are not produced in
significant quantities by normal adult organs. However, neoplastic transfor-
mation may cause the genes governing their production to be depressed and
thus allow renewed production of the fetal antigens. This change is believed
to be a result of alterations in gene regulation, which allows the cell to revert
to its primitive embryonic state.
Since most of the fetal antigen systems have been defined using antisera
produced in foreign species, the possible role of these antigens in influencing
tumor growth in the human host is unknown. Until recently, there was little
evidence that antigens were immunogenic in humans. However, Irie 9 recent-
ly demonstrated oncofetal antigens that are capable of eliciting antibodies in
humans, although their role in host tumor defense remains unclear. It appears
that there are two types of these antigens — one that is capable of inducing an
immune response in humans (e.g., Oncofetal Antigen —
Immunogenic [OFA-
I]) and another that is nonantigenic in humans (e.g., CEA). Nevertheless, it is
likely that the nonimmunogenic class of fetal antigens will become useful in
clinical practice in two malignancy

situations: (1) as a diagnostic tool to detect
at an early stage (patients with positive tests but no overt signs of malignancy
can be singled out for frequent and close study), and (2) as a prognostic tool
for the treatment of cancer (the disappearance of this antigen from the pa-
tient's circulation immediately after cancer surgery would suggest that all
tumor had been removed; the reappearance of this antigen during the post-
operative period might indicate the presence of a recurrence and provide the
basis for a second-look operation or further therapy).
The fetal antigens known at present are probably only a few examples of
many fetal antigens yet to be discovered. Since morphologic dedifferentiation
is a common characteristic of the malignant state, probable that fetal
it is
antigens are present in a wide variety of human neoplasms. These antigens

may be specific for the malignancy of a given organ, such as the alpha fetal
globulin of hepatomas, or they may be common fetal antigens shared by many
neoplasms such as the oncofetal antigen recently described by Irie et al. 9
These antigens are probably most important as diagnostic tools for the
presence of malignancy. A batten- of antisera that are highly specific to the
different types of fetal antigens could be used not only to diagnose the
presence of a malignancy but also to determine the site by testing the patient's
serum with a sensitive radioimmunoassay.
Alpha Fetal Globulin. This is a unique alpha globulin discovered in
1964 by Tatarinov 10 and occurs in approximately 70 per cent of patients with
primary hepatomas, but it is found in human normal serum only during fetal
development and in the first year of life. Therefore, the test for alpha fetal
globulin has been found to be clinically useful for the diagnosis of hepa-
tomas. 11 It is not positive, however, in patients with rapidly dividing hepatic
cells after liver resection or in those with cirrhosis. The serum level of this
globulin falls after successful surgical resection of hepatomas but reappears
with recurrence. Although alpha fetal globulin appeared to be specific for
hepatomas, it has been found occasionally in patients with gastric cancer,
prostatic cancer, or primitive testicular tumors, such as teratoma.
Carcinoembryonic Antigen. The carcinoembryonic antigen reported
by Gold and Freedman in 1965 also occurs in fetal gut, liver, and pancreas
during the first two trimesters of gestation. 12 This antigen was originally
thought to be specific for adenocarcinomas arising in the gastrointestinal tract
and pancreas, but more recently, a similar or identical antigen has been found
in a variety of carcinomas, sarcomas, lymphomas, and neoplasms of many
different histologic types. 13
Because the carcinoembryonic antigen appears in the blood, it was thought
to be of great importance as a diagnostic tool for early clinical evidence of
cancer. A radioimmunoassay capable of detecting nanogram quantities of
CEA in the blood was developed. 14 However, elevated CEA levels were
found in patients with a variety of nonmalignant conditions, including alco-
holic cirrhosis, pancreatitis, cholecystitis, colonic diverticulitis, and ulcera-
tive colitis. As a result, the incidences of elevated CEA levels in mass screen-
ing of normal or hospitalized populations has been over 10 per cent in some
series.
However, serum levels of carcinoembryonic antigens appear to correlate
with the extent of known carcinomas of the colon. Less than 20 per cent of
patients with early lesions (Dukes stage A or stage B) have elevated CEA
levels, whereas one half of patients with Dukes stage C lesions and almost all
patients with Dukes stage Dlesions have elevated levels of CEA. Metastases
to the liver are frequently associated with the highest levels. Thus on a
limited basis, the presence of CEA may be useful for detecting early carcino-
ma of the bowel.
CEA may be extremely useful for following the clinical course of patients
with known malignancy in order to detect evidence of recurrence prior to it
becoming clinically detectable. CEA levels drop during the postoperative
period in patients who have had successful resection of their neoplasm, and
those who develop tumor recurrence often have a rise in their CEA titer to the
preoperative levels. It should be pointed out that in our experience the CEA
level must continue to rise on repeated observations and must reach a level of
20 ng in order to diagnose subclinical recurrence accurately. Otherwise,
minor CEA fluctuations up to 12 ng may occur during the postoperative
period in patients who are explored but in whom no evidence of recurrent
tumor is found.
Evidence for Tumor-Specific Immune

Responses in Cancer Patients
Until the 1970s, there was little direct evidence of any human tumor-
specific antigens capable of eliciting a specific immune response. The trans-
plantation techniques that were used demonstrate tumor-specific antigens
to
in animal tumors were not applicable to humans because of the lack of
syngenic recipients, as well as the ethical and moral limitations. Therefore,
any demonstration of tumor-specific antigens in human neoplasms had to
depend upon the sensitive in vitro immunologic techniques used to establish
the tumor-specific antigens in animal neoplasms.
Tumor-associated antigens have been found in a variety of human neo-
plasms by sensitive techniques. Antibodies or lymphocytes that were specifi-
cally reactive with the antigens of autologous tumor tissue have been demon-
strated in the blood of cancer patients. Such studies have shown that most, if
not all, human neoplasms contain tumor-associated antigens that are capable
of inducing an immune response in the tumor-bearing host.
Humoral antibodies in cancer patients have been studied by immunofluo-
rescence, complement fixation, immunocytolysis, and immunodiffusion tech-
niques. Cell-mediated immunity has been demonstrated by lymphocyte-
mediated cytotoxicity (the ability of lymphocytes to kill tumor cells in tissue
culture), lymphocyte blastogenesis (the ability of lymphocytes to proliferate
when stimulated by tumor-specific antigens), colony inhibition (the ability of
lymphocytes to prevent the growth of tumor cell colonies in culture), and
migration inhibition tests (the inhibition of the migration of macrophages
or other blood leukocytes by specific factors released by lymphocytes that
are stimulated by tumor antigens). Cancer patients have been shown to devel-
op delayed cutaneous hypersensitivity reactions to tumor-specific antigens.
Thus, tumor-specific antigens can elicit immune responses that can be moni-
tored by the standard immunologic techniques.
Tumor-associated antigens that have been detected in a wide variety of
human neoplasms by in vitro immunologic methods include those in Burkitt's
lymphoma, malignant melanoma, neuroblastoma, skeletal and soft-tissue
sarcomas, and carcinomas of the colon, lung, breast, bladder, and kidney. The
antigenic patterns of the majority of human neoplasms are similar.
Common Groups of Specific Antigens. Neoplasms of the same his-
tologic type often contain common tumor-associated antigens that are dif-
ferent from those of other types of neoplasms. For example, human sarcomas
share a common antigen that is different from the common antigens shared by
bladder cancer.
Oncofetal Antigens. Irie and her associates at UCLA" have described a
fetal antigen that is common to many types of human neoplasms, including
carcinomas, sarcomas, and melanomas, but is also found in high concentra-
tions in fetal brain tissue of the second and third trimester.
Individually Specific .Antigens. Some neoplasms, such as malignant
melanoma, have antigens of limited specificity in addition to the common
melanoma group-specific antigen. This combination of individually distinct
and common antigens max be characteristic of other types of human neo-
plasms as well.
It is unclear whether or not specific immune responses to tumor-associated
antigens are the primary basis of host resistance to cancer. Both serologic and
cell-mediated immune responses to these antigens can be demonstrated. 15
However, there are also nonspecific mechanisms for suppression of tumor
growth. Macrophages activated by endotoxins or other stimuli can selectively
identify and destroy neoplastic cells based on some means of recognition
other than antigenic differences. 16 Macrophages can also be specifically
armed by T lymphocytes to attack tumor cells selectively. 17 A combined
specific effector mechanism exists whereby antitumor antibody provides the
specificity for a cytotoxic effector cell with a receptor for the immunoglobulin
molecule to attach and complete the destruction of the tumor cell. 18 Some of
these investigations extend to human tumor-host interactions. However,
much remains to be learned, particularly the extent to which these mechan-
isms explain the observed clinical evidence of immunity against cancer, such
as the spontaneous regression of established tumors.
Importance of the Immune Response in

Controlling the Development of
Neoplasia
There considerable evidence for the importance of the cancer patient's

is
immune response in the control of the development and progression of his

disease. Human beings with congenital immunologic deficiency disorders,
such as ataxia-telangiectasia and the Wiscott-Aldrich syndrome, have a high
incidence of spontaneous neoplasms, usually involving the lymphoreticular
system, that is approximately 10,000 times higher than that of the normal
population. 19 Such tumors are a major cause of death in these patients. Evi-
dence of immunologic deficiency almost always precedes the appearance of
tumors.
Similarly, there is a 70-fold increase in the development of malignant
neoplasms in patients on immunosuppressive therapy for renal homografts. 19
For unknown reasons, lymphomas and reticulum cell sarcomas are the most
frequent types reported. As a result, a conflicting theory involving chronic
antigenic stimulation rather than immunosuppression was introduced as the
cause of the high incidence of lymphoreticular neoplasms. However, the
incidence of nonlymphoid neoplasms, such as carcinomas of the skin and
gastrointestinal tract,is also increased in these patients.
Further evidence for the importance of an intact immune response is illus-

trated by observations of patients with renal allografts. Patients receiving
immunosuppressive drugs for kidney transplants have shown an increased
susceptibility to the outgrowth of tumor allografts transplanted from the kid-
ney donor. In these cases, the kidney grafts were derived from patients who
died of malignant disease. The kidney recipients developed metastatic cancer
from the transplanted kidney several months later. In one particularly in-
teresting patient, the cessation of immunosuppressive therapy resulted in
rejection of the kidney but not of the tumor tissue. However, when the
rejected kidney, which contained a large mass of tumor tissue, was removed,
the residual metastases gradually disappeared. Furthermore, there was no
evidence of tumor reappearance when a second successful kidney transplant
was performed nine months later, even though the patient was placed on a full
program of immunosuppressive therapy. Thus, complete destruction of the
allografted cancer tissue seems to have been accomplished by the host im-
mune system during a relatively brief period of normal function, but only after
the bulk of tumor tissue had been reduced. 20
Immune Suppression in Malignancy
A number of studies have tested the general functional capacity of the

cancer patient's immunologic system. Such studies can be grouped into two
categories: (1) those concerned with humoral antibody production, and (2)
those dealing with cell-mediated immune reactions.
Many investigations have shown that almost all cancer patients have the
ability to form humoral antibodies against a variety of antigenic agents, even
in the presence of advanced disease. No defect in humoral antibody produc-
tion in cancer patients could be found.
The integrity of cell-mediated immune reactions has been assessed in
cancer patients by delayed cutaneous hypersensitivity to a variety of skin test
antigens to which most of the normal population is reactive from previous
exposure, such as mumps, PPD, streptokinase, or streptodornase. Primary
immune responses were tested by studying the survival of skin allografts and
by sensitizing patients to a new antigen, such as the contact allergen dini-
trochlorobenzene. DNCB, a hapten, reacts with proteins in the skin to sensi-
tize immunocompetent patient to a hapten-protein complex. Cell-

the
mediated immunity has been monitored by in vitro tests of lymphocyte
function. The ability of lymphocytes to manifest immune reactions that re-
quire recognition and proliferation may be tested in vitro by their response to
foreign tissue antigens or mitogens such as phytohemagglutinin.
These immunologic studies revealed that patients with lymphoreticular
neoplasia have immune reactions. Since
significantly impaired cell-mediated
these diseases usually diffusely involve the immune effector system, such a
reaction might be expected; however, a similar impediment in cell-mediated
immune reactions was also observed in patients with localized or advanced
solid neoplasms that did not directly involve the immune system. Although
the cause for this immunologic defect is unknown, there does appear to be a
significant correlation between impaired cell-mediated immunity and the
clinical course of the malignant disease. 21
Such correlations become particularly evident when the postoperative
course of a cancer patient is compared with his or her ability to become
sensitized to DNCB. More than 95 per cent of normal individuals, patients

22
with benign neoplasms, patients who are free of disease five or more years
after cancer surgery, and patients with a history of spontaneous regression of
cancer can be sensitized to DNCB. Conversely, only 65 per cent of the
patients presented for definitive cancer surgery can be sensitized. Seventy-
two per cent of DNCB-positive patients have localized neoplasms that can be
resected. These patients subsequently remain free of disease for at least six
months. Patients who are anergic have a uniformly poor clinical course fol-
lowing operation. Most of these patients either have unresectable disease
resulting from local or metastatic spread or, if resected, they have recurrence
of disease within six months of operation.
There are considerable differences in the pattern of DNCB reactivity in
patients with different types of solid neoplasms. Patients with epidermoid
carcinoma of the cervix, mouth, pharynx, or larynx show a significant correla-
tion between a positive DNCB response and a good prognosis after cancer
surgery. The majority of patients who could be sensitized were resectable and
free of disease for at least six months postoperatively, but those who were
anergic had a uniformly poor clinical course. However, little correlation
between a positive DNCB test and recurrence after surgery was observed in
patients with the skeletal or soft-tissue sarcomas and melanomas. Many of
these patients developed a recurrence even though they developed sensitivi-
ty to DNCB. Therefore, the prognostic significance of an intact cellular im-
mune response, as measured by DNCB skin tests is very much dependent on
the histologic type of neoplasm being studied.
The reason for the observed differences in cutaneous reactivity with various
tumor types is not known at the present time. These different patterns may
indicate some important variations either in the etiology of the immune
suppression or in the immune response to the different types of human
neoplasms. In some instances, the immunosuppression is clearly related to
the presence of tumor because resection results in a return of immunologic
competence in patients with large, bulky skeletal and soft-tissue sarcomas.
Correlations Between Clinical Course of

Human Cancer and Immune Response to
Tumor-Associated Antigens
More sophisticated immunologic studies show that some patients with a

normal immune response to DNCB may have abnormalities response
in their
to the tumor-associated antigens of their neoplasms.
Although the role played by antibody in helping to control tumor growth is
controversial at present, there is a marked correlation between the antitumor
antibody titer that is detectable by immunofluorescence and complement fix-
ation with the clinical course in patients with melanomas and sarcomas. This
correlation was especially striking in sarcoma patients. 22
Lymphocytes specifically sensitized to tumor-specific antigens appear to be
present at all stages of malignant disease. However, it is likely that their
effectiveness in mediating inhibition of tumor cell growth is dependent upon
circulating serum factors, which are probably antigen-antibody complexes or
free antigen that inhibits the activity of sensitized lymphocytes. These block-
ing factors, found in the sera of patients with growing tumors, can be neu-
tralized by specific antibodies that are frequently found in the sera of patients
who are free of malignant disease. Thus, both cellular and humoral immune
responses are probably important for controlling the growth of human can-
cer.
In this regard, any cancer therapy that produces a reduction in tumor
burden is probably a form of immunotherapy. Present evidence suggests that
the host's immune defenses are limited because the growing neoplasm seems
to be able to evade an immune attack by producing specific and nonspecific
immunosuppression in the cancer patient. This growing neoplasm constantly
sheds soluble tumor-associated antigens into the blood, which circulate alone
or combine to form antigen-antibody complexes. These serum antigens can
inhibit lymphocyte-mediated destruction of tumor cells in vitro and may play
a similar role in vivo. 23 In addition to this tumor antigen specific blocking, a
growing neoplasm often causes a nonspecific or generalized suppression of
the cancer patient's immune competence. Humoral factors produced by or in
response to the neoplasm can be found in the sera of cancer patients and are
believed to be the cause of the general immune depression. These concepts
are illustrated in Figure 6-1. The extent of immunosuppression correlates
with the stage of disease and level of tumor burden and can be reversed by
removal of the tumor. Therefore, any therapeutic maneuver that lowers tumor
burden appears to reverse both the specific and nonspecific immunosuppres-
sion to alter the immune balance in favor of the host. In this respect, all cancer
therapy is immunotherapy if it effectively removes the cancer cell mass that
produces immunodepression in order to allow the patient's immune re-
sponses to recover. Once the tumor mass is eliminated, the immune mechan-
isms can overcome such clinically silent micrometastases that may remain in
many patients who appear to have localized solid tumors. These host defenses
are capable of destroying small numbers of tumor cells on the order of 1 to 10
million but not masses of 100 million or more. Since a neoplasm only 1 cm in
diameter contains approximately a billion tumor cells, by the time most
CANCER SURGERY AS IMMUNOTHERAPY
Combines
^_-^- w '' n
Immunosuppressive _^^
~^~~"\
tumor antitumor
factors * /\. .JX^ântigens antibody
Antigen/antibody
I
comple, esor
Blocking factors
1 excess free
;
antigen
+ lymphocyte^/
cytotoxicity
FIGURE 6-1. Cancer cell "factory" is depicted as a function of immunodepression

inthe host. Theoretically, cancer surgery interrupts this process, so that tlie host im-
mune response returns to normal. (Morton DL
et al.. Chest 71:640, 1977.)
tumors are clinically detectable they have outgrown the patient's immune
defenses. Thus, surgical therapy, radiation therapy, and chemotherapy may
owe their effectiveness to the role they play in reducing tumor mass to a level
that can be controlled by host immunity. Evidence for this hypothesis comes
from observations that cancer cells are often found in the washings of opera-
tive wounds, in the regional lymphatics, or in the circulating blood of patients
who are cured of their disease by operation or local radiation therapy. Thus it
would appear that the success of cancer therapy depends upon the effective-
ness of the patient's immune response. It is not surprising, therefore, that
patients who have defective cell-mediated immune responses are likely to
have poor prognoses.
IMMUNOTHERAPY
Introduction
Similarities in the biochemical constituents and metabolism of cancer and

normal cells contribute to many of the problems associated with the standard
forms of cancer therapy. Anticancer drugs and x-rays that are designed to kill
cancer cells often have similar effects on normal cells. Although some cancer
cells have a rapid rate of cell division when compared with normal cells of the
same organ, there are other normal cells in the body (e.g., those in the bone
marrow and intestinal epithelium), that grow even more rapidly. Hence, any
therapy designed to inhibit the proliferation rate of cancer cells may also
inhibit the function of these normal cells. Herein lies the fundamental defi-
ciency of both radiation and chemotherapy. Similarly, cancer surgery often
requires the sacrifice of normal tissues and organs to ensure an adequate
margin of tissue resection around the cancer mass. In contrast, immunothera-
py depends upon basic antigenic differences between neoplastic and normal
cells for its therapeutic effect. Thus, because the immune attack is directed to
those cells possessing tumor-specific antigens but not to normal cells, immu-
notherapy can be specific for cancer cells. At the present time, however, this
modality has limited potency.
Immunity against cancer is a relative rather than an absolute phenomenon.

Host defenses are quite capable of destroying small numbers of tumor cells (1
to 10 million), but 100 million tumor cells almost always results in progressive
tumor growth. Therefore, it is unlikely that immunotherapy alone will ever
bolster host defenses sufficiently to reverse tumor growth in patients with
advanced disease.
In contrast, immunotherapy is a logical adjunct for the treatment of subclini-
cal microscopic disease following definitive cancer surgery, radiation therapy,
or chemotherapy for the following reasons: 24 (1) Patients who have only small
foci of cancer cells remaining after the destruction of most of the tumor bulk
by other types of therapy are most likely to benefit from immunotherapy,
because the tumor mass to be destroyed is smallest immediately after other
therapy has been administered. (2) The specificity of the immune response for
cancer cells provides a possible therapeutic tool that has selectivity for small
numbers of cancer cells, which is not possible with any other therapeutic
modality. (3) Patients with earlier disease are more likely to respond to
immunotherapeutic maneuvers, since the cancer patient's general immune
competence is greatest when his or her disease is localized and is often
impaired after metastasis. (4) Immunotherapy should complement rather than
interfere with currently available methods of cancer therapy. The use of
immunotherapy in combination with these therapeutic modalities must be
carefully controlled, since both irradiation and chemotherapy are immuno-
suppressive. Because these treatment modalities can induce an enhanced
immune response when immunization is carried out under special conditions,
the results of cancer therapy may improve when there is a better understand-
ing of their influence upon the immune response.
In the last few years, there has been an intense interest in immunotherapy
for the treatment of malignant disease. Hundreds of clinical trials in progress
are listed in the International Registry of Tumor Immunotherapy. 25
Historically, three studies of the late 1960s reawakened interest in
this form
of therapy. Klein 26 observed that skin carcinomas regressed after the induction
of local delayed cutaneous hypersensitivity with certain chemicals. Mathe et
27
al. reported that the disease-free interval and survival could be prolonged
for patients in remission from acute lymphoblastic leukemia by treatment
with BCG or allogeneic leukemia cells, or both. Morton et a/. 28 reported
dramatic regressions of cutaneous nodules of malignant melanoma following
intralesional injection with BCG. These reports suggested that immunothera-
py could be significant in the management of human cancer.
This enthusiasm has been tempered by the realization that immunotherapy
alone has had little effect on established disease except in a few clinical
situations such as those employing local immunotherapy for accessible
tumors. After an initial period of excitement, a stage of careful reassessment of
the practical role of immunotherapy in cancer management is in progress. A
review of the published clinical trials reveals a substantial amount of in-
conclusive data that could lead one to a degree of pessimism. In contrast,
there are numerous reports containing evidence of therapeutic benefit that
cannot be ignored. Even though many of these reports are in the early stages
of confirmation, they suggest that immunotherapy will have a role in the
treatment of cancer. These positive reports are the substance of this brief re-
view.
A word about clinical trials is in order. Immunotherapy is a potentially
useful tool for the management of malignant disease, but it is unproved. If its
role is to be established, studies must present an accurate and undistorted
view. Since clinical trials vary tremendously in their structure and content,
only adequately controlled and carefully conducted trials can be accepted as
evidence of effectiveness. Careful selection of the control group is essential if
valid conclusions are to be drawn regarding the treatment in question. Such
selection can best be achieved by random allocation. If the data are to be
meaningful, the trial must possess an adequate number of patients, accurate
diagnoses and staging, sufficient follow-up, and appropriate statistical analy-
sis of the results. The significance of a clinical trial depends on how well it
excludes conflicting interpretations of its findings which, in turn, are based on
the variables mentioned.
Immunotherapeutic Agents
Agents that stimulate host resistance to cancer may be described as nonspe-
cific, active specific, or passive immunotherapy. Nonspecific immunotherapy
involves the use of agents such as BCG or Corynebacterium parvum, which

are potent activators of multiple host defense mechanisms. Active specific
immunotherapy attempts to elicit specific antitumor immune responses by-
vaccination with tumor cells or tumor antigens. Various means are used to
increase the immunogenicity of these tumor cell vaccines. Passive immuno-
therapy is an effort to transfer immunocompetent cells or serum from an
appropriately sensitized host to the cancer patient. Another approach involves
the transfer of subcellular fractions from immune cells to instruct the cancer
patient's own lymphocytes to specifically attack the tumor.
Nonspecific Stimulation of the Immune Response. The rationale
for thismethod of immunotherapy is based upon the observation that certain
substances, such as mixed bacterial toxins and fractions of the tubercle bacil-
lus, have the ability to nonspecifically stimulate host resistance to most viral,
fungal, and bacterial agents. The exact mechanism of action is unknown, but it
appears to increase the immune responses to a wide variety of antigens,
including tumor-specific antigens.
One of the earliest and most impressive examples of this type of therapy
was Coley's series of experiments at the turn of the century. 16 He became
interested in the possible therapeutic value of nonspecific immune therapy
when a patient with a recurrent inoperable sarcoma of the neck enjoyed a
seven-year regression after two attacks of erysipelas. Coley next attempted to
produce erysipelas in patients with recurrent cancer. This led him to develop
"Coley's" toxins. The toxins were combinations of living or heat-killed strep-
tococcus and Serratia marcescens that were mixed in varying proportions and
were then injected directly into a tumor or, in some cases, were given intrave-
nously. Impressive regressions and long-term cures were attributed to these
agents, even though more recent experiments with similar preparations were
not as impressive.
BCG. During the early part of this century, Calmette and Guerin 29 devel-
oped an attenuated strain of Mycobacterium bovis that has been used success-
fully worldwide as a vaccine against tuberculosis. This organism, known as
BCG, is also a potent stimulator of host defensemechanisms. 30 When adminis-
tered to experimental animals, BCG increases their resistance to the growth of
tumor inoculations. 31,32 Moreover, direct intralesional injection of BCG
causes the regression of cutaneous deposits of tumor as well as significant
systemic antitumor responses. 28, 33_35 This body of experimental work has been
thoroughly reviewed by Bast and colleagues, 36 who identified several factors
critical to successful BCG antitumor immunotherapy. These factors are as
follows: (1) The tumor host must be immunocompetent, (2) enough BCG must
be given, (3) the tumor burden must be relatively low, (4) the BCG must be in
close association with the tumor cells, and (5) the tumor must be immunogen-
ic.
The mechanisms underlying tumor regression after BCG

treatment are not
completely understood. BCG does not have a direct antitumor effect, since
tumor regression occurs only if the host can generate a delayed hypersensitiv-
ity response to BCG. 28, 37 The necessity for close contact between BCG organ-
isms and tumor cells suggests that the tumor cells are destroyed as innocent
bystanders. However, after local tumor regression occurs, animals resist
tumor challenges at distant sites, which indicates that a systemic antitumor
response has occurred. 38 Moreover, in some melanoma patients, intralesional
injection of BCG causes adjacent uninjected lesions to regress as well. 28
It is not known whether antibodies or specifically sensitized cells are
involved in tumor destruction following BCG injection, but specific antitumor

responses do occur in this setting. The titer of antimelanoma antibody in-
creases in melanoma patients treated with BCG, 28 and in a guinea pig hepa-
toma model, antitumor antibody also increased after BCG injection. 38 Another
possible mechanism for destruction may involve macrophages that are activat-
ed by the BCG. Macrophage infiltration is a major feature of the histologic
response to this treatment. 38
Side effects from intradermal BCG, by either the multiple puncture Tine
technique or Heaf gun, are relatively mild and consist of low-grade fever,
malaise, local inflammation, and mild ulceration. However, intralesional in-
jection may cause more serious toxicity, such as anaphylaxis, granulomatous
hepatitis, systemic BCG infection, high fever and chills, or abscesses. 39 In
general, BCG immunotherapy should be administered only by personnel who
are experienced in its use.
BCG has been widely used as cancer therapy for the local control of
accessible tumors, as an adjuvant for the supression of microscopic residual
disease, and in combination with chemotherapy for disseminated disease.
Corynebacterium Parvum. C. parvum is a microorganism with potent
immunostimulatory properties. In contrast to BCG, C. parvum is killed by
physical or chemical means before it is used for immunotherapy. In animals,
treatment with C. parvum inhibits the growth of tumor inoculations and, at
least for methylcholanthrene-induced sarcomas in mice, can cause regression
of established tumor. 40 42 C. parvum is maximally effective when injected into
"
"
the regional lymph node drainage of the tumor. 43 45 Given intralesionally, it
can induce regression of cutaneous malignancies. 46
6 / Cax\cer Immunology and Immunotherapy 137
C. parvum is a potent macrophage activator that can cause tumor regression

in animals depleted of T cells, suggesting that macrophage stimulation may
be critical to the antitumor response.
47
An additional manifestation of the
activation of the reticuloendothelial system is a more rapid clearance of
injected particles from the bloodstream in C. paruum-treated animals. 48 Spe-
cific immune responses, including antibody production to a variety of an-
48
tigens, are also stimulated after administration of C. parvum.
Side effects from the subcutaneous administration of C. parvum include
local inflammation, swelling, mild fever, and chills. When given intravenous-
ly, side effects can be more serious, e.g., high fever and chills, changes in
blood pressure, nausea and vomiting, "flulike" syndrome, headache, and
some central nervous system changes. 49,50
In clinical trials, C. parvum has been tested primarily in combination with
chemotherapy for treatment of disseminated malignant disease. 49 51 Several
"
investigators indicate that this combination is beneficial, 51, 52 but others have
had less favorable experiences. 53
Levamisole. Levamisole is a low molecular weight synthetic antihel-
minthic drug. It stimulates immune responses in immunodepressed hosts.
Mice have displayed enhanced resistance to Brucella abortus infection after
being given levamisole. 54 In humans, antibody responses to influenza were
increased after levamisole treatment. 55 Delayed cutaneous hypersensitivity
responses have been augmented or restored by levamisole administration in
cancer patients. 56 The drug also stimulates increased phagocytic activity in
macrophages. 57
Levamisole has been reported to help clear recurrent aphthous stomatitis
and warts, and it gives symptomatic relief in systemic lupus erythematosus,
rheumatoid arthritis, and herpes infections. 48
Levamisole can be taken orally and may cause gastrointestinal distress and
fatigue. Some cases of agranulocytosis have occurred in patients who were
taking the drug for rheumatoid arthritis. 63
The results of testing levamisole as an antitumor immunotherapeutic agent
in experimental tumor systems have been highly variable. 48 No firm conclu-
sions can be drawn except that levamisole does not increase the resistance to
tumor inoculations in immunologically normal animals. 58 60 However, levami-
"
sole has been tested in humans, and initial results suggest benefit. 61,62
Active Specific Immunotherapy. Theoretically, the most direct way to
generate effective tumor immunity is by stimulating the immune system with
tumor antigens. Despite their weak immunogenicity and pre-exposure to the
tumor host, an alteration in the presentation of these antigens to the immune
system can result in a more effective antitumor response. Such alterations
might include a change in the antigen dose, the timing or route of sensitiza-
tion, or the configuration of the antigen on the tumor cell surface. Allogeneic
tumor cells provide one method of change because tumors of the same his-
tologic type share common antigens. 64 Furthermore, such cells will not grow
at the site of injection because of their normal histoincompatability. Animal
experiments have shown that intradermal administration is a good route for
sensitization. Allogeneic tumor cell vaccines are being tested clinically as
adjuvant immunotherapy for several malignant diseases including lung and
"
breast carcinomas, malignant melanoma, acute leukemia, and sarcomas. 65 70
138 II General Principles
Alteration of the tumor cell surface

is another method for increasing immu-
nogenicity. Thecapacity of murine leukemia cells to induce tumor transplan-

tation resistance can be markedly increased by treating them with neuramin-
idase, an enzyme obtained from Vibrio cholerae. 6 * Neuraminidase cleaves
sialic acid from cell surface glycoproteins, which may increase antigen expo-
sure. Virus infection may increase the immunogenicity of tumor cells, and the
viral products on the cell membrane may act as helper antigens to stimulate an
increased antitumor response. 71 Lysates of virus-infected tumor cells have
been used clinically to treat several kinds of cancer. 72, 73
Passive Immunotherapy. The adoptive transfer to the cancer patient of
immune cells or antiserum with appropriate specificity may assist in suppress-
ing tumor growth. However, adoptively transferred allogeneic cells are even-
tually rejected, so that a continuous source of sensitized cells must be found.
In humans, such a supply is usually unavailable, although one success was
achieved by the transfer of blood from a patient who experienced a complete
remission of melanoma. 74 Another approach involves matching patients with
the same tumor, sensitizing them to each other's tumor with subcutaneous
transplants, and then exchanging their leukocytes. Response rates of 15 to 20
"
per cent have been reported. 75 77 However, some serious transfusion reactions
have occurred with this method when the patient becomes sensitized to HLA
antigens. Immunocompetent cells from closely matched siblings might be an
alternative. 78 Because these procedures are logistically difficult, potentially
toxic, and help relatively few patients, they have limited use as adjuvant
therapy.
An alternative theoretic approach is the transfer of subcellular fractions of
immune cells such as immune RNA or transfer factor to induce specific
antitumor reactivity in the patient's own lymphocytes. Transfer factor is a low
molecular weight dialyzable substance from sensitized lymphocytes that can
confer specific reactivity on unsensitized lymphocytes. 79 No direct exposure
to antigen is required. Transfer factor has been effective against congenital
immunodeficiency disease such as the Wiskott-Aldrich syndrome, ataxia-
telangiectasia, and chronic mucocutaneous candidiasis. Limited clinical trials
in cancer patients have been undertaken, although a source of transfer factor
"
with appropriate tumor specificity was a problem. 80 82 Reports of initial results
suggest some benefit.
Mannick and Egdahl 83 showed that specific transplantation immunity could
be transferred in rabbits by RNA extracted from sensitized lymphocytes. Pilch
and coworkers 84 confirmed these observations and extended them to anti-
tumor responses. They showed that RNA extracted from lymphocytes of
guinea pigs sensitized to mouse tumor conferred specific antitumor reactivity
on untreated mouse spleen cells. This demonstration of the transfer of specific
reactivity by xenogeneic immune RNA was important for clinical trials, since
it meant that appropriately sensitized animals could be used as a source of
antihuman tumor immune RNA. This agent has virtually no toxicity, since
lymphocytes cannot be instructed to attack self antigens. Allergic reactions to
RNA are not a problem, since it is of low immunogenicity. Human lympho-
cytes exposed to immune RNA from sheep sensitized to human tumor destroy
thattumor in vitro. Controls indicate that the activity is specific for the tumor
and dependent upon exposure to the RNA. Initial clinical trials in humans
is
with xenogeneic immune RNA were recently summarized by Ramming and

colleagues 85 and suggest that the value of this approach must be considered
questionable at the present time.
CLINICAL EVALUATION OF
IMMUNOTHERAPY FOR SPECIFIC
NEOPLASMS
Immunotherapy has been investigated as a local treatment for accessible
tumors, as an adjuvant to other forms of therapy for control of occult microme-
tastases, and as an agent combined with chemotherapy for the treatment of
disseminated cancer.
LOCAL IMMUNOTHERAPY
Local immunotherapy is, by definition, the intralesional injection or topical
application of agents to induce delayed cutaneous hypersensitivity (DCH)
responses in the immediate vicinity of an accessible tumor. Regressions of
cutaneous neoplasms following these procedures are dramatic and reproduc-
ible. The patient must be immunocompetent to respond to the agent or agents
injected into the tumor, 28 but tumor destruction may not be caused by specific
cytotoxic cells or antibodies. 86 Histologic examination of the response to local
immunotherapy shows an infiltrate of both lymphocytes and macrophages, 38
and it may be the latter that actually destroy the tumor. 87 89 '
Even though the mechanism of tumor destruction remains undetermined, it

is clear that local immunotherapy eradicates tumor. These procedures work
best for cutaneous neoplasms, but only when tumor burden is small. Local
immunotherapy is much subcutaneous, nodal, or visceral
less effective for
disease. Systemic antitumor responses appear to be generated as a result of
local immunotherapy, but the significance of these responses has not been es-
tablished. 28
Malignant Melanoma
A large part of the current interest in immunotherapy

malignant disease
for
was stimulated by results obtained from BCG therapy of malignant melano-
ma. Morton and his colleagues 28 observed that 90 per cent of cutaneous
metastases of malignant melanoma regressed following intralesional injection
"
of BCG. These findings have been confirmed by numerous investigators. 89 95
Moreover, in 17 per cent of patients, uninjected lesions regressed concomi-
tantly with injected lesions, although this phenomenon was usually limited to
lesions in the same lymphatic drainage bed. 92 Approximately 20 per cent of
patients have had long tumor-free intervals following the control of cutaneous
metastases with BCG therapy; the longest survival rate is more than ten years
(Morton, unpublished data). Tumor regression occurs only in immunocompe-
tent patients as measured by response to PPD or DXCB skin testing. New
lesions can be controlled by BCG injections.
Intralesional injections of BCG are usually well tolerated, but significant
toxicity can occur, and these reactions may require termination of the therapy.
The Glaxo strain of BCG should be used for intralesional injection, as there
are fewer organisms and less debris in this preparation. In general, BCG
treatment should be administered by experienced personnel.
Intralesionally administered DXCB and vaccinia virus (smallpox vaccine)
successfully eradicate cutaneous metastases of malignant melanoma. Hunter-
Craig and colleagues 96 reported that intralesional administration of vaccinia
virus induced complete regression of cutaneous metastases of malignant mel-
anoma in six often patients. Responses were limited to intradermal disease.
At the time of the report, the longest regressions were 11 and 22 months.
Toxicity was that of smallpox vaccination. DXCB stimulates brisk DCH re-
sponses. Malek-Mansour 97 reported that six of ten patients with in-transit
metastases of malignant melanoma had complete tumor regressions after
intralesional DXCB treatment. The disease was controlled for one to six
years, although periodic recurrences required treatment with intralesional
DXCB. Toxicity was limited to local inflammation. These intralesional treat-
ments are potentially beneficial and may be used sequentially for the control
of cutaneous metastases of malignant melanoma as long as the patient is im-
munocompetent.
Breast Carcinoma
Cutaneous recurrences of breast carcinoma respond to intralesional injec-

tion of BCG. Complete regression of skin lesions in breast cancer patients was
achieved in three different studies 95, 98, " (50, 60, and 87 per cent, respec-
tively). Recurrent lesions in irradiated tissue were also effectively controlled.
However, only PPD-positive patients, or those who became so during the
course of treatment, showed tumor response.
Skin lesions of breast cancer have been controlled with intralesional injec-
tions of mechlorethamine. In addition to its chemotherapeutic properties,
mechlorethamine is a topical sensitizing agent and induces DCH responses in
75 per cent of patients. Goldman 100 obtained complete regression of cutaneous
recurrences of breast carcinoma in five of six patients treated with this tech-
nique. Women who developed DCH responses to the drug had tumor regres-
sion. DXCB has been tested for this disease but apparently is less effective
than for treatment of malignant melanoma. 101
Responses in these investigations were limited to injected lesions, and the
effect on survival could not be determined. Nevertheless, local immunothera-
py is clearly beneficial for the control of cutaneous metastases of breast carci-
noma.
Skin Cancer
Edmund Klein's initial reports of local immunotherapy for skin cancer also
created interest in this form of treatment. 26
Patients sensitized to DNCB or
TEIB (triethylene iminobenzoquinone) had regression in 90 per cent of
superficial basal cell orsquamous cell carcinomas after topical applica-
102
tion to their lesions. 26, Premalignant keratoses, leukoplakia, and squamous
cell carcinoma in situ also responded to treatment. Toxicity was minimal, and
normal skin was relatively unaffected. The local effect could be improved by
adding a second sensitizing agent, topical 5-fluorouracil. 103
Other investigators confirmed Klein's findings to some extent. Levis and
colleagues 104 found that individual patient responses for basal cell carcinomas
varied from 22 to 70 per cent. 104 Overall, their complete response rate was 32
per cent, with an additional 29 per cent of lesions showing partial regression.
Local immunotherapy can be effective for skin cancers and is particularly
suitable when surgical excision is not feasible.
Other Accessible Tumors
Topical immunotherapy has been effective for the control of early vaginal
cancer. 105 Six posthysterectomy patients, in whom malignant cells were pres-
ent in repeated Pap smears, were sensitized to DNCB followed by intravagin-
al application of DNCB cream. After the marked local response subsided, Pap
smears from all six women reverted to normal and remained so for 2 to 35
months (median 21 months).
Bladder irrigations with BCG have been used to reduce the rate of recur-
rence of superficial bladder cancers. 106 This treatment has not been tested in a
prospective randomly controlled fashion, but the initial results suggest a
reduction in the recurrence rate and an increase in the duration of remission.
Both these applications of local immunotherapy could offer practical solutions
to vexing problems.
Preoperative Local Immunotherapy
Patients who are able to generate an immune response to injected agents are
capable of destroying cutaneous neoplasms. Whether or not the mechanisms
involved in local tumor destruction result in systemic antitumor resistance has
not been clearly defined. In the clinical setting, uninjected lesions of malignant
melanoma occasionally regress concomitantly with injected lesions. Some
patients who are at high risk for systemic metastases survive for long periods
with immunotherapy. 28 92 In addition, there is a
after the control of local disease *
rise in titer of antimelanoma antibodies following intralesional injection of

BCG. 28 These observations suggest that systemic antitumor resistance devel-
ops.
In a guinea pig hepatoma model, destruction of local tumor by intralesional
injection of BCG results in systemic resistance to the growth of reinoculation of
cells of the same neoplasm. 38 In

this tumor model, the most effective means of
curing disease is injection of the local lesion with BCG followed by operative
removal of the tumor and the regional nodes." The results are clearly superior
to BCG injection alone or operation alone.
Because improving systemic control of the disease may be
this potential for
applicable to human cancer, preoperative local immunotherapy has been
tested as part of the primary treatment for high-risk lesions of malignant
melanoma. The surgery branch of the National Cancer Institute has started
such a program. Primary lesions invading into the skin deeper than 2.25 mm
were injected with BCG two to four weeks before wide surgical excision and
dissection of the regional lymph nodes. 107 Patients were randomly selected to
receive the preoperative immunotherapy or operation only. However, because
very high doses of BCG (1 to 6 x 10 8 organisms) were given, this intralesional
treatment was accompanied by significant toxicity as a result of dissemination
of the BCG organisms. 107 Preliminary' results did not show benefit in terms of
recurrence or increased duration of survival (Rosenberg, personal communica-
tion). In vitro testing showed that these patients had depressed lymphocyte
function, which might account for the lack of benefit. 107
A prospective randomized trial of preoperative BCG followed by excision of
the primary lesion and regional lymph node dissection has been initiated in the
Division of Surgical Oncology at UCLA. A lower dose of BCG (10 7 organisms)
than that used at the NCI is employed, and severe toxicity has not been a
problem. Follow-up is too short for even a preliminary evaluation of survival
and recurrence. Everall and colleagues, 108 at the Royal Marsden Hospital in
London, tested intralesional vaccinia virus as preoperative immunotherapy for
primary lesions of malignant melanoma. At a median time of three years, the
recurrence rate was less in the patient given preoperative intralesional small-
pox vaccine than that in a group of control patients treated concurrently by
operation only. However, the difference is not statistically significant.
Since preoperative injection of BCG is useful for malignant melanoma, and
postoperative intrapleural injection of BCG appears to be beneficial for lung
cancer patients, preoperative BCG injection of lung lesions was started by
Holmes and colleagues at UCLA. 109 Preliminary results from this preoperative
immunotherapy trial showed that the treatment could be given safely and that
necrosis and the typical granulomas occurred in the injected tumors. Whether
or not this treatment improves recurrence and survival rates for lung cancer
patients is now being determined.
Conclusions
Local immunotherapy is clearly effective treatment for skin lesions and

cutaneous metastases of malignant melanoma and breast carcinoma. It works in
an irradiated field or with concurrent chemotherapy, provided that the patient
is immunocompetent. Systemic side effects are mild. It has not been es-
tablished that local immunotherapy leads to the control of systemic microme-

tastases, but there are patients who have long-term survival following the
control of regional malignant melanoma with BCG injections. Preoperative

local offers considerable promise of therapeutic benefit, since
immunotherapy
it works wellexperimental systems, but whether it will yield good results in
in
practice must await completion of ongoing trials.
ADJUVANT IMMUNOTHERAPY
Many cancers that appear to be localized at the time of diagnosis are in reality
systemic diseases. Since surgery and radiation therapy control only local and
regional disease, cure rates will not improve unless the disseminated small foci
of tumor can be eliminated. The potential for a highly selective systemic attack
on tumor cells makes immunotherapy a logical modality for adjuvant treatment.
Part of the evidence for systemic antitumor resistance resulting from immuno-
therapy was discussed in the section on preoperative local treatment. In
addition, it has been found that intraveneous administration of BCG in rats can
prevent the development of pulmonary metastases from IV inoculations of
tumor cells. 110 However, the main support fora systemic antitumor effect comes
from clinical trials that indicate benefit from adjuvant immunotherapy.
Lung Carcinoma
The most successful trial of adjuvant immunotherapy for visceral cancer was
reported by McKneally and associates from Albany Medical College. 111, 112 It
was initiated because of the observation that patients who develop empyema
following lung resection for carcinoma seemed to survive longer. 113, 114 All
patients in this trial had resectable carcinoma of the lung and were randomized
postoperatively to receive one dose of BCG (10 7 organisms) given intrapleural-
ly (via the chest tube) or no additional therapy. In patients with stage I disease,
the treatment was highly beneficial. At two years follow-up, 26 of 28 patients
receiving BCG were free of disease (93 per cent) compared with 22 of 33
patients treated by operation only (67 per cent) (p = .009). There was no
apparent benefit for patients with stage II or stage III disease. This result was
not unexpected, since immunotherapy is more effective in patients with
smaller tumor burden. An attempt to confirm these data is in progress in a
multiuniversity prospective randomized trial.
The Albany study emphasizes two important aspects of adjuvant immuno-
therapy: (1) As noted, the best results are obtained in patients with smaller
tumor burden, and (2) the immunoadjuvant works best if it is administered
through the lymphatic bed that drains the tumor. Another study indicated that
repeated courses of intradermal BCG following surgical resection of lung
cancer reduced the recurrence rate in stage I patients at two years follow-up,
but the differences were not as great as those with intrapleural BCG and were
not statistically significant when compared with control patients treated by
operation only. 17 A single dose of intradermal BCG given postoperatively was
not beneficial in this situation. 118
Staging of lung cancer has improved considerably in the last few years. It has
been shown that with careful sampling of lymph nodes, true stage I patients
have an 81 per cent disease-free survival rate at two years, 115 which is much
higher than the 47 per cent listed earlier by the American Joint Committee for
Cancer Staging and End Results Reporting. Nevertheless, if McKnealK's
findings can be confirmed, a significant advance in the treatment of lung
cancer will have been made.
Levamisole has been tested in a prospective randomized trial as an adjuvant
to operation for lung cancer. 119 The initial evaluation of this trial did not show a
significant difference in recurrence or survival rates between the levamisole-
treated patients and a placebo-treated control group. However, careful evalua-
tion of the data revealed that patients weighing less than 70 kilograms showed a
striking and significant difference in favor of the levamisole treatment — at
two years follow-up 71 per cent remained disease free in the levamisole group
compared with 49 per cent in the placebo group. In patients weighing more
than 70 kilograms, there was no difference between the two groups. It appears
that there is a dose response relationship to the immunostimulation. A new trial
has been undertaken in which the levamisole dose is determined by patient
weight (2.5 mg/kg/day) in an effort to confirm the earlier findings. 119
Active specific immunotherapy in the form of a tumor cell vaccine has been
tested as adjuvant therapy for patients with advanced lung cancer at Roswell
Park Memorial Institute. 120 Thirty patients with stage III disease had tumor
resection and irradiation if tumor remained in the bronchus or on the
residual
chest wall. Patients were then randomly assigned to receive either no addition-
al treatment or a vaccine of autologous tumor cells treated with neuraminidase
and concanavalin A administered intradermally in complete Freund's adjuvant

(CFA). The results suggested that the treatment was beneficial: 7 of 15 patients
who received vaccine were alive at a median survival of 35 months compared
with 3 of 15 nonimmunotherapy patients who had a median survival of 12
months. Another study reported similar benefit from soluble lung tumor
antigens given in CFA in combination with adjuvant chemotherapy.
121
In
general, active specific immunotherapy has had relatively little benefit in the
treatment of solid tumors. Thus, the significance of these results can only be
determined by further investigation and confirmation.
A trial of passive immunotherapy for adjuvant treatment of operable lung
cancer has been reported. 122 The study was undertaken because of beneficial
results inanimal studies using tumor-directed antibody in combination with
anticancer drugs. Following operative removal of advanced bronchial carcino-
ma, patients were selected to receive two courses of chemotherapy with or
without xenogeneic antilung carcinoma antibody. There was a trend in favor of
the immunotherapy group for decreased recurrences and increased survival,
but again the significance of the results depends on further investigation with
random allocation of patients to treatment groups and longer follow-up. The
antitumor antibody treatments were well tolerated, and no evidence of tumor
enhancement was noted.
The promise of improved treatment results from these initial trials makes
lung cancer an exciting area for investigation of adjuvant immunotherapy.
Benefit is seen primarily in patients with limited disease, but as chemotherapy
forlung cancer results in greater reduction of tumor burden, applications for

immunotherapy may expand in patients with advanced disease.
Malignant Melanoma
Patients with malignant melanoma metastatic to the regional lymph nodes

(stage II) are at high risk for occult micrometastases in other parts of the body, so
that even after operative removal of these lymph nodes, the risk of systemic
recurrence is very high. The results of intralesional BCG therapy for cutaneous
metastases of malignant melanoma (outlined in the previous section) suggested
that a systemic tumor effect was generated from this treatment. Investigation of
repeated doses of intradermal BCG as an adjuvant therapy for stage II malig-
nant melanoma was initiated at UCLA several years ago, and results were
reported in 1976. 67 At a follow-up of two years, 63 per cent of patients given
BCG following surgical resection of regional node metastases were free of
disease compared with 33 per cent of patients treated by operation alone (p
< .05). This result suggested a clear reduction in the recurrence rate for patients
receiving BCG. Control patients in this study were treated concurrently by
surgery alone, but selection to this group was by patient choice rather than
random allocation.
Based on the results of this trial, a fully randomized prospective study, in
which patients were treated by operation alone, or operation plus BCG, or
operation plus BCG and tumor cell vaccine, was undertaken. The results of this
trial do not confirm the beneficial reduction in recurrence rate seen in the
previous study. The recurrence rate was the same in all three groups at two
years follow-up. 123 However, there was a significant increase in the length of
survival in those patients who had recurrence if they received BCG (23 months
median survival compared with 13 months median survival in the operation
alone group) (Morton, unpublished data). Tumor cell vaccine did not improve
the BCG results. These findings are similar to those from a study done at MD
Anderson Hospital and Tumor Institute. These investigators reported that
repeated doses of intradermal BCG following operative removal of regional
lymph node metastases of malignant melanoma extended survival time signifi-
cantly but did not lower the recurrence rate. 124 The need for improved adjuvant
therapy for this disease is evident, but the findings in these studies indicate that
BCG is beneficial and should be used in the treatment of stage II malignant
melanoma.
The difference in the results of the two UCLA studies illustrates the vagaries
of clinical investigation and the difficulty in controlling variables. However,
there does seem to be a beneficial systemic effect from BCG therapy that is
encouraging and should serve as a stimulus to further investigation. It is
possible that treatment results can be improved by altering the time or method
of BCG administration, e.g., preoperative injection of the primary lesion or
systemic IV injection. Combining immunotherapy with anticancer drugs might
improve results for high-risk melanoma cases, but the drugs for malignant
melanoma are minimally effective and by themselves have not proved benefi-
cial as adjuvant agents. 125 However, a preliminary report from the Massachu-
setts General Hospital suggests that combined BCG and DTIC treatment
reduces the recurrence rate in high-risk melanoma patients. 126 With improve-
ments in both immunotherapy and drug treatment programs, better control of
this disease may be possible.
Breast Carcinoma
Interest in immunotherapy as an adjuvant treatment was encouraged be-

cause cutaneous metastases of breast cancer responded to local immunothera-
py. Since aggressive recurrences of this disease may appear many years
following primary treatment, it is possible that host resistance mechanisms
were active in the interim.
Levamisole is reported to be effective in patients treated by radiation for
advanced breast carcinoma. In a study from Argentina, patients with stage III
disease were treated with 4000 rad and then assigned alternately to receive
either levamisole or placebo. 61 Ninety per cent of the patients taking levami-
sole remained free of disease at 30 months follow-up compared with 35 per
cent of the patients in the placebo group. Those taking levamisole who did
have recurrence experienced a much longer median disease-free interval (25
months) than did the patients taking placebo (9 months). Whether this dra-
matic difference is due entirely to the levamisole is not clear, since the placebo
control group did worse following radiation therapy than might be expected.
In the United States, reported survival figures at 30 months following radiation
therapy for stage III disease were greater than 50 per cent. 127 The method of
patient assignment to the levamisole or placebo groups may have failed to
control adequately for other variables. Nevertheless, the results found in the
levamisole patients are very good and should be investigated further. A full
randomized controlled trial is in progress. 61
Significant reductions in the recurrence rate in patients receiving adjuvant
chemotherapy following operation for stage II breast carcinoma have been
reported in two major trials. However, in these studies, it appears that post-
menopausal patients do not benefit from adjuvant chemotherapy. 128 129 A clini-
'
cal trial that is in progress at UCLA shows an apparent reduction in the

recurrence rate for this group, which is receiving adjuvant cyclophosphamide,
methotrexate, and 5-FU, plus repeated intradermal BCG (Sparks, unpublished
data). Unfortunately, this study is not adequately controlled for patients receiv-
ing chemotherapy only, so the effects of the BCG cannot be fully evaluated. A
similar trial of adjuvant chemoimmunotherapy has been reported from MD
Anderson Hospital and Tumor Institute. After all gross disease is removed,
patients with stage II, stage III or stage IV breast cancer are given 5-FU,
doxorubicin, and cyclophosphamide (FAC) chemotherapy plus repeated in-
tradermal BCG. A significant improvement in survival and the disease-free
interval is reported for nearly all groups tested compared with historic con-
130, in
trols. However, once again, there is no control group for the immunothera-
py, so its contribution is unknown. The role of immunotherapy in adjuvant
treatment for breast cancer must be evaluated, and it is essential that adequate-
ly controlled trials be performed. These studies are in progress at UCLA and
MD Anderson Hospital 130 (Sparks, personal communication).
Colorectal Carcinoma
A trial
of adjuvant immunotherapy following surgical resection of colorectal
carcinoma has been reported by Mavligit and colleagues from MD
Anderson
Hospital and Tumor Institute. 132 Following operation, patients with Dukes
stage C disease were randomly assigned to receive repeated intradermal BCG
or this therapy plus oral 5-FU. These patients were compared to historic
controls treated by operation alone. The longest follow-up was 42 months;
median follow-up was less than 2 years. There were no differences in results
between the two adjuvant groups, but when compared with the historic
controls, there was a significant increase in the disease-free interval and length
of survival by several months. The results of this study are potentially very
important, but benefit from adjuvant treatment of any kind is unproved in
colorectal carcinoma, and the survival figures were too similar to draw conclu-
sions without confirmation in a more stringently controlled trial.
Sarcomas
Sarcoma patients show strong immune responses to their tumors, suggesting

that stimulation of host resistance would be beneficial for treatment. 133 Howev-
er, adjuvant immunotherapy with BCG plus tumor cell vaccine has been
unsuccessful in osteosarcoma patients. 134 Osteosarcoma is a biologically agres-
sive tumor that probably overwhelms even the most stimulated host defenses.
It disseminates very early in the course of disease, and even after the primary is
completely resected, there is probably a large tumor burden of micrometas-

tases. A combination of active tumor immunization and adoptive transfer of
immune cells also showed no benefit in a controlled trial. 135 Transfer factor has
been reported to produce palliation in patients with osteosarcoma, but these
were uncontrolled studies. 80
Fortunately, potent adjuvant chemotherapy has improved the prognosis for
osteosarcoma patients. 136, 137 Recurrence rates are decreased and the disease-
free interval increased following operation. Presumably, a significant reduc-
is
tion of tumor burdenis achieved with drug therapy, and this may provide a new
opportunity for adjuvant immunotherapy given either in combination with the

drugs or following the period of intensive chemotherapy. In a current UCLA
trial, patients are given high-dose methotrexate and doxorubicin following
operative removal of the primary tumor. In addition, half the patients receive
repeated intradermal BCG by random selection. There appears to be a slight
trend in favor of the BCG group, but it is too early in follow-up to draw
conclusions (Eilber, unpublished data).
Adjuvant immunotherapy for the treatment of soft-tissue sarcomas has yield-
ed somewhat better results. A controlled trial reported by Townsend and
colleagues from UCLA 70 showed that intradermal BCG and allogeneic sarcoma
cells reduced the two-year recurrence rate following resection of these tumors.
For stage I and stage II patients, the recurrence rate in the immunotherapy
group was 39 per cent compared with 67 per cent for patients treated by
operation alone. This difference was not statistically significant. The study was
not randomized, so benefit from adjuvant immunotherapy in this setting has not
been established. Combination chemoimmunotherapy following surgical re-

section of soft-tissue sarcomas is under investigation also (Eilber, unpublished
data). Potentially, the two forms of adjuvant treatment could be complementa-
ry. However, despite the demonstrated immunogenicity of sarcomas, a role for
immunotherapy in the treatment of these tumors has yet to be defined.
Head and Neck Cancer

Patients with squamous cell carcinoma of the head and neck have defects in
their immunologic function that are particularly evident by in vitro testing. 139
Levamisole appears to be immunorestorative in these patients. In a trial at the
Memorial Sloan-Kettering Cancer Institute, patients were randomly selected
to receive either levamisole or a placebo following complete resection of
tumor. 140 In the levamisole group, the median time to recurrence has not been
reached, and 82 per cent of patients were free of disease at 12 months. Patients
in the placebo group showed a median time to recurrence of 9 months, with
only 34 per cent remaining free of disease at 12 months. These preliminary
results suggest that levamisole was beneficial and, if confirmed in more exten-
sive testing, would lead to an advance in treatment of this disease. These
findings support the beneficial results reported for levamisole as adjuvant
therapy for lung and breast cancers.
Conclusions
The most important immunotherapy may be as adjuvant treatment,

role for
since its potency is Immunotherapy may extend the benefit derived
limited.
from treatments that substantially reduce tumor burden but cannot eliminate it.
The data from the trials suggest that a systemic effect on occult micrometastases
can be achieved. However, the major effect from nonspecific immunostimula-
tion seems to be an increase in the survival rate rather than a decrease in the
recurrence rate. This finding suggests a cytostatic rather than a cytotoxic effect
on tumor cells. Nevertheless, the results from intrapleural administration of
BCG in early lung cancer indicate that a potential exists for the elimination of
occult metastases. It may be possible to increase the potency of immunothera-
py or to use it in combination with drugs to achieve improved benefit. Clearly,
there are enough good results to warrant further investigation.
CHEMOIMMUNOTHERAPY FOR
DISSEMINATED MALIGNANT
DISEASE
Immunotherapy is of limited value as the sole treatment for disseminated
malignant disease. Although it is possible to achieve remissions, the proce-
dures are logistically difficult and potentially toxic, and the response rates are
low. An example of this type of therapy is the pairing of patients with advanced
similar cancers in order to crosstransplant their tumors. The patients then

exchange leukocytes which presumably contain cells sensitized to the trans-
planted tumor. Response rates of 15 per cent, including some complete re-
sponses, are consistent in clinical trials of this technique. 76, 141 However,
because of sensitization of HLA antigens, serious transfusion reactions occur,
and some deaths have been reported. 76 A more fruitful endeavor may be the
addition of immunotherapy to chemotherapy for the treatment of disseminated
disease. Chemotherapy attacks cell processes that are essential to normal
immune function. However, it has been shown that the immunosuppression is
temporary, and with intermittent drug administration the patient's immune

system can function normally most of the time. 141 142 Thus, stimulation of host
'
resistance in combination with chemotherapv to treat malignant disease is feas-

ible.
Solid Tumors
Beneficial results have been reported from the addition of immunotherapy to

chemotherapy for a variety of solid tumors. Unfortunately, many of these
reports could not be confirmed. Subcutaneous administration of Corynebac-
terium parvum added to five-drug chemotherapy (cyclophosphamide, 5-FU,
methotrexate, vinblastine, streptonigrin) appeared to extend the median
survival by several months in patients with disseminated lung cancer when
compared with patients treated with the same drugs alone. 51 A more recent
study of intravenous administration ofC. parvum in a combination with drugs
for the same disease showed considerable toxicity with no benefit from immu-
notherapy. 53 For disseminated malignant melanoma, repeated intradermal
administration of BCG added to DTIC drug therapy reportedly improved the
response rate from 14 per cent for DTIC alone to 27 per cent for the combina-
tion therapy. 143 However, the beneficial effect from intradermal BCG in this
situation has not been confirmed in other studies. 144 145 In the treatment of
'
advanced gastrointestinal cancer, initial studies with the methanol extractable

residue of BCG (MER) indicated that this agent combined with chemotherapy
improved response rates, but these findings were not sustained in a subsequent
investigation. 146
Gutterman and colleagues from MD
Anderson Hospital and Tumor Insti-
tute 52
have investigated combined IV C. parvum, DTIC, and dactinomycin for
the treament of disseminated malignant melanoma. They reported an overall
response rate of 41 per cent for the combined treatment, plus a prolongation in
survival for responders compared with nonresponders. This response rate is
higher than that generally reported for drug treatment alone in this disease.
Although the results are promising, the regimen is rigorous, and side effects of
IV C. parvum are significant.
Patients with disseminated breast cancer who were given C. parvum subcu-
taneously with five-drug chemotherapy (cyclophosphamide, 5-FU, methotrex-
ate, vinblastine, streptonigrin) survived several months longer than pa-
tients given the same drug alone. 51 However, no benefit could be demonstrated
for similar treatment with subcutaneous C. parvum and anticancer drugs for
this disease in a study done at Memorial Sloan-Kettering Cancer Institute
150 I / General Prim hi i
-
(Pinsky, personal communication). Investigators from MD

Anderson Hospital
and Tumor Institute tested repeated intradermal BCG in combination with
FAC chemotherapy for disseminated breast carcinoma. The study was se-
quential in that the initial 44 patients were given chemotherapy only, and the
next 45 patients were given chemotherapy plus BCG. The results showed a
significant improvement in median survival by several months for the ehemo-
immunotherapy patients, but these were preliminary results."'- Mercurio and
colleagues 147 found that neither BCG nor C. parvum improved response rates
to FAC for advanced disease.
Preliminary results from a randomized trial of BCG plus doxorubicin and
cyclophosphamide for advanced ovarian carcinoma were promising. 148 The
response rate in patients given chemoimmunotherapy was three times that for
drugs alone (66 per cent versus 22 per cent), and the length of survival was
significantly improved. Another trial of combined BCG and chemotherapy for
ovarian carcinoma also showed beneficial results, but this was in comparison to
historic controls. 149 Intravenous C. parvum in combination with chemotherapy
appeared to improve treatment results for ovarian carcinoma in initial studies,
but the findings were not supported in a subsequent randomized trial. 150
Results from two trials suggested that combined chemoimmunotherapy was
beneficial for advanced head and neck cancer. In a study from MD Anderson
Hospital and Tumor Institute, all patients with recurrent squamous cell carci-
noma of the head and neck were given five-drug chemotherapy (bleomycin,
doxorubicin, CCNU, vincristine, and mechlorethamine) and randomized to
receive either intradermal BCG or no additional treatment. 151 Median survival
was significantly longer in patients who received BCG therapy (30 weeks
compared with 13.5 weeks for those treated with drugs only). A study at
Northwestern University showed a similar trend in head and neck cancer
patients receiving BCG and tumor cell vaccine in addition to drug thera-
152
py.
Whether or not there is combined chemoimmunotherapy in the
a role for
treatment of disseminated solid tumors has not been established. It is probably
true that chemotherapy must significantly reduce tumor burden before an
effect from immunotherapy can be seen. Because of the relatively low toxicity
of immunotherapy and its potential for eliminating a small residual tumor
burden, it is reasonable to continue testing this combined treatment.
Leukemia
In 1969, Mathe and colleagues 27 encouraged investigations of immunothera-

py for the treatment of leukemia patients. Their work indicated that immuno-
therapy was beneficial for patients with acute lymphoblastic leukemia. This
study showed a marked improvement in the duration of remission in patients
given BCG and allogeneic leukemia cells as maintenance therapy. These
beneficial results in ALL have not been confirmed in other studies, however,
and the chemotherapeutic treatment of the disease has improved in the
interim. A recent prospective randomized trial from the NCI showed that the
results with the addition of BCG and allogeneic leukemia cells to maintenance
chemotherapy were no better than those with drug treatment alone. 153
For patients with acute myelogenous leukemia, BCG plus allogeneic leuke-
mia cells added to maintenance chemotherapy improved the duration of
remission and survival in several clinical trials. 69, 154, 155 However, this approach
has produced negative results in equally good studies. 156, 157 There are some
promising, innovative approaches to immunotherapy for AML, however. Leu-
kemia cells treated with the enzyme neuraminidase are more potent stimula-
68
tors of antitumor immunity than untreated cells. Neuraminidase cleaves sialic
acid from glycoproteins on the cell surface, possibly increasing antigen expo-
sure. Neuraminidase-treated leukemia cells, in combination with maintenance
chemotherapy, have been tested in a randomized trial of AML patients. 158 At
one-year follow-up, 60 per cent of patients receiving the chemotherapy only
had relapsed, whereas 70 per cent of patients on maintenance chemoimmuno-
therapy remained in remission. Confirmation of these results would mean a
major advance in the treatment of AML.
In studies of local immunotherapy it is apparent that contact between the
immunoadjuvant and the tumor cell is essential for tumor destruction. In
clinical trials with ALL and AML, intradermal BCG therapy results in clearing
of the BCG in the regional lymph nodes. Based on the possibility that contact of
BCG with tumor cells in the bone marrow would increase and augment host
resistance mechanisms, a trial of IV BCG in AML was initiated. 159 AML
patients who were brought into remission with drug treatment were given
maintenance chemotherapy, and half the patients were randomly selected to
also receive IV BCG. Intravenous antihistamines were given to prevent an-
aphylactic responses to the BCG. Survival times were significantly longer in
the BCG-treated patients than in those given drugs only, and the IV BCG was
well tolerated. This departure from the conventional route of administration is
a promising avenue for investigation.
There are enough positive results from clinical trials of immunotherapy for
leukemia that its role in the management of this disease must be defined. The
new approaches being tested make it an exciting area for investigation.
SUMMARY AND CONCLUSIONS

Expectations for dramatic effects from immunotherapy in malignant disease
have been very high, but results of the many clinical trials have not met these
expectations. This outcome was probably predictable, since host resistance
mechanisms can control only limited amounts of tumor. Nevertheless, host
resistance to naturally occurring malignancies appears to be a legitimate
biologic phenomenon. This phenomenon is best demonstrated in clinical trials
of immunotherapy. Trials indicate that stimulation of host resistance can help
control neoplastic disease, particularly when systemic tumor burden is limited.
The production of local DCH responses is effective treatment for skin cancers
and cutaneous metastases of breast carcinoma and malignant melanoma. A
significant systemic antitumor effect derived from these treatments appears to
be evident, but it is far from established. However, occult systemic microme-
tastases appear to be suppressed by adjuvant immunotherapy for early lung
cancer and possibly for malignant melanoma. The same may be true for breast
cancer, colorectal carcinoma, sarcomas, and head and neck cancer, although
these results need to be reproduced.
Combined chemoimmunotherapy for the treatment of disseminated solid
tumors has shown very little benefit. Although some current trials are promis-
ing, there have been no studies confirming the effectiveness of this approach.
This difficulty may result from the failure of drug therapy to reduce the tumor
burden to a level at which host resistance mechanisms can gain control. In
studies of AML, there is a suggestion at least that immunotherapy improves the
results of chemotherapy. In this situation, the combination treatment is used to
maintain remission, at which time the tumor burden is at its lowest. Advance-
ments in drug therapy may achieve more effective reduction of disseminated
solid tumors, so that an additive effect from immunotherapy may become evi-
dent.
Although based on the concept of specific immunity to tumor-specific trans-
plantation antigens, the approach to immunotherapy of human neoplasia has
been strictly empiric. As indicated, the animal models may not be an accurate
reflection of naturally occurring human malignancies. Nevertheless, beneficial
results have been obtained in clinical trials from the stimulation of host
resistance mechanisms. If immunotherapy is to advance, these mechanisms
must be defined. The majority of gains from immunotherapy have come from
the use of nonspecific stimulators —
BCG, C. parvum, and levamisole. Active
specific immunotherapy, in the form of tumor cell vaccines that were expected
to directly elicit specific antitumor immunity, has shown no conclusive benefit
for the treatment of solid tumors in any clinical trial. The relative contributions
of nonspecific resistance mechanisms versus specific immunity in host resis-
tance to neoplasia must be explored. Animal models that more closely resem-
ble human neoplasia must be developed. The continued investigation of
host-tumor interactions is essential.
A problem that is intimately intertwined with the investigation of host
resistance mechanisms is the development of accurate monitors of immuno-
therapy. A test of immune function that clearly correlates with the clinical
course of patients treated with immunotherapy is needed. At this time, the
response of patients on immunotherapy is determined by whether they have
recurrence less frequently or survive longer than comparable patients who do
not receive immunotherapy. Although this is the most important test of a
therapeutic modality, it is an end point that is reached slowly. Clinical trials
could be completed much more rapidly and many patients spared unneces-
sary treatment if accurate monitors of immunotherapy were available.
Despite the relative impotence of immunotherapy in its present form, there
are some promising avenues for investigation. Preoperative local immunother-
apy may prove to be an effective adjuvant treatment. Active specific immuno-
therapy may yet be effective if the results of the neuraminidase-treated
leukemia cells for AML can be confirmed. Systemic administration of
immunoadjuvants may be the best means of stimulating the reticuloendothelial
system, which could be the essential feature of host resistance to neoplasia.
Immunotherapy's major role may be the systemic control of small amounts of
tumor. Many treatment failures are the result of incomplete control of occult
systemic micrometastases. The obvious alternative for systemic control of
disease is chemotherapy, but there are still relatively few diseases that can be
effectively suppressed or eradicated with the drugs available at the present
time. Advances both forms of therapy are badly needed.
in
The efficacy of cancer treatmentis being subjected to stringent review. This
is as it should be. It is significant that under these circumstances, immunothera-
py has clearly shown beneficial results for selected cancer patients. It is

reasonable to expect that, with a refinement of concepts of the host-tumor
relationship and careful clinical investigation based on these concepts, immu-
notherapy will become an effective arm of a multimodality attack on malignant
disease.
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139. Zighelboim J, et al: Cancer 44: In 159. Whirtaker JA and Slater AJ: Br J Haema-
press. 1979. tol 35:263, 1977.
Part II
TREATMENT
OF SPECIFIC
NEOPLASMS
CHAPTER 7
BREAST CANCER
Charles M Haskell Frank C Sparks
Ronald W Thompson
INTRODUCTION
Breast cancer is common malignant neoplasm in women. In the
the most
United States 1 out of every 14 women (7 per cent) is likely to develop the
disease, and 1 out of every 4 women with cancer will have breast cancer. 1,2
There are approximately 90,000 new cases each year and 34,000 deaths
caused annually by this neoplasm. Among women between the ages of 35 and
54 years, breast cancer is the leading cause of death, and among those in
subsequent years, it is second only to heart disease.
The annual mortality rate from breast cancer has not changed in recent
years despite improvements in medical management. Misinterpretation of
this findinghas resulted in the gloomy conclusion that there has been little
progress in the therapy of breast cancer in the past three decades. Actually,
the duration of survival for most women has improved modestly over the past
four decades, but a rising incidence of breast cancer has resulted in a stable
annual mortality rate.
Indeed, steady progress is being made, and we predict continued improve-
ments management of breast cancer. Some of the factors contributing to
in the
this prediction include the following: (1) mammography may diagnose cancer
earlier and perhaps increase "true" survival; 3,4 (2) we are becoming more
sophisticated in identifying high-risk patients who might benefit from more
intensive screening or even "prophylactic" therapy; 5,6 (3) primary treatment
options that are less deforming than radical mastectomy are more frequently
used and are under intensive study in the hope that more women will seek
care earlier in the natural history of the disease, when it is more treatable;
7, 8
(4) it appears that reconstructive surgery may have a place following mastec-
tomy in some patients; 9, 10 and (5) systemic adjuncts to local treatment are
under active study as a possible means of increasing survival. 11, 12 Clearly,
there is a better appreciation of the biology of breast cancer by many physi-
cians, and both patients and physicians are increasingly willing to participate
in controlled studies to help answer some of the unresolved questions that are
impeding progress.
159
160 II / Treatment of Specific Neoplasms
Epidemiology and Etiology
The etiology of breast cancer is unknown. A variety of interrelated genet-

13 14 15
ic, hormonal, environmental, sociobiologic, 16, 1? and physiologic fac-
18, 19
tors exert an influence on the development of this disease. A positive
family history increases the risk, but in first-degree relatives (mother, sister, or
daughter) the risk is dependent upon whether the cancer was bilateral and
whether it occurred in the pre- or postmenopausal period. 20 When the relative
had breast cancer in the premenopausal period, the risk is approximately
three times higher than in control subjects. However, when the relative had
breast cancer in the postmenopausal period, the risk is only about 1.5 times
higher than that of controls. Among relatives of women with bilateral breast
cancer, the risk is 5.4 times that of controls. Relatives of women with premen-
opausal and bilateral breast cancer have an approximate 8.8 times greater risk,
and in those with postmenopausal bilateral breast cancer the risk is 4 times
greater. 20
International differences in the incidence of breast cancer and mortality
rates and studies of migrating populations point to the importance of environ-
mental factors in the etiology of breast cancer, especially high total fat intake
and high saturated fat intake. 15
Hormonal regulation of the breast is important in the development of breast
cancer. Early pregnancy and early oophorectomy lower the incidence of this
neoplasm, whereas late menopause is associated with an increased incidence
of breast cancer. However, attempts to define and quantify the endocrine
factors thatpromote or contribute to breast cancer have proved difficult. 14 No
clear-cut pattern of hormonal imbalance has been widely accepted. Differ-
ences in estriol excretion in women have been associated with an increased
risk of breast cancer, but this may be a spurious association resulting from
alterations in steroid metabolism that are secondary to age, the use of oral
contraceptives, sampling errors related to menstruation, or other unknown
factors. Oral contraceptives may decrease the incidence of certain types of
21
mammary dysplasia and are not associated with an increased incidence of

breast cancer. 17 However, estrogens that are given to relieve menopausal
symptoms may increase the incidence. 22
These are only a few of the myriad factors that have been studied in the
hope of unraveling the mysterious development of this tumor in so many
women. The reader who is interested in a more detailed discussion of this
fascinating problem is referred to reviews of the subject. 5, 23, 24
Davies et a/. 5 have developed an interesting and potentially useful method
of estimating the quantitative impact of five prognostic factors on the risk of
dying from breast cancer during a ten-year period for women of different ages.
Although the technique is yet to be fully validated, its and potential
simplicity
clinical value warrant further comment. To use their method, one must es-
tablish, from Table 7-1, the quantitative value of each of five risk factors (RF)
for the patient. Each risk factor is a standardized estimate of the relative risk of
that factor in the individual compared with that in the general population. The
product that is obtained by multiplying each of these factors by the other is
called the composite risk factor or CRF. If one multiplies the CRF by the age-
7 / Breast Cancer 161
TABLE 7-1. Relative Risk (RF) of Breast Cancer for Five Selected
Prognostic Characteristics by Age°
RF for Current Ace (Yrs)

Characteristic
40-44 45-49 50-54 55-59 60-64 40-64
Family history of breast cancer

None .91 .91 .89 .88 .87 —
1 cancert 2.03 2.00 1.97 1.95 1.94 -
2+ cancers t 3.14 3.10 3.06 3.02 3.00 —
Pregnancy history
No term pregnancy
<20 yr old at 1st term pregnancy, with 1.43
1 term pregnancies
to 2 .66
3+ term pregnancies .33
20 to 24 yr old at 1st term pregnancy, with
1 to 2 term pregnancies .94
1 to 2 term pregnancies 1.21
35+ yr old at 1st term pregnancy, with
3-1- term pregnancies .89
History of benign breast disease

Present 3.57
Absent .71
Menstrual status
Still menstruating 1.11 1.26 2.11 2.97
Natural menopause age:
<45 yr .37 .41 .54 .68 .68
45 to 49 yr .84 .88 1.10 .95
50+ yr .79 1.03 1.10
Surgical menopause age:
<35 yr .25 .27 .27 .34 .28
35 to 39 yr .47 .52 .54 .68 .46
40 to 44 yr .70 .78 .59 .74 .39
45 to 59 yr .56 .77 .97 .45
50+ yr .75 .94 1.22
History of annual breast examination or

recent self-examination
Yes .83
No 1.32
"Modified from Table 7-2, in Davies DF, et al.J. Natl Cancer Inst 60:1519, 197)
t Among mothers, sisters, or aunts.
adjusted ten-year risk of death from breast cancer for the normal population
shown in Table 7-2, one has an estimate of the ten-year incidence of death
from breast cancer in women with the characteristics utilized in the calcula-
tion. For example, a 42-year-old menstruating woman (RF 1.11) with a strong
family history of breast cancer (RF 3.14), with one term pregnancy at age 32
(RF 1.49), with a history of benign breast disease (RF 3.57), and with no breast
i62 II / Treatment of Specific Neoplasms
TABLE 7-2. Risk of Dying from Breast Cancer Within

10 Years of Current Age
Age (Years) Deaths/ 100,000 Women

25-29 40
30-34 102
35-39 195
40-44 350
45-49 525
50-54 686
55-59 799
60-64 849
65-69 912
70-74 1001
"Based on tables by Geller and Steele, in Davies DF, et ah] Natl Cancer Inst 60:1519, 1978.
Data are combined for black and white women.
examination within the last year (RF 1.32) has a CRF of 24.47 (1.11 x 3.14 X
1.49 x 3.57 X 1.32). The ten-year risk of death from breast cancer for the pa-
tient's age would be 350/100,000 (Table 7-2), but the adjusted risk would be
8564 cases/ 100,000 people or 8.56 per cent. This extremely high risk would
suggest the need for especially careful observation of this patient.
Biology
The Tumor Doubling Time. The concept of the tumor doubling time
(TDT) is useful in estimating the duration of the preclinical stage of breast
cancer and in understanding the clinical course of the disease. The TDT is a
function of many variables, e.g., rate of cell division, proportion of cells
actively dividing, rate of cell death, proportion of tumor composed of cells as
opposed to fibrotic tissue, intermitotic interval, tumor burden, desquamation,
dormancy, and effects of therapy.
Kusama et al. 25 found a direct correlation between the tumor doubling time
and the duration of survival after radical mastectomy. Gershon-Cohen et a/. 26
reported that the average tumor doubling time was 128 days in patients with
negative axillary node involvement and 85 days in patients with positive
axillary node involvement. In addition, it appears to make a great deal of
difference whether the tumor doubling time is being measured in early breast
TABLE 7-3. Doubling Times of Breast Carcinomas
Doubling Times (Days)

Site Reference
No Pts Min Max Mean
18 23 209 117 Primary tumor Gershon-Cohen et al. 26

28
16 45 260 122 Primary tumor Herman utz et al.
78 3 211 40 Skin metastases Philippe and Le Gal 29
40 3 86 17 Soft tissue Lee and Spratt50
29 16 426 82 Lung metastases Sprattand Spratt31
6 23 745 69 Lung metastases Breur32
7 45 330 143 Lung metastases Sparks and Alberts 33
cancer or in late breastcarcinoma. In a comprehensive review of this subject,

Shackney and others have shown that early breast cancer has a mean dou-
27
bling time of 25 days, whereas late breast cancer has a mean doubling time of
129 days. The difference in mean doubling time in early and late breast
cancer is statistically significant (p < 0.0001), providing convincing documen-
tation of growth retardation advanced human tumors (so called Gompert-
in
zian growth, as discussed in Chapter 4 and as illustrated in Figures 1-2 and
4-5). Table 7-3 gives the tumor doubling times in breast cancer, as culled
from a variety of reports. 2H 2S 33
-
-
A 1-cm "early" breast cancer contains 10 9 cells and has already undergone
30 of the 40 doublings that occur prior to the woman's death. The tumor
doubling time of primary breast cancer varies from 23 to 209 days for early
27
lesions, but in advanced lesions it may exceed 500 days. Multiplying the
usual tumor doubling time by 30 doublings, we see that the 1-cm "early"
breast cancer may have been present for 2 to 17 years prior to diagnosis.
Despite the uncertainty of applying the TDT to such estimates, we consider it
likely that: (1) Many months or years pass between the onset and clinical
detection of all breast cancers. (2) Metastasis has ample time to occur before
the primary lesion is detectable. (3) Even "early" breast cancer may not be
cured by either surgery or radiation therapy.
The natural history of untreated breast cancer suggests that it is an acute or
chronic disease, depending upon the tumor doubling time. 54 Daland 35 report-
ed an average survival from first symptoms of 40 months in 100 untreated
patients. The median survival was 2.5 years; 22 per cent of the patients were
alive at the end of 5 years, and 5 per cent were alive at 10 years. The "chronic"
forms of breast cancer result from tumors with the longest tumor doubling
times. In contrast, about 20 per cent of untreated cases survive less than one
year from the first symptoms, and this fraction represents those with the more
rapid tumor doubling times.
Breast Cancer as a Systemic Disease. In the majority of women,
breast cancer appears to be a systemic disease at the time it is first diag-
nosed. 36 Contrary to previous belief that breast cancer universally spreads in a
stepwise fashion from the primary tumor to the lymph nodes and then to
distant sites, breast cancer can bypass lymph nodes and spread directly to the
bloodstream. Indeed, breast cancer can present as a metastasis without any
evidence of a primary tumor. 37,38
The concept of breast cancer as a systemic disease is not new. In 1896,
Beatson 39 suggested that "the tumor in the breast is only a local manifestation
of a blood affection." More recently, Mueller and Jeffries 40 reported that 80 to
85 per cent of all women who die after developing breast cancer die of their
breast cancer and that the rate of dying is constant up to 15 years following
operation. If breast cancer were truly a localized disease susceptible to cure,
one would expect the survival curve to eventually show a plateau. Unfortu-
nately, this probably does not occur. 40,41 Since breast cancer is a systemic
disease in the majority of women at the time of diagnosis, it is not surprising
that varying the extent of operation or adding one regional modality (radiation
therapy) to another modality (operation) fails to increase the survival rate in
the vast majority of studies.
Microscopic or histologic cancer does not always progress to clinical cancer,

and even advanced breast cancer may rarely undergo spontaneous regres-
sion. 42 Although the pathologist can frequently find histologic evidence of
multiple lesions in the breast, the presence of two or more clinically apparent
cancers in one breast is rare. 43 Also, the incidence of clinically apparent
cancer developing in the opposite breast is much lower than the incidence of
histologic cancer detected by "mirror image" biopsy or autopsy. Finally, the
frequency of tumor growing in untreated axillary nodes is much lower than
would be expected based on the frequency of regional node involvement in
patients undergoing radical mastectomy. 44, 45 All these factors further serve to
complicate attempts to assess the natural history of breast cancer in individual
patients and to devise rational plans of therapy.
Estrogen (ER) and Progesterone Receptors (PgR) In Breast Can-
cer. Beatson's 39 demonstration of hormone responsiveness in mammary car-
cinomas in 1896 led to the important principle that neoplasms retain some of
the differentiated functions of the tissue of origin. Endocrine organ ablation
and hormonal manipulation have been widely used in the treatment of meta-
static breast cancer. The biologic basis for such benefit has only recently been
defined through the demonstration that steroid hormone action depends upon
specific binding to high-affinity cytoplasmic receptors that have great specific-
ity for the hormone. 46 48 The mechanisms involved are also discussed in
"
Chapter 5 and are illustrated in Figure 5-15. Their practical value in making
therapeutic decisions is discussed subsequently in this chapter.
Books and reviews of estrogen receptors and progesterone receptors as they
relate to breast cancer and other tumors are available for the reader who is
interested in more details. 46-48 In addition, it should be noted that these
assays are clinically available in all major cities, and it is strongly recommend-
ed that determinations of estrogen receptors and, if possible, progesterone
receptors be made on breast cancer tissue whenever feasible for their poten-
tial value in making therapeutic decisions. Since these determinations can
only be performed on freshly frozen tissue, the surgeon performing such

biopsies must not place specimens directly into formalin. Rather, the portion
of the biopsy to be processed for ER or PgR should be carefully trimmed of
normal tissue and promptly frozen for shipment to a laboratory that is quali-
fied to perform the study. 49
NATURAL HISTORY
Classification (Pathology)
Most breast cancers are adenocarcinomas arising from the ductal or lobular
43
epithelium. The relative incidence, some clinical features, and the survival
data for the various forms of breast cancer are listed in Table 1-4l. 50 Patients
with infiltrating ductal carcinoma and infiltrating lobular carcinoma — the
two most common forms of breast cancer —
have similar prognoses. Inflam-
matory carcinoma of the breast deserves special mention because of its ex-
tremely poor prognosis. This form of breast cancer is characterized by inflam-
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matory changes in the skin overlying the breast that are secondary to
extensive dermal lymphatic spread. 51,52
Clinical Features and Diagnosis
Most breast carcinomas by the patient when a painless mass

are discovered
in the breast is noticed. Less commonly, the tumor may be discovered by a
physician at examination or on a screening mammogram.
The cancer is most often a hard mass with an irregular border, but it may
present as an area of thickening in what appears to be a physiologic nodularity
of the breast. Breast pain, skin dimpling, and nipple discharge, retraction, or
erosion occasionally lead to the diagnosis. Fixation of the cancer to the skin or
pectoral fascia, as well as skin edema or ulceration, satellite nodules, and the
presence of large axillary metastases are all signs of more advanced breast
cancer and are seen less frequently at present than in the past. 53
The accuracy of diagnosing a breast cancer on physical examination in-
creases as the patient's age increases. The diagnostic accuracy in premeno-
pausal women may -be as low as 30 per cent. Because of the inaccuracy of
clinical diagnosis, any woman with a dominant mass in her breast should have
the mass either biopsied or aspirated. Aspiration frequently removes the need
for biopsy and should be considered in every case. The details and principles
"
of aspiration and biopsy are well described in widely available reviews. 53 55
Whenever possible, tumor tissue should be tested for the presence of ER and
PgR, as discussed previously. 46 48
"
Controversy surrounds the potential value of screening mammograms in

patients who are less than 50 years of age. 4 The National Cancer Institute
carefully considered the wisdom of this diagnostic method and, following an
expert panel review, has recommended that screening mammograms in
asymptomatic women be restricted to those over 50 years of age. Indications
for mammograms younger patients include strong family history of breast
in
cancer, previous diagnosis of breast cancer, or suspicion of breast disease on
the part of the patient or the physician. When available, yearly mammograms
3,
after the age of 50 years have been recommended. Although this is not
always feasible, it should be possible to obtain at least a single mammogram
on nearly every woman over this age in an attempt to assess whether or not
breast disease exists. Wolfe 56 has suggested that certain patterns of mammo-
graphic change may be associated with a high incidence of cancer. If these
patterns are found, one would clearly need to follow the patient closely for the
development of an occult or early carcinoma.
An alternative approach to assessing the need for a yearly mammogram
would be to calculate the adjusted risk of breast cancer in the patient, as
described previously, using the method of Davies et al. 5 If the risk is substan-
tially greater than that seen in the average 50-year-old woman (i.e., >686
cases/100,000 population, as taken from Table 7-2), one is probably justified
in using every available technique for early diagnosis. If the risk is lower than
average, even if the patient is more than 50 years old, yearly mammograms
would not be needed. This approach appears to be sensible, although it has

not been widely tested and has not received governmental sanction.
In general, thermograms 47 and ultrasound 58 and intensive efforts to encour-
age women to undergo regular self-examination of the breast 59 have proved
difficult to evaluate, unuseful, or difficult to achieve.
Staging
Once a histopathologic diagnosis of breast cancer has been made, it is
the clinical stage (CS) of the disease. The clinical staging

critical to establish
system developed at Columbia University by Haagensen 53, 60 has been widely
used for many years, but it has more recently been supplanted by the
TWI (tumor-nodes-metastasis) system, as recommended by the American
Joint Committee for Cancer Staging and End Results Reporting.
61
A major
advantage of the TXM system is that it allows clinical staging prior to defini-
tive surgical or radiation therapy, as well as surgical evaluative or postsurgical
treatment classification using the results of the histologic examination of
resected tissue. 61,62 Tables 7-5 and 7-6 provide the recommended TXM
system and stage groupings for the reader's reference.
The extent of the preoperative or preradiation therapy evaluation depends
on the initial clinical stage of the patient. In patients with clinical stage I
disease and no symptoms of metastases, a chest x-ray, mammogram, complete
blood count, and screening blood chemistry panel (such as the SMA-12) are
63 65
sufficient. A bone scan is not necessary,
"
and a liver scan is not obtained
unless symptoms or liver function tests suggest metastases. 66 In patients with
clinical stage II disease, a bone scan is recommended, but a liver scan is not
ordered unless symptoms or liver function tests suggest metastases. In pa-
tients with clinical stage III or stage IV disease, both a bone scan and liver
scan are recommended, as well as any other test that is required to define the
meaning of the symptoms. A bone marrow biopsy is generally unnecessary,
unless the patient has unexplained bone marrow dysfunction. 67
Prognosis
The survival rate of patients with breast cancer correlates poorly with the
histopathologic type of disease (Table 7-4), 50 but the correlation is good
between prognosis and the TXM
clinical classification.
62
Even greater preci-
sion can be achieved if the patient's primary therapy involves an axillary* node
dissection, since the histopathologic evaluation of these nodes provides im-
portant prognostic information. This is clearly demonstrated in Table 7-7,
which presents the prognoses of patients undergoing radical mastectomy in a
large series treated by the Xational Surgical Adjuvant Breast Program
(XSABP). 68 69
'
TABLE 7-5. TNM System for Clinical or Pathologic Staging of

Breast Cancer 61
T (Primary Tumor)
T : No demonstrable tumor in the breast
TIS: Paget's disease of the nipple with no demonstrable tumor;

carcinoma in situ
T,:° Tumor 2 cm or less in its greatest dimension
T Ia : With no fixation to underlying pectoral fascia and/or muscle

T, b : With fixation to underlying pectoral fascia and/or muscle
T 2
:° Tumor more than 2 cm but not more than 5 cm in its greatest dimension
T2a : With no fixation to underlying pectoral fascia and/or muscle

T2b : With fixation to underlying pectoral fascia and/or muscle
T3 :° Tumor more than 5 cm in its greatest dimension
T3a With : no fixation to underlying pectoral fascia and/or muscle

T3b With : fixation to underlying pectoral fascia and/or muscle
T 4 : Tumor of any size with direct extension to chest wall or skin (chest wall in-
cludes muscles, and serratus anterior muscle, but not
ribs, intercostal
pectoral muscle)
T4a With fixation to chest wall

:
T4b With edema (including peau

: d'orange), ulceration of the skin of the
breast, or satellite skin nodules confined to the same breast
T 4( : Both of above
T4d : Inflammatory carcinoma
N (Regional Lymph Nodes)

N : No palpable homolateral axillary nodes
N, : Movable homolateral axillary nodes
N la : Nodes not considered to contain growth clinically, but may contain

minimal histologic metastasis (less than 0.2 cm)
\, h : Nodes considered to contain growth clinically, or gross metastatic tumor
confined by surgery
N 2 : Homolateral axillary nodes considered to contain growth and fixed to one

another or to other structures
N3 : Homolateral supraclavicular, infraclavicular, or internal mammary nodes

considered to contain growth, or edema of the arm (edema of the arm may
be caused by lymphatic obstruction; lymph nodes may not then be palpable)
M (Distant Metastasis)
M„: No evidence of distant metastasis
M,: Distant metastasis present, including skin involvement beyond the

breast area
"Dimpling of the skin, nipple retraction, or any other skin changes except those in T4b may
occur in T T l7 2 , or T3 without affecting the classification.
TABLE 7-6. Clinical Staging of Breast Cancer 61
Preinvasive carcinoma
Stage TIS Carcinoma in situ
Invasive carcinoma
Stage I T, V or \"
la M„
Stage II To N Mo
T, Nlh M„
T, \ .
\'
u or Nlb M.
Stage III T, or T, \. M„
T N„. N,. or \ M,
an) T with N : M
any T with N M„
Stage IV any T 4 an) N an)M
anv T N am M
any T an> \ M,
"See Table 7-5 for identification of abbreviations.
TABLE 7-7. Prognosis of Patients after Badical Mastectomy
Recurrence Survival
18 a 10 5 10
Involvement Months Years Years Years Years
-%-
Negative node involvement 5 18 24 78 65
Positive node involvement 33 65 76 46 25
Positive node involvement (1 to 3) 13 50 64 62 38
Positive node involvement (>3) 52 79 86 32 13
All patients 17 40 50 64 46
'Abstracted from data of the National Surgical Adjuvant Breast Program: Fisher B et td.: Ann Surg 168:337,
1968 and Fisher B et ai: Surg. Gynecol Obstet 140:528, 1975
LOCAL TREATMENT OF BREAST

CANCER
The traditional image of the surgeon obtaining a frozen section diagnosis of
primary breast cancer while the patient is anesthetized, followed by an imme-
diate radical mastectomy, is currently under siege. Consumer groups,
women's magazines, and professional medical journals have all contributed to
a new era in breast cancer treatment, in which the diagnosis is made in the
outpatient clinic or operating room and is followed by a period of evaluation
and discussion, during which time the patient is informed of the available
therapeutic options. 73 74 Physicians and their patients are increasingly includ-
'
ing cosmetic and psychologic concerns among the factors to be weighed in

choosing a program of definitive primary local therapy. 7 10,75,76 '
Clearly, the contemporary clinician concerned with breast cancer has a

delicate and difficult task in advising patients; there are myriad data, the
interpretation of which is difficult at best. We shall therefore try to present the
relative merits of the contemporary choices for primary treatment and will
discuss some guidelines for their implementation.
Surgery
Thegoal of the surgeon in treating women with stage I or II breast cancer is

to achieve local control. A secondary goal, but one that most oncologists
consider very important, is to stage the cancer. This is accomplished by
removing axillary nodes and, rarely, internal mammary lymph nodes to deter-
mine the risk of recurrence. This latter goal will probably assume increasing
importance because of our growing appreciation of breast cancer as a systemic
disease in which decisions about systemic treatment must be made. A corol-
lary of this is the increasing trend away from radical surgery for many of these
patients toward lesser operations, which are often combined with radiation
therapy.
Historically, the radical mastectomy that was devised by Halsted 77 over 90
years ago has been the standard of excellence primary breast cancer
for
60, 7H
treatment. Haagensen's results with this operation provide a contempo-
rary standard of what can be achieved by an experienced surgeon using
careful clinical staging and operative technique. However, Halsted™ saw
patients with much more advanced breast cancer than we usually see today.
In the case records of the Johns Hopkins Hospital, he described a woman with
"... a small 7x8 cm tumor upper outer quadrant." To gain local control
in the
in patients with such large tumors, radical mastectomy, frequently with skin
grafting, was necessary.
Efforts to improve upon Halsted's mastectomy initially involved extending
the operation to include more and more normal structures. 80,81 However,
since higher morbidity without improvements in survival were generally
achieved, most surgeons have abandoned this approach. 82,83
Another approach to improve Halsted's operation has been to delete the
more deforming aspects of the radical mastectomy. 83 Modified radical mastec-
tomy, which spares the pectoralis muscle and results in a more functional
upper extremity, is currently the most frequently performed operation for
breast cancer because it usually achieves local control, and it removes the
axillary lymph nodes for accurate pathologic staging. The cosmetic and func-
tional results from modified radical mastectomy are superior to those from
standard radical mastectomy. The technical details for the operation have
been published by Maier et a/. 84 This operation, which is more aptly termed
total mastectomy with axillary dissection, has been carefully compared with
the Halsted procedure by surgeons at the Mayo Clinic. 85 They found no
difference in the local recurrence and survival rates. Additional time is need-
ed, however, for a clear definition of the 10- and 15-year survival results of this
operation compared with the classical radical mastectomy.
What is the significance of clinically negative and histologically positive
involvement of the axillary lymph nodes? Do they universally predict the
development of local problems or are they important mainly for predicting a
high likelihood of distant metastases? Data from both the National Surgical
Adjuvant Breast Project44 and the King's-Cambridge Hospitals 45 suggest that
the latter is true. In a NSABP trial, only 15 per cent of women with clinical
stage I disease who were treated with total mastectomy alone have developed
histologically positive axillary node involvement requiring a delayed axillary
node dissection. 44 On the basis of findings in patientswho were treated by
radical mastectomy, as main as 40 per cent would be expected to have
histologically positive node involvement. In a trial conducted by the King's-
Cambridge group, 45 only 14 per cent of women who received no treatment of
the axillae have required subsequent treatment to the axillae after four or five
years, whereas 32 per cent would have been expected to have had histologi-
cally positive node involvement.
Patients that have very small lesions (<2 cm) may be candidates for lesser
operations than total mastectomy, 86 87 but we do not recommend this unless
'
the operation is combined with radiation therapy. Similarly, patients with

large lesions may benefit from a careful combination of surgery and radiation
therapy for local control, 88 as discussed subsequently in this chapter. Haagen-
sen 53 60 has defined some of the findings that portend a poor result from
'
surgery alone and has called them the five "grave signs." They include edema
of the skin over the breast, skin ulceration, solid fixation of the tumor to the
chest wall, massive involvement of axillary lymph nodes (^2.5 cm in trans-
verse diameter), and fixation of axillary nodes. Radical mastectomy is con-
traindicated in such cases.
Radiation Therapy Plus Surgery
During the earliest days of its history, radiation therapy was used to treat
breast cancer. Although regressions occurred, cures were not obtained, and
complications were frequent. Contemporary radiation therapy for this disease
has been markedly improved thanks to better technology, a greater under-
standing of the biology of irradiated tissues, and a deeper appreciation of the
clinical behavior of breast cancer. Therefore, much of what has been written
in the literature regarding the use of radiation therapy in this disease, al-
though reasonable at the time of publication, must be re-evaluated with great
caution.
In order to utilize irradiation effectively in the treatment of cancer, an
understanding of dose-response relationships is required. The frequency of
local control is directly related to the dose of irradiation delivered.
Fletcher 89 90 has demonstrated that doses in the range of 5000 rad delivered
*
over five weeks will control subclinical aggregates of disease 90 per cent of
the time. However, the dose that is required to achieve local control is also
dictated by the volume of tumor. Whereas 7000 rad may control 90 per cent of
clinically positive axillary nodes 2.5 to 3 cm in diameter, doses in the neigh-
borhood of 8000 to 9000 rad given over eight to ten weeks will control only 56
per cent of primary breast cancers greater than 5 cm in diameter. 89
The proper use of radiation therapy, either as an adjunct to surgery or as the
predominant local treatment modality, depends upon an appreciation of cer-
tain factors. The long-term sequelae of radiation treatments are proportional
to the total doses delivered and the volume of tissue irradiated. Soft tissue
changes are minimal when doses of 5000 rad are delivered with modern
megavoltage equipment, but marked changes will occur with doses greater
than 7000 rad, particularly if the volume irradiated is large. Delayed risks are
also possible, including radiation-induced neoplasms.
The initial treatment of primary breast cancer should eliminate local dis-
ease and prevent any local recurrence. Classically, this has been achieved by
the use of radical mastectomy. However, in recent years the question has
been raised as to whether or not a lesser surgical procedure combined with
radiation therapy can achieve the same goal. However, this is only reasonable
if overall patient survival is not sacrificed. Radiation therapy has been com-
bined with a variety of surgical techniques in pursuit of this goal, including

simple mastectomy, wide local excision, or even simple incisional or excision-
al biopsy.
Local Excision and Radiation Therapy. There has been considerable
debate over whether or not a moderate or limited surgical procedure com-
bined with effective postoperative radiation therapy is equivalent to radi-
cal surgery. Table 7-8 summarizes selected studies utilizing this tech-
nique. 8, 91 98 Survival is not statistically different in those studies comparing
"
limited and radical surgery with modern postoperative irradiation, with the
exception of a series from Atkins et a/. 94 of clinical stage II patients. In this
group, survival was decreased with the lesser operation. However, local
control rates in these studies were excellent, and the survival rate appears to
be comparable to reports in the surgical literature. Of particular note are the
excellent cosmetic results, as assessed by both physicians and patients. Harris
et al., H reporting on 80 similarly treated cases receiving primary curative
radiation therapy after limited surgery, found a short-term local control rate of
100 per cent for stage I patients and 98 per cent for stage II patients. The
corresponding estimated actuarial five-year survival rates in this series were
88 per cent for stage I patients and 72 per cent for stage II patients. Among the
breasts that were evaluated for cosmetic results, 66 per cent were judged good
or excellent by physicians, and 81 per cent were judged good or excellent by
patients.
TABLE 7-8. Effect of Radiation Therapy (RT) after Limited and Radical Surgery
Limited Surgery" + RT Radical Mastectomy + RT
Survival (%) Survival (%)

Author NoPts Stage 5 yr 10 yr xNo Pts Stage 5 yr 10 yr
Rissanen 91 415 I 79 71 593 I 82 71.5

Peters 92 145 I 84 71 145 I 78 62
Mustakallio 93 127 I 84 72
Atkins, et (U. M 112 I 80 80 108 I 77 77
70 II 56 30 80 II 72 60 f
95
Prosnitz, et fl/. 49 I 97
101 II 75
96
Pierquin, et a/. 13 I 92
21 II 86
Brown, et al" 7 100 I, II 70
Calle, et aL M 120 I 85 75
203 II 77 54
8
Harris, et a/. 28 I 88
56 II 72
"Surgery limited to biopsy, "wedge" resection, or local excision with total gross removal of tumor or
quadrant resection.
t Differences considered statistically significant (p < .05).
should be pointed out that the survival data reported in many of these
It
reports are very preliminary and that not all of these patients are free of
disease. For this reason, we consider the minimal operative procedure for
patients choosing this therapeutic option to be a complete excisional biopsy
with margins wide enough to remove all visible gross disease. Carefully
selected patients with small primary lesions and clinically absent or min-
imally present axillary- disease are potential candidates for this technique.
Patients with large or bulky primary or nodal disease are probably best
debulked with whatever surgery that is deemed appropriate, followed by
careful consideration of radiation therapy, in order to gain complete local-
regional control.
Simple Mastectomy and Radiation Therapy. The most vocal supporter of
this technique has been McWhirter," who also made the important observa-
tion that survival is directly dependent on radiation dose. In patients receiv-
ing less than 3750 rad to the axilla, the five-year survival rate was 29 per cent;
when the dose was greater than 3750 rad, the rate was 46 per cent. This dose
dependence is an important factor in interpreting older data because in-
adequate radiation doses certainly account for some of the apparent discrep-
ancies and reduced survival rates that have been reported.
McWhirter 100 reported the following survival rates in operable cases treated
by simple mastectomy and postoperative radiation therapy: 62 per cent at 5
years, 46 per cent at 10 years, and 38 per cent at 15 years. Kaae and Johansen 101
reported the following survival rates in a study comparing simple mastectomy
and postoperative radiation therapy with extended radical mastectomy and a
similar radiation therapy technique: 66 per cent and 67 per cent at 5 years and
46 per cent and 50 per cent at 10 years for all operable cases treated.
In a study conducted by the NSABP, 102 patients with clinically negative
axillary node involvement were randomized to undergo radical mastectomy,
total mastectomy plus postoperative radiation therapy, or total mastectomy

followed by axillary dissection when positive node involvement subsequent-
ly developed. With a mean follow-up of three years (range of two to six years),
there are no significant differences in the treatment failure or survival rates.
Two other studies from England warrant comment. 103,101 In both studies,
patients with stage I or stage II breast cancer were randomized to receive
simple mastectomy alone versus simple mastectomy plus radiation therapy.
There was no difference in the survival rate, but in the study from Manches-
104
ter, reduction in local-regional recurrence rates for stage I patients was
achieved only by the addition of radiation therapy.
We conclude that the overall survival rate is similar for primary operable
breast cancer, whether initial primary treatment is by radical mastectomy,
simple mastectomy plus optimal radiation therapy, or simple mastectomy
alone. The major disadvantage of the final option is a higher local recurrence
rate.
Radiation Therapy as an Optional Adjunct to Radical Sur-
gery. The rationale for individualized optional postoperative irradiation
following radical surgery is based on the major assumption that in some
high-risk patients malignancy remains in the local-regional area and that it
will grow locally and shorten or diminish the quality of the patient's life. The
validity of this assumption remains to be proved, and considerable con-
troversy exists concerning the value of such adjuvant radiation therapy. This
technique was used frequently in the 1950s and 1960s, but its value has come
under scrutiny since the early NSABP report of Fisher et al., 105 which demon-
strated no significant difference in disease status and survival rates in a large
randomized trial. However, the radiation therapy community still feels that
this report did not settle the issue because of the large number of exclusions
in the study and the variation in radiation techniques and doses applied.
What, then, is the evidence that postoperative radiation therapy is worth-
while?
Jackson 106 followed 1461 patients who were treated solely with radical
mastectomy and found that 174 patients (12 per cent) developed ipsilateral
supraclavicular lymph node metastases. In 81 (5.5 per cent) of these patients it
was the initial site of recurrence, and only 5 per cent survived ten years.
Another important lymph node chain is the internal mammary group. The
frequency of internal mammary node metastasis was approximately 29 per
cent with inner quadrant lesions, 43 per cent with central lesions, and 17 per
cent with outer quadrant lesions in the large series (1007 patients) of Haagen-
sen. 53 He further demonstrated increasing internal mammary node involve-
ment with increasing size of the primary breast carcinoma. The involvement
was 16 per cent with lesions measuring less than 3 cm., but 57 per cent with
those that were 8 cm or more. Internal mammary nodes contained metastases
in 20 per cent of patients with clinically involved axillary nodes.
Regardless of the operative procedure, the chest wall recurrence rates in
operable breast carcinoma vary from 10 to 22 per cent. 107 109 Fletcher et al. n0
"
demonstrated that when axillary node involvement was negative, chest wall
recurrence occurs in 5 per cent of patients. When there was less than 50 per
cent axillary node involvement, the recurrence rate was 12 per cent, but when
there was greater than 50 per cent involvement, the rate was 26 per cent. With
judicious use of megavoltage techniques, the development of supraclavicular
or internal mammary node metastases seldom occurs, and recurrence in the
chest wall is dramatically reduced. 111 115 This is best accomplished with post-
"
operative radiation therapy, as reviewed by Fletcher and Montague; 116 there

is no evidence suggest any superiority of preoperative radiation. 117
to
What is the clinical impact of local-regional recurrence of breast cancer?
Although this, too, is a controversial topic, it would appear that grossly appar-
ent local disease is more difficult to control than subclinical disease. For
example, pain relief of a brachial plexus recurrence is uncommon with radia-
tion therapy, and control of gross chest wall recurrence is possible in only
about 50 per cent of cases. 90, 118
Although there has been little question that radiation therapy can usually
prevent local recurrences, a major question has always existed as to whether
or not survival is influenced. Almost all studies seem to indicate that there is
no improvement in the survival rate. 119 One report suggests that some patients
with medially located tumors and four or more involved axillary nodes may
have an improved survival rate. 120 Conversely, Stjemsward 121 has analyzed the
data from ten randomized trials and noted that in eight of these trials the
survival rate was from 1 per cent to 10 per cent less in the group receiving
postoperative radiation therapy. Given the fervent debate about the actual
effect of radiation therapy on the survival of these patients, it is probably
prudent to base any recommendations for radiation therapy in this setting on
its potential for local control of the disease.
The patients who are most likely to benefit from radiation therapy adminis-
tered as an adjunct to radical surgery include those with medial half and
central lesions, with or without axillary metastases, and those with lateral half
lesions with positive axillary node involvement.
Radiation Therapy for Advanced (Inoperarle) Breast Can-
cer. The management of advanced clinical breast cancer by surgical meth-
ods alone is at best futile; 88 radiation therapy offers the best chance for local
control. However, the techniques required are complex, and the volumes to
be treated are large. Profound skin and soft-tissue changes are inevitable, and
extreme care must be taken to avoid severe complications. Although advanced
breast carcinomas may be technically resected, when primary mastectomy is
used as the only therapy, it may increase the rate of local recurrence and result
in widespread massive carcinomas of the chest wall.
Montague 122 has pointed out that doses of 4000 to 5000 rad over four to five
weeks produce only about 30 per cent local control. Treatment given over 70
days using megavoltage equipment delivering 6000 rad to a comprehensive
area encompassing the chest wall, breast, internal mammary chain, axilla, and
supraclavicular area, with an additional boost of 2000 to 3000 rad through
reduced fields over residual masses, produces a local control rate of 70 per
cent or more. The key to this success is prolonged, protracted irradiation
accurately delivered.
Irradiation is the most effective treatment for local control of unresectable
breast cancer; however, usually provides incomplete control of inflamma-
it
tory carcinoma, massive lesions in the chest wall and axillae, or extensive
disease in the skin, even when combined with simple mastectomy. 121 Atkins
124
and Horrigan reported on 39 such patients treated with 4250 rad, and,
although they responded initially, 87 percent had local failure in three to five
years. At the M. D. Anderson Hospital and Tumor Institute (MDA), 123 a
program was developed to remove the largest bulk of disease by simple
mastectomy, leaving the skin of the chest wall and intercostal and peripheral
lymphatics for radiotherapeutic management. Minimal tumor doses of 5000
rad were delivered to all areas, with 1000 to 2000 rad boosts to regions of
bulkier disease. They observed 90 per cent of the local regional recurrences,
or both, by three years after treatment. The frequency of chest wall recurrence
was correlated with the size of the primary lesion. There were no recurrences
in 30 patients who had lesions 3 cm or less in diameter, whereas the recur-
rence rate for 79 patients who had lesions greater than 5 cm in diameter was
16 per cent. Recurrence was further correlated with dose and was 12 per cent
in 103 patients with doses less than 5000 rad but only 5 per cent in 86 patients
with doses greater than 5000 rad (boost technique). Complications have been
quite low and acceptable.
A basic question remains as to which is the most appropriate therapeutic
technique for initially inoperable breast cancer patients: radiation therapy
alone or radiation therapy followed by mastectomy. Several trials have been
undertaken to investigate this problem. 125 129 The aim of the radiation therapy
"
in these studies was to achieve local control of the tumor delivered in such a
way that surgery could be performed and primary wound healing could occur
with a minimum incidence of local recurrence. It was hoped that the radio-
therapy would shrink the tumor, thereby making it operable, and that if no
distant metastases were found, the operation might cure the patient. The
study of Yarom et a/. 125 suggests that the hope of cure is unfounded, since the
survival rate for the operated group was 58 per cent versus 57 per cent for the
nonoperated group. Nevertheless, such procedures may be justifiable for their
palliative value.
Modern radiobiology teaches that large tumor masses contain substantial
numbers of anoxic cells but that the periphery of the tumor is well oxygenated
and contains cells that are more sensitive to irradiation. It would therefore be
reasonable to irradiate large breast masses and nodal disease preoperatively
to reduce the overall bulk of tumor, improve the technical resectability, and
sterilize the surgical margins of subclinical disease. At the same time, either
gross or microscopic disease in the axilla or supraclavicular or internal mam-
mary areas would be treated. Zucali et a/. 127 demonstrated improved survival
of 3.9 years compared with 2.1 years in patients who had radical mastectomy
after radiation therapy for large tumors, as opposed to those who had radiation
therapy alone.
Stoker et a/. 126 selected 24 patients for mastectomy 4 to 16 weeks after they
received radiation therapy for locally advanced breast carcinoma (so-called
toilet mastectomy). Although 1 patient was lost to follow-up, 23 patients
demonstrated microscopic evidence of residual tumor. Three patients devel-
oped local recurrence — all three in association with disseminated disease.
The remaining 20 had local disease completely controlled until death or the
time of the report.
Based on these considerations, we generally initiate radiation therapy for

the patient with locally advanced, inoperable breast cancer. Depending on
the patients response to treatment, the presence or absence of distant metas-
tases, and the patient's acceptance of the cosmetic result expected, we make
an individualized decision regarding subsequent mastectomy.
Radiation Therapy as Local Treatment for

Symptomatic Metastases
Radiation therapy is the most effective local palliative treatment available

for nearly any form of metastatic disease causing pain in a patient with breast
cancer. Approximately 60 to 65 per cent of all breast cancer patients will
ultimately need palliative or symptomatic treatment because of the progres-
sive nature of the disease. 130 Indeed, palliative forms of radiation therapy are
employed far more frequently than is primary radiation therapy. Relieving
local symptoms and making the patient's remaining days more tolerable are
important therapeutic challenges.
As far as any palliative therapy is concerned, several general rules, which
dictate the aggressiveness of the treatment, should be kept in mind. 131 If a
patient is close to death, the purpose of palliation is to make the remainder of
bis or her life more comfortable and tolerable, and effective treatment should
be done in the shortest time with minimal morbidity. After careful documen-
tation of the precise extent of metastatic disease, one should choose the best
available treatment modality, whether it be systemic or local, or both. In some
cases, a localized asymptomatic metastasis may be excluded from local treat-
ment so that it may serve as a marker of the value of systemic treatment. If
radiation therapy is used, the precise radiation field must be documented,
since retreatment at a later time may be necessary- (e.g., the retreatment of
painful bone metastases).
Almost any neoplasm can be sterilized by ionizing radiation if the dose
delivered to that local area is sufficiently high. The limiting factor in almost all
situations is the sensitivity of the surrounding normal tissues. With this in

mind, the total dose, the number of fractions, and the field size become critical
issues that at times can seriously limit what one wishes to accomplish. This
may require abandoning the original goal of treatment and instituting sophis-
ticated treatment planning, radical alterations of standard treatment practices
and techniques, and careful integration with other treatment modalities, espe-
cially chemotherapy. Decisions about palliative therapy can be as difficult,
and perhaps even more meaningful to the patient and the family, as those for
curative therapy, because at this time the patient is often in great discomfort,
has had time to adjust to the diagnosis, is more concerned about health care
costs, and is often very concerned with maintaining personal dignity for as
long as possible.
Chu 131 has neatly outlined the standard approaches to follow when various
organ systems are involved. Harwood et al., 132 Fitzpatrick et a/., 133 and
Saenger et al. 134 have discussed some of the innovative methods of handling
metastatic disease. Under the usual circumstances of minimal metastatic dis-
ease and recurrences in nonvital structures, such as the skin, lymph nodes, or
bone, ordinary megavoltage units or specific electron energies are usually
sufficient. Approximately 3000 to 4000 rad over three to four weeks will
alleviate symptoms. However, bulky disease may require additional irradia-
tion doses of 1000 to 2000 rad. Weight-bearing bones may require prophylac-
tic pinning prior to irradiation to stabilize an unstable bone or joint before
irradiation. 135, 136 Other areas, such as the brain, mediastinum, ureter, choroid,
or orbit, require definitive treatment to preserve function and require 3000 to
5000 rad over three to five weeks. Again, higher doses may be required if
bulky disease is present.
New techniques of radiation therapy are used increasingly in patients with
breast cancer to increase the efficiency and reduce the time required for
treatment. For example, single, large fractions of radiation delivered to isolat-
ed organs or to large portions of the body have been tested with some success.
This technique appears to be well tolerated, effective, and especially useful
for patients with a very short life expectancy. The major limitations of large-
have been pulmonary pneumonitis and fibrosis, but these rare
field irradiation
complications are seen only after a considerable time delay.
SYSTEMIC TREATMENT OF
ADVANCED OR METASTATIC
BREAST CANCER
General Considerations
The
precise choice of systemic therapy for a patient with metastatic breast
cancer requires an understanding of the natural history of the disease and a
careful evaluation of the individual patient. The hormone-receptor status of
46 " 48
the patient's tumor is of paramount importance. widely accepted that
It is
hormonal manipulation is unlikely to benefit a patient with breast cancer

tissue that lacks an estrogen-receptor protein. This fact is illustrated in Table
7-9, which summarizes the frequency of ER and PgR in both primary and
metastatic breast cancer, as well as their likelihood of responding to hormonal
manipulation. 46 In contrast, it has been noted that patients with tumors con-
taining ER may be less likely to benefit from combination chemotherapy than
those with ER-negative tumors. 137 Although this latter observation is con-
troversial, 138 it correlates well with observations that ER-negative tumors tend
to grow more rapidly and have much higher growth fractions than ER-positive
tumors. 139 These kinetic characteristics are often associated with a higher
benefit from cytotoxic chemotherapy.
Primary and metastatic breast cancers in the same patient usually have
similar ER activity; however, ER-positive tumors may occasionally change to
ER-negative tumors, and vice versa. 140 This variation appears to be an integral
part of the biology of a given breast cancer and is not simply a change due to
treatment. For example, it has been shown that radiation therapy does not
selectively eliminate ER-positive cells, and the endocrine responsiveness of a
7 Breast Cancer 179
TABLE 7-9. Receptor Distribution and Response to Endocrine Therapy
Distribution and Response Total Primary Metastatic
fifi
ER° ,66r?l
Distribution of
H*75*' fff<77* Too
Distribution of PeR
ER- is 19 ""
M 112 "'
35
< 3 ^
250 __
ER-
M^" 32^ |(59%)
Response to endocrine therapy -

7
(39f
ER- P2R- ii y (0% I
p£(41%)
ER-. P2R- ^1 (64^) (33 ^ 81 *)

2o 1 '
ii<
"ER-. Total SS - 4S components >3 fmol mg protein; PgR~. Total 8S > 2 fmol mg protein. From
McCain: UL Cancer 39:2934. 1977
:
tumor after radiation therapy continues to correlate with the presence or

absence of ER. 141 Ideally, therefore, decisions regarding therapy should be
based on observations from recently obtained tissue.
There is a correlation between the quantitative level of ER and the clinical
response to hormonal manipulation. 142 The frequency and concentration of
ER increases in the order of peri-, pre-, and postmenopausal periods. 143 This
correlates with the observation that endocrine manipulation tends to be more
useful in postmenopausal patients of advanced age than in the perimenopau-
sal age group. For example, estrogen treatment is more effective in women
who are more than five years postmenopausal than in younger women, 143 and
the response rate to adrenalectomy is higher in postmenopausal women than
144
in pre- or perimenopausal women.
A variety of other factors in addition to or at times instead of the hormone-
receptor status of a tumor may affect the choice of therapy. These include: (1)
the disease-free interval, 145, 14ri
(2) the site of metastatic disease. 145 (3) the age
70 144
of the patient. and (4) the response to previous therapy. It is widely
recognized that a short disease-free interval (less than one year) between
primary treatment and subsequent metastatic disease is associated with a
rapidly growing tumor. These patients tend to respond poorly to hormonal
manipulation, but the more rapid growth of tumor may allow some degree of
control by cytotoxic chemotherapy.- 7 139 Conversely, a very long disease-free
-
interval (longer than five years) is often associated with a better response to
hormonal manipulation.
The site of metastatic disease may influence the choice of systemic treat-
ment. Metastatic disease in the soft tissues, skin, regional lymph nodes,
pleural cavity, or bone responds better to endocrine manipulation than does
involvement of the abdominal or thoracic viscera or the brain. 144 For this
reason, experimental trials of hormonal therapy in patients lacking informa-
tion about the ER and PgR status of their tumor may be justified in the former
group but are less likely to be useful in treating patients with advanced
visceral disease.
As stated previously, endocrine manipulation is generally more effective in
elderly women than in young women. Moreover, cytotoxic chemotherapy is
not tolerated as well in elderly patients. Age is therefore an important consid-

eration in the individualization of therapy.
A previous response to oophorectomy or other hormonal manipulations may
be useful in predicting a response to other forms of hormonal or ablative
therapy. 144 Thus, patients responding to one type of endocrine manipulation
may well respond to another. Conversely, in this era of frequent adjuvant
chemotherapy (see later discussion), it is unknown whether cytotoxic chemo-
therapy will diminish or modify the value of subsequent endocrine manipula-
tion in patients failing chemotherapy.
L-Dopa (levodopa) may also be used in some patients as a predictive test of
147
hormonal responsiveness. It inhibits prolactin synthesis by the pituitary
gland, and in some patients with severe bone pain, its use may produce
dramatic temporary relief. Such a response tends to predict subsequent ben-
efit from endocrine manipulation. The dose of L-dopa is 500 mg orally every
six hours. It must be given on schedule because it inhibits prolactin synthesis
for about four hours only. A dose that is missed because of emesis may be
repeated with food if necessary, but the drug should be discontinued if the
patient develops tachycardia. 147
Before discussing specific programs of treatment, it is worth stressing two
other general principles in treating the patient with disseminated carcinoma
of the breast. First, only one course of therapy at a time is employed. An
exception to this rule is the irradiation of destructive lesions of weight-
bearing bone in combination with other modalities of treatment. Second,
therapy is changed only if disease is advancing and not, as a rule, if it is static.
This point is especially important in following the patient whose only mani-
festation of metastasis is destructive or osteoblastic bone metastases. Such
lesions are notoriously difficult to evaluate, and they rarely show evidence of
healing. In this case, the development of new lesions may be the best indica-
tor of disease progression and the need for a change in therapeutic strategy.
Endocrine Manipulation
The quality of during a remission that is induced by endocrine manipu-

life
144 148, 149
lation is usually superior to that seen with cytotoxic chemotherapy.
-
Thus, most patients receive such therapy soon after they develop metastatic
breast cancer. Exceptions to this general approach include patients with
ER-negative tumors and those with rapidly growing tumors, particularly in
vital visceral organs.
The precise choice of endocrine therapy varies with the menopausal status
of the patient. The initial choice of endocrine manipulation is commonly
called "primary" hormonal manipulation, whereas subsequent manipulation
is called "secondary" or even "tertiary" therapy. 144
Premenopausal Patient. who are menstruating or are within
Patients
one year of their last menstrual period are considered premenopausal.
Primary Endocrine Manipulation. Bilateral oophorectomy is the usual

initialtherapy in premenopausal women who are candidates for endocrine
"
therapy. 149 151 This is presumed to work by the elimination of ovarian hor-
mones, including estrogen, progestin, and androgen, all of which may stimu-
late the growth of breast cancer. Bilateral oophorectomy causes an objective
regression in about one third of all premenopausal women (range of 15 per
cent to 56 per cent), but this response rate can probably be doubled by
excluding patients who have ER-negative tumors. Responses generally last
from 9 to 15 months; the longest response on record is 18 years. 152
If the patient is an acceptable operative risk, surgical castration is prefera-
ble to ovarian radiation because it more complete
acts rapidly, results in a
reduction in hormone and does
levels, not compromise bone marrow areas
that may be needed during later cytotoxic chemotherapy. Hysterectomy is not
necessary in these patients nor should they be given postoperative estrogen to
relieve attendant menopausal symptoms, although other measures to control
vascular instability may be considered, such as the administration of clon-
idine or the ergot alkaloids.
Oophorectomy is not useful in patients who are more than one year past
menopause. 153 Prophylactic castration in menstruating women at the time of
mastectomy may delay recurrence, but it does not increase the survival rate. 154
Prophylactic castration is unnecessary in patients who may be cured by
primary surgery or radiation therapy, and it will not increase the survival rate
in those who develop breast cancer recurrence. Finally, the response to
castration may be useful in predicting the response to subsequent hormonal
therapy, and this guide is lost by prophylactic castration.
It should be noted that some clinicians prefer to use tamoxifen as the
primary form of endocrine manipulation in premenopausal patients. The

overall objective response rate is 35 per cent with tamoxifen, 155 but the
duration of response is undefined. Further experience with this drug is need-
ed before it can be accepted as standard initial treatment for premenopausal
patients.
Secondary Endocrine Manipulation. Patients who fail to respond to oo-
phorectomy usually proceed to treatment with cytotoxic drugs. Those who
respond to oophorectomy and then relapse may be considered for a variety of
secondary endocrine treatments, 149, 156 160 which may include ablative therapy
'
(medical or surgical adrenalectomy or hypophysectomy) or hormonal adminis-

tration (tamoxifen, progestins, or androgens). Some clinicians consider
tamoxifen to be the best choice. We have generally selected an ablative
approach for these patients if at all possible, because of the long duration
of benefit that may result. This may be accomplished medically by the use
of the experimental drug aminoglutethimide 149- 156- 157 (see Chapter 5) or by
posterolateral adrenalectomy. l5T> 158, 16°- 161 Adrenalectomy or hypophys-
ectomy can be expected to benefit 30 to 50 per cent of patients who have
responded to castration but fewer than 10 per cent of those who have not. The
duration of response averages from 1 to 1.5 years, or more. Adrenalectomy is
the preferred approach in our clinics, since hypophysectomy is not superior
either in rate or duration of remission. It has been our impression that an
adrenalectomized patient is easier to manage than one who has undergone
hypophysectomy, although this view is not universally held.
After adrenalectomy, replacement therapy is required. Administration of

hydrocortisone, 25 to 50 mg/day orally, and fluorohydroeortisone, 0.1 mg
every other day, usually suffice. During periods of stress the dosage should be
increased. In most large treatment centers the operative mortality rate for
adrenalectomy is 5 per cent or less. However, in extremely ill patients, the
mortality rate is much higher, and alternative methods should be used. Major
contraindications to adrenalectomy and hypophysectomy include symptomat-
iccerebral metastatic disease, incapacitating respiratory insufficiency, tumor
involvement of more than 30 per cent of the liver, or jaundice. 160, 162
Patients who refuse ablative treatment or who have medical contraindica-
tions may be considered for other forms of secondary' hormonal manipulation.
In the past we have used androgens in such patients, but more recently we
have employed either tamoxifen 149, 155, 164_166 or a progestin (Megace). 149, 163 We
presently avoid androgens because of their major toxic effects and lack of
superiority in achieving antitumor responses in these patients. A more de-
tailed discussion of these three drug classes can be found in Chapter 5.
Postmenopausal Patient. whose last menstrual period
Patients oc-
curred more than one year before the development of metastatic disease are
considered postmenopausal. A subgroup including those who are one to five
years postmenopausal may also be identified; these patients are commonly
called perimenopausal.
Primary Endocrine Manipulation. The initial therapy of choice for most
postmenopausal women with metastatic breast cancer is tamoxifen. 149155,164166
Diethylstilbestrol is a cheaper but more toxic alternative. 144, 167, 168 In un-
selected postmenopausal patients, a response rate of more than 30 per cent
can be expected with tamoxifen, but this rate is approximately doubled in
patients with ER-positive tumors. The usual duration of response is 12 to 15
months. The dose of tamoxifen is 10 mg twice daily, but higher doses are
occasionally employed. 155 More complete details, including toxicity informa-
tion, can be found in Chapter 5.
Secondary Endocrine Manipulation. Postmenopausal patients who re-
spond to DES or tamoxifen but subsequently relapse are candidates for
secondary endocrine manipulation. As with the premenopausal patient,
this usually means either ablative therapy or the use of a new hormone. In
many centers the recommended treatment is endocrine ablation, either
medically with aminoglutethimide or surgically by adrenalectomy or hypo-
physectomy. 156 160 This is especially true for patients who are more than
"
five years postmenopausal, with a long disease-free interval between the

initial diagnosis of breast cancer and recurrence, who have high ER levels in
the tumor, and who have minimal metastatic disease that is limited to soft
tissues or bone. Benefit lasting one to two years can be predicted in 30 to 50
per cent of such patients.
Patients who are candidates for secondary endocrine manipulation at UCLA
are most commonly treated with a change in hormone. Megestrol acetate, 149, 163
tamoxifen, or DES may be used, depending upon the patient's prior exposure
to hormones. Androgens may also be considered, but we generally avoid
this type of hormonal treatment because of its toxicity. The dose, mechanism
of action, and toxicities of these drugs are given in Chapter 5.
Chemotherapy
Candidates for nonhormonal chemotherapy include patients with dissemi-

nated breast cancer who fail hormonal manipulation, patients with rapidly
advancing and widespread disease, and patients with metastatic tumors that
lack estrogen receptors. Alkylating agents and
other drugs, all of
at least five
which are commercially available, are known to have useful activity as single
agents in the treatment of metastatic breast cancer (Table 7-10). 169172 It should
be noted that these responses are only rarely complete and that the duration of
response varies between four and six months. Mitomycin-C is an additional
TABLE 7-10. Response Rates in Metastatic Breast Cancer from

Nonhormonal Single-Agents
NO. OF P ATI EN I S Per cent

Drug Evaluated Res PON's e
Alkylating Agents
Mechlorethamine 92 35
||Cyclophosphamide 529 34
Thiotepa 162 30
Melphalan 86 23
Chlorambucil 54 20
Antimetabolites
Methotrexate 356 34
5-FIuorouraci] 1236 26
6-Mercaptopurine 44 14
Hydroxyurea 16 12
Cytosine arabinoside 64 9
Antibiotics
Mitomycin-C 60 38
|]
Doxorubicin 221 37
Bleomycin t 24 8
Others t 99 13
Miscellaneous
Vincristine 226 21
Vinblastine 95 20
Hexamethylmelamine 39 28
Dibromodulcitol _"
22
BCM 76 21
CCNU 155 12
Dacarbazine 29 7
Procarbazine 21 5
Cisplatin§ 26
Streptozotocint 20
"Modified from Broder L and Tonne) DC: Cancer Treat Ret 1 183, 1974 und from Carbonc PP and L'oroiey
.
DC: In Breast Cancer: Advances in Research and Treatment, Current Approaches to Therapy, VoL 1. McGuire
WL ed>. New York, Plenum Press, 1977.
I From Band PR: Cancer Treat Rep 61 :1365, 1977
Includes dactinomycin, mithramycin, streptonigrin, bleomycin, and daunomycin.
I
From Yap HY et al. Cancer Treat Rep 62:405, 1978.

§
Drugs of accepted value based on our assessment of their relative therapeutic index, cross resistance with
other drugs and usefulness as single agents. Specific applications are discussed in the text.
1 M II Treatment of Specific Neoplavm««
drug that is known to have activity, but its use is limited because of severe t<
icity.
Because of the success of combination chemotherapy in treating acute

leukemia. Hodgkins disease, and a variety of childhood tumor>. it was natural
that combination chemotherapy should be tested extensively in metastatic
breast cancer. Although the first report of >ucce»>tul combination chemothera-
py in breast cancer was published in 1963 by Greenspan et a/., 173 it was only
with the report of Cooper 174 in 1969 that it became a widely accepted ap-
proach to management. A variety of modifications of Cooper's regimen have
been tried subsequently, and nearly all of them have been associated with an
antitumor response rate in excess of 50 per cent. 17 " These responses are rarely
complete, and they commonly last about nine months. Patients who respond
to treatment live about two to three times as long as those who fail chemother-
apy. 17 " Combination chemotherapy is superior to single agent treatment in
terms of the overall response rates, the frequency of complete remissions, and
the impact on the rate of survival. In the few studies that directly compare
combination chemotherapy with single agent treatment this conclusion is
17 *- 179
confirmee: although contradictory results exist.
There are two major types of combination chemotherapy regimens avail-
able. One group includes the many variations of the Cooper regimen 'Table
7-11 176 180 1SJ commonly referred to as CM F cyclophosphamide, methotrex-
"
'
,
ate, and 5-fluorouracil The most widely used and accepted form of this
>.
regimen is that reported by Canellos and coworkers.' in which cyclophos- 1
phamide is given in a daily oral dose of 100 mg m 2 for two weeks, methotrex-
ate is given intravenously in a dose of 40 mg m 2 on days one and eight of each
cycle, and 5-fluorouracil is given intravenously on days 1 and 8 of each cycle
in a dose of 600 mg nr. For each two weeks of treatment there is a subsequent
TABLE 7-11. Combination Chemotherapy Regimens Lacking Doxorubicin

for Metastatic Breast Cancer
No OF Drugs •
Patient* Per cent
Reference E\ALlATED Re >PONSE CYC MIX 5-FU VCR PRED OTHERS
- "
Carter"* X X X X X
Carter*** IIS 5
'
X X X X
Canellos.ef a/."*-'*1 93 X X X
Creech, et al. 1*1 46 46 X X X
'
Rossi, et aL"1 _ X L-PAM
Pouillart. et aV* 51 72 X X X
Rubens, et 1
aL * 50 62 X X X VRL
Hansen, et al. im 35 34 X X L-PAM. CCNU
Muss, et al.'" 31 6 VBL 6-TC
Longacre. et a/.*** 11 X X HMM
Odujinrin, et al. ,m 14 X X m-C
Deemarsky and
Chernomordikova*'*
1
31 59 X X
Freckman** 1 71 34 X CHL
Cziraki and Oo**8 52 90 X CHL
•Drug abbreviations: CYC, cyclophosphamide. MTX, methotrexate; 5-FU. 5-fluorouracil; VCR, vincristine;
6-TC. 6-thioguanine; HMM. hexaniethylmelaniine; ara-C. cytarabine; CHL. chlor-
ambucil; PRED, prednisone; L-PAM. alkeran; VBL, vinblastine; CCNU. lomusbne.
TABLE 7-12. Combination Chemotherapy Regimens Including Doxorubicin

for Metastatic Breast Cancer
NO OF Drugs Added to Doxorubicin"

Patients Per cent
Reference Evaluated Response CYC MTX 5-FU VCR PRED OTHERS
Brambilla, et al.
m 52 52 X
Eagan, et al.'
94
20 20 X
Tranum, et a/.
195
105 42 X
Jones, et al.
1 *8
55 80 X
Kennealey, et al.'
97
26 50 X
Tranum, et al.
m 134 42 X
Tranum, et al.
19 "
152 45 X X
Gutterman, et al.
199
44 79 X X
Hoffken, et al. 200 11 73 X X
Smalley, et al. 20 '
59 64 X X
Bull, et aL m 38 82 X X
Vogl and Love 203 12 92 X X ara-C
"Pouillart, et al. 1 **
73 71 X X X
Kennealey, et al.'
97
22 55 X X X
Tranum, et a/.
195
105 49 X X X
Abeloffand Ettinger JM 34 56 X X X
Presant, et mi al. 32 44 X BCNU
Lokich, et al. 2m 20 65 X L-PAM
Mattsson, et al. 207 50 78 X X X
Irwin, et «/.'-"" 49 52 X X X X
Tranum, et al.' 9 * 138 44 X X X X X
Chauvergne, et al. 2 '" 209 43 X X
Russell, et al.
209
48 67 X X
Lokich, et al.
20t
20 45 L-PAM
Muss, ('/ al.
2 " 31 29 CCNU
Watt, et al.
2'2
57 16 CCNU
Einhorn, et al.
2 ' 3
13 62 CCNU
Tormey, et al. 2 ' 4
50 46 DBD
Vogl, et al.
2 "-
6 17 DDP
Drug Abbreviations: CYC, cyclophosphamide; MTX, methotrexate; 5-FU, 5-fluorouracil; VCR, vincristine;
ara-C, cytarabine; PRED, prednisone; L-PAM, alkeran; DBD, dibromodulcitol;
DDP, cisplatin; BCNU, carmustine; CCNU, lomustine.
two-week rest period, followed by a repeat of this cycle. The doses of chemo-
therapy are modified on the basis of the patient's age and the functional status
of the bone marrow, liver, and kidney. Specifically, women under the age of
60 years with normal blood counts, normal liver and kidney function, no
previous cytotoxic chemotherapy, and minimal radiation therapy receive full
doses. Methotrexate is omitted in the face of azotemia; drug doses are reduced
by one half for women past the age of 60 years, for jaundice or liver dysfunc-
tion, for previous chemotherapy, or for grade 1 or 2 bone marrow toxicity, as
defined in Chapter 4. Chemotherapy is withheld for grade 3 or 4 bone marrow
depression or serious gastrointestinal dysfunction.
In general, the CMF
regimen described by Canellos et al. lsl is the most
common regimen of combination chemotherapy employed as adjuvant treat-
ment after surgery. It is also commonly used for patients with metastatic
disease, although some physicians use lower doses of drugs without apparent
compromise of therapeutic benefit. 182
The second group of regimens employs doxorubicin as a cornerstone of
treatment (Table 7-12). 184, 193215 Nearly all these regimens appear to give
slightly higher response rates than CMF, and responses tend to last somewhat
longer. However, these regimens also tend to be more toxic. Nevertheless,
comparative randomized clinical trials strongly suggest that the regimens
containing doxorubicin are superior to CMF

as primary treatment in patients
with metastatic disease. The trials leading to this conclusion are depicted in
Figure 7—1 169, 193, 195, 197, 198, 201, 202, 216_22 °
We
share the conclusion reached by others 198 that a combination of dox-
orubicin and cyclophosphamide is as good as any other drug regimen avail-
able for patients with metastatic disease. We prefer the one used by Jones et
19,i
«/. because of its ease of administration, relatively high response rate of 75
to 80 per cent, and good patient tolerance once the possibilities of alopecia
and cardiac damage have been accepted. The regimen involves the intraven-
ous administration of doxorubicin in a dose of 40 mg/m 2 on day 1 of each
course, followed by 4 days of oral cyclophosphamide in a dose of 200 mg/m 2
given on days 3, 4, 5, and 6. Every 28 days, a new cycle starts, with dosage
reductions for severe bone marrow depression or liver dysfunction. Once the
total dose of doxorubicin reaches 450 mg/m 2 the patient is converted to a CMF
treatment regimen. 196
It should be noted that a wide variety of combination regimens are being
studied. Numerous modifications of drug dosage and schedule are being

tested, and drug combinations that are not cross resistant, are being employed
together in the hope of increasing response rates and minimizing drug resis-
tance. 204 -
221
Patients who fail a first-line combination chemotherapy regimen may be

treated with a different combination of drugs or with different single agents
used alone in sequence.- An additional trial of hormonal therapy, such as with
megestrol acetate, may also be considered. Depending on the details of
previous drug therapy we rank the useful single agents as follows: doxorubi-
cin > cyclophosphamide or melphalan) > 5-fluorouracil >
alkylators (usually
methotrexate > vinblastine > vincristine > prednisone > mitomycin-C. Rare-
ly, very elderly patients or those with serious organ dysfunction that makes
combination chemotherapy unsafe may be candidates for single agent chemo-

therapy from the beginning. In this latter setting, treatment is generally
initiated with an alkylating agent rather than with doxorubicin.
Chemotherapy Plus Endocrine

Manipulation
all the studies combining endocrine manipulation with nonhormon-

Nearly
alchemotherapy antedate the widespread availability of ER measurements.
Examples of such studies include those from Boston 222 combining adrenalec-
CMFP FIGURE 7-1. Comparative trials in
advanced breast cancer. A connecting
line indicates equivalence of the regi-
mens. Arrows point to the more effec-
ACMFVP— AG CMFVP- "CMP tive regimen. Abbreviations: A.Adria-
mi/cin (doxorubicin); V, vincristine;
M, methotrexate; C, cyclophospha-
mide; F, 5-fluorouracil; P, prednisone.
CMFV
Numbers refer to references. (Modi-
fied and updated from Tormeij DC and
Carbone PP. Int J Radiat Oncol Biol
Phys4:30J, 1978.)
tomy with from Buffalo 223 combining adrenalectomy

5-fluorouracil, studies
with combination chemotherapy, studies from South Africa
224
and the Mayo
225
Clinic combining oophorectomy with chemotherapy, other studies combin-
ing endocrine ablation with chemotherapy, 226, 227 and numerous studies com-
bining various hormones with single agent 228 230 or multiagent chemothera-
"
231,232
py. In general, those studies combining endocrine ablation and
chemotherapy have suggested benefit from the combination, whereas little, if
any, benefit has resulted from combinations lacking endocrine ablation. This
discrepancy in results, the relatively small numbers of patients studied, and
the inability to relate benefit to ER status leads us to consider combined
endocrine manipulation and cytotoxic chemotherapy to be investigational.
One should follow the medical literature closely for new guidelines on this
subject as the final results of several ongoing trials become avail-
17() 233 234
able ' '
SYSTEMIC TREATMENT FOR

MICROMETASTATIC BREAST
CANCER
Adjuvant Chemotherapy
Detailed comprehensive discussions of the theoretic basis, historic results

and achievements, and problems of adjuvant chemotherapy are available in
numerous reviews." 12,235 237 Thus far, the major experimental accomplish-
'
ment concerning systemic chemotherapy in patients who have recently been

treated with potentially curative local therapy, but who have a high risk of
recurrence, has been a clear-cut demonstration that some subgroups have
delayed relapse and modestly improved survival. 11 12 Multiple studies con-
'
ducted by the NSABP, 11,236 most notably one that involves a comparison of
alkeran with a placebo, as well as a large study conducted in Milan, Italy, 12 237 '
comparing CMF with no treatment, have shown reductions in early recur-

rence following operation in premenopausal patients. Both studies show a
trend toward an improved survival rate. However, these studies do not show
any benefit from adjuvant chemotherapy for postmenopausal patients.
Because of the preliminary nature of these results, along with the financial
and emotional costs, 238 the possibility of therapy-induced acute leukemia 239 or
other delayed side effects, and the decreased quality of life of women while
under treatment, 240 the long-term value of adjuvant chemotherapy is uncer-
tain. However, it appears that the principle that these patients have a systemic
disease in need of systemic therapy has been supported. 11, 236 237 241 The prob-
' '
lems are to define those patients who are most likely to benefit from such
therapy, given its present limitations, and to identify better programs of sys-
temic treatment. For the present, we use CMF in premenopausal patients
but consider postmenopausal patients to be candidates for investigational
therapy.
If Ongoing and future trials continue to document an improved rate of
survival with adjuvant chemotherapy, accurate staging by axillary node dis-
section and possibly internal mammary node

biopsies will become an increas-
ingly important part of the primary treatment of this disease.
Immunotherapy
Immunotherapy has been used alone, 242 with chemotherapy, 238, 243, 244
or
245
with radiation therapy to treat breast cancer patients with metastatic dis-
ease. A host immune response to breast cancer is suggested by the natural
history of the disease and by the observation that lymphoid infiltration of the
primary tumor or sinus histiocytosis of the regional nodes correlates with the
survival rate. 71,246 Antibody to tumor-associated antigens of breast cancer has
been demonstrated to correlate with the clinical course. 246 However, systemic
immunotherapy remains of unproven value.
The intralesional injection of bacillus Calmette-Guerin (BCG) used alone
or in combination with hormonal therapy or chemotherapy appears to be an
effective method of treating selected patients with chest wall recurrence
following radiation therapy. 247 However, further studies are needed to define
the possible role of experimental local immunotherapy in the treatment of
248
breast cancer. 71,
INTEGRATION OF TREATMENT
MODALITIES
The treatment modalities for the management of breast cancer are in a state
of and recommendations must be made in the context of the results of
flux,
current therapeutic research. Because of this evolving situation, some experi-
enced physicians, including the authors of this chapter, may disagree about
the specific management of some patients. In addition, one should remember
that each patient is unique, with a distinct socioeconomic and psychologic
background, spectrum of associated organ dysfunctions, and stage of disease
activity. The tumor is also distinctive, both in terms of the rate of tumor
growth and the areas of dominant disease. The experienced physician will
individualize therapy when it is appropriate; nevertheless, it is useful to have
a generalized approach to treatment as a guide. Figure 7-2 presents one such
schema.
Primary operable breast cancer is usually treated with a modified radical
mastectomy in our institutions. However, an acceptable alternative in select-
ed patients with small lesions, who are fully informed of the uncertain long-
term benefits and risks, is a lesser operative procedure (wide local excision-
total gross removal) followed by radiation therapy. Patients with positive
axillary node involvement or central or medial lesions (which are primarily
treated with a modified radical mastectomy) are potential candidates for post-
operative radiation therapy to the supra- and infraclavicular areas and internal
mammary nodes, depending upon the therapeutic philosophy. One of the
present authors (RWT) usually recommends such therapy, whereas the other
two (FCS and CMH) usually recommend experimental adjuvant chemothera
PRIMARY TREATMENT
Nodes
FIGURE 7-2. A
sequential program of treatment for Premenopausal Postmenopausal
women with breast cancer. Abbreviations are as fol- C*2 I
lows: + nodes, regional nodes contain metastatic carci-

,
I
'
Relapse-
noma; — nodes, regional nodes free of tumor; ER +, the Cure
tumor contains an estrogen receptor in its cytoplasm;

ER«or ER-or
ER' the tumor has either no or very low concentrations
, ER ' Ibetterrial ER ? ipoor risti
J
of estrogen receptor; £R. .the estrogen-receptor status I
Primary endocrine Adriamycin * cyclophosphamide

of the tumor is unknown or the results are considered to manipulation
be technically in question. See text for discussion of Benefit Failure Ongoing Failure Delore
variables that may modify therapy for individual response

atlyr
lyr
patients. junta] I
endocrine 5-FU
manipulation
Methotreiate
Vmciastine
Reconsider endocrine manipulation
py without radiation therapy, especially for premenopausal patients with four

or more involved axillary nodes.
Patients with untreated metastatic breast cancer or those who relapse after
adjuvant chemotherapy are shown in Figure
treated as 7-2. When the
hormone-receptor status of the tumor is known, patients are treated with
primary endocrine manipulation if they have ER-positive disease, or they are
treated with doxorubicin plus cyclophosphamide (AC) if ER is lacking. 196
Patients for whom the ER status is unknown are treated on an individual
basis, depending upon the pace of the disease, sites of dominant metastases,
menopausal status, and age. Secondary endocrine manipulation is generally
reserved for patients who have shown benefit from primary manipulation and
in whom the pace of disease is extremely slow and limited to soft tissues or
skin. Patients who have been treated with AC and progress are treated with
sequential single agent chemotherapy (as described earlier in this chapter) or
with experimental agents. Patients who respond to AC, but who must discon-
tinue doxorubicin to avoid cardiac damage, are usually continued on a CMF
regimen.
SPECIAL PROBLEMS
Psychologic Factors and Rehabilitation
The American Cancer Society, through Reach to Recovery program, has

its
pioneered in efforts to help the woman who has had a mastectomy to adjust to
her altered body image. Main of the factors discussed previously regarding
the extent of surgery needed for optimal treatment relate to the fear most
women have of losing a breast. A complete discussion of this problem is
beyond the scope of this chapter, but the reader may pursue further details of
description and management in other available reviews. 75,76 249 250 ' '
It should be noted that a sensible and attentive approach is critical in trying
to assess the patient's emotional resources in dealing with the problem of

breast surgery. Most patients do adjust; however, the speed of this adjustment
may be markedly influenced by attentive and sensitive physicians.
A newapproach that is used for some patients is breast reconstruction. 9 I0 -
This is usually achieved by performing a reduction mammoplasty of the

remaining normal breast plus reconstruction with an implant in the area of the
mastectomy. This technique requires additional evaluation, but for some
women the psychologic benefit has been enormous.
Pregnancy
Although it was once held that pregnancy adversely affected breast cancer,
this is no longer considered to be true. Reviews of this issue are avail-
252
able. 251 -
Bilateral Breast Cancer
Although bilateral breast cancer occurs most commonly in the context of a

strong family history- of the disease, it occasionally occurs as an isolated
255
event. 253 may be diagnosed as a
"
In some cases, bilateral breast cancer
microscopic process by performing a blind biopsy of the clinically normal
breast in the "mirror image" area corresponding to the clinically apparent
tumor. Such patients have a good prognosis. However, synchronous clinically
evident bilateral breast cancer carries a very poor prognosis and usually is
followed in short order by metastatic disease. Current programs of experimen-
tal adjuvant chemotherapy do not commonly include such patients, but the
risk of metastatic disease is equivalent to that seen in patients with positive

axillary node involvement.
Asynchronous bilateral breast cancer is not unusual and carries a less
serious prognosis than the synchronous form of the disease. For this reason, a
woman who has had unilateral breast cancer should have a careful lifelong
follow-up with careful attention to the possible development of a new primary
tumor in the remaining breast.
Prophylactic Therapy
A major new trend, which is primarily reflected in articles in the plastic

surgery literature and in commercial magazines devoted to the women's
movement, has been the attempted prophylactic therapy of breast cancer in
high-risk women. This involves a subcutaneous mastectomy followed by a
prosthetic implant. Although it may be overutilized in some parts of the
country, for selected patients the procedure may be of value. The merits of
6
this approach have been reviewed, but the long-term value of this treatment
has yet to be defined.
Male Breast Cancer
men. 256 260

"
Cancer of the breast is a rare disease in It composes less than 1
per cent of all breast carcinomas and less than 1.5 per cent of all malignant
tumors in men. There are multiple reports of familial male breast cancer, 261 263
"
and altered estrogen metabolism has been proposed as a possible etiologic

256
factor. However, with the exception of idiopathic gynecomastia and Kline-
felter's syndrome, predisposing conditions for the development of male breast
cancer are poorly defined. 256
Numerous reports have confirmed a high frequency of ER and PgR in male
breast cancer tissue. 264 268 The disease also mimics female breast cancer in the
"
histologic appearance, the clinical presentation, and the tendency to metasta-

256 260
"
size to bone. Therapeutic considerations are also similar. In 1944, Treves

269
et a/. reported clear-cut benefit from orchiectomy in these patients, and this
256, 27 °
has subsequently been widely con finned. The disease may also respond
to diethylstilbestrol,
271
tamoxifen, 272
androgens, 273 adrenalectomy, 256, 274 and
256 275
hypophyseetomy. -
Although little has been published on the use of non-

hormonal chemotherapy, our personal experience suggests that response rates
and response durations are very similar to diose seen in women with breast
cancer.
Based on these considerations, we recommend that males with breast can-
cer be managed in a manner analogous to female breast cancer management.
The concentration of ER and PgR in tumor tissue should be assessed. Patients
with metastatic ER-positive tumors or with slowly growing disease that is
limited to soft tissues, nodes, or bones should initially be treated with endo-
crine manipulation. This will usually be orchiectomy, although tamoxifen or
diethylstilbestrol are reasonable alternatives. Secondary endocrine maneu-
vers would include other hormones or adrenalectomy (either "medical" with
aminoglutethimide, if available, or surgical). The indications for combination
chemotherapy are the same as those for female breast cancer.
Reviews are available for more detailed discussions of this entity. 256 261
"
New, more effective chemotherapeutic drugs need to be developed and

tested for the treatment of women with metastatic breast cancer. Successful
treatment should be further tested in the adjuvant setting. In vitro assays for
differential sensitivity of breast cancer cells to chemotherapy max be devel-
oped. The increased use of estrogen, progesterone, prolactin, and possibly
other hormone-receptor proteins should allow more precise treatment plan-
ning, and efforts to reduce the amount of tissue required for such assays are
under way.
Tumor markers may prove to be useful in defining the effectiveness of
treatment and the subsequent need to continue or reinstitute treatment. Com-
bination chemotherapy-hormonal therapy and chemotherapy-immunotherapy
need to be evaluated to determine the possible roles of such combinations.
Radiation therapy may supplant surgery as the usual treatment for primary
breast cancer. Defining the role of adjuvant chemotherapy will depend on
longer follow-up in ongoing adjuvant trials regarding recurrence, survival,
quality of life, and long-term effects.
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8 / Lung Cancer 197
CHAPTER 8
LUNG CANCER
Gregory P Sarna E Carmack Holmes
Zbigniew Petrovich
INTRODUCTION
Cancers of the lung are a major health problem in the United States. The
incidence and resulting mortality rates of these tumors are excessive and have
been increasing in both males and females. The estimated number of lung
cancer cases in the United States for 1978 is 102,000 (79,000 males and 23,000
females), whereas the estimated mortality rate is 92,400 (70,500 males and
21,900 females). Lung cancers have accounted for 15 per cent of cancer
incidence (22 per cent in males and 7 per cent in females) and 23 per cent of
cancer mortality (33 per cent in males and 12 per cent in females) in 1978. *'
The incidence may be increased in blacks and decreased in Mexican Ameri-
cans. 2,3
The control of lung cancer is a formidable problem. The clear identification
of tobacco smoking as a major etiologic factor has been reviewed by Wynder
and Hoffman 4 and by Harris. 5 This strong relationship suggests that control
of this disease might be more effectively improved by preventive rather than
by therapeutic advances. Although attempts to modify American smoking
habits through education and to decrease tobacco carcinogenicity through
filters have had some effects, lung cancer remains largely a smoker's dis-
ease. 6 '
7
In addition to tobacco, risk factors may include exposure to uranium and

other radiation sources, chromates, nickel, asbestos, and chloromethyl-methyl
ether. 5,8 There may be genetic 9 or familial risk factors. A biochemical risk
10
factor — the inducibility of aryl hydrocarbon hydroxylase — has been report-

11
ed.
NATURAL HISTORY
Classification
In an attempt to standardize the histologic typing of lung tumors, a commit-

tee of the World Health Organization developed a classification system that
has proved reliable and reproducible and that has been accepted, with or
without minor modifications, by most pathologists and oncologists. Table 8-1
*Excluding nonmelanomatous skin lesions and carcinoma in situ of the uterine cervix.
TABLE 8-1. Histologic Types of Lung Cancer
I. Epidermoid carcinomas
II. Small cell anaplastic carcinomas
III. Adenocarcinomas
IV. Large cell carcinomas
V. Combined epidermoid and adenocarcinomas
VI. Carcinoid tumors
VII. Bronchial gland tumors
VIII. Papillary tumors of the surface epithelium
IX. "Mixed" tumors and carcinosarcomas
X. Sarcomas
XI. Unclassified
XII. Mesotheliomas
XIII. Melanomas
presents the histopathologic types of lung tumors. 12 Modifications of types I

through IV (the predominant histologic types: epidermoid carcinoma, small
cell carcinoma, adenocarcinoma, and large cell carcinoma) have been pro-
posed. 13 A
survey of several major series suggests that epidermoid carcinoma
composes 35 to 71 per cent of cases, small cell carcinoma composes 12 to 25
per cent of cases, adenocarcinoma composes 9 to 29 per cent of cases, and
large cell carcinoma composes 3 to 16 per cent of cases. 14 20 There is also
"
evidence that adenocarcinoma of the lung may be increasing in prevalence,

particularly in females. 15
Epidermoid carcinomas are presumably derived from bronchial epitheli-
um. 21 They tend to be centrally located 19 22 and locally invasive, and they are
'
16 19
less likely to have distant metastases than are other histologic types. Of '
the four major histologic types, these are the most likely to be resectable, and,
accordingly, they are associated with the best prognosis. 14 19 20 The relation-
' '
ship of the degree of differentiation of epidermoid tumors to survival is not

clear. 17
Small cell carcinomas may arise from granular basal cells (Kulchitsky-type
cells of possible neuroectodermal origin that are present in bronchial muco-
sa) 21
or from a variety of other potential precursor cells. 23 They tend to be
centrally located 19, 22, 24 but are the most likely of the histologic types to have
distant metastases. 19,25,26 Sites of metastases frequently include the brain,
bone, bone marrow, liver, adrenal glands, and abdominal lymph nodes. 26 30
"
The dismal survival rate with resected small cell carcinoma 14 24, 26:il suggests '
that this histologic type is usually disseminated at diagnosis, regardless of the

results of staging studies. Small cell carcinoma tends to be the most rapidly
growing histologic type of lung cancer, with a representative growth faction of
5i per cent and a representative doubling time of approximately 33 days. 32 33 '
This tumor is aggressive and bears a poor prognosis when it is untreated or

treated by surgery alone. It is rarely resectable but is generally responsive to
chemotherapy or radiation therapy. Data regarding the differential survival
rates of subtypes of small cell carcinoma (lymphocyte-like, fusiform, and
polygonal) are preliminary. 21 34 '
Adenocarcinomas of the lung may arise from bronchoalveolar epithelium or

from mucous glands. 21 They tend to be peripheral, small, and confined to one
lobe. 19, 22 In addition to the risk factors previously mentioned (tobacco, asbes-
8 / Lung Cancer 199
tos, and so pulmonary disease, pulmonary scars, and

on), chronic interstitial
fibrosis may predispose tumor type. 21 Adenocarcinomas frequently
to this
16
involve the pleura and often metastasize to the scalene nodes. Females are
likely to have adenocarcinomas. 15, 19 Bronchoalveolar carcinoma, along with
bronchogenic types (acinar and papillary), are included in this category. The
bronchoalveolar type of carcinoma usually arises peripherally as a unicentric
It may arise from CLARA
35
lesion and may be related to pre-existent scars.
36
cells (nonciliated bronchiolar epithelial cells). Although this type of car-
cinoma tends to metastasize by aerogenic spread, resulting in multiple
metastatic pulmonary nodules, the early diagnosis of limited disease may
37 " 39
lead to surgical cure. 35-
Tobacco smoking is a strong risk factor for each of the four major histologic
types of lung cancer, but the relationship is least strong for adenocarcinoma,
and it is this histologic type that the nonsmoker who develops lung cancer is
18 - 40 - 41
likely to have. 15 '
Large carcinoma of the lung may be peripheral or central and is often
cell
19-22
bulky. Giant cell and clear cell carcinomas are included in this category.
Etiologic factors are similar to those for adenocarcinoma, and the histologic
distinction between them is sometimes unclear.
Other, less common histologic types of tumors are also listed in Table 8-1.
Combined epidermoid carcinoma and adenocarcinoma (adenosquamous) is a
rare entity, accounting for less than 1 per cent of diagnoses at initial biop-
sy 18, 19 but for perhaps more (up to 5 per cent) at autopsy. 41
Bronchial carcinoid tumors compose less than 1 per cent of lung tumors. 42
They, like small cell carcinomas, may be related to Kulchitsky-type cells. 43
However, the epidemiologic pattern of these tumors differs from that of small
44
cell carcinoma, making the relationship between the two unclear. Although
bronchial carcinoid tumors have previously been classified by some as "bron-
chial adenomas," they are frequently invasive and metastasize. 45- Histologic 4,i
criteria do not predict well for malignant behavior. 42 These tumors tend to be
central and to present with local obstructive symptoms (cough, wheeze, dysp-
nea, and hemoptysis). When they are peripheral, they tend to be silent or to
present with hemoptysis. 47 Carcinoid syndrome with or without hepatic
metastases is may occur. 4 -45-48 51 The elevation of 5-hydroxyindole-
rare but - "
acetic acid (5-HIAA) may occur with or without carcinoid syndrome. 45 The
treatment of choice for resectable carcinoids of the lung is clearly surgery,
with the five-year survival rate for local-regional disease in the 60 to 80 per
cent range. 48,52 Radiation therapy has had some efficacy in a small series. 42
When distant metastases are present, the five-year survival rate has been
estimated at 1 1 per cent. 52
Bronchial gland tumors (cylindromas [adenoid cystic] and mucoepidermoid
carcinomas) are less frequent than carcinoid tumors, but, like carcinoids, they
may behave malignantly.4** 58 These lesions tend to present with bronchial
obstruction. The cylindroma is likely to be infiltrative and locally invasive,
whereas the mucoepidermoid carcinoma may be pedunculated. Surgery is the
treatment of choice, but frequently the disease is unresectable or fails sur-
gery. 54
Papillary tumors of surface epithelium are rare exophytic tumors. Although
theymay be infiltrative, they tend to have a better prognosis than the more
common lung tumors, and they may be radiosensitive. 12
Like the papillary tumors, mixed tumors and carcinosarcomas are rare.
Carcinosarcomas may have a better prognosis than more common lesions,
particularly when they are endobronchial. 12, 13 Hamartomas, usually present-
ing as an asymptomatic finding or as bronchial obstruction, are generally be-
nign. 55
Mesotheliomas are pleural rather than lung parenchymal tumors. A minori-
ty are localized (usually fibrous and histologically benign but sometimes
fibrosarcomatous), but the majority are diffuse (malignant, epithelial, fibrosar-
comatous, or mixed). 56 58 The localized type is often asymptomatic and is
"
diagnosed as a mass on a screening chest x-ray. The incidence of this type of

mesothelioma is not clearly related to asbestos exposure. 58,59 Localized mes-
othelioma is frequently surgically curable. The diffuse mesothelioma usually
presents with chest pain, pleural effusion, and weight loss. 58, 59 The incidence
of this type of mesothelioma is related to asbestos exposure, and the prognosis
57
is poor, with a median survival rate of 12 months. Surgery alone is ineffec-
tive in diffuse mesothelioma, but it may play a role in combination with
radiation therapy or chemotherapy, or both. 57, 60
Sarcomas of the lung are discussed under soft tissue sarcomas in Chapter
15, and melanomas will be discussed in Chapter 16. Unclassified tumors
cannot be discussed homogeneously.
The identification of high-risk patients may be useful both for preventive

measures and for the selection of patients to be "screened" for bronchogenic
carcinoma. Trials of "screening" high-risk patients with frequent chest x-rays
and sputum cytologies are ongoing at the Mayo Clinic, 61 the Johns Hopkins
University, 62 and the Memorial Sloan-Kettering Cancer Institute. 63 Early data
from those studies suggest that baseline screening may detect a prevalence
rate of approximately five per thousand and that patients at high risk who are
detected may have lower stage and more curable disease than those who
present with symptoms. Long-term follow-up will be necessary to assess the
overall impact of such screening programs on the survival rate of patients who
develop lung cancer. An earlier study, however, using screening chest x-rays
alone, showed only a 12 per cent five-year survival rate in patients who were
diagnosed within six months of a negative chest x-ray. 64
Although the diagnosis of asymptomatic patients may occur with routine
screening, greater than 90 per cent of patients with lung cancer are sympto-
matic at the time of presentation. 65, ^ Symptoms may be classified as local
(direct effects of local tumor related to site), metastatic (direct effects of
metastatic tumor related to site), or systemic (indirect effects of tumor not
directly related to site).
Presenting symptoms and signs of lung cancer have been reviewed by
Hyde and Hyde 67 and by Cohen. 68 Local effects of lung cancer and estimates
of their frequency at presentation are shown in Table 8-2. Central lesions fre-
quently cause cough, hemoptysis, and dyspnea. They also may cause hoarse-
8 / Lung Cancer 201
TABLE S-l. Local Effects of Lung Cancer at Presentation
Symptom or Sign Frequency
Cough 70%
Hemopt ~40%
Dyspnea ~ 40%
Chest pain ~ 35%
Hoarseness 5%
Effects of superior vena caval obstruction 5%
Pericardial effusion Rare
Effects of brachial plexus compression and/or Homer's syndrome Rare
Wheezing ~2%
ness, dysphagia, wheezing, and symptoms due to superior vena cava] ob-
struction or to pericardial involvement. Peripheral lesions may be more com-
mon than central lesions. w They frequently do not cause local symptoms, but
they may cause cough, chest pain, and dyspnea due to pleural effusion or
restrictive changes. Weiss et al." have noted that new or increased chronic
cough or expectoration in an older male smoker may herald the appearance of
lung cancer.
Distant effects relate to the frequent sites of distant meta^ta^x. Table 8-3
reflects the tendency for tumors to spread to bone, liver, lymph nodes, and
brain. The frequency of those manifestations at presentation are variable.
Systemic effects are listed in Table 8—4. These include endocrine and
nonendocrine manifestations of disease. Endocrine manifestations of bron-
chogenic carcinoma have been reviewed by Primack. 7 " Small cell carcinoma
has been claimed by some to be a tumor of APL'D cells (cells of neural crest
origin that are capable of "amine precursor uptake and decarboxylation"). 71 It
frequently produces ACTH, melanocyte-stimulating hormont M^H or an- .
tidiuretic hormone (ADH), but may also produce other hormones. 71 Other
histologic cell types have been noted to produce hormones as well, particular-
ly ACTH and parathyroid hormone (PTH
7"
It has been estimated that 10 per
).
cent of patients with lung cancer have clinical manifestations of ectopic

hormone production. Biochemical evidence of ectopic hormone production
may be more common. 7 - Hypercalcemia may be found in more than 10 per
cent of patients with advanced lung cancer. This is most prevalent in epider-
moid and large cell carcinomas and may or may not be related to lytic bone
lesions. 73 Prostaglandins, as well as PTH. have been suggested as a cause of
this phenomenon in patients without bone metastases. 74 Constitutional symp-
toms, neurologic syndromes, cutaneous changes, skeletal changes, and throm-
botic events are prominent among nonendocrine systemic manifestations.
They are detailed in Table 8—4.
TABLE 8-3. Metastatic Effects of Lung Cancer at Pi resentation
Symptom or Sign Frequency
Bone pain up to 1
Hepatomegaly
Lymphadenopathy 20
Neurologic manifestation of intracranial metastases o^-lO^c
TABLE 8-4. Systemic Effects of Bronchogenic Carcinoma
Constitutional
Weight loss
Anorexia
Weakness
Fever
Neurologic
Corticocerebellar degeneration
Spinal-cerebellar defeneration
Carcinomatous myopathies
including Eaton Lambert Syndrome)
i
Carcinomatous neuropath)
Polymyositis
Cutaneous
Acanthosis nigricans
Dermatomyositis
Scleroderma
Skeletal
Clubbing
Hypertrophic osteoarthropathy
Vascular-Coagulation
Thrombophlebitis
Disseminated intravascular coagulation
Marantic endocarditis
Endocrine
ADH secretion
Hypercalcemia
(PTH, prostaglandins, ? osteoclast activating factors)
ACTH
Gynecomastia
PTH
MSH
In the patient whoevaluated because of symptoms or in the asymptoma-

is
tic "screened" patient, radiographic abnormalities may suggest the diagnosis

of lung cancer. Radiographic findings that are suggestive of malignancy in-
clude a new or enlarged pulmonary nodule (particularly if the outline is
regular or notched and if calcium is shadow, a

absent), an enlarged hilar
rapidly increasing or nodular infiltrative lesion, unresolved pneumonia, local-
ized atelectasis or emphysema, and bronchostenosis.
75
Byrd et al. 22 have
correlated radiographic findings with histologic type. Small cell carcinoma
frequently presented with a hilar or perihilar mass or prominence (78 per
cent); less frequently a peripheral nodule was seen (32 per cent). This tumor
tended to be large (>4 cm in diameter) when it was peripheral. Epidermoid
carcinoma was also infrequently peripheral (31 per cent), and it tended to be
large when it was peripheral. It was commonly associated with hilar promi-
nence (40 per cent) and was frequently associated with bronchial obstruction
(53 per cent). Cavitation was not rare in epidermoid carcinoma (22 per cent),
unlike other histologic types (<6 per cent). Adenocarcinoma and large cell
carcinoma were frequently peripheral and usually les than 4 cm in diameter
76
(72 per cent and 64 per cent, respectively). Miller has reviewed radiographic
findings in lung cancer; Cohen and Matthews 77 have reviewed such data for
small cell carcinoma.
8 / Lung Cancer 203
In a patient with an abnormal chest x-ray suspicions for tumor, it is

that is
important to diagnose or exclude malignancy. Cytologic examination of ex-

pectorated sputum is a noninvasive procedure that may be diagnostic. Freshly
processed samples of early morning sputum are best. Expectoration of sputum
may be enhanced by manual or mechanical percussion or by aerosol induc-
7-
tion.
If adequate sputum is not produced or is nondiagnostic, endoscopy may be
rewarding, particularly for relatively central lesions. The fiberoptic broncho-

scope allows for visualizing and sampling some lesions beyond the central-
hilar regions and is generally well tolerated. The relative roles of rigid versus
fiberopticbronchoscopy have been reviewed by Marsh et al. n Bronchoscopy
can provide visualization and biopsy of endobronchial lesions, differential
washings of bronchi, aspiration and brushings from various areas, and trans-
bronchial biopsy of peribronchial lesions. It may also stimulate the produc-
tion of good expectorated sputum samples. In a patient with a normal chest
x-ray but a positive sputum cytologic finding or other suggestion of broncho-
genic carcinoma, this technique may allow the identification and localization
of an occult carcinoma. 80* 81 A positive finding on cytopathologic examination
of sputum or bronchial washing is very reliable for the diagnosis of malignan-
82 8 " "
cy (98 per cent) and reasonably good (75 per cent) for identifying cell type.
4
It is important to realize, however, that, rarely, a positive sputum cytologic
finding may be due to aspirated tumor cells shed from a head and neck malig-
nancy.
In tumors that are too peripherally located for bronchoscopic diagnosis,
transthoracic needle aspiration or biopsy, usually performed under fluoros-
copy, may provide a diagnosis. 85 Pleural or pericardial fluid aspiration, me-
diastinoscopy or parasternal mediastinotomy. and scalene or supraclavicular
node biopsies max be appropriate for individual cases.
In some patients, the techniques just described will not be diagnostic, and a
thoracotomy may be necessary. The role of thoracotomy for the diagnosis of
the otherwise undiagnosed solitary pulmonary nodule in an asymptomatic
patient is controversial. 8 " ss The decision as to when or if thoracotomy should
be done must be individualized on the basis of a number of variables, includ-
ing the radiographic appearance of the lesion, the growth rate of the lesion,
the patient's age, and the prevalence of locally endemic fungal infections.
However, in a patient with a "coin lesion" that is undiagnosed after other
diagnostic studies, thoracotomy should be strongly considered because of the
significant cure rate for these carcinomas. 88,89
Although carcinoembryonic antigen levels are frequently elevated in all
histologic types of lung cancer, this test is not sensitive or specific enough to
be of great clinical use in screening or diagnosis. 90
Staging
Because there is significant morbidity and mortality associated with the

surgical treatment of lung cancer, it is important to identify and to exclude
from primary surgical therapy those patients who will not benefit from at-
tempts at resection. Studies that identifv distant and local disease and a
204 II Treatment of Specific NEOPLASMS
staging system that organizes such information into categories of prognostic

and therapeutic importance are usefulin planning and evaluating the efficacy
of therapy.
Clearly, the majority of patients with lung cancer are not curable. Five-year
survivorship tor all patients is less than 10 per cent. For surgically treated
1
patients, it is in the 20 to 40 per cent range but will van with selection
criteria. A frequent cause of treatment failure is nonresectable or residual
disease — both local and distant. A large number
of patients may exhibit
evidence of nonresectability of their cancer at a preliminary clinical investiga-
tion. Estimates of the percentage of patients whose disease is not resectable at
presentation vary with criteria for resectability and patterns of referral, but
65 9ia4
probably only 20 35 per cent of lung carcinomas are resectable.
to
One criterion for nonresectability is the presence of distant metastases. If
Mich metastases are present and detectable, they should not be overlooked in
a patient for whom surgery is otherwise planned. Approximately half of the
patients who have inoperable cancers at presentation may have distant metas-
27
tases. Frequent sites of these metastases include bone (39 per cent), thorax
(contralateral lung, mediastinum, and pericardium) (34 per cent), skin-
peripheral lymph nodes (34 per cent), liver (16 per cent), and brain (15 per
7
cent).-
In autopsy studies, distant metastases are common. Frequent sites include
lymph nodes — 70 (per cent), liver (30 to 40 per
cent), adrenal glands (20 to 33
per cent), brain (9 to 28 per cent), bone (14 to 31 per cent), lung (10 to 23 per
cent), pleura (9 to 30 per cent), kidney (15 to 17 per cent), pancreas (7 to 12 per
per cent). 95 98
"
cent) and heart and pericardium (6 to 12
Lung cancer, therefore, is frequently a disseminated disease. The limited
patient five-year survivorship in operated and resected disease suggests that it
is common for nonresectable disease to be undetectable or undetected prior
to surgical attempts at cure. Supportive evidence is found in the work of

Matthews et «/." who have reviewed autopsy findings in patients who died
within 30 days of a "curative" surgical resection of lung cancer. They found
persistent disease in 35 per cent of those patients. Metastases were predomi-
nantly distant in patients with histologic types other than epidermoid carcino-
ma, and they were equally distant and local in patients with epidermoid
carcinomas. Frequent sites of distant metastases included adrenal glands,
liver, lymph nodes,brain, bone, kidney, and lung.
reasonable to attempt to evaluate patients with potentially operable
It is
disease to ensure that no detectable distant metastases preclude surgical

therapy. In addition to history, physical examination, screening chemistries,
and chest x-ray, other diagnostic studies have been used for the staging of
patients with lung cancer.
Because the liver, pancreas, and adrenal glands are frequent sites of meta-
static tumor involvement, the investigation of those organs may be appropri-
100
ate. Bell has reported a 17 per cent rate of diagnosis of occult metastases
with staging laparotomy. However, this procedure may be too aggressive for
routine use. The yield and cost efficacy of surveying the upper abdomen for
occult disease withnewer techniques (e.g., abdominal ultrasound and com-
puter tomography) are presently not defined.
8 / Lung Cancer 205
Hepatic involvement may be suspected from physical findings or screening

chemistries. Detectable metastases are almost always associated with an ele-
vated alkaline phosphatase level, but abnormalities of that test, as well as tests
for levels of bilirubin and serum glutamic-oxaloacetic transaminase (SGOT)
are not specific, and false positive elevations may be more frequent than true
positive elevations. 101 Liver scans have had a disappointing yield and rate of
error in patients without other evidence of hepatic involvement, but they may
be of value in patients with small cell carcinoma or with other suggestive
evidence of liver involvement. 100 102 Liver biopsy with peritoneoscopy has
"
been advised by some in order to stage that area more accurately. 101, 103
Bone involvement is frequently detectable with noninvasive staging. Bone
scans are often positive (46 per cent), even in patients who have otherwise
limited disease (32 per cent). 104 Radiographic bone surveys also have an
appreciable yield; lesions are primarily lytic but may be blastic, particularly
with small cell carcinoma or adenocarcinoma. 105, 106 The value of bone scans in
asymptomatic patients has been challenged, however, 107 and the true role of
this procedure in staging lung cancer is not yet resolved.
Radioisotopic brain scans are rarely abnormal in patients without neurolog-
108 110
"
ic findings. Computed tomography, 111 however, might improve that
yield, particularly in patients with small cell carcinoma.
Bone marrow examination is a useful staging procedure in small cell carci-
noma (^17 per cent positive), but it is not of great value in other histologic
types. 28
Unresectable local disease, like distant metastases, max be a cause of
surgical failure. Mediastinoscopy is a safe, effective diagnostic technique that
may show otherwise occult mediastinal tumor in significant numbers of pa-
117
tients with lung cancer. 112
'
The prognostic implications of mediastinal node
tumor and the procedure itself will be discussed further in the next section.
Scalene node biopsy is another technique for evaluating regional disease.
Although this may be of value in a patient with palpable nodes, it has a
considerably lower yield than mediastinoscopy if the nodes are not palpa-
ble.
117 118
'
A recommended approach toward diagnostic "staging studies" is
provided in Table 8-5.
There have been multiple staging systems devised for the categorization of
disease patterns in patients with lung cancer. The system devised by the Task
Force on Lung Cancer of the American Joint Committee for Cancer Staging
and End Results Reporting 119 122 is useful and popular. This system classifies
"
disease as to characteristics of T (primary tumor), X (regional lymph nodes),

and M (distant metastases) and then defines stage on the basis of the TNM
patterns. Table 8-6 defines criteria for assigning TNM
categories and stages
for lung carcinomas. Stage I disease includes most tumors that lack nodal or
distant metastases and small (^3 cm) tumors with ipsilateral hilar node metas-
tases. Stage II disease is limited to tumors >3 cm in diameter with ipsilateral
hilar nodal metastases. Stage III disease includes tumors directly extending
into structures that are adjacent to the lung, tumors within 2 cm of the carina,
tumors associated with pleural effusion, and tumors associated with atelecta-
sis or obstructive pneumonitis of an entire lung. It also includes any tumor
with mediastinal lymph node or distant metastases.

TABLE 8-5. Recommended Staging Work Up
Small cell carcinomas

History, physical examination
Chest radiography ± tomography
Liver-spleen scan
Bone scan with x-rays of abnormal areas
Computed tomography of brain
Bone marrow aspirate and biopsy
Screening chemistries, blood count, urinalysis
Other histologic types

History, physical examination to include mirror exam of larynx and nasopharynx
Chest radiograph ± tomograms
Bone scan with x-rays of abnormal areas
Screening chemistries, blood count, urinalysis
Mediastinoscopy at the time of surgery if otherwise resectable (optional for small differen-
tiated peripheral lesions with negative mediastinal and hilar tomography)
Prognosis
With the AJC staging system, the 18-month survival rate for subsets of stage
I disease is in the 49 to 65 per cent range, and for stage II disease, it is about
35 per cent. For stage III disease, it ranges from 4 to 15 per cent (excluding 24_
per cent for T3 N M
lesions that include superior sulcus tumors) (Table
8-7). 121
Small cell carcinoma has a two-year survivorship of less than 6 per
cent, regardless of stage. Histologic types other than small cell carcinoma
TABLE 8-6. Staging of Carcinoma of the Lung"
T,N,M
T: Primary Tumor
Tu No evidence of primary tumor.
:
T x Tumor occult except for positive cytology.

:
T, Tumor ^3 cm in diameter surrounded by

:
lung pleura or parenchyma, and without
evidence of invasion of lobar bronchus.
T2 Tumor >3 cm in diameter or tumor extending to the hilar region. Tumor must be
:
g2 cm distal to the carina and not have T, characteristics.

T Tumor of any size with direct extension into adjacent structures (e.g., chest wall, dia-
:1
:
phragm, mediastinum) or tumor <2 cm distal to carina or tumor associated with

atelectasis or obstructive pneumonitis of an entire lung or with pleural effusion.
N: Begional Lymph Nodes
N No demonstrable metastasis to regional lymph nodes.
:
\, Metastasis to lymph nodes in the ipsilateral hilar region (including direct extension).
:
N 2 Metastasis to lymph nodes in the mediastinum.

:
M: Distant Metastasis
M„: No distant metastasis.
M, : Distant metastasis, such as in scalene, cervical, or contralateral hilar lymph nodes,
brain, bones, lung, liver, and so forth.
Stage Grouping
Occult carcinoma: T X N M,, (1
Stage I: T,, N or N,, orT2 N M M

Stage II: T2 N,M
Stage III: Any T8 ; any N 2 any M, ;
"Adapted from Carr DT and Mountain CF: Semin Oncol 1 :229, 1974.
8 / Lung Cancer 207
°
TABLE 8-7. Stage-Grouping in Carcinoma of the Lung
Cumulative Percentage Surviving ± SE

No. OF
TNM Set Patients 12 Months 18 Months
Stage I
T,\„M„ 135 ,72± .04 .65 ± .04

T2 N Mo 358 .64 ± .02 .53 ±.03
T.N.M, 24 .62 ±.10 .49 ± .10
Stage II
T,N,M U 109 .49 ±.05 .35 ±.01
Stage III
T, Lesions Insufficient Data
T,N 2 Mo 44 .26 ±.07 .14± .07
TA.M, 51 .24 ±.06 .10 ± .06
T2 N M, 74 .10 ±.04 .04 ± .04
TjNjM, 28 .11 ± .06 .07 ± .06
T,\„Mo 216 1 .38 ± .03 .24 ±.03
T,N,M 96 .26 ± .05 .15 ±.05
T,\,M 210 .21 ± .03 .11 ±.03
TjNoM, 116 .14± .04 .11 ±.04
T.N.M, 57 .09 ± .04 .06± .04
T,N,M, 306 .10± .02 .04 ± .02
•(From Mountain CF«* «/.: Am J Rocntucnol Rod Titer Xucl Med 120:130, 1974.
t Superior sulcus tumors included.
have similar survivorships for stage I disease (42.8 to 46.6 per cent) and stage
III disease (7.9 to 12.9 per cent), but their two-year survival rate in stage II
disease may differ (39.8 per cent with epidermoid versus 14.3 per cent and
119
12.9 per cent with adenocarcinoma and large cell carcinoma, respectively).
Other complex staging systems have also been offered. 19 ,23125 '
126
Perioperative risk may be greater in men than in women. 19, ' 127
It also
tends to increase with age, particularly in men aged 70 years or older.
19, I26 " 128
Perioperative risk may also be greater in right-sided than in left-sided pneu-

monectomy and greater in pneumonectomy than in lobectomy. 19, ,26128 Signifi-
cant comorbid nonpulmonary disease is also a poor prognostic factor. 127
In addition to those factors influencing perioperative mortality rates, other
factors may relate to three- and five-year survival rates. Tumor size may be
inversely related to prognosis. 121129 Lymph node involvement also corre-
131 "
lates negatively with survival. Patients with intersegmental, or interlo-

hilar,
bar lymph node involvement may have five-year survival rates in the range of
10 to 30 per cent. 112, 121, 127, 132 Patients with mediastinal lymph node involve-
ment fare worse (five-year survival rate <10 per cent), but patients with
intranodal rather than perinodal and ipsilateral rather than contralateral me-
diastinal lymph node involvement compose a subset that may do considerably
128, 132
better. 19, Radiation therapy may additionally improve survival in pa-
tients with nodal metastases.
The histologic type in several series is unrelated to survival if one corrects
for stage and excludes small cell carcinoma. 19,93, 127 132, 133 Other series, how- '
ever, suggest a better prognosis for epidermoid carcinomas, particularly

may
stage II.i«.M».w
The symptomatic status is prognostic-ally important in operable can-
cers. 65 '
129
In Feinstein's series, asymptomatic patients had the best five-year
survival rate (18 per cent), and this decreased as symptoms increased to
primary pulmonic symptoms (12 per cent survival), systemic symptoms (6 per
cent survival), and metastatic symptoms (0 per cent survival). 65, 129 Patients
with "long" primary symptoms had better five-year survival rates than those
widi "short" symptoms (16 per cent versus 9 per cent). Similar relationships,
although with better survival, have been noted in other series. 19, 133, 135 Fein-
stein 129 has suggested a "clinicoanatomic staging system" that combines
symptomatic status and anatomic features (local versus regional versus dis-
65
tant). This has been found to be of prognostic value.
For patients with inoperable or nonresectable disease, "performance
status" is strongly correlated with survival duration. The assessment of perfor-
mance status by the Karnofsky performance scale (See Chapter 4) 136 or by
137139
similar scales has been shown to correlate strongly with survival, 92, 135,
particularly when linked to the classification of disease as limited or exten-
sive. Limited disease has been defined by the Veterans Administration Lung
Cancer Study Group (VALG) as nonresectable disease that is confined to one
hemithorax plus ipsilateral supraclavicular nodes, encompassed by a single
radiation port and not previously treated by irradiation. 139 Extensive disease
includes all other nonresectable disease. The median survival rate for
placebo-treated patients with extensive disease ranged from 5 weeks (small
cell carcinoma) to 11 weeks (large cell carcinoma). For limited disease, the
median survival rate ranged from 11.7 weeks (small cell carcinoma) to 22.4
weeks (large cell carcinoma). Within limited and extensive groups, however,
survival was more closely related to performance status than to histologic
type. In extensive disease, the median survival rate varied from 2 weeks
(performance status 3) to 7 weeks (performance status 5) to 25 weeks (per-
formance status 10). For limited disease, the median survival rate varied from
139
7 weeks (performance status 3) to 28 weeks (performance status 10).
Other factors correlating with poor prognosis in patients with nonresectable
disease include weight loss, brain metastases, patient age of more than 70
years, and hepatic metastases. 130, 140 Superior vena caval obstruction is also a
poor prognostic factor, 141 but Perez et al. 142 have noted a 10 to 20 per cent
survival rate of >2 years for patients with this problem.
An important variable, which is not clearly defined in most studies dealing
with the natural history of patients with operated or resected lung cancer, is
therapy after surgical failure. This variable may alter the median survival rate
but is unlikely to alter the five-year survival rate.
The natural history of untreated advanced (nonresectable or recurring after
resection) lung cancer has been addressed by the Veterans Administration's
studies of placebo-treated groups 139, 143 and by earlier studies of untreated
patients. 93, ,44149
Tables 8-8 and 8-9 present representative survival data from multiple
and resectable lung cancer
series of patients with surgically treated operable
and with untreated advanced lung cancer. The latter data include information
8 / Lung Cancer 209
TABLE 8-8. Survival Rate in Surgically Treated Lung Cancer
NO. OF
Patients Patients Survival Rate Reference
179 Resected cases

Overall 26.5% 128
Negative lymph nodes beyond 5-year survival
the hilum 41.5%
Mediastinal lymph nodes positive 7.3 f r
1076 Operated cases (720 patients resected) 5-year survival 126
141 Resected cases

Overall 18% 123
Stage 1° 47^
5-year survival
Stage 11° 33%
Stage 111° 7%
150 Resected cases
Overall 27 % 129
5-year survival
Negative lymph nodes 30%
554 Resected cases
Overall 24 134
Stage It 53% 5-year survival
Stage lit 35%
Stage Hit 14%
4 37 Resected
Overall 36% 112
LN negative 49.3% • 5-year survival
Hilar LN 31.3%
Mediastinal LN _
(received radiation therap>
626 Resected
Stage I 42% 5-year survival
121
Stage II 13%
686 "Curatively" Resected Patient 46% 5-year survival 93

148 Operated 27% ',
5-year survival
130
Resected 33%
140 Resected 8% 5-year survival 91
915 Resected
All patients 27% 5-year survival
132
Negative lymph nodes. 1960 to 1969 45%
(33 patients
308 "Localized disease" 31% 5-year survival 19

Resected
115 Resected Stage I (by Pathologic 86% 3-year survival 131
Staging; 74 patients clinically Stage I
were found to be Stage II or III

after mediastinal node dissection)
"Memorial Hospital Staging system: Stage I and II roughh correlate with AJC Stage I; Stage II would in-
clude AJC II and III
tStaging system: Stage I included in AJC Stage I. Stage II included in AJC Stage I and T3 N M Stage . III
T3 N MStage IV multiple nodules in lung.
,
TABLE 8-9. Survival Rate in Untreated Patients with Advanced Lung Cancer
\(). OF
Patients Patients Survival Rate Reference
1078 Extensive disease Median 9 weeks varies with per- 139

Limited disease Median 16 weeks formance status
and histologic
appearance
340 Including patients with Mean 1.9 months 144
radiologic diagnosis only
Only patients with tissue Mean 4.2 months
diagnosis
279 All patients 30' r 1-year survival 145
1.4% 2-year survival
443 Includes operable and resectable 57% survival at 5 months 146
patients not treated surgi calk 25% survival at 11 months
186 All patients Mean 4.2 months 147
559 Inoperable patients 29% 6-month survival 148
Palliative resection 50% 6-month survival
5% 1-year survival
from early series. It is possible that survivorship from the time of diagnosis
would be improved in present times because of earlier diagnosis and better
support facilities.
Therefore, multiple factors are of prognostic significance in both resectable
and nonresectable cancers. The accurate assessment of prognosis may be
based upon the patient's age, sex, symptom status, performance status, weight
loss, comorbid diseases, tumor histology, tumor location, tumor size, charac-
teristics of regional and distant metastases, and therapy. The impact of thera-
peutic regimens on survivorship is difficult to evaluate unless the pertinent
prognostic factors of the treatment group are defined.
TREATMENT
Surgery
Although surgical resection is the preferred treatment for lung cancer, only
a minority of patients with this disease are eligible for this mode of therapy.
However, the development of improved techniques for earlier detection and
the development of more effective adjuvant therapy may increase the percent-
age of candidates for curative resection.
The surgical management of patients with bronchogenic carcinoma begins
in the preoperative period with careful preoperative assessment and staging.
In order to select the appropriate management and to estimate prognosis, it is
necessary to identify the extent of the disease carefully by preoperative and
intraoperative staging. Only in this way can the appropriate surgical resection
be performed and the optimal postoperative treatment be tailored to the
needs of the patients.
8 / Lung Cancer 211
Preoperative Assessment. Disseminated metastatic disease is a con-

traindication to pulmonary resection. This includes dissemination in the su-
praclavicular lymph nodes and the contralateral mediastinal lymph nodes.
The presence of metastases to the ipsilateral mediastinal lymph nodes is
generally considered a contraindication to surgery. However, recent reports
indicate that the histologic type is squamous carcinoma and if the metas-
if"
tases are not extensive, mediastinal lymph node dissection followed by radia-
tion therapy results in an acceptable five-year survival rate. 112
Pleural effusion containing malignant cells is also a contraindication to
pulmonary resection. However, pulmonary resection is possible in
rarely,
patients with cytologically negative effusions, and they will have prolonged
survival. Certainly, the presence of chest wall involvement that does not
involve the vertebral bodies or the sternum is not a contraindication to
surgery. Recurrent laryngeal nerve paralysis on the side of the tumor is
considered an absolute contraindication to pulmonary resection. In addition,
superior vena cava] obstruction secondary to tumor is considered a contraindi-
cation to curative resection, although, technically, in some instances resection
of the superior vena cava may be feasible.
The involvement of the main stem bronchi within 2 cm of the carina is a
contraindication to resection because it is difficult to get an adequate surgical
margin widi these tumors. However, in some radiosensitive tumors that are
close to the carina, an occasional prolonged survival can be obtained by using
a combination of preoperative radiation therapy and surgery. A repeated
biopsy following radiation therapy that reveals no evidence of tumor within 2
cm of the carina indicates that an adequate surgical resection may be feasible.
Problems with bronchial stump healing may occur, however, if excessive
radiotherapy' is given.
The involvement of the phrenic nerve or diaphragm is not an absolute
contraindication to pulmonary resection, although a poorer prognosis is indi-
cated. Occasionally, resection of these structures, with adequate margins, will
result in a prolonged survival rate.
All cell types of lung cancer, with the exception of small
cell carcinoma, are
amenable to surgical resection when appropriate stage. It is generally
in the
believed that small cell carcinoma should not be resected, although rare
patients with this form of carcinoma may present with a small peripheral
nodule and negative involvement of the hilar and mediastinal nodes. These
patients may have prolonged survival following pulmonary resection. 150, 151
Surgical Staging. Since the presence or absence of lymph node metas-
tases and the location of lymph node involvement are of primary prognostic
importance, it becomes obvious that the determination of lymph node spread
by mediastinoscopy important in the preoperative evaluation of patients.
is
Surgical staging accomplishes two purposes: (1) It helps to determine resec-

tability and avoid unnecessary thoracotomy; and (2) it allows for more precise
pathologic staging and more accurate prediction of postoperative survival.
There is no uniformity of opinion regarding the indications for mediastinos-
copy prior to pulmonary resection. The diagnostic yield of this procedure
ranges from 10 to 75 per cent and, of course, it varies considerably depending
on the histologic type of the tumor, the size and location of the primary tumor,
and the extent of the disease. Therefore, the incidence of positive findings on
mediastinoscopy depends on patient selection. Clearly, patients with ad-
vanced disease and those with more undifferentiated tumors will have a
higher incidence of positive findings. Although some surgeons recommend
routine cervical mediastinal exploration prior to a thoracotomy, 152 whereas
others use it infrequently, it is clear that the development of mediastinoscopy
has decreased the incidence of patients with unresectable disease having to
undergo thoracotomy. Patients who have negative findings on cervical me-
diastinal exploration should have an incidence of unresectability at the time
of thoracotomy of less than 15 per cent. However, many surgeons feel that not
all patients with bronchogenic carcinoma require mediastinal exploration
preoperatively. Patients with peripheral carcinomas of a differentiated cell

type and a normal mediastinum on x-ray have a low incidence of positive
mediastinal node involvement. 153 Most surgeons would recommend that cer-
vical mediastinal exploration be employed in patients with a diagnosis of
undifferentiated carcinoma and in those who have central lesions. Usually,
routine cervical mediastinoscopy is not performed for peripheral well-
differentiated tumors when there is no evidence of abnormality of the medias-
tinum on chest x-ray and computed tomography.
Mediastinoscopy is especially indicated when x-rays show mediastinal in-
volvement in a patient with an otherwise resectable cancer. It is also useful in
the elderly patient or one with severe cardiovascular or pulmonary disease for
whom a thoracotomy carries a high risk. Occasionally, patients have enlarged
mediastinal and hilar nodes secondary to hyperplasia and no tumor involve-
ment. These patients would be inappropriately denied curative resection if
cervical mediastinal exploration was not performed to prove the absence of
metastases. 113
Mediastinal exploration can be performed either by a cervical or a paraster-
nal incision. In the cervical approach, a small incision is made in the lower
neck over the trachea, and a plane of dissection is established just anterior to
the trachea and deep to the innominate vessels. Through this approach, the
right and left paratracheal lymph nodes can be carefully evaluated, and in
most instances the carinal nodes, as well as the right and left main stem
bronchial lymph nodes, can be biopsied. The azygos lymph nodes on the right
side can also be evaluated through this approach. The parasternal approach is
performed through a vertical or transverse incision over the second or third
costal cartilage on the right or left side. A small portion of rib and costal
cartilage can be removed, and the parahilar areas can be more thoroughly
evaluated than from the cervical approach. The parasternal approach is com-
monly indicated for left-sided lesions, since the presence of the aortic arch
prevents an adequate evaluation of the distal left main stem bronchus from a
cervical approach. Juxtahilar lesions are more easily evaluated through the
parasternal approach than through the cervical approach.
The routine use of scalene lymph node biopsy is not recommended, since
yield is very low unless the lymph nodes are palpable.
Surgical Resection. Since the first successful pneumonectomy was
performed for lung cancer in 1934, a variety of surgical procedures have been
evaluated. Recently, the trend has been for more conservative surgical resec-
8 / Lung Cancer 213
dons with adequate staging at the time of thoracotomy. It has become clear
that pneumonectomy has no advantage over lobectomy if the tumor can be
154
properly encompassed with the lesser procedure. Radical excision with
extensive mediastinal and hilar lymph node dissection in conjunction with
pneumonectomy or lobectomy has not resulted in improved cure rates. How-
ever, careful evaluation of the hilar and mediastinal nodes should be per-
formed at even- thoracotomy for lung cancer. The excision or sampling of the
mediastinal and hilar lymph nodes results in more accurate surgical staging
131
and greater accuracy in reporting results of various therapeutic modalities.
Segmental resections for very small lung cancers can produce good five-year
survival rates and are indicated in patients with very small tumors in which
155
conservation of pulmonary tissue is indicated.
With the recent development of more effective screening devices, more
lung cancers may be detected at an early stage, with excellent prognoses
following surgical resection. Unfortunately, in many of these patients second
primary tumors occur. For this reason, surgical procedures that conserve lung
tissue are indicated in patients with these small tumors, which are frequently
occult on radiologic examination. In view of the high incidence of second
primary tumors, patients should have tissue-sparing operations whenever
possible, such as segmental resections or lobectomy, along with adequate
mediastinal and hilar lymph node sampling for adequate staging.
The involvement of the chest wall, phrenic nerve, or diaphragm does not
contraindicate resection. The diaphragm can be resected and reconstituted
with prosthetic material, as can the chest wall.
The superior sulcus tumor appears to be somewhat unique. In properly
selected patients, the results of preoperative radiation therapy followed by
15
surgical resection have been quite good. Paulson * reports a 35 per cent
five-year survival rate in patients undergoing preoperative radiation therapy
and surgery including chest wall resection. In general, however, when these
patients have vertebral body involvement, the tumor is unresectable, regard-
less of the preoperative treatment.
Results of Surgical Resection. The survival rate following surgical
resection of bronchogenic carcinoma is directly related to the histologic type
and the TNM
classification or the stage of the disease (Tables 8-6 and 8-7).
Patients with stage carcinoma of the lung, in whom careful surgical staging
I
has been performed, can anticipate an excellent five-year survival rate. 131157
As Table 8-7 indicates, patients with T,X„ lesions or T,\, lesions have a very
favorable prognosis following pulmonary resection. The survival rates rapidly
diminish in stage II and stage III resectable lung cancer. Small peripheral
squamous carcinomas, with positive hilar node involvement but negative
mediastinal lymph node involvement, have a 50 per cent five-year survival
rate. However, patients with adenocarcinoma of the lung with positive hilar
lymph node involvement, plus or minus positive mediastinal node involve-
ment, who have required a pneumonectomy have had a much lower survival
112
rate. The presence of mediastinal lymph node involvement, regardless of
the cell type, is associated with a very poor five-year survival rate following
surgical resection.
It is becoming clear that more and more lung cancers are being detected in
214 II / Treatment of Specieh Neoplasms
an earlier stage, when the survival rate following resection is excellent. In

addition, the improvements in surgical technique and in pre- and postopera-
tive management have markedly reduced the mortality and morbidity from
thoracotomy and pulmonary resection. The mortality rate from a lobectomy in
a good-risk patient should be less than 1 per cent and that from a pneumonec-
tomy in a good-risk patient should be less than 10 per cent. These advances
and the development of adjuvant therapy, such as chemotherapy, immuno-
therapy, and radiation therapy, should result in continued improvement in the
results of surgical treatment of carcinoma of the lung.
Radiation Therapy
Radiation as Primary Therapy. Radiotherapy in the management of

lung cancer may be used with curative or palliative intent. When used for the
latter, it is reserved for patients with advanced disease who exhibit distressing
symptoms and signs caused by the primary tumor or metastatic lesions. Ir-
radiation may be administered as a single modality or as part of a mul-
timodality approach, interfacing with surgery, chemotherapy, and immuno-
therapy. The goal of and approach to radiation therapy should be based upon a
careful clinical evaluation, including staging and a precise histologic diagno-
sis. The recommended pretherapy staging work-up has been summarized in
Table 8-5. The most critical histologic distinction is the separation of small
cell carcinoma from the other cell types.
Radiation for cure may be effectively used in patients with stage I or stage
II nonsmall cell carcinoma who are not surgical candidates. It has also been
employed for the treatment of patients with operable lung cancer. In one
study of 40 patients with operable cancer who were treated with radical
radiation, 9 (22 per cent) patients survived five years and 3 (7 per cent)
survived ten years. 158 Of the 40 patients treated, 27 had diagnoses of squamous
cell carcinoma and 8 had diagnoses of small cell carcinoma. In five patients
the diagnosis was made on the basis of positive cytologic findings. In a
159
randomized trial of surgery versus radiotherapy, Morrison et evaluated
a/.
the results of treatment in 58 patients with operable lung cancer. Of the 28

radiation-treated patients, 18 (64 per cent) survived one year; of the 30 surgi-
cally treated patients, 13 (43 per cent) survived one year. At four years, the
surgically treated patients fared better, with 23 per cent survival versus 7 per
cent survival for the patients treated with radiation therapy alone. Analysis of
the survival rate by treatment and cell type showed a statistically significant
longer survival rate of surgically treated patients with a diagnosis of squamous
cell carcinoma. Although radiation therapy has shown the potential to "cure"
some patients with operable disease, surgical resection remains the treatment
of choice for operable nonsmall cell bronchogenic carcinoma.
Radiotherapy was found to be at least equivalent to surgery for the treat-
ment of patients with "operable" small cell carcinoma in a randomized trial
conducted by the British Medical Research Council. 31, 160 In a group of 144
patients, those who were surgically treated had a mean survival rate of 199
days, whereas the radiotherapy patients had a mean survival rate of 300 days.
The differences in mean survival were attributable to the presence of two
8 / Ling Cancer 215
long-term (>10 years) survivors in the radiation group. Median and twenty-
fifth percentile survivorship did not vary with treatment. At five years, 1 per
cent of patients were alive in the surgical group, and 48 per cent of patients
were alive in the radiotherapy group. Similar figures were observed at ten
years. Radiation therapy appears to be the cornerstone of treatment of stages I
and II small cell carcinoma, with the exception of the rare small peripheral
stage I lesion, which should be resected. The treatment of this disease,
however, should be by combined modalities rather than radiation or surgery
alone.
Radiotherapy the treatment of choice for inoperable or unresectable
is
limited disease nonsmall cell carcinoma. In a Veterans Administration ran-

domized study of patients diagnosed as having limited-disease lung cancer,
improvement in the survival rate was demonstrated for the radiotherapy
181 163
"
patients when compared with the placebo-treated control patients. Sug-
gested indications for and contraindications to radiotherapy for cure are out-
lined in Table 8-10.
In a study of 95 radiation-treated patients with unresectable lung carcinoma
whose status was established by biopsy at exploratory thoracotomy, the one-
sear survival rate was .58 per cent and the five-year survival rate was 7.4 per
20 additional patients with unresectable disease, who were treated
cent. 164 In
with radiation therapy after incomplete removal of tumor or removal of tumor
for palliation only, there was no survival beyond 13 months. The average
survival rate of these 20 patients was similar to the average survival rate of
untreated patients. This simuests that radiotherapy combined with an incom-
plete surgical excision in unresectable patients does not improve patient sur-
vival.
Treatment Techniques. The total gross tumor should be included
within the radiation ports. To avoid marginal recurrences, the treated area
should be contoured to exceed the visible tumor by a margin of 2 to 3 cm. In
more centrally located tumors the ipsilateral hilum and mediastinum should
be included. Apical tumors should have the ipsilateral supraclavicular region
treated. In some peripheral lesions the treatment of the hilar and mediastinal
regions may not be necessary. Usually, it is possible to treat patients with
TABLE 8-10. Indications and Contraindications for Radiation Therapy

of Curative Intent
Indications
"Resectable" nonsmall cell carcinoma in a patient who is not operable due to somorbid disease
or refusal of surgery
Nonresectable nonsmall cell carcinoma limited to primary tumor with or without ipsilateral
hilar and mediastinal node involvement (whether biopsied or partially resected)
Post surgical recurrence limited to hemithorax
Limited small cell carcinoma (treated with chemotherapy as well)
i
Contraindications
Distant metastases including contralateral lung or hilar
i
Malignant pleural effusion

Performance status less than 3 on the Karnofsky scale
Severe impairment of pulmonary function
Severe active pulmonary infection
shaped parallel opposing fields, preferably limited to 250 cm 2 in area. Follow-

ing the administration of 4000 to 4500 rad tumor dose at 200 rad a day, it is
necessary to decrease the treatment field to less than 100 cm 2 and to deliver an
additional 1500 to 2000 rad tumor dose to the visible tumor. This narrowing of
radiation ports for the final part of treatment may minimize the possibility of
serious radiation injury to sensitive structures (e.g., the spinal cord).
The optimal dose-time relationship for radiotherapy in lung carcinoma has
not been established. The probability of local tumor control increases with
the increase in the radiation dose. 165 In half of the patients with nonsmall cell
lung carcinoma, the cause of failure can be attributed to the lack of local tumor
167
control. 166, reasonable to expect that an increase in radiation dose that
It is
would improve tumor control would also improve the survival rate. This
local
concept is supported by a retrospective analysis of 138 radiation-treated pa-
tients with locally advanced lung cancer. 168 At this time, a continuous course
of radiation to 6000 rad at 200 rad a day appears most popular among radio-
therapists.
In addition to the continuous-course approach to irradiation, various split-
course radiation programs have been evaluated. The rationale for split-course
radiation is threefold: (1) It may help to spare patients with early metastatic
disease (appearing during a rest period) from the necessity of a full course of
high dose irradiation, i.e., 6000 rad in six weeks. (2) The first part of treatment
may produce sufficient palliative effect. (3) Split-course treatment may be
better tolerated by the patient.
In a study of 84 patients with locally advanced lung cancer, Abramson and
Cavanaugh 169 compared a dose schedule of 6000 rad tumor dose in six weeks
with 2000 rad in five days followed by another 2000 rad in five days three
weeks later. The one-year survival rate of 42 patients treated with split-course
radiotherapy was superior to that of the same number of patients treated with
the continuous course of radiotherapy. A subsequent report, however, showed
an increase in the incidence of serious complications in the patients treated
with split-course radiotherapy. 170 Other reports suggest an excellent tolerance
of the split-course irradiation, as well as a good palliative effect and a survival
rate equal to or slightly better than that achieved with conventional continu-
ous irradiation. 171 174 However, a recent preliminary report of a prospective
"
randomized trial evaluating several doses and schedules of irradiation, in-

cluding the split-course technique, supports continuous-course over split-
course therapy with regard to long-term survival. 175
Preoperative Irradiation. Preoperative irradiation was introduced in
an attempt to (1) reduce the high incidence of local spread of the tumor and
thus increase the resectability rate, (2) decrease the incidence of tumor spread
to the regional lymphatics, (3) decrease the possibility of tumor spread during
the surgical procedure, and (4) decrease the incidence of postsurgical recur-
rence.
Preoperative radiotherapy is valuable in the treatment of superior sulcus
tumors. Paulson 156 and Mallams et a/., 176 using 3000 to 3500 rad tumor dose in
10 to 15 treatments over 19 days, followed by surgical resection 4 weeks later,
demonstrated increases in resectability and survival rates. Similar favorable
results were reported by Hilaris et al. 177 179 with the use of preoperative
'
8 Lung Cancer 217
lS0
radiotherapy and interstitial implants. Shields et al. found that the routine
use of preoperative radiotherapy for lung tumors other than those of the
superior sulcus may result in a shorter survival rate. Opposing data, however,
come from a recent report in which 53 selected patients with locally advanced
lung cancer, who were treated with preoperative radiation and subsequent
1M
surgical resection, demonstrated the clear superiority of this approach.
At this time it appears that preoperative radiotherapy is indicated for patients
with superior sulcus tumors; it may also be indicated for selected patients with
locally advanced lung cancer.
Postoperative Radiotherapy. The rationale for postoperative radio-
therapy is the considerable incidence of persistent local disease that is found in
patients who have had sureical resection for cure. In a retrospective study of
_ I patients who died within 30 days after a curative pulmonary resection.
Matthews et al." found that 73 (35 per cent) patients had persistent disease.
The addition of postoperative radiotherapy has improved the survival rate in
some series. 112, 182
Although radiation has not been shown to improve the survival rate when
given to all patients resected for "cure," postoperative radiotherapy signifi-
cantly improves the survival rate of the subset ot patients with hilar and
mediastinal lymph node metastases. 112
Kirsh et al.
- 1 *2 u reported a 27 percent
'
five-year survival rate among the 33 patients with involvement of mediastinal

lymph nodes who had received postoperative radiotherapy. In a similar group
of 20 patients who had not received postoperative radiotherapy, there were no
survivors at five years. 112
The recommended dose of radiation is approximately 5000 rad given at 200
rad tumor dose a day to the residual tumor and to the immediately adjacent
areas that have a high risk of tumor involvement. It appears that radiotherapy
following curative pulmonary resection is primarily indicated in patients with
mediastinal and hilar lymph node involvement, particularly with epidermoid
carcinoma. Other selected patients may also benefit from judicial postoperative
radiotherapy.
Radiation Therapy of Small Cell Versus Xonsmall Cell Carcino-
ma. Small carcinoma of the lung almost always is disseminated
cell at diagno-
IST
sis, even when it appears to be confined to one hemithorax. 24 ls:i
Con-
sequently, the employment of local or regional treatment modalities, such
surgery or radiotherapy, has a low success rate. With radiation therapy or
surgery alone, the median survival rate is less than six months, and the five-year
survival rate is per cent. 23,31, I60, 168, 183,
less than 5 m
Systemic chemotherapy has improved the survival rate in this disease and is
discussed further subsequently. A significant cause of failure for chemotherapy
alone, however, is the presence of persistent or recurrent disease at the primary
site.
163, 183, 188 189
*
The efficacy of radiotherapy in controlling local and regional
disease in small cell carcinoma of the lung has been well established. The
reported objective response rate with radiotherapy is over 80 per cent. 185, 19°
This would suggest the concept of a combined modality approach, using both
aggressive systemic chemotherapy and radiotherapy.
Brain metastases have been noted in almost half the patients with small cell
carcinoma of the lung during the course of their disease. 125 Elective whole-
brain irradiation decreases the incidence of this problem. 191 193 The results of
"
combined modality therapy and of chemotherapy alone in the treatment of

small cell carcinoma of the lung are discussed further subsequently.
The treatment
of nonsmall cell carcinoma using a combination of adjuvant
single agent chemotherapy along with radiotherapy has generally failed to
increase the incidence of long-term survivors. 194, 195 Although a recently report-
ed Veterans Administration study found the median survival rate of radio-
therapy-chemotherapy treated patients to be greater than that of patients
treated with radiotherapy alone, 163 long-term survival was poor in both groups
and was greater after radiotherapy alone (15 per cent two-year survival com-
pared with 7 per cent after radiotherapy plus chemotherapy). It is apparent that
more effective modalities must be developed to make the combined approach
as successful in nonsmall cell carcinoma patients as it is in small cell carcinoma
patients.
Palliative Treatment. The value of radiotherapy as an excellent
palliative tool in lung cancer has been well established. When
161, 185, 196, 197
skillfullyadministered, palliative radiotherapy can prolong the functional life

of the patient and control pain. Symptomatic relief can be achieved in 75 per
cent of treated patients. 164 Thus, palliation may last for months and in some
patients for years.
is indicated to relieve distressing symptoms caused by
Palliative treatment
the presence of primary tumor or metastatic disease. It is also indicated to
prevent the occurrence of such symptoms and signs, e.g., radiographic evi-
dence of a metastatic lesion of the femur without symptoms is an indication for
palliative radiotherapy to prevent a pathologic fracture.
Palliative radiotherapy should not be delayed until all other treatment
measures have failed. Frequently, ongoing chemotherapy drug schedules can
be continued while radiotherapy is being given to control a local problem.
Sometimes, however, it is necessary' to modify or even temporarily discontinue
chemotherapy in order to give a palliative course of radiotherapy to control an
urgent medical problem caused by the tumor (e.g., hemoptysis, endobronchial
tumor causing severe pneumonia, or central nervous system [CNS] metas-
tases).
The treatment program should be enough, both in total dose and
flexible
schedule, to accommodate the individual status of each patient. Palliative
radiotherapy should encompass the tumor-bearing area causing the relevant
clinical problem but should include as small a volume of normal tissue as
possible. This will minimize morbidity of the therapy. The treatment plan
should be modified whenever necessary to the best advantage of the pa-
tient.
Palliative treatment can be designed for short-term control of a particular
clinical problem caused by the tumor. Usually 3000 rad tumor dose delivered
in two weeks, or its equivalent, will relieve symptoms for three months.
Palliative treatment for long-term control requires larger doses of radiation
(i.e., 5000 rad in four weeks). The resulting relief is expected to last a minimum
of six months. A palliative treatment program that is designed to control
subacute or acute oncologic emergencies may require up to 6000 rad given in
six weeks to control a local problem. 198 Sometimes it is necessary to use
8 / Lung Cancer 219
increased daily doses of radiation initially in order to evoke a rapid re-

sponse.
The evaluation of the patient with advanced lung cancer and selection of an
optimal treatment program challenges the skills of the surgical, medical, and
radiation oncologists. Best results can be achieved by the close cooperation of
these oncologi
Chemotherapy
Patients with advanced lung cancer have been treated with chemotherapy in
attempts to palliate symptoms and to prolong survival. Early trials emphasized
the usage of single agent chemotherapy, whereas more recently, combination
chemotherapy regimens have been tested.
Response and survival data associated with trials of single agent chemothera-
199 201 "
py have been reviewed by Selawry. For small cell carcinoma of the lung,
response rates in the 30 to 40 per cent range have been reported with mech-
lorethamine. vincristine, cyclophosphamide, and epipodophyllotoxins. Re-
sponse rates in the 25 to 30 per cent range have been reported with doxorubi-
cin, hexamethylmelamine, and procarbazine. Response rates approximating
20 per cent were found for BCXU. CCNU, methotrexate, and dibromodulcitol;
lower response rates (0 to 11 percent) were noted with meCCNU, mitomycin-
C. and bleomycin.
For other histologic types of lung cancer, response rates are low. Although for
each drug there may be differences in response rates reported for epidermoid
carcinomas, adenocarcinomas, and large cell carcinomas, those differences are
generally small and are often inconsistent from study to study. The range of
199201
response rates in those cell types, adapted from the reviews of Selawry,
are presented in Table 8-11.
The single agent response rates just given, both for small cell and nonsmall
cell histologic types, are useful as approximations. However, they tend to be
overestimates of partial plus complete response rates, since they may include
TABLE 8-11. Single Agent Chemotherapy in Nonsmall Cell

Carcinoma of the Lung
Range of
°
Drl g Response Rate
Cyclophosphamide 20%—22%
Doxorubicin 13 r c-17 r r
Methotrexate 13%-24%
Mechlorethamine 21%-28%
CCNU 12%-20%
Mitomycin-C 12%-27%
Hexamethylmelamine 12%— 18%
Procarbazine 13%-35%
MeCCNU 10%-21%
5-fluorouracil O^r-lS^c
BCNU 0%-9%
'Complete. partial and lesser objective responses: data from re\ ievv b> Selawry OS: In Lung Cancer, Clini-
cal Diagnosis and Treatment. Straus MJ ied>. New York. Grune & Stratton. 1977.
lesser responses. Current literature would suggest that in nonsmall cell carci-
nomas, the complete plus partial response rate to single agent therapy may be
in the 10 to 20 per cent range. 202214 Methotrexate, 210 mechlorethamine, 199
cyclophosphamide, 215 and CCNU 2M appear to be the most useful agents. Hex-
amethylmelamine, procarbazine, 199 doxorubicin, 211 bleomycin, 199 and mito-
mycin-C may have some role. 5-Fluorouracil is probably ineffective in
epidermoid and large cell carcinomas, 21 but it is inadequately evaluated in ad-
'1
enocarcinomas. 217
Responders to therapy generally have a longer survival rate than nonre-
sponders. 203 209,211 Improvement in median survival, however, is rare with
'
single agent therapy. 65 This is not surprising, since response rates are consider-
ably less than 50 per cent. Prolongation of the median will only occur if
chemotherapy also improves the survival rate of patients other than responders
(e.g., patients with "minimal responses" or with "stable disease"). Although it
seems likely that improved survival in responders is, at least in part, due to
positive effects of chemotherapy, it is not impossible that responders constitute
a subgroup that would have had a more favorable prognosis even without treat-
ment.
In patients with limited small cell carcinoma, regimens utilizing radiation
therapy plus combination chemotherapy have resulted in response rates of 70
to 100 per cent and median survival rates of 10 to 12 months with, in some
series, a small percentage of patients alive and disease free at one to two
years. 218 These results in small cell carcinomas are clearly superior to those that
are achievable with radiation therapy alone, in which the median survival rate
ranges from 21 to 31 weeks. 187, 21 «- 220 The "curative" potential of these combina-
tion regimens is yet to be demonstrated. Representative results are presented
in Table 8-12.
Combination chemotherapy regimens, with or without radiation therapy,
have made a significant impact on the treatment of extensive small cell
carcinomas. A variety of regimens have resulted in response rates of 60 to 80 per
cent and have prolonged the median survival rate to 8 to 12 months, with rare
long-term disease-free survivors. 221 The recent trial at UCLA of MOCA
(biweekly regimen of methotrexate, vincristine [Oncovin], cyclophosphamide,
and doxorubicin [Adriamycin]) resulted in a response rate of 68 per cent and a
median weeks in patients with extensive small cell carcino-
survival rate of 42
222
ma. Similar statistics have been achieved by other regimens (Table 8-12).
For extensive small cell disease, radiation therapy when added to combination
chemotherapy does not clearly result in improved survival (Table 8-12).
Prophylactic whole-brain irradiation, however, clearly decreases the inci-
dence of brain metastases. 190 192 2:{4 The treatment of small cell carcinoma of the
"
'
lung has been reviewed by Broder et a/. 150 and by Weiss. 235
Histologic types other than small cell carcinoma do not respond as well to
chemotherapy. Livingston 236 has reviewed the role of combination chemother-
apy in "nonoat cell" bronchogenic carcinoma. A variety of combination chemo-
therapy regimens result in response rates ranging from less than 5 per cent to
more than 40 per cent. Better response rates were seen with BACON* (bleomy-
cin, doxorubicin [Adriamycin], CCNU, vinblastine [Oncovin], and mechloreth-
amine [nitrogen mustard]); MACC (methotrexate, doxorubicin [Adriamycin],
8 / Lung Cancer 221
TABLE 8-12. Combination Chemotherapy ± Radiation Therapy for

Small Cell Carcinoma of the Lung
E\I INT OF No. OF REnPONM Median

Dim w PAT1EN !* Treatment RATE SCRXTVAL Reference
, -
Limited 7 MOCA 67 % 42 weeks

Extensive MT.Y VCR. CTX. ADR 42 weeks
Limited 4 HIGH DOSE 96<~r 10.5 months

Extensive 19 CTX. MTX. CCM
Limited 19 CTX and CCM eeks 208
Extensive 91
Limited 4 BLEO. ADR. CTX. VCR 100% 39 weeks

Extensive
Limited _ CTX. VCR. ADR and LOCAL -_ 38 weekv __

Extensixe RT for limited disease 63<~c 28
Limited 19 CTX. ADR. VCR. MTX and LOC IL to 12 months __

Extensixe 14 RT for limited dis< ( hemotherapy 5 months
Limited 108 ADR. CTX. VCR and LOCAL " eeks 227
Extensixe 85 and W B. RT 26 weeks
Limited 24 "COPAM CTX. VCR. MTX. 64^ 32 sveeks

Extensixe
"
PRED and LOCAL RT U
Limited 4 CTX. VCR. MTX and LOCAL RT S5 9.5 months
Extensixe 22 from
diagnosis
Limited 1 CTX. VCR, MTX and LOCAL RT 72 9 months 230

Extensive 17
Limited CCM . CTX. MTX and LOCAL RT 11.5 months 231

Extensixe 51 CCM . CTX. MTX and EXT RT ^ 10.5 months
Limited PRED. VCR. CTX. CCM and - 46 weeks 192
24 \VB RT
Extensixe PRED. VCR. CTX. CCM and — 39 week>
LOCAL RT and \VB RT
Limited 36 CTX. ADR. VCR and \\ B RT 78* - 14 months
Extensive and LOCAL RT 60% 10 months
Limited 16 CTX. ADR. VCR and BCG. _ 57 « 233

LOCAL RT - 45 weeks
cyclophosphamide and CCN'U); CAMP cyclophosphamide, doxorubicin i
[Adriamycin], methotrexate, and procarbazine); cyclophosphamide and metho-

trexate: and CCXU. cyclophosphamide and methotrexate. Data regarding
those and other trials are presented in Table 8-13. With some drug combina-
tions (e.g.. BACON or COMB [cyclophosphamide, vincristine [Oncovin],
meCCXU and bleomycin]', relatively high response rates that were seen in
early studies 239,241 were not confirmed by later similar trials. 204 208242 It re- -
mains to be seen whether or not response rates in excess of 35 per cent that
were found with preliminary trials of the other combinations are reproducible.
The combination regimens, like single agent chemotherapy, have not caused
significant prolongation of the median survival rate in nonsmall cell carcino-
mas. Responders. however, generally have an improved survival rate, with
median values for that group of roughly one year. Chemotherapy tends to be
ineffective in patients of low-performance status. 2 " 24 " and. because of its
toxicities, it plays a limited role for that group. Patients of higher performance
status may benefit from a trial of combination chemotherapy, but significant
TABLE 8-13. Combination Chemotherapy in Nonsmall Cell Carcinoma of the Lung
No OF KfsFowi Mf N \\
Dm (.- HlSTOLOt.1 Patij n rs Rate Si KvrvAt Rth tKl\( I
ARA-C. ADR. MTX. Epidermoid 13 7 months 237

PROC CAMP Adenocarcinoma 8 63* 6 - months
ARA-C. MTX Large cell r 71* weeks

Adenocarcinoma 8 63% 39+ weeks
BLEO. ADR. CCNU; NCR, Epidermoid 50 42% 16 weeks 239
M BACON
BLEO. ADR, CCNU, VCR, Epidermoid 116 21'
M BACON 16 weeks 240
M, ADR, CCNU NAC Epidermoid 94 16% J
CTX. MeCCNU, NCR. Epidermoid 33 9 weeks 241

BLEO COMB Adenocarcinoma 28 11% 22 weeks
CTX. MeCCNU, NCR, Epidermoid 30 10%
BLEO COMB I and II Adenocarcinoma .
29* 242
Large cell 9 0%
CTX. MeCCNU, N CR, Epidermoid 20 5% 10 weeks 204
BLEO COMB (ambulatory
patients
MTX. N CR. CTX. ADR, Epidermoid 12 14%)

MOCA Adenocarcinoma 20 15% 29 weeks 222
Large cell 10 30% )
NITX. ADR. CTX. CCNU Epidermoid 10 40% 13+ months 243

M.V Adenocarcinoma 17 35% 7 months
benefit is unlikely for those who do not respond. It appears nn orthNvhile to treat
high-performance status nonsmall cell carcinoma patients with combination
chemotherapy, choosing a regimen Nvith manageable toxicity and risk in an
attempt to benefit the subset of responders. Current therapy, however, is
clearly suboptimal, and investigational approaches or supportive care alone are
reasonable alternatives for appropriate patients.
Adjuvant single agent chemotherapy has been extensively studied in pa-
tients Nvith nonsmall cell carcinoma of the lung and has not been shown to be of
"
value. 244 247 Adjuvant combination chemotherapy has not yet been adequately
studied.
Immunotherapy
Several studies have indicated that lung tumors, as Nvell as other human
tumors, contain antigens against which the host can generate an immune
response. In addition, it has become apparent that patients with lung cancer
may be highly immunosuppressed. They demonstrate depressed delayed
cutaneous hypersensitivity reactions and depressed in vitro Lymphocyte func-
tion, and many have serologic factors that are responsible for diis immunosup-
pression. The degree of immunosuppression and the level of the serologic
immunosuppressive factors are directly related to the stage of disease, to
surgical resectability, and to prognosis. MN The mechanism of this immunosup-
pression is poorly understood. The degree of immunosuppression is related to
the tumor burden, and it is conceivable that the tumor itself releases immuno-
suppressive factors.
8 / Lung Cancer 223
The immunotherapy of lung cancer is very much in its infancy, but there are
several promising reports. In a prospective, randomized trial, McKneally et
a l 249,250 re p 0rted that the administration of bacillus Calmette Guerin in-
trapleural ly following pulmonary resection for lung cancer has resulted in a
statistically significant improvement in patient survival with stage 1 resected
lung cancer. Patients with stage II and stage III resectable lung cancer
apparently did not benefit from such therapy. The toxicity of the intrapleural
BCG is quite acceptable if excessive amounts are not administered. Severe
toxicity has been reported in patients who have received larger doses than
recommended. The intrapleural administration of BCG remains a highly
experimental treatment, and it is not recommended for routine use at the
present time.
Another immunotherapeutic approach treatment of lung cancer is the
to the
preoperative, direct instillation of BCG into the lung tumor followed by
251
standard pulmonary resection two to three weeks following injection. This
technique of BCG immunotherapy more closely approximates the successful
animal tumor models; however, the therapeutic efficacy of this technique has
not been proved.
Levamisole has been used as a surgical adjuvant immunotherapeutic agent,
and the preliminary results are promising.- 52 In these studies, patients were
randomized preoperatively to receive levamisole or placebo. Following pul-
monary resection, levamisole or placebo therapy was continued. The results of
these studies indicate that a fixed dose of levamisole was effective in diminish-
ing the recurrence rate in patients with more advanced, unfavorable, resectable
lesions. Best results were seen in patients weighing < 70 kg, suggesting that
the effectiveness of levamisole may be dose dependent. 253 The toxicity of
levamisole was quite acceptable in these studies, but occasional patients have
been reported to develop agranulocytosis.
Although these clinical studies using immunotherapy as an adjunct to surgi-
cal resection are quite promising, the immunotherapy of lung cancer remains
experimental, and further studies are currently in progress to detennine the
precise role of these immunotherapeutic agents in patients with resectable
lung cancer.
Immunotherapy has also been tried in patients with advanced lung cancer.
Although some investigators have claimed survival benefit from immunothera-
py with Corynebacterium parvum (C. parvum), 2b4 255 BCG, or BCG cell wall
' 256
257 258
others have failed to show benefit with similar approaches. 259 262
'
skeleton, '
Studies at UCLA of BCG and C. parvum added to combination chemotherapy

demonstrated no improvement of response rate, response duration, survival, or
hematologic tolerance of chemotherapy. 222 The role of immunotherapy in
advanced disease remains unproved and experimental.
Supportive Care
Patients with lung cancer are frequently inneed of emotional as well as

medical supportive care. Successful support would include physicians, nurses,
social workers, psychologists, and psychiatrists. Hospices and specialized
units may also provide care for dying patients.
Specific problems frequently arising in cancer patients include coping with

death and dying, maintaining quality of life until and through the dying period,
dealing with feelings of helplessness, anger, depression, loss of self esteem,
guilt (e.g., regarding smoking history), dealing with rejection and pity from
peers and employers, preparing financially for medical care, settling financial
affairs and preparing for the family's well-being, coping with pain and dyspnea,
and dealing with the side effects and risk of therapy.
It is important to deal with both the patient and the family and to deal in an
understanding manner, protecting patient dignity, assuaging guilt, and giving

"permission" to be ill. Honesty is critically important, but the maintenance of
some hope (of worthwhile quality if not quantity of life) is also essential.
Education regarding die illness and therapy may be helpful.
A full discussion of the management of these problems is beyond the scope of
this chapter. Emotional supportive care is discussed more fully in Chapter 32.
Cox et a/. 263 have written a useful book for patients with lung cancer and their
families.
Integration of Treatment Modalities
Small Cell Carcinoma. Patients with small cell carcinoma of the lung
that diagnosed prior to thoracotomy (e.g., by bronchoscopy, percutaneous
is
needle biopsy of the primary tumor, or biopsy of a metastatic site) would be

extensively staged prior to therapy. Recommended studies (after history,
physical examination, and screening chemistries) would include chest x-ray,
radioisotopic scans of bone, liver, and spleen, computed tomography of the
brain,and bone marrow aspiration and biopsy. The rare patient who has a small
peripheral primary tumor would be evaluated with mediastinoscopy. If the
mediastinal exploration is negative, the disease would be surgically resected
(lobectomy, if possible).
In order to maximize the potential for cure, a program of combined modality
adjuvant therapy using radiation therapy and combination chemotherapy fol-
lows: Radiation therapy would include 4000 to 4500 rad to the bed of the tumor,
ipsilateral hilum, and mediastinum (with or without supraclavicular nodes), as
well as "prophylactic" radiation therapy to the whole brain. This would be
followed by one year of combination chemotherapy (e.g., MOCA) (Table 8-14).
The same combined modality approach would be applied to the patient with
stage I or stage II lung cancer that is identified histologically as small cell
disease after resection. The patient who is known to have the spread of small
cell carcinoma limited to the ipsilateral hilum or mediastinum would not
undergo resection of tumor, but rather would be treated with combined
TABLE 8-14. "MOCA" Chemotherapy 222
Methotrexate 50 mg/m 2 IV
Oncovin (vincristine) 1.4 mg/m 2 IV («2 mg)
every 2 to 3 weeks
Cyclophosphamide 500 mg/m 2
IV
Adriamycin (doxorubicin) 30 mg/m 2 IV
8 / Lung Cancer 225
radiotherapy-chemotherapy as discussed earlier. The patient with distant

metastases would be treated with combination chemotherapy (e.g., MOCA)
plus spot radiation to bulky disease or to areas needing palliation.
A patient who enters complete remission would then receive whole-brain
radiation therapy "prophylactically." Chemotherapy would be continued until
failure or, in patients with a prolonged complete remission, for two years.
Restaging would be done (possibly including a repeated bronchoscopy), in
patients for whom cessation of chemotherapy is entertained. Patients failing
combination chemotherapy would be treated with single agent chemotherapy.
palliative radiation when needed, or supportive care, or both.
NONSMALL Cell Carcinoma. Patients with nonsmall cell carcinoma of
the lung would be staged with a bone scan and the other studies shown in Table
8-5. Radionuclide scans other than of bone would be applied only if pre-
existing evidence of organ metastases is present. For the patient with an
operable central or poorly differentiated tumor, mediastinal exploration would
precede attempted resection. A patient with a well-differentiated peripheral
lesion would be studied with mediastinal tomograph) if mediastinoscopy is not
planned. In those patients with operable disease not requiring mediastinos-
copy or with mediastinal findings that are negative or limited to small ipsilat-
eral intranodal involvement, resection would be performed (lobectomy if the
tumor can be properly encompassed).
Patients with superior sulcus tumors would be treated with preoperative
irradiation. Preoperative radiation may also be applied to the patient in whom
radiation-induced tumor shrinkage may aid surgical resection (e.g., the patient
with tumor close to the carina or involving the chest wall). Patients with
resected stage I disease would be considered candidates for investigational
adjuvant immunotherapy (e.g., intrapleural BCG or levamisole). Patients with
resected stage II or stage III disease that is limited to the mediastinum would
receive adjuvant radiation therapy. Patients with stage I or stage II disease that
is inoperable because of comorbid disease would be treated with radiation
therapy for cure.

Patients with disseminated disease (not including the brain) who are of good
performance status and are less than 70 years of age would be treated with a
combination chemotherapy regimen. This would be continued as tolerated in
responders but discontinued in those who progress, show no tumor shrinkage,
or develop brain metastases. Patients of poor performance status or those who
are 70 years of age or more would be treated with sequential single agent
chemotherapy, usually with CCXU as an initial approach followed sequen-
tially by methotrexate, cyclophosphamide and doxorubicin, for therapeutic
failure. Selected patients may be better treated with supportive care only.
Palliative radiation therapv would be given for brain metastases and as need-
ed.

Although it seems clear that the improved control of lung cancer in the
foreseeable future would best be achieved bv elimination of risk factors
(smoking, and so forth), the prevention of lung cancer poses a formidable

problem, and therapeutic advances may make a more immediate impact on this
disease. These advances may come from the application of surgical techniques
to patients who are diagnosed earlier and are "more curable"identified through
radiographic-cytologic screening programs or, should tests of sufficient speci-
ficity and sensitivity be developed, by screening programs using tumor mark-
ers (antigens, ectopic peptides, hormones, and so forth).
Surgical results may be improved by utilization of adjuvant therapy. The
promising early studies with intrapleural immunotherapy may be comple-
mented by intralesional or systemic immunotherapy. The integration of combi-
nation chemotherapy or radiation therapy, or both, into the adjuvant setting
may benefit selected groups of patients.
The use of pre- and postoperative radiation therapy may be better defined.
Radiation therapy (other than photon beams) may be advantageous for se-
lected patients. Treatment with neutrons, protons, heavy ions, pi-mesons, or
hyperthermia may offer a potential advantage in the treatment of bulky, poorly
vascularized, and poorly oxygenated tumor or in the second treatment of
previously x-irradiated disease.
Chemotherapeutic advances may come from the development of new agents
and the better utilization of existing drugs. Studies of mechanisms of tumor
resistance to drugs may allow the development of techniques (scheduling, drug
carriers, drug synergism) to overcome such resistance.
For small cell carcinoma of the lung, intensive combined modality therapy
followed by a "rescue" with autologous bone marrow that had been frozen and
stored when only limited disease was present, is a technique that may improve
therapeutic effectiveness. 264
The further understanding of optimal methods for combining existing modal-
ities of therapy, and increased attention to the multimodality treatment of this
disease, may also improve patient care.
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18:333, 1977.
CHAPTER 9
GASTROINTESTINAL
TRACT
NEOPLASMS
Kenneth P Ramming Charles M Haskell
Alan S Tesler
INTRODUCTION
Malignancies of the gastrointestinal tract constitute a tremendous health
problem throughout the world. In the United States, fully one third of the
annual cancer mortality rate can be attributed to malignancies of gastroin-
testinal origin. In 1976, approximately 169,000 of the 675,000 new cancers
and 102,000 of the 370,000 cancer deaths were the result of gastrointestinal
tract malignancies. The incidences and deaths caused by cancers of the
various gastrointestinal organs are noted in Table 9-1.
Common themes are apparent when approaching this large group of
human neoplasms, in which prognoses are so poor that the incidence and
mortality rates are virtually identical in several tumor types.
The primary therapy for gastrointestinal malignancies is surgery,
first-line
and, in general, excision techniques have been well developed. However,
232 II / Treatment of Specific: Neoplasms
TABLE 9-1. Cancer of the Gastrointestinal Tract'
Site Estimated New Cases Estimated Deaths
Male Female Total Male Female Total
Esophagus 5600 1900 7500 4800 1800 6600
Stomach 14,000 8900 22.900 8500 5900 14.400
Small intestine 1200 1000 2200 350 350 700
Large intestine
Colon 31.000 38,000 69,000 18,000 20,900 38,900
Rectum 17,000 13,000 30,000 5700 4600 10,300
Liver and biliary tract 5800 6000 11,800 4800 5000 9800
Pancreas 12,000 9700 21.700 10,900 8700 19,600
Other and unspecified digestive 1600 2300 3900 750 850 1600
Totals 88,200 80,800 169,000 53,800 48,100 101,900
'From American Cancer Society. 76 Facts and Figures, New York. American Cancer Society, 1975.
because these lesions are asymptomatic for long periods, resulting in far-
advanced disease at diagnosis, surgery, which is designed for focal, local-
ized, and limited disease, often is not curative and becomes palliative only.
Since systemic therapeutic modalities are generally of limited effective-
ness, it is clear that much of the thrust of investigative efforts in this field
must be directed toward earlier diagnosis. Innovations such as mass screen-

ing diagnostic techniques, correlation of serum markers such as carcinoem-
bryonic antigen and alpha-fetoprotein with early disease, and the develop-
ment of more sophisticated and accurate endoscopy techniques are only a
few areas that might effect earlier diagnosis. Conversely, when locally ad-
vanced disease is encountered, it is likely that improvement in mortality
rates will be achieved only by blending surge ry with other therapeutic
modalities, e.g., chemotherapy, immunotherapy, and radiotherapy. Thus, it
is important to keep abreast of the numerous adjuvant therapy trials cur-
rently ongoing.
This chapter will focus on current aspects of epidemiology, diagnosis,
treatment, and the integration of therapeutic modalities in the management
of these malignancies.
Section 1
Esophagus
INTRODUCTION
Epidemiology
Cancer of the esophagus is primarily a disease of men (sex ratio 4:1) in

the later decades of life. Approximately 7500 new cases occur annually in
the United States, and about 6600 fatalities are reported yearly. Esophageal
cancer ranks fourth among malignant tumors of the alimentary tract. 2 Ap-
proximately ten cases will be observed per 100,000 men in the United
States. This incidence varies around the world and is particularly high in
Scotland, China, Russia, Scandinavia, and in the natives of South Africa. In
-4
Japan, there are 46 cases per 100,000 men over 35 years of age.'
There is a large socioeconomic gradient in the distribution of this dis-
ease. It is much more common in urban areas and is more often seen in
less affluent individuals. Construction and outdoor laborers, waiters, bar-
tenders, and metal craftsmen demonstrate a notably higher incidence of
esophageal cancer than do professionals and agricultural workers. One
striking feature of the epidemiology of esophageal cancer is the extremely
rapid rise of the mortal ity rate in the nonwhite population in the United
States, which has been increasing for at least 30 years and shows little
sign of diminishing. 5,
Etiology
Smoking and ahigh consumption of alcohol have traditionally been

linked to the etiology of esophageal cancer. 7 However, several studies indi-
cate that smoking is not an etiologic factor. 8,8 Table 9-2 lists those factors
commonly associated with or implicated in cancer of the esophagus.
The incidence of esophageal carcinoma in patients with achalasia is es-
timated to be seven to eight times greater than in the general population. 10
The Plummer- Vinson syndrome predisposes to carcinoma of the postcricoid
and cervical esophagus. 11 Patients with tylosis, a hyperkeratosis of the
palms and soles, have a high incidence of esophageal noeplasms. 12 Esopha-
geal cancer is seen in 2 to 5 per cent of patients who have lye burns of the
esophagus, which often occurs in young adults. 13 The association of reflux
esophagitis with esophageal cancer has frequently been made but is not
absolutely documented. 14 ' 15
Most of these associations suggest that chronic irritation is related to the

development of this disease. Recently, epithelial dysplasia was shown in a
high percentage of patients with esophageal cancer and in situ malignan-
TABLE 9-2. Etiologic Factors Associated with

Esophageal Cancer
Etiologic Factor Examples
Nutritional status Malnutrition, vitamin deficiency, anemia, poor oral hygiene,

previous gastric surgery
Specific carcinogens Hot tea, alcoholic beverages, tobacco, irradiation esophagitis,

zinc, nitrosoamines, metallic compounds
Associated disorders Achalasia, Plummer-Vinson syndrome, tylosis, esophageal

diverticula, reflux esophagitis, hiatal hernia, Barrett's
esophagus, lye stricture, leukoplakia, ectopic gastric mucosa
cies. 16, 17
This irritation-induced entity may be a precursor of esophageal
cancer, although at present no single factor or group of factors can be impli-
cated.
NATURAL HISTORY
Pathology
The esophagus conventionally divided into a cervical portion and

is
upper, middle, and lower third sections. Figure 9-1 illustrates the distribu-
I i
Clavicle
FIGURE 9-1. Anatomic loca-

tion of cancer of the esophagus.
(From Ellis HF: Disorders of
esophagus in the adult. In
Gibbon's Surgery of the Chest.
Sabiston DC. |r and Spencer
FC (eds). Philadelphia. \VB
Saunders Co, 1976.)
9 / Gastrointestinal Tract Neoplasms 23.5
tion of carcinoma of the esophagus by anatomic location in over 1600 cases

observed at the Mayo Clinic. 18
Almost all cancers arising from the body of the esophagus are squamous
cell carcinomas, whereas primary adenocarcinoma is exceedingly rare in
this area." However, most lesions of the esophagogastric junction are ade-
nocarcinomas and compose half of all malignancies of the esophagus. 1" -
Some are submucosal extensions of true gastric carcinomas, whereas others

develop in the distal esophagus of patients with prolonged and severe gas-
troesophageal reflux. In a situation such as this, the distal squamous muco-
sa of the esophagus may undergo metaplastic changes that result in islands
of columnar epithelium replacing normal squamous epithelium (Barrett 's
esophagus). 21 These lesions tend to be infiltrative, encircling, ulcerating,
—
and constricting. Much rarer composing less than 1 per cent of all esoph-
ageal neoplasms —
are the polypoid lesions such as carcinosarcoma, pseudo-
sarcoma, and leiomyosarcoma. 22 Malignant melanoma, apparently of primary
esophageal origin, has been reported
Because of the rich network of lymphatics in the submucosa, ^n well
the mucosal layers of the esophagus, early dissemination of these tumors i»
common, and submucosal spread 4 or 5 cm on each side of the gross lesion iN
not unusual. The lack of a serosal envelope may contribute to early invasion
of the mediastinal structures. Involvement of the trachea, left main stem bron-
chus, recurrent nerves, carotid, and aorta is often observed at the time of
diagnosis or exploration. Hematogenous spread is common in all esophageal
malignancies, frequently with liver, lung, or bone implants. Cervical cancers
spread through lymphatic channels to anterior jugular and supraclavicular
nodes particularly. Those cancers of the thoracic esophagus spread to local,
mediastinal, and occasionally subdiaphragmatic nodes. Cancers at the esopha-
gogastric junction involve local nodes, as well as the celiac, gastric, pan-
4
creatic, and periaortic groups.-
The primary symptom of esophageal cancer is dysphagia. Unfortunately,

it is usually necessary for these flattened, invasive malignancies to almost
encircle the esophagus before significant symptoms occur. This critical fea-
ture of delay in diagnosis is the single, most important reason for the poor
survival rates associated with this disease. The dysphagia is usually pain-
less, insidious, and slowly progressive, initially noted with ingestion of
solid foods but eventually progressing to difficulty swallowing liquids and
even saliva. Thus, the most important contribution of the physician in im-
proving survival in this disease is to maintain a high index of suspicion for
the slightest esophageal symptom and to carefully establish or eliminate
carcinoma as its cause.
Esophageal studies with the conventional barium swallow will provide
the diagnosis in over 90 per cent of cases. The usual finding is an irregular,
ragged mucosal pattern with luminal narrowing. Prestenotic dilation of the
esophagus is usually present above benign but not above malignant ob-
structive lesions. It has recently been reported that double contrast studies
236 II / Treatment of Specifh Neoplasms
TABLE 9-3. TNM Classification of Cancer of the Esophagus'*
Stage Description
T Primary tumor (for all three segments of the esophagus)

T„ No demonstrable tumor in the esophagus
TIS Carcinoma in situ
T, A tumor that involves 5 cm or less of esophageal length, that produces no
8
obstruction, and that has circumferential involvement and no extraesnpliagetil
spreadt
T 2 A tumor that invokes more than 5 cm of esophageal length without extraesophageal
spreadt or a tumor of any size that produces obstruction* or involves the entire
circumference hut without extraesophageal spread
T, Any tumor with evidence of extraesophageal spreadt
N Nodal involvement
Cervical esophagus
The regional lymph nodes in the cervical esophagus are the cervical and
supraclavicular nodes
N No clinically palpable nodes
N, Moveable, unilateral, palpable nodes
N 2 Moveable, bilateral, palpable nodes
N 3 Fixed nodes
Thoracic esophagus
Regional lymph nodes for the upper, midthoracic, and lower thoracic esophagus
that are not ordinarily accessible for clinical evaluation
NX Clinical evaluation
N„ Surgical evaluation — No positive node involvement
N, Surgical evaluation — Positive node involvement
M Distant metastasis
MX Not assessed
M No (known) distant metastasis^
M, Distant metastasis present
Specify
"Roentgenographic evidence of significant impediment to the passage of liquid contrast material past the
tumor or endoscopic evidence of esophageal obstruction.
f Extension of cancer outside the esophagus as seen by clinical, roentgenograpliic. or endoscopic evidence
of (1) recurrent laryngeal, phrenic, or sympathetic nerve involvement; (2) -fistula formation; (3) involvement
of the tracheal or bronchial tree; (4) vena cava or azygos vein obstruction; and (5) malignant effusion — medias-
tinal widening itself is not evidence of extraesophageal spread.
Jin the cervical esophagus, any lymph node involvement other than that of cervical or supraclavicular
lymph nodes is considered distant metastasis. For the thoracic esophagus any cervical, supraclavicular,
scalene, or abdominal lymph nodes are considered distant metastases
may be of value in very early lesions. 25 Esophagoscopy should be per-

formed to establish a tissue diagnosis, to evaluate the anatomic extent of
gross disease, and to aid in planning therapy. 26 We prefer the rigid esopha-
goscope rather than flexible endoscopes because the system of direct biop-
sy using rigid forceps has proved to be more reliable than the system using
the forceps necessitated by flexible endoscopes. Cytologic studies have be-
come an effective way of diagnosing esophageal cancer. 27 Bronchoscopy to
determine the presence or absence of tracheobronchial tree involvement is
mandatory in lesions above the gastroesophageal junction. Whenever palpa-
ble, clinically suspicious cervical nodes are present, a biopsy is indicated.
Staging
The staging of carcinoma of the esophagus can conceivably be done at

the time of clinical diagnosis, at surgery, in the postoperative period, dur-
ing retreatment, or at autopsy. Table 9-3 gives the TNM staging system
28
established at the time of original surgery, which probably provides the
best correlation between the extent of disease and prognosis. However, it
should be remembered that in a disease in which the best Eve-year surviv-
al rates are between 5 and 11 per cent, a single unfavorable designation in
any category predicts with virtually unerring finality an eventual cancer-
related death.
TREATMENT
Surgery
Philosophy of Surgical Management. The goal of surgery in esoph-

ageal cancer, as for all gastrointestinal malignancies, is to totally excise both
the lesion and regional metastases and to re-establish intestinal conti-
nuity, i.e., effect a cure. However, the advanced state of disease that is seen
in most patients requires a tempering of this dictum, and the more reason-
able goal of palliation must be considered the primary objective in most
instances. Because of the limited effectiveness of other modalities, poor
prognostic signs (such as significant [celiac] node involvement outside the
field of resection), which might dictate lesser procedures in other neo-
plasms (although not necessarily curative) often do not preclude major sur-
gery in cancer of the esophagus. The goal of surgery, therefore, is most
often to prolong and improve the quality of life through nutrition and the
ability to handle oral secretions.
Preparation Prior to Surgery. Ahigh incidence of chronic pulmo-
nary disease is observed in patients with esophageal carcinoma. Although
this is often caused by the long-term use of tobacco, chronic aspiration
pneumonia is not infrequent. Almost all patients are nutritionally depleted.
Dehydration is common. The red cell mass is frequently low, although the
patient's hematocrit might be deceptively high because of the general re-
duction of circulating volume.
Although prolonged periods of preoperative preparation cannot be jus-
tified in a disease in which survival is often short, we think it is important
that short, but intensive, in-hospital preoperative treatment be initiated.
This includes meticulous pulmonary toilet and instruction in postoperative
pulmonary supportive methods. Blood volume, fluid, and electrolyte bal-
ance should be normal. This usually requires the infusion of both colloid
and blood. Hyperalimentation, if necessary, by the parenteral route has
been reported to be beneficial. 29
The surgeon must be prepared to deal with any contingency, such as the
necessity to excise or mobilize great vessels, pericardium, or lung to
achieve removal of the tumor. An operative plan that includes options for
logical alterations in technique for the various possible anatomic findings
will greatly reduce surprise, anxiety, and poor judgment at the operating
table if local extension should be encountered. The use of newer diagnostic
tests, such as mediastinal tomography and the CAT scan, may afford greater
preoperative staging information in the future as experience with these

techniques enlarges.
Surgery for Esophagogastric Junction and Lower Thoracic
Esophageal Cancer. Surgery for esophageal cancer must be determined
by the location of the tumor. When
the esophagogastric junction and lower
thoracic area are involved, a left thoracic incision through the bed of the
seventh rib provides excellent exposure, especially if it is carried through
the costal cartilages and is extended slightly into the abdomen. The dia-
phragm is incised eircumferentially down to the hiatus, protecting the
phrenic nerve. Mobilization of the tumor and the stomach is then effected.
The spleen and pancreas, if involved, can be removed en bloc, although it is
not necessary to remove the spleen in every instance. After appropriate
resection, the gastric remnant is anastomosed to the esophagus in the left
chest.
The advantage of this approach is the excellent exposure it provides,
especially in mobilization of the stomach. disadvantage is that the upper
Its
resectable portion of esophagus is limited, and a high anastomosis frequent-
ly is rendered technically demanding by the obstructing presence of the
aortic arch. Since submucosal, microscopic invasion of the esophagus so
frequently extends to or beyond the highest margin obtained on the left
side, we have largely abandoned this approach and use it only rarely for
lesions of the gastroesophageal junction without esophageal involvement.
In preference we have adopted the combined abdominal-right thoracotomy
approach, which is described in the next section.
Surgery for Lower and Midthoracic Esophageal Cancer. We
prefer the combined abdominal-right thoracotomy approach for these le-
sions as well. In this operation the patient is placed in the oblique position
with the right chest at about an 80° angle and the abdomen torqued to the
left. The chest and abdomen are prepped. Exposure is greatly facilitated by
keeping the right arm free, prepping it in a sterile wrap, and positioning it
as necessary during the procedure. A midline laparotomy is made, and the
stomach is mobilized. Particular care is taken to protect the right gastroepi-
ploic artery at its origin, as it runs parallel and posterior to the descending
portion of the duodenum. As mobilization continues, a second operating
team performs a posterior lateral thoracotomy through the bed of the fifth
rib and carefully mobilizes the esophagus. The intra-abdominal team con-
tinues mobilization, preserving the right gastric and gastroepiploic arteries.
Node-bearing tissue along the upper border of the pancreas and the celiac
artery is removed, and the left gastric artery is doubly ligated. Working
from above and below, mobilization is completed and a pyloroplasty or py-
loromyotomy is fashioned. The stomach is divided with the 90-TA stapler
using 4.8 mmstaples. The staple line is reinforced with a single running
suture; a short transverse incision is made in the anterior surface of the
upper gastric tube; and an end-to-side esophagogastric anastomosis is made
in two layers with 4-0 silk interrupted sutures. Appropriate sutures from
gastric serosa to parietal pleura are taken to reduce tension on the anas-
tomosis (Fig. 9-2).
The advantages of this approach are that a large length of esophagus can
9 Gastrointestinal Tract Neopl 239
<
FIGURE 9-2. Technique of
esophaanaastrectomy and
esophagogastrostomy for carci-
noma of upper thoracic esopha-
guv .A. Right thoracotomy and
upper abdominal incisions They
may be combined as a thoraci-
coabdominal incision dotted
lines B. Extent of esophageal
ied area Com- C
pleted esophagogastrostomy and
pvloromvotomy. i From Ellis
FH. Jr: May Clin Pr, 5 5
196<
be resected and the anastomosis can be constructed without anatomic con-

finement. The use of two teams greatly shortens the operation time. We
believe these advantages warrant this approach to be the procedure of
choice for esophageal resection.
Surgery for Upper Esophageal Lesions. When possible, right tho-
racotomy and esophagogastrectomy. as described, are used. However, for
very high thoracic lesions in which the superior margin must be at the low
cervical esophagus, colon interposition may be preferable. In this proc
dure, a segment of colon and its blood supply are isolated by preserving
one nutrient vessel and the corresponding marginal artery. Figure 9-3
FIGURE 9-3. Esophagectomy

with interposition of left colon.
A. Incision A left cervical inci-
sion is preferred by many sur-
geons. B. Extent of esophageal
resection shaded area C. Mo-
bilization of left colon. D. Com-
pleted operation. (From Ellis
FH. Jr: The
Esophagus. In
Christopher'^, Textbook of Sur-
gery, 9th ed. Davis Led. Phila-
delphia. WB Saunders Co. p.
6.37. 1968.)
shows the left branch of the midcolic artery, which has been so isolated,
and the left colon, which has been rotated on this pedicle and carried sub-
sternally to be anastomosed with the esophageal remnant in the neck and
with the stomach in the abdomen.
In palliative procedures it is not necessary to open the chest. Simple
blunt substernal dissection from the abdominal and cervical incisions will
safely create a channel through which the colonic segment can be passed.
Right, transverse, or left colon segments can be so interposed, as anatomy
and preference dictate. Our preference under ideal circumstances is to mo-
bilize the left colon based on the left colic artery.
Clinical maneuvers that are necessary for the success of this procedure
include preoperative arteriography to assure that appropriate vascular anat-
omy to the colon exists, resection of the sternoclavicular angle to prevent
constriction or venous obstruction of the distal colonic segment, and the
necessary arterial clampings and evaluations prior to resection of the colon
to ensure an adequate blood supply to the transplanted colon segment that
was chosen.
The advantage of this procedure is that it provides maximal length. Dis-
advantages include long operative time, the demand for technical expertise
and experience, and a certain percentage of failures of the cervical anas-
tomosis, usually because of compromised vascularity.
Surgery for the Cervical Esophagus. Except for low-lying lesions
at the thoraco-cervical junction that may be amenable to colon interposi-
tion, we have largely abandoned surgery for cancers of the cervical esopha-
gus and treat them with irradiation. Several procedures have been success-
fully utilized, such as the Wookey 30 procedure, which creates a pharyngeal
tube linked with skin inside and outside for establishing esophageal conti-
nuity. These procedures are usually performed after pharyngectomy and
laryngectomy. Their main disadvantage is the necessity for multiple,
lengthy staged manipulations prior to the formation of the tube in a patient
who often has had extensive surgery or radiation, or both, in that area.
Palliative Procedures. In patients with advanced disease, extensive
local unresectable tumor with obstruction, or complications such as tracheo-
esophageal fistula, palliative bypass without resection may be indicated.
Orringer and Sloan 31 have advocated substernal bypass using the stomach
while simply excluding the unresected esophagus, but mortality with this
procedure has been high. Heimlich and Winfield 32 proposed the gastric
tube fashioned from the greater curvature of the stomach to provide a simi-
lar bypass. Griffen et a/. 33 have advocated using the reverse gastric tube
in all patients who have carcinoma of the esophagus. Thereafter, patients
who do not have metastatic disease can undergo resection, and those who
already have advanced disease may obtain reasonable palliation for the re-
mainder of their lives. Steiger et al. 34 reported on 54 patients with far-
advanced carcinoma of the esophagus in whom no attempt was made to
resect the lesion while gastric or colonic bypass was performed. The 30-day
operative mortality rate was 7.5 per cent, and the average survival was five
months.
Other nonresectional procedures have also been reported. Atkinson and
ROEVTESTINAL TRACT NEOPLASMS 241
Ferguson 15 used fiberoptic endoscopy, preliminary dilation, and Celestin

tube insertion in 13 patients. One death resulted from the procedure. Pal-
liative pulsion intubation was also reported by Haffejee et aL
M They noted
a meandaily positive nitrogen balance ol 7 gm three weeks after intuba-
tion, without any episodes of tube blockage observed when an elemental
diet supplement was used. Kairaluoma et al. i7 used a Celestin tube intuba-
tion on 108 patients, with a hospital mortality rate of 16 per cent. This
latter experience has been more consistent with our observations, i.e.. high
mortality or morbidity from insertion of the tube itself, usually from esoph-
ageal perforation. In addition, we have not been impressed by the de-
gree of palliation obtained, noting frequent blockage of the tube and tube
dislodgements. Perhaps use of the elemental diet would prevent thi
Virkkula et a/. 19 have reported the use of a reversed pectoralis skin pedicle
flap and free skin grafts to create an extrathoracic conduit from esophagus
to stomach.
Surgical RESULTS. The five-year survival rate after surgery for carcino-
ma of the esophagus rarely approaches 20 per cent and is significantly less
when f adenocarcinoma of the gastroesophageal junction are elimi-
nated. *' The results of several large surgical series are presented in Table
9-4.
Perhaps one of the most extensive recent series in the management of
carcinoma of the esoph - the one recently reported by Appelqvist and
-
hi- ..ttes.
31
Two hundred sixteen patients with carcinoma ot the esoph-
agus underwent _ etion. There were 104 patients with esopha-
geal cancer and 112 patients with carcinoma of the cardia. Esophagpg
trectomy was the most widely used procedure, with colon interposition
TABLE 9—4. Results of Surgical Treatment of

Cancer of the Esopha -
Series author Resections Operative Selected 5-Year

Mortality P vtien Scrviv\l
at 5 Year* oe Patients
Resected
Adams et c _ 69 11
Boyd and fcim* — —
Dunlo- _ "
91 :
•
Goodie 61
GunnJaugsson et a
_
""
_
" "
-
v 5
Kockef «JL-
"•
_ 10
Miller'" 31 5 175
Nakayama* i 6 8861 12f
Pear,*: — — 36.3 11
Sweet5" 303 Gf
r r
Total ; _ L4 9.7
'M .-! -- :
~ Me rtel '
irtctr Medicine Holland JF and Frei
. E. Ill eds . Philadelphia. Lea &
Includes adenocarc iinaii al the cardia.
t-
:I: ;-•
242 II / Treatment of Specific; Neoplasms
utilized in only 13 cases. The hospital mortality rate was 21 per cent, but
the five-year survival rate for the whole series was 23 per cent. We agree
with the conclusion of these authors and others that the surgical approach
to carcinoma of the esophagus and cardia is recommended in all cases in
which the patient's tumor may be resectable. 52 Results of surgery for this
lesion have also been presented by Stone et «/./'•'' Gatzinsky et al.,54 and
Murray et al.'°'° in recent reports. In the report of Stone et a/., 53 an operative
mortality rate of 11 per cent was achieved, and the mean survival of all
resected patients was 2.1 years.
Radiation Therapy
Radiation therapy has been advocated in carcinoma of the esophagus, al-

though the survival rate with radiotherapy alone in this disease is generally-
less than 5 per cent. 56, 57 Pearson 58 has reported on over 2000 patients with
squamous esophageal carcinoma given 5000 rad over four weeks. He con-
cluded that in the upper two thirds of the esophagus, radiation is preferable
to surgery because of better survival. 58
Techniques. Megavoltage therapy is essential to deliver the high doses
needed for local control while keeping the morbidity of therapy to a mini-
mum. In the thoracic esophagus, the following treatments have been used:
anteroposterior-posteroanterior followed by obliques for a boost, a rotation-
al field, or anteroposterior-right posterior oblique-left posterior oblique. In
the cervical esophagus, two wedged anterior obliques may offer a better
dose distribution. Care must be taken to avoid excessive dosage to the
heart and spinal cord. Lewinsky et a/. 59 have demonstrated that the prone
position can move the esophagus anteriorly as much as 2 to 3 cm compared
with the supine position, thereby easing the problem of spinal cord spar-
ing.
It has not been shown that treatment of the draining lymph nodes (su-
praclavicular, epigastric) of value, since virtually no patients with posi-
is
tive node involvement gain long-term survival. 60,61 Some authors advocate
radiation of the entire esophagus, but this has not been shown to have an
advantage over confining treatment to the primary tumor with 5-to-6 cm
margins.
Complications. Complications are related to tumor extent, treatment
volume, and radiation dose. Fistulae, pulmonary fibroses, pericarditis, and
myelitis are potentially fatal events. Persistent stenosis, requiring long-term
dilatations, is not uncommon among long-term survivors.
Results
Radiation Alone. The
evaluation of reported results is complicated by
the differing patient selection processes used. Considering all cases, the
five-year survival rate is less than 10 per cent, and in most series it is not
more than 6 per cent. When
only those patients treated for cure are sur-
veyed, however, the five-year survival rate has been reported to be as high
as 21 per cent, 58,62 with a 29 per cent five-year survival rate in the cervical
esophageal lesions, a 19 per cent five-year survival rate in the upper thorac-
ic esophageal lesions, and a 15 per cent five-year survival rate in the lower
thoracic esophageal lesions.
Failures are largely due to local recurrence, which accounts for 50 per
cent of failures, even in a highly selected series such as Pearson's. 49 Pier-
quin et a/. 83 treated more than 100 patients with high doses (6900 rad over
5.5 weeks or 8700 rad over 8 weeks, split course) and still had 80 per cent
local recurrence.
In spite of these poor survival figures, significant palliation can be
achieved with clinical improvement of dysphagia in 65 to 75 per cent of
patients. Relief of dysphagia comes more slowly (two or more weeks), but
the operative mortality of resection is avoided. In the lower thoracic esoph-
agus, however, results have been better surgically. Hankins et a/. 64 have
carefully outlined their philosophy of palliation in this disease and also
suggest that radiation therapy is beneficial in patients in whom surgery is
not possible.
Preoperative Radiation. Because of the poor results using either surgery
alone or radiation alone, and after consideration of the high local recur-
rence rate following radiation, a number of groups have tried to combine
the modalities. Doses have been either short (500 rad x 4 or 5, a sequence
of 700 rad, 700 rad, 600 rad, or 800 rad x 3) with surgery within two weeks
or protracted (4000 to 6000 rad in four to seven weeks), with surgery usual-
ly following after two to eight weeks.
Long-term survivorship has not clearly been improved by such tech-
niques, with survival of those successfully completing the program ranging
from 7 to 33 per cent. The overall survival rate has still been less than 10
per cent, since most patients do not have resections because the primary
lesion is too far advanced or there is regional node involvement or hema-
togenous metastases.
Two Japanese groups have reported better survival rates, but the group
of Akakura et al. m apparently exluded patients who did not come to explo-
ration. Considering that the radiation took five to six weeks and there was a
two- to four-week delay from radiation to surgery, it must be assumed that
there were some deaths in that two- to three-month presurgical period,
which would lower the reported 25 per cent five-year survival rate. Na-
66
kayama et a/.reported a 37.5 per cent survival rate of five years (three of
eight patients), but survival rates of only 31.8 per cent at four years and
27.5 per cent at three years. Applying the actuarial method of Berkson and
Gage 67 to the data from Nakayama's 1974 paper 68 yields approximately a 24
per cent five-year survival rate. Of interest, however, is the 100 per cent
survival rate reported in patientswho were resected in the absence of posi-
tive node involvement after preoperative radiation (700 rad, 700 rad, 600
rad on three consecutive days). In his most recent report, using preopera-
tive radiation therapy with a concentrated dose between 2000 and 2500 rad,
Nakayama's" three-year survival rates, when compared with survival rates
with surgery alone, were essentially the same. However, at five years, lon-
gevity was markedly improved in the group that received preoperative radi-
ation therapy. The operative mortality- rate was 6 per cent, and the five-year
in m m m
in
3C CC in CO CI
2.
co co
CC CO — co ~H r^
35 W o M <M fN
>. 3 I
In
M 5
oo co
-HOC)
co oo co
t^
CO
<M
co
o
* f
CO
CO
in O-.
oo
s bl
,0) B
O .5
.2 S § 5
-c
o
w
3 *
CO
o
CO in
I t- CO in
TT
- o <n m
EC in en
CQ
T S -3
35
cc cc t~-
35 05 05
05
- oo
co
co
r~ CO
m
cc
in
cc
CO t-
cc cc
35 35 35 35 3? 35 35
bl cu
cu
-3
C
a n a
CD
01
-
-X — X<
a
< ^X o a.
cu
en
TABLE 9-6. Single-Agent Chemotherapy for

Esophageal Cancer
No. Responses/No. Response

Drug Selected Patients Rate (%) Reference
Bleomycin 11/57 19 80 and 81
5-Fluorouracil 3/18 17 80 and 81
CCM 3/19 16 82
Pacarbazine 0/3 - 80 and 81
Hexamethylmelamine 1/3 - 80 and 81
Dibromomannitol 0/1 - 80 and 81
Bleomycin pins cisplatin 9 47 19 83
was 10.8 per cent for men and 29.3 per cent for women when
survival rate
therapy was used. Fraser et al., n Xygaard et al.,~ Hut-
x
combined modality
chinson and Hutchinson, 72 Parker and Gregorie, 75 and Groves and
Rodriquez-Antunez 74 have all recently suggested that preoperative radiation
improves survival following surgery for this disease. It might well be that
experience with this multimodality approach to this disease will lead to
improved survival rates.
The data regarding preoperative radiation are summarized in Table 9-5.
As already noted, improvement in survival with the use of radiation in ad-
dition to surgery has not been clearly shown by these reports.
Chemotherapy
Wehave rarely observed benefit from the use of chemotherapy in esoph-

ageal cancer. Bleomycin has minimal value, with an accumulated re-
sponse rate of about 19 per cent; however, such responses rarely last longer
than two or three months. Most other agents are useless or have been in-
adequately evaluated. Table 9-6 provides a summary of available data on
single-agent chemotherapy for this disease. 80
"
82
Combination chemotherapy
83
remains relatively untested in this neoplasm.
Immunotherapy
Immunotherapy has not been widely applied in cancer of the esophagus.

We have noted a suppression of the immune response generally in pa- —
tients with far-advanced cancer of the esophagus such as that observed —
in patients with other far-advanced malignancies. At present there are no
adjuvant immunotherapy trials ongoing.

In some which the incidence of gastroesoph-
countries, such as Japan, in
ageal malignancies is very high, survival rates have been improved by mass
screening programs utilizing endoscopy and cytology, which result in earli-
er diagnosis of the cancer. It is unlikely that such programs are feasible in
thiscountry or that they would find acceptance.
Since, to date, the effectiveness of chemotherapy for advanced disease
has been limited, and since immunotherapy is almost nonexistent, it seems
unlikely that postsurgical adjuvant therapy with these modalities will find
applicability in the future.
A combination of the two major cytoreductive modalities —
radiation
therapy and surgery —
might be better than either approach alone. Al-
though some reports have indicated no benefit when they are used in com-
bination, there are recent series suggesting that combination surgery and
radiation therapy is the best way to treat the disease (see section on Radia-
tion Therapy). We currently favor postoperative radiation therapy in all
cases in which any unfavorable staging criterion was found at surgery. The
ultimate usefulness (or sequence, or both) of modalities when used in com-
bination is yet to be determined.
Section 2
Stomach
INTRODUCTION
The marked variability in the incidence of gastric cancer with regard to

geographic area, race, diet, heredity, and sex has made this cancer one of
the most intensely investigated with respect to etiology and environment.
During the last several decades, cancer of the stomach has become more
prevalent in Japan, Chile, and Scandinavia. However, during the same
period, the incidence of gastric cancer in the United States has fallen from
29 per 100,000 population in 1930 to 7 per 100,000 population in 1966. 84
In the period between 1950 and 1965 the decrease in the incidence of the
disease in males was 46 per cent and in females was 49 per cent. 85 This
striking decrease in the national incidence of gastric cancer, the reasons for
which are unknown, has not been observed in any other malignancy. How-
ever, several factors that have been related to populations in which the
incidence of gastric cancer has varied greatly are shown in Table 9-7 and
are discussed in multiple references. 86 94
"
9 Gastrointestinal Tract Neoplasms 247
TABLE 9-7. Factors Associated with Cancer

of the Stomach
Low Cancer Rate High Cancer Rate
Not related to gastric cancer patients Relatives of gastric cancer patients
Blood group O Blood group A
Females Males
Younger patients Older patients
Meat-eating population Fish-eating population
Bland diet Salty or spicy diet
Low cabbage diet High cabbage diet
Norma] gastric secretions Atrophic gastritis, achlorhydria
White Black
A number of authors have commented on a possible relationship between

the hot rice, rice wine, raw fish, and pickled-vegetable diet
Japanese of the
and the fact that Japan has the highest incidence of gastric cancer in the
world. Dungal and Sigtirjonsson8* noted that in Iceland the distribution of
gastric cancer corresponded roughly with the consumption of smoked salm-
on and smoked trout. However, no significant dietary factors have been
noted in gastric cancer patients in the United States, although there is a
suggestion that the ingestion of cabbage might be a factor influencing the
incidence of the disease. It has also been suggested that the increased use
of refrigeration and cold beverages may have contributed to the decreased
incidence in the United States. 91
The transformation of benign polyps to cancer has not been proved. 89
However, a recent report by Watanabe et a I. 90 noted a higher incidence of
gastric lesions in patients with familial adenomatous coli. The authors spec-
ulate that the same factors that make patients with familial adenomatosis
susceptible to tumors of the colon can also induce tumorogenicity in other
organs.
Pernicious anemia, with its associated achlorhydria and severe gastric
mucosal atrophy, seems to be well established as a condition predisposing
to gastric carcinoma. 95 A pathogenetic mechanism to explain this increased
incidence of gastric cancer has been proposed. Mean nitrite concentration
of gastric juice from 13 fasting patients with pernicious anemia was nearly
50-fold greater than that of age-matched controls, and it is possible that
intragastric production of carcinogenic \-nitroso compounds could be re-
sponsible for carcinogenesis. 96
Biology
The stomach is a hollow organ with the thickest wall and greatest lumen
diameter of any structure within the gastrointestinal tract. Unfortunately, it
is and be present for long

likely that lesions there will attain a large size
periods prior to diagnosis. Although cancers may occur anywhere in the
stomach, most develop in the pyloric and antral regions, particularly along
the lesser curvature. In a study of more than 5000 gastric carcinomas, 51
per cent were found to involve the pylorus and antrum, 18 per cent were
found to involve the lesser curvature, 21 per cent were found to involve the
body, 7 per cent were found to involve the cardia, and 3 per cent were
found to involve the greater curvature. Benign ulcers, which frequently
have an appearance similar to gastric cancer, rarely appear on the greater
curvature. 9T
Gastric cancer spreads in typical patterns: by continuity on the mucosal
surface— infiltrating the gastric wall and sometimes resulting in wi de-
spread scirrhous inflammation plastica) — or by direct extension out-
(linitis
side the stomach — involving adjacent organs such as the omentum, liver,
pancreas, and colon. Nodal metastases involve the inferior gastric, subpy-
loric, and celiac axis nodes when the neoplasm begins in the distal stom-
ach. Pancreatic, splenic, pericardial, and nodes

superficial diaphragmatic
are most often involved with proximal lesions. Vascular spread most com-
monly involves the liver and whether by this means or through direct inva-
sion, hepatic involvement is noted in about 30 per cent of patients coming
to operation.
A advanced gastric cancer is involvement of the left
typical finding in
supraclavicular node (Virehow's node), indicating spread through the tho-
racic duct. Gastric cancer also spreads by transperitoneal extension, and
seeding of the peritoneal cavity is frequently a late manifestation with asci-
tes and metastasis to the ovaries (Krukenberg's tumor) or to the pouch of
Douglas (rectal shelf metastasis). Pulmonary, osseous, brain, and cutaneous
metastases are not uncommon in the later stages of the disease. 89,98,99
NATURAL HISTORY
Classification
Most neoplasms of the stomach are adenocarcinomas, although lympho-

mas, sarcomas, and other rare tumors may occur. 89, 97, 10° Adenocarcinoma
may present as a polypoid mass (about 10 per cent), as a superficial muco-
sal lesion (about 5 per cent), as a diffuse scirrhous lesion (about 10 per
cent), or as an ulcer (about 75 per cent). About 2 per cent of cases have
multiple gastric carcinomas.
The amount of differentiation in carcinoma of the stomach may vary, and
this affects prognosis. Broder's classification has been employed to quanti-
tate the differentiation of these lesions, with grade 1 being well-
differentiated lesions and grade 4 being highly anaplastic lesions. 101
Another classification is that of Borman, which utilizes the gross charac-
teristics of the tumors: group 1, solitary polypoid circumscribed carcinomas
without ulceration; group 2, ulcerated carcinomas with marginal elevation
and sharply defined borders; group 3, partially ulcerated carcinomas with
marginal elevation and partial diffuse spread; and group 4, diffuse carcino-
mas. In this classification, group 4 correlates with the poorest prognosis. 10 -
Ming 103 has recently suggested a simpler classification, in which

much
gastric cancers are separated simply into the expanding type and the infil-
trative t>pe. It is postulated that these two types of carcinomas may be
different in their histogenetic origins and may be of prognostic value. The
staging system of Masson, Rember, and Mulligan also may eventually be of
prognostic usefulness. 1 *4, 1<B
Clinical Features
_ue epigastric discomfort is the most common presenting symptom,

followed by anorexia, early satiety, eructation, weight loss, weakness, iind
dysphagia or obstruction, or both. Pain has been reported as a common first
symptom and has been observed in as many as 85 per cent of patients by
the time the diagnosis of carcinoma of the stomach is made. The type of
pain may be similar to that of benign peptic ulcer and may be relieved by
food or antacids. Continual pain, however, generally suggests tumor in-
volvement outside the stomach wall. Substernal or precordial pain may also
be associated with tumors of the cardia. 106
Diagnosis
As with all gastrointestinal malignancies, a relentless search to find the

cause of the slightest persistent gastrointestinal complaint is the best diag-
nostic approach. Such a vigorous approach, utilizing cytology and endos-
copy, was used in England, where it was possible to diagnose 10 out of
101 early cases of gastric cancer that is. diagnosis of cancer confined to the
muscularis propia>. whereas in the previous 720 cases only 4. or 0.5 percent
were diagnosed at such an early stage. 107 The integrated use of all modal-
ities (including x-ray, cytology, endoscopy, biopsy, and perhaps some of the
current developmental serologic tests) will undoubtedly increase the
number of early gastric cancers found in the future.
X-RAY STUDIES. Barium swallow with an upper gastrointestinal series
has been the foundation for the diagnosis of gastric carcinoma. Criteria for
radiologic diagnosis consist of constant changes in the structure of the
stomach, such as tumor or filling defects in the normal outline, loss of flexi-
bility and distensibility, or an alteration in the relief partem of the mucosal
folds, with or without ulceration.
Differentiation between malignant and benign ulcers is frequently very
difficult. The characteristic malignant ulcer crater lies in a mass and does
not extend beyond the boundaries of the gastric wall. The mucosal folds do
not radiate toward the center of the crater but instead remain with their
usual contour up to and beyond the ulcer. Malignant ulcers are usually
larger than 1 cm and on fluoroscopy, the surrounding gastric wall is rigid.
Benign ulcers often penetrate beyond the limit of the stomach wall, there is
often no surrounding tumor, and the rugal folds radiate outward from the
center of the crater.
Hamed and Wolf10* have suggested that the presence of an air-fluid level
within a gastric ulcer is a very accurate way of establishing the presence of
malignancy. Dekker and Op Den Orth 109 have emphasized the importance
of following up even the slightest radiologic suspicion to accomplish an

earlier diagnosis. It has been suggested that if an ulcer does not change
after seven to nine days of treatment with acetazolamide, its malignancy is
confirmed. 110
ENDOSCOPY. The introduction of the flexible endoscope has greatly fa-
cilitated the diagnosis of gastric cancer, and when this technique is per-
formed together with x-ray examination, the diagnostic accuracy for gastric
cancer is increased. One large series in Japan demonstrated a diagnostic
accuracy of 99.4 per cent through the utilization of biopsy and cytology
during the years from 1970 to 1974. U1 Prolla et al. u - evaluated direct-vision
endoscopy, biopsy, and cytology in 183 patients, and the findings of at least
one technique were positive in 94.8 per cent of these cases. However,
since the cytologic findings were positive in only 85 per cent and the endo-
scopic biopsy findings were positive in only 79 per cent of the patients,
they emphasize the complementary nature of these tests in achieving a
diagnosis. Dekker and Tytgat 113 also emphasized that endoscopy by itself —
without x-ray, cytology, or biopsy — is not sufficiently reliable in determin-
ing the nature of lesions. An incorrect endoscopic interpretation was made

in 7.3 per cent of 1005 patients examined by endoscopy alone, and in 8.2
per cent no firm conclusions could be reached.
Exfoliative Cytology. Tumor cell cytology is a valuable adjunct in
the diagnosis of gastric cancer. As with most techniques, it is best used in
conjunction with other diagnostic aids. Its use has been greatly facilitated
by the flexible endoscope and brush biopsy technique. Pilotti et a/. 114 re-
corded an accuracy rate of 83.3 per cent from brush biopsy cytology alone
in 78 patients with gastric carcinoma. Tamura et a/. 115 performed endoscopic
examination on 65 cases of small gastric carcinoma, including 27 cases of
early carcinoma. With histologic findings alone, 89 per cent were diagnosed
accurately, with touch smear cytologic findings alone, 85 per cent were diag-
nosed accurately, and with combined examination, 95 per cent were diag-
nosed accurately.
Testing for Previous Gastrectomy Patients. The advent of the
flexible endoscope has focused interest on the large population of patients
who have had previous gastric surgery. Osnes et a/. 116 in a series of 830
consecutive routine gastroscopies, found 43 patients with gastric carcino-
mas, 13 of whom had had previous Billroth operations for ulcer disease. All
patients were symptomatic. Multiple biopsies and brush cytology from the
entire gastrojejunal anastomosis were responsible for detecting these early
cancers. Of 676 patients who had undergone Billroth I and Billroth II re-
sections 10 to 20 years earlier and were re-examined by gastroscopy, 14
patients were found to have carcinomas. Domellof and Janunger 117 concluded
that patients who were resected for benign ulcer disease more than 11
years previously were at high risk to develop gastric cancer. Schrumpf et
UH
al. examined 421 patients who had had partial gastrectomy 25 years earli-
er for benign disease. Although the endoscopic appearance was normal in
every instance, histologic examination of multiple biopsies revealed infil-
trating carcinoma in four patients and carcinoma in situ in three patients.
Normal mucosa was noted close to the anastomosis in only one patient.
Gastrointestinal Tract Neoplasms 251
These authors advocate routine endoscopy with multiple biopsy for pa-
tients who are long-term survivors of partial gastrectomy. An alternative to
this point of view has been reported, however. In an autopsy study using
matched retrospective controls, only 9 of 464 patients dying of gastric can-
cer had undergone previous partial gastrectomy, whereas the respective
number among the controls was 5. 119
Other Dl\GNOSTIC TESTS. Investigations are ongoing to develop other
tests that might be useful in the early diagnosis of gastric cancer. No diag-
nostic significance has been attached to serum gastrin, -" serum copper, or
1
ceruloplasmin. 121 The isolation of a sulfated glycopeptidic antigen from

human gastrictumors has been reported and may eventually be of diagnos-
tic significance.
122
The value of the carcinoembryonic test in gastric cancer
~'
remains to be determined. 12 12 '
Staging
The staging system adopted by the American Joint Committee for Cancer
Staging and End Results Reporting is based on the fact that prognosis in
gastric cancer is dependent upon the degree of penetration into the stoni-
FIGURE 9-4. "T" category in cancer of the stomach. A. T,: Primary tumor confined to mucosa
or mucosa and submucosa. Two lesions are shown. B.T Primary tumor involves the mucosa and
2
the submucosa including the muscularis propria but does not penetrate the serosa. C. Ta Pri-
1
mary tumor penetrates serosa without invading contiguous structures. D, T 4 Primary tumor
:
penetrates through serosa and invades contiguous structures. (Adapted from Longmire \VP. Jr: In
Davis-Christopher Textbook of Surgery, 11th ed. Sabiston DC, Jr (ed), Philadelphia. \VB Saun-
ders Co., p986, 191
FIGURE 9-5. \" category in

cancer of the stomach. A, N,: In-
volvement of perigastric lymph
nodes within 3 cm of the priniarv
tumor along the lesser or greater
curvature. B. \ 2 Involvement of
:
the regional lymph nodes farther

than 3 cm from the primary tumor,
which are removed or are remova-
ble at operation. (Adapted from
Longmire \VP, In Daiis-Chris-
Jr.
topher Textbook of Surgery. 11th
ed. Sabiston DC, Jr (ed), Philadel-
phia, WB Saunders Co. p.
C
JST.
1977.)
ach wall by the primary lesion, the involvement of regional lymph nodes,
and the presence of distant metastases. The size or location of the primary
tumor is considered to be less important, and the histopathologic grade of
the carcinoma has not been useful in assessing prognosis. Thus, the stage
of disease is defined in terms of the three components of the system. TNM
The designation "T" is expressed in terms of the degree of penetration by
the cancer through the stomach wall, as illustrated in Figure 9-4. The "N"
category is based on the involvement of the perigastric lymph nodes in the
immediate vicinity of the primary tumor, as illustrated in Figure 9-5. The
TNM staging system, as recommended by the American Joint Committee in
1977, is presented in Table 9-8. 12e
TABLE 9-8. The TNM Staging System for Gastric Carcinoma

Proposed by the American Joint Committee for Cancer
Staging and End Results Reporting 1 -'*
Stage Description
T Primary tumor (The principal factor is the degree of penetration of the stomach
wall by the carcinoma)
TX Degree of penetration of stomach wall not determined
T No evidence of primary tumor
T, Tumor limited to mucosa or mucosa and submucosa regardless of its extent
(or location)
T 2 Tumor involves the mucosa, the submucosa (including the muscularis propria!
and extends to or into the serosa but does not penetrate through the serosa
T, Tumor penetrates through the serosa without invading contiguous structures
T 4 Tumor penetrates through the serosa and invades contiguous structures
N Nodal involvement (The regional lymph nodes are the intra-abdominal
subdiaphragmatic nodes)
NX Metastases to intra-abdominal lymph nodes not determined (i.e.,
laparotomy not done)
No No metastases to regional lymph nodes
N, Involvement of perigastric lymph nodes within 3 cm of the primary tumor along
the lesser or greater curvature
N, Involvement of the regional lymph nodes farther than 3 cm from the primary
tumor, which are removed or removable at operation, including those located
along the left gastric, splenic, celiac, and common hepatic arteries
N 3 Involvement of other intra-abdominal lymph nodes, such as the para-aortic.
hepatoduodenal, retropancreatic, and mesenteric nodes
M Distant metastasis
MX Not assessed
M No (known) distant metastasis
Mi Distant metastasis present
TABLE 9-9. Staging System for Gastric Carcinoma
Stage Description
No positive lymph node involvement, serosal involvement, or tumor cells at

the line of resection
1 Any one criterion present and the other two not present or not reported
2 Any two criteria present and the other one not present or not reported
3 All three criteria present
Prognosis by Stage
Oneof the most extensive correlations between stage of disease and

prognosis has been obtained from a cooperative study initiated by the Na-
STAGE NO OF PATIENTS
o 1
55
1 104
> 2 116
cr
3
to
cr
o
Q.
o
cr
o.
oJ
>
3
o
FIGURE 9-6. A. Survival .li-
ter curative surgery for gastric

cancer. B, Survival after pallia- YEAR AFTER OPERATION
tive surgery for gastric cancer.
(Adapted from Dixon WJ, et al..
Ann Stir" 173:36. 1971.) O 1 00-| STAGE NO OF PATIENTS
4
1 50
> 2 125
cr
en
80- 3 74
70-
60-
o
a.
o 50-
cr
o.
LlI
40-
>
i- .30
<
_i
Z) 20 H
=)
o 10
00
3 4 5 6 7 8 9 10 11
YEAR AFTER OPERATION

tional Cancer Institute. In this study patients were divided into stages 0, I.
II, and III according to the criteria in Table 9-9. The survival rates by stages
for both palliative and curative resections are indicated in Figure 9-6. The
30-day operative mortality is excluded from these calculations in this coop-
erative study. 127
TREATMENT
Surgery
Since the successful partial gastrectomy by Theodore Billroth in

first
1881, surgical removal of gastric cancer has been the only known successful
treatment of this disease. It has been demonstrated that the routine use of
total gastrectomy has failed to yield a better five-year survival rate than
subtotal gastrectomy, and the immediate mortality rate and side effects are
greater. 128 Thus, the location and size of the tumor dictate the type of
operation to be performed.
FIGURE 9-7. Subtotal gastric resection for cancer includes removal of the proximal duodenum
and greater and lesser omenta, proximal ligation of the left gastric artery, and excision of regional
lymph nodes. (Adapted from McNeer G: In Management of the Patient with Cancer, 2nd ed.
Nealon TF, Jr (ed), Philadelphia, VVB Saunders Co, 1976.)
A 6-cm margin of grossly uninvolved normal stomach wall is manda-

5- to
For proximal lesions at the gastroesophageal junction and the cardia,
tory. 129
we prefer proximal gastrectomy and resection of the involved esophagus, as
described in the section on esophageal cancer. For lesions in the distal
gastric segment, a subtotal gastric resection is usually performed, as illus-
trated in Figure 9-7. If there is infiltration proximally or if large cancer of
the midgastric segment is encountered, total gastrectomy may be required,
since adequate margins on either side will not be attained with anything
less than total extirpation of the stomach.
Direct invasion of contiguous organs such as liver or pancreas should not
be a deterrent to resectional surgery if partial resection of these organs is
feasible and safe. There are recorded instances of patients with contiguous
organ involvement who have been cured.
Reconstruction in partial gastrectomy is usually by gastroduodenostomv
when possible, but more often by gastrojejunostomy (Billroth II), as the
amount of resected stomach often is of insufficient length to allow for gas-
troduodenostomv. The construction of these anastomoses and the division
of the stomach are greatly facilitated by the use of stapling devices. The
position of the efferent and afferent limbs with respect to the colon is de-
termined by the preference of the surgeon. We prefer a retrocolic anas-
tomosis. For re-establishing intestinal continuity in cases of total gastrec-
tomy, we have not favored the construction of intestinal pouches but prefer
that a jejunal loop be brought up and an end-to-side esophageal-jejunal an-
astomosis be constructed with an end-to-side Roux-en-Y jejuno-jejunostomy
fashioned distally to provide flow of bile and pancreatic secretions.
The results of surgery for gastric carcinoma are directly related to the
stage of the cancer when first seen. In a New York Memorial Hospital
study, the five-year survival rate was 57 per cent when the neoplasm was
isolated to the stomach but was 5 per cent when regional nodes were in-
volved. 130 At the Mayo Clinic, these figures were 58 per cent and 14 per
cent, and at the Lahey Clinic, they were 57 per cent and 12 per cent.""
Costello et a/. 131 reported a series of 226 consecutive cases of carcinoma of
the stomach, in which laparotomy was performed in 96.5 per cent of cases.
In those patients with small tumors in which Billroth I gastrectomy could
be performed, a 32 per cent five-year survival rate was obtained. However,
the overall survival rate was 8.5 per cent. Dupont et al. ta2 reported a review
of 1497 patients. The operability rate was 82 per cent, and the resectability
rate was 48 per cent. The five-year survival rates were 22 per cent after
radical subtotal gastrectomy, 30 per cent for those with localized disease, 2
per cent after esophagogastrectomy, and 7.4 per cent overall. Of 403 pa-
tients with gastric cancer who were seen between 1957 and 1966 at the
Lahey Clinic, the operability rate was 94 per cent, the resectability rate
was 58 per cent, and the five-year cure rate was only 11 per cent. 133
Radiation Therapy
The use of radiation for the local control of unresectable gastric carcino-
ma has been explored in a number of centers. Although occasional sympto-
2.56 II / Treatment of Specific Neoplasms
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matic improvement may be seen with photon radiation alone (4500 rad in
4.5 weeks), 134, 135 Falkson 136 observed no objective responses in 13 patients
(doses up to 6000 rad in 6 weeks), and in a retrospective analysis, Moer-
137
tel's group found no difference in survival between an untreated group
and a radiation-treated group.
Groups in England 138, 139 and Germany 140 are exploring the use of neu-
trons, alone or in combination with photons, for localized unresectable
stomach cancer. Early data indicate an increased ability to achieve local
tumor sterilization, but progressive adverse changes are seen in the normal
tissues. Nevertheless, Catterall's 138 group reported relief of pain in 18 of 20
patients, disappearance of a palpable mass in 16 of 19 patients, relief of
vomiting in 13 of 14 patients, and resolution of bleeding in 6 of 6 patients.
Macdonald et <v/. 141 have also recently reported a group of seven patients
treated with combined 5-fluorouracil and neutron irradiation, with a median
months and one patient surviving more than 15 months.
survival of 7.5
Although radiation has not definitively been shown to be of value in lo-
cally advanced gastric cancer, further trials of neutron therapy, neutrons
plus chemotherapy, and photons plus chemotherapy appear to be warrant-
ed. A summary of these trials is shown in Table 9-10.
Chemotherapy
Single Agents. Although a large number of commercially available

agents have not been adequately tested in gastric adenocarcinomas, at least
"
four drugs have been shown to be clinically active (Table 9-1 1). 144 146 The
most extensively studied and probably most useful drug is 5-fluorouracil,
TABLE 9-11. Single-Agent Chemotherapy for Gastric Carcinoma
No. Responses/No. Response

Rank" Drug Selected Patients Rate (%) Reference
1 5-Fluorouracil 101 448 23 144-146

2 Doxorubicin 15/37 40 147 and 148
3 Mitonncin-C 63/211 30 144-146
4 BCNU 6/33 18 149
NE Mechlorethamine 4 25 16 145 and 146
NE Chlorambucil 3/18 17 145 and 146
NE Hydroxyurea 6/31 19 145 and 146
NE Dacarbazine 2/15 13 145 and 146
NE Melphalan 1/16 — 150
NE Streptozotocin 4 — 145 and 146
NE Cytarabine 3/11 — 145 and 146
NE Methotrexate 0/2 — 145 and 146
NE Vincristine 0/11 _ 151
Inactive Cvclophosphamide 5/72 7 145. 146, 152 and 153
Inactive CCNU 1/35 3 145 and 146
Inactive MeCCNU 7/75 9 149 and 154-156
"Relative value or rank as single agents assigned by Charles M Haskell as a function of personal experience
and a review of the literature.
NE = not able to be selectively evaluated because of inadequate personal or published experience.

with an approximate response rate of 23 per cent using a wide variety of

doses and routes of administration. The usual duration of response is four
to five months, although response sometimes extends beyond a year in
some patients. There is no compelling evidence that any particular sched-
ule or dose is superior, and we have generally used a weekly dose sched-
ule or a loading course followed by weekly maintenance when this drug is
used as a single agent (see Chapter 5).
Doxorubicin shows great promise as an active agent in gastric carcinoma,
with an overall response rate of 40 per cent in a small number of patients. 147, 148
It is too early to define the full duration of such responses, although prelimin-
ary experience suggests that it is in the range of three to four months.

Mitomycin-C has also been extensively studied, although its severe bone
marrow toxicity has limited its use in the United States. 144 146 With the
"
adoption of an intermittent high-dose schedule of administration, drug-

related mortality has decreased, and the drug has become more widely
used. We rarely use this drug as a single agent, however, except as a last
resort in patients who have failed previous therapy with combinations of
drugs (as will be described). This recommendation is also related to the
average duration of response with mitomycin-C, which is only one to three
months.
The only nitrosourea with well-established clinical activity as a single agent
against gastric carcinoma is BCNU, with a response rate of 18 per cent. 152 Both
single-agent me-CCNU and single-agent CCNU appear to be less active,
although, as will be discussed, me-CCNU has been included in various
programs of combination chemotherapy. 145 147, 154 156 At the present time, none
" "
of the nitrosoureas are recommended as single agents, except in patients who

have failed previous single-agent 5-fluorouracil therapy.
As shown in Table 9-1 1, a wide variety of other commercially available drugs
are unevaluable at the present time. Some physicians believe that certain
alkylating agents (mechlorethamine and chlorambucil) are useful in treating
this disease, although the low response rate in a small number of patients so
treated makes the evaluation of their value difficult.
Combination Chemotherapy. A wide variety of combination chemo-
therapy regimens have been tested in gastric adenocarcinomas. The earliest
systematic study of combination chemotherapy in gastric carcinoma was con-
ducted at the Mayo Clinic, although the small number of patients made it
impossible to assess response rates accurately. 157 However, even in the small
experience conducted initially, there appeared to be benefit from combining
5-fluorouracil and BCNU. Subsequently, this preliminary experience was
extended in 167 patients with advanced adenocarcinoma of the stomach and
pancreas, and a response rate of 41 per cent was confirmed in a series of 34
158
e valuable patients with adenocarcinoma of the stomach. The patients
receiving this combination lived approximately twice as long as those receiv-
ing either no therapy or BCNU as a single agent, and one fourth of the patients
were alive at 18 months, compared with 6 months for those receiving no
treatment or BCNU alone. Thus, a modest survival advantage was seen with
this combination. The treatment procedure includes 5-FU in a dose of 10
mg/kg/day as a rapid intravenous injection daily for five days combined with
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BCNU dose of 40 mg/m 2 /day for five days. Therapy is discontinued if the
in a
patient develops stomatitis or diarrhea during the five-day treatment, and a
repeat course can be given every eight weeks if the patient shows a beneficial
response. Careful follow-up of the white blood cell count and the platelet count
is necessary because of the relatively severe bone marrow suppressive effect of
BCNU. This regimen is well tolerated, is relatively convenient for patients, and
probably represents an acceptable standard of reference for combination
chemotherapy of this disease at the present time.
Table 9-12 summarizes a wide variety of combination chemotherapy regi-
"
mens utilized in this disease, including experimental studies. 157 175 Although
some of these regimens give a higher response rate than the combination of
5-FU and BCNU, their impact on survival is not clearly superior at the present
time, and they are more toxic. Further time and study appear to be needed
before wider acceptance of these alternative regimens can be recommend-
ed.
Immunology and Immunotherapy
Immunologic investigations in gastric cancer have centered around the

correlation among lymphoid morphology, the immune response, and survival.
To date, there are only limited and inconclusive trials of immunotherapy. In a
study of 138 carcinomas, the morphology of the paracortical areas of the
regional lymph nodes was carefully examined. The activity of the regional
lymph node paracortex was directly and positively correlated with the survival
and inversely related to the appearance of the nodal metastases, which were
ominous prognostic signs. 176
A somewhat similar study compared the regional lymphatics in patients with
gastric carcinoma with those in patients with gastric ulcer. It was noted that
assays of the cell-mediated immune system were depressed more often in the
nodes of the carcinoma patients. The potentially interesting comparison of
patients with gastric cancer and good prognoses and patients with gastric-
cancer and poor prognoses was not made. 177
The immunologic reactivity of peripheral blood leukocytes from patients
with gastric cancer and other malignant diseases has been compared with those
obtained from normal healthy volunteers. When tested against antigens ex-
tracted from gastric carcinomas, it was found that the lymphocytes in 91 per
cent of the patients with gastric carcinoma could be sensitized, as compared

with 5 per cent of those patients with malignant but nongastric diseases or
normal controls. 178 In another system, when gastric cancer patients' leukocytes
were exposed to a panel of tumor extracts, leukocyte migration reactivity was
positive before operation in 90 per cent of the cases, then declined after
surgery, and reappeared in patients with local recurrence or metastases.
Modifications of this procedure might eventually prove valuable in making an
early diagnosis of recurrence. 179
has been suggested that incidental splenectomy might reduce the immun-
It
ologic reactivity of the host and thereby perhaps increase the chance of
recurrence. However, an interesting study by Orita et al.
1S0
has shown that
splenectomy done shortly before or shortly after injection of lethal tumor cells
in mice actually provided an improvement in survival when compared with
sham-operated controls. They went on to obtain follow-up observations of 389
patients with gastric cancer who underwent gastrectomy alone and 89 cases
who received gastrectomy combined with splenectomy. The five-year survival
rate of the latter group tended to show a better prognosis in a relatively early
stage. Establishing the significance of this finding will require corroborative
studies.
Attempts immunotherapy have been few and limited. Edynak et al. iai
at
treated gastric cancer patients with BCG and solubilized tumor antigens.
Survival in this small group was much better than that with matched, untreated
controls. Ambus et a/. 182 have combined BCG immunotherapy with 5-FU
chemotherapy for patients with advanced gastric malignancies. Survival in this
study seems to be more favorable in those patients with combined treatment,
although the results are not statistically significant. Dykes and Trejdosiewicz 183
have reported a pilot study of intratumor Corynebacterium parvum therapy
prior to conventional surgery. Survival data are not available, but this study is of
potentially great interest, since intralesional immunotherapy has been most
effective in animals, and the intimate association ofC. parvum and tumor cells
prior to excision might be the ideal wax to induce an antitumor immune re-
sponse.
There have been numerous recent reports of trials of adjuvant therapy in

FUDR, 5-FU, and other agents in combination.
gastric cancer, using thiotepa,
It must be emphasized that most of these trials are not prospective randomized
studies. The reader directed to investigate the experimental design of these

is
"
therapeutic trials very carefully. 184 190
Several prospective randomized controlled studies are ongoing in the Unit-
ed States to see if adjuvant chemotherapy consisting of 5-FU and Me-CCXU is
of value. 191 These studies are of potential importance. However, at present
the status of adjuvant therapy must be considered unsettled.

The unexplained but continuing decrease in the incidence of gastric carcino-
ma in this encouraging. However, the results of treating established
country is
gastric carcinoma have remained dishearteningly static. Although the support

^> stems for surgical procedures continue to improve, the results of surgery in
this disease reflect little improvement over those obtained 20 years earlier.
The encouraging early reports of immunotherapy suggest that this modality
may have a role in adjuvant therapy, particularly when combined with chemo-
therapy. At present, however, these approaches must be considered experi-
mental.
Section 3
Small Bowel
INTRODUCTION
Incidence and Etiology
Small bowel tumors make up approximately 1.5 per cent of all benign
and malignant gastrointestinal neoplasms. It is estimated that in 1975 there
were 2200 new cases of malignant tumors of the small bowel in this coun-
try, approximately divided evenly between males and females. 192 About one
half of all small bowel tumors are malignant.
The etiology of these neoplasms is not clear. Although the small bowel
composes approximately 75 per cent of the gastrointestinal tract and has an
enormous mucosal surface that presumably is in constant contact with en-
teric carcinogenic substances, it is of interest that the incidence of neo-
plasms is much lower than that observed in other gastrointestinal organs.
For instance, there are about 12 gastric carcinomas and 46 rectal carcino-
mas for each small bowel malignancy. Lowenfels and Sonni 193 studied the
distribution of 784 small bowel carcinomas and found that most tumors,
with the exception of carcinomas, occur in the duodenum and proximal je-
junum, and relatively few occur in the terminal bowel. The incidence of
small bowel cancer was positively correlated with high fat and protein con-
sumption. Ingestion of fat and protein has been correlated with a higher
incidence of other gastrointestinal cancers, notably colorectal carcinoma,
and perhaps the etiologic link is similar to that of small bowel cancer.
NATURAL HISTORY
Pathology
Table 9-13 shows the location and frequency of both benign and malig-
nant tumors of small bowel extracted from several large series. 194 In the
experience of many centers, the most common malignant tumor of the small
bowel is actually metastatic tumor from other organs — most frequently pri-
mary neoplasms of the ovary, stomach, and pancreas, as well as malignant
melanoma. Most benign tumors of the small bowel are undiagnosed in the
lifetime of the patient and have been discovered as incidental findings at
the time of autopsy.
The carcinomatous lesion in the small intestine is characterized by a nar-
rowed intestinal lumen, with an ulcerated mucosal surface. The histology is
typical for adenocarcinoma of gastrointestinal origin. Leiomyosarcomas are
TABLE 9-13. Neoplasms of the Small Bowel
Neoplasm Duodenum Jejunum Ileum Total
Malignant
Adenocarcinoma 92 90 28 210
Lymphoma 3 57 69 129
Sarcoma 15 23 33 71
Miscellaneous 1 4 4 9
111 174 134 419
Carcinoid 15 19 229 263
Benign
Leiomyoma 31 77 54 162
Adenoma 39 38 38 115
Lipoma 25 11 42 78
Miscellaneous 33 18 23 74
Hemangioma 3 39 21 63
Neurofibroma 2 6 3 11
Lymphangioma 2 4 6
Fibroma 2 2 4
Fibroniyoma 1 1
133 194 187 514
1196
"From Mason CG: In Davis-Christopher Textbook of Surgery. Sabiston, DC, Jr (ed), Philadelphia, WB
Saunders Co, 1977.
vascular tumors of smooth muscle origin, arising in the muscular wall of the
intestine. They and vascular. Lymphosarcoma is
are usually spheroid, firm,
segment several centimeters long with involvement into
often a rather rigid
the mesentery. These polypoid lesions often will not cause the typical
napkin-ring appearance of obstruction but can lead to a more frequent in-
cidence of perforation. 195
Several syndromes are associated with small bowel neoplasms. A com-
mon factor in most of these syndromes is the degree of polyposis in other
segments of the gastrointestinal tract, which is frequently determined by
heredity. These include the Peutz-Jeghers syndrome, 196 the Cronkhite-
Canada syndrome, 197 Gardner's syndrome, 198 von Recklinghausen's dis-
ease, 199 and juvenile polyposis. 200 Small bowel lesions have also been asso-
ciated with protein-losing gastroenteropathy, 201 and with patients with vas-
cular anomalies that are presumed to be due to defects in collagen
metabolism. 202204 Further discussion of carcinoid tumors of the small bowel
may be found in Chapter 14.
Clinical Course and Diagnosis
Intermittent abdominal pain, which is usually vague and indistinct but is

occasionally described as cramps, usually results from the partial bowel ob-
struction caused by these neoplasms and is the most common symptom. 204
Other clinical signs and symptoms of small bowel lesions in decreasing

order of frequency include anorexia, nausea and vomiting, obstruction,
bleeding, anemia, abdominal mass, weight loss, and, rarely, perforation.
Diagnosis is usually by physical examination, abdominal x-rays, and most
importantly, barium contrast studies of the small bowel. Tumors of the ter-
minal ileum that cause an ileocolic intussusception can usually be diag-
nosed by barium enema.
Prognosis
The survival for adenocarcinoma of the small bowel ranges from 20 to 25

per cent in most series, 205 209 reflecting the wide degree of extension that is
"
frequently noted by the time diagnosis is made. Recently, excellent clinical

210
series of small bowel neoplasms have been reported by Sager, Rich, 211
and Freund et a/. 212
They emphasize the common features seen in these
malignancies, which include a long delay between the onset of disease and
213
diagnosis and concomitantly poor survival rate. Smith et al. have empha-
sized diagnostic x-ray findings, which may be useful in making earlier diag-
noses of metastatic disease of the small bowel.
TREATMENT
Surgery
The treatment of these primarily surgical. Segmental resection

lesions is
suffices for benign lesions, and extended segmental resection is used for
malignant lesions. Very frequently, particularly in metastatic disease, there
will be extension of the malignant process beyond the scope of total surgi-
cal excision. Palliative operation should be performed, however, to lessen
the chance of obstruction, perforation, and hemorrhage. In malignant
tumors of the duodenum, a radical pancreaticoduodenectomy may be nec-
essary. When malignant tumors of the terminal ileum are encountered, a
right colectomy is usually part of the operative procedure, along with an
ileotransverse colostomy. If malignant lymphoma is encountered, staging
procedures to determine the extent of intra-abdominal spread must be per-
formed. This includes a sampling of intra-abdominal and periaortic nodes,
a liver biopsy, and often a splenectomy. In addition, the discrete focal disease
is usually resected, and the patient is given proper systemic therapy.
The surgical therapy of small bowel carcinoid tumors is discussed in

Chapter 14 and in several good reviews. 217, 218
Radiation Therapy
Radiation therapy is limited by morbidity in the treatment of the rare

carcinomas of the small intestine, and no significant responses have been
reported.
Chemotherapy
Adenocarcinomas of the small bowel are rare, and very little has been
published on the role of chemotherapy for this group of tumors. The con-
sensus expressed in several reviews is that chemotherapy is without value
for this group of tumors; our personal experience is consistent with this
view, although it is impossible to define the true role of this modality
based on the available data. As a working approach to this problem we
concur with Moertel, 214 who suggests that palliative chemotherapy for this
disease be the same as used in colorectal carcinoma.
Chemotherapy for other forms of small bowel tumors is described else-
where in the book (Chapter 14, carcinoid tumors; Chapter 15, sarcomas;
Chapter 24, malignant lymphomas).
Section 4
Colorectal Malignancies
INTRODUCTION
Carcinoma of the large bowel represents a tremendous hazard to health
in most affluent countries. In the United States alone, approximately
110,000 new cases were expected in 1979, second in incidence only to
skin cancer, and about 50,000 people died of the disease. 215 This section
is intended to provide an in-depth coverage of current trends of investiga-
tion and practice in the many facets of colorectal cancer.
Etiology
Global epidemiologic studies have revealed that colorectal cancer is

much more prevalent in North America and most developed countries than
in South American, African, and Asian countries. This strongly suggests that
cancer of the large bowel is associated with environmental factors. 216,217
This concept is strengthened by the observation that the incidence of co-
lorectal cancer is significantly higher in first- and second-generation Japa-
nese immigrants in Hawaii and California than in Japanese in Japan. 218
Studies have not related large bowel cancer to factors such as constipation,
weight, tobacco, and alcohol usage, or to any primary large bowel diseases
except for inflammatory bowel disease and familial polyposis. 219 However,
dietary and other factors have received intense scrutiny in recent years. A
brief synopsis of areas of investigation follows.
Dietary Fiber. Burkitt 220 pointed out the strong association between
the low incidence of colorectal cancer and a diet high in fiber content,
which and large bulk in the stools of the South
results in rapid transit time
African Bantu. He
suggests that a rapid transit time reduces the time the
actual carcinogens or their precursors are held in contact against the colon-
221
ic mucosa. However, there is little evidence that a decreased transit time
reduces bacterial action on colon contents, 218 and recent studies of popula-
tions with widely varying incidences of colon cancer show no differences
222
in bowel transit times.
The role of dietary fiber itself is unclear. Mendeloff 223 suggests a beneficial
role of a diet high in fiber, but Drasar and Irving 224 found no relationship
between dietary fiber and cancer of the colon. Haenszel et a/. 225 established a
positive correlation between colon cancer and the ingestion of legumes,
which are high in fiber content.
Dietary Sugar. The elevated consumption of refined sugar has been
noted as a possible etiologic factor in some populations with a high in-
cidence of colon cancer. 225 However, in Argentina, where the incidence of
colon cancer is relatively high, the consumption of refined carbohydrates is
low, 226 and a positive correlation between intake of sugar and colon cancer
224,227
is not uniform on a worldwide basis.
Dietary Fat. A correlation between the intake of animal fat and large
bowel cancer has been made in several studies. 219,228 231 Since 35 to 45 per
"
cent of fat in the American diet comes from meat —

predominantly beef
the association of fat and colon cancer usually also includes beef, although
whether or not beef itself contains specific carcinogenic components has
not been determined. Current hypotheses as to how dietary fat contributes
to colon cancer development include (1) the conversion of cholesterol and
dehydrocholesterol, normally present in the colon mucosa, to reactive me-
tabolites that act as carcinogens; (2) the alteration of the concentration of
colonic bile acids and metabolic activity of colonic bacteria to produce tu-
morigenic compounds; and (3) the influence of intestinal mucosal microsomal
mixed-function oxidases, which may play a role in carcinogenesis. 232 234
"
In a recent study, specimens of feces collected in Kuopio, Finland a —

city with a low-risk population for colon cancer —
were compared with
specimens collected in the New York metropolitan area, where the popula-
tion is at high risk to develop colon cancer. The dietary intake of fat and
protein were the same in the two populations, but the sources of fat were
different. A great portion of the fat ingested came from meat in the New
York population and from dairy products in Kuopio. The excretion of fat
was similar, but the bulk of the stool from Kuopio was much greater result-
ing from a higher intake of cereal products rich in fiber. The investigators
concluded that the greater fecal bulk in Kuopio diluted any tumorigenic
compounds coming in direct contact with colon mucosa. 235 Whether the
source of the dietary fat or the stool bulk or other unknown factors are
responsible for the differences in colorectal cancer incidence cannot be de-
finitely determined.
It should be noted that the association of fat consumption and colorectal
cancer has not met with uniform acceptance. 236

Alteration in Bowel Microflora. Hill 237 postulated that the nature
Gastrointestinal Tract Neoplas - 267
ot the bacterial flora of the bowel can be determined by the diet and that
diet also provides substrate for any bacteria-induced change of normal
bowel contents Since people living in areas with
to carcinogenic potential.
high incidences of colon cancer have high fecal concentrations ol bile
acids — both normal and degraded —
he felt the capacity of the bacteria to
desaturate the bile acid nucleus may be an important factor in carcinogenes
Some investigators have noted changes in the microflora of subjects at
high risk. 234 23 " whereas others have not found significant differences in
-
239 240
fecal microflora of individuals consuming different diets. For instance,
-
Goldberg et a/. 241

compared the fecal microflora of Seventh Day Adventi-
who are vegetarians, with individuals consuming a general western diet.
No statistically significant differences were identified between the fecal mi-
croflora of the two groups.
It is possible that the induction or repression of bacterial enzymes can
occur, which changes their metabolic activity — and
possibly their carci-
nogenic potential —
without appreciable changes in the actual number or
types of bacteria that are present in the stool. 24 -
Because of the tremendous potential of bacteria for substrate alteration
and subsequent carcinogenesis, most theories ot dietary etiology of colon
cancer postulate a form of bacterial interaction at some stage ot cancer de-
velopment, although the precise mechanism is unclear at present. Research
in this area is of particular interest, since an active bacterial pathway to
carcinogenesis, if identified, could probably be blocked by appropriate anti-
biotic treatment.
Other Possible Etiologic Agents. Numerous factors have been
linked to the presence of colon cancer, including viral infection, 244 beer
drinking, 245 asbestos exposure, 2 *' and the presence in the diet of metabo-
lites of tryptophan, tyrosine, and \-nitrosoamine^
Epidemiology
Several factors appear to have a significant influence on the incidence of

colorectal malignancies, as noted in Table 9-14. Each will be discussed
separately.
TABLE 9-14. Factors Predisposing to Colorectal Cancer
Fvmily History P\>t History \->ociated Di>e\-e Ace
Juvenile polyps Colon cancer or polyps L'lcerative colitis Over 40
Colon cancer or Female genital or Granulomatous

polyps breast cancer syndrome
Familial polyposis Peutz-Jegh-

syndrome syndrome
Familial poIyp<
"From Winawer SC, Sherlock P: Hap Pra

Age. In the general population, the incidence of colon cancer begins to

rise significantly after the age of 40 to 45 years and increases each decade
thereafter by a factor of about two peaks at age 75 years. 248 This may
until it
well result from the action of carcinogenic elements on colonic cells over
an increasing period. 249 The risk is about the same for men and women
over 40 years. When colon cancer occurs before the age of 40 years, it
usually does so in conjunction with some of the other risk factors, usually
familial.
POLYPS. Although the question of whether or not polyps are premalig-
nant is unsettled in the minds of some, it is definitely true that there is a
higher incidence of colon cancer in patients with colonic polyps. 250 It
seems logical to consider patients with adenomatous polyps or villous
adenomas at high risk for colon cancer, since a large body of direct and
indirect evidence suggests that most carcinomas, rather than arising de
novo, evolve from adenomatous tissue. First, about one third of operative
specimens of colon cancer have at least one adenomatous polyp. Second,
invasive cancer is frequently seen contiguously with adenomatous tissue.
In some specimens, there is a spectrum of change from benign adenoma-
tous tissue to atypia to focal cancer to invasive cancer. Third, as polyps
grow, there is increasing cellular atypia and increasingly abnormal chromo-
some patterns similar to those seen in invasive cancer. Fourth, many aden-
omatous polyps seen in familial polyposis, a well-documented premalignant
state, are histologically similar to adenomas that occur as individual
253
lesions. 251
"
A must be drawn between hyperplastic and adenomatous

distinction
polyps. Of 1000 colonic proliferations, about 900 are small, hyperplastic
polyps, which are of little if any precancerous significance. However, of the
remaining 100, about 10 will be large adenomas (greater than 1 cm), and 1
of these 10 polyps will contain a cancer. Therefore, although the overall
incidence of cancer in polyps is about 1 in 1000, the incidence is high (10
per cent) among large adenomas, and becomes even higher when polyps
greater than 2 cm or polyps of the villous type are encountered. 251,254
The effectiveness of prophylaxis (polypectomy) in reducing the incidence
of colon cancer also suggests a link between polyps and cancer. Gilbert-
sen 255 reported a 25-year study of more than 100,000 proctosigmoidoscopies
in 18,000 patients. Annual follow-up examinations were made, and the
equivalent of 85,000 patient years of experience was obtained. Whenever
any polypoid lesion was encountered, it was removed. Statistically, 75 to 80
rectosigmoid cancers could have been expected to develop in this group,
but only 11 occurred in these patients who had all polypoid lesions re-
moved.
High-Risk GROUPS. At Memorial Hospital, the number of colorectal
cancer patients with previous (3.6 per cent) or simultaneous (1.9 per cent)
colon cancer was 5.5 per cent. The annual incidence of multiple primary
cancers was 3.5 per 1000. The highest risk for a second colon cancer exist-
ed in those patients whose initial lesions were in the cecum. The presence
of adenomatous polyps in the resected specimen increased the risk of fu-
ture colon cancer to six times that seen in the general population. 251
Families with a high incidence of carcinoma in other anatomic sites, such

as endometrium, ovary, and breast, have a greater than normal risk of malig-
nancy. In addition, the specific risk of cancer of the colon in relatives of colon
cancer patients, is three times that noted in the normal population. If a family
member has multiple cancers of the colon, the onset of colon cancer in his
relatives occurs five to ten years earlier than would be expected.
Assoclvted Diseases and Colon Cancer. Almost all patients with
familial polyposis, a condition with an autosomal dominant mode of inheri-
tance with 80 per cent penetrance, will develop colon cancer unless colec-
3 '5
tomy is performed.- Another high-risk group consists of patients with
Gardner's syndrome, in which adenomatous polyps develop in the colon
and are associated with soft tissue and lung tumors. 198 Patients with either
Turcot's syndrome (CNS tumors) or Oldfield's syndrome (extensive seba-
ceous cysts are at high risk to develop colon cancer. Peutz-Jeghers syn-
drome can occasionally be associated with cancers of the stomach, ileum,
and duodenum. 196 Patients with juvenile polyposis are also at high risk for
cancer, and their relatives are more likely to develop adenomatous polyps
251
and colon cancer.-'*"
Ulcerative colitis is frequently associated with the later development of
colon cancer. When age is not considered, the likelihood of developing
colon cancer is five to ten times higher in colitis patients than in the gener-
al population. The risk begins to rise about 10 years after the onset of the
disease, and it has been estimated to be 20 to 30 per cent at 20 years. The
risk doubles in those patients in whom the onset of colitis occurs before the
age of 25 years. In patients who develop colorectal cancers, the average age
of cancer onset is earlier, and the cancers tend to be multicentric and often
highly malignant. The cancers often develop during an asymptomatic
period.- 51 -
Granulomatous colitis, or Crohn's disease, is also generally thought to be

premalignant. especially when the age of onset is before 21 years. Howev-
er, the order of magnitude of risk here is probably much less than that in
ulcerative colitis (Table 9-14).
NATURAL HISTORY
Classification
Recently, it has been realized that there is a shift in the distribution of

colon neoplasms to the more proximal colon, yet 70 to 80 per cent of these
25S
lesions are still located below the middescending colon. 252
Gross patho-
logic features of colon cancer that imply a poor prognosis include narrow-
ing of the bowel circumference. Annular lesions have a shorter survival
than those that involve only a portion of bowel wall. 259,260 The shape of the
tumors is significant. Nearly twice as many patients with polypoid or pro-
jecting growths survived five years as compared with those with infiltrating
growths. 260 261 In general, the size of the tumor has less bearing on survival
'
than on nodal metastases. 262 The location of the tumor has been of variable
significance, although it is generally thought that those of the right colon
have a more favorable prognosis than those of the left colon. 2 " 3,264
Histologic features related to prognosis include grade of tumor, lymphat-
ic, vascular, and perineural infiltration, and the presence or absence of an
inflammatory response. In histologic grading, as in the system of Broders, 265

most observers utilize either a numbering system from 1 to 4, with larger
numbers indicating less differentiation, or a series of modifying terms des-
ignating tumors as well, moderately, or poorly differentiated. 266 The per-
centage of cells showing differentiation or the arrangement of cells to form
glandular structures or tubules are usually used as criteria of differentia-
tion. Poorly differentiated signet-ring cells and mucinous carcinomas cany
a less favorable prognosis than more differentiated neoplasms. 263, 267
The character of the periphery or advancing margin of the tumor has
been correlated with survival. A worse prognosis has been described in
those with infiltrating margins as opposed to pushing margins. 260,268 Lym-
phatic invasion in the absence of nodal metastases has not been of proven
significance. 269 However, involvement of the perineural space has definitely
been related to local recurrence. Venous invasion by cancer cells also is a
grave prognostic sign. 270 Bowel wall and lymph node invasion are, of
course, of utmost importance in colorectal cancer and are discussed in de-
tail in the upcoming section on staging.
The inflammatory response of the regional lymphatics also appears to be

significant in determining prognosis. The presence of well-developed para-
cortical immunoblast proliferation and an associated sinus histiocytosis de-
fined a group of patients with a particularly good five-year survival regard-
less of the Dukes stage of the tumor —
83 per cent in contrast to 35 per
cent in those without significant numbers of paracortical immunoblasts. 266
Patients with only a paracortical immunoblastic response also did better.
These observations suggest that the cellular immune response may have a
favorable influence on prognosis in colon cancer. 271 273
"
The clinical features with colorectal carcinomas relate to

associated
tumor size and tumors occur more com-
location. Large, exophytic bulky
monly in the right colon, with its large diameter and fluid contents, and
result in symptoms of abdominal pain, bleeding, and weight loss rather
than obstruction. The pain is vague, dull, and may be confused with gall-
bladder disease or peptic ulcer. Anemia may be present. In the left colon,
with its smaller diameter and semisolid or solid contents, tumors are more
often infiltrating or annular and cause obstructive symptoms, changes in
bowel habits, or bleeding. Gas pains, decrease in stool caliber, and in-
creased use of laxatives are not uncommon. 262
The diagnosis of colorectal carcinomas, as in all malignancies, requires a
high index of suspicion and diligent follow-up of all symptoms, especially
in those segments of the population in which the incidence of colorectal
cancer may be expected to be high.
HIGH RISK INDIVIDUALS
Hemoccult Physical exam

I
Negative' Positive Positive
Followup
FIGURE 9-8. This schematic

Special diet
diagram indicates appropriate
follow-up for positive Hemoc- -Repeathemoccult
cult test or physical examination
in individuals at high risk to de-
Negative Positive
velop colon cancer.
Sigmoidoscopy
Followup
Barium enema
Negative Positive
Followup Diagnosis
Therapy
Tests for Fecal Blood. The best test for screening asymptomatic
subjects is the hemoccult guaiac impregnated paper. It is essential that the
patient be on a high fiber, red meat-free diet for at least 48 hours. Two
samples are taken from each of three stool specimens, and the slides are
developed within three days. If just one of the six slides is positive, further
work-up is performed. The advantages of this test include low cost, ease of
performance, and a relatively low false-positive rate (1 per cent). Those
asymptomatic patients with positive test results can then be followed in a
regular fashion as suggested in Figure 9-8. This test has been applied to
large groups of asymptomatic patients, with a false-positive test rate of less
than 1 per cent. It is likely that the wide-scale application of this test in a
population at high risk to develop cancer will significantly increase the
number of early, more readily treated cases of colorectal cancers diagnosed.
Results of several such screening programs are indicated in Table 9-15.
The ingestion of barium, iron, or laxatives does not adversely affect the
quality of the test, whereas large amounts of vitamin C, a low concentration
of stool hemoglobin, and intermittent bleeding can cause false-negative
279 " 282
reactions. 276 '
Proctosigmoidoscopy. This is an important diagnostic aid in the

follow-up of lesions seen in other tests or in the symptomatic patient. The
cost effectiveness is low in the asymptomatic patient, since the results
reveal only about one cancer in every 667 patients examined. 283 However,
the routine removal of adenomatous polyps by proctosigmoidoscopy, as in-
dicated earlier in this chapter, has been shown to decrease the incidence of
subsequent cancer. 255 Polyps have been reported in 4 to 9 per cent of pa-
tients who are more than 40 years of age. 284, 285 Newer flexible instruments
have been developed that provide much better patient tolerance and a
marked increase in diagnostic accuracy. 286
TABLE 9-15. Screening Projects for Early

Detection of Colon Cancer
Reference Patients Cancer Found
Glober 274 (1974) 1689 3 (A, C, C)
Hastings 275 (1972) 2625 5 (A, B, B, C, D)
Greegor 276 (1971) 2000 7
Ross 277 (1974) 1103 4
Miller 278 (1977) 2332 3 (A, B, B)
9747 22
"Illustrated are the number of occult colorectal carcinomas found after appropriate follow-up of initially
positive hemoccult tests in five studies. Letters denote Dukes stage at time of diagnosis.
Barium Enema. The full-column barium enema has been reported to

miss one fifth to one fourth of all colon cancers and two fifths of all poly-
poid lesions. However, the double contrast barium enema will detect al-
most all colonic lesions of at least 5 mm
in diameter and must be consid-
"
ered the radiologic procedure of choice. 287 289 Contraindications include
acute, severe, inflammatory bowel disease, suspected perforation, and re-
cent bowel wall biopsy. 290
COLONOSCOPY. Most practitioners use colonoscopy after air contrast
barium enema, so that detected lesions can be biopsied or removed, or
both. The two examination techniques are complementary, and by using
both an excellent diagnostic resolution can be obtained. Limitations in-
clude failure to reach or fully examine the splenic flexure (10 per cent), the
hepatic flexure (15 per cent), or the cecum (20 per cent). 291 295 Symptomatic
"
patients with negative radiologic examinations or patients with equivocal

x-ray examinations should undergo colonoscopy. In a recent series, 146 pa-
tients who had double contrast studies that suggested benign polypoid dis-
ease underwent colonoscopy. Thirty-six (25 per cent) did not have a neo-
plastic lesion at the suspected site. Seven of the 36 patients (19 per cent) had
unsuspected, benign polypoid adenomas elsewhere and 4 patients (11 per
cent) had benign neoplastic lesions at the suspected area and unsuspected
malignant lesions elsewhere. Of the remaining 110 patients who had neoplas-
tic lesions correctly identified at the suspected site, 17 (15 per cent) were
either adenocarcinomas or neoplastic polyps with invasive cancer. 296
Other Tests. Stool cytology techniques are well developed and very
accurate. However, the necessity for meticulous, time-consuming bowel
preparation and lavage has limited its applicability and probably will con-
tinue to do so. 296,297 Preoperative CEA values often correlate with tumor
burden and prognosis, 298 but the usefulness of this information remains to
be determined. (See subsequent section on CEA in this chapter.) Conven-
tional tests such as chest x-ray, liver scan, and intravenous pyelogram, give
information about the extent of disease that is necessary for appropriate
surgical intervention.
COMPARISON OF STAGING SYSTEMS FOR

CARCINOMA OF THE COLON AND RECTUM
CATEGORIES CLASSIFICATION
A B, B2 C, c2 Dukes 1929/30- (rectum)

A A A B C c c c Dukes 1932 (rectum)
A A A B C, c, c, c2 Dukes 1935 (rectum)
A B, B, B2 C c c c Kirklin et.al. 1949 (rectum & sigmoid)
A B, B, B2 c, c 2 c2 Astler-Coller 1953 (rectum 8< colon)
A A B c c c Turnbull etal 1967 (colon)
MJV-VBpr^T** *^!**
1
ANATOMIC EXTENT of NEOPLASM
••mucosa
••muscularis mucosae
!*submucosa
^muscularis propria
serosa (colon only)
* • lymph nodes (any)
lymph nodes (apical)
not "removable,
adjacent organs,
distant sites,
FIGURE 9-9. The is shown, as are subsequent systems based

evolution of Dukes classification
upon it. system are derived entirely from examination of the resected
All except Turnbull's
bowel. Not illustrated is the fact that Dukes system included both curative and palliative resec-
tions and many of the class C cases would have qualified as stage D in the system of Turnbull.
(From Donegan YVL and DeCorse JJ: In Carcinoma of the Colon and Rectum, Enker (ed), WE
Chicago, Year Book Medical Pubs, p. 55, 1978.)
Staging and Prognosis
The early Dukes pathologic staging system, which was introduced more
than 40 years ago, separated colorectal malignancies into three groups.
Those lesions confined to the bowel wall but not penetrating the muscu-
laris were designated A, those lesions penetrating the muscularis into sur-
rounding fat or adventitia were designated B, and any lesion with positive
lymph node involvement was designated C. 299 Kirklin et a/. 300 modified the
TABLE 9-16. Distribution of Colorectal Carcinoma

and Five-Year Survival
Per Cent
Stage No Cases
. Per Cent Five -Year Survival
A 1 0.28 100
B, 48 13.64 66.6
B2 164 46.59 53.9
c, 14 3.98 42.8
C, 125 35.51 22.4
Total 352 100.00 44.1
'Data from Astler VA and Coller FA: Ann Surg 139:846, 1954.
TABLE 9-17. Five-Year Survival Rates of Surgical Survivors

After Curative or Palliative Resections of Rectal Carcinomas
% Survival Rate
Class No. Cases Crude Corrected
A 308 81.1 97.7

B 692 64.0 77.6
C 1037 27.4 32.0
C, 680 40.9
C, 282 13.6
"Data from Astler VA and Coller FA: Ann Sura 139:846, 1954.
TABLE 9-18. Staging System for Colorectal Cancer

(Prepared by International Union Against Cancer)
Colon
T Primary tumor; no categories
NX Regional lymph nodes (intra-abdominal and subdiaphragmatic), pathologic-

confirmation only, i.e., NX— = no metastases, NX+ = metastases present.
M Distant metastases
M Absent
M, Present
P Histopathologic categories
P, Confined to mucosa only
P, Invasion to submucosa only
P3 Invasion of muscularis propria or to subserosa
P4 Invasion to serosa or beyond
G Histopathologic grading
G! Highly differentiated
G 2 Moderately differentiated
G :,
Anaplastic
Rectum
T Primary tumor
T, Primary occupies no more than one third of the length or circumference of the
rectum; no invasion of muscle
T 2 More than one third but no more than one half of rectal dimensions occupied,
or invasion of muscle coat,no fixation of rectum
T ;i
More than one half of rectal dimensions occupied or fixation, but no extension
to neighboring structures
T., Tumor extends to neighboring structures

Dukes classification. Lesions limited to the mucosa were designated A,

tumors extending to but not through the muscularis were designated B l5
tumors penetrating the muscularis with negative node involvement were
designated B 2 and any lesion with nodal metastases was designated C.
,
Astler and Coller

301
modified this scheme further by dividing the C group
into C,, or lesions limited to the wall, and C 2 or lesions penetrating through
,
all layers. More recent modifications have added a category for distant me-
tastases (D) and have noted the presence or absence of serosal involve-
ment. 302 304 A comparison of the criteria for staging in the various systems
"
can be seen in Figure 9-9.

Several series illustrate that despite the vagaries of the various modifica-
tions of the Dukes system, the classifications permit separation of cases on
the basis of local extent and prognosis, as shown in Tables 9-16 and 9-17.
TABLE 9-19. AJC Definitions of TNM and pTNM for

Clinical-Surgical Postsurgical
Evaluative Definition Assessment Definition
T
To No tumor demonstrable pTIS Carcinoma in situ
T, Clinically benign or pT, Confined to mucosa

confined to mucosa or or submucosa
submucosa
T 2 Confined to muscular wall or P T, Same

serosa
T, Involvement of all layers of PT. Same

bowel wall with extension to
adjacent structures or organs,
no fistulas
T, Fistula present pT 4 Same
T-, T.j or T 4 with extension to pT, Same

other organs or structures
TX Depth of penetration not PTX Same

specified
\
N„ Nodes not involved pN Same
N, Nodes involved P N, Same
NX Status of nodes unknown pNX Same
M
M No distant metastases or pM„ Same
nodal metastases beyond the
base of the mesocolon
M, Evidence of distant metastases pM, Same
'From Manual for Staging of Cancer 1977, Chicago, American Joint Committee, pp 66-67, 1977.
Table 9-18 shows the system representing the most recent efforts to stage
TNM classification has been presented by the Inter-
colorectal cancer. This
national Union Against Cancer. Since the system is for testing only, no
stages are offered.
The TNM been proposed
staging system, illustrated in Table 9-19, has
by the Task Force on Colon and Rectum of the American Joint Committee
for Cancer Staging and End Results Reporting. It utilizes both a clinical
and surgical evaluation, as well as histologic information from resected
specimens. Cases are assigned the highest value that applies. Whether or
not any of these newer staging systems will replace or augment the more
established Dukes system remains to be seen.
TREATMENT
Surgery
The management of primary colorectal malignancies has been almost ex-

clusively surgical since the advent of therapy for these diseases. Progres-
sive improvement in surgical skills, aggressiveness, and patient support
systems have increased operability and resectability, whereas operative
mortality rates have declined. 305,306 Resectability now approaches 90 per
cent, and mortality ranges from 2 to 10 per cent, the lower figure reported
by institutions with special interests in colorectal malignancies. 307 As in all
applications of surgery for malignancy, the key determinant to success is
the degree to which disease has spread by the time of operation. A summa-
ry of the experience of more than 100 hospitals by the End Results Group
indicates that about 25 per cent of patients with colorectal cancer have dis-
tant metastases with hardly any prospect of cure when first seen. In 40 per
cent of patients, the tumor is localized in the bowel wall, and in 35 per
cent it has spread to the lymph nodes. Since the distribution of these le-
sions has remained relatively constant, there has been little change in rela-
308
tive survival in the United States following surgery in the last two decades.
Still, in the individual patient, the proper application of appropriate
it is
surgical judgment and techniques that will lead to the greatest possibility of
cure or the longest and most satisfactory palliation.
Operative Principles. The aims of surgery are to excise the primary
lesion cleanly with adequate margins, to reconstitute continuity of the
bowel whenever possible, and to avoid complications. The various routes
of spread must be considered, including lymphatic, intramural, venous, im-
plantation, and direct extension, and the course of the disease must be
modified or eliminated by appropriate surgical intervention.
Wide removal of the involved segment to include lymphatic drainage
areas described by Rouvier309 and Miles 310 is imperative. Thus, the standard
treatment of tumors of the cecum and ascending colon is by right colec-
tomy, including a segment of the terminal ileum, the cecum, and the right
half of the transverse colon, with the removal of corresponding mesocolon
at its base around the superior mesenteric artery to the takeoff of the mid-
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278 II / Treatment of Specific \eoplas\is
die colic vessels. Carcinomas of the splenic flexure or the descending or

sigmoid colon are treated by excision of the distal transverse, descending,
and sigmoid colon, along with the associated mesocolon excised to the
aorta.For tumors of the sigmoid colon, some surgeons limit the proximal
For carcinomas in the upper part of
resection, excluding the transverse colon.
the rectum an anterior resection and reanastomosis can be performed if a
4-to-5-cm margin can be achieved. Below this, the anteroposterior resection
generally has provided the best possibility for cure. (See Figures 9-10 and
9-11 for a diagrammatic representation of resection methods for various co-
lonic tumors.)
By adhering most important surgical principle
to the —
total excision of
draining lymphatics —adequate surgical margins of the bowel itself will be
assured. The exception is in the low anterior resection, at which point the
311
distal margin will never approximate the proximal margin. Black has
shown by the examination of excised specimens that the intraluminal
spread of cancer is surprisingly short, less than 2 cm in most instances. Yet,
in practice, theincidence of suture line recurrence following anterior resec-
tion, in which circumstance well-meaning surgeons may have the inclina-
tion to "fudge" the distal margins in order to preserve rectal function, far
exceeds that for any other procedure, and certainly the frequently narrow
margin obtained must have a direct bearing on this. The choice of opera-
tion for tumors of the upper and midrectum depends upon the evaluation of
the configuration of the pelvis, the size and location of the tumor, and the
skill and judgment of the surgeon in these procedures, including familiarity
with newer techniques or "pull through" procedures and the trans-sacral
approach.
Results. The survival rate after appropriate elective surgery is most
dependent upon the extent of disease found at operation. Survival in com-
bined, recent, large series is listed in Table 9-20. As expected, the best
results are obtained in early disease (Dukes stage A) and the worst when
nodal involvement is noted (Dukes stage C).
A more subjective aspect of surgery, i.e., the aggressiveness of the opera-
tive team, was addressed in a study by Peloquin. 312 An analysis was made
of operations done on over 1200 patients by three small groups of surgeons.
One group was extremely conservative, performing limited resections and
frequently not removing all mesenteric nodes. The second was moderately
aggressive, and the third group was extremely aggressive, advocating initial
vascular ligation and wide and even extended resections. When operative
mortality, complications, and patient-group characteristics were compared,
there was no difference between the surgical groups. However, survival
was better in every Dukes category in patients treated by the most aggres-
sive group. This correlated best with the operability and resectability rate,
which was highest for the most aggressive group. Thus, in this series, the
more aggressive the surgeons were in deciding to resect, the better were
the results.
Anterior Resection or Abdominal Perineal Resection for Can-
cer OF THE Rectum. Duer et al. 313 showed that distal intramural spread
of rectal cancer usually was very restricted and that a margin of 2.5 cm of
2H0 II / Treatment of Specific Neoplasms
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FIGURE 9-12. The shaded

area shows the extent of removal
for carcinoma of the upper rec-
tum by abdominoperineal re-
section (A) and by anterior re-
section (B). (From Butcher HR.
Jr: Cancer 28:204, 1971.)
~" Anterior
Tissue Removed In
J J
' Resection
Abdo- Perineal
Excision
grossly normal wall was adequate. Grinnell, 314 however, showed that cancer
cells could be found as far as 4 cm distal to the tumor in more advanced
311
cases. As mentioned earlier, Black has also noted a generally short in-
traluminal spread of tumor distally. Most pathologists now agree that a
5-cm segment of normal rectum distal to the neoplasm is adequate.
Although Miles 310 wrote that lymphatic spread took place upward, lateral-
ly, and downward, subsequent reviews of patients who usually have less
advanced disease than that confronting Miles have shown that upward dis-
placement is by far the most frequent type of spread. Nodal metastases
distal to the primary cancer were noted in only 98 of 1500 abdominoperin-
315
eal resection specimens examined by Goligher et a/. Since most inves-
tigators now agree that spread is predominantly upward, through superior
hemorrhoidal and inferior mesenteric lymphatics, the decision to perform
combined abdominoperineal resection or low anterior resection is deter-
mined primarily by the distance of the lower border of the cancer from the
anus. The lateral pelvic extension of the two operations, both of which re-
move the upper lymphatic drainage areas, should be essentially the same
(Fig. 9-12). 316
Generally, tumors within 7 to 8 cm of the anal verge are treated by ab-
dominoperineal resection, whereas those that are 12 cm or more from the
anal verge are adequately treated with anterior resection. Lesions between
7 and 11 cm from the anal verge require the most judgment, and factors
such as pelvis size, size of the lesion, and tumor differentiation must be
considered. The narrow pelvises of many males can make low anterior re-
section very hazardous. A general rule is that if the lesion is easily palpated
with the examining finger, abdominoperineal resection is indicated. How-
ever, if the lesion can be brought to the level of the abdominal incision after
mobilization of the rectum from the levator ani, an adequate resection may be
performed. 316 We have found that the use of the circumferential stapling de-
vice greatly facilitates the construction of a low lying anastomosis.
If these principles are followed and patients are carefully chosen, the
survival rates obtained from these operations are generally comparable. 316
"
322
Survival obtained with these two procedures is noted in the large, repre-
sentative series reported by Slanetz et al. (Table 9-2 1). 323
TABLE 9-21. Five-Year Survival in Rectal Cancer—

Comparison of Patients Treated with Anteroposterior Resection
and Low Anterior Resection
Five-Year Sl RMVAL
No.
Procedure Dukes Stage Patients .Number Per Cent
Abdominoperineal
resection A 42 34 81
B 91 47 52
C 129 43 33
Total 262 124 47
Anterior resection A 50 43 86
B 98 56 57
C 86 33 38
Total 234 132 56
"From Butcher HR: Cancer 28:204, 1971.
There was no difference in operative mortality. The slight superiority of

the anterior resection in every Dukes category can be attributed to a gener-
ally slightly smaller tumor size in the anterior resection group, and a slight-
ly greaterpercentage of Dukes stage A and stage B lesions in that group.
Local recurrences have ranged from 7 per cent for anterior resection and 18
to 21 per cent for anteroposterior resection. 316,323 Women have fewer local
recurrences in most series, and the higher the lesion, the less likely is re-
currence.
Other Sphincter-saving Operations. The case for other operations
that preserve the sphincter derives from the opinions of many investigators that
midrectal lesions drain exclusively upward. 324 327 Guernsey et a/. 328 studied 42
"
cases of rectal cancer that were 2 cm or less above the insertion of the levators,
and in no case was there spread along the levators or lateral lymphatics. Miles 310
had devised the anteroposterior resection after dissatisfaction with the results
of partial excision, but the observations of cancer spread in all directions that
led to his operation were based on autopsies of patients who had died from
advanced and inoperable cancer. More recently, Dafoe 329 studied 133 cases of
advanced rectal cancer that were located within 4.5 cm of the anorectal junction
and found only one instance of lateral spread along levator ani. After evaluating
100 specimens, Gabriel et a/., 330 concluded that "lateral or downward lymphat-
ic spread is only found in a later stage of the disease when hemorrhoidal
lymphatics are choked by metastases." Thus, it would seem reasonable to de-

sign operations that would, in earlier cancers, achieve local control but pre-
serve sphincter function. A brief description of some of these operations
follows.
In the Kraske operation (an eponym many American physicians incorrectly
was original-
associate with all trans-sacral rectal resections), a sacral colostomy
lymade. Later, trans-sacral resection and transanal anastomosis were per-
formed (Figs. 9-13 and 9-14). 331 The operation was notorious for incontinence,
and it did not contain the upward spread of cancer.
FIGURE 9-13. Kraske operation

with resection of coccyx and lower
left sacral ala. sacrifice of the rec-
tum and amis, and a sacral colosto-
my. The perineum is drained.
(From Localio SA: Surg Annu 6.
213. 1974
FIGURE 9-14. Kraske operation

with sacral resection and preserva-
tion of the anus and small portion of
the rectum. The peritoneal cavity is
entered to mobilize enough colon
for posterior colostomy. The perine-
um is drained. (From Localio SA:
Surg Annu 6:213. 1974
Later operations were designed to control both local and upward spread of
the pull-through procedures of Babcock 332, i! Figs. 9-15 and 9-16),
cat iter as in !
(
Bacon384 ' 838 9-17 and 9-18), Black,336 337 Turnbull,338 and Cutait 339
(Figs. -
(Fig. 9-19). These operations, which derive from the original work of Hoehen-
e gg 34o iuvoJve segmental rectal resection, preservation of an anal stump, and
sliding down residual bowel with an attachment made between the stump and
the advanced colon.
In the method of Bacon, 334 the colon is pulled through a denuded anal canal.
A short stump protrudes and is tied over a tube. Healing takes place between
the serosa of the colon and the raw lining of the anal canal. The amputation of
excessive bowel takes place in ten days. This technique permits a very low
anastomosis but definitely compromises anal sensation, an important factor in
continence. In the Black 337 modification, the anal canal is left intact, and union
takes place with the cut edge of the colon. Anastomosis disruption and retrac-
tion are the main risks. In the Turnbull-Cutait operation, the anorectal stump
is inverted, the proximal colon is delivered through, and after 10 to 14 days, the
redundant bowel is amputated. Healing takes place by the union of the serosa
of the colon to the serosa of the everted anorectal stump. 338 This has the
advantage of preserving sensation. The Maunsell-Weir341, 342 operation is simi-
lar.The anorectum is everted, and the colon is delivered and sutured to the
everted rectum through all layers immediately. The segment is then inverted,
and a protecting colostomy performed.
The roles of these procedures in the surgical management of cancer is
unsettled. Certainly, care must be taken not to compromise complete excision.
Thus, they are more appropriate for smaller lesions or in situations in which
there are very favorable technical considerations (i.e., broad female pelvis). No
FIGURE 9-15. Babcock operation.

abdominal approach: The colon is
brought through the anus and permit-
ted to protrude until union occurs.
From Localio SA: Surg Annu 6:213,
1974
PLASMS 28.5
F1CT.BE 9— 16. B.ibcock operation.

metmrni -.rime T'u- pBaaimui nlon
- ;<- :: .m. im r -• ra; -•:- •
I :
'.- :> r--.. ;.
-
j i, n .i
» retracr. F" :m L.
FIGURE 9-17. Bacon operation.

Lbdomi The
i. .i. :..• •
s.i
-iphmc.rer, parser — :. Fr m Localio

FIGURE 9-18. Bacon operation. The

proximal colon is pulled through the
denuded anus (durch zug of Hoche-
negg), and the excess is excised after
union (two to three weeks). (From
Localio SA: Surg Anna 6:213, 1974.)
FIGURE 9-19. Turnbull-Cu-

tait operation. A, Abdominal
operation: eversion of anal canal;
anastomosis of anal edge to the
protruding colon. B, Excess
colon is excised after 10 to 14
days. The incised end of the
colon and the anus are sutured.
C, Anastomosis is permitted to
withdraw spontaneously. (From
Localio SA: Surg Annu 6:213,
1974.)
matter what the procedure, a certain number of patients will have wound
complications, incontinence, pelvic infections, or necrosis. Techniques to help
avoid these problems have been suggested by Cutait. 343 The fact that bladder
and sexual functions are usually preserved in addition to sphincter function
gives great impetus for their use when appropriate.
Stearns 344 reported a cure rate with pull-through operations that was indeed
better than that for anteroposterior resection or anterior resection, although it
was only feasible in 8 per cent of the 495 patients reported. Bacon 334 reported a
53 per cent five-year survival rate in 778 pull-through operations for cancer, a
rate identical to that obtained in 663 abdominoperineal procedures. It is of
interest that the local recurrence rate was only 6.9 per cent at the anocolonic
anastomosis. However, Mann 345 reported an unacceptable operative mortality
and morbidity procedures at St. Marks in London and
for 61 pull-through
discouraged their use. The role of these intriguing procedures will become
more established as their use increases.
Localio,331 in his beautiful monograph, has detailed the trans-sacral tech-
nique he has utilized in over 100 patients (Figs. 9-20, 9-21, and 9-22).
In his series of 48 patients who had resection for cure by the abdominosacral
technique, 22 were alive and free of disease at two years. (Not all patients had
been followed for five years.) The operative mortality rate was 2 per cent. All
patients were continent, and in males erectile and orgasmic function was
uniformly preserved.
Specific Areas of Special Importance in the Surgical Management

of Colorectal Malignancies
Surgery for Obstruction and Perforation by Large Bowel Carcino-
ma. Complete intestinal obstruction occurs in 8 to 23 per cent of patients with
FIGURE 9-20. Point of ligation

of the superior hemorrhoidal artery.
The splenic flexure is mobilized; if
additional mobilization is neces-
sary, the left colic artery is ligated
at its source. (From Localio SA:
SurgAnnu 6:213. 1974
FIGURE 9-21. The coccyx is
removed, the levators are in-

cised, the specimen is delivered,
and distal and proximal colon are
poised for anastomosis. (From
Localio SA: Sur[> Annu 6:213,
1974.)
348
colorectal cancer. 346
"
The predominant symptom is abdominal pain. Although
the slow growing annular carcinoma might be expected to cause a gradual onset
of symptoms, obstruction frequently appears rapidly without any antecedent
warning. Of 1556 cases of colorectal cancer reported from the Massachusetts
General Hospital, the median duration of symptoms in obstructed patients was
one quarter of that observed in nonobstructed patients. Hypokalemia, hypo-
chloremia, anemia, and hypoproteinemia were uncommon. The median
preoperative interval was 12 hours.
Of 124 patients in this series operated on for obstructing carcinoma, the
overall mortality rate was 15 per cent, and the postoperative complication rate
FIGURE 9-22. A, Incorrect. When peristalsis begins, enlargement of proximal colon places
tension on the anastomosis. B, Correct. The proximal colon has reserve capacity for filling before
tension is exerted on the anastomosis. (From Localio SA: Surg Annu 6:213, 1974.)
was higher than that observed in elective colonic surgery. Yet, 40 per cent of
those resected for cure survived five years or more. When the obstructed
patients who survived operation were analyzed by Dukes criteria and com-
pared with patients from the same institution who underwent elective colonic
surgery, the proportions of patients in the various Dukes categories did not
346
differ significantly. Thus, the most important determinant of survival after
successful emergency surgery is the pathologic staging of the lesion when first
349 352
"
seen, just as in elective operations. This has been observed in other series
and encouraging, since the significant difference between the groups, i.e.,
is
the operative mortality, continues to drop each year.

The addition of perforation to acute obstruction of the large bowel can
353
increase the mortality rate greatly. Glenn and MeSherry noted a 31 per cent
operative mortality and a 7 per cent five-year survival rate in 29 patients with
combined perforation and obstruction. Crowder and Cohn 354 reported that 42
per cent of patients with proximal perforation of an obstructed colon died, and
mortality rates up to 100 per cent have been reported. 355 357
"
The traditional surgical management for acutely obstructing colon cancer has
been proximal diversion, followed by resection and then cecostomy or a
diverting colostomy. Dissatisfaction with cecostomy and a recognition of the
greater mortality rates inherent in right-sided obstructions (very thin bowel,
leading to a greater degree of distention, perforation, and ischemia), led some
authors to advocate primary resection of right-sided lesions. However, more
than two thirds of obstructing lesions are distal to the transverse colon, and in
these instances the classic three-stage surgical management has predominated.
The rationale has been that only one of the three procedures is truly an
emergency and that the last two can be done safely and electively on a colon
that is prepared, defunctionalized, and empty. However, theoretically, the
manipulation of the tumor at more than one operation probably sends tumor
cells into the circulation at a greater rate than that seen after one operation, and
the disability from just one procedure surely is much less than that incurred in
multiple operations. Fielding and Wells 358 compared the age-adjusted survival
in 22 primary resections for obstructing colon cancer with 28 patients who
underwent staged resections. The groups were similar in terms of tumor
differentiation and Dukes stage. Survival was significantly better in the group
that had primary resection. Bose and Sachdeva 359 have advocated emergency
hemicolectomy in all cases of perforation, reasoning that the bowel is already
decompressed and that the management of the complication of peritonitis as
well as minimizing potential wound seeding is much better performed by
"
primary resection. This viewpoint has been advocated by others. 360 363
The surgical management of either acutely obstructed or perforated carcino-
ma of the colon, or both, must rest, as with all things surgical, in the judgment
and experience of the surgeon. The dilation and viability of the bowel, the
physical status of the patient, and the degree of contamination are all factors. If
the diverting colostomy must be used, consideration should be given to placing
the colostomy as close to the lesion as possible in order to make the column of
stool above the obstruction or leak, which is a source of potential contamina-
tion, as short as possible. The use of a cecostomy has been attended by many
complications in most series, and unless absolutely necessary in unique
situations, it should be avoided. Although the ideal preoperative randomized
series comparing primary resectional therapy with the traditional staged man-
agement for obstructing colon cancer has not been (and probably never will be)
performed, enough evidence is in the literature to suggest resectional manage-
ment should be and will be more widely applied.
Extended Surgery for Colon Cancer. Although the number of patients in
whom extended surgery might have application is small, several observations
should be kept in mind when extensive lesions are encountered and wider
resections than conventional colectomy are contemplated. It has been es-
tablished in several series that size of the primary is not a determinant of
regional metastases in large bowel cancer. 364, 365 Thus, direct neoplastic exten-
sion into an adjacent organ is not statistically a more adverse prognostic sign
than are one to five regional lymph node metastases, the latter being a situation
in which conventional colectomy is performed uniformly without hesitation. In
fact, the seemingly advanced colorectal tumor that has invaded another organ
may bear favorable biologic characteristics, such as a tendency to well-
differentiated histologic appearance and an inflammatory response around the
primary. The finding that the tumor has achieved a large size usually indicates
that metastases have not occurred in the relatively long period of growth the
tumor has taken to achieve such size. Finally, metastases via the drainage
routes of the invaded organ almost never occur.
Polk 366 reported 24 patients who underwent extended surgery —
i.e., colec-
tomy and partial or total excision of at least one invaded organ. There was only
one hospital death. Eight patients died of recurrent cancer, with a median
survival of 28 months. Ten patients were alive and well at a median survival of
25 months, and the remainder were alive with disease or dead of other cancer at
33 to 41 months. An aggressive approach to locally advanced disease has been
advocated by others. 367 368 We do not consider invasion of the sacrum a
'
contraindication to anteroposterior resection, and when used in continuity

sacral resection from the extended lithotomy position it is both feasible and
safe. The fact that patients with large, locally advanced tumors might have
tumors with biologically favorable characteristics, such-as slow growth and late
metastases, should encourage extended surgery with excision of invaded
organs whenever possible.
Suture Line Recurrence. The incidence of suture line recurrence following
colectomy has been reported to be from 1.2 369 to 36 per cent370 with various
incidences between. 371 373 This subset of recurrent cancer deserves special
"
attention, for if locally recurrent disease is due to judgmental or technical errors

at the time of surgery, the correction of these errors might be expected to lower
the recurrence rate. Conversely, if local recurrence can be found prior to the
widely disseminated stage, appropriately timed repeated surgical resection
might be curative.
Numerous theories to explain suture line recurrence have been advanced.
One school of thought holds that the intact mucosa normally acts as a barrier to
intraluminal tumor cells that are constantly shed from the tumor. As the suture
passes through the bowel wall, it breaks this barrier and carries the viable
tumor cells with it into the submucosal and muscularis layers, in which the
proper nutritional milieu for growth exists. 374 The second theory is
tumor cell
similar, in that the inverted, raw, viable ends of the cut bowel serve as a
hospitable environment onto which shed tumor cells can adhere and
grow. 875
Another theory explains the suture line recurrence as a local metastasis
resulting from tumor cells suspended in the fine reticular lymphatic system
within the bowel wall. Although most of these cells die, some can become
implanted at the site of resection at which point the lymphatic flow is obstruct-
ed. 376 The most easily understood explanation for local recurrence is simply
377
that the margin of resection is inadequate. Manson et a/. reported that the rate
of recurrence is constant until a margin of 7 cm is reached. He found no
recurrence with margins 7 cm or greater, although 5 cm is generally accepted as
adequate, and other series suggest that a 7-cm margin is not necessary (see
previous discussion on Operative Principles). It is of interest that two patients
in one series failed to develop recurrent cancer, even though the distal margin
was involved with tumor. 3 8 '
In experimental models, a number of maneuvers have been devised to lower

the incidence of local recurrence. A closed anastomosis, in which sutures do
not enter the lumen of the bowel, has been shown to be superior to an open
anastomosis. 374 Devitalizing the cut ends of bowel has lowered the incidence of
375
local recurrence. The use of various intraluminal agents to kill viable tumor
379,380
cells has been accompanied by lessened local recurrence. Cohn 381 care-
fully analyzed various measures to reduce local recurrence in an experimental
model in which anastomoses were constructed in bowel that contained in-
traluminal tumor cells. Tumor implantation was not affected by bacteria in the
peritoneal cavity, by use of the automatic stapler, or by irrigation with chlorpac-
tic, DMSO, iodine, mechlorethamine, or saline. Suture line recurrences were
reduced by the use of iodized sutures or a closed anastomosis, and peritoneal

implants were reduced by irradition, low molecular weight dextran irrigation,
and clamping the lumen of the bowel close to the anastomosis.
Clinically, many maneuvers have been suggested to lower the incidence of
recurrent cancer. 382 384 Although few have been universally adopted, it is likely
"
that more emphasis in this area could reduce recurrence. Logical and practical
measures include wide local excision, intraluminal irrigation with a cytotoxic
agent, avoidance of contamination and hemorrhage, cauterization of freshly cut
bowel edges, and, particularly, prevention of laceration or injury to the bowel at
any other site during the construction of the anastomosis. The adoption of the
closed anastomosis technique, however effective in experimental prepara-
However, the use of iodized sutures, which has been
tions, is unlikely to occur.
effective experimentallyand clinically in killing cancer cells that come into
contact with it and which requires no modification of technique, probably
should be more widespread. Postoperative radiation and chemotherapy are
discussed later in this section.
The Second Look Operation and the Use of Carcinoembryonic Antigen in
Diagnosing Recurrence. Local recurrence is an ominous finding. Over 90 per
cent of patients with this finding shortly expired in Welch and Donaldson's
experience. 346 Taylor384 found that 75 per cent of patients with recurrent
colorectal cancer will die directly from complications of local recurrene. Aware
of this, Wangensteen's group 385 systematically reoperated upon patients who
were at high risk for recurrence six to nine months after colectomy for
colorectal cancer. Forty per cent were found to have recurrence, and 14 per
cent eventually were rendered tumor free. However, the mortality rate initi-
ally reported with this study essentially negated the therapeutic benefit, and
the concept of reoperation for all high-risk primary colon cancers did not gain
wide acceptance.
Mackman et al. am employed second look operations to assess the effective-
ness of adjuvant 5-FU therapy. Recurrence was found in 10 of 60 patients, 5 of
whom were made tumor free by resection. Later recurrence occurred in 3 of
the 50 patients with second look procedures and in 2 of the 5 patients who had
been rendered tumor free by repeated resection. There was no operative mor-
tality. When Gunderson and Sosin
387
analyzed the results of 75 patients who
were found at reoperation to have recurrence after presumably curative
colectomy, local recurrence or regional lymph node metastases, or both, were
responsible for 50 per cent of recurrences and were a component in 92 per
cent.
Routine reoperation subjects too many tumor-free patients to unnecessary
surgery to be widely adopted. Yet the tendency for colorectal carcinoma to
recur locally provides a possibility for significant surgical salvage if asymp-
tomatic patients with recurrent cancer can be identified early in the course of
their recurrence and then brought to prompt operation.
The use of immunologic markers of recurrence, such as the determination of
the serum carcinoembryonic antigen level, may make it possible to more
selectively choose patients who would maximally benefit by reoperation.
Although it was originally thought to be a relatively specific diagnostic indica-
tor of gastrointestinal tumor recurrence, 388 the CEA determination, which
presumably measures shed antigen from the tumor itself, was found to be
variably positive in other disease states. 389,390 However, recently reported
series suggest that it can be an important auxiliary tool for diagnosing recurrent
tumor. In general, the CEA usually declines over the first three postoperative
months, but in the presence of recurrence will often rise weeks or months
before recurrent disease is clinically evident. 391 394 This, of course, is the time
"
when surgical intervention is likely to be most beneficial. Although enthusiasm

for this test has not been uniform, 395 in several institutions the CEA level, along
with other clinical diagnostic tests, has been instrumental in determining
which patients will be subjected to reoperation. 396 400 Wanebo et al. 401 recently
"
reported 16 asymptomatic patients who underwent second look surgery solely

on the basis of elevated CEA. Two patients had negative findings on explora-
tion. Repeated resection for cure was performed in seven patients, and pallia-
tive resection or biopsy was performed in seven patients. The long-term
survival rate is not yet known.
It is likely that the development of tests for other tumor markers will
complement and increase the accuracy of CEA and make the identification of
those asymptomatic candidates for re-exploration more reliable. 402 404 At pres-
'
ent, the exact level of CEA at which to initiate surgery, the interval between
CEA determinations for good follow-up, and the elimination of false positive
and false negative results are not settled. Retrospective analyses of CEA data
from current ongoing national randomized adjuvant trials, especially NCI-
GITSG 6175, will answer many of these questions. 405 Certainly in those
patients in whom recurrence cannot be prevented, early diagnosis and appro-

priate repeated resection is critical to its control.
Surgery for Metastatic Disease. Although conventional logic might sug-
gest that a focal localized therapeutic modality such as surgery is ill-suited for
attack on disseminated disease, many authors have demonstrated that the
judicious application of surgery for metastatic disease in other tumor systems
can often prolong life and actually effect a cure (five-year follow-up) in 25 to 30
per cent of cases. 406 408 Since colorectal cancer metastasizes preferentially to the
"
liver, familiarity with liver resection techniques is an absolute prerequisite. In

institutions in which these procedures are well established, the results are
encouraging. Foster409 in 1970 reported 123 patients from the world literature
who had undergone liver resection for metastatic cancer. Of 83 patients with
colorectal metastases, 47 per cent of the operative survivors lived two years and
21 per cent lived five years. Wilson and Adson 410 evaluated 60 patients who
underwent hepatic resections. Xo patient with multiple metastases lived five
years or more, but 15 to 36 patients who had resection of solitary' lesions lived
longer than five years, and 8 patients were alive 10 years after operation.
Fortner et al. 4lx reported 23 hepatic resections for colorectal metastases (in a
series of 108 resections for primary and metastatic hepatic tumors). Seventy-
two per cent of the 17 patients undergoing curative resection were alive at three
years. There were no two-year survivors for the six patients undergoing
palliative resection. Attiyeh et al. lu reported a three-year survival rate of 56 per
cent for 19 patients who underwent wedge resection for metastatic colon can-
cer.
Our surgical approach to metastatic colon cancer is similar to that for other
diseases. The
metastasis must be confined to the organ being operated upon.
Single lesions cam a better prognosis than multiple lesions, and smaller
-
lesions are better than larger ones, but a reasonable measure of success will
accompany any effort that leaves the patient grossly tumor free. A right
thoracoabdominal approach is used most often for larger right hepatic lobe
lesions, but abdominal incision may suffice and is almost always used for
smaller and left-sided lesions. It is not necessary to have formal anatomic
resections when removing metastatic disease, as long as a rim of uninvolved
liver is excised with the lesion. The use of large liver clamps for such "extended
wedge resections" 41 and intrahepatic control of vascular and ductal structures
'
facilitates this.
In extended resections, the arteries, extrahepatic ductal systems, portal vein,
and hepatic veins are controlled in that order, and the line of hepatic resection
is made by finger fracture and electrocautery. T-tube drainage is generally not
employed. The size of the lesion is not a contraindication to surgery if total

excision can be achieved. If this is not possible, we feel attempts at partial,
"debulking," or "palliative" excision are not indicated. In this instance, a
catheter is inserted into the hepatic artery for prolonged chemotherapy infu-
sion (see the section on Cancer of the Liver —
Metastatic).
Isolated pulmonary metastases, without involvement of the liver or other
organs, occur in less than 10 per cent of patients with metastases. However,
five-year cures have been reported following pulmonary resections for meta-
static colorectal cancer that was confined to the lungs. All patients considered
294 II / Treatmfm of Specific Neoplasms
for theseprocedures must have negative work-ups for hepatic metastases.

However, we advocate a small laparotomy with the patient in the lateral posi-
tion just prior to as a last check to eliminate the chance of a false-
thoracotomy
negative work-up. intra-abdominal disease is not present, the surgeon may
If
proceed with immediate thoracotomy. Conventional wedge excision or lo-
bectomy, or both, are performed as indicated. Median sternotomy for resec-
tion of bilateral disease is applicable in some patients. 414
Palliative Surgery for Colorectal Cancer. In the presence of multiple,
unresectable, synchronous metastases that are found at the time of initial
operation, the management of primary colon cancer consists of resection of the
primary. Although mortality in such patients is determined by progression of
the metastases, it has been demonstrated in several series that those who
undergo primary resection have a more favorable course. Nielsen et a/. 415
studied 103 such patients. Fifteen patients receiving no surgical treatment
lived an average of only six weeks. Fifty patients who had laparotomy and a
bypass procedure lived an average of 20 weeks, whereas those 38 patients who
had resection lived an average of 55 weeks. The duration of symptoms had been
the same in all three groups. Resection prevented anemia, protein loss, obstruc-
tion, and pain but was contraindicated in the presence of ascites. Survival
correlated inversely with the extent of metastases. 415 Cad> et a/. 416 also reported
longer survival in those patients who underwent resection compared with
those receiving nonresectional therapy in a review of 269 patients with simulta-
neous liver metastases. Takaki et a/. 417 recently reviewed 78 palliative resec-
tions and concluded that resection in patients with local or distant metastases
should be performed whenever feasible. After a review of 217 patients. Wan-
ebo et a/., 418 also strongly advise primary resection in patients with synchro-
nous liver metastases.
Our approach has been to resect the primary cancer and re-establish continu-
ity of the bowel whenever possible. In addition, we advocate the placement of a
hepatic artery infusion catheter at the time of surgery for constant infusion of
5-FU 419 (see the section on Cancer of the Liver —
Metastatic).
Patient Age and Survival. Advanced age does not appear to be a major
determinant of survival following surgery for colon cancer. Block and Enker 420
reported a survival rate of 57 per cent in 111 patients older than 70 years of age
following conventional surgery, compared with 61 per cent in 1197 patients
younger than 70 years during the years from 1950 to 1965. The operative
mortality in the octogenarians was 15 per cent greater than that in the younger
groups. Most complications were cerebrovascular or cardiovascular in origin.
However, if death from operation was excluded, the five-year survival rate was
67 per cent.
The mean age for the diagnosis of colorectal cancer has been stated to be from
67 to 69 years, 421 although analysis of recent ongoing studies suggests that the
median age of onset might be lower. 422 Certainly, colon cancer in the very
young is a much worse disease than in the very old. 425 Most of the patients in
Block and Enker's 420 series were operated upon 15 to 20 years ago, and it is
likely that mortality would be somewhat lower with today's operative manage-
ment.
Adam et a/. 424 reported 156 patients more than 80 years of age operated upon
for colorectal cancer. Twenty-two per cent were alive and well at five years.
Fifty-fiveper cent of these patients had Dukes stage C and stage D lesions. The
five-year survival for patients undergoing surgery for colorectal cancer of all
ages was 22 per cent during the same period. Thus, although major abdominal
surgery in the older population is associated with a higher mortality than in the
younger patients, the survival rates of those who recover from surgery are as
good as, if not better than, those in the younger population. Advanced age, then,
does not justify withholding surgery unless specific, identifiable contraindica-
tions are present.
Alternatives to Conventional Surgery- Electrocoagulation and Local Exci-
sion. The use of electrocoagulation in cancer of the rectum was advocated by
Strauss et al. in 1935, 425 and various reports of its use have since appeared by
Pettit and Edgcomb, 426 Swerdlow and Salvati, 427 Crile and Turnbull,428 Mad-
den and Kandalaft, 429 and others. In this method of treatment the patient is
hospitalized, and under spinal anesthesia the anus is dilated, the lesion is
identified, and the entire area is cauterized and usually scraped. Ten to 12
days later this process is repeated. In a series of 131 patients so treated,
Madden and Kandalaft 429 used an average of 3.5 fulguration sessions per
patient. Anular lesions were not treated, and only those below 10 cm, i.e., be-
neath the peritoneal reflection, were considered amenable to cauterization.
The controversy that has always surrounded this modality stems from the
claims of some of its advocates that this should be the primary method of
treating rectal cancer rather than conventional surgical excision. 428,430 This
position is arrived at by comparing the five-year survival rate of patients treated
by electrocoagulation with that obtained in large surgical series in which
anteroposterior resection was done. For instance, the five-year survival rate in
the series of Madden and Kandalaft 4 was 78 per cent, which exceeds virtually
'
all conventional surgical series, and complications and mortality were less.
However, these data were based on only 63 of 131 patients treated by cautery;
the rest of the cases were not followed.
Since the incidence of local recurrence is relatively low following electro-
coagulation, this modality must be considered effective in controlling localized
cancer. The problem is that the procedure does not include regional lymph
node removal, which is considered to be essential to appropriate cancer
treatment. Since the incidence of positive node involvement in large series of
anteroposterior resection for rectal cancer is around 45 to 50 per cent, 431-434
good results from electrocoagulation could be presumed to result from the
induction of a systemic response or from patient selection factors that are not
operative in conventional series. Although it has been suggested in the past, 433
that electrocoagulation induces immunologic resistance to tumor, there is
little, if any, evidence to support this. However, it is very likely that the
cauterized lesions have more favorable characteristics, such as being smaller,

earlier, polypoid, and noncircumferential, than those in large surgical series. A
prospective, controlled series to compare modalities will probably never be
undertaken, since by its very nature the use of cautery prevents the staging
necessary for such a clinical trial. The suggestion by Crile and Turnbull 428 that
fulguration be used first, and if it fails that anteroposterior resection be applied,
is not appropriate, since nodal or distant metastases can develop in the interval
between inadequate cauterization and definitive surgery. In addition, the

results of conventional surgery following electrocoagulation have been notably
poor. 435
Surgical excision, with the removal of regional lymph node-bearing tissue
remains the treatment of choice for primary cancer of the rectum. However, it is
of interest that there are reports in large surgical series by prominent surgeons
that 2 to 3 per cent of their patients were treated by cauterization. 427, 436, 437 The
use of cautery as local therapy for advanced, symptomatic, metastatic, or
inoperable rectal cancer is undeniable. However, there is probably a small
subset of patients in whom it is applicable as primary treatment. The indica-
tions used by Turell 438 perhaps can be used to identify the patients who are
well-treated by fulguration. He has utilized cautery (1) in patients who have
Dukes stage A and stage B carcinoma —
small superficial lesions —
especially
when located on the posterior or lateral rectal walls; (2) in patients who
represent poor surgical risks or who have advanced senility or concomitant
serious systemic disorders, or both; (3) in blind or senescent institutionalized
patientswho are unable to care for themselves or cannot procure adequate care;
(4) in patientswho have bleeding from inoperable lesions or metastases; and (5)
in patients who refuse conventional surgery.
The use of local excision rather than conventional colectomy has also been
described. Again, it must be emphasized that this alternative to conventional
surgery has only been applied to very carefully selected patients. For instance,
at St.Mark's Hospital in London, of 3999 operations done for colorectal cancer,
only 143 were local excisions. The selection factors included completeness of
excision, depth of spread into the bowel wall, and histologic grade of malignan-
cy. Survival in these carefully selected patients, all of whom were followed a
minimum of five years, was excellent. 439 '
440
Radiation Therapy
A variety of radiotherapeutic approaches has been advocated for adenocarci-

nomas of the colon and rectum. These include contact therapy and interstitial
implantation for early lesions, preoperative and postoperative external radia-
tion for more advanced lesions, and palliative external radiation for inoperable
lesions.
In a selected group of patients with small, well-differentiated, largely ex-
ophytic tumors within 12 cm of the anal verge, Papillon 441 reported a 67 per cent
five-year disease-free survival rate after contact therapy or implantation, or
both. Others in the United States are attempting similar techniques. 442
Several groups have explored the use of preoperative radiation in conjunc-
tion with curative surgery for rectal lesions. A retrospective study of 971
resected cases at Memorial Hospital indicated that preoperative radiation of
1200 to 1600 rad increased survival in patients with Dukes stage C lesions. 443 A
subsequent prospective study at the same institution of 790 patients, 376 of
whom received 2000 rad from two days to six weeks preoperatively, demon-
stratedno advantage for the radiated group. 444 Others have also studied low-
dose preoperative radiation in controlled, randomized studies, with more
Gastrointestinal Tract Neopla- 297
encour _ g results. The Veterans Administration

Surgical Adjuvant Group
studied a dose of 2000 rad in two weeks (with a 500-rad perineal boost for
445
low-lyins lesions) in TOO patients. The radiated group had a reduction in the
percentage of positively involved lymph nodes and an improvement in the
five-year survival rate for Dukes stase C lesions. Of patients having ab-
dominoperineal resections, the radiated group also had an increase in the
five-year survival rate of Dukes stage A and stage B lesions and a decrease in the
448
local recurrence rate. In a randomized study of 125 cases treated at Toronto, a
single dose of 500 rad a few hours prior to surgery gave an increased five-year
survival rate only for patients with Dukes stage C lesions.
Two groups have studied higher doses of preoperative radiation. The group
in a study of 31 cases, used a dose of 4400 to 4600 rad in 4.5 weeks,
447
at Yale.
including the para-aortic nodes. As in the VA study, a decreased percentage ot
patients with positive node involvement was seen in the radiated group. At the
Univ ersity of Oregon. 97 patients receiv ed 5000 to 6000 rad preoperativ ely and
^
were compared with historic controls. Of the 57 initially resectable patients,
inderwent curative resection after radiation. Only 4 of these 40 patients
developed recurrent tumor, with no pelvic recurrences, and 53 per cent were
alive and disease free after five years (compared with 38 percent historicall
Of the 40 initially unresectable patients. 20 were converted to reseetability.
and 4 of the 34 patients who were evaluable at five years were alive and dis-
e free. Three patients in the series apparently had their tumor sterilized
by radiation, and one was alive, disease-free after seven years. These studies
have been confined to rectal lesions.
Several reports of postoperative radiation for high-risk patients have rt-
ed that local control can be increased with moderate doses (4500 to 5000
""
4 49 451
rad'.
"
A cooperative, randomized prospective trial to evaluate adjuvant

postoperative radiation therapy is currently ongoin_
There are many reports of good palliation for patients with unresectable or
~
recurrent lesions throughout the colon. 45;3 455 Although only a small percentage
will be cured, symptomatic benefit is seen in 70 to 90 per cent of such pa-
tients.
Chemotherapy
The vast majority of commercially available drugs are not useful in the
"
treatment of colorectal carcinoma. 45 1 458 Table 9-22 is provided as a guide to the
*
reader who wants to avoid these ineffective agents, and Table 9-2-3 summarizes
and ranks those agents that we consider useful. 45 *"461 It should be noted that
none ot these drugs are of substantial benefit, and in all cases the usual duration
of response is short (approximately two to five months). The impact of chemo-
therapy on survival is extremely modest, and improved survival is seen only in
the minority oi patients who have an objective response to treatment.
Single Agent Chemotherapy. The drug 5-fluorouracil remains the
standard of reference for the treatment of colorectal carcinoma. Its use is
discussed in detail in Chapter 5. An objective response rate of about 20 per cent
has been well established for 5-FU. although individual investigators have
TABLE 9-22. Chemotherapy of Colorectal Carcinoma: Mayo

Clinic Experience with Single Agents of No Clinical Value"
No. of Selected Responsi

Agent Patients Rate (%)
Vincristine 9
Bleomycin 15
Dacarbazine 17
Hydroxyurea 22
Cytembena 25
5-Azacytidine 27
Streptonigrin 27
VP 16 28
( )isplatin 33
Camptothecin 49
Doxorubicin 56
Methotrexate 38
Emetine 18
Fluorometholone 18
Streptozotocin 18
Cyclophosphamide 25
"Extracted from a review by CG Moertel based on studies at the Mayo Clinic. 456 Reviews including data
from cooperative group studies and from miscellaneous reports are less pessimistic, 457,458 but our experience
is most consistent with the results summarized here.
TABLE 9-23. Chemotherapy of Colorectal Carcinoma:

Clinically Useful Single Agents
No. of Selected Response

Rank' Agent Patients Rate (%) Reference
5-Fluorouracil
IV, SLD 1355 19 457 and 458
IV, SLD + q wk 134 39 457 and 458
IV, q wk 197 21 457 and 458
Modified SLD 227 30 457 and 458
8 to 24 hr infusions 106 17 457 and 458
Oral 88 19 457 and 458
Total 2107 21 457 and 458
MeCCNU 168 11 459
BCNU 128 13 459
CCNU 222 9 459
Mitomycin C 248 18.5 460
"Rank as a single agent assigned by Charles M Haskell, MD, as a function of personal experience and a
review of the literature.
Abbreviations: SLD, standard loading dose; q wk, every week.

reported response rates varying from 8 to 85 percent. Moertel 458 has analyzed
this phenomenon and has identified a wide variety of factors that may explain
this dispersion. Among the factors that may influence the reported response
rates for a given dose and schedule of 5-FU administration are the site of the
measured metastatic lesion, the performance status of the patient, whether or
not the patient has been previously treated with chemotherapy, and whether or
not modest leukopenia is achieved with treatment. 456, 461 463 These factors, the
-
quantitative impact of which is summarized in Table 9-24, probably influence

the reported response rates of colorectal cancer to other drugs as well. There-
fore, one must be very cautious in interpreting the results of current therapeutic-
trials in this disease.
Clearly, single-agent chemotherapy with currently available drugs is of
marginal value in colorectal cancer, and the search for effective new drugs in
previously untreated patients is both necessary and ethically reasonable. When
experimental agents are not available, we initially use 5-FU. A nitrosourea
(me-CCXU or BCXU) is used when 5-FU fails, and mitomycin-C is reserved as
a final choice in patients who are still candidates for chemotherapy.
Combination Chemotherapy. There has been widespread use of drug
combinations in colorectal cancer based on preliminary results from the Mayo
Clinic suggesting that combination chemotherapy with 5-FU, me-CCNU, and
vincristine was superior to 5-FU alone. 4 " 4 Table 9-25 summarizes the results of
these studies. Unfortunately, they have not confirmed a useful role for combi-
nation chemotherapy in colorectal cancer, as shown by the composite response
rate of 20 per cent in more than 800 patients who were treated with variations of
the me-CCXU plus 5-FU regimen. Even with the higher response rates seen in
TABLE 9-24. Factors Modifying the Response of Colorectal

Cancer to 5-Fluorouracil or FUDR
\ vriable Response Rate (%)
Previous Chemotherapy4"
None 25
Melphalan
Performance Status (ECOG

Normal (0) 31°
Mild reduction (1) 17°
Moderate reduction _ 9°
>50% bedridden (3) 7
Leukocyte Count During Treatment 456

>4,500/ M L 8.7°
1500 to 4500 M L 22.7°
<1500/ M L 15
Site of Measured Metastatic Lesion 463

Abdominal mass 32°
Lymph nodes 25
Liver 24°
Skin and subcutaneous 16
Lungs 6.4°
'Statistically significant difference in response rates compared with other subsets of a given variable.
TABLE 9-25. Combination Chemotherapy of

No. OF Response Drlcs

Reference Selected Rate
(1st Name Only) Patients (%) FU MeCCNU VCR MMC Other
Moertel 464 39° 43.5 X" X X

Matdonald 465 25 40 X* X X
Falkson 466 46° 37 xb X X
Engstrom 467 81° 12 X X X
Kenieny 468 69 12 X" X X
Baker 41* 96° 32 .V X
Lokich 470 52 3 xb X
Engstrom 467 88° 10 X X
Buroker 471 111° 17 X X
Ravry 47 -'
19 16 X b.
X
Kane 473 13 31 X X
Posey 474 37 37 X" X
Engstrom 467 71° 15 X X X DTIC
Engstrom 467 83° 14 X X DTIC
Perry 47
"'
27 19 X" X Daunomvcin
Kemeny 476 54 27 xb X X STZ
Diggs 477 21 9.5 X Ftorafur = MER
Buroker 47 * 15° 20 X Ftorafur
Valdivieso 479 57 30 X MTX
Ftorafur and
Richards 480 95° 12 X X MTX ± MER
Ratkin ,K1 35 23 X'' X CCM
Reitemeier482 18 6 x° X
Lokich 4 >" 8 12 xb BCNU
Lokich 484 11 18 X" BCNU; STZ
Falkson 485 52° 43 xb X BCNU; DTIC
von Eyban 486 33 21 xb X BCNU; DTIC
Stolinskv 487 85 9.4 X BCNU
Ota 4Sh 15 60 X" X ara C
Dejager489 37 8 X* X ara C
Buroker 490 20 45 x<- X
Buroker 471 124° 19 X X
Kraus 491 24 33 x- X
Buroker 478 13° 31 X Ftorafur
Haller 492 35 17 X" X Doxorubicin
Engstrom 467 73° 21 X Hvdro.w urea
Richards 493 38° 18 \ MTX; CYC
Gailani 494 43 12 X" araC
Seligman 495 14 14 xb STZ
Douglass 496 63 10 X" 6-TG
Chlebowski 497 60° 10 X* CYC
Al-Sarraf498 17 6 X" Vinblastine
Lokich 499 17 X* Hydroxyurea
Muss 500 15 X r
ara C
"Randomized trial.
Abbreviations: FU, 5-fluorouracil; MeCCNU, semustine; VCR, vincristine; MMC, mitomycin C; DTIC,
dacarbazine; STZ, streptozotocin; MER, methanol extractable residue of BCG; MTX. methotrexate; CCNU.
lomustine; BCNU. carmustine; ara C. cytarabine; CYC. cyclophosphamide; 6-TG. 6-thioguanine;^ b, FU by
I\" bolus x 4 to 5 days; w, weekly FU 1>> I\ bolus, c, continuous IV infusion of FU x 4 to 5 days
some reports, there has been no improvement in survival when compared

with 5-FU used as a single agent. For this reason, we do not currently
recommend combination chemotherapy for colorectal carcinoma unless it is
part of an experimental program of therapy.
Immunology and Immunotherapy
Morphology and the Immune Response. Black et a/. 501 correlated sinus
histiocytosis in resected regional lymph nodes with a better prognosis in those
patients operated upon for breast cancer than in those patients whose regional
lymph nodes did not demonstrate histiocytoactivity. Pdttet al. 502 made similar
associations in colon cancer, claiming that an increased number of paracortical
immunoblasts or sinus histocytosis in the resected regional lymph nodes
correlated with longer survival than resected specimens that did not show such
changes. Pihl et a/. 503 evaluated perivascular lymphocyte cuffing in tissues
that were immediately adjacent to resected colorectal tumors and paracortical
lymph nodes. The presence of lymphocytes correlated with an 85 per cent
five-year survival rate in Dukes stage B patients who exhibited them, which
was much better than those patients who did not have such findings. Watt and
House 504 associated lymphocytic infiltration of the periphery of colon tumors
with a good prognosis. Green et fli. 508 suggested that colon carcinomas exhibit
a decreased production of secretory IgA and a decrease in intraepithelial
lymphocytes compared with non-neoplastic bowel. Similar findings of lym-
phocytic infiltration and malignancy were found by Sion and Friedell. 506
Thus, morphologic findings usually associated with immunologic reactivity
have been correlated with clinical prognosis. Although usually a favorable
correlation has been found, which is strongly suggestive of an important role of
the host immune response, the criteria are not as yet uniform nor are the clinical
correlations absolute.
Tests of the Immune Response and Colorectal Cancer. The surviv-
al rate was found to be worse in colorectal cancer patients whose pretreatment
lymphocyte counts were low. 507 This finding has not been confirmed to date in a
prospective randomized trial in which this is being evaluated. However, in
general, tests that indicate general suppression or even anergy usually corre-
late with a poor prognosis. 422 In colorectal cancer, tests used to assess patients'
immune reactivity have included skin reactivity to DNCB, 508 510 lymphocyte
"
blastogenesis, 511 513 inhibition of mononuclear cell migration in gels, 514 516
" "
lymphocyte-mediated cytotoxicity of colorectal cancer cells in vitro, 517 520 leu-

'
kocyte adherence inhibition, 521 measurement of T cell immunocompetence, 522

and antibody-mediated cytotoxicity of colorectal cells in vitro. 523 525
'
Immune response is a field of intense investigative interest at present, and it

is possible that specific tests of prognostic and diagnostic value will be
developed. It would be of particular benefit if such tests could identify groups

of patients within the population with colorectal malignancies who would be
responsive to adjuvant immunotherapeutic intervention. At present, these tests
generally support the contention that a low level of immunoreactivity is seen
with advanced disease and that it correlates with a poor prognosis. Determina-
tion of the further general usefulness of these tests will require more laboratory
and clinical investigation.
Carcinoembryonic Antigen. It is one of the goals of modern oncology to
establish a simple, uniform, cheap, reproducible, and accurate test to deter-
mine the presence or absence of malignant cells. It was thought that the
carcinoembryonic antigen test, as originally described by Gold and Freid-
man, 388 might closely approximate this goal. It was subsequently found that
since this antigen was measurable in some normal and non-neoplastic disease
526 528
"
states, its diagnostic specificity was less than originally desired. However,
CEA can be quantified by radioimmunoassay, 529 and its usefulness will become
more defined with experience and clinical trials. The reader is directed to
reviews in the extensive recent literature about CEA. 528, 530 535
"
Based on the facts just presented and our clinical experience, our current
opinions about the clinical applications of CEA follow. As a screening test, it
has demonstrated little usefulness. In patients with colorectal cancer the
higher the CEA level is preoperatively, the poorer the prognosis. If the CEA
level fails to fall within eight to ten weeks postoperatively, it is very likely that
neoplastic disease is still present. The use of CEA as a monitor for the
effectiveness of therapy of metastatic disease has not been helpful in our
experience to date, nor has it in some other reports. 536
Our approach to the diagnosis of recurrent disease is noted in the section in
this chapter on Surgery — Second Look Operations. Although in the past we
have explored patients on the basis of persistently elevated serum CEA levels
and have found no recurrence (false-positive results) and, conversely, have
demonstrated recurrence in patients in whom the serum CEA level never rose,
we currently consider the CEA level to be a valuable adjunct to the total
evaluation of the patient at risk for recurrence. Although its use in the recent
past has been inadequate to diagnose recurrence in some previous series, 396 we
feel optimistic that information gained from ongoing, randomized, prospective
trials will greatly increase the resolution of this test. Perhaps the best guide-
397
lines for its use at the time of this writing are those of Holyoke et a/. and
Wanebo et a/. 418
Immunotherapy. Trials of immunotherapy for established disease, in-
cluding colorectal carcinoma, have been summarized by Pilch et al. 537
'
Humphrey et al. 5 38 have exchanged tumor immunizations and white blood cell
539
infusions between matched patients with gastrointestinal tumors. Falk et al.
have administered BCG intraperitoneal^ to patients with advanced gastroin-
testinal cancers. Moertel et a/. 540 reported several partial regressions of meta-
static colon cancer in patients receiving methanol-extracted residue of BCG.
These studies and others, although initially reporting isolated and encouraging
results,have not been consistently reproducible either in the authors' experi-
ence or in the hands of others. At present, there is little, if any, indication for the
use of immunotherapy in advanced disease outside an investigational setting.
Immunotherapy as adjuvant treatment is discussed in the next section.
Surgery remains the treatment of choice for resectable colorectal cancer,

but many patients present with unresectable lesions or lesions of borderline
resectability. Such patients are candidates for preoperative or postoperative
radiation therapy, depending on the treatment philosophy of the physicians

involved. In our institution we are currently studying the role of postopera-
tive radiation therapy as part of a national study.
Main patients with Dukes stage B 2 and stage C colorectal carcinoma recur
despite the removal of all grossly apparent disease. This presumably occurs
because of the dissemination of micrometastatic tumor cell deposits outside
the limits of the local-regional therapy, so it would appear logical to use sys-
temic therapy for these patients. However, despite this reasonable premise,
the application of adjuvant chemotherapy has not significantly altered the
course of colon cancer following appropriate surgical resection. Perhaps this
is because the chemotherapeutic regimens that have been devised to date
show only modest effectiveness in advanced colorectal malignancy (see
section on Chemotherapy) when compared with those used in other diseases,
such as breast cancer and testicular carcinoma, in which the response rate in
advanced disease is better and adjuvant therapy seems to hold more promise.
Adjuvant 5-fluorouracil has been given to many individuals in the last ten
years, in various regimens and doses following surgery and has even been ad-
vocated by some authors on the basis of uncontrolled, retrospective evalua-
541
tions, partialis because of its ease of administration and the understandable,
if unfounded, attitude that "two modalities must be better than one." How-
ever, the hard fact remains that in randomized, controlled studies, the use of
5-FU has not been effective to date as an adjuvant agent, as shown in Table
9-26.
Thus, as stated by Moertel, 545 at present there is no evidence that surgical
adjuvant treatment with fluorinated pyrimidines alone produces a significant
TABLE 9-26. Randomized Concurrently Controlled Clinical

Trials of 5-FU or FUDR as Adjuvants to Potentially
Curative Colorectal Cancer Surgery
No. OF Survival
Reference Regimen Patients Comparison
Higgins ei al. Ma No treatment versus 5-FU 522 No significant

12 mg/kg/day x 5 IV q 6 weeks difference
for 1 to 1.5 years
Dwight ct «/. 543 Notreatment versus 5-FUDR IV 548 No significant

20 mg/kg on postoperative days 1. 2, difference
and 3. 30 mg/kg/day x 5 plus 15 mg/kg
QOD x 4 started 5 to 6
weeks postoperative
Lawrence et a/. 54 1
"
No treatment versus 5-FU 30 mg/kg 156 No significant
intraluminally at surgery: 10 mg/kg difference
IV on postoperative days 1 and 2, oral
5-FU, 12 mg/kg/day X 4 and 7 mg/kg
every other day x 7 — these courses
repeated q 2 mo X 5
Moertel" 45 Notreatment versus 5-FU 12 mg/kg/day 189 No significant

x 4 IV plus 6 mg/kg QOD x 5; then difference
12 mg/kg weekly for 1 year
304 II / Treatment of Specific Neoplas\i>
advantage for the patient who has large bowel cancer resected with curative
intent. Combinations of chemotherapentic agents currently being tested by
cooperative groups may prove to be of benefit, and the recent encouraging
report of Taylor et al. 546 utilizing postoperative, adjuvant hepatic chemoinfu-
sion via the umbilical vein may have application in the adjuvant setting.
However, at present, the use of adjuvant chemotherapy can only be justified in
rigidly controlled experimental studies. The current applications of adjuvant
radiation therapy are discussed in the section on Radiation Therapy.
Section 5
Anal Cancer I
INTRODUCTION
Etiology
Cancer of the anus is a relatively uncommon lesion, representing only

about 3 per cent of malignancies of the bowel. It seems to be more fre-
quently observed in women and has been associated with anal fissures,
hemorrhoids, and squamous lesions of the female genital tract. 347 549 Carci-
"
noma of the anus is most commonly observed in patients in their midfifties,

although it has been reported in virtually all age groups.
The etiology of these lesions is not known. The anus represents a blend-
ing of epithelial surfaces of soft tissues that can give origin to a variety of
carcinomas and sarcomas, as noted in Figure 9-23. Thus, adenocarcinomas
and adenoacanthomas can arise from anal crypts and glands; squamous cell
carcinomas and malignant melanomas can arise from squamous epithelium
of the anal canal; basal cell epitheliomas, Paget's disease, and Bowen's dis-
ease can arise from the perianal skin; and lymphomas and sarcomas can
arise from the soft tissues. 550
Pathology
Squamous compose almost 90 per cent of lesions in the area

cell cancers
of the anus. They and 20 per cent have
are generally poorly differentiated,
a basaloid appearance, characterized by small basophilic cells. These have
been designated cloacogenic or transitional cell anal tumors, and may have
an appearance similar to that of large bowel carcinomas. 551
Early carcinoma of the anus often presents as a small nodule resembling
a hemorrhoidal tag. As it increases in size, it becomes ulcerated and even-
Membranous ( Cloacogenic) Epithelium

Basaloid (transitional eel
Nonkeratinizing squamous
cell ca
Basaloid small cell ca
Anal Crypts and Ducts

Adenocarcinoma
Mucoepidermoid ca
(adenoacanthoma
Soft Tissues
Malignant lymphoma
Rhabdomyo-, leiomyo-, and
Anal (Squamous) Epithelium liposarcoma and other
Squamous cell ca
Malignant melanoma
Perianal Skin''
Basal cell epithelioma
Adnexal tumors
Extramammary Paget's disease
Bowen's disease
FIGURE 9-23. Diagram illustrating malignant lesion originating from the various tissues in the
area of the anus. (From Harrison EG. Jr. et ai. Dis Colon Rectum 9:255. 1966.)
tually may become an exophytic mass. Internally, it may extend beneath

the intact rectal mucosa and become ulcerated farther above in the form of
an apparently separate rectal tumor. Most arise in the anterior or posterior
anal quadrants. Progressive growth can result in invasion of perianal skin,
sphincter muscles, perirectal fat, prostate, bladder, cervix, and pelvic struc-
tures
At the time of initial surgical treatment, from 28 to 64 per cent of patients
have been found to have involvement of perirectal or mesenteric nodes,
and up to 27 per cent have inguinal node metastases. 553,554 Ten per cent of
patients may have hepatic metastases at the time of surgery. 555
Clinical Features
One of the first symptoms observed in carcinoma of the anus is pruritus

and bleeding. Tenesmus and pain that is not relieved by defecation may
become increasingly noticeable. Common constitutional symptoms, such as
fever, weight loss, anemia, and weakness, are usually absent, unless the
lesion is far advanced. If the mass becomes large enough to obstruct the
bowel lumen, severe constipation may result.
TREATMENT
Surgery
The surgical management is governed by the loca-

of anal malignancies
tion and histology of the Although there are series reporting five-
lesion.
year survival rates of approximately 90 per cent with local excision, 556 the
marked variability of tumors in this area makes it difficult to analyze com-
parative results. Resection should be complete enough to remove the tumor
without entering it and to provide wide margins. Since these tumors often
have considerable local invasion by the time they are diagnosed or treated,
it has been our experience that the required surgery is usually abdominal
perineal resection.
In the absence of clinically palpable inguinal nodes, there is little justifi-
cation for inguinal lymphadenectomy. In cases of malignant melanoma, we

routinely perform staging lymphadenectomy in patients who may qualify
for entrance into experimental prospectively randomized immunotherapy
trials. However, other than in a clinical investigation situation, lymphade-
nectomy should be deferred, unless there is a suggestion by physical exami-

nation that the nodes may be involved with the tumor.
If the nodes are clinically involved, the prognosis is poor. 557 However, if
there is an interval between the time of the resection of the primary and
the time that node dissection is required because of clinical involvement, a
five-year survival rate exceeding 60 per cent has been reported. 558 The five-
year survival rate of patients treated by combined abdominal perineal re-
section has ranged between 30 and 50 per cent, comparing favorably with
patients receiving the same treatment for carcinoma of the rectum.
Radiation Therapy
In the United States, the traditional management of squamous cell carci-

noma of the anus has been surgical, but a number of reports from Europe
of primary treatment with radiation bear reviewing; there are two recent
reports from this country of combined modality approaches that are very
promising.
The perineum has been avoided by radiation therapists because of its
poor tolerance of high doses of external beam therapy. Meland559 in 1947
and Roux-Berger and Ennuyer560 in 1948 reported series of combination
interstitial therapy with external beam therapy and noted local control in
more than 50 per cent of cases, with a 35 per cent five-year survival rate in
both series. Dalby and Pointon, 56 using a single interstitial implant for
'
each of 46 patients, achieved a five-year survival rate of 43.5 per cent. Thir-
teen of their survivors, however, required surgical salvage. Later, Delouche
et a/. 562 reported 41 cases treated with radiation alone, half of whom had
both external radiation and an implant (total tumor dose of 7000 to 8500
rad). Twenty of the 41 patients survived for five years. Two additional pa-
tients were treated with external radiation followed by surgery, and both
survived five years. In the entire group of 43, there were only 12 (28 per
cent) local recurrences, and only 5 of 22 (22 per cent) local recurrences were
seen in patients having external beam therapy plus an implant.
Papillon583 reported 98 patients treated by radiation alone. He excluded
T4 lesions, referring them for surgery. Of the 64 patients who were evaluable
at five years,44 (69 per cent) were alive and well, 4 of whom had surgical
salvage. Overall, there were 10 (16 per cent) local failures. He advocates
fractionation of the implantation, giving 3000 to 4000 rad in two to three
days and then waiting two months before giving an additional 2500 to 3000
rad. Occasionally, a third implant (2000 rad) follows after another two months.
Large lesions get 3000 rad over three weeks externally and an implant five
to eight weeks later.
Two sas
have combined radiation, 5-
small series (three patients each) 564,
fluorouracil (5-FU), mitomycin-C, and surgery. There was apparent steril-
ization of the tumor in the five patients completing combined radiation
(about 3000 rad) and intravenous chemotherapy. Of the six cases entered in
these two studies, one patient died very early of a perforated duodenal
ulcer, and the others were alive for more than one year (three patients had
surgery, with no identifiable tumor found, and two patients had no surgery).
These studies indicate the efficacy of radiation therapy in achieving local
control of squamous cell carcinoma of the anus. Judicious use of this mo-
dality, emphasizing interstitial implantation, may lead to improved cure
rates and reduced morbidity.
Chemotherapy
The chemotherapy in the treatment of carcinomas of the anal

role of
canal undefined. Scattered case reports exist with anecdotal comment on
is
responses to CCNU, doxorubicin, and cisplatin; 566 567 however, we are not
'
aware of any systematic study of chemotherapy used alone for the tumors
occurring in this area. It is hoped that a recent report from Buroker et a/., 568
in which 5-FU and mitomycin-C were given with preoperative radiation
therapy to ten patients who underwent abdominoperineal resection, will
stimulate further chemotherapeutic research in the future. A greater than 50
per cent reduction in the size of the tumor occurred in all ten patients, and
six were free of evident tumor at the time of surgery. Such multimodality
therapy may become even more useful once optimal regimens of chemo-
therapy have been defined.
The low incidence and marked variability in size, presentation, location,

and histology of tumors around the anus make it unlikely that prospective
randomized studies to evaluate different modes of therapy will ever be un-
dertaken. These factors will necessarily have to be evaluated in each case
by the therapist and the treatment plan formulated accordingly. It does ap-
pear that in larger lesions, the addition of radiation therapy to surgery
might have end results that are better than either modality given alone.
Section 6
Cancer of the Exocrine

Pancreas
INTRODUCTION
Etiology and Epidemiology
There were approximately 22,000 new cases of pancreatic cancer in the

United States in 1975, and its severity is such that in that year there were
the same number of deaths caused by this disease. 569 The cause of pancre-
atic carcinoma remains unknown, and circumstantial evidence from experi-
mental animal studies, or epidemiologic investigations on which to base
even a tentative hypothesis, are obscure. Associated factors cited in the past
include chronic pancreatitis, diabetes mellitus, and alcoholism. Another as-
sociation that has been made is cigarette smoking. Mortality rates from pan-
creatic carcinoma for cigarette smokers are approximately two to three
times higher than those for nonsmokers, and it is of interest that the rise of
pancreatic carcinoma incidence parallels that of lung cancer, although they
may be unrelated.
It is clear, however, that during the past 40 years, the incidence of pan-
creatic carcinoma has increased almost 300 per cent and now exceeds the
incidence of stomach cancer and cancer of the rectum. 570, 571 In the United
States, the incidence of cancer of the pancreas is rising most rapidly in the
nonwhite population. 576 The majority of patients range in age between 30
and 70 years, with the average age at the time that symptoms appear being
about 56 years. The male-female ratio is about 2 to 1.
NATURAL HISTORY
Classification
Carcinoma of the pancreas produces a hard, nodular, poorly-defined en-

largement of that portion of the gland from which it arises. The distribution
of primary cancers of the pancreas are listed in Table 9-27. 572
Adenocarcinomas of the pancreas are irregular, whitish masses, which are
often accompanied by fibrosis and surrounded by pancreatitis. In most sur-
gical series, 75 per cent of these tumors are located in the head area, and
carcinomas of the head of the pancreas often cause fibrosis, duct obstruc-
tion, and pancreatitis after they reach a significant size. Invasion of the por-
tal vein, superior mesenteric vein, and bile ducts is common. Carcinomas
of the body and tail of the pancreas are usually found at autopsy, probably
TABLE 9-27. Cancers of the Pancreas by Histologic Cell Type
Cell Type Occurrence
Adenocarcinomas
Ductal cell
Acinar cell 13*
"
Anaplastic
Cv -âdenocarcinoma Rare
Adenocanthomas Rare
Squamous cell carcinomas Rare
mas Rare
because these are often silent lesions in patients who die of other car.
They may remain asymptomatic for lone periods and present as larse. pal-
pable tumor masses frequently invading the surrounding structures of
splenic artery and vein and the stomach.
The most frequent sites of metastases are the regional and periduodenal
lymph nodes, the mesocolic and peripancreatic lymph nodes, and the
nodes in the hilum of the liver. Other mesenteric, periaortic, or posterior
mediastinal nodes may become invoked as the disease progresses. Meta-
static spread to the liver is seen almost invariably at the end stage of the
div nd direct peritoneal seeding of the abdominal cavity is common.
Le>s common sites of met.. are lime and bone.
Recent studies of pancreatic pathology have focused on the histology of
this neoplasm. Capella et til.* * have made an ultras tructural study and clas-
7
sification of endocrine cells of the pancreas and have proposed up to seven

different cell types they feel may be the basis for a new cytologic classifica-
tion. Tschang et td. sa have described a pleomorphic carcinoma of the pan-
creas. This is characterized by a noncohesive. sarcoma-like growth pattern
with bizarre mono- and multinucleated giant cells. The clinical course in
patients with this lesion is worse than with conventional adenocarcinoma.
This pleomorphic, sarcoma-like cell architecture with a correspondingly
poor prognosis has also been noted by others. "" Webb, 577 who described
carcinomas of the pancreas that have mixed cell type, emphasizes the need
for future epidemiologic studies to account for the variance in histologic
types ol pancreatic carcinoma.
In an interesting in vitro study, Wu et al.
: :*
were able to purify and char-
-
acterize a plasminogen activator secreted by cultured human pancreatic car-

cinoma cells that shared many properties with urokinase. This is of interest
because abnormal clotting states are frequently associated with carcinoma
of the pancreas, and the identification of a substance responsible for induc-
ing embolic phenomena may make it possible to isolate and utilize a clini-
cal preparation for its neutralization.
Clinical Features
The symptoms usually observed in pancreatic cancer in the head

triad of
area of the pancreas is pain, weight loss, and progressive jaundice. Unfortu-
nately, these symptoms are generally ill-defined and vague early in the
310 II / TREATMENT] OF SPECIFIC \EOPLAs\is
course of disease, and conventional roentgenographs findings arc often

normal. The epigastric pain is often relieved by changes in posture such as
sitting up or bending forward. Diabetes mellitus is demonstrable in 20 to
40 per cent of patients. Gastrointestinal tract hemorrhage is rare. Emotional
disturbances characterized by depression, agitation, and anxiety have been
reported in the majority of patients. 579
Physical findings are usually few. In the tail and body area, the lesions
may achieve a large size and be palpable prior to the development of se-
vere symptoms. Late in the stage of the disease, ascites may become evi-
dent. The interval from the onset of symptoms until the death of the patient
is usually from five to nine months.
Diagnosis
The evaluation of the upper gastrointestinal tract by x-ray after ingestion

of barium has been the most effective conventional test in diagnosing carci-
noma of the pancreas. Noted abnormalities have been duodenal or pyloric
obstruction, narrowing of the first and second portions of the duodenum,
indentation of the duodenum caused by tumor extension, widening of the
duodenal loop, or distortion of the mucosal pattern from direct tumor inva-
sion.
Because of the unique position of the pancreas deep within the upper
abdomen, and because these lesions usually have to achieve a large size to
cause symptoms, a high degree of resolution in the diagnostic accuracy of
various tests is mandatory before the course of this disease is likely to be
significantly altered. An intense interest has therefore been associated with
developing tests for the earlier and more precise diagnosis of pancreatic
cancer. A review of the most recent reports follows.
ENDOSCOPY. Freeny and Ball 580 recently reported a series of 118 pa-
tients with suspected pancreatic disease, in which endoscopic retrograde
cholangiopancreatography was 95 per cent accurate in the prospective diag-
nosis of pancreatic carcinoma. The addition of angiography to the testing of
these patients was of value because it obviated the need for exploratory
laparotomy in some patients with unresectable tumors and encouraged ag-
gressive treatment of resectable lesions.
Endoscopic aspiration biopsy of the pancreas was used by Tsuchiya et
581
a/. preoperatively in 51 patients, and a diagnosis of pancreatic cancer was
made in84 per cent, with three false-negative and no false-positive diag-
noses. Endoscopic aspiration cytology and endoscopic retrograde cholangio-
pancreatography was evaluated in 44 patients. The former technique alone
was diagnostic in 91 per cent of cancers of the head of the pancreas and 55
per cent of cancers of the body and tail of the pancreas, and the latter
technique was diagnostic in 59 per cent and 75 per cent of patients, respec-
tively. By combining the two approaches, diagnostic success was obtained
in 95 per cent of cancers of the head and in 90 per cent of cancers of the
body and tail of the pancreas. 582 Hall et a/. 583 have reported a diagnostic
sensitivity of 92 per cent and a specificity of 90 per cent using retrograde
cholangiopancreatography in the diagnosis of periampullary cancers.
9 Gastrointestinal Tract Neopla- -
311
In general, a great deal of enthusiasm exists for endoscopy with retro-

grade cannulation of the pancreatic duct. All our investigators acknowledge
that this procedure requires technical expertise and experience and is sub-
ject to anatomic limitations. such as gastric outlet obstruction. The greatest
diagnostic accuracy has been observed when used in combination with
other modalities — particularly cytologic studit
Ultrasound. Studies describing ultrasonic methods of diagnosis in
early pancreatic cancer report mixed results. Gosink and Leopold 584 stated
that ultrasound is obstruction is severe enough to cause
helpful only if
dilation of the common and Templeton 585 describe the ultrason-

duct. Walls
ic demonstration of anterior wall compression of the inferior vena cava by
advanced, enlarging lesions in the head of the pancreas. After following the
clinical course of 28 patients with pancreatic cancer subsequent to initial
detection of this malignant neoplasm by ultrasonic scanning, McCormack et
586
a/.. suggested that diagnosis by this technique had no effect on the sur-
vival of patients with pancreatic carcinoma. In fact when combined with
other diagnostic tests, ultrasound probably is a useful modality. However, it
tends to be more useful in identifying the changes associated with ad-
vanced disease rather than in diagnosing early lesions.
Computerized Trans axlal Tomography. As experience with compu-
terized transaxial tomography scanning grows, many details from studies
investigating the use of this test for pancreatic disease are being accumulat-
ed. Haaga et a/. 587 studied 188 patients and determined that CT scans were
the most effective means of detecting neoplastic and inflammatory diseases
of the pancreas. They emphasize that the full extent of the disease process,
including involvement of the retroperitoneum and metastasis to the liver,
can be visualized with one examination. Stanley et a/. 588 studied 352 pa-
tients and believe that this noninvasive method often precludes the neces-
sity for more invasive procedures, such as angiography. The use of the con-
ventional radionuclide pancreatic scan has been of little clinical value. 589
Needle Biopsy of the Pancreas. Percutaneous fine needle aspiration
biopsy has had several advocates. In one series. 89 per cent of patients
with pancreatic cancer were diagnosed by this method, making surgery un-
necessary in 5 of 18 patients. 590 Favorable results have also been reported
by others. 591 594 Indeed, in several series clinical pancreatitis has been ob-
"
served following biopsy. Also, the difficulty in obtaining an operative diag-

nosis when the pancreas is accessible has made many surgeons feel that
obtaining a positive diagnosis through a fine needle when the organ cannot
be seen is unlikely. However, it should be remembered that these are aspi-
ration biopsies, and cytologic examinations in addition to microscopic tis-
sue examination are performed. Kline et a/. 595 have reported needle aspira-
tion biopsies of the pancreas at the time of laparotomy. In 36 carcinomas
the accuracy was 94 per cent, and there were no false-positive results in
the 20 benign lesions biopsied.
As with all invasive techniques, the usefulness of the information ob-
tained is critically dependent on the institutional environment and the ex-
pertise and enthusiasm of the investigators. Many surgeons are reluctant
to biopsy the pancreas even at the time of operation, thus they find the
312 II / Trfai mini of Specific Neoplasms
idea of percutaneous biopsy of nonpalpable masses worrisome. It is likely

that this technique will gain acceptance and accuracy with time.
ANGIOGRAPHY. Angiography is an invasive test that is probably recom-
mended one of the earlier screening tests is positive. In this setting,
only if
its principal aims are to map vascular anatomy, to differentiate non-
neoplastic disease from cancer, and to assist in the estimation of operabi-
596
lity. The evolution of some of the newer, less invasive tests has probably
reduced the incidence of angiography for diagnosis of pancreatic cancer.
However, when used in combination with other tests, this procedure can
occasionally add to the degree of resolution not obtained when tests are
used singly. 597599
Overview of Diagnostic Tests for Pancreatic Cancer. In a pros-
pective comparison of current diagnostic tests for pancreatic cancer, Di-
Magno et a/. 600 determined that when pancreatic cancer is suspected, ab-
dominal ultrasound should be performed first, and if findings are negative,
a pancreatic function test should follow. A positive result from either test
warrants an endoscopic retrograde pancreatography for definitive diagnosis.
Fitzgerald et a/. 601 recently assessed the accuracy of diagnostic tests in
184 patients suspected of having pancreatic cancer in a study sponsored by
the National Cancer Institute. In this study, computerized transaxial tomog-
raphy, celiac angiography, determination of the serum alkaline phosphatase
level, pancreatic scan, and ultrasonography —
in descending order gave —
the highest percentage of correct diagnoses. However, they noted that
false-positive and false-negative diagnoses prevented any single test from
being conclusive. Freeny and Ball 602 used a combination of tests in which
ultrasonography and barium studies of the upper gastrointestinal tract were
followed by inpatient endoscopic retrograde cholangiopancreatography, an-
giography, and percutaneous biopsy. The diagnostic accuracy was 96 per
cent, and although this combination of methods did not increase the diag-
nosis of resectable tumors, it did result in a rapid and accurate diagnosis of
pancreatic carcinoma at a relatively low cost, with a minimum of patient
discomfort. Evaluation took no more than two hospital days, and explorato-
ry laparotomy for diagnosis only was not needed. Barkin et a/. 603 compared
computerized tomography, diagnostic ultrasound, and radionuclide scan-
ning. They concluded that a rational approach to the examination of a pa-
tient with suspected pancreatic carcinoma should begin with ultrasound
when available, because they believed the detection rate with this method
was equal to that with computerized tomography, at a substantially lower
cost.
It is apparent that a continuing evolution of tests to diagnose pancreatic
cancer is occurring. No one test is completely free of false-positive or false-

negative findings. However, it is likely that the use of a combination of
these tests, which are constantly being refined and expanded, will eventu-
ally lead to an earlier diagnosis of pancreatic carcinoma.
Staging
A system to stage carcinoma of the pancreas has been devised, but the
collection of objective data to clarify and correlate findings with prognosis
is still in progress by the American Joint Committee for Cancer Staging and
End Results Reporting. our opinion that the

It is TNM
system, which
has been useful in other tumor systems, might be less applicable in this
disease, in which nodal involvement and local infiltration often are difficult
to determine. In recent national chemotherapy and radiation therapy trials,
the single factor that has consistently been of greatest prognostic signifi-
cance is the performance status. The higher the level of performance, as
determined by any of the commonly used systems, the better the response
or survival rate, or both.
TREATMENT
Surgery
Curative Operations. Cancer of the pancreas may be more locally ad-

vanced at the time of diagnosis than any other gastrointestinal malignancy.
This finding, combined with the fact that local invasion frequently affects
vital structures to which surgical access is limited —
such as the portal
vein, vena cava, common bile duct, and liver, makes curative surgery for-
midable indeed. For lesions of the head of the pancreas, radical pancreati-
coduodenectomy (Whipple procedure) is still the procedure of choice. In
this operation, the distal stomach and the duodenum, the first portion of the
jejunum, and the head and part of the body of the pancreas are resected en
bloc. The bile duct is anastomosed end-to-side to the jejunal remnant, and
the pancreatic remnant is anastomosed end-to-end or end-to-side with the
jejunal remnant (Figs. 9-24 and 9-25). A gastrojejunostomy is then per-
formed. Most surgeons feel that it is essential to perform a vagotomy during
this procedure, since a well-recognized postoperative complication is upper
gastrointestinal hemorrhage.
The most troublesome part of the procedure is the pancreatojejunostomy,
which has led some surgeons to advocate total pancreatectomy in most
cases of radical pancreatic excision for carcinoma. Total pancreatectomy
also has the advantage of preventing local recurrence of the tumor in the
pancreatic remnant. The major disadvantage rests in the fact that total pan-
createctomy results in varying degrees of exocrine insufficiency and perma-
nent diabetes mellitus, with a continuing requirement for insulin thera-
604
py.
Few surgeons will achieve the excellent results of Afton and Longmire, 605
in which 31 patients underwent pancreaticoduodenectomy, with no result-
ing operative deaths. Sato et a/. 606 recently reported a study of 66 patients
undergoing pancreaticoduodenectomy. The hospital mortality rate was 7.5
per cent, and the five-year survival rates were 7.8 per cent in 20 patients
with carcinoma of the head of the pancreas, 16.7 per cent in 31 patients
with carcinoma of the bile duct, and 38 per cent in 15 patients with carci-
noma of the ampulla of Vater. Fortner et al. 607 have advocated en bloc pan-
creatic, portal vein, and lymph node resection, with portal vein repair by
end-to-end anastomosis without a graft. The thirty-day mortality rate was 17
per cent, and actuarial survival was 62 per cent at one year compared with
a 36 per cent one-year survival rate for patients undergoing more conven-
tional pancreaticoduodenectomy. Ihse et al. 608 considered total pancreatec-
FIGURE 9-24. Extent of pan-

creaticoduodenectomy Whip-I
ple procedure'. The distal stom-

ach, duodenum, gallbladder,
and right half of the pancreas
are removed. A vagotomy is
usually added to protect against

the development of marginal ul-
ceration. (From Bradley EL. et
al.: In Davis-Christopher Text-
book of Surgery. 11th ed. Sabis-
ton DC, Jr (ed). Philadelphia,
WB Saunders Co. p. 1311, 1977.)
FIGURE 9-25. Preferred

method of reconstruction after
pancreaticoduodenectomy. The
pancreatic anastomosis is placed
proximal to the biliary anastomo-
sis, whiph is. in turn, followed by
a gastrojejunostomy of the Hof-
meister type. (A, aorta; PV. por-
tal vein; SV, splenic vein; VC,
vena cava; K, kidney; SMA, su-

perior mesenteric artery. From ) |
Bradley EL. et al.: In Davis-

Christopher Textbook of Sitr-
gery, 11th ed. Sabiston DC. lr
(ed), Philadelphia. WB Saun-
ders Co, p. 1311. 1977.)
tomy to be superior to the conventional Whipple procedure in a review of

65 cases.
Palllative Operations. More often than not. laparotomy will reveal
that the pancreatic malignancy is not resectable for cure. Palliative proce-
dures are often performed to treat obstructive jaundice and real or impend-
ing obstruction of the gastric outlet of the duodenum. Choledochojejunos-
tomy and eholecystojejunostomy have been performed to relieve
obstructive jaundice. Weprefer the former with a Roux-en-Y loop of jejun-
um and a two-layer choledochojejunal anastomosis in either end-to-end or
end-to-side fashion. If enlarged tumors of the head of the pancreas with
duodenal obstruction are found, gastrojejunostomy should also be per-
formed. These operations do not prolong survival but may well improve the
quality of the remaining months of life.
Results and techniques that were used in large numbers of patients treat-
ed surgically for cure or palliation have recently been reported. 809 617 As
"
with surgery for most other gastrointestinal malignancies, perioperative hy-

peralimentation has been reported to improve postoperative nutrition and
function. 61 * A second goal of palliation at the time of surgery is the reduc-
tion of pain. There is no uniform agreement among surgeons that such pro-
cedures are generally effective. However, there are several recent series in
which excellent postoperative pain control has been achieved by maneu-
vers such as injection of the splenic nerve with phenol at the time of lapa-
rotomy 619 and combining such injections with pancreaticojejunostomv 62 °
-.
Radiation Therapy
Both external beam radiation as well as interstitial implants have been

advocated for the palliative (and potentially curative) management of unre-
sectable carcinoma of the pancreas. Some early reports were disappointing,
with no significant palliative effect from 3000 rad giveo externally over
three weeks 6 - and palliation in only a few patients with doses of 5000 rad
1
or more. 622 Falkson's group 623 similarly reported no objective responses in

12 patients receiving 1500 to 4000 rad alone, but 56 per cent of 81 cases
had partial remissions for 1 to 20 months when the radiation was combined
with 5-fluorouracil in multiple short courses (1500 to 2000 rad with 12.5
mg/kg/dav 5-FU x 5 days). Moertel's group, 624 in a retrospective analysis,
found no difference in survival between an untreated group and a radia-
tion-treated group. However, by adding 5-FU. in a controlled trial, they
demonstrated statistically significant prolonged survival (mean = 10.4
months).
More recently. Wiley's group 625 reported on ten patients who had been
staged and treated aggressively with arteriography, CT scanning, a 15-day
intra-arterial infusion of 5-FU
(15 mg/kg/dav), 4000 rad to the pancreas,
2000 rad to the liver, and a 1500 rad boost to the primary lesion (total 5500
rad). Of eight patients with localized disease, six have survived — four from
626
9 to 22 months after therapy. Cavanaugh, using radiation alone (6000 rad,
split-course) got fair to good results in 69 per cent of treated cases, with a
24 per cent two-year survival in a series of 23 cases. He believed there was
a dose-response relationship in the patients who had been previously treat-

ed with lower doses (2000 4500
Another attempt to increase local
to rad).
control is described in a recent report from Macdonald's group. 627 Eleven
patients were treated with 15 MeV fast neutrons (1716 rad), with or without
5-FU, and 11 have had partial remissions from 4 to 14 months or more.
Further trials of external beam therapy (photons and neutrons) with concur-
rent chemotherapy appear justified and are continuing.
Hilaris 628 reviewed 118 cases treated at Memorial Hospital in New
York. Twenty-nine of these patients had had bypass and external beam
therapy, and 19 had had an interstitial implant (usually iodine-125). The
radiated groups, particularly the implanted group, had a prolonged median
survival and an increase (to 20 per cent) in two-year survivors. Suit 629 has
also reported 14 patients who were treated with implantation, 6 of whom
also had resection. Local-regional control was achieved in 11 of the 14 pa-
tients, with no local failures among those receiving implants alone. Implan-
tation may be a promising means of improving local control rates, but tech-
nical considerations may limit its applicability.
Chemotherapy
Single Agents. Patients with advanced adenocarcinoma of the pancre-

as only occasionally benefit from single-agent chemotherapy. Objective
benefit has been reported in more than 20 per cent of patients treated with
5-fluorouracil or mitomycin-C, but such responses rarely last longer than
two or three months. Detailed reviews of single-agent chemotherapy for
this disease are available,630 631 and Table 9-28 summarizes some of this
'
456 630 632 - 638

information. - '
TABLE 9-28. Single-Agent Chemotherapy of

Pancreatic Adenocarcinoma
No. Responses/No.
Agent Selected Patients Rate (%) Reference
5-Fluorouracil 60/212 28 630

Mitomycin-C 11/53 21 632
Streptozotocin 7/41 17 630, 633-635
CCNU 3/19 16 630
MeCCNU 4/68 6 636
BCNU 0/37 630
Doxorubicin 3/36 8 638 and 639
Dactinomycin 1/41 2 638 and 639
Neocarzinostatin 11/88 12 637
Mechlorethamine 1/7 NE° 630
Cyclophosphamide 1/5 NE 630
Chlorambucil 4/6 NE 630
Dacarbazine 0/12 NE 630
Hexamethvlmelamine 0/6 NE 630
Methotrexate (oral) 0/6 NE 638 and 639
Fluorometholone 0/7 NE 638 and 639
"NE = not evaluable.

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Combination Chemotherapy. Following a Mayo Clinic study of 5-FU

plus BCNU, more than 460 patients with carcinoma of the exocrine pancre-
as have been treated with
experimental drug combina-
various
489 491
tions. 469 -
-
-
492 >
498,«39-647
Table 9-29 summarizes
these results. Unfortu-
nately, we do not consider any of these regimens to be of established
benefit. Responses have generally been of short duration, and there is no
good evidence that survival has been prolonged by these regimens. In
nearly every case the enthusiasm engendered by preliminary reports has
not been sustained with more extensive testing of each regimen. For this
reason, we consider patients with advanced untreated pancreatic cancer to
be candidates for experimental therapy. If this is inappropriate or unavail-
able, we utilize 5-FU as a single agent because of its simplicity and relative
safety (See Chapter 5).
Immunology
Leukocytes from pancreatic cancer patients have been reported to react

specifically with extracts from the pancreatic tumor tissue, whereas they do
not react with extracts from other gastrointestinal malignancies. The contin-
ued development of such a test may result in the ability to detect the alter-
ation of specific tumor immunity early in pancreatic cancer. 648 An analysis
of carcinoembryonic antigen, alpha-fetoprotein, and pancreatic oncofetal an-
tigens was made in patients who were suspected of having a major abdomi-
nal malignancy. In this study, a negative pancreatic oncofetal antigen test
was found to be useful in excluding a diagnosis of pancreatic cancer. 649 No
adjuvant immunotherapy programs have been initiated in this disease.
is no known adjuvant therapy following surgical resec-

Currently, there
tion forcarcinoma of the pancreas. The only ongoing randomized study is
the evaluation of postoperative radiation and 5-FU chemotherapy. Results
650
to date are inconclusive.
In a prospective, randomized with locally unresectable
trial in patients
carcinoma of the pancreas staged at the time of laparotomy, patients treated
with 5-FU and 6000 rad radiation therapy had a better survival rate than
those receiving either modality alone. The mean survival was 49 weeks in
the group receiving both modalities, as opposed to 15 weeks in those who
did not receive combined therapy. 651 National studies designed to inves-
tigate other radiosensitizing agents either are being planned or are in prog-
ress.
CYSTADENOCARCINOMA OF THE
PANCREAS
Cystadenocarcinomas are rare lesions that present as cystic neoplasms
filled with mucoid material. The lining of the cysts are columnar epitheli-
um with papillary formation and a low grade of neoplasia.
The main reason for the special mention of these lesions is that patients
with this tumor have much better prognoses after surgical treatment than
do patients with conventional acinar adenocarcinoma, and they should be
treated aggressively. Although reported series are small, a 40 to 50 per cent
five-year survival ratenot an unrealistic expectation following pancreati-
is
coduodenectomy. Several recent reports are noted. 652 654

"
Section 7
Cancer of the Liver
INTRODUCTION
Primary' hepatic carcinoma is rare in the United States; approximately

2500 new cases are diagnosed yearly. However, it is among the most com-
mon of visceral cancers affecting males in many regions of Africa and the
Far East. In Southeast Asia, where cholangiocarcinoma is endemic, parasit-
ic infections may be related to its incidence. Nutritional deficiencies and
exposure to aflatoxin, a substance derived from peanuts infected with Asper-

gillus flavus, have also been implicated.
There is an association between cirrhosis and hepatoma, and it is now
believed that approximately 4 per cent of patients with cirrhosis eventually
develop hepatoma. 655 Alcoholism and malnutrition are etiologic factors asso-
ciated with each disease, but whether or not the presence of cirrhosis spe-
cifically induces hepatoma is unknown.
A with the hepatitis B virus, has
viral etiology, particularly in association
been postulated. From their studies inAfrica, Larouze et a/. 656 be-
West
lieved the inter-relationship among several events to be related to hepatitis
B virus infection and primary hepatocellular carcinoma. Common findings
were the presence of hepatitis B surface antigen, antibody to hepatitis B
core antigen, chronic liver disease, and elevated alpha-fetoprotein levels. A
and hepatocellular carcino-
similar association of cirrhosis, hepatic fibrosis,
ma has been proposed by Blenkinsopp and Haffenden. 657 Tan et a/. 658 demon-
strated hepatitis B antigen 74 per cent of patients with
in the liver cells of
cirrhosis and hepatocellular carcinoma. The role of hepatitis B antigen in
inducing hepatoma, possibly in a synergistic role with other carcinogens, is
many current investigations. 659
" 661
the subject of
NATURAL HISTORY
Pathology
Ninety per cent of adult primary hepatic cancers arise in the hepatocellu-
lar parenchyma. Approximately 10 per cent originate in the cells lining the
bile ducts and are called cholangiocarcinomas. More rare types include he-
mangioepithelioma, Kupffer cell sarcoma, hepatoblastoma, and mixed sar-
comas. The tumors can present as a single large mass or as multiple nod-
ules. Often, there is a central large mass with numerous satellite nodules.
Vascular invasion is a common feature and is diagnostic.
Death ensues from liver failure, often with no extrahepatic extension of
the cancer. Venous extension of the tumor may progress to the vena cava
and extend as far as the right atrial cavity. Metastases usually involve peri-
portal lymph nodes and lung and, less frequently, bone, adrenal gland, and
663
brain. 662 *
Clinical Course and Diagnosis
Ahigh index of suspicion should be maintained in patients with cirrhosis

who manifest unexpected clinical deterioration. Increased jaundice, the de-
velopment of ascites, abdominal pain, weight loss, cachexia, fever, or a
rapid increase in hepatic size may be observed. Sudden hypotension or
abdominal pain, or both, may be observed in patients with rapid hemor-
rhage into the tumor mass or the peritoneal cavity. Paraneoplastic syn-
dromes such as hypercalcemia, hypoglycemia, polycythemia, carcinoid syn-
drome, gynecomastia, porphyria, and coagulopathies have been reported. 664
The diagnostic aids that are useful in detecting hepatoma, including liver
scan, angiography, needle biopsy, and peritoneoscopy, are discussed fully
under the section of this chapter on metastatic neoplasms of the liver.
The presence of alpha-fetoprotein, a material that is frequently present in
the serum of the fetus but not in normal adults, is fairly specific for the
presence of adult hepatoma. Less than 1 per cent of adults with elevated
alpha-fetoprotein levels have had false-positive levels in past studies. How-
ever, less than half of patients with hepatoma show increased alpha-
fetoprotein levels. 665 More recent studies have detected this substance in
some normal adults and in patients with viral hepatitis, information that
670
decrease the reliability of this diagnostic test. 666
"
may tend to
Correlations of the presence of alpha fetoprotein, hepatoma, and other
isoenzymes are ongoing and may eventually provide improved diagnostic
accuracy. 671 However, at this time, it must be said that there is no single
" 673
serologic or immunologic test that is diagnostic for hepatoma, and a combi-

nation of diagnostic modalities must be used.
TREATMENT
Surgery
Surgical resection represents the only possibility for cure. Although most
hepatic carcinomas have diffuse or multiple involvement of the liver pre-
cluding surgery, when anatomically feasible resection should be performed
in every instance. Five-year relapse-free survivals have been achieved with
surgery in several institutions, including our own. 409,411,674 Unfortunately,
most tumors are not suitable for surgical resection at the time they are diag-
nosed. 675
Radiation Therapy
There is little information in the literature regarding the radiation of pri-

mary liver tumors. Phillips and Murikami 676 reported 32 cases from Me-
morial Hospital, 26 of whom had hepatocellular carcinoma. Fifteen patients
were treated with 200 to 250 kVp x-rays, 10 patients were treated with 1000
kVp x-rays, and 1 patient was treated with a 4-gm radium pack. Patients
receiving less than 2000 rad (four cases) had no objective response. Of the
22 patients remaining (average dose of 2956 rad in 23 days), 14 had tumor
regression and at least 11 noted symptomatic improvement. It appeared
that there was a prolongation of life (median survival of 9 months, mean of
12 months), but no definitive conclusion could be reached from this ret-
rospective study.
For hepatoblastoma in children, there are several reports of conversion
from nope lability to operability by radiation or chemotherapy, or both. 677 680
"
i
Moderate doses of radiation (2000 to 3000 rad over three to five weeks) to
all or part of the liver may be valuable in attempts to increase resectability,
but this requires further study.
Chemotherapy
This discussion summarizes the role of chemotherapy for hepatomas in

the adult. Childhood hepatoblastomas, 681 primary hepatic sarcomas, 682 cho-
langiocarcinomas, and other primary hepatic neoplasms will not be consid-
ered. The reader who is interested in additional reviews is referred to
those by Lee,683 Falkson,684 and Shiu and Fortner. 685
Systemic Chemotherapy. Patients with advanced hepatoma who re-
spond to chemotherapy appear to live longer than those who do not re-
spond or those who are treated with placebo. The median duration of sur-
vival in patients responding to chemotherapy is approximately seven to
nine months, and occasionally patients survive as long as two years or
more. However, the majority of patients fail to respond to systemic chemo-
TABLE 9-30. Systemic Ch emoth erapy for Hepatoma

No. Response Druc§
SFI FfTFO
'III' 1 II' R\TEt
Reference" Patients t (%) Doxo FU BCNU Others
Collected series 686 -690 110 25 X

Collected series 690 -892 61 10 yo
Collected series 692 -694 44 7 X
Baker 695 38 13 X X
Chlebowski 696 9 11 X MeCCNU
Moertel 697 19 37 X X
Mclntire 698 14 7 X X
Falkson 690 36|| 6 X MeCCNU
Falkson 690 18|| 17 X Streptozotocin
Umsawasdi 699 13 38 X Mitomycin-C
Buroker700 6 50 X'- Mitomycin-C
Gailani 693 16|| 6 X Cytarabine
Umsawasdi 701 11 18 X MTX; Prednisone
Cochrane 702 10 X MTX; CYC; VCR
Al-SarraP594 5 X Vinblastine
Balasegaram 703 60 23 ±x MTX; CYC; ±VCR
"First author only.
f Randomized trial ndi< .ated by||.
tObjective complete and partial remission (>50% reduction in measured mass lesion or 30% decrease in
enlarged liver).
§ Abbreviations: Doxo, doxorubicin; FU, 5-fluorouracil; po, FU given orally; c, FU given by continuous IV
infusion; FU given by IV bolus unless otherwise indicated; MeCCNU, semustine; MTX, methotrexate;
CYC, cyclophosphamide; VCR, vincristine.
therapy and expire two to four months after diagnosis. Even the most active
single agents, doxorubicin and 5-fluorouracil, yield response rates of only
25 per cent or less. 686 694 Unfortunately, combination chemotherapy as em-
"
"
ployed to date does little better. 695 703 This unimpressive record is sum-
marized in Table 9-30 for the reader who is interested in an overview of
contemporary efforts of systemic chemotherapy.
Regional Chemotherapy. Since the early work of Klopp et al. in
1950, 704 there has been a great deal of controversy about the role of hepatic
artery infusion chemotherapy or other regional approaches to administering
chemotherapy to patients with hepatoma and other kinds of primary or met-
astatic hepatic neoplasms. 705, 706 In theory, it is an attractive concept, al-
though the expense in terms of money, time, and morbidity of placing and
maintaining a hepatic artery catheter has dissuaded many physicians from
its use. Moreover, no one has completed a good randomized trial compar-
ing systemic chemotherapy with chemotherapy given by continuous hepa-

tic artery infusion. Nevertheless, with improvements in catheters and infu-
sion pump technology, this procedure warrants careful consideration in
selected patients.
Table 9-31 summarizes the available published experience with hepatic
artery infusion in hepatoma patients, utilizing catheters placed at laparoto-
my or by the percutaneous Seldinger technique. 674, 7,)7721 It is obvious that
results vary greatly from center to center and that there is little uniformity
in what constitutes an objective response. For example, the objective re-
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sponse rate of seven patients who were treated at UCLA was only 14 per
cent; however, all but one patient had substantial subjective improvement
and survival appeared to be prolonged. fi74 It is possible that some of these
patients would have been considered objective responders to treatment had
they been analyzed in the past at other centers. These aggregate results
support a role for hepatic artery infusion chemotherapy for selected pa-
tients with unresectable hepatoma. The overall response rate to fluorinated
pyrimidine therapy with either 5-fluorouracil or FUDR in this literature
series is 42 per cent, 694, 71172 ° which is clearly superior to the 7 to 10 per
"
cent response rate reported for 5-FU when given systemically. 690 694 More-
over, the approximate median survival of all patients treated with 5-FU or
FUDR by the hepatic artery route is 8.5 months, which is superior to the
3-month median seen with systemic 5-FU administration. Finally, the hepa-
tic artery route is occasionally associated with very long survival times and
rarely is associated with the complete eradication of visible tumor. 713, 716 In
our most recent review of patients with unresectable hepatoma who were
treated with hepatic artery infusion of 5-FU at UCLA, the median survival
in 13 patients was 14 months (range 3 to 28 months).
Because of the results reported in the literature and our own personal
experience, we currently recommend initiating chemotherapy for patients
with unresectable hepatoma with a continuous infusion of 5-FU delivered
through a catheter placed in the hepatic artery, either at the time of explor-
atory laparotomy or percutaneously using the Seldinger technique. This
procedure is discussed in greater detail under the section on liver metas-
tases. The recommendation for hepatic artery infusion is contingent upon
the availability of a treatment team who is experienced in the management
of hepatic artery catheters and upon a patient who is willing to accept this
form of therapy. Alternatively, patients with unresectable hepatoma may be
treated with systemic doxorubicin or 5-FU in standard doses, as described
previously.
Immunotherapy
The intriguing correlation among the presence of virus, viral surface an-
tigens,and a variety of hepatic pathologic entities, including cirrhosis and
hepatoma, have led to numerous immunologic investigations. In general,
these inquiries have attempted to detect the presence or absence of viral-
associated antigens in populations at risk to develop, or already demonstrat-
ing, hepatoma. It is likely that continued investigations will result in
722 728
'
greater diagnostic resolution of currently existing tests.
Despite these immunologic observations, we are unaware of any studies
involving immunotherapy for hepatoma.
Section 8
Management of Lesions
Metastic to the Liver
INTRODUCTION
Metastases to the liver result almost exclusively from tumor cells that are
carried from the primary site by the circulatory system and are lodged
within the hepatic parenchyma. They can result from virtually any malig-
nancy. When the liver is only one of several, metastatic sites, systemic che-
motherapy is used, and the choice of a drug or drug combination is dictated
by the primary origin of the tumor, as discussed in each section of this
volume. However, there are therapeutic alternatives when the liver is the
sole site of metastatic disease. Because of its unique situation as filter and
recipient of all blood flow, the liver is the most frequent site of me-
portal
tastases from the gastrointestinal tract, and often this is the sole site of met-
astatic involvement. This discussion will therefore focus on hepatic metas-
tases of gastrointestinal origin, with a special emphasis on metastatic
colorectal neoplasms.
Well over half of the annual deaths from colon cancer occur from or with
hepatic metastases. 729 Jaffe et al., 730 Bengmark and Hafstrom 731 and others
have demonstrated that the average duration of survival after diagnosis is 4
to 6 months, with a median survival time in untreated patients of 75
days. 732-734 Studies have shown that only 34 per cent of patients with metas-
tases from colon and rectal carcinoma, 13 per cent with metastases trom
gastric carcinoma, 13 per cent with metastases from pancreatic carcinoma,
and 10 per cent with metastases from gallbladder carcinoma survive six
months. At 12 months, the survival rates drop to 18 per cent, 9 per cent, 3
per cent, and percent, respectively. 733
NATURAL HISTORY
The diagnosis of liver metastases is generally not difficult. The presence

of pain, weight loss, anorexia, fatigue, malaise, unexplained fever, jaundice,
or virtually any unexplained symptom in a patient who has previously un-
dergone treatment for colorectal malignancy demands further evaluation.
Almost 10 per cent of large bowel metastases are palpable at the time of
laparotomy for primary disease. 736 Aids to the diagnosis of liver metastases
are discussed in the following paragraphs.
LABORATORY Aids. The serum alkaline phosphatase level was elevated

in 58 per cent of patients with liver metastases from primary sites outside
the liver in one series" 7 and in 49 per cent of 110 patients with resectable
liver metastases in a more recent series. 737 However, elevation may also be
seen in cancer patients without liver metastases; 737 therefore, this test can-
not provide absolute evidence of liver involvement. 694
Although the serum glutamic-pyruvate transaminase (SGPT) determina-
tion is believed to be more liver-specific than the serum glutamic-
oxaloacetic transaminase (SGOT) determination, the latter has often proved
more abnormal in patients with primary and secondary liver tumors. Cas-
tagna et al. 737 found elevation of SGOT levels in 29 of 48 patients with liver
metastases from other primary sources, but they also found SGOT eleva-
tions in 10 of 48 patients with carcinoma not involving the liver. SGPT did
not help to differentiate between patients with extrahepatic primary tumors
who had liver metastases and those who did not. 694, 738, 739 SGOT levels
were elevated in 33 per cent of patients with resectable metastases and in
38 per cent of patients with resectable primary tumors in a survey taken of
patients with liver tumors in 1974. 740
An elevated serum bilirubin level is often suggestive of metastatic dis-
ease and, in general, has been thought to be a poor prognostic sign for
resectional therapy. 741 However, it should be noted that recently patients
with elevated bilirubin levels have had successful surgical resections and
uncomplicated postoperative courses.
The value of carcinoembryonic antigen in the diagnosis of metastatic dis-
ease has been discussed earlier in the section on colon cancer. Unfortu-
nately, a host of benign conditions including colon polyps, inflammatory
bowel disease, cirrhosis, pancreatitis, and chronic lung disease, many of
which may mimic hepatic metastases, can also induce an elevation in car-
cinoembryonic antigen levels. The quantitative aspects of CEA determina-
tion may eventually prove more important than its qualitative aspects. 742
Radioisotope Liver Scan. Scanning is probably more effective than
any other laboratory test in picking up primary and secondary liver tumors
and is certainly easier to perform and more comfortable for the patient than
invasive techniques. It is said that lesions as small as 1 to 2 cm
diameterin
can be picked up by modern equipment. The comprehensive review of
Spencer 743 summarizes the current knowledge.
However, the information about whether scans can pick up multiple nod-
ules of primary malignant disease or demonstrate the smaller metastatic le-
sion is not as reassuring. Although some authors believe that scans are of
much greater value than liver function tests and even exploratory laparoto-
my in picking up liver metastasis from primary gastrointestinal cancer, 744
others provide evidence that false-positive and false-negative scan reports
are common with metastatic tumors. 737, 745, 746 Generally, positive liver scans
have been reported in 70 to 90 per cent of patients who histologically dem-
onstrated metastases, and false-negative findings have been reported in 7 to
27 per cent. In one series, liver scanning was 85 per cent accurate in de-
tecting metastases in 500 cases, with 9.7 per cent false-positive and 5.3 per
748
cent false-negative results. 747 There is also a degree of observer error.
Most authors would probably agree that if there is no clinical or laboratory

evidence of chronic benign liver disease, and if the metastatic deposit is at
least 2.5 cm in diameter, it will be demonstrated on liver scan.
ANGIOGRAPHY. Selective arteriography may supply useful information
about a patient with hepatic metastases. In addition to providing evidence
about the type, size, and number of lesions, arteriography can confirm clini-
cal impressions about portal vein involvement and can give a road map of
the arterial supply to tumors of the liver in an area in which anomalies are
very common.
Among those arteriographic changes that give information about the pres-
ence of tumor are dilation of the hepatic artery, distortion and displacement
of the vessels, hypervascularity, tumor blush, neovascularity, arterial ve-
nous shunting, vessel encasement, pooling, and focal nodular hyperplasia.
When angiogram, scan, and laparotomy were performed on 118 patients
with a mixed group of liver lesions, the angiograms demonstrated the dis-
ease in 93 per cent of the patients and were accurate regarding the specific
749, 75 °
location and number of lesions in 69 per cent. Unfortunately, some
tumors have only slightly altered neovascularity, in which case this tech-
nique loses some of its accuracy.
Other Diagnostic Methods. Blind needle biopsy is 65 to 75 per
cent accurate in detecting metastatic liver tumors. However, this technique
cannot be used in many instances (coagulopathies, vascular tumors, portal
hypertension), and it does not demonstrate the extent of liver involvement.
Thin-walled, fine needle biopsy has been advocated recently for palpable
nodules. 731 It should be kept in mind, however, that occasionally the hepa-
tic lesions are very vascular, and deaths due to intra-abdominal hemorrhage
"'
following needle biopsy have been reported. 7 2

Peritoneoscopy can be helpful in establishing the diagnosis and evaluat-
ing the operability in patients with metastatic disease, primarily by dif-
ferentiating between single and multiple nodules. In addition, a biopsying
needle can be guided to a focus of obvious tumor under direct con-
738- 75:1 '
54
trol
TREATMENT
Surgery
Surgery is the treatment of choice for isolated colorectal hepatic metasta-

sis. Since colorectal cancer metastasizes preferentially to the liver, familiar-
ity w'ith liver resection techniques is an absolute prerequisite. In institu-
tions in which these procedures are well established, the results are
encouraging. Reports by Foster,409 Wilson and Adson,410 Fortner, 411 and
412
Attiyeh et al. contain cases in which five-year relapse-free survival was
obtained by surge ry for hepatic metastases.
The number of patients who qualify for resectional therapy are only a
fraction of those with metastatic disease, but this number in such a com-
mon malignancy is probably greater than might be suggested initially. For
instance, Raben 755 studied 818 patients at the Royal Marsden Hospital who
underwent operation for cancer of the gastrointestinal tract. Of these pa-
tients, 186 (23 per cent) had hepatic metastases, and 42 (5 per cent)had
metastases that were judged to be resectable on the basis of solitary metas-
tasis or multiple metastases confined to one lobe. He concluded that about
1 inevery 20 patients operated on for cancer of the gastrointestinal tract
has technically resectable hepatic metastases. In the study of Jaffe et al. 730
of 390 patients with liver metastases, 173 had metastatic lesions that could
be located; they found 56 with solitary nodules and 45 with multiple nod-
ules confined to one lobe. Ozarda and Pickren 756 found only four in-
stances of solitary liver metastasis in 150 autopsies of patients who had
liver involvement with secondary carcinoma. However, in an additional 30
patients, multiple nodules were confined to one lobe of the liver. Metastat-
ic cancer was confined to the liver in only 11 patients, but these autopsy
cases were obviously very late in the course of disease. Thus, it is likely
that any practitioner with a reasonable exposure to colorectal malignancies
will find both synchronous and metachronous metastases amenable to sur-
gical resection.
In their excellent monograph, Foster and Berman 740 updated their origi-
nal survey of the surgical literature for cancer metastatic to the liver. When
operative mortality was excluded in 109 patients with metastatic colorectal
cancer, 48 per cent were alive two years after liver resection and 22 per
cent were alive after five years. In reviewing 127 patients with metastases
of all kinds, including colorectal cancer, there seemed to be little differ-
ence in results when were performed on synchronous lesions,
resections
those that appeared less than two years after operation for the primary le-
sion, or those that appeared more than two years after resection of the pri-
mary lesion, although the numbers are too small to make valid statistical
comparisons. However, these data lend support to the concept that surgery
should be considered for lesions that fulfill criteria for resectability no mat-
ter when they appear.
Radiation Therapy
Many groups have attempted to palliate liver metastases with external

beam radiation, and the results have been moderately successful. A small
number of patients in every series have terminal disease on presentation,
and die during the planned course of radiation. However, of those who
complete therapy (2000 to 3500 rad over two to four weeks), at least 70 per
cent achieve significant pain relief (Table 9-32), about 50 per cent have
improvement of liver function tests, 759-762 and most have improvement of
constitutional symptoms (anorexia, weakness, fever). 757 Megavoltage thera-
py, using opposing anteroposterior and posteroanterior fields to the whole
liver, appears to be indicated for symptomatic relief, particularly of carcino-
matous metastases. When doses to the whole liver (2500 rad over three
weeks to 3000 rad over four weeks) are used, radiation hepatitis is rarely
seen in this group of patients whose survival is usually less than six
TABLE 9-32. Pain Relief by Radiation To Liver Metastases
Author Year No. Pts. No. Decreased Pain (%)
Phillips ei al. 1954 757 36 26/30 (87)

Guttman 1955 758 15 11/15(73)
Turek-Maischeder and Kazem 1975™ 11 8/11 (73)
Prasad ei al. 1977 760 27 19/27 (70)
76 2
Langdon x 97 8 11 8/11 (73)
months. The Radiation Therapy Oncology Group is currently piloting a

study of various dosage schedules. 763
Our impression is that radiation therapy may provide significant pallia-
tion for the pain caused by liver metastases. Survival has been prolonged
rarely.
Chemotherapy
Appropriate systemic chemotherapy for colorectal malignancies and other

lesions is discussed elsewhere in this volume. The alternative method of
treatment when disease is confined to the liver is regional chemotherapy.
The delivery of chemotherapeutic agents directly to the liver was pio-
neered by Klopp et al. 704 in 1950 and popularized by Sullivan and Zurek 705 in
1959. Since the 1950s, numerous clinical series of arterial infusions have
been reported. Initial studies involved the placement of the catheter by
various routes with either intra-aortic or intra-arterial infusions of 5-
fluorouracil for various periods, usually not exceeding 10 to 14
"
days. 711,764 766 Several dramatic results were obtained. Anderson et al. 716
reported the complete disappearance of hepatic malignancy with this thera-
767
py. Earle et al. reported favorable responses of an insulin-secreting islet
cell carcinoma of the pancreas and a squamous cell carcinoma of the lung
producing pseudoparathyroid hormone; both were metastatic to the liver.
In these instances, regression could be well monitored by assaying de-
creased serum levels of the endocrine products. One of the largest series of
patients so treated is the group reported by Ansfield et al. 712 Of 113 patients
studied, 61 per cent had objective improvements with a median survival
time of 8.7 months. Of the 39 per cent that failed to respond, the median
survival time was 2.5 months.
The rationale supporting continuous intrahepatic artery infusion of 5-FU
is compelling. Very large doses of the chemotherapeutic agent can be in-
fused into the target organ with minimal toxicity. Doses as high as 12 to 16
mg/kg/day can often be tolerated for weeks with manageable leukopenia
and virtually no other side effects. Continuous infusion of chemotherapeu-
tic agents would appear to offer the greatest chance of delivering a high
dose of drug to the hepatic neoplasm. In addition, since 5-FU must be

metabolized to be active, it may be possible to achieve a higher concentra-
tion of the active metabolites inside the cancer cells by giving the liver a
high concentration of drug.
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Unfortunately, no one has completed a good randomized trial directly

comparing systemic chemotherapy with that given by continuous hepatic ar-
tery infusion. Historic controls are inadequate to compare results accurately
with the two methods of therapy. Nevertheless, clinicians must base cur-
rent treatment decisions on those often inadequate and variable compari-
sons. In addition, value judgments about the relative morbidity and the
acceptability of regional approachesneed to be considered.
Table 9-33 summarizes the published experiences of 11 institutions with
hepatic artery infusion for colorectal cancer metastases, administered either
continuously or as an initial short induction course followed by systemic
"4
therapy. 70 *- 711_713, 768 Other regional approaches such as umbilical vein
or portal vein infusion are not listed because they have not been found to
be superior to hepatic artery infusions. ""^ 77fi The largest experience with
hepatic artery infusion comes from the Lahey Clinic, with the reported re-
sponse rates varying between 58 and 73 per cent. Overall, 54 per cent of
the patients summarized in Table 9-33 were said to have an objective re-
sponse. Thus, hepatic artery infusion chemotherapy appears to achieve
about twice as many objective responses as the best available single-agent
systemic treatment. This yields an improved survival rate for the group as a
whole, since patients with an objective response appear to survive two to
three times longer than those who fail to achieve a response to treatment.
One problem in asses si mi these results relates to the timing of hepatic
artery therapy. In most cases it was given as the initial treatment, but in the
study of Buroker et al.. 774 it was used only after systemic 5-FU chemothera-
py had failed. Indeed, they were able to achieve a 35 per cent response
rate with FUDR in patients who had already failed 5-FU therapy, and the
survival of responding patients was still comparable to that in other sen
in which 5-FU was initially given by hepatic artery infusion.
The UCLA Experience with Continuous 5-FU Intra-Arterial In-
fusion. Because of the reports in the literature, and our favorable results
with infusion therapy for unresectable primary liver cancer, we have treat-
ed 25 patients with hepatic metastases using continuous infusion of 5-FU.
Our operative mortality rate has been zero, and the complications have
been acceptable. Because the duration of infusion is. in our experience,
much greater when the cathether is placed operatively, we have surgically
inserted the catheters in most patients.
The operative technique was similar in all patients. At laparotomy, the main
hepatic artery was isolated within the portal triad, and a Silastic tube was
inserted distal to the gastric duodenal artery. This was secured with circum-
ferential ligatures of nonabsorbable suture material (Tevdeck), and the artery
was divided proximally. Elective cholecystectomy was performed on the first
two patients, but it has not been necessary to continue this procedure. A
catheter was brought out through a stab wound incision in the left upper
quadrant, and a slight redundancy of the tubing was left in the abdomen to
prevent dislodgment from inadvertent traction on the tubing. The tube was
fixed to the abdominal wall internally and externally, and saline infusion was
begun immediately with a batten -driven Sigmamotor pump (Sigmamotor
Corp. Littleport. New York'; 5-FU infusion was usually begun on the third
or fourth postoperative day.
332 II / Treatment] of Specific Neoplasms
TABLE 9-34. Continuous 5-FU Infusion of the Hepatic Artery for

Unresectable Metastatic Colon Cancer: UCLA Experience
Survival After
HAI Initiated
Ace Days Infused (Months)
57 120 32
60 30 26 (Living)
39 60 23
52 180 22 (Living)
73 45 18
41 180 18
60 75 17
64 135 17
68 30 12
53 120 12
72 15 11
64 30 9°
60 15 9
44 60 8
63 120 8 (Living)
46 15 6
82 30 6 (Living)
63 150 5
67 15 4
72 120 4
56 30 3
63 30 2
47 45 2
66 30 2
61 30 (HAI in progress) 1 (Living)
"Median survival after HAI — 25 patients, 9 months.
The Sigmamotor pump is a battery-powered, continually running, low

flow infusion pump that is compact, quiet, and reliable. The reservoir holds
about 110 ml, which usually sufficient for 2.5 to 3 days of infusion with-
is
out refilling. It is usually worn in a cloth, slinglike holster above the belt,
or in a belt of the patient's design.
5-FU was begun at 8 mg/kg/day in dosages gradually increased to toler-
ance levels. The average dose was 10 mg/kg/day, ranging from 2.5 to 14
mg/kg/day. Relative leukopenia was noted in all patients, and saline was
substituted for 5-FU when the white blood cell count dropped below 4000.
All patientshad to have at least one period of medication cessation, after
which therapy could be resumed. Therapy was terminated because of an
occluded catheter in all but one patient. All patients had a temporary wor-
sening of hepatic function following surgery, as shown by conventional
liver function tests. Inevery case hepatic function spontaneously returned
to at least preoperative values within three weeks. Median survival after
continuous 5-FU infusion was begun was found to be nine months, with
two patients alive longer than and two patients alive shorter than the me-
dian survival (Table 9-34).
The patients illustrated in Table 9-35 are remarkable in several respects.
They received systemic 5-FU therapy prior to hepatic artery infusion, and
infusions were begun only after evidence of disease progression was found
TABLE 9-35. Survival in Patients with Progression of

Colorectal Metastases While on Systemic 5-FU
Followed by Hepatic Artery Infusion of 5-FU
Total Survival
From Time of
Duration' of Duration of Survival After Diagnosis of
Systemic 5-FU HAI HAI Metastases
Age (Months) Months) (Months) (Months)
60 27 1 26 58 (Living]
52 17 6 22 39 (Living)
60 13 3 17 32
64 18 5 17 40
64 16 1 9 48
60 6 1 9 19
63 18 4 8 19 (Living)
46 4 1 6 11
63 19 5 5 38
56 30 1 3 55
66 17 1 2 20
61 6 1 1 33 (Li\i
Median survival after HAI— 12 patients, 8 to 9 months.
while they were receiving systemic treatment. From the duration ot sys-
temic 5-FU administration noted in the second column, it is clear that most
of these patients had an excellent response to this drug. Yet, as noted in the
third column, an excellent prolongation of survival was obtained after the
administration of 5-FU by the hepatic artery, and the total survival from the
time of diagnosis of metastasis, noted in the last column, was excellent. In
this small series of patients, it is likely that patient selection factors iden-
tified those who had a good biologic response to 5-FU therapy. Nonethe-
less, it is of interest to note that these patients did very well after the same
drug was given as regional rather than systemic chemotherapy. In addition,
the symptomatic palliation, along with the sense of well-being, mainte-
nance of weight, and ability to perform the activities of daily living, was
quite good, and many were able to continue to work and have a productive
existence up to the time shortly before their demise.
Complications of continuous hepatic artery infusion are listed in Table
9-36. The operative mortality rate has been zero, and no deaths have been
TABLE 9-36. Complications Observed in 38 Cases of Hepatic

Artery Infusion for Neoplasms of the Liver
Complication Per Cent
Nausea, vomiting 36*7

Fatigue 34 cr
Anorexia 29%
Epigastric pain (during infusion) 26*7
Stomatitis 16%
Leukopenia 16%
Bleeding 13 r r
Anxiety 139c
~c
Sepsis 'c
caused by treatment toxicity or catheter malfunction. All deaths have been

from the eventual progression of disease.
Until a randomized study of systemic 5-FU and infusional therapy is un-
dertaken, the benefits derived from regional chemotherapy as opposed to
conventional therapy are not evaluable. In most cases, systemic 5-FU or
experimental chemotherapy is initiated when patients present with in-
operable metastatic disease. However, in cases in which the diagnosis of
metastatic liver involvement is made at the time of exploratory laparotomy,
we place an hepatic artery catheter during the operation and initiate long-
term continuous 5-FU by this route. Patients who fail systemic chemotherapy
and who are willing and able to undergo hepatic artery infusion may be
initially treated with a catheter placed percutaneously by the Seldinger
technique or they may be candidates for intraoperative placement, as dis-
cussed previously. In either case, hepatic artery infusion should not be
undertaken unless an experienced team of physicians and nurses is available
to manage the potential problems of this technique and the patient is fully
informed.
Section 9
Carcinoma of the
Gallbladder
INTRODUCTION
Carcinoma of the gallbladder an almost invariably fatal disease, primar-

is
ily affecting elderly females (ratio of female to male = 5:1). Approximately

6000 patients are afflicted annually in the United States, and the frequency
of this carcinoma in autopsy series has ranged from 0.2 to 1 per cent. 777
Gallbladder cancer almost always occurs in the presence of gallstones.
Indirect evidence linking gallstones and cancer of the gallbladder includes
studies that report a negligible incidence of this form of cancer in those
populations that rarely harbor gallstones, such as the Bantu. However, pop-
ulations with an extremely high occurrence of cholelithiasis, such as the
American Indians, exhibit carcinoma of the gallbladder as the most fre-
quent malignant neoplasm at postmortem examinations; it has been report-
ed in up to 25 per cent of all cancers detected. 778 Despite this clear associa-
tion of the occurrence of gallstones in patients with carcinoma of the
gallbladder, the incidence of gallbladder cancer is relatively low in the
total population of patients with cholelithiasis (0.66 per cent in one
series). 779
NATURAL HISTORY
Pathology
Histologically, cancer of the gallbladder is almost always adenocarcino-
ma. It advances through submucosal lymphatics into the expected lymphat-

ic centers, including cystic duct nodes, pericholedochal nodes, and superior
pancreaticoduodenal nodes. Direct extension is common, and distant metas-

780
tases, particularly in the abdomen, are not infrequent. Survival is rare,
even when small foci are found in gallbladders at exploration for other dis-
eases. In a report from the Mayo Clinic, the median survival time found in
114 patients after histologic proof of unresectable disease was only 2.5
months.
symptoms of gallbladder cancer

Initial are usually those of cholecystitis
and cholelithiasis. Right upper quadrant pain, anorexia, nausea, vomiting,
and weight loss are frequently observed. In patients with common duct
obstruction, an elevated serum alkaline phosphatase level and obstructive
jaundice may occur. Calcification of the wall of the gallbladder may indi-
cate the presence of carcinoma. Any change symptomatology,
in pre-existing
particularly an increase in the severity or duration of pain, should alert the
clinician to the possibility of carcinoma of the gallbladder.
TREATMENT
The carcinoma of the gallbladder are notoriously
results of therapy for
poor. 781 The only possibility for cure
is surgical excision. If only local inva-
sion is noted, partial hepatectomy should be performed. Piehler and Crich-

low 782 recently reported clinical records of 48 patients with primary carcino-
ma of the gallbladder. Eleven were resectable, and one survived five years.
Two died before five years without evidence of recurrence, and the re-
mainder died with locally recurrent tumor. They emphasize that wedge re-
section of the liver and regional 1\ mphadenectomy in addition to cholecys-
tectomy are theoretically advantageous and should be performed in the
case of resectable tumors, even if reoperation is required.
Cancer of the gallbladder is so strongly linked to cholelithiasis that the
advisability of elective cholecystectomy to prevent this virulent cancer is
frequently discussed. Indeed, recently Blalock, 785 after the analysis of 15
cases, advocated prophylactic cholecystectomy in good-risk surgical pa-
tients. However, the tremendous number of patients in clinical and autopsy
series would lead one away from this conclusion. It must be remembered
that carcinoma of the gallbladder is unusual when one considers the many
patients with cholelithiasis. Its rare occurrence, as low as 0.66 per cent,
argues against prophylactic surgery. Of 526 patients with known gallstones
followed for as long as 20 years by Lund, 786 only three cancers developed.
However, symptomatic patients should be certainly operated upon, particu-
larly when symptoms, however subtle, are worsening.
In a retrospective study, Treadwell and Hardin, 783 compared 26 gallblad-
der cancer patients who were treated surgically with 15 patients who re-
ceived additional adjuvant therapy (3 received radiation, 6 received chemo-
therapy, 6 received both radiation and chemotherapy). Radiation doses
were generally 3000 to 4500 rad. It was seen that patients with widespread
disease survived longer when given adjuvant therapy. None of those with
apparently localized disease who received surgery alone died of cancer
more than one year after operation, but in the adjuvant group, four of the
five one-year survivors later died of cancer. This may also indicate prolon-
gation of survival by adjuvant therapy (delaying recurrence until after one
year). Smoron 784 treated six patients with gallbladder carcinoma with radia-
tion (approximately 4500 rad over five weeks to a small field). Only one of
five symptomatic patients improved. The sixth patient, however, was treat-
ed "prophylactically" after total surgical removal, and this patient was alive
and well six years later. Aggressive adjuvant therapy may deserve further
evaluation in gallbladder carcinoma.
Section 10
Extrahepatic Bile Ducts
INTRODUCTION
Carcinoma of the extrahepatic been considered a relatively
bile ducts has
infrequent disease, with the autopsy frequency ranging between 0.01 and
0.46 per cent. 787 Neibling and his colleagues 788 reported 41 cases of bile
duct cancer out of 14,000 biliary tract operations at the Mayo Clinic from
1937 to 1946, an incidence of 0.3 per cent. More recently, Kuwayti and his
associates 789 described 63 cases out of a total of 24,029 autopsy records, an
incidence of 0.26 per cent. Goldenberg 790 noted an incidence of 1.8 per
cent in biliary tract operations performed during a 24-year period. An es-
timated 4500 new cases of bile duct carcinoma are expected in this country
during the present year — an incidence comparable to that anticipated for
new cases of carcinoma of the tongue. 791
Most patients with disease are in the sixth and seventh decades of life. 3
The sex ratio has varied, but the incidence generally is about 5 men to
every 2 women afflicted.
Although the etiology of bile duct carcinoma remains unknown, many
authors have speculated on the importance of gallstones as a possible etio-
logic factor. However, the relationship of gallstones to bile duct cancer has
always been far less impressive than the relatively high incidence of gall-
stones observed in patients with carcinoma of the gallbladder. For example,
Jones 792 reported gallstones coexisting with gallbladder carcinoma in 65 to
88 per cent of patients in the series he reviewed, whereas Stewart and
associates 793 reported only a 20 per cent incidence of patients with bile
duct carcinoma who also had gallstones. In the 416 cases of bile duct can-
cer collected by Sako and his colleagues, 794 161, or 39 per cent, had stones
either in the gallbladder or in the bile ducts. Of 103 patients reported by
Ross et al., 795 31 were known to have had gallstones.
796
Bile duct carcinoma has also been associated with ulcerative colitis,
797
infection with Clonorchis sinensis, congenital anomalies such as polycys-
tic disease or congenital hepatic fibrosis, which may slow the flow of
bile,
798
or the conversion of environmental agents commonly detoxified
in the liver — such as bile acids and deoxycholic acid — to form carcin-
798
ogens. Although it has not been confirmed, it seems likely that an inflam-
matory reaction in the duct wall, when combined with the presence of bile,
may create an appropriate environment for the development of a malignant
tumor.
NATURAL HISTORY
Classification
Malignant neoplasms of the bile ducts can be divided into three types:
(1) local or nodular, (2) diffuse, and (3) papillary.
Local tumors have been described as measuring approximately 2 cm
in diameter and usually consisting of an anular, constricting, grayish-white
lesion. The duct is generally distended above the tumor and collapsed dis-
tal to it. Diffuse growths produce extensive thickening of the entire duct
with resultant constriction of the lumen. The duct is often converted to a

firm, rigid tube that can easily be confused with sclerosing cholangitis or a
benign stricture. 798 A single, prominent tumor mass may not be present.
Depending on its primary site and size, any tumor of this type may ex-
tend from the hilus into the liver parenchyma. The diffuse tumor, without a
specific tumor nodule but generalized, dense, fibrotic thickening of the
duct wall, may be particularly confusing and can make a biopsy of the
tumor difficult. 799 The papillary tumor that projects into the lumen of the duct
is usually readily identified when the thickened duct is opened. Such a
tumor frequently involves multiple areas of the duct mucosa and may be
quite extensive.
On histologic examination, these tumors are almost always found to be
various types of adenocarcinoma. The histologic type generally correlates
with the gross characteristics of the tumor, ranging from poorly differentiat-
ed to well differentiated. The diffusely fibrotic tumor shows a dense scle-
rotic fibrotic adenocarcinoma, and the grossly nodular tumor is identifiable
as papillary adenocarcinoma.
These tumors metastasize to the liver and to regional lymph nodes in the
hepatoduodenal ligament. Kuwayti et al. 789 reported metastases or direct
spread in 71.4 per cent of their 63 cases. Extension or metastases to the
liver, lymph nodes, pancreas, gastrohepatic lymph, or mediastinum oc-
curred in about 50 per cent of the cases reported by Stewart et al. 79:{ Fre-
quent invasion of the regional nerve plexus has also been noted.
The cause of death is usually liver failure or infection. The median sur-
vival time after proof of unresectability in 59 patients was 5 months with a
mean of 7.2 months at the Mayo Clinic. 800
The principal signs and symptoms are those of obstructive jaundice, but
there are unfortunately no unique clinical features that will specifically
identify a malignant bile duct tumor. Sako et al. 794 described jaundice in 90
per cent of their parents, usually occurring within four months before ad-
mission and becoming progressively more severe. Occasionally, a history of
mild postprandial epigastric discomfort, which occurred approximately two
months before the onset of jaundice, can be obtained in retrospect. Pain is
present in about one third of patients and is the second most noticed symp-
tom. Often, severe persistent pruritus is the most distressing symptom for
the patient. The combination of anorexia and weight loss generally appear
as the disease progresses. Other signs and symptoms include clay-colored
stools, weakness, fever, diarrhea, and chills.
Laboratory studies generally reveal elevated alkaline phosphatase and
serum bilirubin levels, anemia, and leukocytosis.
In the face of a markedly elevated serum bilirubin level, the usual oral
and intravenous cholangiograms are of no value. A most valuable diagnostic
test has been percutaneous transhepatic cholangiography. At UCLA, this
test has been successful in demonstrating the intrahepatic biliary system in
100 per cent of patients whose ducts were obstructed and in 60 per cent of
those patients with nonobstructed intrahepatic biliary systems. 791 The meth-
odology of this procedure has been well described. 801,802
The endoscopic retrograde choledochopancreatography is a diagnostic
technique that will assist in establishing a definitive diagnosis in certain
cases of obstructive jaundice. It is possible for skilled endoscopists to can-
nulate the papilla vater and visualize radiographically the bile ducts or the
pancreatic duct in 75 to 95 per cent of cases. In a series of 146 patients,
duodenoscopy was successfully performed in 144 patients, the papilla of Vater
was located in 140 patients, and the ampulla was cannulated in 114 pa-
tients. The definitive diagnosis was established in 109 patients, and useful
information was obtained in an additional 11 patients. 803 We feel that the
use of endoscopic retrograde choledochopancreatography is indicated in
cases in which the etiology of jaundice cannot be determined. If cannulation
of the papilla is unsuccessful and the ductal system cannot be adequately
visualized, percutaneous transhepatic cholangiography is performed. 804
TREATMENT
Surgery
The hope for cure and significant palliation of bile duct cancer has rested
to date almost exclusively in the hands of the surgeon. At the time of sur-
gery, the first problem is to locate the site of obstruction and identify the
true nature of the lesion.
The bile duct is conventionally divided into three general areas: (1) the
upper region, including the left and right hepatic ducts, the confluence,
and the common hepatic duct; (2) the common duct from the region of the
cystic duct to the pancreas; and (3) the intrapancreatic portion of the com-
mon duct not included in the papilla of Vater. When the tumor has been
visualized and the biopsy specimen procured, the extent of the tumor must
be assessed. Endoscopic examination at the time of surgery using choledo-
choscopy, as reported by Tompkins et al., 808 may demonstrate widely scat-
tered multicentric intraductal tumor growths in patients who otherwise
might be considered resectable.
Less than 20 per cent of upper lesions are resectable. The most frequent-
ly performed procedure is dilation at the site of obstruction and intubation
of the ducts above and below the tumor, usually with a T-tube. Terblanche
806
et al. have reported their experience with 21 cases of carcinoma in the
upper third region and describe their adaption of the U-tube technique for the
palliation of malignant biliary obstruction. With the aid of a dilator, one
end of the U-tube is passed through the tumor into the right or left hepatic
ductal system and is forced through the liver parenchyma, the surface of
the liver, and a stab wound in the anterior abdominal wall. The common
bile duct is tailored around the middle of the tube, and then the other end
of the tube is also brought to the outside through the abdominal wall.
Tumors of the middle region of the ductal system are treated, when pos-
sible, by excision and duct-enteric biliary bypass. Hepatic resection and
cholangiojejunostomy might be necessary.
Tumors that are located in the intrapancreatic portion of the common
ducts are generally grouped with the periampullary tumors. When possible,
these are resected by pancreaticoduodenectomy. An excellent illustrated re-
view of surgery of the hepatic ducts has been assembled by Longmire, 791
including significant contributions of other surgeons in this field. 799, 807_8n
812
Andersson have recently reported a series of 76 patients with
et al.
cancer of the extrahepatic bile ducts. In lesions located above the ampulla
was 6.8 months after palliative bypass, as compared
of Vater, survival time
with a median of 23 months after resection. 812 Iwasaki et al. 813 operated on
14 patients with carcinoma of the extrahepatic biliary system and per-
formed curative resection in 9 of them; 6 of these patients are still alive
after a follow-up of 5 to 25 months.
II / Treatment of Specific Neoplasms
340
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Radiation Therapy
For carcinomas of the biliary system, several authors have noted good
palliation of obstructive jaundice and pain by small-field (less than 10 x 10
cm), moderate dose (4500 to 5000 rad) megavoltage radiation to the site of
obstruction. At least 50 per cent of patients appear to have temporary im-
provement from this well-tolerated course. Green et al. 814 noted similar pal-
liation regardless of whether or not a T-tube had been placed prior to radia-
tion. The summary of the data suggests that external beam radiation may
well have a role in the palliation of tumors of the biliary system (Table
9-37). Of interest is a report from Japan 816 of a series of eight patients who
received intraoperative radiation (3000 rad with 11 to 18 MeV electrons to *£
10 cm cone) for carcinoma of the bile duct or gallbladder, and these patients
also had some relief of obstructive jaundice.
Chemotherapy
Although the majority of cytotoxic agents have not received an adequate

trial in this group of tumors, the published experience thus far leaves little
room for optimism. Table 9-38 summarizes the results of trials known to
us 8i7, 83o Mitomycin-C appears to be the only active single agent, and com-
bination chemotherapy is not evaluable. Even with an objective response,
however, the duration of response is minimal. We conclude that chemo-
therapy currently holds little promise for useful palliation in this group
of patients; therefore, we usually recommend experimental approaches
to chemotherapy for patients with unresectable disease who wish active
therapy.
TABLE 9-38. Chemotherapy of Carcinoma of the Gallbladder

and Extrahepatic Biliary System
No. Respov 5ES/ Response

Agent No. Selected Patients Rate (%) Reference
Single Agents
Mitomycin-C 7/15 47 817
5-Fluorouracil 3/62 5 818-821
BCXL 2/4 — 818
MeCCNU 1/4 — 822, 823
CCM 0/4 _ 822
DTIC 1/3 _ 824
Streptozotocin 0/3 — 818
Doxorubicin 0/2 — 825, 826
Cyclophosphamide 1/1 - 827
Combinations
FU, DTIC, VCR, BCM 2/2 _ 828
BCNU, MMC 1/2 _ 818
BCNU, VCR 0/3 _ 829
FU, MMC 0/2 — 818
FU, MMC, ara-C 0/5 - 830
"Abbreviations: DTIC, dacarbazine; FU, 5-fluorouracil; VCR. vincristine; MMC. mitomycin-C; ara-C,
cytarabine.

Combined or adjunctive therapy is clearly necessary to improve the cur-
rent results of surgical therapy, although few such studies have been con-
ducted. The recent review of Kopelson et al.
831
describes the current status
of such efforts.
Section 11
Ampulla ofVater
INTRODUCTION
Carcinoma of the ampulla of Vater is an uncommon neoplasm that mim-
ics lesions such as distal common duct carcinomas and, to some extent,
carcinoma of the pancreas. Because it has different pathologic features than
these diseases, and because its prognosis after excision at surgery is infin-
itely better than the other lesions, it is discussed singly here. The etiology,
and indeed even the exact incidence, of these tumors is unknown.
NATURAL HISTORY
Classification
These carcinomas may be quite similar carcinomas in the

in histology to
periampullar regions of the common duct, duodenum, and pancreas. Usual-
ly, they are soft and polypoid and can be confused grossly with a benign
lesion. The surface frequently is necrotic and may be ulcerated. Microscop-

ic architecture is papillary in about 50 per cent of these tumors. Occasion-
ally, infiltrating, mucous producing, and undifferentiated adenocarcinomas
are seen.
The spread of ampulla carcinoma is by local infiltration into the walls of
the adjacent common duodenum, and the
ducts, the second portion of the
head of the pancreas. With more extensive local spread, the portal and
splenic veins may be involved, and secondary thrombosis of these vessels
may occur. Local nodal metastases are demonstrable in about one patient in
four at the time of surgical diagnosis. The course is often indolent, and the
survival time in unresectable disease is often greater than one year after
" 834
diagnosis. 832
Symptoms of periampullar carcinoma are similar to those seen with ob-

structive lesions in other parts of the extrahepatic biliary duct — especially
the lower common duct. Obstructive jaundice and pain are the most com-
mon symptoms, followed by constitutional findings such as weight loss,
nausea, and chills. Anemia is frequent.
Diagnosis of this lesion is similar to the diagnostic work-up outlined in
the sections on Cancer of the Pancreas and Cancer of the Extrahepatic Bili-
ary Ducts. Hypotonic duodenography, flexible endoscopy with examination
of the duodenum and ampulla, and transhepatic percutaneous cholangiog-
raphy are the tests most likely to produce the diagnosis, and they are used
in that order.
TREATMENT
Surgery
important to realize that because of the usual low grade of malignan-

It is
cy in these tumors and the early symptoms of small lesions because of their
location, the results following surgery are much better than with any other
malignancy in this area. Pancreaticoduodenectomy is the treatment of
choice, and there are generally fewer technical problems when this proce-
dure is performed for carcinoma of the ampulla of Vater than when it is
performed for carcinoma of the duodenum or pancreas, which tend to be
more locally invasive. In a collected series of 370 cases of pancreaticoduo-
denectomy for ampullary carcinoma, the death rate was 24 per cent. 881,835
Cure rates of 30 to 35 per cent are reasonable expectations. Excellent re-
cent reviews have been published by Wise et al., 838 Akwari et al., s:!T and
838
Stephenson et al.
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CHAPTER 10
GENITOURINARY
NEOPLASMS
Section 1
Cancer of the Prostate

Jean B deKernion
INTRODUCTION
Prostate cancer is peak incidence in patients
a disease of the aged, with a
between 60 and 70 years of age. The natural history of the tumor is poorly
understood and quite variable. Autopsy studies have reported occult carci-
noma of the prostate in as many as 40 per cent of patients over the age of
70 years. Furthermore, the aggressiveness of the tumor varies greatly;
1
many are extremely slow growing and indolent, prompting a therapeutic

nihilism on the assumption that the patient will usually succumb to other
illnesses. Although certain tumors display prolonged latent periods and
very long tumor doubling times, the true malignant potential of the tumor
cannot be understated.
Cancer of the prostate is the second most common cause of death in
American males. In 1974, 12 men per 100,000 population died of this type
of cancer in the United States, and the incidence of new diagnosis was 3
per 100,000. Approximately 55,000 new cases of cancer of the prostate were
diagnosed in 1977. 2
358
10 / Genitourinary Neoplasms 359
NATURAL HISTORY
is detected either by unsuspected tumor found in a

Early prostate cancer
transurethral resection specimen or by routine rectal examination that leads
to the discovery of a nodule or mass in the gland. The tumor in the early
stages usually presents no symptoms, and early detection depends on rou-
tine, periodic, thorough rectal examination in men over 40 years of age.
Symptoms are generally not apparent until the tumor is far advanced, at
which time there may be urethral obstruction, pelvic pain, or pain from
distant metastases. P itients with stage A tumors (definitions to be given)
usually present with symptoms secondary to benign prostatic hypertrophy.
Occasionally, the rapid onset of symptoms of prostatism may indicate a rap-
idly growing undifferentiated stage A2 tumor, which can be detected only
by awareness of this presentation.
A biopsy of every suspected prostatic mass is essential. The most widely
employed method in the United States is needle biopsy, either transperin-
eally or transrectal ly. The diagnosis can be established with a high degree
of accuracy (approximately 80 per cent), and major complications such as
"
hemorrhage, sepsis, and abscess formation are rare. 3 5 Accuracy depends
upon the skill of the urologist and the size of the lesion; most false-
negative biopsies occur in lesions that are smaller than 0.5 cm. 6 Open biop-
sy through a perineal incision is the most accurate method (96 per cent) but
may be associated with impotency and other complications of perineal sur-
7
gery'. Transurethral biopsy with the resectoscope is usually not as accurate
as other approaches. When needle biopsies have failed to provide a diagno-
sis in the patient who clinically has a prostate cancer, vigorous transure-
thral resection of the suspected area may establish the diagnosis.
Cytologic examination of percutaneous needle aspiration specimens is a
popular diagnostic tool in some European countries. The use of the modi-
fied Franzen needle is now the diagnostic method of choice in some medi-
cal centers. 8 Accuracy seems to be equivalent to that of punch biopsy, per-
haps with fewer complications, 9 but it is dependent upon the skill of the
participating cytologist. The cytologic study of urine and expressed prostat-
ic fluid is positive in as many as 85 per cent of patients with prostate can-
cer. However, this technique adds little to the more standard diagnostic
methods. It has little value as a screening procedure but may be useful as
an adjunctive diagnostic method in certain patients. 10
Various serum factors have been studied as diagnostic tests. The isoen-
zymes of lactic dehydrogenase have been shown to be elevated in the
serum of patients with prostate cancer, specifically, an increased ratio of the
fifth to the first isoenzyme.
11
Grayhack et al. vl found a similar LDH isoen-
zyme pattern in the prostatic fluid of prostate cancer patients. Urinary poly-
amines 15 and carcinoembryonic antigens 14 also have been studied in patients
with carcinoma of the prostate.
The most important serum assay currently in use is the determination of
the serum acid phosphatase level. Until recently, a high degree of correla-
tion was present only in patientswith skeletal metastases: 65 to 92 per cent

of those with known osseous metastases, 30 per cent of those without clini-
cally detectable bone metastases, and 5 to 10 per cent of those with local-
ized primary tumors. 15 The radioimmunoassay recently described by Coo-
per and Foti 16 is more accurate in detecting occult skeletal metastases, and
the serum acid phosphatase level is often elevated in patients with local-
ized prostatic disease. Paulson, 17 in an excellent review of the value of diag-
nostic methods in prostate cancer, reported an elevation of prostatic acid
phosphatase secondary to lymph node invasion. The newer assays for pro-
static acid phosphatase will undoubtedly play an increasingly important
role in the future.
The detection of osseous metastases by routine skeletal survey has been

supplanted by the use of radioactive bone scans. Technetium-99m phos-
phate is most sensitive and is capable of detecting lesions in the absence of
radiographic changes. False-positive results are not uncommon but can
usually be resolved by the comparison of the area of suspicious isotope
uptake with plain radiographs. Increased isotope uptake due to trauma, ar-
thritis, or benign lesions can often be defined in this way.
The measurement of acid phosphatase levels in bone marrow aspirate has
been advocated. Recent studies show conflicting results, and the benefit of
"
this method over other standard assays has not been established. 18 20
An important relationship between prognosis and histologic grade has
been confirmed in recent years. 21 Pool and Thompson 22 related prognosis to
grade alone and showed a decreased five-year survival rate with increased
grade: grade 1, 59.5 per cent; grade 2, 34.1 per cent; grade 3, 16.2 per cent;
and grade 4, 5.6 per cent. A correlation has also been shown between grade
and the incidence of metastases and grade and the extent of tumor. 23 24 '
Gleason et al. 25 used multiple histologic criteria to categorize prostate

tumors into five groups and showed excellent correlation with prognosis.
Clearly, the histologic differentiation of the tumor is an important deter-
minant of treatment planning.
In addition to grading, the stage of prostate cancer has a direct bearing
on survival. Numerous staging classifications have been proposed, but the
most widely accepted is that proposed by Whitmore. 26 This staging system
is outlined in Table 10-1 and closely resembles the stages used by most
centers in the United States. 26, 27 Briefly, these stages are stage A —
tumor
not clinically palpable but detectable in microscopic sections by biopsy or
transurethral resection, stage B — palpable tumor confined to the prostate,
with no distant metastases, stage C — tumor extending beyond the prostatic
capsule, with or without invasion of contiguous organs, but with no distant
metastases, and stage D —
distant metastases. More recent survival data,
however, have prompted further revisions in this basic system, especially
with respect to (1) occult tumors found in prostatic tissue transurethrally
resected for treatment of clinical obstruction due to prostatic hypertrophy,
TABLE 10-1. Staging Systems for Prostate Cancer
Current US Nomenclature
Stage A, Clinically occult carcinoma, well differentiated, focal
Stage A, Clinically occult carcinoma, poorly differentiated, multifocal
Stage B, Palpable tumor, involving less than one lobe
Stage B2 Palpable tumor, involving more than one lobe
Stage C Extraprostatic extension (including seminal vesicles)
Stage D, Metastases confined to pelvis (including positive pelvic nodes)
Stage D 2 Distant metastases
TNM System!
Primary Tumor (T)
T.\ Minimal requirements cannot be met
To No tumor palpable; includes incidental findings of cancer in a biopsy or
operable specimen. Assign all such cases a G, N, or M
category
T, Tumor intracapsular surrounded by normal gland
T 2 Tumor confined to gland, deforming contour and invading capsule, but
lateral sulci and seminal vesicles are not involved
T3 Tumor extends beyond capsule with or without involvement of lateral
sulci or seminal vesicles, or both
T Tumor fixed or involving neighboring structures. Add suffix (m) after "T"
to indicate multiple tumors (e.g., Tan)
Nodal Involvement (N)
NX Minimum requirements cannot be met
N No involvement of regional lymph nodes
N, Involvement of a single regional lymph node
V Involvement of multiple regional lymph nodes
N3 Free space between tumor and fixed pelvic wall mass
N« Involvement of juxtaregional nodes
Distant Metastases (M)
MX .Not assessed
M„ No (known) distant metastases
M> Distant metastases present
Specify
Modified after Whitmore WF, Jr: Am Med

./ 21:697, L956,
*'
tAmericai) Joint Committee for Cancer Staging and End-Result Reporting.
and (2) the appreciation of the importance of tumor size in stage B disease
(Table 10-1).
Stage A carcinoma is clearly a pathologic rather than a clinical diagnosis.
Although it is true that most of these tumors are indeed latent and slow
growing, the potential for metastasizing varies. Correa et al. 28 reported a

relationship between the extent of occult involvement, as well as the de-
gree of undifferentiation, and survival. Diffuse involvement, i.e., multifocal
tumor within the transurethral resection specimen, was usually associated
with poorly differentiated tumors, and the prognosis for these patients was
poor. When only several foci were detected, these tumors were usually
well differentiated and associated with a good prognosis. Other authors
have also reported a poorer prognosis for patients with diffuse or poorly
differentiated clinically occult tumors than for patients with stage B x
lesions. 29 31 It appears that the diffusely infiltrating occult tumor that is in-
"
cidentally discovered at transurethral resection of the prostate is more bio-

logically aggressive than the tumor that is present in one or two foci and is
well differentiated. The diffuse tumors are also associated with a higher
incidence of lymph node metastases.
Many A
tumors follow a more benign course. Hanash et al. i2 report-
stage
ed that the survival rate of 39 patients with well-differentiated stage A
tumors was identical to that of the general population of similar age. Byar
and the Veterans Administration Cooperative Research Group 33 observed
that only 6.8 per cent of patients with stage A focal cancer developed pro-
gressive tumor spread, probably in association with a higher degree of dif-
ferentiation. Therefore, it may be appropriate to subdivide stage A into
stage Ai, to include patients with a focal well-differentiated tumor, and
stage A2 to include multifocal tumors or undifferentiated tumors.
,
Jewett- 7 suggested the subclassification of stage B into stage B, (tumor

involving less than one lobe) and stage B 2 (tumor involving more than one
lobe). The justification of this subdivision was apparent by the difference in
the survival rates between stage B, patients (27 per cent at 15 years) and
stage Bo patients (19 per cent at 15 years). The incidence of lymph node
involvement is likewise significantly higher in patients with stage B 2
tumors. 34 Barzell et al. 35 showed a correlation between the size of the pri-
mary tumor and the incidence of lymph node metastases and survival.
26
Stage C carcinoma, as defined by Whitmore, includes extension through
the prostatic capsule or involvement of the bladder neck or seminal vesi-
cles. prognostic significance of seminal vesicle involvement was em-
The
phasized by Arduino and Glucksman36 who reported an 82 per cent inci-
dence of metastases to the pelvic lymph nodes in patients with seminal
vesicle involvement, without extension to other pelvic structures. Jewett et
al.
37
found no patients who remained tumor free for 15 years after radical
prostatectomy when the seminal vesicles were involved. Stage C carcinoma
is. unfortunately, a more common presenting clinical stage than stage A or
stage B, occurring in approximately 40 to 50 per cent of patients.
Stage D
carcinoma is the most common presenting clinical stage, repre-
senting almost 60 per cent of patients who are newly diagnosed. The most
common sites of involvement are the pelvic lymph nodes and the skeletal
system.
Only in recent years has the significance of lymph node involvement and
the incidence in which it occurs been given appropriate attention. The in-
cidence of lymph node metastases in patients with well-differentiated local-
ized stage A lesions is low, but it appears to be greater in those patients
with poorly differentiated diffuse occult tumors. 34 38 Similarly, the inci-
'
dence of lymph node metastases is higher in patients with clinical stage B 2

lesions than in patients with stage Bj lesions (14 to 45 per cent versus 8 to
20 per cent). 36 Clinical stage C lesions are associated with proven lymph
node metastases in approximately 50 per cent of cases. 39 Therefore, the im-
portance of accurate identification of tumor in the lymph nodes is obvious.
Lymphangiography has not proved to be sufficiently accurate to warrant its
routine use as a staging procedure in prostate cancer. Loening et al.
w cor-
related findings of lymphangiography with node dissection and found a 59
per cent false-positive and a 36 per cent false-negative result. Thus, there is
a need for staging pelvic node dissection in patients with clinical stage B or
stage C tumors.
The TXM
system suggested by the American Joint Committee for Cancer
Staging and End-Result Reporting, 41 listed in Table 10-1, has several ad-
vantages. The importance of the extent of lymph node involvement is re-
flected in the subdivisions of N to N 2 and the extent of metastases is de-
t ,
fined. However, the system suffers from not separating the types of occult,
incidentally diagnosed tumors into those with several foci of well-
differentiatedtumor and those with multifocal undifferentiated tumor. Also,
although T, seems to be equivalent to B l5 and T 2 seems to be equivalent to
B 2 the importance of actual size and extent of tumor is not as explicitly
,
addressed as in the current US

nomenclature. Finally, recent evidence
shows that the volume of tumorthe lymph nodes is a determinant of
in
prognosis rather than simply the number of nodes involved.' 2 Nonethe-
less, an internationally standardized system of staging is vitally important,
and future refinement of the TNM
system should provide an acceptable
alternative to the multiple classifications now in use.
TREATMENT
Surgery and Radiation Therapy
Few malignancies are associated with as much controversy regarding

treatment as that surrounding the therapy for prostate cancer. Since the pio-
neering work of Young, 42 surgery lias been the mainstay of treatment for
yi
this tumor. Flocks et al. later recognized the curative potential of radia-
tion therapy. With the refinement of radiotherapeutic methods and the ad-
vancement of technology in recent years, it has become apparent that this
modality has an important place in the treatment of prostate cancer. At
present, the physician and the patient are presented with data that support
the use of either modality for the treatment of localized tumors.
The exact roles of radiation therapy and surgery in prostate cancer thera-
py have still not been clearly delineated. When a method of treatment is
recommended to the patient, the clinician must also be familiar with the
efficacy, as well as the potential complications, of alternative methods,
since it is his obligation to inform the patient of all possible modes of ther-
apy. The currently available data are presented in this section and a plan of
therapy is outlined.
Endocrine Manipulation
Hormone Therapy. The current understanding of hormonal therapy

for prostate cancer has evolved through extensive research in endocrino-
logy and biochemistry. The Nobel Prize-winning work of Huggins and
Hodges 44 revealed the estrogen dependency of the human prostate gland.
Hypothalamic-pituitary release of luteinizing hormone (LH) is stimulated
by a low circulating testosterone level. The luteinizing hormone stimulates
testosterone synthesis by the testis (Leydig cells), which then exerts a feed-
back on the hypothalamus to decrease LH
production. The adrenal glands
produce a small percentage (5 per cent) of androgens in the form of andros-

tenedione and dehydroepiandrosterone. The principal intracellular andro-
gen is dihydrotestosterone, which is formed by intracellular conversion
from testosterone in the testis by the enzyme 5-alpha reductase. The intra-
cellular effect of the androgen is dependent upon binding with intracellular
receptor protein. 45 It is then obvious that the end point of hormonal therap)
is the influence on the prostate tumor cell at the macromolecular level. Am
mechanism or therapy that blocks any step in the process will produce po-
tentially effective inhibition of the prostate tumor cell. This can be accom-
plished by the inhibition of the release of luteinizing hormone (i.e., by oral
estrogen therapy or by removal of the organs that produce androgen
[orchiectomy or adrenalectomy]) or by agents that interfere with intracellu-
lar androgen activity (cyproterone acetate and flutamide). 46 The most impor-
tant and best-established methods are either orchiectomy or oral estrogen
treatment.
The responsiveness of some tumors to hormonal manipulation has been
firmly established, and prompt relief of symptoms secondary-to hormonal
therapy occurs in the majority of patients with disseminated tumors. How-
ever, several pertinent issues and controversies must be brought into focus
before a clear understanding of the role of hormonal therapy in various
stages of prostate cancer can be achieved.
The first important question is the influence of hormonal therapy on sur-
vival. Although it appears reasonable that treatment that affords marked re-
lief of symptoms may lead to the prolongation of life, considerable con-
troversy still exists. Early studies that were based on historic published
controls showed a significant increase in the survival rate of patients who
were treated with hormonal therapy for advanced prostate cancer versus
those who received no therapy. 47 However, their untreated control popula-
tion was taken from an earlier study, prior to the advent of modern antibiot-
ic therapy and before the wide use of transurethral resection for obstruc-
48
tion. Subsequent studies questioned the effect of estrogens on survival,
but only recent randomized prospective trials have provided reasonable ev-
idence to answer this question. The Veterans Administration Cooperative
Urologic Research Group (VACURG) showed that in patients with stage D
disease, there was no significant increase in the rate of survival with any of
the following: placebo, orchiectomy, 5 mg diethylstilbestrol, or diethylstil-
bestrol plus orchiectomy. The overall survival rate was similar whether pa-
tients received placebo or therapy, suggesting that hormonal manipulation
did not prolong survival. 49 A subsequent study by this same group compar-
ing placebo, 0.2 mg diethylstilbestrol daily, 1 mg diethylstilbestrol daily,
and 5 mg diethylstilbestrol daily revealed that 1 mg was as effective as 5
mg but did not have the associated cardiovascular toxicity, and it also in-
creased the survival rate over the placebo. 30 It therefore appears that there
is a relationship between response and estrogen level. This must be bal-
anced against potential toxicity, and the maximum impact on survivorship

may the identification of groups of patients who are likely to benefit
lie in
from therapy with the least likelihood of cardiovascular complications.
A second major issue with respect to hormonal manipulation is the meth-
od ofhormonal treatment —
specifically oral estrogen therapy versus or-
chiectomy. At present, no firm data exist that show benefit of one method
over the other. Certain advantages of each should be considered and the
selection for the patient individualized. Surgical removal of the hormone-
producing tissue is unquestionably the most certain way of reducing testos-
terone production and serum testosterone levels. 51 Furthermore, the poten-
tial cardiovascular side effects of exogenous estrogen are thereby avoided.
It has been noted that 1 mg estrogen does not uniformly reduce testos-
terone levels to the castration level. 51,52 However, 3 mg estrogen daily ef-
fectively produces anorchid levels, but the potential for cardiovascular com-
plications at this dosage level has not been determined. 52,53 The most
important issue is clinical response, and it is apparent that even the 1 mg
dose, and certainly the 3 mg dose, produces the needed clinical effect.
Since this can be given without known significant cardiac toxicity, orchiec-
tomy is usually not necessary. However, the patient with significant cardiac
disease is probably more safely treated by orchiectomy rather than oral
diethyl stilbestrol.
The major complication cardiogenic problems, in-
of diethylstilbestrol is
cluding cardiac failure and edema. Although propitious use of diuretics

may alleviate some of these problems, patients at high risk for cardiac dis-
ease or aged patients with known cardiac disease should probably be given
estrogens in low doses with caution. Other side effects include those of
feminization, including painful gynecomastia, loss of libido, and impotency.
Gynecomastia can be alleviated by low-dose radiation (300 to 400 rad) to
the breasts prior to institution of therapy. Patients are also at higher risk for
thromboembolic phenomena and should possibly receive daily aspirin, al-
though the efficacy of this has not been proved.
Although the role of hormonal manipulation in patients with stage D can-
cer is undeniable, a third major area of controversy exists as to when the
therapy should be instituted. The current concepts of adjuvant chemothera-
py postulate that systemic therapy is maximally effective at a time when
tumor burden is minimal, such as immediately after prostatectomy. This
would suggest a role for early therapy of metastatic disease. However, ex-
perience with hormonal therapy has shown the contrary. The VA study
demonstrated no increased benefit in the asymptomatic patients with dis-
seminated disease. The delay of onset of therapy until patients developed
symptoms produced a similar survival rate, although the disease-free inter-
val was shortened when estrogen therapy was begun prior to the onset of
symptoms. 49,50 The side effects of estrogen treatment support the concept
that therapy should be withheld until symptoms develop.
debate exists regarding the appropriate therapy for patients with
Little
symptomatic distant metastases. Such patients should receive hormonal
therapy, either by orchiectomy or by oral estrogen therapy. Considerable
debate exists with respect to which method should be offered to the patient
first. The Veterans Administration Cooperative Studies showed that or-
chiectomy had no distinct advantage over the administration of oral diethyl-
stilbestrol, which was similar to the findings of Brendler. 54 We feel, there-
fore, that individualization is important. Each patient is offered
orchiectomy, although this presents an undue psychologic stress to a few

patients. If the patient refuses orchiectomy, oral estrogen therapy is given
(3 mg DES per day). There is recent evidence that patients who fail to
respond to oral estrogen therapy do not benefit from subsequent orchiec-
tomy, 51 and this has been our experience.
Surgical procedures for patients with D, carcinoma are relegated mainly
to transurethral resection of the prostate for obstructive symptoms. Patients
whose symptoms of obstruction are not severe often respond to hormonal
therapy. Those with severe obstruction or partial obstruction refractory to
hormonal therapy should have a palliative transurethral resection to im-
prove the quality of life and to obviate the need for indwelling catheter
drainage. Selected patients with far-advanced medical problems are still oc-
casionally best managed by indwelling catheter drainage. Immediate or-
chiectomy seems to be the treatment of choice for patients with urethral
obstruction due to prostate carcinoma. 55
Adrenalectomy. Since most patients who respond
to hormonal thera-
py undergo a relapse and progressive tumor growth within a variable

period, accelerated adrenal androgen production was postulated as a possi-
ble cause for this seeming hormone unresponsiveness. Adrenalectomy was,
therefore, proposed as further hormonal therapy. The report by Huggins
and Scott56 showed that this seldom produced long-term remissions, al-
though most patients witnessed a brief palliative interval. The mortality
rate was significant, and the prolongation of life was not impressive.
Murphy 57 has shown that patients frequently have subjective improvement,
although long-term regressions are uncommon. He suggests that the opera-
tion may be indicated in young patients who have relapsed after respond-
ing to other forms of hormonal therapy.
Hypophysectomy. Hypophysectomy offers the advantage of ablating
both the adrenal and the testicular production of androgens. Patients who
have not undergone orchiectomy appear to have a reasonable response.
However, those who have failed hormonal therapy, i.e., those in whom hy-
pophysectomy would be most reasonable, have a poor response and have a
very short survival rate after the procedure. This is not surprising, since it
has been shown that relapse on estrogen therapy is not associated with a
rise in circulating plasma androgens. Therefore, one would not expect fur-
ther hormonal therapy to be significantly effective. Transsphenoidal or cryo-
surgical hypophysectomy can produce significant relief of symptoms in
some patients; moreover, morbidity is minimal, and complete destruction of
57
the pituitary gland does not seem to be essential. Hypophysectomy still
has a limited role in the treatment of prostate cancer at this time.
Antiandrogens and Inhiritors of Androgen Synthesis. Spirono-
lactone depresses plasma testosterone levels and plasma androstenedione
and dehydroepiandrosterone levels significantly. 58 Aminoglutethimide in-
hibits the production of cortisone and aldosterone, and reduces plasma
testosterone levels significantly. 53 Other authors 52 failed to demonstrate
significant plasma testosterone depression secondary to this agent. Cy-
proterone acetate interferes with androgen synthesis and produces de-
59
pression in total plasma testosterone levels. xNo significant benefit has
been shown by using agent in the treatment of estrogen-refractory

this
prostate cancer. 60 Similarly, flutamide (Sch 13521) has not shown any ben-
efit over orchiectomy and has not proved to be effective in the management
of estrogen-unresponsive prostate cancer. 61
Chemotherapy
Until recently, the treatment of disseminated prostate cancer with cyto-

toxic drugs has been disappointing. The responsiveness of the tumor to
hormonal therapy discouraged extensive investigation of the use of other
modalities, and patients usually received cytotoxic drugs only in the ter-
minal stage, when all methods of hormonal manipulation had been exhaust-
ed. The lack of response to chemotherapy in such patients is understand-
able. Early reports of response to chemotherapeutic agents were limited to
anecdotal studies of response achieved in a few patients. These studies
generally were not controlled or randomized, and the criteria of response
were not standardized.
The more recent studies reported by the National Prostatic Cancer Proj-
ect have demonstrated significant responsiveness of metastatic prostate can-
cer to certain cytotoxic drugs. Both cyclophosphamide and 5-fluorouracil
produced a greater incidence of objective response in patients who re-
lapsed after initial hormonal therapy than when standard hormonal therapy
was continued. Four of 33 patients treated with 5-FU and 3 of 41 patients
treated with cyclophosphamide had partial tumor regression, whereas none
of 36 patients treated with hormonal manipulation had documented regres-
sion. 57 Schmidt et al. m treated 165 patients with stage D carcinoma who
had tumor progression after previous use of hormonal therapy. They found
an objective response of 24 per cent for cyclophosphamide, 27 per cent for
DTIC, and 13 per cent for procarbazine. Merrin and Beckley reported a
6:5
69 per cent response in 42 patients with estrogen-resistant stage D prostate

cancer treated with cisplatin. White et al. 94 reported an 80 per cent re-
sponse rate in a nonrandomized study of ten patients with stage D cancer
using the combination of cyclophosphamide, doxorubicin, and methotrex-
65
ate. Murphy et a/. randomized patients with progressive metastatic pros-
tate cancer who had previously received extensive radiotherapy to receive
either estramustine phosphate or streptozotocin and compared these results
with results from patients who received hormonal therapy. The latter pa-
tients had a 19 per cent objective response rate, compared with 30 per cent
for those receiving estramustine phosphate and 32 per cent for those re-
ceiving streptozotocin. With respect to multiple parameters of response and
toxicity, estramustine seemed to be the superior agent. Merrin et a/. 66 treat-
ed stage C and stage D patients with a combination of 5-FU plus cyclo-
phosphamide or doxorubicin plus cyclophosphamide. The response rates
were 15 per cent and 25 per cent, respectively.
Several new agents have been introduced that combine a cytotoxic agent
and a hormonal agent. Estramustine phosphate is a combination of estradiol
and mechlorethamine. 67 In patients who are refractory to hormonal therapy,
368 II / Treatment of Specifw Neoplasms
estramustine phosphate produced a 19 per cent objective response rate and

a 36 per cent subjective response rate without hematologic toxicity. 68 As
already noted, in a randomized trial of patients who received extensive ir-
radiation, the response rate to estramustine was 30 per cent. 65 Another che-
mohormonal agent that has recently been studied is prednimustine (Stereo-
cyt, Leo 1031), an ester of chlorambucil and prednisone. This agent has
proved to be effective in human lymphoma 69 and may have use in other
human tumors. Combined with estramustine, the agent produced a 24 per
cent objective response rate and a 44 per cent subjective improvement in
patients with advanced hormone-resistant prostate cancer. 70
The use of the steroid moiety as a carrier for the alkylating agent seems,
therefore, to have rationale not only in animal studies but also in prelimi-
nary human trials. The toxicity is acceptable. Less feminization occurs than
with diethylstilbestrol treatment, and cardiotoxicity does not appear to be a
problem. It seems, therefore, that these agents, especially Estracyt or a
combination of Estracyt and prednimustine, may eventually be indicated
for patients with less advanced disease in lieu of diethylstilbestrol. Fur-
ther trials are necessary, however, before substituting any agent for stand-
ard hormonal therapy as initial treatment for patients with metastases.
Treatment by Stage
Stage A. The decision regarding therapy for stage A tumor should de-
pend upon the extent of tumor involvement and the degree of undifferen-
tiation.
The importance of determining the extent of tumor involvement and the

extent of tumor differentiationwhen incidental tumor is found in the trans-
urethral resection specimen has been emphasized. 71 It is currently our
practice to recommend
multiple transperineal or transrectal needle biopsies
of both lobes of the prostate in such patients. Prostate cancer occurs in the
peripheral posterior glands of the prostate, and a transurethral resection
might simply take the "tip off of the iceberg." Another approach advocated
by McMillen and Wettlaufer 72 involves a second transurethral resection in
such patients three months after the initial procedure. Using this approach,
they found that 26 per cent of patients initially classified as having stage A,
lesions had A 2 lesions. When watchful waiting is advocated in a patient
with a few foci of well-differentiated tumor, the patient must be carefully
followed by rectal examination, biopsy, and acid phosphatase determination
if clinical suspicion is aroused. We have treated several patients with an
original diagnosis of stage A tumor who subsequently developed diffuse,

florid metastases several years later. Another important consideration in
decision-making regarding stage A 2 tumors is the possibility of regional
node metastases. The percentage of positive node involvement in clinical
stage Aj disease is very low, but Varkarakis et al. ri reported positive node
involvement in one of four patients with stage A tumor who underwent
lymphadenectomy. More importantly, the presence of dedifferentiation is
associated with a higher likelihood of nodal metastases (see earlier discus-
sion). The efficacy of radiotherapy for stage A 2 tumors is difficult to assess

time because of the small numbers of patients treated.
at this
Based on this available information, our current plan for patients who are
found to have occult tumor in the prostate is as follows: Patients who have
one or several foci of well-differentiated tumor undergo multiple random
biopsies of the prostate. If these biopsies fail to show tumor, the patient is
classified ashaving stage A, disease and is simply followed carefully with

frequent rectal examinations and repeat needle biopsies, only if indicated
by changes detected by rectal examination. If the repeat biopsy results are
positive and show multifocal disease or less well-differentiated tumor, the
patient is reclassified as having stage A 2 disease. Patients who demonstrate
multifocal disease or poorly differentiated tumor on the original resection
specimen are having stage Aj disease. At present, we
initially classified as
recommend pelvic lymph node dissection in such patients. If there is no
gross involvement of the pelvic nodes, and the prostate is felt to be resect-
able, the patient undergoes a radical prostatectomy. If gross nodal disease
is present, the patient receives external beam radiotherapy to the prostate
and the pelvic nodes. A further qualifying factor is the age of the patient.
Patients over 70 years should probably be treated more conservatively,
since life expectancy outweighs the potential risks of surgery. Patients with
several microscopic foci in the transurethral resection specimen, with little
or no apparent dedifferentiation, appear to enjoy a survival rate equal to the
age-matched general population. 52 Not only is surgical therapy unneces-
sary" but hormonal therapy also does not appear to be essential. The poten-
tial complications of estrogen therapy in the aged population outweigh the
potential benefit of the treatment.

Since multifocal involvement and the presence of poorly differentiated
cell type are associated with a poor prognosis, as already indicated, aggres-
sive therapy is indicated in these patients. Most urologists advocate radical
prostatectomy74, "** and consider the role of radiation therapy unclarified.
Stage B. Most clinicians agree that patients with detectable palpable
malignant tumors in the prostate require definitive therapy. However, the
aged patient (over 70 years of age), whose tumor is well differentiated,
might be better served by a more conservative approach. Since this has not
been clearly defined, treatment should be individualized, depending upon
the patient's medical status, degree of function, potency, and the size of the
tumor.
The standard therapy for stage B tumors is radical prostatectomy. The
5-year survival rate is approximately 80 per cent, and the 15-year survival
rate is approximately 33 per cent following prostatectomy (Table 10-2).
These statistics were derived prior to the advent of pelvic node dissection
for prostate cancer and prior to the clear understanding of the prognostic
significance of stage B, versus stage B 2 disease. Undoubtedly, about 20 to
30 per cent of these patients actually had stage D tumors by virtue of
lymph node metastases, which accounts for part of the attrition. Correa et
76
a/. reported a 5-year survival rate of 92 per cent and a 15-year survival
rate of 62 per cent following radical perineal prostatectomy without lym-
phadenectomy for stage B carcinoma. This suggests that few of their pa-
TABLE 10-2. Survival After Prostatectomy for Prostate Cancer
% Survival
Stage 5-Yr. 10-Yr. 15-Yr. Reference
A 86 64 57
91 50 89
B 80 62 57
69 37 89
76 61 39 20
C 67 29 57
56 19 89
64 36 20 20
tientshad occult lymph node involvement, and that most of their tumors
were probably truly stage Bj.
Since the distinction between stage Bj and stage B 2 tumors appears to
carry a prognostic significance, our current plan is not only to biopsy the
palpable nodule but also to perform random biopsies of the clinically nor-
mal part of the prostate. Patients with clinical stage B 2 tumors or with oc-
cult tumor diffusely involving the prostate gland appear to be at a higher
risk for metastases. It therefore seems appropriate to recommend a staging
lymphadenectomy in such patients. In contrast, patients with a small nod-
ule, 1 cm or less, seem to have a very low incidence of pelvic node disease
(as already indicated). Lymphadenectomy in such patients probably has a
low yield and may not be necessary.
Pelvic lymphadenectomy is associated with a definite morbidity, espe-
cially in older patients, although the mortality rate approaches zero. Pulmo-
nary embolus, sepsis, wound infection, and hematomas are the most com-
monly reported complications. McCullough et al." reported the formation
of lymphoceles in 10 per cent of patients, and this problem has been a
major cause for concern when advocating staging pelvic lymphadenectomy.
However, the problem has been completely eliminated by the Baylor Un-
iversity group, with careful ligation of the lymphatic bundle medial to the
external iliac vein.* In view of the other morbidity factors and the uncer-
tainty about therapeutic value staging lymphadenectomy is probably impor-
tant only in patients with stage A 2 stage B 2 or stage C disease.
, ,
The role of radiation therapy for stage B carcinoma is controversial. The

results of Bagshaw 78 suggest a five-year survival rate equal to that produced
by prostatectomy. However, the 10- and 15-year survival figures appear to
be the most important, and the true worth of radiotherapy for stage B
tumors cannot be assessed until such long-term follow-up is available.
The treatment of patients with stage A or stage B disease by hormonal
therapy as adjunctive therapy has not been widely accepted or proved ef-
fective. Barnes and Ninan 79 reported a 33 per cent 15-year survival rate in
patients with stage A and stage B prostate cancer who were treated with
*Baylor University, C Eugene Carlton, personal communication.

endocrine therapy alone. When compared with the approximately 30 per

cent 15-year survival rate after prostatectomy reported by Jewett, 27 primary
endocrine therapy appears to produce reasonable results. However, signifi-
cant differences were present in the populations of both studies, since
Barnes' study was of an older age group, whose tumors possibly were
slower growing and intrinsically different from the younger patients of
Jewett's study. Furthermore, it is important to cite the work of Franks, 80
which showed that approximately 20 per cent of patients failed to respond
to hormonal therapy and that, of those treated, 70 per cent still died within
three years, emphasizing the danger of relying on hormonal therapy. It is
further worth pointing out that no therapy has proved to produce results
superior to radical prostatectomy in long-term follow-up of patients with
stage A and stage B prostate cancer.
STAGE C. In patients with stage C cancer of the prostate, the incidence
of occult skeletal metastases and the approximate 50 per cent incidence of
occult metastases in pelvic nodes 81 explain, in part, the poor survival rate
reported in some series after radical prostatectomy. The 5- and 10-year sur-
vival rate is only slightly less than that for stage B carcinoma, but the 15-
year survival rate is considerably lower (Table 10-2). Prostate cancer is, in
many cases, a slow growing tumor, and 15-year follow-up probably more
accurately reflects the efficacy of treatment.
Some have reported a surprisingly high long-term survival rate
series
after radical prostatectomy. Schroeder and Belt
2:i
reported a 15-year survival
rate of 20 per cent after perineal prostatectomy without lymphadenectomy.
White et a/. 82 reported a 57 per cent 10-year survival rate in a small series
of patients after radical perineal prostatectomy for stage C disease. Tomlin-
son et al. m found a slightly improved five-year survival rate, a significant
decrease in local recurrence, and an improved quality of life after radical
perineal prostatectomy, compared with other methods of surgery. Similarly,
Scott and Boyd 84 treated patients with stage C disease with hormonal thera-
py. Those with well-differentiated tumors that showed clinical regression
then underwent prostatectomy, resulting in a 15-year survival rate of 20 per
cent. Survival similar to that reported by Schroeder and Belt 23 was noted in
the UCLA series by Boxer et a/. 85 Flocks et al. m reported a 28 per cent
15-year survival rate in stage C disease following radical prostatectomy,
lymph node dissection, and The similar survival
interstitial radiotherapy.
rate for patients widi positive node involvement was approximately 14 per
cent. It is interesting to note that the 5-year survival rates of patients with
lymph node metastases were similar to those of patients without lymph
node metastases, again emphasizing the importance of the 15-year follow-
up. Local recurrence was much lower than the 20 to 50 per cent that had
been previously reported, as already indicated. The report of Flocks et al. m
shows a local recurrence rate ofapproximately 4 per cent, indicating the
salutory effect of local radiation therapy. This subject will be discussed fur-
ther later.
Improper clinical staging, as already noted, is an unquestionable factor in
the disparity of results following prostatectomy for stage C disease, and
local recurrence is a major problem. Staging can be improved by newer
methods of detecting skeletal metastases, such as the new radioimmunoas-

say for prostatic acid phosphatase, and by performing routine pelvic node
dissection. The hormonal therapy, or interstitial radio-
role of postoperative
therapy, in preventing local recurrence has not been clarified, although hor-
monal therapy may reduce edema and render operative a previously inop-
erable tumor. In addition to these variables, however, perhaps the most
important factor determining survival is the grade of the tumor. Most re-
ports have not assiduously separated tumors according to grade, and the
effect of the tumor grade on results of surgical therapy are not ascertainable
at present. It seems reasonable, however, to advocate radical prostatectomy
in patients with well-differentiated or moderately well-differentiated
tumors, since their chance for having occult metastases is much smaller
than that of patients with anaplastic tumors.
Radiation therapy appears to have a role in stage C disease. However,
interpretation of the data suffers from the same disqualifiers as those of
surgical therapy, i.e., clinical understanding and inconsistent histologic
grading. Furthermore, even the most optimistic reports do not have 15-year
78
survival data, which are essential to appropriate interpretation. Bagshaw
advocates external beam radiotherapy alone in patients with negative
lymph node involvement and clinical stage B 2 and stage C lesions. He re-
ports 10-year survival rates of 47 per cent for stage B

disease and 28 per
cent for stage C disease. The retropubic implantation of radioactive gold
87
grains at the time of staging lymphadenectomy, as advocated by Carlton,
is based on the principle of delivering maximum radiation directly to the
prostate. The results may prove to be at least as good as those of external

88
beam therapy. Whitmore has reported equivalent results with the implan-
I. These various methods of radiotherapy have their own advan-
,25
tation of
tages, limitations, and complications. Two points have been made by pro-
ponents of radiotherapy. First, the early survival rates seem to approximate
those of prostatectomy for stage B 2 and stage C disease. Second, impotency
and incontinence, the most disabling complications of prostatectomy, are
less common following radiotherapy. However, major questions still exist.
The significance of positive prostate biopsy results after external beam ther-
apy must be delineated, since cure can only be equated with eradication of
the tumor. In addition, the long-term survival rates have not yet been es-
tablished for radiation therapy.
Based on die available data, we currently recommend the following ap-
proach to patients with stage C prostate cancer: All patients should undergo
a staging pelvic lymph node dissection. If lymph node involvement is posi-
tive, the patient was understaged and the tumor is at least a stage D,. We
would not then perform prostatectomy but would recommend either inter-
stitial or external beam radiotherapy to the prostate. If lymph node involve-
ment is negative grossly and on frozen section, careful assessment of the

prostate is made. If the gland is fixed to the pelvis or grossly invades the
bladder neck, radiotherapy is advised. If the gland is freely moveable and
prostatectomy is feasible, we recommend this procedure. If tumor invades
the bladder neck or seminal vesicles, we recommend either radiotherapy or
hormonal therapy after surgery. The choice should be tailored to the indi-
vidua] patient, since both procedures have potential significant complica-

tions following prostatectomy. When the biopsy demonstrates a very an-
aplastic, rapidly growing tumor, pelvic node dissection is still indicated,
followed by radiotherapy or prostatectomy. In such patients, the decision
should weigh more heavily toward radiotherapy, possibly combined with
hormonal therapy.
The place of hormonal therapy in stage C disease is controversial, and
that controversy mainly surrounds the use of hormonal manipulation as an
adjuvant to prostatectomy or definitive radiation therapy. Although many
clinicians still advocate orchiectomy or oral estrogen therapy along with
radical prostatectomy, no evidence has yet been produced to support that
contention.
Others have advocated the treatment of stage C tumor by hormonal thera-
py alone. The expected average survival rate of patients with stage C dis-
ease who are untreated is two to three years, and there is no evidence that
hormonal therapy improves the rate of survival, although the quality of life
might be improved. 88, s9 With the advent of newer methods of radiation
therapy, the therapeutic options should be radical prostatectomy or radia-
tion therapy as primary treatments, and hormonal therapy should probably
be reserved for patients with more advanced disease. There is little doubt,
however, that some patients with clinical stage C disease can be rendered
operable by preoperative hormonal therapy.8* Whether or not this repre-
sents true tumor regression or simple resolution of local edema is unclear,
but the end result is the same.
Stage D,. Patients with proven limited pelvic node involvement are
treated as already outlined, following staging pelvic node dissection. Pa-
tients with extensive pelvic node involvement probably would not benefit
from node dissection, and simple biopsy should probably suffice. We then
recommend hormonal therapy and possible chemotherapy.
Stage D 2 Initial treatment for stage D 2 prostate cancer is hormonal ma-
.
nipulation, as already described. Chemotherapy may then be used for hor-

monal treatment failures. Cyclophosphamide and 5-FU seem to be the most
effective currently available drugs and should be the initial drugs of choice.
Estracyt. cisplatin, streptozotocin, and DTIC may prove to be even more
effective in further trials. With the identification of other effective ehemo-
therapeutic agents, such drugs may, in the future, occupy a more important
role in early treatment of metastatic disease. Corticosteroids may be of
particular use in relieving pain in these patients, and local radiation thera-
py may be employed for patients with painful bone metastases.
Section 2
Bladder Cancer
Jean B deKernion
INTRODUCTION
Bladder cancer is a major cause of death in the United States. In 1977,

approximately 22,000 new cases of bladder cancer were diagnosed in
males, whereas 8,000 new cases were diagnosed in females. The estimated
number of deaths in the United States in 1977 due to bladder cancer was
approximately 10,000. 2
Since the observation by Rehn in 1895 90 relating the increased risk of
bladder cancer to the exposure to products of the dyestuffs industry, many
epidemiologic studies have shown an increased incidence of bladder can-
cer in highly industrialized areas. 91 The risk of developing bladder cancer
in the urban dweller is two to three times that in individuals living in rural
areas. 92 In areas associated with a high incidence of bladder cancer, a spe-
cific industry that is known to produce carcinogens can often be identified.
Another major source of epidemiologic data has been the study of popu-
lations exposed to potential carcinogens, based on experimental studies in
which carcinogenicity is demonstrated in animal models. By these various
approaches, an expanding list of known bladder carcinogens has been com-
piled.
Occupational Bladder Carcinogens. Specific industries have been
associated with an increased incidence of bladder cancer, although the spe-
cificcarcinogen often remains unidentified. Workers in rubber, 93 leather, 94
chemical and dyestuffs, pigment and paint, and textile dyeing and printing
industries have been shown to have an increased probability of developing
bladder cancer. 95 A similar association has been made in laboratory work-
ers, rodent controllers, and fuel, tar, and pitch workers. 96 Finally, Hoover
and associates 91 incriminated factories that produce heavy vehicles and
electric equipment.
Although most of the specific carcinogens have not been identified, four
chemical-industrial carcinogens are known to cause bladder cancer in
humans: xenylamine (4-aminodiphenyl), 97 beta-naphthylamine, 98 benzi-
dine, 99 and 4-nitrodiphenyl. 100 The further identification of specific indus-
trial carcinogens has been hampered by several poorly understood factors.
First, data suggest that the latency period from the time of exposure to the
carcinogen to development of bladder cancer may be as long as 40 years. 101
Second, the exact amount of carcinogen necessary to induce neoplastic
change unknown. Third, extrapolation of data from animal experiments to

is
human carcinogenesis must be made with caution. Nonetheless, the control

of bladder cancer will depend largely on the detection and elimination of
industrial carcinogens.
Tryptophan Metabolites. After the demonstration of Dunning et
al.
mof the carcinogenic potential of tryptophan metabolites in experimen-
tal animals, such metabolites were identified in human urine and found to
be carcinogenic. 103 Recent studies have shown that carcinogenic metabo-

lites of tryptophan appeared in higher concentration in the urine of patients
with bladder cancer than in the urine of normal controls after administra-
104
tion of a loading dose of tryptophan. The
exact relationship of tryptophan
intake to carcinogenesis and to other potential carcinogens is still unclear.
TOBACCO. Epidemiologic studies in the United States and Canada in-
criminated cigarette smoking as a cause of bladder cancer in humans. A
study by Weir and Dunn 103 demonstrated an increased death rate from
bladder cancer in cigarette smokers as opposed to nonsmokers. The mech-
anism by which tobacco may cause bladder cancer is unknown, and no
firm cause-effect relationship has been established. Beta-naphthylamine
has been found in small amounts in cigarette smoke, although the signifi-
cance of this is unknown. 106 Tryptophan metabolites have also been found
"7
in increased amounts in the urine of cigarette smokers.
1
Dietary Sweeteners. The demonstration of carcinogenicity of sodium

cyclamate in the bladders of adult rats prompted the temporary ban on
human consumption of eyclamates in the United States. 108 Saccharin has
long been suspected of being a bladder carcinogen in experimental ani-
mals. 109 Recently, large doses of saccharin were shown to produce papillary
tumors in a small percentage of exposed rats, and steps have been taken to
control the ingestion of the artificial sweetener. Several studies failed to
show an increased incidence of bladder cancer in patients with a history of
heavy consumption of saccharin in the diet, 110, nl and Armstrong and Doll 112
failed to identify an increased incidence of bladder cancer in patients with
chronic diabetes mellitus. However, a study by Miller and Howe 113 showed
an increased incidence of bladder cancer in male saccharin users as opposed
to those with no history of saccharin intake.
In view of the animal experiments, and in spite of the large doses re-
quired to induce carcinogenesis in rodents, saccharin should be considered
a potential carcinogen. Perhaps a relatively small number of bladder can-
cers are caused by saccharin, and this percentage will be too small to de-
tect by epidemiologic studies. It seems prudent to restrict dietary intake of
saccharin until further evidence is demonstrated.
COFFEE. Early studies identified carcinogenic substances in the soot
produced by roasting coffee beans. 114 Cole 115 found an increased relative
risk of bladder cancer in women who drank large amounts of coffee, com-
pared with those who did not drink coffee. Fraumeni et a/. 116 found an
increased incidence in some groups who drank large amounts of coffee. It
is not possible at this time to conclude that coffee is a human bladder car-
cinogen.
Schistosoma Haematobium. This is a rare disease in the United
376 II / Treatment of Specikk Neoplasms
States but is a common affliction in many

countries, especially Egypt
Schistosomiasis is squamous cell carcinoma rather
associated mainly with
than transitional cell carcinoma. In regions where the infection is endemic,
the proportion of squamous cell tumors to transitional cell tumors is much
higher than in other parts of the world. 117 Also, in endemic regions, a high
percentage of patients with squamous cell carcinoma of the bladder were
found to have Schistosoma haematobium ova in the bladder wall. 118 The
mechanism of the suspected carcinogenesis of the parasite is unknown.
NATURAL HISTORY
Classification
The majority of bladder tumors in North America are tumors of the uro-
thelium (transitional cell), accounting for 90 to 95 per cent of the diagnosed
tumors, and most of the present discussion will deal with this histologic
type. Squamous cell carcinoma accounts for only 5 to 10 per cent of the
diagnosed tumors, and only approximately 2 to 3 per cent are true adeno-
carcinomas. Squamous cell elements and adenocarcinoma elements are
often found in association with transitional cell tumors, especially high-
grade tumors. The extensive study by Melicow 119 shows that most bladder
tumors occur between the ages of 50 and 80 years. He showed that tumors
of lower histologic grades were more frequent and occurred mainly in the
sixth and seventh decades of life. High-grade tumors were distributed
through all decades. Melicow 120 also postulated that all bladder tumors
began as carcinoma in situ and progressed to either papillary or sessile
invasive tumors if untreated. Tannenbaum and Romas 121 present an excel-
lent discussion of these and other aspects of the natural history of bladder
cancer.
Hematuria is the presenting complaint in approximately 70 per cent of

patients with bladder cancer. 122 Although the hematuria typically persists
throughout the voiding stream, the type of hematuria should not be relied
upon to differentiate tumors, and bladder tumor must always be ruled out
in a patient with microscopic or gross hematuria. The second most common
presenting symptom is bladder irritability, occurring in approximately 25
per cent of patients. This often indicates a large invasive tumor, a tumor
near the bladder neck, or the presence of carcinoma in situ. Therefore, the
clinical history that should arouse suspicion of the presence of bladder can-
cer consists of hematuria, either microscopic or gross, irritative symptoms,
or the occurrence of urinary tract infection in the male patient in whom
urethritis and prostatitis have been ruled out.
Another group of patients present with symptoms due to distant metas-
tases. At the time of diagnosis, approximately 70 per cent of bladder can-
cers are localized,and only 7 per cent have clinical evidence of metastases.
This is in contrast to tumors in the prostate and kidney. However, if low-
stage bladder tumors are excluded, the percentage of patients with metas-
tases would definitely be higher. No matter what the presenting symptom,
once the suspicion of bladder cancer is aroused, the urologist must proceed
without delay to firmly establish or exclude the diagnosis.
The definitive diagnostic method for detecting bladder cancer is cysto-
scopic examination. The presence of tumor in the bladder or urethra should
be diagnosed with 100 per cent accuracy by this method. A careful biman-
ual examination under anesthesia is also an important adjunct to proper
staging (see later discussion). A biopsy of the tumor is a critical step in the
diagnosis of tumor type.
Intravenous pyelography has been proposed as a method of diagnosis for
bladder tumors but is not a reliable diagnostic tool. It is important, howev-
er, in the evaluation of the suspected bladder cancer patient for several
reasons. First, the entire urothelium should be considered as a unit when
diagnosing and treating bladder cancer. The incidence elsewhere in the
urinary tract in patients with bladder cancer is approximately 10 per cent,
and even' bladder cancer patient must undergo complete and thorough vis-
ualization of the upper urinary tract. Second, the pyelogram provides infor-
mation with respect to staging; 70 per cent of patients with hydronephrosis
will have a deeply invasive tumor. Finally, the status of the upper urinary
tract is important in a patient who is being considered for radical surgery
and urinary diversion.
Once the presence of the bladder tumor has been established, accurate
staging of the extent of local tumor invasion and distant spread become
important in decision-making for treatment. Biopsy of the tumor is a critical
part of staging to demonstrate the presence or absence of muscle invasion.
Attempts to pinpoint the exact depth of muscle invasion are too inaccurate
to warrant the effort (see later discussion).
If the tumor is believed to be deeply invasive, biopsy rather than total
resection may be more appropriate, in view of the report by Dretler et al. i23
of improved survival in patients who had biopsy rather than complete re-
section. Regardless, adequate staging requires that deep biopsy specimens
be taken both from the center of the tumor and at the border of the tumor
adjacent to uninvolved bladder mucosa. It has been found that carcinoma
in situ is frequently associated with invasive bladder cancer and must be
sought in every patient. This necessitates random bladder biopsies of the
rest of the bladder mucosa using a cold forcep so as not to distort mucosal
histology. We prefer the large, flexible biopsy forcep, since the rigid cup
forcep takes an unnecessarily deep biopsy and often causes troublesome
bleeding. Multiple biopsies are taken from the bladder neck, the trigone,
and the anterior and lateral walls. A careful bimanual examination under
adequate anesthesia is important to assess the presence of a palpable mass
or induration and the presence or absence of fixation of the tumor to the
pelvic wall. The absence of induration or a mass suggests a superficially
invasive or noninvasive tumor, whereas the presence of induration or a
mass after tumor resection usually indicates deep muscle invasion. Indura-
tion or the presence of a mass extending from the base of the bladder later-
ally to the obturator fossa usually indicates inoperability. In females, inva-
sion of the urethra, vagina, or uterus can often be detected on bimanual
examination.
Numerous methods have been devised to detect definite invasion, in-
cluding double contrast and triple contrast cystography with the insufflation
of oxygen into the perivesical space and intravesical instillation of air or
contrast material. 124 A staging accuracy of 87 per cent for stage B 2 lesions
and 95 per cent for stage C and stage D lesions was reported by Lang et
12s
al. using pelvic arteriography. All these methods are limited in their use
by the presence of inflammation, multiplicity of tumors, previous transure-
thral surgery and radiotherapy, and the position of the tumor in the blad-
der, especially tumors near the dome or near the bladder neck and prostatic
urethra. They do not have a definite application at this time. Tests de-
signed to determine the presence and extent of dissemination of bladder
cancer either to the regional lymph nodes or distant sites are, however,
extremely important and influence decisions regarding therapy.
Pedal lymphangiography has not been shown to be accurate in the stag-
ing of bladder tumor. 126 Kabler and associates 127 found only a 50 per cent
correlation between radiographic interpretation of the lymphangiogram and
histologic findings. The lymphangiogram fills the iliac and para-aortic
nodes and often does not visualize the obturator and internal iliac nodes,
which are the primary nodes of drainage from the bladder. However, John-
son et a/.and Wajsman et a/. 129 found a good correlation between surgical
128
findings and lymphangiography interpretation. Our experience has been

contrary to this, however, and we have found the study useful only in de-
termining the presence of far-advanced disease, in which case the patient
may be spared exploratory surgery. However, we have explored patients
whose lymphangiogram showed the presence of malignancy in the para-
aortic nodes and found that the tumor was limited to the bladder and was
curable by cystectomy. We believe that the tests should be relegated to
poor-risk patients with high-grade invasive tumors in whom a high suspi-
cion of extensive dissemination is present and who are not considered can-
didates for aggressive surgery.
Immunodiagnosis of bladder cancer has recently stimulated interest.
Serum carcinoembryonic antigen is elevated in most patients with bladder
cancer. 130, 131 However, a significant number of false-negative levels are
found, and changes in the level of CEA often do not parallel changes in the
clinical status. The CEA determination in the 24-hour urine sample appears
to be more accurate and may warrant further investigation.
132
The associa-
tion between the prognosis of bladder tumors and the presence of blood
group antigens on the bladder mucosa has recently been studied. Lange et
al.
133
associated the absence of the antigens on the surface of the bladder
tumors with a poor prognosis. These results were confirmed by Bergman
and Javadpour. 134 This simple test may be a valuable adjunct in the future
treatment of bladder cancer patients.
Urixe Cytology. Urine cytology is now an important part of the eval-
uation of patients with suspected bladder tumors. Its major role is in the
detection of occult urothelial tumors, the screening of large high-risk popu-

lation groups, and the follow-up of patients after the excision of bladder
tumors. It is especially important in the detection of high-grade or sessile
13 136
tumors and extremely accurate in the diagnosis of carcinoma in situ. *'
is
It is also a useful tool in the long-term follow-up of patients who have
previously had urothelial tumors. 137

The accuracy of cytologic examination of the urine in the detection of
bladder tumors varies from 25 to 100 per cent and depends greatly on the
method of collection of the specimen, the promptness of fixation, and the
skill of the cytologist in the interpretation. When properly employed for
appropriate indications, cytology has become an important part of the eval-
uation of bladder tumors and upper tract urothelial tumors.
Detection of Distant Metastases. The physical examination of the
bladder cancer patient should include a careful scrutiny of the lymph
nodes, since metastases to distant nodes are not uncommon. The presence
of abdominal and subcutaneous masses should be detected. Radiographic
studies include a careful chest x-ray, since the lungs are a common site of
metastases. The isotopic bone scan is very important in detecting silent foci
of metastases, and its accuracy surpasses that of plain radiographs of the
skeleton.
The liver scan is no longer a routine part of our evaluation of bladder
cancer patients. Felix and associates 8 reported almost no positive liver
1 '
scan results in patients who had normal liver function and no palpable he-
patic masses. We reserve liver scans for patients who have either abnormal
liver function chemistries or a suspected palpable mass. In this respect,
ultrasonography of the liver is often very helpful.
Staging Criteria and Prognosis
The prognosis of bladder cancer depends on both the stage and the grade
of the tumor. In 1922, Broders 139 formulated a grading system that correlat-
ed prognosis with the degree of cellular dedifferentiation and identified
specific histologic criteria. Criteria such as cell proliferation, cell type, and
degree of cellular change have been well described. 140, 141 However, the
extent of local and systemic spread of the tumor at the time of diagnosis is
an even more important determinant of prognosis and is more germane to
this discussion.
The concrete demonstration of the relationship of bladder dissemina-
first
tion to the extent of local invasion was made by Jewett and Strong in
142 143
1946. Subsequently, Jewett, and later Marshall et al., 144 subdivided the
groups, as depicted in Figure 10-1. The staging system of Marshall is the
one most commonly accepted in the United States today. Current informa-
tion, however, suggests that carcinoma in situ should be a separate category-
and that the subdivision of stage B is not clinically applicable. Although
there is little doubt that the depth of muscle invasion is an important deter-
minant of prognosis, the accurate detection of the depth of muscle invasion
into the bladder wall is usually not plausible. Indeed, several studies have
BLADDER CANCER
STAGING
1946 1952 1952 1974. TNM

Jewett- Jewett Marshall Clinical Patho-
Strong logical
1
No tumor definitive specimen T-0 P-0
Carcinoma-in-situ TIS PIS
° 1
Papillary tumor s invasion
I
A A
i
Invasion lamina propria

)t. P-l
1
A
B B Superficial 1 T-2 P-2
I -l -l
B-2 B-2 Deep ' T

-3A |
P-3
C C C Invasion perivesical fat T-3B 1
Invasion contiguous viscera T P

4A-B -4
D
-l Pelvic nodes N
l-3
Distant metastases
M -1
Nodes above aortic bifurcation
FIGURE 10-1. Bladder cancer staging systems. See text for discussion.
shown that the error in detecting the depth of invasion is as high as 40 to

50 per cent.
In 1974, in an attempt to establish an international method of invasion
classification, the InternationalUnion Against Cancer (UICC) proposed the
TNM system, depicted in Figure 10-1. 146 The advantages of this system are
that tends to provide uniformity of staging among all countries. Also,
it
there isa separate classification for clinical and pathologic staging. Impor-
tantly, carcinoma in situ, originally grouped in Stage by Marshall classifi-
cation, 144 is separated as a distinct entity in the System. The major TNM
shortcoming of the system is that it also attempts to separate superficial
muscle invasion (T 2 ) from deep muscle invasion (T 3 ) and thereby propa-
gates the inaccuracy of the older classification systems. It is nonetheless a
step in the direction toward the uniformity among various reporting groups.
TREATMENT
Superficial, Low-Grade Lesions
Stage A (noninvasive) bladder tumors are best managed by transurethral

surgery. 145Resectoscope excision is the most widely used method, but
excision with the cold punch or the cold forcep is often suitable. Single or
multiple lesions and tumors of all sizes can be treated in this manner. Oc-
casionally, the multiplicity of tumors precludes completed resection, and
fulguration of multiple small lesions is often practical. Using these rather
conservative methods, the majority of patients with superficial bladder
tumors can be cured. However, tumor recurrence is the rule rather than the
10 Genitourinary Neopla- 381
eption. In the Mayo Clinic serie- 73 per cent of patients had tumor
recurrence, half of those recurring within one year after the original tumor
resection. In the study by Althausen et a/.. 14* 85 per cent of patients had
recurrence of low-grade, low rumors during a follow-up period ol
eight years. The probability of tumor recurrence is directly related to the
size of the tumor, the multiplicity of tumors, and the presence of carcinoma
in situ U9 (see later discussion*. The recurrence rate, however, does not re-
flect the relatively good prognosis of patients with superficial tumors. The
five-year reported survival rate for patients following treatment of stage A
tumors is from 65 130
to 80 per cent. A dire prognostic factor is the recur-
151
rence of tumors of higher grade or higher stage muscle invasion). Approxi-

mately 10 per cent of patients with superficial tumors will develop more
aggressive lesioi id the likelihood of this occurrence is increased in
patients who have frequent, multiple tumor recurrence.
Total cystectomy is rarely required in the patient with noninvasive transi-
tional cell carcinoma. The presence of diffuse, frequently occurring, multi-
ple tumors requiring frequent extensive transurethral bladder resection is
often an indication that the patient is better served by removal of the blad-
der, since a scarred, irritable,and poorly functioning bladder can result
from such therapy. Most patients with diffuse and rapidly recurring tumors
will be found to have a diffuse urothelial tumor diathesis, usually carcino-
ma in situ. The appropriate therapy for such patients is radical prostatoc> 5-
tectomv
The tendency tumors to recur prompted the investigation
for transitional
of the use of intravesical chemotherapy. Thiotepa is the most widely used
agent in the United States. " Yeenema et a/. 154 recommended the instilla-
1
tion of 60 mg of Thiotepa in 60 ml of sterile water for one to two hours

weekly for four weeks, and at monthly intervals thereafter. The incidence
of tumor recurrence was reportedly decreased by this method in a signifi-
cant number of patients. 153 Subsequently. Thiotepa was used to eradicate
multiple superficial tumors and was reported to have a beneficial effect in
approximately one third of patients. 1Vi Toxicity from Thiotepa can be severe
and can include severe bladder irritability, myelosuppression. and renal
failure if reflux is present.
7
We generally begin with a 30- mg dose and
1 '
increase it to 45 mg if it is tolerated. Prior to the onset of therapy, the

patient must have a cystogram to rule out vesicoureteral reflux. Also, the
bladder must be free of infection, and any surgical sites should be com-
pletely healed.
Numerous other agents have been employed as intravesical chemothera-
py treatment of superficial tumors. Etoglucid (Epodyli has been ex-
tor the
tensively used in Europe and Japan and seems to have a degree of efficacy
similar to Thiotepa 158 Cisplatin and bleomycin have also been shown to
be relatively safe when instilled intravesicallv and may have some effi-
cacv. 159 *° \iitomycin-C may be one of the most effective intravesical
- 1
agents, as reported in preliminary studies. 181 Immunotherapy may also have

a role in the treatment of superficial tumors (see later discussion). It has
become apparent in recent years that many agents are effective when ap-
plied intravesicallv, although the mechanism of activity is uncertain. The
task in the future will be to identity the most effective agent among the
many drugs now being studied.
Carcinoma In Situ
Melicow 162
first described the finding of abnormal urothelium in the blad-
ders of patients with exophytic papillary tumors. Subsequently, especially

with the aid of urinary exfoliative cytology, the phenomenon was found to
be much more widespread than had previously been appreciated. Carcino-
ma in situ may independent of obvious tumors or may be
exist as a finding
present in the mucosa adjacent to or distant from bladder tumors. The cys-
toscopic findings vary from an essentially normal-appearing bladder to one
with varying degrees of patchy, velvety mucosal inflammation. The patient
usually presents with symptoms of urgency, frequency, and dysuria, and a
presumptive diagnosis of urethritis, trigonitis, or chronic prostatitis pre-
cludes the accurate identification of the true premalignant condition. Multi-
ple random bladder biopsies and specific biopsies of suspicious areas will
reveal the epithelial atypia. In many instances, microscopic multiple foci of
invasion will have already occurred.
The distribution of carcinoma in situ has been extensively studied. Koss
et a/. 163 examined the urothelium of surgically excised bladders and found
carcinoma both adjacent to and distant from true invasive lesions.
in situ
The lateraland posterior walls appeared to be more frequently involved,
with the trigone and dome of the bladder less frequently involved. Farrow
et a/. 164 determined the base of the bladder and trigone to be the, most
frequently involved areas. An important point when treating carcinoma in
situ is that it is multifocal and potentially involves all the urothelium. The
ureters are known to be involved in a number of cases, especially as an
extension of trigonal involvement. 165 The entire urethra or the prostatic
ductsmay also be involved, and the distribution in the urethra may be
random and not necessarily contiguous with the bladder process. 166
The treatment of carcinoma in situ depends to a great extent on such
factors as patient age, presence of associated bladder tumors, severity of
symptoms, and degree of epithelial atypia. Treatment decisions are compli-
cated by two factors. First, the extent of epithelial atypia varies from mini-
mal and the degree of atypia influences prognosis. The aggres-
to severe,
siveness with which patients with minimal to moderate epithelial atypia
should be treated is still unclear. Second, although it seems reasonable to
assume that minimal epithelial atypia progresses to severe epithelial atypia,
the time interval required for progression is unknown. It appears that the
process may be more indolent in some patients, requiring many decades to
progress to frankly invasive cancer (carcinoma in situ). Once true carcinoma
in situ is present, however, progression to invasive carcinoma can be ex-
pected.
Tannenbaum and Romas 121 followed 140 patients with carcinoma in situ
of the urinary bladder, none of whom had had previous bladder tumors, for
a period of 14 to 21 years. In four to six years, 40 per cent of the patients
10 Genitourinary Neoplasms 383
had developed stage A or stage Bj bladder tumors, and 10 per cent had
developed stage B 2 or stage C tumors. By 10 years, 60 per cent had devel-
oped stage A or stage B, tumors, and 20 per cent had developed stage B 2 or
stage C tumors. Further evidence of the malignant nature of carcinoma in
situ comes from a report from the Mayo Clinic;
167
73 per cent of patients
followed developed invasive cancer, and 65 per cent died of bladder carci-
noma. This suggests that the lesion is an aggressive and progressive proc-
that usually culminates in frank carcinoma. However, the natural histo-
ry of severe epithelial atypia (i.e., carcinoma in situ) may be significantly
different from the lesion of minimal epithelial atypia. It is this last group in
which the major uncertainty currently exists. It is the treatment of the true
severe epithelial atypia (carcinoma in situ) to which our further discussion
will be addressed.
Surgical treatment of carcinoma in situ has produced the most satisfactory
results. Electroresection and fulguration are occasionally beneficial, but the
process is a diffuse urothelial instability, and persistence or recurrence in
other foci is the rule rather than the exception. If the lesion is limited to an
identifiable, discrete, velvety patch and does not involve the prostatic
urethra or ureteral orifice, thorough electro fulguration has been advocated.
Of the 12 patients so treated at the Mayo Clinic, 168 invasive cancer devel-
oped 2 patients. However, if symptoms or cystoscopic findings suggest
in
recurrence, careful follow-up after conservative treatment with prostatocys-
tectomy may be an acceptable alternative to immediate radical surgery in
such patients.
The aggressiveness of the process, the diffuse multifocal nature of the
lesions, and the apparent failure of most forms of conservative therapy have
prompted the use of radical cystectomy with urinary diversion for true car-
cinoma in situ. This is especially important in the patient with diffuse, se-
vere involvement and in the patient with severe symptoms, since the se-
verity of symptoms appears to be directly related to prognosis. 147 The
results of this form of aggressive therapy have been excellent. The patient
treated by cystectomy immediately upon the diagnosis of the disease has
almost a 100 per cent rate of survival. 188 However, the patient who has
diffuse, microscopic invasion or metastases to the regional nodes has a poor
prognosis.
The surgical procedure for carcinoma not dissimilar to the
z'/i situ is
standard prostatocy stectomy for known invasive bladder cancer. We believe

that excision of the regional lymph nodes is an important staging proce-
dure, especially when microscopic invasion has occurred. Since carcinoma
in situ extends into the ureters in a significant number of patients, frozen
sections of the divided ends of the ureter must be obtained to be certain
that areas of contiguous involvement are completely resected. Recurrence
of tumor following cystectomy may follow if the implanted ureter has se-
vere carcinoma in situ, although this probably occurs rarely. Similarly, the
resected margin of the prostatic urethra should be carefully inspected, and
if atypia is present, a urethrectomy must be performed. In patients with
severe epithelial atypia and known involvement of the prostatic urethra, we

teel it is prudent to perform a urethrectomy at the time of prostatocystec-
tomv.
Radiation therapy has no proven value in the treatment of carcinoma in

situ. 1 *8,190
Indeed, following preoperative radiotherapy for invasive tumors,
the multifocal carcinoma in situ frequently persists even after regression of
the exophytic tumor. Intravesical chemotherapy with Thiotepa has not
proved be of value, although occasionally the process temporarily re-
to
gresses. Similarly, it has been our experience that immunotherapy with le-
vamisole may have a temporary effect on the process, but it does not ap-
pear to be curative. Experience with intravesical mitomycin-C is too
limited to be conclusive.
It therefore appears that the patient with minimal or moderate epithelial
atypia as an isolated finding may be best served by careful, frequent obser-

vation and biopsy. The patient with severe epithelial atypia, i.e., carcinoma
in situ, has the best chance of cure and survival by undergoing radical
prostatocystectomy, often with urethrectomy. Until more conservative
methods of treatment, such as chemotherapy and immunotherapy, are
found to influence the diffuse epithelial process, radical surgery must con-
tinue to be the treatment of choice in appropriate patients.
High-Stage, High-Grade Tumors
The incidence with which tumors occur in high grade and high stage
varies according to the nature of the reporting hospital. In centers to which
patients are referred for tertiary care, 50 per cent of bladder tumors may be
high grade or high stage. 170 However, the true distribution of tumors that
present as high-grade, high-stage lesions is probably 25 to 30 per cent of
bladder tumors. 171 The inverse relationship between grade and stage and
survival was clearly demonstrated by Marshall et al. UA in 1956. Although
approximately 80 per cent of patients with low-grade and low-stage lesions
survived years, approximately 20 per cent of patients with high-grade and
high-stage lesions survived for the same postoperative interval. The de-
creasing survival rate with increasing stage of tumor invasion has been re-
peatedly demonstrated. It is therefore obvious that although the majority of
tumors are not high grade or high stage, the impact on mortality is greatest
in this group of patients, and more aggressive therapy for the local tumor
has evolved over the past 40 years.
Simple transurethral resection is seldom adequate for invasive tumors.
The true depth of invasion is difficult to assess during the procedure, and
in many instances the extent of resection will be inadequate to remove the
entire microscopic extension of the tumor. Another reason for failure of
transurethral resection is the presence of carcinoma in situ in other parts of
the bladder. As mentioned earlier, the majority of patients with invasive or
high-grade tumors will have diffuse carcinoma in situ.™ 2 However, Barnes
et a/.
149
and Flocks 122 both reported a five-year survival rate for stage B
carcinoma similar to results following more radical procedures. Other au-
thors, however, have reported results that are significantly poorer than
those following more aggressive therapy. 150 151
'
Segmental bladder resection has been proposed for patients with high-
grade, high-stage lesions that are confined to the dome of the bladder. This
allows the patient to maintain continuity of the urinary tract and precludes
the need for a troublesome and unpleasant urinary diversion. However, the
appeal of the operation has often prompted its use in inappropriate circum-
stances, and few patients are truly candidates. Only 6 per cent of patients at
the Mayo Clinic, 17 -
2 per cent at the Cleveland Clinic, 173 and 7 per cent at
the Ochsner Clinic 174 were candidates for partial cystectomy when criteria
were rigidly followed.
We must be fulfilled before segmental re-
feel that the following criteria
section of a high-grade or high-stage tumor is considered. First, the tumor
should be confined to the dome of the bladder and be of such size that at
least 2 to 3 cm of normal-appearing bladder can be excised circumferen-
tially.Second, the frozen sections that are obtained of the cut margin from
the remaining bladder must be free of any evidence of tumor. Third, the
patient must have had multiple random biopsies to rule out the presence of
carcinoma in situ. Fourth, the tumor should be solitary and not multifocal.
Within these constraints, the results of segmental resection are equivalent
to those of radical cystectomy.
175 17,i
A potential complication of the proce-
-
dure is the implantation of tumor cells into the incision, which we have
witnessed on several occasions, even when there was no tumor recurrence
within the bladder. The experience of van der Werf-Messing 177 indicates
that wound implantation of tumor cells can be effectively prevented by ad-
ministering less than 1000 rad to the bladder prior to surgery. This dose of
radiation is not sufficient to interfere with bladder function and is well tol-
erated.
The failure of conservative management and seg-
(transurethral resection
mental resection) to control most invasive and high-grade tumors prompted
the philosophy of aggressive local therapy. Total cystectomy with urinary
diversion became the standard method of treatment. Results, however,
were disappointing. More extensive local excision was advocated, and the
true "radical cystectomy," encompassing the bladder and the pericystic fat,
became popular. Excision of the pelvic lymph nodes was then included but
failed to significantly improve the results of radical cystectomy. Following
the development of more effective technology, full-dose definitive radiation
therapy was advocated as a method of preventing the disabling morbidity
of radical surgery. The reported results following radiation therapy alone
varied considerably, but the five-year survival rate for stage B2 to stage C
178, 179
lesions was approximately 15 to 20 per cent. This certainly represent-
ed no improvement over radical surgery alone. Two subsequent, more re-
cent randomized trials have shown that definitive radiotherapy alone is in-
ferior to a combination of radiodierapy followed by surgery. Miller and
Johnson 180 showed a five-year survival rate of 46 per cent for patients treat-
ed surgically, compared with 16 per cent for patients who received defini-
tive radiotherapy' alone. A similar finding was reported by Wallace and
Bloom, 181 who found a doubled survival rate in patients after preoperative
radiotherapy plus surgery, compared with those who received radiotherapy
alone.
Having thus demonstrated the importance of surgical excision, what re-
mained was to demonstrate the contribution of preoperative radiotherapy.

The National Cooperative Bladder Cancer Group, under the direction of
Prout, 182 performed a randomized prospeetive study to assess the impor-
tance of preoperative radiotherapy. Two hundred thirty-three patients com-
pleted the study, all of whom had proven muscle invasion with no evi-
dence of distant metastases. One hundred were randomly assigned to
receive 4500 rad over a four- to six-week period, followed later by surgical
excision —usually radical cystectomy. The remaining patients received sur-
gery with no prior radiotherapy.
A number of important observations were made. First, radiotherapy did
not increase the operative mortality or morbidity. Second, 37 per cent of
patients who received preoperative radiotherapy were found to have a
tumor-free bladder after resection. Nine per cent of patients who did not
have radiation therapy also had no tumor in the specimen, presumably be-
cause of complete excision of the tumor during the diagnostic biopsy or
excision. Therefore, it can be concluded that approximately 28 per cent of
patients had sterilization of their tumors due to the radiotherapy. Third,
patients who received preoperative therapy had a higher incidence of pul-
monary metastases as the first evidence of tumor dissemination. This sug-
gests a change in the tumor cell population due to the radiotherapy. Final-
ly, the overall survival rate of the two groups, when considering all eligible
patients who completed the protocol, was not materially different at five
years. Patients who had surgery alone had a five-year survival rate of 23 per
cent, compared with a 26 per cent five-year survival rate for those who also
received preoperative radiotherapy. 182 A more recent report by Slack and
Prout 183 indicated that the patient whose tumors were controlled by the
preoperative therapy were those with exophytic papillary tumors. The pa-
tients with sessile endophytic tumors seemed to be uninfluenced by radio-
therapy. In the future, this type of computerized study of the available data
may allow us to select the patients who are suitable for preoperative radia-
tion therapy and spare some patients the financial and physical burden of
added therapy. For the moment, however, these statistics, and those of
Whitmore et a/. 184 suggest that preoperative therapy has some role in the
treatment of high-grade, high-stage tumors, although the slight increase in
survival may not merit the routine use of therapy in all patients.
A compromise has been proposed in recent years. The concept of the
short-course, high-dose therapy was advocated by Whitmore and asso-
ciates 185 on the theory that the biologic effect on the tumor cell would be
equivalent to that of a more protracted course of therapy. This theory was
further supported by a proven decrease in local wound implants following
a very low dose of preoperative therapy. The initial results appear to sup-
port the practice of low-dose therapy. Whitmore et a/. 185 reported a 58 per
cent five-year survival rate for patients with stage B 2 and stage C tumors,
following cystectomy with 2000 rad preoperative therapy administered over
four days. Similar results were obtained by Reid and associates 186 and Ri-
chie et e//. " 7 Therefore, it appears that the short-course therapy is a justifi-
1
able modification that conserves time and expense.

Radical cystectomy has been defined in many ways in the literature but
is usually used synonymously with prostatocystectomy. The proeedure

should include excision of the bladder with the pericystic fat, the attached
peritoneum, and the entire prostate with the seminal vesicles. In the fe-
male, the uterus and adnexa are excised en bloc with the bladder, urethra,
and a cuff of vagina.
The lymphadenectomy has not been
issue of the therapeutic value of
resolved, and evidence that lymphadenectomy improves survival is sparse
and inconclusive. However, it seems reasonable that the procedure may be
curative in the occasional patient who has metastases to only one or two
pelvic nodes. The procedure adds little to morbidity and does not appear to
increase" mortality. 188 The most concrete virtue of lymphadenectomy is in
the Staging information that is obtained, and such information will become
increasingly important as trials of adjuvant therapy are instituted. The dis-
section is begun at the aortic bifurcation. The highest nodal tissue isimme-
diately sent for frozen section analysis. If the tumor is found in the para-
aortic nodes, the procedure is usually abandoned unless palliative cystec-
tomy for severe symptoms is indicated. The dissection otherwise proceeds
distally to include Cloquet's lymph node on each side. The presacral, com-
mon iliac, external iliac, and obturator lymph node groups are excised. The
lateral extent of the dissection the genitofemoral nerve on each side.
is
Posteriorly, the obturator vessels mark the limit of dissection. We believe

that important to
it is submit lymph node specimens in separate, distinct
groups proper interpretation by the pathologist.
to facilitate
The method of radical cystectomy depends on the preference of the sur-
geon. We have found it easiest to first ligate the vessels to the bladder from
the hypogastric artery on each side. This is most easily done with large
metallic clips and has not resulted in any incidence of postoperative hem-
orrhage. After dividing the peritoneal reflection between the bladder and
rectum, the bladder and prostate are bluntly dissected from the anterior
wall of the rectum, and the tissue that extends from each lateral aspect of
the rectum to the posterior wall of the bladder is ligated and divided. The
puboprostatic ligaments are ligated and divided immediately before divi-
sion of the urethra as close to the distal margin as possible. Bleeding from
the dorsal vein of the penis and the retropubic venous plexus is controlled
by traction on a catheter with a large balloon inserted through the penile
urethra. In females, the broad ligament and ovarian vessels are ligated and
divided. The uterine vessels are also divided as the dissection proceeds
distally. The peritoneal reflection between the uterus and rectum is in-
cised, and the cervix and proximal vagina are bluntly separated from the
rectum. The entire urethra with a cuff of anterior vagina is removed with
the specimen.
The operative mortality rate for radical cystectomy ranges from 3 188 189 to *
8 per cent. 185 These results are comparable to the previously reported re-
sults following more conservative surgical management. The procedure,
however, is not without significant morbidity.
In addition to the problem of management of an external drainage con-
duit and the psychologic burden of impotency in the male, other early and
late complications have been reported. Ureterocutaneous fistula, wound de-
388 II / Treatment Of Spe< ific Neoplasms
hiscence, partial small bowel obstruction, wound infection, and small

bowel fistula (which is associated with a 50 per cent mortality rate) have all
been documented. The major postoperative complication rate is approxi-
mately 25 to 30 per cent. 187 189
"
In an attempt to decrease the incidence of complications, Grimes et a/. 190

advocated performance of the operation in two stages —
urinary diversion
followed later at a separate operation by radical cystectomy. Bredin and
Prout 191 found that did not materially decrease the complication rate
this
and significantly added to the expense. In addition, the psychologic and
physical discomfort to the patient is increased. However, in the patient
who has had high-dose definitive radiotherapy and has tumor recurrence,
the operation may best be performed in two stages. The ileal conduit diver-
sion is first performed through an upper abdominal transverse incision,
which is associated with a minimal incidence of wound dehiscence and
allows the surgery to be performed out of the radiated field. Later, the
bladder is excised through a low transverse incision. When radiation fibro-
sis is severe, we often first separate the rectum from the prostate through
the standard perineal prostatectomy approach. This method takes little time
and adds to the safety of separating the scarred bladder from the rectum.
The mortality rate from these so called "salvage" cystectomies (after defini-
tive radiotherapy) is somewhat higher than that following planned preoper-
ative therapy and cystectomy. 192 However, the mortality rate and morbidity
rate, especially when reduced by the performance of a procedure in two
stages, are acceptable, and the patient with radiation-resistant or recurrent
tumor should not be denied the option of radical surgery.
In addition to radiotherapy, other adjuvant modalities have been pro-
posed for the treatment of patients with high-stage, high-grade bladder
tumors. In an attempt to decrease the incidence of recurrence after the de-
finitive local therapy, the use of systemic adjuvants has been advocated and
will be discussed further.
Advanced Bladder Cancer
Surgery. Transurethral resection or fulguration of large tumors causing

hemorrhage and irritative symptoms is often palliative. 149 Palliative total
cystectomy is seldom indicated, except if needed to control profuse hemor-
rhage. Radical excision of tumors that involve the anterior abdominal wall
may be palliative and, in some even curative.
instances, The indications
19-3
for radical cystectomy in patients with advanced bladder cancer, however,

are few indeed.
The use of supravesical urinary diversion is also seldom beneficial. Local
pain is rarely an indication for diversion, since this indicates invasion of
the pelvic nerves or pelvic bones. However, in the patient with severe irri-
tative symptoms due to bladder tumor, diversion can often improve the
quality of life, especially when local therapy such as radiotherapy is practi-
cal. Diversion to prolong survival in patients with obstructed ureters and
impending uremic deatii is seldom warranted, since the average survival
rate of such patients is about three months, during which time pain is often
194
severe and difficult to control.
When diversion is indicated, cutaneous ureterostomy can sometimes pro-
vide the necessary palliation with considerably less morbidity. 195 It must be
emphasized that all patients with metastatic disease who are suffering from
severe local bladder symptoms should first be treated with more conserva-
tive measures to control symptoms before resorting to major surgical inter-
vention. 196
Radiation Therapy. As already noted, radiation therapy is capable of
eradicating localized transitional cell carcinoma.However, few patients
with stage D, carcinoma are cured by radiotherapy alone. 197 Hemorrhage
can be improved in about half the patients, but local irritative symptoms
are seldom improved and are often worsened by therapy. 198 Urinary diver-
sion may be important in such patients. Radiotherapy has an important role
in the treatment of painful local metastatic lesions to the skeletal system.
Chemotherapy. Until recently, the effect of various chemotherapeutic
agents on bladder cancer has been studied sporadically. The patient popula-
tions have been heterogeneous, the criteria for response have been inconsis-
tent from author to author, and series have often included patients without
measurable metastases. The interpretation of such reports is difficult and
accounts for the variability in response that has been reported. 199
S-Fluorouracil. This was one of the earliest agents used in the treatment of
bladder cancer. Response rates vary from to 75 per cent, depending on the
stage of tumor treated, the dosage, and the criteria of response. A randomized
study of patients with metastatic bladder cancer was conducted by Prout et
which patients received either 5-fluorouracil or a placebo. They found
«/.-"" in
no improved survival in those treated with the chemotherapeutic agent. How-

ever, most patients did not have measurable metastases and had far-advanced
disease that would not be expected to respond to any cytotoxic agent. This drug
has also been combined with radiotherapy, 197 and it has been reported to
improve survival when combined with radiotherapy prior to cystectomy.-" 1
At this time, the true efficacy of 5-fluorouracil is not understood, but it

appears to have some limited cytotoxic effect. However, the published experi-
ence does not appear to justify its use as a single agent for the treatment of
advanced bladder cancer.
Cyclophosphamide This drug appears to produce approximately 25 to 30
.
per cent incidence of regression of metastatic transitional cell carcinoma. 202

The agent is well tolerated when administered in high-dose intermittent
therapy intravenously every three weeks. Its major role may be in combination
with other agents or as a long-term maintenance drug after initial control with
more toxic agents.
Doxorubicin (Adriamycin). Doxorubicin appeared to produce a 24 percent
overall response rate in two collected series. 199, 203 More optimistic reports of a
35 per cent response rate prompted further clinical trials. 204 Yagoda et al. 2m
subsequently reported an objective response rate of only 16 per cent. In a
prospective randomized trial comparing doxorubicin to other chemotherapeu-
tic agents, the response rate of patients at MD
Anderson Hospital and UCLA
Hospital was 35 per cent. Most patients had only partial regression or tempo-
ran stabilization of tumor growth. One patient had almost complete disappear-
ance of measurable tumors (unpublished data).
Although doxorubicin appears to have some function in bladder cancel
therapy, the published results fail to demonstrate a consistent effect, and
toxicity can be severe. Cardiotoxicity limits the dose of the drug and restricts its
use to patients without cardiac disease. In the age group of patients with
advanced bladder cancer, a significant percentage of patients have cardiac-
disease, and this limits the applicability of the agent.
Methotrexate. This drug has been known to have an effect against bladder
cancer, especially when used in high doses with leucovorin detoxifica-
202 2<Mi
tion. -
Further studies with this agent are justified, and it may have an
important role in bladder cancer therapy in the future.
Cisplatin. This agent was shown to be effective against an experimental
bladder tumor, 207 and it has since been reported to produce regression of
advanced human transitional cell carcinoma. Yagoda 202 and Yagoda et a/. 208
reported a 50 per cent response rate in patients who had not received previous
chemotherapy. However, side effects were severe, and responses were of short
duration. Other studies have also supported the efficacy of this agent in bladder
cancer therapy. 209 The agent has significant auditory and renal toxicity in
addition to the severe gastrointestinal side effects. 210 Further prospective
randomized studies are needed before the value of this toxic drug can be
accurately determined.
Other Agents. Other single agents have occasionally been used in the
treatment of advanced bladder cancer. Mitomycin-C, vincristine, and YM-26
have been shown to produce occasional response but do not appear to be
significantly effective against transitional cell carcinoma. 211
Intra-arterial infusion of chemotherapeutic agents provides a high level of
drug in the tissue of the tumor area. Constant arterial infusion of 5-
fluorouracil 212 or mitomycin-C 213 has been shown to produce marked reduction
in tumor size in some patients. We have seen occasional dramatic response of
tumors that were too large to resect primarily. Complications of this form of
therapy, however, can be significant, both from the insertion and placement of
the catheters and from the effects of high levels of cytotoxic drugs in the soft
tissue of the pelvis.
The combination of several chemotherapeutic agents provides the theoretic-
advantage of additive cell kill to different cytotoxic mechanisms and the
practical advantages of dissimilar toxicities. Initial combinations of agents
214
failed to show an additive therapeutic value, 208,
but the preliminary report by
215
Sternberg et al. demonstrated an objective response in nine often patients
treated with a combination of DDP, doxorubicin, and cyclophosphamide.
Other combinations will certainly be forthcoming and may prove to be more
beneficial than single agents.
Symptomatic Therapy. Treatment of the patient with advanced bladder
cancer should be directed not only at the control of tumor growth and dissemin-
ation but also at the control of debilitating symptoms. The judicious use of
various methods of symptomatic therapy may improve the quality of life to a
196
greater extent than more definitive therapeutic methods. Stewart and Novick
thoroughly described the available methods for the control of symptoms.
216
Hydrostatic pressure has been advocated by Helmstein for the control of
hemorrhage and is especially effective in patients with large, superficial
tumors. The instillation of formalin has been shown to control bladder hemor-
rhage, and toxicity can be minimized by using a dilute solution (4 per cent) and
157
by careful attention to the details of instillation.
Our experience has been gratifying, and we have obtained control of hemor-
rhage due to radiation, cyclophosphamide cystitis, and large bladder tumors.
Bleeding usually ceases 24 hours after instillation, but may recur, and several
instillations may be necessary. Silver nitrate and phenol have also been
advocated as potentially useful intravesical chemicals for the control of hemor-
2IH
rhage. 217 -

An important area of future effort must be in the identification of carcinogens
and the mass screening of high-risk populations. Current methods of urine
cytology arc inadequate for mass screening, but efforts are presently underway
19
to develop rapid mechanical analysis of urine samples.-' In the near future,
screening urine cytology may be rapid and inexpensive and may become a
routine part of the physical examination.
The tumor depends not only on the
natural history of an individual bladder
innate malignant potential of the tumor but also on poorly understood host-
defense mechanisms. Recent research has attempted to provide explanations
regarding the implications of both aspects. Several methods have recently been
proposed that assist in determining the potential for a tumor to recur or
metastasize. Chromosome studies have indicated a relationship between chro-
mosome number and pattern and the potential for tumor recurrence. 220 The
recent observation that the loss of the blood group antigens from the surface of
bladder tumors is associated with poor prognosis also suggests a relatively
simple method for segregating tumors according to likelihood of recurrence
and metastases. 133, 134
The influence that the host-immune response exerts on the bladder tumor
has been extensively studied in recent years. Although the data are not always
consistent, the weight of evidence suggests that patients with bladder tumor
have an altered cellular and humoral immune response. 221 Immunotherapy was
then felt to be a logical method to improve the host-immune response against
bladder tumors, and several studies have been reported. Morales and Ei-
dinger 222 reported a decreased recurrence rate of superficial bladder tumors
following intravesical instillation of bacillus Calmette-Guerin combined with
'
cutaneous sensitization. Brosman, 22 however, found no objective regression in

5
31 patients with metastatic bladder cancer so treated. Corynebacterium par-

vum was demonstrated in our laboratory to be effective against the experimen-
tal FANFT-induced bladder tumor model.
224
An effect against human bladder
cancer has thus far not been demonstrated. To date, levamisole, when used as
an adjuvant following surgical therapy, has not been shown to be effective in
decreasing the incidence of tumor recurrence (unpublished data). Therefore,
up until the present, immunotherapy has not found a significant role in bladder
therapy. However, the principle is still viable, especially in the presence of

microscopic disease, and further immunotherapy trials based on sound labora-
tory experiments may yet have an important influence on bladder carcino-
ma.
An area of major importance in the future of bladder cancer therapy is the role
of adjuvant therapy. As noted previously, even after the most skilled surgerj
and radiation therapy, the incidence of recurrence or persistence of invasive
tumor is greater than 50 per cent. The five-year survival rate for patients with
invasive bladder cancer is approximately 30 per cent after definitive therapy,
and only a small percentage (approximately 8 per cent) have local recurrence in
the pelvis. It therefore appears that most patients succumb to micrometastatic
disease that is present at the time of definitive surgery. The role for systemic
adjuvants is therefore clear. An important prerequisite to adjuvant therapy,
however, is the availability of effective therapeutic agents to justify the imposi-
tion of the toxicity on many patients who indeed are tumor free. The response
rate to DDP, doxorubicin, and cyclophosphamide seems to justify their use as
adjuvant agents. However, such adjuvant therapy is justifiable only in the
context of a controlled prospective randomized study. Anecdotal reports tend
to encourage a form of therapy that subjects an entire patient population to risk
and discomfort for the purpose of aiding only an undefined portion of that
population, i.e., those who harbor micrometastatic tumor. Within these con-
straints, however, adjuvant therapy must be pursued, since it appears that
surgery and radiation therapy will have little further impact on survival. This
explains, in part, the important observations of McCarron and Marshall,
225
who
reported only a slight improvement in the survival rate of patients with invasive
bladder cancer over the past 25 years, in spite of refinements in the treatment of
the primary tumor.
Section 3
Renal Cell Carcinoma

Jean B. deKernion
INTRODUCTION
Renal cell carcinoma (renal adenocarcinoma, hypernephroma, Grawitz'

tumor) is the most common malignancy of the kidney and accounts for ap-
226
proximately 3 per cent of adult malignancies. It is a cancer of adults,
primarily those in the fifth to seventh decades of life, but may occasionally
226 227
occur in the period between infancy and young adulthood.
'
Renal carcinoma occurs most frequently in urban-dwelling males. 228

cell
Familial associations have occasionally been reported, with as many as
226,228
five family members developing the tumor. Other diseases, such
229
as von Hippel-Lindau's disease and polycystic kidney disease, have
been shown to predispose to the development of renal adenocarcinoma.
Neither viral agents nor specific genetic defects have been identified in
these patients.
The origin of the tumor is the proximal convoluted tubule, 2 '
but the
stimulus for neoplastic transformation has not been determined. Many etio-
22
logic agents have been identified in various animals, " but similar associa-
tions have not been firmly established in the human tumor. Cigarette smok-
ing has been shown have a relative risk factor of 2.46 in males, and other
to
epidemiologic studies have supported the role of tobacco as an etiologic
agent. 231,232 Pipe and cigar smoking were associated with a high incidence
of renal carcinoma in the British study by Bennington and Labuscher. 233
Hormonal and chemical agents have not been proved to play an important
role in the etiology. Dieth\ lstilbestrol, which causes a typical renal cell
234
carcinoma in adult Syrian hampsters, has not been shown to be associat-
ed with an increased risk of cancer in humans. Occupational exposure to
carcinogens has not been linked to renal carcinoma, although a recent
study suggested an increased risk in men exposed to cadmium, especially
in those who also smoked cigarettes. 23: Exposure to radiation does not seem
'
to be associated with an increased incidence of renal cancer. However, pa-

tients who had received the radiographic agent thorotrast, an alpha emit-
ter, had a significantly higher incidence of development of renal carcinoma
6
than the general population. 2 '
NATURAL HISTORY
Classification
Renal cell carcinomas are classified according to stage (to be given),

grade, and histologic type. Nuclear and cellular grading seems to have a
direct effect on prognosis, irrespective of the stage of the disease. 237-2 8 His- '
tologic pattern and cell type also appear to influence the prognosis. A re-
cent series found that tumors with a papillary pattern had a better progno-
sis than other histologic patterns. 239 Patients with clear cell tumors have a
slightly better survival rate than patients with those tumors also containing
granular cells. The spindle cell form is associated with the worst prognosis,
with an approximate 23 per cent survival rate at five years. 237
Small tumors composed of well-differentiated clear cells have occasion-
ally been designated adenomas. Bell 240 used size as the criterion of malig-
nancy, suggesting that lesions over 3 cm in diameter had a greater malig-
nant potential. His report has been misinterpreted to suggest that lesions
under 3 cm in diameter are benign and those greater than 3 cm are malig-
nant. No such division is practical or defensible, and all renal tumors
should be considered renal adenocarcinomas. Proper histologic grading is a
better criterion of propensity for metastases than size alone.
Clinical Features
The major presenting symptoms of renal cell carcinoma are pain, hema-
turia, presence of an abdominal mass, or stigmata of local extension or met-
astatic disease, such as weight loss and anemia. The classic triad of symp-
toms ascribed to renal carcinoma —
hematuria, abdominal mass, and flank
pain —
is found in only a very few patients and usually indicates far-
advanced disease. 241 The tumor is not infrequently an incidental finding on

routine physical examination, or metastases may be noted on examination
for nonspecific symptoms. Fever and sudden onset of a varicocele may be
the only presenting complaint.
Paraneoplastic syndromes are sometimes associated with renal carcinoma
and may present as the diagnostic sign. Hypercalcemia occurs not infre-
quently but is usually a manifestation of extensive skeletal involvement
Parathyroid-like hormone production by primary renal carcinomas has been
reported. 242 In approximately 3 per cent of patients, the presence of a pri-
mary renal carcinoma stimulates an erythropoietin-like substance by an un-
known mechanism. The resultant erythrocytosis may produce the present-
ing symptoms, and approximately 3 per cent of patients with this condition
have been reported to have occult renal carcinomas. 243 In 15 to 40 per cent
of patients, hypertension is present. Sufrin et al. 244 have demonstrated ele-
vated peripheral renin levels, especially in patients with high-stage and
anaplastic lesions. Nephrectomy caused a fall in the plasma renin level,
and the authors suggest the future use of this determination as a marker to
detect occult disease. An increase in the erythrocyte sedimentation rate has
been reported in most patients with renal cell carcinomas, and some au-
thors have suggested that a marked elevation correlates with poor surviv-
245 - 246
al.
A recognized syndrome of hepatic dysfunction in the absence of liver

metastases has been reported to occur in approximately 40 per cent of pa-
tients with renal carcinoma. 247 This idiopathic syndrome is characterized
by various combinations of hepatosplenomegaly, elevated alkaline phos-
phatase levels, prolonged prothrombin time, or elevated serum haptoglobin
levels. Liver function may return to normal, and the associated hepatomega-
ly may disappear after nephrectomy, but most of these patients die within
five years. 248
Diagnosis
Significant advances have been made

study of renal mass lesions
in the
in recent years. Sophisticated invasive and noninvasive techniques have
been devised to discern whether a space-occupying renal lesion is a cyst or
a solid tumor. Intravenous urography, nephrotomography, selective arteri-
ography, pharmacoangiography, venacavography, ultrasonography, radionu-
clide scan, percutaneous needle aspiration and biopsy, and computerized
axial tomograph) are all in common use. The degree to which each contrib-
utes information that is important to decision making, and the cost-
effectiveness ratio of each are subjects of interest and controversy among

radiologists and urologists. Considerable disagreement exists as to the se-
quence which the various tests should be utilized and the point at which
in
diagnostic studies should yield exploration and treatment.
A
systematic approach to diagnosis is suggested in Figure 10-2. This is a
modification of that suggested by Lang. 249 The scheme is first initiated on
the basis of the presence or absence of symptoms and relies upon the accu-
racy of infusion nephrotomography and ultrasonography to determine the
sequence of renal angiography and puncture of the renal mass. Nephroto-
mography has been shown to be highly accurate in diagnosing renal cysts,
and when cyst puncture added, the accuracy approaches 100 per cent. 250
is
Ultrasonography should be used only as an adjunct in the diagnosis of renal

mass lesions. In view of the small, but definite, misinterpretation of ultraso-
nography, even in the most skilled hands, it should never be the final step
in the diagnostic evaluation of renal masses. It should assist in deciding
when the presence of a benign cyst is likely, making aspiration a rational
next step.
The imposition of needle aspiration and biopsy of suspected renal cysts
have been promulgated by interested radiologists, who view this procedure
as an extension of their diagnostic acumen. The procedure is not without
complications, such as hemorrhage and perforation of adjacent viscera.
However, in skilled hands with proper radiographic monitoring, major com-
plications rarely occur. 251 The greatest concern has been the prospect of
seeding tumor in the needle tract, and this has been reported. 252 We have
also observed tumor growth in needle tracts in two patients after percutane-
ous aspiration of renal carcinoma metastases. However, with the use of the
thin-walled 20-gauge needle, this has never been reported. Nonethele^.
blind percutaneous puncture of a mass, which has a high possibility of con-
taining tumor, is not warranted and will add little to accuracy or decision
ASYMPTOMATIC SYMPTOMATIC
MASS MASS
SCREENING
EXAMINATION NEPHROTOMOGRAM
l~~---^_
^ ULTRASOUND
I
STEP I. RADIONUCLIDE SCAN CYST PUNCTURE RENAL ARTERIOGRAM
STEP Z CYST PUNCTURE-*'' RENAL ARTERIOGRAM NEPHRECTOMY
STEP 3. NEPHRECTOMY
•••••Column of Berlin
—— Avosculor, Cystic
Not Proven Cyst by oil Criteria
Înconclusive; or Diagnostic
of Renal Cancer
FIGURE 10-2. Systematized diagnostic approach to the assessment of renal mass lesions: cyst
puncture and aspiration test complex (CPATC).
making. Percutaneous needle aspiration should be limited to patients in

whom the diagnosis, which is reached by nephrotomography or ultrasound,
or both, is a benign cyst or to patients in whom mitigating circumstances
make angiography or surgery unduly hazardous.
This approach to the evaluation of renal masses is controversial, especially
with respect to the use of percutaneous needle aspiration and the role of
ultrasound. Many of these issues may become moot if computerized axial
tomography proves to be reliable in the diagnosis of intrarenal masses.
Staging
As with any malignant tumor, staging must be based on factors that in-
fluence survival. Renal vein involvement has long been thought to be asso-
ciated with a poor prognosis, 253,254 but recent studies fail to show such a
correlation. 237 This is perhaps due to the emphasis in recent years on com-
plete excision of the renal veins and identification of renal vein involve-
ment preoperatively. If properly managed, the extension of tumor into the
renal veins and inferior vena cava does not significantly compromise sur-
vival. 255 256 The size of the primary tumor is only loosely correlated with
*
survival and is not a major factor in staging. 240, 245

The staging factors that have been shown to influence prognosis are re-
gional lymph node involvement, invasion through the renal capsule, exten-
sion to contiguous organs, and distant dissemination. The presence of
tumor in the lymph nodes draining the renal parenchyma is a dire prognos-
tic sign, and the five-year survival rate is approximately 33 per cent. Tumor
invasion through Gerota's fascia into the perinephric fat was a greater detri-
ment to survival prior to the widespread adoption of radical nephrectomy
when the renal capsule was not excised. Even after radical excision of
Gerota's fascia with the kidney, the extension of tumor into the perinephric
fat decreases the five-year survival rate to about 45 per cent.
255
When tumor
extends to contiguous organs, rarely does a patient survive five years, even
after surgical excision. The significance of local tumor recurrence (or persis-
tence) is reflected in our study of patients with metastatic renal carcino-
ma. 260 Those who had the tumor incompletely excised (usually owing to con-
tiguous extension) had a much poorer prognosis than those who developed
distant metastases without local recurrence of tumor.
The staging system commonly in use is Robson's 257 modification of the
system of Flocks and Kadesky, 258 which is graphically depicted in Figure
10-3. The shortcomings of the system become obvious when it is noted that
the survival rate of patients with stage II (or B) tumor is less than that of
patients with stage III (or C) disease, indicating an inappropriate assign-
ment of prognostic factors. The grouping of renal vein, vena cava, and
lymph node involvement into stage III causes the survival rate to be
higher, since simple renal vein extension is not a dire prognostic factor.
The TNM system proposed by the American Joint Committee for Cancer
Staging and End-Results Reporting separates venous involvement from
nodal invasion, and quantitates each, and as such, is an improvement over
STAGE E - 22
5yr = 65% 5yr = 47%

10yf56% Oyr >(20%)
FIGURE 10-3. Long-term survival

after nephrectomy in 309 patients
with renal cell carcinoma. Results
are grouped according to the patho-
STAGE TH - 108 STAGE H - 77
logic stage of the lesion, From Skin-

t
ner DC;, ei at.: J Urol 707:705, 1972.)
PLUS rjisloni metastases
or eilension lo contiguous
•iscerol structures
the system in common use (Table 10-3). Tumors extending into the capsule
are grouped with those extending into the vein in the T category but art- :!
separated by subclasses (T 3a T 3b T^). The shortcoming of the proposed

, ,
TXM system is the number of subgroups, which are cumbersome and deter
enthusiastic acceptance by clinicians.
Prognosis
Thenatural history of renal cell carcinoma is more unpredictable than

that of most tumors and has been a subject of interest to urologists for main
decades. The tumor is the second most common tumor known to undergo
spontaneous regression following resection of the primary lesion. Thus
far, approximately 60 cases of spontaneous regression of renal cell carcino-
ma have been reported in the literature, 243 although biopsy confirmation of
TABLE 10-3. Stage Classification of Renal Cell Carcinoma
Tumor Status Robson-' TNM

No primary — To
Small primary, minimal distortion A T,
Large tumor, renal distortion A T 2
Involving perinephric tissues B T3a

Involving renal vein C T 3b
Involving renal vein and inferior
vena cava C T*
Invading adjacent structures D T 4a
Involving superior vena cava C T 4„
No nodes involved A, B No
Single, ipsilateral node involved C N,
Involvement of multiple regional
nodes C Ni
Fixed regional nodes C N 3
Involved juxtaregional nodes C N 4

Distant metastases D M,
metastases was usually not obtained. A further unusual manifestation of

renal cell carcinoma is the variability in growth of the primary tumor,
which occasionally remains localized for many years. Sometimes metastatic
foci appear to have a propensity for long periods of growth arrest, and met-
astatic lesions have been identified many years complete removal of
after
the primary tumor. Finally, the behavior of metastatic foci is unusual in the
frequently observed varying growth rate and tumor doubling time of metas-
tases, particularly pulmonary lesions. Pulmonary parenchymal metastases
may temporarily regress or undergo growth arrest for varying periods, fol-
lowed by a sudden decrease in tumor doubling time. This unusual behav-
ior in some patients, however, does not detract from the lethality of this
neoplasm.
The largest series of patients with untreated renal cell carcinoma was
reported by Riches in 1964. 259 The three-year survival rate was 4.4 per cent,
and the five-year survival rate was 1.7 per cent for 443 untreated patients.
Only occasionally have patients with disease limited to the kidney not
been operated on, and most develop local progression and metastatic
spread within five years.
Survival appears to be dependent mainly upon the extent to which tumor
has invaded and spread locally and upon the presence or absence of distant
metastases. The influence of local invasion and spread will be discussed
subsequently. Once metastases develop, survival depends primarily on the
extent of the disease and the interval between nephrectomy and the ap-
pearance of metastases. 260 Figure 10—4 demonstrates the cumulative surviv-
al rate for 86 patients with metastatic renal cell carcinoma who were fol-
lowed at UCLA and affiliated hospitals between 1972 and 1976. The
one-year survival rate of 42 per cent and the five-year survival rate of 12
per cent are higher than those previously reported. 261, 262 However, when
the patients are segregated into groups according to the time of appearance
of metastases, the dire prognosis of those with metastases when first diag-
nosed is apparent. Figure 10-5 demonstrates that patients who had metas-
tases at the time of diagnosis, or developed them within six months, had a
one-year survival rate of only 10 per cent, and all had died by two and a
half years. Those who developed metastases more than two years after
nephrectomy had a one-year survival rate of 55 per cent and a five-year
<
>
>
cr
FIGURE 10-4. Cumulative survival of 86 pa-

> tients with metastatic renal cell carcinoma treated
I-
< atUCLA and affiliated hospitals between 1972
and 1976. 261262
3
O
MONTHS
,0 DISEASE FREE INTERVAL (mo.)

7
.8-
<
FIGURE
rate
10-5. The cumulative survival
from the date of diagnosis of metasta-
>
>
cr .6-
w
sis forpatients at UCLA who had metasta-
<r>
ses at the time of diagnosis or developed
them within 6 months (line marked 0-6), > .4-
compared with the cumulative survival of I-
< >24
/
patients who developed metastases more
than 24 months after nephrectomy (line .2-
.0-6
marked >24). 261262 <_>
—— ———
"i
i
12
~i
24
i i
36
i r~
48
~~
60
I
— I
72
1
MONTHS
survival rate of 22 per cent after recognition of metastases. Katz and

Davis 262 reported an 18 per cent one-year survival rate in such patients, and
Middleton 261 reported no survivors after two years. These statistics empha-
size that most patients who develop metastases have an unrelenting pro-
gression of tumor within a short time.
Spontaneous regression occurs in less than 1 per cent of cases, 263 empha-
sizing the rarity of this occurrence. Furthermore, some of these regressions
may not have been permanent spontaneous cures but simply transient re-
gressions of lesions that were never biopsied.
TREATMENT
Surgery
Primary Renal Carcinoma. The mainstay of treatment of primary

renal carcinoma is surgical excision. The objective must be to completely
excise all been advo-
the local tumor. In the past, simple nephrectomy had
cated, but the current practice of radical nephrectomy appears to have sig-
nificantly increased patient survival. 264, 265 Radical nephrectomy includes
the excision of Gerota's fascia and its contents, including the kidney and
adrenal gland. In all previous reports, the invasion of perinephric fat has
been shown be an important determinant of survival, and this can be
to
expected to be seriously compromised by leaving microscopic or gross
tumor in Gerota's fascia after a simple nephrectomy. 255-257 Similarly, al-
though the importance of renal vein invasion has been debated, failure to
remove gross tumor from the renal vein results in a decreased prognosis.
The importance of the radical nephrectomy is, therefore, obvious. The role
of adjuvant preoperative or postoperative radiotherapy is discussed in a
subsequent section of this chapter.
Those who have reported an improved survival rate in renal carcinoma
following radical nephrectomy have also attributed this improvement to the
excision of the regional lymph nodes. 241,284 Regional nodal involvement is
unquestionably an important prognostic factor, since it indicates dissemina-

tion. In most not possible to segregate and analyze the survival
series, it is
rate of patients with lymph node metastases to assess their influence on the
rate of survival. Skinner et a/. 255 reported a 17 per cent ten-year survival
rate in patientswith regional node involvement. The extent and location of
the involvement of regional nodes, as well as the number of patients who
received postoperative radiotherapy, is not known. It seems reasonable that
the improved survival rate that has occurred since the advent of radical
nephrectomy with lymphadenectomy more likely stems from more com-
plete excision of the tumor than from excision of involved regional lymph
nodes. Although an occasional patient may be cured when only one or two
nodes contain tumor, the true contribution of lymphadenectomy to survival
has not been demonstrated. It is, however, a valuable method of staging
and will become more important as adjuvant clinical treatment trials are in-
stituted.
The surgical technique of radical nephrectomy has been graphically de-
scribed by several authors, 2 "" -268 and the approach is guided more by indi-
vidual preference than by necessity. Stewart 269 prefers a transperitoneal ap-
proach through a subcostal incision, thus allowing early ligation of the
renal artery and vein before tumor manipulation. This is an essential factor
in surgery for renal carcinoma, and any approach used must incorporate
this prerequisite. Others have employed extraperitoneal and extrapleural
flank incisions or midline transabdominal incisions.
A modification of the thoracoabdominal incision described by Chute et
270
al. is especially suitable for large and upper pole lesions. The surgical
technique of approach has been thorough-
this intrapleural, extraperitoneal
ly described. Considerable dissection is performed prior to ligating the ves-
sels, but this can be done safely in skilled hands without tumor manipula-
271
tion. The dorsolumbar osteoplastic flap, as described by Nagamatsu, also
provides excellent exposure. The main limitation of transperitoneal anterior
approaches is the difficulty in dissecting the para-aortic and paracaval
lymph nodes above the renal pedicle, especially on the left side. Advocates
of this approach, however, feel comfortable with the thoroughness of the
procedure and have little difficulty removing the large upper pole tumors
after early ligation of the vessels. Occasionally, a flank approach utilizing
the eleventh interspace allows excellent exposure without producing the
added morbidity of entering the chest or peritoneum. We have used this
approach for lower pole renal tumors and have had excellent exposure as
long as the eleventh rib costovertebral ligaments are divided, allowing the
rib to be deflected downward.
With the advent of more sophisticated angiographic methods, preopera-
tive percutaneous transaortic occlusion of the renal artery has been advocat-
ed as a routine procedure. This makes radical nephrectomy technically eas-
ier, since the renal vein can then be divided without first having to dissect
the renal artery, which has already been occluded. This maneuver also de-
creases hemorrhage, especially in patients with large, locally extensive
tumors. Another reason for routine preoperative renal arterial occlusion is
that the destruction of tumor is associated with a stimulation of host im-
mune response. This, however, has not been conclusively demonstrated.

Furthermore, the procedure is sometimes associated with complications
even in the best hands, and the patients suffer considerable pain, fever,
and nausea, which may occasionally compromise their ability to tolerate
extensive surgery. Urologic surgeons have safely and effectively performed
radical nephrectomy, including early ligation of the renal artery and vein,
for years without the benefit and cost of catheter occlusion. Thus far, little
evidence has been produced to suggest that this is appropriate as a routine
measure. However, in patients with very vascular tumors or very large
bulky tumors, this procedure can facilitate radical nephrectomy.
The outcome of surgical therapy for renal carcinoma is affected by tumor
stage, grade, and histologic type. The type of surgical therapy also in-
fluences survival, and statistics prior to the widespread practice of radical
nephrectomy cannot be compared with more recent survival figures. In ad-
dition, the use of various staging systems makes comparison of data impos-
sible. Broad statements can be made, however, with respect to survival
after surgical therapy.
The five-year survival rate after radical nephrectomy for stage I renal car-
cinoma is from 65 to 76 per cent, 2M* *** whereas the survival rate for
241, a45,
patients with stage II lesions varies from approximately 47 to 65 per cent.

In Robson's series, 2,i4 in which all patients underwent radical nephrectomy,
the survival of patients with stage II tumors (extension through capsule)
was identical to that for patients with stage I disease, presumably resulting
from a more thorough excision of tumor and a decreased local tumor recur-
rence. The survival rate of patients with stage III disease varied from 35 to
51 per cent, again depending upon the number of patients included who
had renal vein involvement without lymph node involvement or extracap-
sular extension. It is also important to note that the interpretation of renal
vein invasion varies among pathologists.
Surgery for Bilateral Tumors or Tumor in a Solitary Kid-
ney. There are three treatment options for these problems: in vivo partial
nephrectomy with regional hypothermia, ex vivo ("bench") excision and au-
totransplantation, or complete removal of renal tissue with subsequent
chronic dialysis. 287 Generally, in vivo partial nephrectomy, if feasible, is the
preferred choice for patients with a solitary kidney after prior nephrectomy
for carcinoma. In this case the operation is for a presumed metastasis. In
patients with a tumor in a solitary kidney and no prior history of renal
carcinoma, a more radical regional operation is indicated, combined with
either an in vivo or ex vivo partial nephrectomy, depending on technical
considerations. The final option —
complete removal of renal tissue and di-
alysis —
should be avoided if possible. The quality of life with a residual
partial kidney is better than that for dialysis patients, although five-year
survival rates for these two options are similar.
Metastatic Renal Carcinoma. Since approximately one third of pa-
tients with renal carcinoma have metastases when first diagnosed, and
since approximately 50 per cent of those patients operated on for cure will
develop metastases, the need for systemic therapy is obvious. Surgical in-
tervention, hormones, chemotherapy, and immunotherapy have been used
to treat patients with metastatic renal carcinoma.
Adjunctive Nephrectomy. The practice of excising the primary renal

carcinoma in the presence of metastases has been advocated both for relief
of symptoms secondary to the primary lesion and in the hope of inducing
spontaneous remission of the metastatic foci. Palliative nephrectomy for se-
vere symptoms, such as local pain, hemorrhage, and endocrinopathy, ap-
pears to be justified in the patient who has a reasonable expectation of
survival for at least six months. Several factors, however, influence the pal-
liationproduced by such surgery. First, although pain is a common symp-
tom, few patients have pain that cannot be controlled by narcotic analge-
sics. The presence of severe pain usually indicates invasion of the
abdominal wall, precluding complete surgical excision. As noted, patients
in whom completely excised rarely survive for six months after
tumor is
surgery. 260 Second, life-threatening

hemorrhage from the primary tumor is
not a common occurrence. Third, when performing surgery for palliation, it
is important to understand the prospects for survival. The mean survival
rate of patients with metastases at the time of diagnosis is approximate 1>

four months, and only 10 per cent of such patients survive one year. 260-263
In spite of these qualifiers, however, nephrectomy can produce relief of
troublesome symptoms and improve the quality of life in a selected group
of patients.
The practice of nephrectomy in patients who
present with metastases at
the time of diagnosis and in whom the primary tumor
is not producing
severe symptoms was based upon the hope of inducing spontaneous regres-
sion of metastases or prolonging survival. 272 No clinical trials have affirmed
the benefit of this practice, which stems from observations about the natu-
ral history of renal carcinoma rather than from established fact. First, no
therapy for disseminated renal carcinoma is currently effective, and the sur-
geon is compelled to pursue any method that has even the most remote
potential for benefit. Second, the natural history of renal carcinoma sug-
gests that intrinsic host factors play a role in growth and dissemination of
the tumor. From these observations the concept was extrapolated that an
association existed between the behavior of the distant foci and the pres-
ence of the primary lesion. Third, spontaneous regression of metastases has
been reported in some instances after removal of the primary tumor. 272-274
Since the phenomenon of spontaneous regression is most often inculcated
to justify the practice of palliative or adjunctive nephrectomy, it is impor-
tant to scrutinize the literature to ascertain the validity of the observations
and the incidence with which it occurs.
In 1973, Bloom 274 reported approximately 40 cases of spontaneous regres-
sion of renal carcinoma, and many more have been anecdotally described
in recent years. In all but two instances, regression occurred in patients
with pulmonary metastases, and in 80 per cent of cases the patients were
males. Itimportant to note that most of the patients did not have his-
is
tologic documentation of the metastatic foci, and regression as reported

cannot be equated with long-term cure. Finally, the frequency of spontane-
ous regression of metastases is more important than the absolute number of
reported cases. The frequency of regression is only 0.4 per cent, or one in
250. 263 In many series, spontaneous regression was never noted. No in-
stance of regression was noted in 533 patients reviewed at the Mayo Clin-
ic,-
75
and Mostofi276 reported only two survivors two years after diagnosis in
a substantial series of patients who presented
with metastatic disease.
The frequency of regression of distant metastases after palliative or ad-
junctive nephrectomy is, perhaps, more germane to the discussion. A sum-
mary of recent series of patients undergoing palliative nephrectomy indi-
cates that the frequency of regression was only 0.8 per cent. 263 It is
important to reiterate that many of the metastatic lesions were not docu-
mented by biopsy and that regression was often only for a brief period.
Furthermore, the mortality rate varies from 2 to 15 per cent, depending
upon patient selection. Based on these statistics, it is difficult to support the
routine practice of palliative nephrectomy for the purpose of inducing re-
gression of metastatic lesions.
The impact of palliative or adjunctive nephrectomy on the survival of
patients with metastatic disease, rather than the induction of spontaneous
regression, may be important. Johnson ct al.- 7 ' did not find a significant
difference in the rate of survival between patients who underwent pallia-
tive nephrectomy and those who did not, except in the case of patients
with metastases confined to the skeletal system. In a series of patients stud-
ied at UCLA, a significantly greater survival rate of patients who under-
went palliative nephrectomy was noted. 260 However, this was obviously on
the basis of selection, since only patients in good clinical condition were
considered to be candidates for surgery. In order to assess the influence of
palliative nephrectomy on survival, we compared the cumulative survival
rate of all patients who underwent palliative nephrectomy with the cumula-
tive survival rate of the entire series of patients with metastatic renal carci-
noma, regardless of therapy (Fig. 10-6). It is obvious that the survival rates
of the two groups are identical, suggesting that factors other than the
nephrectomy determined the clinical course. In certain situations, however,
palliative nephrectomy can be supportable.
Patients occasionally present with a limited number of metastases that
are treatable by surgery or definitive radiotherapy. The five-year survival
rate following excision of pulmonary metastases is between 25 and 35 per
cent. 241,261 The excision of other solitary foci of tumor can sometimes pro-
<
>
>
cr
FIGURE 10-6. Cumulative survival rate
of patients at UCLA who underwent pal-
</)
liative nephrectomy, despite metastatic Ld

>
renal cell carcinoma, compared with the r-
cumulative survival of all UCLA patients
<
in the series with metastatic disease, re-
"
gardless of treatment.-' 1
Z>
o Total series
12 24 36 48
MONTHS
duce significant palliation. In the series of patients studied at UCLA, 2,iu

ag-
gressive therapy of solitary skeletal CNS and skin or subcutaneous lesions
produced a significant palliation interval. It seems reasonable, therefore, to
recommend nephrectomy such patients, along with definitive therapy of

in
the limited metastatic foci.A second potential indication for palliative
nephrectomy is in the patient who has been shown to respond to some
form of systemic therapy. Our current management of the patient with an
asymptomatic primary lesion and widely disseminated metastases is to rec-
ommend a three- to four-month trial of systemic therapy, either chemother-
apy or immunotherapy or a combination of both modalities (to be dis-
cussed). If, at the end of the trial period, the metastatic lesions have either
decreased in size or remained stable, no new lesions have developed, and
the patient's general clinical status has not deteriorated, palliative nephrec-
tomy is offered to the patient. It is difficult to determine whether the thera-
py or simply the growth characteristics of the tumor are operative. Regard-
less, such patients can be expected to have a reasonable survival period
and might be well served by excision of the large primary lesion.
Johnson et al. 278 have recently advocated percutaneous renal artery occlu-
sion followed by nephrectomy and hormonal therapy. Several patients in
their series have undergone regression of metastases following the combi-
nation of infarction and nephrectomy, suggesting an immunologic effect.
However, long-term survival occurs rarely, and the data do not yet support
this approach in routine practice.
Radiation Therapy
Radiation therapy has been applied in the treatment of renal cell carcino-
ma in two major areas, including the treatment of metastatic foci and as an
adjuvant to surgical therapy. The role of preoperative radiotherapy is still
controversial. Several reports have shown an increased survival with the
preoperative use of radiotherapy. 279, 28 ° The Genitourinary Oncology Group
has completed a prospective cooperative study to evaluate preoperative ra-
diation therapy (4500 rad) followed by radical nephrectomy versus nephrec-
tomy alone. Preliminary data suggest that the radiotherapy had an impact
on survival, 281 but further long-term follow-up will be necessary to deter-
mine the significance of the findings. The randomized study conducted by
van der Werf-Messing 28 compared 3000 rad of preoperative therapy with
-
no preoperative radiotherapy. The five-year survival rate was not improved,

although the incidence of recurrence in the renal fossa was significantly di-
minished.
264,283
Postoperative radiotherapy has not been shown to affect survival. 245,
Indeed, the rate of survival after postoperative radiotherapy was dimin-
ished in several studies. 284,285
An irrefutable role of radiation therapy is in the treatment of metastatic
foci. Skeletal metastases usually respond with marked relief of pain and
often complete necrosis of the tumor. We have witnessed complete resolu-
tion of abdominal wall and pulmonary metastases after low-dose radiation
therapy. Therapy to the renal fossa in patients in whom tumor has been
incompletely resected has not proved to be very effective in our experi-
ence. The radiotherapist should be an important part of the treatment team
in patients with metastatic renal cell carcinoma.
Hormonal Therapy and Chemotherapy
The observation that progestational agents growth of the

inhibit the
diethylstilbestrol-induced kidney tumor of the golden Syrian hamster pro-
vided the stimulus for clinical trials in humans. 286 The initial report was
encouraging, and isolated reports of tumor regression after progestational
therapy continued to appear. In 1973, Bloom 274 reviewed the literature and
reported an objective response rate of approximately 15 per cent in patients
with metastatic renal carcinoma. These statistics were derived from nonran-
domized studies, and it is possible that the "responses" were simply mani-
festations of the natural history of the tumor. In recent years no report has
substantiated the role of progesterones in the treatment of this disease. In
65 patients treated with either progestational agents or androgens, or both,
at UCLA between 1971 and 1974, no evidence of a single objective re-
sponse was noted. Although the toxicity of progestational therapy (nausea,
vomiting, edema, and breast tenderness and uterine bleeding in the fe-
male) usually is not severe, little evidence exists to support its benefit in
this disease.
Chemotherapeutic agents had no significant effect on metastatic renal
cell carcinoma. Numerous review articles have documented trials of many
single agents with dismal results. 2H:! 28T 2KK Hrushesky 289 recently reviewed
• •
retrospectively the activity of 35 chemotherapeutic agents. He found a 25

per cent objective response rate following therapy with vinblastine sulfate.
This surpassed the activity of any other single agent or any combination of
agents. We have treated 14 patients with vinblastine sulfate and noted sta-
bilization of the growth of metastatic lesions in 3 patients and partial re-
gression in 1 patient. No patient had complete regression of tumor. No re-
sponse to any other chemotherapeutic agent or combination of agents was
observed in 71 patients reviewed. It, therefore, appears that vinblastine sul-
fate is the most effective agent currently available, although its true effect
in inducing regression must be established by future randomized trials.
Immunotherapy
As mentioned previously, the unusual clinical behavior of metastatic

renal cell carcinoma suggests that host immune factors are operative. Fur-
thermore, in recent years considerable evidence has been accumulated that
demonstrates the presence of both circulating and cellular immune re-
sponses in patients with renal cell carcinoma. 290 One of the first reports of
immunotherapy was that of Horn and Horn, 291 who transfused serum from a
cured patient into a family member with metastatic carcinoma. Transfer of
allogeneic lymphocytes has also been reported. 292 Bacillus Calmette-Guerin
increased the survival rate of a small series of patients compared with an

untreated control group, but the difference was not statistically signifi-
cant. 293 The use of passive immunotherapeutic agents has also been report-
ed.
Montie et al. 294 observed stabilization of the growth of metastatic lesions
in a few patients treated with transfer factor. Ramming and deKemion 295
reported the results of a trial of treatment with xenogeneic immune RXA in
patients with metastatic renal cell carcinoma. No patients were cured of
their disease by the therapy, but the survival rate of RXA-treated patients
was improved over that of a matched historic control population of patients
from the same institution. A randomized prospective trial of patients with
minimum residual disease will be necessary to determine the role of im-
mune RNA in the treatment of renal carcinoma.
Section 4
Testicular Carcinoma
Donald G Skinner Robert B Smith
INTRODUCTION
Carcinoma of the is a relatively rare tumor, accounting for approxi-
testicle
mately 1 per cent of malignant neoplasms in the male; 296 however, it
all
represents the most common solid tumor of males between the ages of 29 and
35 years. 296 297 Testis tumors have been noted in males ranging from the new-
«
born to those in the ninth decade of life.

Seminoma is the most common histologic type of testicular germinal neo-
plasm reported in the literature, composing from 27 to 71 per cent of testicular
tumors. Upon review of 7500 cases of testis tumor in the literature, the
incidence of pure seminoma is 47.7 per cent (3540 of 7401 cases of testis
tumors), and seminoma mixed with other tumor elements occurs in 13.2 per
cent of cases. 296 298 The average age of patients presenting with seminoma is
'
37 years.
There are three peak age groups in which testis tumors are usually seen,
and within each age group the usual cell type encountered varies. In the
infant group, embryonal cell carcinoma and yolk sac tumors predominate,
whereas seminomas have never been reported. In the young adult, all varie-
ties of germinal tumor occur, but in the older group (over 50 years), seminoma
is by far the most common testicular neoplasm.
The incidence of testis tumor

is 2.1 per 100,000 males per year in the
United States, 297 ' 2 " but

incidence varies significantly within other geo-
this
graphic areas, such as Denmark, where an incidence as high as 6.3 per
100,000 per year has been recorded. 298-300 Differences are also present among
racial groups. The incidence of testicular malignancies in blacks is one sixth
to one eighth that of the white population. This difference occurs regardless of
which geographic black population is studied, including the American Afri-
can blacks. 301 A less dramatic lower incidence also exists among those of the
Oriental race.
There are potential causative factors that have more than a casual relation-
ship to testis tumors, the strongest of which cryptorchidism. Patients with
is
cryptorchid testes can be expected to have a 10- to 40-fold increase in the

incidence of malignant degeneration of the testicle, compared with those who
have had normal testicular descent. Gilbert and Hamilton 302 and Saueref a/. 303
have reported that 1 in 80 inguinal testes and 1 in 20 abdominal testes will
become malignant. Orchiopexy may not prevent this malignant degenera-
tion, 804, 305 but only a few cases of testis tumors have been reported in children
who had undergone this procedure prior to the age of 10 years and no cases
have been reported when the procedure was performed prior to the age of six
years. Early orchiopexy, therefore, may have a preventive role in regard to
subsequent tumor formation.
The fact that 20 per cent of crypto rchid-associated testis tumors occur in the
contralateral, normally descended scrotal testis indicates that testicular dys-
genesis may be an important etiologic factor in these children, rather than
increased temperature as was previously believed. The dysgenetic theory is
further enhanced by the high incidence of testis tumors in the testicular
feminization syndrome. 306 The higher-than-expected incidence of bilateral
tumors (either synchronous or asynchronous) also points to some underlying
dysplasia.
Trauma, testicular atrophy (from mumps orchitis), 307 familial genetic predis-
position, and radiation have also been mentioned as possible factors affecting
the incidence of testicular tumors.
NATURAL HISTORY
Classification and Pathology
The and natural history of germinal tumors of the testis are

classification
based on embryology and a realization that nearly all these neoplasms arise
from the primordial germ cell, the multipotential cell that migrates in the
embryo from the yolk sac to line the somatic portion of the testis. 308 The
acceptance of this concept clarifies the understanding of testis tumor classifi-
cation and explains why a wide variety of cell types may be found within the
primary tumor or why metastatic foci may be composed of more mature or
differentcomponents than those found in the primary tumor, and vice versa.
Figure 10-7 illustrates the current concept of pathogenesis or development of
the various tumor types from the primordial germ cells.
SPERMATOCYTES
t
Spermatogenesis
t
PRIMORDIAL GERM CELLS
Pathogenesis
GERMINOMA (Seminoma) EMBRYONAL CELL CARCINOMA FIGURE 10-7. Pathways of differentiation and
i transformation of testicular tumors. (From Fried-
Vitelliculogenesis man NB: West] Med 726:302, 1977
I
YOLK SAC
TERAT0CARC1N0MA TUMOR
Maturation
I
ADULT TERATOMA
(Frie4»«., 1976)
There continues to be some controversy as to whether or not embryonal

carcinoma, the stem cell for all other nonseminomatous tumors, arises directly
from the primordial germ cells or whether it is derived from seminomas,
suggesting that the seminoma or germinoma may give rise to the more biologi-
cally active tumors —
the embryonal carcinoma group. 309 The natural history
suggests that in most cases they are distinct groups, arising by pathogenesis
from the primordial germ cells. Pure choriocarcinoma is an exceedingly rare
tumor, composing only 0.4 per cent of all primary germinal tumors. 310 Strict
histologic criteria are required to warrant such a diagnosis. Two cellular
components, syncytial trophoblastic and cytotrophoblastic cells, must be
readily identified and arranged in a papillary or pseudovillous pattern. 310
Focal areas of choriocarcinoma, however, are seen in approximately 12 per
cent of embryonal carcinomas and teratocarcinomas.
So-called "adult teratomas" usually contain microscopic foci of embryonal
elements that can be found only on complete serial section of the entire testis.
Hence, they often metastasize and should be considered and treated as terato-
carcinoma. Several points should be emphasized concerning nonseminoma
classification and staging. If pure choriocarcinoma is excluded, survival is not
statistically influenced by cell type. This observation includes patients with
pure embryonal carcinoma, teratocarcinoma, and mixtures with seminoma or
choriocarcinoma. Also, there is a natural tendency toward maturation or the
development of adult teratomatous tissue. Thus, it comes as no surprise to
find primary tumors containing a wide variety of cell types as well as different
and often more mature histologic patterns in metastases. There are increasing
clinical reports of extremely primitive anaplastic primary tumors metastasiz-
ing as adult mature teratomas, often following or associated with chemothera-
py 3ii-3i4 c urren t evidence suggests that this may occur naturally or may be
hastened by chemotherapy.
There are two variants of seminoma in addition to the classic form: anaplas-
tic seminoma and spermatocytic seminoma. Anaplastic seminoma, which is
the type found in 10 per cent of seminoma patients, is diagnosed if more than
three mitoses per high-powered field are noted, without trophoblastic ele-
ments. Although the age incidence is identical to that of typical seminoma,
patients have a 70 per cent overall survival rate, compared with a nearly 90
314
per cent survival rate with classic seminoma. 313, This decrease in survival
seems to be related to the fact that anaplastic seminoma presents with a higher
stage of disease when is made
the diagnosis than does the classic seminoma.
When one compares seminoma and anaplastic seminoma of similar
the classic
stages, the survival rate is identical. 315-317 Kademian and associates, 318 howev-
er, have reported eight patients with anaplastic seminoma with survival sug-
gesting that the prognosis poorer than with typical seminoma, even when
is
diseases are compared stage for stage. The treatment of anaplastic seminoma
should be the same as for classic seminoma, although some workers recom-
mend 500 to 1000 rad additional radiation therapy for those with anaplastic
seminoma. 319 Others state that anaplastic seminoma should be treated with
retroperitoneal lymph node dissection 320 or adjuvant chemotherapy. 318
Spermatocytic seminoma, the other variant, appears to be a neoplasm that is
distinct from seminoma with a different natural history. Features that dif-
ferentiate this tumor from typical seminoma include the advanced age of
onset (70 per cent of patients are over 50 years of age 321 ) and its tendency not
to metastasize.
321
However, Jackson and Magner322 reported four of five pa-
tients with spermatocytic seminoma dying of disease. A review of these cases
by other workers has shown that these four patients were incorrectly diag-
nosed as having spermatocytic seminoma and, in fact, had anaplastic semino-
ma.
This variant has never been reported to occur in a cryptorchid testis and has
not been reported to be mixed with other nonseminomatous germinal tumors,
as occurs frequently with classic seminoma. Of all seminomas, 3.5 to 7.5 per
cent are of the spermatocytic variety. Six per cent are bilateral, compared with
only 2 per cent of classic seminomas. Macroscopically, spermatocytic semino-
mas are yellow-white or gray and are softer than typical seminomas. They are
often gelatinous with inner space cystic areas.
Rosai et al. 323 postulate that spermatocytic seminomas originate from dif-
ferent cells than do classic seminomas. They feel that classic seminoma is
derived from an undifferentiated germ cell, whereas spermatocytic seminoma
originates from relatively mature spermatogonia. The prognosis of spermato-
cytic seminoma is excellent. There have been no documented cases of metas-
tatic disease. It is not certain whether or not radiation therapy is indicated in
spermatocytic seminoma patients.
Metastases
The natural history of germinal tumors of the testis is to metastasize via the
lymphatics to the regional nodes located in the retroperitoneum medial to the
insertion of the spermatic vein into the vena cava for right-sided tumors and to
nodes immediately caudal and medial to the insertion of the spermatic vein
into the renal vein for left-sided tumors. 324 Lymphatic cross-over may occur
and has been clearly shown by lymphangiography, but this has rare clinical
324
application. An exhaustive study by Ray and associates of 321 patients with
germinal tumors of the testis treated at Memorial Sloan-Kettering Cancer
Center over a 27-year period has shown that contralateral nodal involvement
occurred in 15 per cent of right-sided tumors with retroperitoneal metastases,

but in all cases except one, the primary ipsilateral nodes were also involved.
Figure 10-8 illustrates the normal area of possible involvement for right- and
left-sided tumors unless massive disease is present, in which case nodes in
more remote areas may be involved. Approximately 60 to 70 per cent of
patients with nonseminomatous tumors and 25 percent of patients with pure
seminoma will have evidence of lymph node metastases when initially seen
for therapy.
Direct metastases to the external iliac or obturator nodes are seen only
when the primary tumor invades the epididymis or extends up the spermatic-
cord, or they may develop by retrograde filling when the primary retroperiton-
eal area is heavily seeded by tumor emboli, producing considerable mechani-
cal blockage of lymph channels and nodes. Metastases to the groin or inguinal
nodes are rare but may occur if tumor extends through the tunica vaginalis to
involve the scrotum, or if an unsuspected testicular tumor has been explored
transscrotally.
Occasionally, direct vascular spread may occur, but this is usually a late
manifestation of disease and is often associated with extensive retroperitoneal
metastatic tumor. About 20 per cent of 100 consecutive patients seen at the
UCLA Hospital with nonseminomatous testicular tumor presented with ra-
diographic evidence of pulmonary metastases, and nearly all these patients
alsohad concomitant extensive retroperitoneal lymph node metastases. Pure
choriocarcinoma is the only primary testicular tumor with a predilection to
spread via the vascular channels and may bypass the lymphatic route.
Seminoma usually spreads early by way of the lymphatic system and late by
way of the blood system. Up to 26 per cent of patients seen with seminoma
will have positive lymphangiograms.'' 25 Spread to mediastinal or supraclavi-
I
V C AORTA
FIGURE 10-8. The anatomic boundaries for modified retroperitoneal lymph node dissection.
A, The limits of dissection for right-sided tumor. B, The limits of dissection for left-sided tumor.
(From Ray B, et ah: Cancer 33:340, 1974.)
cular nodes usually occurs later, after there is significant retroperitoneal

disease, hut exceptions do exist. Seminomas cause more
ureteral obstruction
commonly than other germinal testis tumors, either by bulk disease or a
"sheet-like growth" in the retroperitoneum. Spread to organs such as lung,
liver, and adrenal gland, or to bone, is a late manifestation of the disease.
When a patient presents with a so-called "pure seminoma" and a negative
lymphangiogram, but has evidence of metastatic disease to the lungs or liver,
one should strongly suspect mat a nonseminomatous tumor element is also
present that was not detected in the primary tumor. Hepatic and pulmonary
metastases are rare in pure seminoma without evidence of other disseminated
disease. It is interesting to note, however, that in an autopsy series of patients
dying from all types of testis tumors, seminoma had a higher incidence of
bony metastases (47 per cent) than did any other germinal neoplasm. - ;i ,;
Clinical Features
Patients with seminoma may have quite bulky primary tumors compared
with the nonseminoma group, which characteristically includes patients in
their early 20s. Nonseminomas may be exceedingly small and difficult to
detect on routine physical examination, even though they may be associated
with extensive metastatic disease.
Most patients complain of a relatively short period of painless swelling,
discomfort, or heaviness in the scrotum. Often they will cite a recent episode
of trauma preceding the swelling; in general the trauma simply draws atten-
tion to the pre-existing tumor. Pain is reported in about 18 per cent of these
patients and prompts some physicians initially to treat a testicular tumor as
epididymitis. Any tender testicular swelling or irregularity that does not re-
spond promptly to antibiotic therapy must be further investigated. Examina-
tion by ultrasound may help differentiate an inflammatory process from a
primary neoplasm. 527
The chance for malignant change in undescended testes, even in those
treated by orchiopexy, occurs often enough to warrant close follow-up and
frequent examination. Any change in testicular consistency calls for surgical
exploration. Some investigators feel that a cryptorchid testis seen after puber-
ty should be removed rather than repositioned in the scrotum.
Diagnosis
A
suspected testicular tumor should first be explored through an inguinal
incision. It is imperative to control the blood supply of the spermatic cord at
the internal ring before the testis is inspected or biopsied. If a malignancy is

confirmed, the cord and its tunica should be further dissected into the retro-
peritoneum proximal to the internal ring. A high ligation is performed, and the
entire specimen is removed. This facilitates removal of the cord stump from
within, should a retroperitoneal node dissection be necessary. Transscrotal
testicular exploration or biopsy should never be done.
Staging
Once the diagnosis of a primary germinal tumor of the testis has been made,
the next step in management is to accurately assess the clinical evidence of
metastatic disease, since proper treatment is highly dependent on staging.
The staging system widely used in the United States is shown in Table
10-4.
Approximately 25 per cent of seminomas are metastatic when first seen. In
an extensive review of the literature of nearly 2400 cases of seminoma, 298 74.7
per cent presented as stage A tumors, 19.5 per cent as stage B tumors, and 5.8
per cent as stage C tumors (Table 10-5).
Certain specific tests are employed in the evaluation and staging of germin-
al tumors of the testis and are generally performed in the sequence that fol-
lows.
Chest X-ray and Full Lung Tomography. Chest x-ray combined with
full lung tomograms is of basic importance in the evaluation of any patient
with a testis tumor. A 6 to 10 per cent higher incidence of metastatic disease
can be detected with tomography than can be seen on a good quality standard
chest x-ray.
Intravenous Pyelography. Intravenous pyelography is a simple
means of evaluating the presence of extensive retroperitoneal disease. Lateral
deviation of the proximal third of the ureter or ureteral obstruction usually
indicates the presence of extensive disease that should be further assessed
with abdominal ultrasound evaluation or occasionally by computerized to-
mography. Patients with evidence of bulky disease based on these studies
require aggressive and special management, as will be discussed later in this
section, and should be designated as having clinical stage B 3 disease.
Bilateral Pedal Lymphangiography. Bilateral pedal lymphangiogra-
phy is capable of detecting the presence of retroperitoneal disease, but there
is controversy regarding its usefulness and application. An overall accuracy
rate as high as 87 per cent has been reported, 328 but most authors report
false-positive rates of 6 to 33 per cent and false-negative rates of 15 to 31 per
"
cent. 329 332 Because of the inaccuracy, the expense of the test, and particularly
TABLE 10-4. Staging System for Testicular Carcinoma
Stage A Tumor is confined to the testicle. There is no evidence of
spread beyond the confines of the scrotum.

Stage B, Evidence of minima/ retroperitoneal lymph node metas-
tases, determined either by retroperitoneal lymph node
dissection or lymphangiogram (less than six positive
nodes, well encapsulated).
Stage B2 Evidence of moderate retroperitoneal lymph node spread
(more than 6 nodes).
Stage B3 Massive retroperitoneal lymph node involvement, usual-
ly a palpable mass on physical examination hut without
evidence of spread above the diaphragm (may directl)
invade contiguous structures).
Stage C Metastatic tumor noted above the diaphragm or to solid
visceral organs (liver, brain, or bone).
TABLE 10-5. Staging of Seminoma Patients at the Time

of Diagnosis*
Stage Number of Patients Percentage
A 1753 74.7
B 457 19.5
C 136 5.8
TOTAL 2346 100.0
"From Smith HB: Iii Genitourinary ('(nicer. Skinner DG and de Kern ion |H rd.sj, Philadelphia, VVB Saunders
Co. HITS
the lymphangitis produced by the oily contrast media, it is our policy not to
perform routine lymphangiography on nonseminomatous tumors. The value
of lymphangiography in the staging of patients with pure seminoma, however,
is unquestioned. It may also be of value in some patients with nonseminoma-
tous stage C disease as a means of documenting the amount of retroperitoneal

tumor prior to the initiation of chemotherapy and subsequent lymphadenec-
tomy.
The radiation therapy treatment plan for seminoma
most centers depends in
on the presence or absence of retroperitoneal disease. Thus, complete evalua-
tion of the retroperitoneal nodes with intravenous pyelogram and bipedal
lymphangiography is essential.
Scalene Lymph Node Biopsy. This test has been advocated by Buck
'
3- 5
and associates but should be reserved for patients with adenopathy, since
'
the morbidity of the procedure approaches the incidence of positive involve-

ment in the absence of palpable adenopathy." 4
Computerized Tomography and Abdominal Ultrasound. These
procedures have been of value in patients with advanced retroperitoneal
disease and can help assess response to therapy as well as surgical planning,
but their routine use in stage A and stage B tumors without other evidence of
massive retroperitoneal involvement is doubtful.
Radionuclide Scanning. These tests have only limited application
in the evaluation of testis tumors. Gallium-67 citrate whole-body scans
may be useful in the accurate localization of tumor in patients with dis-
seminated seminoma 335,336 and should be used for those in whom lymphan-
giograms are not possible because of technical or medical reasons. The
frequent presence of lymphocytic infiltrates in seminomatous tumors most
likely accounts for the accumulation of gallium in these tumors, whereas
nonseminomas rarely have an element of lymphocytic infiltration.
A liver scan should be routinely obtained only in those patients with
abnormal liver function studies.
Bone scans with correlative bone radiographs are rarely positive or indicat-
ed unless the patient has other evidence of disseminated disease. A radionu-
clide brain scan is indicated only when diffuse metastatic disease is present or
when focal neurologic signs indicate a lesion is present.
ANGIOGRAMS. Inferior vena cavography and aortic arteriography are of use
in patients with bulky retroperitoneal disease. 337 The precise localization,
extent of neovascularity, or evidence of vena cava! obstruction not only aids

the surgeon in planning the surgical resection of these extensive tumors hut
also provides a means of assessing the effectiveness of the preoperative
adjuvant chemotherapy.
TUMOR Markers. Measurement of urinary chorionic- gonadotropin has
long been useful in obtaining prognostic therapeutic information regarding
8
testis tumors,'" but it has been replaced by the more sensitive serum markers,
beta human chorionic gonadotropin and alpha-fetoprotein. Carcinoembryonie
antigen is of no use in testicular tumor patients.
Human chorionic gonadotropin is composed of two polypeptide chains
(alpha and beta). It is the beta subunit that is secreted by these tumors, and
recently a specific antibody for this subunit of human chorionic gonadotropin
has been prepared, allowing a sensitive radioimmune assay specific for beta
HCG, even in the presence of significant amounts of luteinizing hormone. 339
Numerous studies have shown that beta HCG is not present in normal males
and that it represents a sensitive specific marker for tumor activity. The beta
subunit of HCG appears to be produced by the trophoblastic elements of
testis tumors, specifically the syncytial trophoblastic cells, and may be elevat-
ed in embryonal carcinoma without recognizable choriocarcinomatous ele-
ments. 340 The presence of beta HCG in a "pure" seminoma should alert the
clinician that an undiagnosed trophoblastic element may be present. 341 Braun-
stein et a/. 342 found an elevated HCG level in 38 per cent of patients with
metastatic seminoma. Elevated HCG, however, does not necessarily correlate
with poor survival, since these patients have been reported to be cured by
orchiectomy and radiation even though presenting with elevated beta HCG.
Therefore, one cannot unequivocally state that an elevated HCG
titer in the
seminoma patient indicates that a nonseminomatous element is present.
Alpha-fetoprotein is an alpha-1 globulin that is an embryo-specific protein
and does not occur in the adult except in pathologic states. It is important that
the aFP be measured by radioimmunoassay methods sensitive to less than 40
ng/cc, since most elevations range from 40 to 1000 ng, less than detectable by
the gel electrophoresis method. Alpha-fetoprotein has commonly been found
in hepatocellular carcinoma, as well as in testis tumors. In cases of testis
tumors in which alpha-fetoprotein has been identified, embryonal carcinoma,
or more specifically primitive yolk sac remnants, have been present. In con-
trast, aFP has never been reported in a case of "pure" seminoma.
The presence of an elevated alpha-fetoprotein or beta HCG level is certain-
ly worrisome in patients with seminoma, and it is our policy tit UCLA to treat
such patients as if they had nonseminomatous tumors —
with retroperitoneal
lymphadenectomy. Subsequent radiation therapy or chemotherapy is dictated
by the pathologic findings in the retroperitoneal tissue.
Both these markers should be measured in all patients with germinal
tumors of the testis. Not only are they helpful in monitoring response to
therapy, but recent experience suggests that high levels of alpha-fetoprotein
indicate aggressive biologic behavior of the tumor, warranting maximum
343
therapy regardless of apparent clinical stage. 341
"
Recent work by Javadpour
344
and associates further indicates that selective venous sampling for the alpha
chain of human chorionic gonadotropin may be helpful in localizing tumor
recurrence that is not clinically apparent.
10 Genitourinary Neoplasms 415
TABLE 10-6. Five-Year Survival Rate of Seminoma Patients

Relative to Stage
Stage Patients Survival Percentage
A 1722 1607 93.3

B 438 304 69.4
C 154 34 22.1
TOTAL 2314 1945 84.1
"From S in i tli BB: In Genitourinary Cancer. Skinner DC and deKemion JB (eds), Philadelphia, \VB Saunders
Co, 1978.
Prognosis
Prognosis varies with the histologic type of testicular tumor and the clinical
and pathologic Table 10-6 summarizes five-year survival data by stage
stage.
for patients with seminoma. Similar data for nonseminomatous tumors are
discussed at length in the section on treatment.
TREATMENT
Seminoma
Stages A and B (Excluding Extensive Bulky Retroperitoneal Dis-
ease — B Seminomas are exquisitely radiosensitive and generally have an
:? ).
excellent prognosis. Radical orchiectomy followed by radiation therapy con-

tinues to be the primary therapy, although some workers have recommended
retroperitoneal lymph node dissection even for classic seminomas. 320
The outline of therapy for stage A, stage B l5 and stage B 2 tumors parallels
that found in die literature. In clinical stage A disease, the ipsilateral inguinal,
iliac, and bilateral para-aortic cava! nodes are treated to the crura of the
diaphragm. A dose of 2500 rad is given over a three-week period. Prophylactic

mediastinal or supraclavicular radiation for stage A patients is not necessa-
ry 345,344 jf a scr otal orchiectomy was performed or if the tunica vaginalis or
spermatic cord were involved with the tumor, the involved hemiscrotum
should be included in the treatment field.
Patients with evidence of retroperitoneal disease should receive irradiation
to the same areas as patients witii stage A disease, with an additional 1000 rad
delivered to areas of known nodal disease. The mediastinal region and both
supraclavicular regions should also be included. Doses to the mediastinum
and supraclavicular nodes range from 2000 to 3500 rad over two to four weeks.
With this treatment regimen in stage A, stage B l5 and stage B 2 an excellent ,
survival rate is possible. A review of the modern literature reveals a 93.3 per
296
cent (1607 out of 1722) survival rate for stage A patients. Patients with stage B
disease have an overall survival rate of 69.4 percent (304 of 438 patients). If
one analyzes the failure in stage B disease (in those series in which this is
possible), it becomes apparent that many of the failures occur in patients with
bulky retroperitoneal disease (stage B ). It is our contention that routine
;J
radiation therapy not adequate for these patients, even when full abdominal
is
radiation and boosts are given to areas of bulky disease. In the UCLA series of
seven patients with stage B., disease, only 28.5 per cent (2 of 7) who were
treated with conventional radiation therapy are alive without evidence of
disease. Three other patients treated aggressively with surgery or chemother-
apy, or both, in addition to radiation therapy have survived. 347
Stage B and Stage
:j
C. The cumulative five-year survival rate for pa-
tientswith Stage C tumors is 22 per cent. 29ti
Because of the extremely poor
prognosis for such patients who are treated by conventional radiation therapy,
we feel that consideration should be given to the use of aggressive adjuvant
chemotherapy. Experience with chemotherapy in this tumor population
is somewhat Alkylating agents, such as cyclophosphamide and
limited.
chlorambucil, have demonstrated activity against seminoma. 348-351 Combina-
tions of other agents, such as vincristine, with the alkylating agents have also
been .suggested. 348 Since 35 per cent of patients dying of seminoma have
nonseminomatous elements at the time of postmortem examination, 352 it
would seem prudent to add an agent, such as dactinomycin, that is effective
against these tumor elements even though it has no proven tumoricidal effect
on seminoma. 353
Currently, we treat patients with advanced seminoma initially by intensive
systemic chemotherapy prior to irradiation 354 in order to deliver optimal doses
of chemotherapy. The dosage schedule of such chemotherapeutic agents
when given subsequent to radiation therapy would almost certainly have to
be reduced. We prefer the combination of dactinomycin, vincristine, and
cyclophosphamide, as indicated in Table 10-7. Severe side effects occur
infrequently; however, should they arise, they can be ameliorated by in-
travenous hyperalimentation and the addition of prednisone. After a two- to
four-week rest period, radiation therapy is given as previously outlined for
stage B
disease.
We
currently feel that follow-up chemotherapy should be started eight
weeks after completion of radiation therapy. This follow-up therapy consists
TABLE 10-7. Plan of Chemotherapy'
Days
Drug
Dactinomycin mg 0.5 0.5 mg 0.5 mg 0.5 mg 0.5 mg

Vincristine 1.8 mg 1.8 mg
Cyclophosphamide 600 mg 600 nig 600 mg
° From Smith KB: In Genitourinary Cancer. Skinner DG and deKemion JB (eds), Philadelphia, W'B Saunders
Co, 1978.
TABLE 10-8. Stage B 3 and Stage C Seminoma
Therapy Patients Alive (NED)t
Conventional 20 3
Pre x-ray Chemotherapy 5 5
"From Smith RB, ct al: J Urol 727:429, 1979.

fNo evidence of disease.
of chlorambucil, 10 mg daily for ten consecutive days, with dactinomycin 1 to

2 mg IV on day 5. This treatment plan is repeated every two months for one
year and every three months for the second year. It is our present feeling that
patients with stage B 3 disease should have retroperitoneal lymphadenectomy
with cytoreductive surgery after completion of the initial courses of chemo-
therapy and x-ray therapy if tumor bulk remains. With this treatment plan, the
survival rate of stage B 3 and stage C tumors has been dramatically improved,
when compared with conventional radiation therapy treatment (Table 10—
8).
Treatment of Recurrent Disease. The treatment of recurrent tumors
depends on the of recurrence and prior treatment. Patients with dissemi-
site
nated disease should receive chemotherapy, and we favor the combination
outlined in Table 10-7. Because these patients will have received prior
radiation therapy, intravenous hyperalimentation and intermittent predni-
sone may be necessary during chemotherapy-, especially if the mediastinal
and supraclavicular nodes have previously been irradiated. If, based on ele-
vated tumor markers, other tissue elements are suspected, vinblastine sulfate,
bleomycin, and cisplatin may be preferable chemotherapeutic agents. Bleo-
mycin occasionally produces pulmonary' fibrosis and may be particularly haz-
ardous in the patient who has received radiation to the lungs or mediastinal
area.
Treatment of Second Primary Seminomas. The same general treat-
ment principles apply to second primary seminomas as to first ones. X-ray
dosage may have to be modified, depending on the amount and location of
prior treatment and the response to such therapy. If nearly full-course radia-
tion has been given in the treatment of the first seminoma, retroperitoneal
lymphadenectomy may be necessary to free the patient of retroperitoneal dis-
ease.
Nonseminoma
Combined modalities of therapy have proved more valuable in the treat-

ment of adults with nonseminomatous germinal tumors of the testis than in
those with any other tumor type. The treatment of nonseminomatous testis
tumors has changed markedly in the past five to ten years. Current survival
rates range from 85 per cent to over 90 per cent. This is a marked contrast to
earlier reports of a less than 60 per cent survival rate. A factor common to the
improved rate of survival has been a meticulous approach to lymph node
dissection and the judicious use of adjuvant therapeutic modalities, particu-

larly combination chemotherapy with clearly effective cytotoxic agents.
Management of Clinical Stage A and B Tumors. The accurate deter-
mination of the extent and histologic composition of retroperitoneal metastat-
ic disease is essential to the rational use of adjuvant chemotherapy, and all
patients without evidence of advanced disease (stage B 3 and stage C) initially

undergo a meticulous retroperitoneal lymph node dissection. As noted pre-
viously, this dissection should he a modified bilateral procedure with the
anatomic limits noted in Figure 10-8. Although it is our preference to perform
this procedure through a thoracoabdominal approach, which allows wedge
resection of unsuspected pulmonary metastases, a careful evaluation of the
mediastinum, and complete removal of all retroperitoneal metastatic disease,
others prefer a transperitoneal anterior approach. Regardless of the approach,
it is essential that a meticulous dissection be performed, with complete
mobilization of the great vessels and removal of all fibroareolar tissue from
behind the vessels within the anatomic limits depicted in Figure 10-8. Expe-
rience with this procedure has demonstrated that it is possible to remove all
retroperitoneal nodes, 355 and the pathologist should be encouraged to search
for as many nodes as possible, since adjuvant therapy depends on an accurate
sampling.
All patients in our program undergoing lymphadenectomy receive 1 mg of
dactinomycin at the time of surgery, followed by 3 mg intravenously over the
four immediate postoperative days (0.5 mg given intravenously postopera-
tively days one and three and 1 mg given intravenously postoperatively days
two and four). We feel there is good rationale for having effective chemothera-
py present at the time of possible tumor manipulation, a concept supported in
experimental tumor models. 35 " This use of chemotherapy has been well toler-
ated, and we do not feel that it has contributed to significant postoperative
morbidity. Others prefer to delay the initiation of chemotherapy until the
sixth or seventh postoperative day.
Subsequent therapy depends on the presence or absence of nodal in-
volvement as well as on the histologic findings. If the nodes are not involved
by tumor, and the primary tumor contains no foci of choriocarcinoma, one
course of chemotherapy with dactinomycin as a single agent is given two
months following therapy. The dosage is based on the patient's weight and is
given as an intravenous push once a day for five days (weight greater than 180
lbs — 5 mg over five days; 130 to 180 pounds — 4 mg over five days; under
130 pounds — 3 mg over five days). Early in our experience, prophylactic
chemotherapy was not used in patients who had no nodal involvement.
However, 24 per cent of these patients returned with pulmonary metastases,
and 16 per cent subsequently died. Since initiating prophylactic chemothera-
py — one course during the immediate postoperative period and one course
two months later — only 2 of 49 consecutive patients have returned with
pulmonary metastases; both have been rendered tumor free by aggressive
chemotherapy, and in one patient, by thoracotomy. Staubitz and associates 357
reported that 6 of their 45 patients without nodal involvement developed
pulmonary metastases, and since 1972 they have recommended the use of
358
prophylactic chemotherapy in all patients with stage A disease. None of
10 ' Genitourinary Neoplasms 419
more than 20 patients treated with chemotherapy subsequently developed re-

currence.
Whitmore,359 however, has steered away from the use of prophylactic che-
motherapy in patients without nodal involvement in the belief that newer
cytotoxic drugs (vinblastine sulfate, bleomycin, and cisplatin) can effectively
eradicate recurrence when it occurs. Donohue and associates 360 also recom-
mend no prophylactic treatment, and they report a 100 per cent survival rate
in 30 patients without nodal involvement treated by surgery alone, although 2
patients developed pulmonary metastases that were successfully treated with
chemotherapy and. in one patient, by lobectomy as well.
It is obvious that the results of lymphadenectomy in patients without nodal
involvement are excellent, and the controversy concerning the use of prophy-
lactic chemotherapy will not be resolved until a cooperative prospective
randomized study is performed. Prejudice continues toward the use of two
courses of daetinomycin, which we feel represents a well-tolerated minor
inconvenience to ensure maximum tumor-free survival.
Patients who have foci of choriocarcinoma in their primary tumor are at a
somewhat greater risk of developing metastases, even though the retroperi-
toneal nodes are not involved. We recommend a two-year course of prophy-
lactic chemotherapy in these patients, beginning at the time of surgery with
daetinomycin and followed by an outpatient course of the combination of
vinblastine sulfate and bleomycin four to six weeks following surgery (bleo-
mycin, 30 units given intramuscularly twice a week for five weeks — 300 units
total, and vinblastine sulfate, 10 mg given intravenously on day 1, 15 mg given
intravenously on day 8, and 20 mg given intravenously on day 22). Cyclic

courses of daetinomycin every two months for one year and then every three
months for the second year are given (dosage as given earlier for stage A
disease). The two-year duration of chemotherapy is largely empiric and based
on the observation that failure or recurrence more than two years beyond
complete surgical resection rarely occurs.
Patients with minimal involvement (stage B,) receive cyclic courses of
daetinomycin every two months for one year and every three months for a
second year. If more extensive involvement is found (stage Bj or greater) or if
any elements of choriocarcinoma are found in the metastatic disease, at least
one course of the combination vinblastine sulfate and bleomycin is given four
to six weeks following surgery, followed by cyclic courses of daetinomycin
every two months for one year and then every three months for a second year.
Occasionally, a second course of vinblastine sulfate and bleomycin is given
four to six weeks following completion of the first course, primarily in those
patients with pathologic stage B 3 disease or with an extensive amount of
choriocarcinoma who were not treated with chemotherapy before surgery.
Figure 10-9 illustrates our chemotherapy protocol, and Table 10-9 lists the
rate of survival according to stage.
Before 1973, postoperative radiation therapy was initially used routinely in
patients with extensive retroperitoneal metastases (stage B 2 disease), but
newer, more effective cytotoxic drugs have largely replaced the need for
radiation tiierapy, which is now reserved only for exceptional circum-
stances.
Clinical
Stage
Abdom. |
mass
(B3 )
6 days
Inpatient Bleomycin: 30 units I.M. twice weekly x 5 wk
Chemo:
Velban: Day 1 (10 mg IV)
Actino D
8 (15 " " )
Cytoxan
22 (20 " " )
Vincristine
Methotrexate Actinomycin D: 4.0mg/5days
Prednisolone q 2 mo x 1 yr
q 3 mo x 1 yr
FIGURE 10-9. Overall plan of management of testicular tumor integrating chemotherapy with
appropriate surgery. (From Skinner DG
and deKernion JB (eds): Genitourinary Cancer. Philadel-
phia, WB Saunders Co, 1978.)
Management of Clinical Stage B 3 and C Tumors. The management

of patients with advanced disease requires a great deal of individualization
and planning, but recent reports by Donohue and associates, 360 Skinner, 361, 362
and Merrin and associates 363 demonstrate that more than half these patients
can be rendered free of disease by an aggressive management plan. Basic to
this plan is the use of intensive combination chemotherapy followed by a sur-
gical debulking procedure and subsequent cyclic chemotherapy. A thorough
and complete initial evaluation of these patients before starting therapy
TABLE 10-9. Tumor-Free Survival Rate of 132 Consecutive Patients Man-

aged at UCLA Hospital 1971-1977. (Minimum Follow-up Period is 12
Months.)
Stage Patients Survival Percentage
A 50 49 98
B, 18 16 88
B2 19 17 89
B3 11 10 90
C 24 16 66
Variants 10 6 60
Overall UCLA 132 114 86

TABLE 10-10. Initial Inpatient Course of Chemotherapy Given to UCLA

Patients With Clinical Evidence of Massive
Retroperitoneal Disease 337
Day Drug Course
Dactinoniycin 1.0 nig intravenously over 3 hours

Cyclophosphamide 2.0 nig/kg of weight intravenously
Methotrexate 5.0 nig intravenously
Repeat dactinoniycin
Repeat cyclophosphamide
Repeat methotrexate
Vincristine 2.0 mg intravenously
Prednisolone" 20.0 nig oralh
Repeat methotrexate
Repeat prednisolone
Dactinoniycin 0.5 mg intravenous] >
Repeat prednisolone
"Prednisolone used to reduce toxicity.
Comment: If disseminated pulmonar) metastases are present (stage C),3 courses of the combina-
tion eisplatin, vinblastine, .mil bleomycin are given as per Table 10-11 before cytoieductive
surgery in substitution for the five-drug combination shown bere.
provides important information relevant to the effect of chemotherapy and

may facilitate subsequent surgical resection. Full lung tomography, abdominal
ultrasonography, aortography, vena cavography, and occasional barium stud-
ies (upper gastrointestinal, barium enema) help to define the extent of metas-
tatic disease before initiating intensive chemotherapy.
Webelieve that all patients with evidence of extensive retroperitoneal
disease as well as those with multiple pulmonary metastases should be ini-
tially treated with intensive chemotherapy before any attempt is made at
surgical resection. Our early experience with a six-day course of intensive
inpatient chemotherapy (Table 10-10), followed two to three weeks later by a
five-week course of the combination vinblastine sulfate and bleomycin (bleo-
mycin, 30 units given intramuscularly twice a week for five weeks 300 —
units total, and vinblastine sulfate, 10 mg given intravenously on day 1, 15 mg
given intravenously on day 8, and 20 mg given intravenously on day 22) has
demonstrated this drug combination to be exceedingly effective in reducing
tumor bulk and rendering massive retroperitoneal disease resectable. Others
advocate different combinations, such as the three-drug regimen developed
by Einhorn and Donohue, 364 which is depicted in Table 10-11, or the five-
drug combination advocated by Cvitkovic and associates 365 (Table 10-12). All
these combinations will dramatically produce at least a partial response, and
in many cases, a complete response with the disappearance of all demonstra-
422 II / Treatment of Sim < u i< Neoplasms
TABLE 10-11. Protocol for Chemotherapeutic Management of

Advanced Disease"
Cisplatin + Vinblastine - Bleomycin Regimen
1 Cisplatin, 20 mg/m 2 administered intravenouslj (over 15 minutes), daily times five during a
continuous saline infusion (100 nil per hour) every three weeks tor three courses
2 Bleomycin, 30 units administered 1>\ intravenous push once weekly tor 12 weeks
3 Vinblastine, 0.15 mg/kg administered hy intravenous push on days 1 and 2 of each cisplatin
cycle every three weeks
a Vinblastine given six hours prior to bleomycin
1) Alter five courses 12 weeks) of vinblastine, maintenance therapy consisted of \ inhlastine,
(
0.3 mg/kg administered 1>\ intravenous push even tour weeks and BCG immunotherapy,
administered by scarification one, two, and three weeks after each dosage of vinblastine
c Therapy to be continued for a total of two years
"From Einhorn LH and Donohue fP: Ann Intern Med 87:293, 19T and Einhorn LH and Williams Si)
Proc \mer Soc Clin Oncol 20:297. 1979.
ble pulmonary disease. Despite this response, it is our opinion that resection
of residual retroperitoneal disease is essential to the long-term successful
management of these cases, and furthermore, histologic findings at the time of
lymph node dissection subsequent need and duration of
will dictate the
chemotherapy. This concept of intensive preoperative chemotherapy has
been responsible for producing a thick, fibrous capsule around the bulky
retroperitoneal disease and for making resection possible in all cases without
tumor spill. In our experience 83 per cent of patients initially harboring bulky
retroperitoneal disease plus pulmonary metastases have had histologically
identifiable tumor —
often mature teratoma at the time of cvtoreductive —
TABLE 10-12. Inductive Phase'
Days
Drug
Bleomycin X X X X
20 mg/irr/day
hy continuous
infusion i
Vinblastine (VBL) X
(4 mg/m2 )
Cyclophosphamide X
'(600 mg/m 2 )
Aetinoinyein-D X
(1 mg/m 2 )
Cisplatin
(DDP)
(120 mg/m 2 )
"Inductive phase for VAB III protocol of Cvitkovic and associates.*" Maintenance with VBL (4 mg m- IV)
every three weeks and with chlorambucil 4 mg/m 2 orally daily is given for two of every three weeks. Dactino-
mycin il mji m- doxorubicin (45 mg/m2 and DDP (50 mg m1 arc alternated. The induction phase is re-
I, I, '
peated at four- to five-month intervals

K) Genitourinary Neoplasms 423
surgery (despite intensive preoperative chemotherapy), which is often asso-

ciated with die radiographic disappearance of all pulmonary lesions. This
type of surgery, however, is extremely difficult, time consuming, and meti-
culous because of an inflammatory reaction and, often, encasement around the
great vessels, and should be performed only by those urologic surgeons
thoroughly trained in this type of retroperitoneal surgery and those who see
sufficient volumes of such cases to maintain their expertise.
Most patients with discrete stage C disease undergo wedge resection of
pulmonary metastases at the time of lymph node dissection or thoracotomy
three to six months after lymphadenectomy. Subsequent chemotherapy
varies with the histologic findings at the time of eytoreduetive surgery. If
all primitive elements have disappeared and only necrosis or mature cystic
elements, or both, remain, a second full course of the combination vinblastine

sulfate and bleomycin is given four to six weeks following extirpation of the
retroperitoneal disease, and cyclic chemotherapy is continued with dactin-
omycin every two months for four courses of therapy and every three months
for a year after that. If primitive elements persist, two or, preferably, three
courses of the three-drug combination reported by Einhorn and Donohue 384
(vinblastine sulfate, bleomycin, and cisplatin) are given every three weeks
beginning six weeks following surgery before resuming cyclic daetinomycin
(Table 10-13). Using this approach, 29 out of 35 patients with stage B and :!
TABLE 10-13. Treatment Plan for Advanced

Testicular Cancer (Stages B and C)° :i
Inpatient Cytoreductive Chemotherapy: 5 Druus

(Daetinomycin, cyclophosphamide, vincristine, methotrexate, and prednisolone)
2-week rest
Outpatient Chemotherapy: 5 Weeks

Vinblastine, plus bleomycin)
2-week rest
Cytoredcctive Scrc.ical Resection Retroperitonei m

Pathology: Primitive Elements
Present Absent
Yinhlastine Yinhlastine
Bleomycin Bleoimcin
Cisplatin over 5 weeks
Every 3 weeks times 3
Daetinomycin every 2 months times 4. then every 3 months times 4
° Modified plan of management with advanced retroperitoneal disease. The doses and schedules
for patients
are given in the text, in Figure 10-9. Tahles 10-10 and 10-11. Note the use of cisplatin combination
and in
chemotheirapy in those patients whose histologic examination reveals persistent primitive elements following
intensive preoperative chemotherapy. If the retroperitoneal bulky disease demonstrates complete maturation
or disappearance of all primitive elements, the plan of management is the same as that illustrated in Figure
10-9 Recent re-evaluation of therapy results suggests that for patients with disseminated disease in addition
to bulky abdominal disease, three courses of the combination of cisplatin, vinblastine, and bleomycin (Table
10-11 over 12 vv eeks. before eytoreduetive surgery, may be preferable to the 5-drug combination followed by
1
vinblastine and bleomycin schedule outlined above.

stage C disease have been rendered tumor free (complete response) and 26 of
35 (73 per cent) remain alive and tumor free for 12 to 72 months.
Similar reports have been published by others. Donohue et al.'im report a
complete response rate in 74 per cent of patients, and 32 of 50 remain tumor
free for 6 to 30 months. These authors employed the combination of vinblas-
tine sulfate, bleomycin, and cisplatin. Cvitkovic and associates 365 report a
complete response rate of 64 per cent, and 45 per cent of their patients with
disseminated disease appear to have maintained a complete regression. It is
unclear from either report how many underwent cytoreductive surgery or
what the extent was of bulky retroperitoneal disease associated with demon-
strable disease above the diaphragm. Donohue et a/. 360 report substantial
toxicity associated with their combination, resulting in an 8 per cent mortality
rate directly attributable to chemotherapy, plus another three deaths (6 per
cent) occurring within two weeks of initiating therapy, attributed to progres-
366
sive disease or possibly related to drug toxicity. Dentino and associates
have also reported a permanent 40 per cent reduction in renal function, as
measured by creatinine clearance, for all patients in the Indiana series who
received two or more courses of cisplatin without saline- or mannitol-
induced diuresis. Because of this toxicity, as well as poor patient tolerance,
we have developed a position of reserving the use of cisplatin in combination
for those patients who present with multiple pulmonary metastases in addi-
tion to bulky abdominal disease and for those who retain histologic evidence
TABLE 10-14. Three-Year Crude Survival Rate (%) in Patients With Non-
seminomatous Testicular Tumors
Histology
Embryonal
Stage Author Carcinoma Teratocarcinomaf Combined
A Blandy 8/23 (35) 41/46 (89) 49/69 (71)

Skinner 7/10 (70) 31/32 (97) 38/42 (90)
B Blandy 2/5 (40) 3/7 (43) 5/12 (42)

Skinner 16/18 (88) 13/18 (72) 29/36 (80)
A+ B Blandy 10/28 (36) 44/53 (83) 54/81 (67)

Skinner 23/28 (81) 44/50 (88) 67/78 (86)
C Blandy 0/17 ( 0) 0/7 ( 0) 0/24 ( 0)

Skinner 5/8 (63) 2/8 (25) 7/16 (44)
All stages Blandy 10/45 (22) 44/60 (73) 54/105 (51)

Skinner 28/36 (78) 46/58 (79) 74/94 (79)
'MTU (MTA, MTIB)

fMTI(MTIA)
Comparison of three-year crude survival between patients managed with combined modalities ot therapy
370
based on lymphadenectomy (Skinner'" 2 and patients managed by radiation therapy (Blandy
)
according to
)
stage and pathology of primary tumor. For ease of comparison all tumors classified as teratocarcinoma by the
Friedman and Moore 310 classification were grouped in the MTI category. The histologic classification of
373
Friedman and Moore 310 is used here. In those reports using one of the classifications ofPugh and colleagues
the following assignments to this table were made: embryonal carcinoma to include malignant teratoma, un-
differentiated (MTU), as well as malignant teratoma, anaplastic (MTA), and malignant teratoma, intermediate
group B (MTIB); teratocarcinoma to include malignant teratoma, intermediate (MTI) and malignant teratoma,
intermediate, group A (MTIA).
of primitive elements following preoperative chemotherapy (Table 10-13) or

who our standard protocol (Fig. 10-9). Table 10-9 lists our experience in
fail
132 consecutive patients with a minimal follow-up of 12 months.

Postoperative radiation therapy has been useful in some cases but should
be individualized and reserved for very specific cases. Prior to 1973, postoper-
ative radiation therapy was given to all patients with extensive retroperitoneal
disease. Table 10-14 compares results with radiation therapy to our results at
UCLA. We continue to avoid irradiating our patients because our patients did
not tolerate radiation therapy well, and chemotherapy was delayed because of
marrow depression. When patients fail surgical therapy, it is nearly always
secondary to disseminated disease or progressive growth of pulmonary metas-
tases, further emphasizing the need for prompt and effective chemotherapy.
Clearly, effective combinations of chemotherapy are changing the concepts
for management. Some authors recommend cytoreductive surgery in patients
with advanced disease prior to chemotherapy,363,367 but our experience and
that of others311,380 indicates that preoperative chemotherapy dramatically de-
bulks tumor mass, rendering previously inoperable disease resectable as well
as reducing operative morbidity and improving the rate of survival. Nonethe-
less, we continue to believe that surgical resection is necessary and should be
performed before total cumulative doses of bleomycin and cisplatin have
been exhausted, precluding the use of effective chemotherapy in the treat-
ment of minimal residual disease, perhaps the time when chemotherapy is
most effective.
Stage directly relates to the tumor-free interval and proves to be significant
for survival. In our experience, no patient has had a recurrence more than two
years after lymphadenectomy. In patients with stage A disease the average
time of tumor recurrence was 12 months, and there was no recurrence later
than 24 months after lymphadenectomy. In stage B patients the average time
of tumor recurrence was 6 months, with no recurrence greater than 13 months
postlymphadenectomy. In stage C patients, the average time of recurrence
was three months, with the range between zero and nine months. No patient
with stage C disease who was free of tumor for longer than nine months after
lymphadenectomy and wedge resection of pulmonary metastases or thoracot-
omy had a recurrence or died of disease. Isolated instances have been report-
ed in which recurrence occured many years after surgical resection, but these
are most unusual.
Within each stage, chemotherapy has improved survival, and the combina-
tion of vinblastine sulfate and bleomycin has proved exceedingly effective in
advanced disease. However, because of the limitations in the cumulative dose
of bleomycin owing to the development of pulmonary fibrosis, dactinomycin
remains an important agent for cyclic long-term therapy and has proven of
benefit as a single agent with acceptable toxicity. 368 Toxicity to chemotherapy
is significant and is discussed in detail in Chapter 5. Toxicity can be partially
alleviated by the judicious use of corticosteroid pulses. For example, the

addition of 20 mg of prednisolone on days four, five, six, and seven markedly
reduces the side effects of the intensive inpatient chemotherapy listed in
Table 10-13. We have also discovered that 30 mg of prednisone given orally
before the simultaneous administration of vinblastine sulfate and bleomycin
reduces the degree of glossitis and the severity of side effects otherwise
noted. It is obviously important, therefore, that whoever takes on the manage-
ment of patients with these tumors be thoroughly familiar with the toxicity of
the various drugs and understand the need and timing for retroperitoneal
lymphadenectomy, thus being able to alter therapy according to histology.
Finally, and perhaps of greatest importance, is the ability to relate closely to
the patient and his family, taking into account their need to be thoroughly
informed regarding the overall plan of management, the rationale for therapy,
the possible side effects, and the fact that they face a difficult and trying
two-year period in which a trusting and emparhetie relationship must exist
among patient, family, and physician.
Others have recommended different approaches to management, different
cytotoxic drugs as single agents, as well as combinations, and different treat-
ment schedules. 360, 363_3fi5 369 It is not the purpose of this chapter to extol our
-
plan of management over that of others, except to point out that experience in
more than 150 consecutive patients with all stages of disease reveals a signifi-
cant improvement in survival with what we feel to be an acceptable morbidity 7
insofar as toxicity, length of hospitalization, and quality of life are concerned.

Other agents, such as mithramycin, doxorubicin, and chlorambucil, have been
used with varying success but remain, in our hands, second-line drugs re-
served for patients refractory to the plan of management described earlier. A
further discussion of the management of refractory cases is available in re-
VIPW* -137, 363 365
CONCLUSIONS. Results of therapy for patients with stage A and stage B

nonseminomatous testicular cancer now indicate a rate of survival exceeding
90 per cent for patients treated by lymphadenectomy and appropriate chemo-
therapy. Basic to this improved survival rate is a meticulous lymph node
dissection that accurately stages the disease, may be curative for patients with
minimal disease, and, in particular, dictates the rational use of cytotoxic drugs
according and extent of disease. Despite these excellent results
to histology
and the minimal morbidity of lymphadenectomy, there continue to be those
" 372
who extol the virtues of radiation therapy as a single modality treatment. 370
Published results, however, do not support this approach, and currently radia-
tion therapy has little to offer the patient with a nonseminomatous tumor and
can jeopardize subsequent effective use of chemotherapy.
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CHAPTER 11
GYNECOLOGIC
NEOPLASMS
Samuel C Ballon Leo D Lagasse
Michael L Berman Watson G Watring
Guy J F Juillard
Section 1
Gestational Trophoblastic
Disease
INTRODUCTION
Gestational trophoblastic disease (GTD) isspectrum of diseases that
a
includes benign hydatidiform mole, invasive mole, and choriocarcinoma.
Hydatidiform mole, the outcome of approximately 3000 pregnancies in the
United States in 1978, invariably precedes invasive mole and is responsible
for 50 per cent of the cases of choriocarcinoma of gestational origin.
NATURAL HISTORY
The clusters of villi associated with a molar pregnancy are characterized

by hydropic changes, absence of fetal vessels, and hyperplasia of the tro-
phoblast.' Invasive mole is histologically identical to hydatidiform mole
and differs only in its propensity to invade locally and to metastasize.
Choriocarcinoma consists of sheets of malignant cytotrophoblast and syncy-
tiotrophoblast with no identifiable villi.
434
1 1 Gynecologic Neoplasms 435
The term GTD is of value because the diagnosis and decision to institute
treatment often are made without knowledge of the precise histology. Of
primary clinical interest is the differentiation between nonmetastatic and
metastatic GTD. In patients with nonmetastatic GTD, the histology is im-
portant, as immediate treatment of choriocarcinoma is indicated. Con-
versely, metastatic disease should be treated without repard for the precise
histology of the metastatic focus.
Human Chorionic Gonadotropin. Human chorionic gonadotropin, a
glycoprotein hormone composed of two noncovalently linked subunits
(alpha and beta), is elaborated by trophoblastic tumors into the plasma and
subsequently is excreted in the urine. 2 Chorionic gonadotropin is always
found in the presence of GTD; the level correlates with the amount of
viable trophoblast and can be measured accurately. Thus, HCG
is a sensi-
3
tive tumor marker for these diseases.
There are two sensitive assays for the measurement of HCG. Using a
kaolin acetone extract of urine, minute quantities of HCG are detected on
the basis of ovarian hyperemia in the rat or uterine weight in the mouse. 4
These bioassay techniques for HCG do not distinguish between HCG and
luteinizing hormone because similarities in their molecular configurations
result in identical biologic activities in these animals. However, this assay
is still used for the initial evaluation of patients with metastatic GTD, since
the HCG titer so obtained is of prognostic and therapeutic importance in

this group. A more specific radioimmunoassay measures the beta subunit
portion of the HCG molecule, which is specific for each of the glycoprotein
hormones. 5
Hydatidiform Mole. mole often develop

Patients with hydatidiform
irregular bleeding during their pregnancies. Fetal heart tones and palpable
fetal parts are absent. Hyperemesis gravidarum, signs and symptoms of tox-
emia early in the course of gestation, and thyrotoxicosis related to the pro-
duction of molar thyrotropin are associated with this disease.
In suspected cases, the diagnosis is made on the basis of ultrasonogra-
phy, amniography, or pelvic angiography. Ultrasound examination has the
advantage of being noninvasive and produces a diagnostic pattern when
viewed by an experienced sonographer. Amniography, the injection of
water-soluble radiopaque dye into the uterine cavity, produces a charac-
teristic moth-eaten appearance on x-ray (Fig. 11-1). When these techniques
are performed properly, angiography, with its attendant morbidity and ex-
posure to higher quantities of radiation, is not necessary. Although hyda-
tidiform mole is often associated with HCG titers that are higher than ex-
pected for a normal gestation, this determination fails to distinguish
between a molar pregnancy and multiple gestation. Although uterine size
classically is large for the duration of gestation, it may also be normal or
smaller than expected. Because these signs are not diagnostic of hydatidi-
form mole, the diagnosis is often delayed until the patient passes grapelike
villi from the uterus.
436 II / Treatment of Shi ( n k Neoplasms
FIGURE 11-1. Amniogram in a pa-

tient with hydatidiform mole; the
moth-eaten pattern is characteristic.
The preferred method of evacuation of a molar pregnancy is by suction

curettage while administering oxytocin intravenously. A sharp curettage of
the uterine cavity follows to ensure complete evacuation. This method is
associated with a low incidence of uterine perforation, trophoblastic em-

bolization, and possible pulmonary infarction.
The tissue that is obtained at the time of uterine evacuation must under-
go careful histologic evaluation to exclude the presence of choriocarcinoma.
Patients delivered of molar pregnancies also require chest x-rays and care-
fulpelvic examination to identify metastases to the lungs and vaginal mu-
cosa.
When the diagnosis of hydatidiform mole without metastases is con-
firmed, the patient is monitored by weekly assays of HCG. Because routine
biologic and immunologic tests for pregnancy are not sensitive or specific,
they have no place in the diagnosis or management of patients with GTD
(Fig. 11-2). A chest x-ray and thorough pelvic examination should be per-
formed monthly. In approximately 80 per cent of patients, the HCG titer
steadily declines to undetectable levels by eight weeks following evacua-
tion of the molar pregnancy. In these patients, malignant sequelae are un-
fi
iformly absent. If the titer rises at any time, or plateaus on two successive
weekly determinations, or persists eight weeks following diagnosis, therapy
is initiated. The appearance of metastases also necessitates immediate treat-
ment.
11 / Gynecologic Neoplasms 437
10,000
(3,500)
(2 - 3.000)
1,000
.PSEGNOST1CON
TUBE (700-750)
O 100
10 .BETA SUBUNIT(IO)
TEST
FIGURE 11-2. Comparison of the sensitivity of various tests for pregnancy.
Invasive Mole and Choriocarcinoma. Since only 50 per cent of ges-

tational choriocarcinoma follows the delivery of a hydatidiform mole, some
patients develop GTD following abortion, ectopic pregnancy, or delivery of
an infant. These patients often present with metastatic disease; however,
on occasion, continued bleeding from the uterus without known metastases
suggests the presence of GTD. In such instances the histologic diagnosis of
the trophoblastic tissue is often choriocarcinoma. All products of conception
evacuated time of a therapeutic or spontaneous abortion require his-

at the
tologic interpretation to rule out the presence of choriocarcinoma. A high
index of suspicion is required when curettage is necessitated in the post-
partum period for uterine subinvolution and continued bleeding.
The diagnosis of invasive mole requires identification of molar villi in
the myometrium. This is difficult, since inadequate myometrial tissue is
often obtained by curettage. Since hysterectomy is now performed infre-
quently in patients with trophoblastic disease, this diagnosis rarely is made.
Patients with invasive mole are subject to spontaneous perforation of the
uterus and occasionally require hysterectomy to control hemorrhage.
The diagnosis of choriocarcinoma on the basis of material obtained at the
time of a curettage can also be difficult. Foci of trophoblast can separate
from underlying villi and be falsely identified as choriocarcinoma. Isolated
sections of myometrium occasionally reveal only sheets of malignant tro-
phoblast following collapse of the villi during fixation and sectioning. If a
tissue diagnosis of invasive mole or choriocarcinoma can be made with cer-
tainty, immediate therapy is instituted. However, when villous structures
are present, and the diagnosis of invasive mole is in question, any attempt
to determine the prognosis on the basis of the histologic material is accom-
panied by a high likelihood of error. 1
TREATMENT
Surgery
Hysterectomy as the primary therapy for a patient with a hydatidiform

mole has applicability in two situations. First, patients over 40 years of age
have an increased incidence of malignant sequelae following hydatidiform
mole and are often best managed by hysterectomy; second, in patients who
have completed their child bearing, hysterectomy could reduce the number
of courses of chemotherapy needed to produce remission and avoid the
development of metastases in those who fail to respond to the initial single
agent. 7 Because 35 per cent of patients with metastases have no residual
disease in the uterus at the time of hysterectomy, this operation as a rou-
tine measure is not indicated.
Chemotherapy
Prophylactic chemotherapy immediately following evacuation of a molar

pregnancy is not indicated because 80 per cent of patients with hydatidi-
form mole will have no malignant sequelae, and those who require treat-
ment after appropriate follow-up with serial HCG titers have an excellent
prognosis.
Systemic chemotherapy is the cornerstone of management for patients
with both nonmetastatic and metastatic GTD. In addition to producing ex-
cellent cure rates, menstrual and reproductive function are preserved. 8
Over 200 pregnancies have followed the use of chemotherapy in patients
TABLE 11-1. Toxicity of Chemotherapy for GTD

System Clinical or Laboratory Findings Comments
Hematologic White blood cell count <3000/mm 3 . Discontinue or reduce chemotherapy,

Polymorphonuclear leukocyte count patient may require reverse isolation and
<15()0/mm 3 . appropriate antibiotic therapy if sepsis
Platelet count < 100,000/ mm 3 . occurs, platelet transfusion if platelet
count <20,000/mm 3 and bleeding occurs.
Renal Blood urea nitrogen level elevated, Discontinue or reduce chemotherapy,

serum creatinine level elevated. correct dehydration, obtain creatinine
clearance determination, obtain intra-
venous pyelogram to rule out obstruction
due to tumor.
Hepatic Serum bilirubin elevated, serum Discontinue or reduce chemotherapy.

transaminases elevated. More common with methotrexate.
Gastrointestinal Stomatitis, gastroenteritis, anorexia, Correct dehydration, maintain adequate

nausea, vomiting. urine output, restore normal fluid and
electrolyte balance. May require change
to alternate drug if severe.
Skin and appendages Alopecia, perifolliculitis, radiation More common with dactinomycin.
recall in skin.
Mesothelial surfaces Pleural irritation and effusion; Seen occasionally with methotrexate.
peritonitis.
with both nonmetastatic and metastatic GTD. A slight increase in the in-
cidence of spontaneous abortion and placenta accreta has been noted in
these patients, but there has been no increase in the rates of prematurity,
stillbirths, congenital anomalies, or reactivation of GTD. 9
When a patient requires therapy, the initial work-up should include a
careful pelvic examination, neurologic examination, chest x-ray, intravenous
pyelogram, liver scan, brain scan, complete blood count, platelet count,
blood urea nitrogen determination, and tests of hepatic function. Patients
with nonmetastatic gestational trophoblastic disease and those with metas-
tases confined to the vagina or lung are treated with single agent chemo-
therapy. Treatment consists either of intravenous dactinomycin in doses of
10 to 12 /xg kg per day or intramuscular methotrexate at 0.3 to 0.4 mg/kg
per day for five consecutive days. 10 Therapy ideally should be given every
two weeks, with careful monitoring of toxicity by a complete blood count,
platelet count, blood urea nitrogen determination, and tests of hepatic func-
tion (Table 11-1). If the usual dose of either drug produces toxicity that
prevents scheduled administration, one should reduce the dosage rather
than increase the time interval between courses of chemotherapy.
The response to therapy is determined by weekly measurements of
HCG, and treatment is continued until HCG is undetectable by a sensitive,
quantitative assay on three consecutive weekly determinations. The alter-
nate dnig should be used if the HCG titer plateaus or rises at any time
following the second course of the first drug or if new metastases appear. 11
At the UCLA Medical Center, as in other trophoblastic referral centers, the
curability of patients with nonmetastatic trophoblastic disease and metastat-
ic GTD confined to the vagina or lung approaches 100 per cent.
A group of patients with metastatic GTD has been identified as being at
high risk to fail chemotherapy using a single agent. These patients often
exhibit common characteristics, including a long delay prior to the institu-
tion of therapy, a high initial titer of HCG, or metastases to the brain or
liver. This concept of a high-risk group of patients with metastatic disease
is used as the basis for their initial treatment with a combination of chemo-
therapeutic agents, because resistance to a single drug results in increased

toxicity and decreased curability from subsequently administered combina-
tion therapy. All patients with an initial HCG titer greater than 100,000 per
24-hour urine collection, with disease present for more than four months
TABLE 11-2. Chemotherapy for Patients with

High Risk Metastatic GTD°
»
Drug Dosage
Methotrexate 0.3 mg/kg INlj .,

Da'-
Dactinomycin 10 /xg/kg IV \ ,
y
Chlorambucil 10 mg/PO j
In Patients with Hepatic Dysfunction:

Dactinomycin 10 uglkg IV JDaily
6-Mercaptopurine 100 mg/PO Jx 5 days
"A course of therapy is given every two weeks until three successive weekly negative titers of HCG are
obtained.
prior to the institution of therapy, or with metastases to the brain or liver

are at increased risk to fail single agent chemotherapy and are treated with
a combination of methotrexate, dactinomycin, and chlorambucil (Table 11-
12
2).
Radiation Therapy
Patients with metastases to the brain or liver also receive external radia-
tion therapy to these areas. 13 The whole brain can tolerate an
initial dose of
2000 to 3000 rad given approximately 200 rad, which, in
in fractions of
conjunction with systemic chemotherapy, can produce a 50 per cent cure
rate. A similar treatment plan directed toward metastatic disease in the
liver has also produced occasional cures. Few protocols of radiation therapy
suggesting a different dose-time relationship have been reported. With the
exception of brain and liver and occasional vaginal lesions, the treatment of
other visceral metastases with adjuvant radiation therapy generally has
been unsuccessful.
Although brain metastases are clinically present in only 10 per cent of
patients with metastatic GTD, autopsy studies reveal that approximately 75
per cent have brain metastases at the time of death. These metastases can
be occult initially and become clinically apparent as the disease progresses,
or they can develop after the disease in other areas becomes resistant to
chemotherapy. Brain metastases can be single or multiple and can produce
intracranial hemorrhages, infarctions, or subarachnoid hemorrhages. The
risk of brain metastasesappears to increase with the following: a delay in
diagnosis of greater than one year after the antecedent pregnancy, pro-
longed or frequent interruptions of treatment in patients with established
metastases, the appearance of choriocarcinoma within one month of term
delivery, increased titer and duration of disease, and resistance to standard
chemotherapy months of treatment. 14 The need for a careful neuro-
after six
logic evaluation, brain scan, or computerized tomogram in all patients re-
quiring treatment is apparent. A diagnostic craniotomy is not indicated in a
patient with GTD
in whom the brain scan is positive; however, operative
intervention might be required for decompression secondary to hemorrhage
or for removal of a solitary focus after an incomplete response to therapy.
At the UCLA Medical Center, an evaluation of the HCG
titer in the cere-
brospinal fluid is being performed. As HCG

does not readily cross the
blood-brain barrier, a ratio of serum to cerebrospinal fluid HCG
of less than
40:1 suggests central nervous system involvement of GTD, with secretion
of HCG directly into the CSF. 15
Immunotherapy
To
the extent that the paternal contribution to the trophoblast carries
genes for transplantation antigens that are not present in the maternal host,
the possibility exists of an immune response to the tumor based on differ-
ences in somatic as well as tumor-associated antigens. This unique immun-
ologic relationship does not account entirely for the responsiveness of GTD
to chemotherapy, but it might help to explain the occasional spontaneous
regression and cure reported.
If the response of choriocarcinoma to chemotherapy is related to histoin-
compatibility between the maternal host and her tumor, and rejection is
acting synergistically with the drugs, this disease is a poor theoretic model
for chemotherapy. If it is unrelated, there is a need to determine the basis
for this unique responsiveness. Not only might an immune response lead to
rejection, but it could also produce enhancement or tolerance. The mater-
nal immune response could be secondary to tumor-associated antigens,
organ-specific antigens, or HLA antigens derived from the father. HLA in-
compatibility is not necessary for chemotherapy to effect cure. 16 Tropho-
blastic disease might be more likely to occur in a mating that is capable of
producing fetal maternal histocompatibility, but this has no effect on the
clinical course.
The mechanism whereby the maternal host fails to reject the fetus and
placenta remains unclear. Accumulated evidence suggests a depression of
cell-mediated and humoral immune responsiveness during pregnancy that
is greatest in the first trimester and decreases throughout the period of ges-
tation.
17
Low levels of circulating gamma globulin, loss of cellularity in the
germinal centers and pericortical areas of the pelvic and periaortic lymph
nodes, reduced lymphocyte blastogenesis in response to mitogens in vitro,
as well as high levels of circulating estrogens and corticosteroids support
this thesis.
Reports of immunotherapy in patients with advanced GTD that is resis-
tant to multiple drug therapy reveal only transient successes in small
numbers of patients. Infusion of paternal lymphocytes, application of full-
thickness paternal skin grafts, and the use of nonspecific stimulants of cell-
mediated immunity such as Corynebacterium parvum and bacillus Calmette-
18
Guerin have produced variable results.

The consistent production of HCG
by tumors of the chorion continues to
stimulate the search for tumor markers in other solid tumor systems. The
level of HCG correlates with the amount of viable tumor present, and the
development of specific and sensitive quantitative assays of HCG allows an
accurate determination of those patients requiring therapy and permits the
assessment of therapeutic response. This ideal tumor marker has obviated
the need in many cases for knowledge of the precise histology. This is most
apparent in patients with metastatic disease, who can be treated appropri-
ately without operation. Patients in whom complete remission is document-
ed by three successive weekly negative beta HCG titers have less than a 1
per cent chance of reactivation of disease.
A
100 per cent cure rate is now obtained in patients with nonmetastatic
GTD. Patients with metastases who are not in the high-risk group may ex-
pect similar results. If the criteria that place patients at risk to fail chemo-
442 II / Treatmi vi 01 Specific Neoplasms
therapy with a single agent are identified, approximate]) 80 per cent of this
group will achieve a complete, sustained response to initial therapy with a
combination of drugs. 19 A small but important group of high-risk patients
with disease that is resistant to triple agent chemotherapy is attracting in-
creased attention and is accounting for the majority of deaths among pa-
tients now treated in trophoblastic referral centers. The combination of
vinblastine, dactinomycin, and bleomycin, a regime producing success in
males with testicular choriocarcinoma, has to date proved unrewarding in
this patient group. High-dose methotrexate infusion, which is of benefit to
patients with sarcomas, lymphomas, and certain head and neck tumors,
does not appear to be successful in high-risk patients with GTD who have
developed resistance to methotrexate in conventional dosage.
The final solution to the problem of GTD lies with the development of
new cytotoxic drugs, as well as with the definition of the unique immun-
ologic relationship between these tumors and the maternal host. Early stud-
ies into this relationship have failed to provide much insight into those
factors that place patients at risk for die development of GTD or the devel-
opment of tumors that are resistant to chemotherapy. When these factors
are determined, they could also provide clues to the diagnosis and therapy
of patients with other solid tumors.
Section 2
Carcinoma of the
Endometrium
INTRODUCTION
The endometrium is the most common site of invasive cancer of the fe-
male genital tract and the third most frequent site of malignancy in Ameri-
can women. There were approximately 27,000 new cases of endometrial
cancer and 3300 deaths during 1977. 20 Characteristically, endometrial can-
cer isdetected early in the course of the disease, with 75 per cent of new
cases confined to the uterus on clinical assessment. 21 The high frequency of
early cancer detection exists because signs of abnormal genital bleeding
usually are seen before metastases occur. Paradoxically, because survival
statistics suggest a high curability rate and because therapeutic measures
often involve commonly performed operative techniques, many patients
with endometrial cancer are treated widiout benefit of careful staging and
without consultation with physicians who are trained in the management of
gynecologic malignancies. Because of a better understanding of the natural
history of endometrial cancer and the risk factors that can necessitate the
modification of therapy, treatment should be initiated only after careful

evaluation of the extent of disease and those factors that can make a patient
at high risk to fail standard therapy. 22
Estrogen, either from endogenous sources or administered exogenously,

can cause varying degrees of endometrial proliferation known as cystic and
adenomatous hyperplasia. Because this finding often precedes or coexists
with endometrial cancer, clinicians have long suspected that estrogens can
cause this disorder. There appears to be a continuum of endometrial hyper-
plasia, which in the most advanced state resembles early carcinoma. This
continuum can be compared with that of cervical intraepithelial neoplasia,
which also can progress to invasive cancer but can remain unchanged or
even regress over months or years. If patients with atypical adenomatous
hyperplasia — the most severe form of endometrial hyperplasia — go un-
treated, it is estimated that 10 to 30 per cent will develop endometrial can-
cer within ten years. Endometrial hyperplasia appears to be reversible in
most instances when the source of estrogen is removed or when proges-
togens are administered cyclically.
Evidence supporting a causal role for exogenous estrogens has been pro-
vided by several independent, retrospective matched control studies of
women with endometrial cancer. 23 The risk of developing cancer appears to
rise four to eight times with increasing duration and higher doses of es-
trogen therapy. In addition, reports of significantly increasing incidences of
endometrial cancer among white women in several geographic areas since
1969 were associated temporally with increased estrogen usage nation-
wide. 24 For example, there was a 50 per cent increase in the incidence of
endometrial cancer in California reported by the California Tumor Registry
during that time interval. Similarly, conditions that predispose to hyperes-
trinism frequently are associated with endometrial cancer (Table 11-3).
Supporting evidence in animal studies includes induction of endometrial
cancer with exogenous estrogens and blockage of methylcholanthrene-
"'
induced endometrial cancer by oophorectomy in rabbits. 2

MacDonald and Siiteri 26 have postulated the "estrone hypothesis" to ex-
plain the association between estrogens and endometrial cancer, suggesting
a permissive role of estrone unopposed by progestogens in the develop-
ment of this malignancy. The constitutional stigmata of obesity, advanced
age, and anovulation, which are seen commonly in endometrial cancer pa-
tients, are associated with increased extraglandular aromatization of an-
drostenedione from the adrenal gland to estrone. Aromatization appears to
occur primarily in adipose tissue and most efficiently in obese, elderly pa-
tients, accounting for the increased estrone levels in these individuals. Sim-
ilarly, young patients with the Stein-Leventhal syndrome who are at high
risk to develop endometrial cancer secrete increased amounts of androsten-
edione from the hyperplastic ovarian stroma or, in some instances, from the
adrenal gland, providing more substrate to peripheral sites for conversion
to estrone.
TABLE 11-3. Conditions Associated with Hyperestrinism and

Endometrial Cancer
Source and Mechanism of

Estrogen Secretion Condition
Ovary Ovarian neoplasm

Increased secretion of E,° Granulosa theca cell tumor
Sertoli-Leycliy cell tumor
Increased secretion of At with Hilar cell tumor
peripheral conversion to Ei
Increased secretion of A with Stromal hyperplasia (seen with ovarian

peripheral conversion to Ei neoplasm)
—» Mucinous tumors
—» Brenner tumors
-* Krukenherg tumors
Increased secretion of A with Stromal hyperplasia without ovarian

peripheral conversion to E, neoplasm (Stein-Leventhal syndrome)
Adrenal
More efficient peripheral Obesity
conversion of A to E,
Same Advanced age
Ovary and/or adrenal

Diminished hepatic sulfatase and Advanced liver disease
glucuronidase for conjugation of E,
Exogenous
Direct effect of E, (which is 35 to 65 per cent Oral or injectable estrogens
of conjugated estrogens)
"Estrone
fAndrostenedione
Profiles of steroid hormones and being studied at

their metabolites are
UCLA Medical Center in women with endometrial cancer and in control
subjects in an attempt to identify differences between the two populations.
In this way, it might be possible to develop a hormone assay to identify
patients who are likely to develop endometrial cancer and to monitor the
course of patients with endometrial cancer following treatment.
Biology
Endometrial cancer disseminates by direct extension to adjacent struc-

tures —
through the lymphatic system to regional and distant nodes and by
hematogenous routes to remote sites (Fig. 11-3). Although it is frequently
confined to the endometrium, the initial route of spread appears to be ex-
tension into the underlying myometrium. Most patients with disease out-
side the uterine fundus who undergo hysterectomy have myometrial pene-
tration extending through at least one third to one half of the thickness of
the uterine wall. Increasing myometrial penetration brings a progressive
LYMPHATICS HEMATOGENOUS
FIGURE 11-3. Patterns of
Vagina Lung
spread of endometrial cancer.
Cuff
Liver
Suburethral
Other sites
Peritoneal cavity
Ovary
Pelvic nodes Vagina
Aortic nodes Parametria
increase in the incidence of lymph node metastases, which are found in 35

to 55 per cent of deeply invasive tumors, in approximately 6 per cent of
superficially invasive tumors, and in less than 1 per cent of noninvasive
tumors. 2728 Tumors that involve the myometrium more extensively can ex-
tend to the serosal surface of the uterus. When this occurs, intra-abdominal
carcinomatosis can develop by the seeding of tumor throughout the perito-
neal cavity, with involvement of omentum, liver, diaphragm, and other vis-
ceral surfaces. Such patients can present with ascites or bowel obstruction.
Lymphatics from the uterus follow the routes of the ovarian and uterine
blood vessels. Therefore, lymph node metastases can follow the uterine
veins to the hypogastric, iliac, aortic, and precaval lymph nodes, or can
result from direct drainage into the aortic and precaval nodes via the lym-
phatics accompanying the ovarian vessels. Autopsy data suggest that
periaortic nodes are the most frequent sites of metastases, often found in
the absence of pelvic lymph node involvement. 29 However, pelvic and
periaortic lymphadenectomies performed in patients undergoing primary
operation for cancer confined to the uterine corpus have documented aortic
lymph node involvement without positive pelvic lymph node involvement
in less than 2 per cent of patients. 30 Conversely, 60 per cent of patients
with pelvic lymph node metastases also had periaortic metastases. There-
fore, the most common route of lymphatic spread appears to be the pelvic
lymph nodes, with secondary involvement of the periaortic nodes.
Local spread to the cervix occurs in 10 to 15 per cent of women with
endometrial cancer. The biologic behavior of such tumors resembles that of
primary cervical carcinoma, with an increased risk of lymph node metas-
tases and extension to the vagina or parametrium. The overall frequency of
pelvic lymph node metastases is reported to increase from 10.6 per cent in
tumors confined to the uterine fundus to 36.5 per cent in tumors with cervi-
cal extension. 31
The vagina also can be a site of metastases by lymphatic spread or possi-
bly from seeding of the vaginal cuff at the time of hysterectomy. Evaluation
of recurrences following hysterectomy in patients who had preoperative in-
tracavitaryradium showed the same risk of vaginal metastases in patients
with no residual tumor as in those with residual tumor. 32 These data suggest
that tumor implantation at operation provides an infrequent source of va-
gina] spread of endometrial cancer and that a more likely source of th<
metastases might be via paracervical and paravaginal lymphatics. The oc-
currence of isolated vaginal metastases in the distal vagina also supports
this hypothesis.
The involvement of the uterine isthmus, as determined by histologic
evaluation of hysterectomy specimens, is associated with an increased risk
of lymph node metastases and hence poorer survival; however, clinical
measures used to evaluate this portion of the uterus are not standardized.
Hysteroscopy and hysterography, which might permit more accurate tumor
localization within the uterus, are being evaluated as diagnostic tools for
this disease.
Ovarian metastases occur in approximately 5 per cent of women with en-
dometrial cancer. The most likely mechanism of ovarian involvement is via
lymphatics in the mesosalpinx and mesovarium. Because primary ovarian
neoplasms often coexist with endometrial cancers, they can be confused
with metastases from the uterus. Therefore, careful histologic evaluation of
the ovaries is necessary to distinguish between coexisting and metastatic
ovarian tumors. In some instances this distinction cannot be made.
The involvement of distant sites, including lung, liver, and skeleton,
probably occurs by the hematogenous route and is infrequent. The lung is
the most common site of distant metastasis and is involved in 2 to 3 per
cent of patients, often concurrently with other sites. 33 Although poorly dif-
ferentiated tumors represent less than 25 per cent of endometrial cancer, 60
per cent of patients with spread to these distant sites have anaplastic can-
cers.
NATURAL HISTORY
Classification
The endometrial carcinoma are shown in Table

five histologic types of
11—4. Ng and Reagan 34
found an incidence of 67.1 per cent adenocarcino-
ma, 20.3 per cent adenoacanthoma, and 12.6 per cent adenosquamous carci-
noma in 542 cases seen from 1942 to 1971. Although they found a progres-
sive increase in the incidence of adenosquamous tumors —
up to 32.8 per
cent of 122 malignancies seen between 1967 and 1971 —
others have not
documented a similar change. 35 Squamous cell and clear cell tumors of the
endometrium are rare and usually very aggressive.
Confusion exists concerning the interpretation and implications of aden-
oacanthoma, adenosquamous carcinoma, and adenocarcinomas because the
terminology is not used uniformly, and precise criteria in establishing the
proper diagnosis are lacking. Adenoacanthoma represents an adenocarcino-
ma with benign squamous metaplasia, and adenosquamous carcinoma con-
tains both malignant glandular and squamous elements, whereas adenocarci-
noma has malignant glandular elements and no squamous components. At-
tempts to subdivide adenosquamous carcinoma further by the degree of
differentiation of the malignant squamous component have compounded
the confusion without providing useful prognostic information.
TABLE 11-4. Classification of Endometrial Carcinomas
Histologic Type Relative Frequency 54
Adenocarcinoma 67.1%
Adenoacantfaoma 20.3%
Adenosquamous carcinoma 12.6%
Clear cell carcinoma <1%
Squamous carcinoma <1%
Endometrial cancer occurs characteristically in postmenopausal obese

women, who are often on estrogen replacement therapy and who have a
prior menstrual and reproductive history that is suggestive of prolonged
anovulation. Eighty per cent of women with endometrial cancer are post-
menopausal, and 65 per cent are in the sixth or seventh decade of life. 36
Although only 5 per cent are under 40 years of age, most of these younger
patients have the Stein-Leventhal syndrome, are infertile, massively obese,
diabetic, or show other evidence of endocrinopathy. 37
Most women with endometrial cancer present initially with complaints of
abnormal bleeding characterized as prolonged, excessive, or intermenstrual
in the premenopausal woman or as recurrent after cessation of menses in
the postmenopausal woman. Postmenopausal bleeding is defined as bleed-
ing at least 12 months after the cessation of menses. Approximately 15 to 20
per cent of women with endometrial cancer are detected while still asymp-
tomatic with an atypical Papanicolaou smear suggesting an adenocarcino-
ma. Five to 10 per cent of patients may present with symptoms of advanced
neoplasm, including ascites, bowel obstruction, jaundice, or respiratory em-
barrassment. Five per cent of patients have occult malignancy diagnosed at
hysterectomy that was performed for an apparently unrelated condition.
Endometrial cancer must be considered in any woman beyond 40 years
of age with abnormal uterine bleeding and in younger women with abnor-
mal bleeding associated with infertility or anovulation. Cytologic evaluation
of exfoliated cells from the uterus is useful when it is suggestive of malig-
nancy but cannot replace biopsy or fractional dilatation and curettage of the
uterus for diagnosis in high-risk patients. Cytologic screening techniques
have varying sensitivities with a 50 per cent accuracy when obtained from
the exocervix and vaginal pool, a 75 per cent accuracy with endocervical
aspiration, a 90 per cent accuracy with saline irrigation of the endometrial
cavity or rotating endometrial brush method, and a nearly 95 per cent accu-
racy with a jet washer technique. 38 Unlike cytologic techniques that are
used to detect cervical neoplasia including invasive cancer and its precur-
sors, those used to detect endometrial neoplasia fail to detect a high per-
centage of patients with premalignant lesions. Definitive histologic diagno-
sis is made by endometrial biopsy or uterine curettage.
Screening measures for endometrial carcinoma are more costly, complex,

and uncomfortable than those that are used to detect cervical neoplasia,
and controlled prospective studies of high-risk populations are needed to
evaluate the usefulness of routine screening with these cytologic and biop-
sy techniques. In patients with histories of abnormal bleeding requiring
diagnosis, endocervical curettage also should be performed to rule out ei-
ther cervical spread from endometrial cancer or a primary endocervical ma-
lignancy. When
endometrial biopsy does not rule out a uterine cancer, a
fractional curettage should be performed.
Staging
The been used since July 1, 1974

staging of endometrial cancer that has
is based on the recommendations of the Cancer Committee of The Interna-
tional Federation of Gynecology and Obstetrics (FIGO) and is shown in

Table 11-5. 39 Diagnostic studies that are necessary for proper staging must
include the measurement of uterine depth and grading of histologic dif-
ferentiation to permit substaging of tumors confined to the uterine fundus.
Endocervical curettage necessary to rule out the cervical involvement of
is
is necessary to rule out spread

stage II disease, a careful pelvic examination
to the vagina, parametrium, or ovary in stage III disease, and cystos-
copy, sigmoidoscopy, and chest x-ray are necessary to identify patients with
stage IV disease. In addition, a general medical evaluation should consist
of a complete blood count, urinalysis, blood urea nitrogen, creatinine, and
TABLE 11-5. Staging of Carcinoma of the Corpus Uteri
Stage Carcinoma in situ. Histologic findings are suspicious of malignancy; cases

of stage should not be included in any therapeutic statistics.
Stage I The carcinoma is confined to the corpus.
Stage la The length of the uterine cavity is 8 cm or less.
Stage lb The length of the uterine cavity is more than 8 cm.
It is desirable that the stage I cases be subgrouped with regard to the histologic type
of the adenocarcinoma as follows:
Gl Highly differentiated adenomatous carcinoma.
G2 Differentiated adenomatous carcinoma with partly solid areas.
G3 Predominantly solid or entirely undifferentiated carcinoma.
Stage II The carcinoma has involved the corpus and the cervix but has not extended
outside the uterus.
Stage III The carcinoma has extended outside the uterus but not outside the true pelvis.
Stage IV The carcinoma has extended outside the true pelvis or has obviously involved
the mucosa of the bladder or rectum. A bullous edema as such does not permit
a case to be allotted to stage IV.
Stage IVa Spread of the growth to adjacent organs.
Stage IVb Spread to distant organs.

postprandial blood glucose levels, liver function tests, and electrocardio-

gram. An intravenous pyelogram and barium enema should be performed to
rule out coexistent gastrointestinal or urologic disease and to permit future
comparison if related symptomatology should develop. A liver scan should
be considered if abnormal liver function tests exist. A lymphangiogram can
help to explain unexpected ureteral obstruction, and bone surveys or scans
can be helpful in evaluating patients with pain of uncertain origin. Thera-
peutic decisions should be made after presentation to a tumor board con-
sisting of gynecologic oncologists, radiation therapists, and pathologists.
Although operative findings cannot change clinical staging, there has
been a trend at UCLA and other medical centers toward initial operation
with stage I tumors. In some patients at high risk for lymph node metas-
tases, pelvic and periaortic lymphadenectomy is carried out along with total
hysterectomy and bilateral salpingo-oophorectomy. In this way it is possi-
ble to evaluate the lymph nodes, assess occult ovarian or intraperitoneal
spread, and evaluate the depth of m\ ometrial penetration and occult cervi-
cal or isthmic extension.Other selected patients with more advanced clini-
cal stage have undergone pretreatment operative evaluation including ab-
dominal exploration with pelvic and periaortic lymphadenectomy. The
initial operative approach in both groups of patients permits subsequent
treatment to be tailored to the extent of disease. An operative staging
scheme utilizing the TNM terminology has been considered for these pel-
vic cancers by the American Joint Committee for Cancer Staging.
Prognosis
Prognosis is a function of several interrelated variables including stage of

tumor, depth of myometrial penetration, lymphatic involvement, histologic
grade, cell type, uterine size, and patient age. 27,36,40 Each prognostic factor
must be assessed independently to determine its relative importance. The
prognosis for each stage of endometrial cancer, as measured by five-year
survival statistics,is shown in Table 11-6.
Published data that relate survival to all prognostic factors other than
stage exist primarily for stage I disease. Of these factors, pelvic lymph node
metastasis is the most critical, with the five-year survival rate estimated at
TABLE 11-6. Endometrial Carcinoma Five-Year Survival
Stage Number of Patients Alive 5 Years % 5-Year Survival
Stage I 12655 (74.4%) 9670 76.4

Stage II 2185(12.8%) 1089 49.8
Stage III 1596 9.4%)
( 480 30.1
Stage IV 585 3.4%)
( 54 9.2
TOTAL 17021 11293 66.3
'Compiled from Kottmeier HL Annual Reports on the Results of Treatment in Carcinoma of the Uterus.
Vagina, and Ovarv. Vol. 16. Stockholm. EOS-Trvckeriema. 1976 and Morrow CP. et al.: Obstet Gynecol 42:
399. 1973.
33 to 40 per cent from collected series of patients with biopsy proven me-
tastases. 27
;!1
Unfortunately, diagnostic studies, including lymphangiogra-
-
phy, have proved unreliable, and operative evaluation of pelvic lymph

nodes can be difficult and morbid in elderly and often infirm obese pa-
tients. Therefore, factors associated with a high frequency of these metas-
tases are utilized to determine risk. Of these factors, the depth of myome-
trial penetration is risk of lymphatic spread.
the best indicator of the
Boronow 30 estimates that50 per cent of patients with deep myome-
up to
trial penetrations can have pelvic lymph node metastases. This increased
incidence of nodal spread with more invasive tumors is reflected in the
reported cure rates. Patients with noninvasive or superficially invasive
tumor have an 80 to 85 per cent five-year cure rate, whereas those with
deeply invasive tumors have a 60 per cent rate of survival. 28- 4 "
Of the factors that can be assessed preoperatively in stage I patients, the
histologic grade has the greatest prognostic significance. Lewis et al. 27 have
demonstrated an increasing incidence of lymph node metastases with pro-
gressive tumor dedifferentiation, finding metastases in 5.5 per cent of 36
patients with grade 1 lesions, 10 per cent of 50 patients with grade 2
tumors, and 26 per cent of 19 patients with grade 3 disease. Similarly,
Cheon 41 found a progressive increase in the incidence of myometrial inva-
sion with advancing histologic grade. He demonstrated deep myometrial
invasion in 12 per cent of 219 patients with grade 1 tumors, 20 per cent of
74 patients with grade 2 tumors, and 46 per cent of 79 patients with grade 3
lesions. As expected, there is a progressive decline in cure rates of patients
with poorly differentiated tumors, as compared with well-differentiated
tumors. Collected series show a five-year survival rate of 80 per cent with
grade 1 tumors, 66 to 74 per cent with grade 2 tumors, and 50 per cent with
grade 3 tumors. 2 *' m
As indicated previously, the cell type can influence the prognosis of pa-
tients with endometrial cancer. The prognosis appears worse for adeno-
squamous tumors than for adenoacanthomas or pure adenocarcinomas. The
most important factor that determines the prognosis of these tumors appears
to be the differentiation of the malignant glandular elements. Because ap-
proximately 75 per cent of adenoacanthomas are well differentiated, 34 they
appear to have the best prognosis of the group, with a 71 per cent overall
five-year survival rate and an 84 per cent survival rate in stage I disease. 28
Less than 20 per cent of adenosquamous tumors are well differentiated,
however, and five-year cure rates range between 20 and 50 per cent. Over-
all, adenocarcinomas without squamous elements have a five-year survival
rate of approximately 60 per cent. Nevertheless, for a given grade of malig-

nant glandular epithelium, the prognosis for a patient with any of these
three types of tumor appears to be equal. 35 The rarer tumors of the endome-
trium, including clear cell or epidermoid carcinoma, have a uniformly poor
prognosis with five-year relapse-free survival rates of approximately 25 per
cent.
Although uterine size influences prognosis, the many benign conditions
that can cause uterine enlargement make this a less valuable prognostic-
indicator. Although uterine enlargement can result from extensive tumor
growth, which might impart a poor prognosis, uterine myomata and aden-
omyosis frequently cause this change. Of all the measures of uterine size,
including uterine weight, length, and correlation with gestational size, the
depth from the external cervical os to the top of the uterine fundus is most
reproducible and useful. Reported series have documented a five-year
relapse-free survival rate of 85 per cent with stage la disease and a poorer
67 per cent survival rate with stage lb disease. 40
Finally, age at the time of diagnosis correlates with prognosis. Older pa-
tients more often present with advanced stage of disease, more extensive
myometrial invasion in early stages, and a poor five-year survival rate even
when corrected for intercurrent disease. 40 The poor survival rate also re-
sults from selective modification of therapy in some patients because of
advanced age and coexisting medical conditions. When possible, optimal
therapy should not be compromised because of age alone. A recent study
conducted at the University of California, Los Angeles, and Magee-
Women's Hospital, Pittsburgh, also has documented distant metastases to
lung and multiple extrapelvic sites in older patients."
TREATMENT
Premalignant Disease
The treatment of premalignant changes in the endometrium can consist

of either operative or medical management Anovulatory women who de-
velop atypical hyperplastic changes in the uterus resulting from unopposed
estrogen stimulation are often managed by cyclic progestational therapy.
When these women want to bear children, they are best treated with elomi-
phene citrate to initiate ovulation. Surgical therapy consisting of bilateral
ovarian wedge resection will frequently establish an ovulatory pattern and
reverse the hyperplastic changes but rarely is employed today because of
the efficacy of pharmacologic therapy.
Perimenopausal and postmenopausal women with these premalignant
changes can be managed by hysterectomy or cyclic progestational therapy
and the cessation of any exogenous estrogen. In all such cases, endometrial
carcinoma must first be ruled out by fractional curettage of the uterus prior
to instituting specific therapy. If conservative therapy is chosen, an endo-
metrial biopsy should be performed after three months of progestational
therapy to ensure reversal of the premalignant findings. Hysterectomy
should be carried out if the changes persist.
Surgery Combined with Radiation

The approach to managing patients with endometrial cancer at UCLA
Medical Center employs surgery- when possible, often combined with post-
operative radiation therapy (Figs. 11-4 and 11-5). The initial management
of patients with stage I disease consists of abdominal exploration with a
total abdominal hysterectomy and bilateral salpingo-oophorectomy. Al-
452 II / Tkeatmkm of Specifk Neoplasms
lAorlBIGl) I A or IB(G2)
Total abdominal Total abdominal
hysterectomy and hysterectomy and
bilateral salpingo- bilateral salpingo-
oophorectomy oophorectomy
None or Intermediate or None or Preoperative
superficial deep myometrial superficial whole pelvis

myometrial penetration (on myometrial Rt. 5,000 rad
penetration frozen section) Nf no penetration over 5 weeks
lymphade-
nectomy 4-6 weeks
f \ FIGURE 11-4. Treatment of endometrial

Give vaginal abdominal
No further Pelvic Total
cancer— stage I.
treatment lymphadenectomy cuff radiation hysterectomy
(7,000 rad to and bilateral
Negative Positive
vaginal mu- salpingo-
/
Give vaginal Give radiation
cosa providing
approximately
oophoredomy
cuff radiation to whole pelvis 2,500 rad to a

17,000 rad to including upper depth of5 mil-
vaginal mu- half of vagina limeters)
cosa providing 5,000 rad in
approximately 5 weeks
2, 500 rad to a
depth of 5 mil-
limetersl
though some investigators have advocated radical hysterectomy with pelvic

lymphadenectomy as the treatment of choice, 42 there are no data substan-
22 43, 44
tiating an improved survival rate with more extensive resections or a '
45
decrease in the risk of subsequent vaginal metastases. Because endome-
trial cancer rarely spreads to the parametrium without cervical involve-
ment, the removal of the parametrium in stage I disease is not warranted.

In addition, radical surgery in patients who often are obese and elderly is
associated with an increased risk of morbidity and mortality. There is, how-
ever, renewed interest in sampling the pelvic and periaortic lymph nodes
30
in some patients with stage I disease at the time of the hysterectomy.
Information gained from lymphadenectomy can reduce the need for adju-
Stage II Stage 1 1 Stage VA
/ \
5,000 rad to Intracavitary
1
1-Ovarian mass
1
4,500-5,500 rad
whole pelvis radium and external
followed by external whole Whole pelvis RTand
modified pelvis RT- Total radium insertion if
1
'
radical 7, 000 rad Pt A technically feasible

hysterectomy 5, 500 rad Pt 8 TAH, BSO
in 4-6 weeks
\ ' '
1
6-10 weeks \ Postop Ext TAH-BSO if technically
\ Whole pelvis Rt. feasible and bleeding

\ 5,000 rad in or infection persists
i
\ \ \ 5 weeks in pelvis
FIGURE 11-5. Treatment of en-
TAH, BSO l\
dometrial cancer — stages II to IV.
\ 2-Vaginal spread Stage IV B
3- Parametria!
spread
1. 4, 500-5, 500 rad external
whole pelvis RT
2. Chemotherapy
(Progestin or other
antineoplastic agent)
J
TAH, BSO if technically
feasible and bleeding or
infect on persists in pelvis
\ ant whole pelvis radiation therapy when and can help

results are negative
to direct radiation therapy when results are positive. It is unclear whether
or not the benefits of this additional information will outweigh the risks of
more extensive operations and the complications of operation followed by
radiation in those patients with lymph node metastases.
When lymphadenectomy is not performed, the decision to administer ra-
diation therapy is determined by the depth of myometrial penetration and
the histologic grade of the tumor. Well-differentiated tumors that are con-
fined to the endometrium or are minimally invasive rarely metastasize to
lymph nodes or vagina and can be managed with operation alone. All other
patients receive vaginal cuff irradiation or external beam therapyinclude
to
the pelvic lymph nodes and vagina. Because adjuvant radiation therapy re-
duces the incidence of vaginal vault recurrence from a range of 10 to 15 per
4T
cent to a range of 2 to 3 per cent, therapy to this area is standard today. 46,
Unfortunately, no studies exist that convincingly show that survival is im-
proved in patients so treated. Patients with poorly differentiated tumors,
even without myometrial penetration, have a reduced five-year survival rate
and an increased risk of vaginal metastases 48 and are managed with radia-
tion to the vaginal cuff. Patients with tumor invading at least one third of
the myometrial depth are treated with radiation to the whole pelvis in an
attempt to sterilize occult lymph node metastases. In such patients the va-
gina is also included to prevent vaginal cuff recurrences. Because' so many
patients with anaplastic tumors have myometrial invasion and need whole
pelvis radiation therapy, preoperative radiation therapy may be used for this
group. There is also evidence that supports preoperative intracavitary radi-
um treatment in these grade 3 tumors. 47

Operation prior to radiation is preferred because this approach provides
prognostic information, not otherwise available, that can modify therapy.
Unsuspected, disseminated intraperitoneal disease would preclude the use
of radiation therapy except for palliation, the absence of myometrial pene-
tration might eliminate the need for radiation directed at the pelvic lymph
nodes, and the presence of positive pelvic or periaortic lymph node in-
volvement would necessitate the extension of radiotherapeutic ports and
the consideration of adjuvant chemotherapy.
When endometrial cancer extends to the cervix (stage II), treatment must
include the parametria, vagina, and pelvic lymph nodes in addition to the
fundus of the uterus. Three treatment regimens currently utilized include
radical hysterectomy with bilateral pelvic lymphadenectomy, radiation ther-
apy consisting of intracavitary treatment utilizing tandem and ovoids with
external whole pelvis therapy, and a combination of radiation and opera-
tion. Because pelvic lymph node metastases are best managed with radio-
therapy, 30 and because the risk of metastases in stage II disease approaches
40 per cent, 31 radiotherapy to the whole pelvis is preferred to primary
operation for the management of the pelvic lymph nodes. Since disease in
the uterine fundus is managed more successfully with surgery than radia-
tion, operation is preferred for disease in the uterine cavity. Hence, the
approach utilized for stage II disease at UCLA Hospital employs both radi-
ation therapy and surgery. 43 Radiation therapy is delivered to the whole
4.54 II / Treatment of Specific Neoplasms
pelvis with external beam and by intracavitary therapy to the uterus. In

order to minimize the risk of rectal and bladder injuries with hysterectomy
that follows radiation, the total dosage of radiation is limited, providing ap-
proximately 7000 rad to point A and 5500 rad to point B. A total abdominal
hysterectomy with bilateral salpingo-oophorectomy follows six to ten weeks
alter completion of radiation therapy.
The treatment of stage III disease, when associated with vaginal or para-
metria] metastases, is similar to that outlined for stage II disease. When
bulky tumor is present in the cervix and parametrium, more extensive radi-
ation delivered, and subsequent operation is abandoned. A total of 8500
is
rad to point A and 6000 rad to point B can be delivered safely, but sub-
sequent operation can cause an unacceptably high risk of gastrointestinal
and urologic injuries. Point A is two centimeters proximal and two centime-
ters lateral to the external os of the cervix. Point B is three centimeters
lateral to point A.
In patients who are controlled for stage of disease, coexistent medical
disease, and uterine size, the five-year relapse-free survival rates with radi-
ation therapy alone are significantly lower than with surgery or a combina-
tion of surgery and radiation. 49 In a total of 190 stage-for-stage matched pairs
of patients there was a significantly higher control rate for surgery with or
without radiation as compared with radiation alone (p <.01). The five- and
ten-year relapse-free survival rates in stage I disease were 87 per cent and
76 per cent, respectively, for the group of patients treated with surgery as
compared with 69 per cent and 52 per cent for the irradiated group. There-
fore, radiationtherapy without operation is reserved only for the poorest
medical with extensive pelvic tumors that are not
risk patients or for those
amenable to operation. When radiation therapy alone is employed in the
management of patients with stage I grade 1 disease, intrauterine packing
with Heyman capsules is utilized, delivering a total of 5000 to 6000 mg
50
hrs of radium in two applications separated by two weeks. Patients with
anaplastic tumors also receive 3500 to 4500 rad external whole pelvis thera-
51
py over four to six weeks. In patients with cervical, vaginal, or parametrial
extension, therapy is delivered as described for primary cervical carcinoma.
Chemotherapy
Recurrent and metastatic endometrial carcinoma is best treated with che-

motherapy. Various progestational compounds, including megestrol acetate
and 17 alpha-hydroxyprogesterone in a wide range of dosages, have pro-
duced objective response rates ranging from 25 to 40 per cent. 52 Patients
who are most likely to achieve palliation with these compounds characteris-
tically have well-differentiated tumors that are metastatic to lung in the
absence of other disease and a long disease-free interval following initial
treatment. Nearly half of these patients will show objective improvement,
and five- and ten-year survivors have been reported. 52 When a patient
does not respond to these medications, a combination of chemotherapeutic
agents, including doxorubicin, cyclophosphamide, 5-fluorouracil, and
11 Gynecologic Neoplasms 455
others, occasionally of benefit. Pelvic exenteration for recurrent pelvic

is
tumor only rarely has been of value, because of the high association with
occult extrapelvic metastases
The treatment of stage IV disease designed primarily for palliation,
is
although a few patients with tumor invading bladder or rectum can achieve
long disease-free survival with aggressive therapy. A recent study from the
Gynecologic Oncology Group has demonstrated a 38 per cent response rate
to doxorubicin chemotherapy in patients with metastatic endometrial can-
cer. Objective responses were seen in many patients who had failed prior
therapy with progestogens, the standard drug of first choice in this disease.
Additional studies of doxorubicin alone and in combination with other an-
tineoplastic drugs currently are under way. The treatment program that is
preferred for patients with stage IV cancer is outlined in Figure 11-5.
Follow-up
After completion of any mode of therapy, patients should be followed

even three months for two years, since 75 per cent of recurrences will
occur within that time interval. 47 Routine follow-up examinations continue
every six months thereafter and should include an abdominal and pelvic
examination with Papanicolaou smear. A chest x-ray should be obtained
semiannually. Specific complaints referable to the gastrointestinal tract and
urologic or skeletal system should be evaluated to rule out metastases.
Treatment Difficulties
The best approach to the management of patients with endometrial can-

cer should provide satisfactory treatment of the primary tumor, known me-
tastases,and those areas at increased risk for metastases. Data that identify
and quantify the risk factors cited previously permit the development of
rational approaches to the treatment of the various stages and substages of
this disease.
Unfortunately, many questions concerning optimal treatment regimens
remain unanswered because of difficult) in interpreting data reported in
the literature.'- For example, there is a lack of uniformity within and be-
tween studies concerning the definitions of stages of disease, determination
of tumor grade, means of detecting cervical involvement, and quantification
of myometrial invasion. In some reports the extent of disease conforms to
the older League of Nations staging, in some it conforms to FIGO staging,
and in others it conforms to no standardized staging system. Many studies
modify staging by operatise findings, such as occult cervical spread,
whereas most conform to accepted standards of clinical staging. The deter-
mination of tumor grade remains subjective, and die comparison of histolo-
gic grading between studies is often meaningless. Some authors utilize
Broder's grading system (groups I to IV) and others use that recommended
by FIGO (grades 1 to 3); some evaluate cellular pleomorphism and others
grade according to the glandular patterns. Cervical involvement might be
evaluated by clinical examination only, cervical punch biopsy, endocervical

curettage, cervical conization, or only after evaluating the hysterectomy
specimen. The determination of myometrial penetration has been made by
dividing the uterine wall in half, in thirds, or by otherwise defining superfi-
cial, intermediate, and deep invasion. The means of reporting patients who
are lost to follow-up or who die of intercurrent disease is often unclear.
These problems are compounded by the inability to standardize radiation
therapy or surgery, or both, between studies or even within studies that
include patient treatment often spanning the experience of an institution
over two or three decades. Hence, there is a great need for prospective
controlled studies that are designed to minimize the many variables cited.
UCLA is collaborating with 24 other institutional members of the Gyne-
cological Oncology Group in an effort to answer many of the questions that
are pertinent to defining optimal management of endometrial cancer.

Advances in the management of endometrial cancer in the future will
involve improved screening methods, better staging techniques, more ef-
fective treatment of patients at risk to fail conventional therapy, and the
identification of tumor markers useful in detecting and following patients
with this diagnosis. The value of existing procedures, including endome-
trial biopsy and uterine aspiration techniques, is being studied through the
National Cancer Institute in the routine screening of women for early en-
dometrial carcinoma. Advances in staging will result from more frequent
and better initial operative evaluation of patients. Preoperative studies in-
cluding hysterography and hysteroscopy might prove useful in localizing
tumor within the uterus, identifying occult spread to the uterine isthmus or
cervix, and predicting depth of myometrial penetration. Aided by improved
staging measures, it will be possible to direct adjuvant radiation therapy to
areas of occult metastases, including the pelvic and periaortic lymph nodes.
Prospective controlled collaborative studies through the Gynecologic On-
cology Group and other related organizations should provide useful guide-
lines for optimal treatment of high-risk patients. Adjuvant chemotherapy
and immunotherapy might prove to be useful therapeutic modalities but
have not been evaluated to date. Finally, initial efforts to identify tumor
markers for this disease have provided assays for estrogen and progesterone
receptors. Whether or not these receptors or other tumor markers prove to
be useful in the management of patients remains uncertain.
Section 3
Cancer of the Vulva
Over 85 per cent of malignant tumors vulva are squamous cell

of the
carcinomas. Five to 10 per cent are malignant melanomas, whereas adenocar-
cinomas, sarcomas, and other rare tumors compose the rest. This section will
primarily address squamous cell carcinoma of the vulva and its precursor
lesions. Melanoma, Paget's disease of the vulva, adenocarcinoma, basal cell
carcinoma, and sarcoma will he discussed briefly.
SQUAMOUS CELL CARCINOMA

Introduction
Squamous carcinoma of the vulva accounts for 3 to 4 per cent of the

cell
malignant lesions of the female genital tract. The disease is most frequent
in women past 50 years of age, although increasing numbers of younger
women with intraepithelial neoplasia of the vulva, vagina, and cervix are at
risk to develop invasive carcinoma of the vulva. 54
A possible viral etiology in the genesis of carcinoma of the vulva is sug-
gested by the association of some precancerous lesions with condyloma
acuminata and the high frequency of the circulating antibodies to herpes
simplex, type II virus in these women. As with endometrial cancer, pa-
tients with invasive squamous cell carcinoma of the vulva tend to be post-
menopausal, obese, hypertensive, and diabetic. A prior history of lues or
other granulomatous venereal disease is frequent. 55
Natural History
A
continuum of disease including dysplasia and carcinoma in situ is seen
in the vulva as in the cervix. Unlike in situ epidermoid carcinoma of the
cervix, the preinvasive stage of squamous cell carcinoma of the vulva is
often associated with a visible lesion. The concept of a multifocal origin of
dysplasia and carcinoma has been emphasized but does not apply to each
patient. Cytology, staining with vital dye, and even colposcopy are of limit-
ed diagnostic value because of the normal keratinization of the skin of the
vulva and the hyperkeratotic nature of many preneoplastic lesions. 56 The
liberal use of biopsy and appropriate histologic interpretation of biopsy ma-
terial is required if the diagnosis of intraepithelial carcinoma of the vulva is
to be made.
Clinical Features and Dlagxosis. Hypertrophic epithelial dys-
trophy, usually presenting as a raised, white hyperkeratotic area on the
vulva (leukoplakia), classically has been associated with squamous cell car-
cinoma of the vulva and precedes invasive cancer in up to 50 per cent of
cases. The malignant potential of leukoplakia has been overemphasized,
since less than 10 per cent of these lesions become malignant. Patches of
skin that appear red, dark brown, or white, and areas that are firm to palpa-
tion or in which the patient has noted pruritis or bleeding must be biopsied
to rule out carcinoma. Other findings that require excisional biopsy and
histologic interpretation include any nevus in the genital region, to ex-
clude melanoma, and any enlargement or thickening in the area overlying
Bartholin's glands, to exclude carcinoma of this structure. Delays in diagno-
sis and institution of therapy frequently exist on the part of both the patient
and her physician. Although improved treatment modalities have increased

the survival rate from carcinoma of the vulva, these delays have not been
reduced.
Staging. The International Federation of Gynecology and Obstetrics
has adopted a TNM system for staging primary squamous cell carcinoma of
the vulva (Table 11-7). Of the many histologic types of cancer of the vulva,
this classification is applicable only to squamous cell carcinoma because of
its unique tendency to invade adjacent structures and its predictable route
of metastases to superficial and deep regional lymph nodes in the groin and
then to pelvic and distant nodes. The initial lesion generally fungating or
is
ulcerating, and with prolonged growth it is associated with discharge sec-

ondary to infection and with bleeding and pain. The tumor originates in order
of decreasing frequency in the labium majus, labium minus, clitoris, and peri-
neum. The advanced presentation of many lesions precludes the determi-
nation of their precise origin. The histologic appearance of these tumors is
typical ofsquamous cell carcinoma, with the presence of epithelial pearls,

penetration of the malignant epithelial cells into underlying tissues, and
lymphatic and vascular involvement.
PROGNOSIS. Survival correlates with tumor size, location, structures in-
57
vaded, and metastases to the regional and distant lymph nodes. The initial
spread of carcinoma of the vulva is to ipsilateral groin nodes; however,
because of the rich, anastomosing lymphatic channels of the vulva, contra-
lateral groin node involvement occasionally has been observed in the ab-
sence of ipsilateral metastases. The frequency of metastases to the groin
nodes increases with the advancing stage of disease, as does the likelihood
of bilateral groin node involvement. Metastases to pelvic or periaortic
nodes in the absence of spread to the groin nodes are unusual but are re-
ported rarely in patients in whom the primary tumor involves the clitoris,
urethra, or anus. Many reports include no patients with positive pelvic
node involvement in the absence of metastases to the groin nodes. 58
Poor correlation exists between the clinical and histologic status of groin
nodes. Nonpalpable nodes (N„) rarely are involved with tumor, whereas nodes
that are matted, fixed, or ulcerated (N 3 ) can be diagnosed with assurance.
Difficulty arises, however, in determining whether or not mobile, palpable
nodes (N,, N 2 contain tumor. In this group of patients, clinical correlation
)
59 60
with histologic findings is no better than 50 to 75 per cent. '
In most series, the five-year survival rate of patients who are treated by
TABLE 11-7. TNM Classification of the Vulva
Primary tumor T) (
T, Tumor confined to the vulva, 2 cm or less in largest diameter.

Tj Tumor confined to the vulva, >2 cm in diameter.
T :!
Tumor of any size with adjacent spread to the urethra and/or vagina, and/or anus.
T 4 Tumor of any size infiltrating the bladder mucosa, and/or the rectal mucosa, or hoth,
including the upper part of the urethral mucosa and/or fixed to the hone.
Regional lymph nodes (N)
\ No nodes palpable.
N, Nodes palpable in either groin, not enlarged, mobile (not clinically suspicious of
neoplasm).
N, Nodes palpable in either one or both groins, enlarged, firm, and mobile (clinically
suspicious oi neoplasm).
\ Fixed or ulcerated nodes.
Distant metastases (M
M„ No clinical metastas
M,., Palpable deep pelvic lymph nodes
Mi b Other distant metastases.
Stage TNM Clinical Findings
I T, N, M„ All lesions confined to the vulva with a maximum diameter

T, N] M„ of 2 cm or less and no suspicious groin nodes.
II Tj N„ M„ All lesions confined to the vulva with a diameter >2 cm

T2 N, M,, and no suspicious groin nodes.
III T :1
N„ M„ Lesions extending beyond the vulva but without grosslj
T.( N, M„ positive groin node involvement
T, N. M„ Lesions of any size confined to the vulva and having

T. N, M. suspicious groin nodes.
T, \. \l
IV T, Nj M„ Lesions with grossK positive groin node involvement, regard-

To N ;
M„ less of extent of primary.
T N M
T 4 N, M„
T 4 N„ M„ Lesions involving mucosa of rectum, bladder, or urethra, or

T 4 N, M„ involving bone.
T 4 N, M„
T- N- M la All cases with distant or palpable deep pelvic metastases.

T- N- Mu ,
radical vulvectomy and groin node dissection is greater than 80 per cent if
no metastases are present and 40 to 50 per cent if there is unilateral inguin-
al or femoral node involvement. Survival is reduced to 25 per cent at five
years with either bilateral groin node involvement or unilateral involve-

ment of both groin and pelvic lymph nodes. Patients with bilateral pelvic
node metastases have an expected 10 to 20 per cent five-vear survival rate
(Table 11-S).
460 II / Treatment of Specxfk Neoplasms
TABLE 11-8. Five-Year Survival Based on the Status of the

Groin and Pelvic Lymph Nodes
I'l R ( IN I Si l<\ I\ \l
Series Groin Nodes Negative Groin Nodes Positive Pelvic Nodes Positive
Rutledge et al'
:
100 33 25
Wax" 1
86 48 22
Green et al.
iS
86 47 13
Morley60 84 38 17
Way 61 77 42 37
Ballon and Lamb 59 74 66
'Not all patients underwent pelvic lymphadenectomy.
Treatment
SURGERY. The standard approach to the treatment of intraepithelial car-

cinomas is wide, complete removal of the skin of the vulva. The basis for
this approach is the documented potential for these preinvasive lesions to
be multifocal and to recur following inadequate local excision. The deci-
sion not to perform a total vulvectomy requires an understanding of the
disease by the patient and her acceptance of the need for frequent exami-
nations and the possibility of multiple wide local excisions. A subtotal vul-
vectomy with preservation of the clitoris is suitable treatment for selected
patients with posterior lesions.
Until 1939, cure rates of only 15 to 20 per cent were reported for patients
with invasive squamous carcinoma of the vulva who were treated with local
excision. Way 81 then established that improved survival related directly
to wide, deep removal of the entire vulva with an aggressive attack on the
regional lymph nodes; this provided a basis for the management of invasive
carcinoma of the vulva. 62 Preoperative evaluation includes chest x-ray,
intravenous pyelogram, cystoscopy, barium enema, sigmoidoscopy, com-
plete blood count, urinalysis, and tests for hepatic and renal function. A
careful pelvic examination is performed to assess the status of the vagina,
cervix, urethra, base of the bladder, and rectovaginal septum. A biopsy of
these areas is performed if indicated. A radical vulvectomy, with removal of
the vulva to the external pelvic fascia and an in continuity dissection of the
inguinal and femoral lymph nodes is now the standard approach to this
disease. Pelvic lymphadenectomy or irradiation of the pelvic lymph nodes
is performed if regional node metastases are present, and this approach is
advocated by some if the primary tumor involves the clitoris, urethra, or

anus.
The incidence of complications that result from the extensive operative
procedure approaches 100 per cent. These complications include the break-
down of the incision overlying the groin and vulva, local infection, sepsis,
thromboembolism, prolonged hospitalization, and chronic edema of the
lower extremities. The transplantation of the head of the sartorius muscle to
cover the denuded femoral vessels, together with the postoperative use of
suction catheters to facilitate drainage, has decreased the morbidity from

sepsis and hemorrhage that was previously seen with groin node dissect-
ion. The concept that this tumor metastasizes to the nodes by embolization
rather than by direct extension has led investigators at UCLA Medical
Center to use separate incisions in selected patients rather than perform a
lymphadenectomy in continuity with the radical vulvectomy. Separate inci-
sions have been shown to decrease the early and late postoperative morbid-
ity that is secondary to groin wound breakdown and have not been associat-
ed with an increase in local tumor recurrence. 59
When the size and location of the primary tumor allow the operator to
use separate incisions, morbidity relates to the breakdown of the vulvec-
tomy incision and frequent postoperative difficulty with urination. At the
UCLA Medical Center, attention now has turned to the reconstruction of
larger defects left by a radical vulvectomy. 68 Myocutaneous gracilis flaps are
rotated from the legs to cover the defect in the vulva. On occasion, when
the radicality of the groin node dissection has prevented primary closure of
the groin wound, a myocutaneous flap is used to cover this defect as well.
SURGERY and RADIATION. Patients with metastases to the groin nodes
that are demonstrated at the time of radical vulvectomy undergo pelvic
lymphadenectomy or radiation therapy, or both, to the whole pelvis. Stand-
ard operative approaches to the pelvic and periaortic nodes involve incision
of the external and internal oblique fascia parallel to the inguinal ligament
or splitting the inguinal ligament. Recently, an extraperitoneal approach to
the pelvic and periaortic lymph nodes has been favored, and bilateral lym-
phadenectomy has been performed through a single left-sided J-shaped in-
cision. 6 ^ Improved exposure by this technique permits more complete
lymph node dissection. The demonstrated absence of morbidity when com-
bined with postoperative radiation allows for potential therapeutic benefit
from lymphadenectomy and extended field radiotherapy in selected pa-
tients with advanced carcinoma of the vulva.
Patients with metastases to the pelvic lymph nodes are treated with
whole pelvis irradiation consisting of 4500 to 5000 rad delivered over four
to six weeks. Therapy is begun as soon as healing is complete, generally
within three weeks of operation. Little controlled data exist to quantify the
benefits of postoperative radiation therapy; however, many series report
long-term survivors treated by this approach.
Local recurrence of squamous cell carcinoma that is confined to the vulva
should be unusual if care is taken to ensure tumor-free margins at the time
of resection. Patients in whom the primary tumor invades the rectum,
urethra, or bladder have disease beyond the limits of a standard radical
vulvectomy. Pelvic exenteration, in combination with radical vulvectomy
and groin node dissection, has not eliminated the problem of local recur-
rence and has resulted in a five-year survival rate of only 15 to 20 per
cent. 65 Studies are ongoing in such patients to assess the benefits of preop-
erative radiation therapy followed by operations that are less extensive than
an exenteration. Preliminary results in patients so managed at the UCLA
Medical Center suggest that the risk of distant disease in these patients is
high. In three such patients treated by preoperative radiation and radical
operation, two died of pulmonary metastases, and one succumbed to a com-

bination of local and distant recurrence.
CHEMOTHERAPY. The drugs dinitroehlorobenzene, and
5-fluorouracil,
bleomycin prepared as hydrophobic ointments have been applied directly
to the skin of the vulva in women with carcinoma in situ.''''' DXCB and
bleomycin also have been injected intradermally. Several preliminary re-
ports have indicated regression of intraepithelial neoplasia using these
drugs; however, in a pilot study performed at UCLA Medical Center, two
patients had progression of their disease while on topical bleomycin therapy.
The potential to avoid mutilating operations by the use of topical chemo-
therapy for in situ carcinoma of the vulva is exciting; however, its status
at present is investigative.
The available chemotherapeutic agents for the treatment of disseminated
squamous carcinoma of the vulva have produced no complete, sus-
cell
tained remissions in our patients. An objective response rate of 10 to 15 per
cent has been observed for up to four months in patients receiving bleomy-
cin, an alkylating agent, or cisplatin. Death has been due to cachexia or
respiratory failure secondary to extensive pulmonary metastases.
MALIGNANT MELANOMA
In most treatment centers 5 to 10 per cent of cancer of the vulva is malig-

nant melanoma. In spite of the fact that the vulva accounts for only 1.5 per
cent of the body surface area and has less than 0.1 per cent of nevi, 5 per
cent of cases of malignant melanoma in the female occur on the vulva,
where virtually all nevi are of the junctional variety. 67 Eighty per cent of
melanomas of the vulva arise from the labium minus or clitoris and often
extend to involve the urethra and vagina.
Malignant melanoma of the vulva is three times more common in whites
than in blacks. The disease is prevalent in warm latitudes and increases
with exposure of the skin to ultraviolet light. A few melanomas occur in
genetically predisposed individuals.
The average age at diagnosis of melanoma of the vulva is 55 years, but
occurrence in young women
is not uncommon. Melanoma is the fourth most
common malignancy associated with pregnancy, following breast cancer,
the leukemias, and lymphomas, and is the most common tumor to metasta-
size to the placenta and fetus.
Natural History
Clinical Features and Diagnosis. Melanoma, a malignant tumor of

melanocytes, can arise from junctional nevi, the junctional component of
compound nevi, or "de novo." Malignant change usually occurs in a flat,
hairless nevus and is suggested by enlargement, ulceration, weeping, crust-
ing, or bleeding. The common symptoms noted include an enlarging mole,

pruritus, and bleeding. The tumor can be flat, elevated, or polypoid; it can
ulcerate and present with a surrounding flare or satellite metastases. The
overlying epidermis often undergoes pseudoepitheliomatous hyperplasia.
In addition to extension to the adjacent urethra and vagina, melanoma
often metastasizes to regional and distant lymph nodes, and in-transit me-
tastases can be demonstrated in the lymphatics of the tissues overlying the
groin. A tendency to hematogenous dissemination is responsible for the
presence of distant visceral metastases and accounts for the high incidence
of recurrence long after the diagnosis and treatment of the primary lesion.
PROGNOSIS. The presence or absence of symptoms associated with the
primary lesion does not appear to affect prognosis. Similarly, the degree of
nuclear and cytoplasmic atypism of the tumor cells does not correlate with
outcome. Nodular melanoma carries a poor prognosis, as do lesions arising
from mucous membranes. Women tend to have a better survival rate from
malignant melanoma than do men. Survival has been shown to decrease
with advancing age at diagnosis. Prognosis worsens with increasing extent
of disease, lymph node metastases (30 per cent of cases), involvement of
the urethra or vagina (10 per cent of cases), the presence of satellite lesions
(5 per cent of cases), and distant metastases (less than 5 per cent of cases).
As with melanoma found elsewhere, the depth of invasion of the primary
lesion correlates with both the tendency to metastasize and survival.
Clark's classification for melanomas can be applied to those arising in the
vulva. 68 One more classification, which is specifically related to the unique
structures of the tissues of the vulva, has also been used to correlate depth
of invasion with prognosis (Table 11-9). 69
Morrow and Rutledge noted that the TNM staging for epidermoid carci-
noma of the vulva reasonably reflects the prognosis from malignant melano-
TABLE 11-9. Classification of Melanoma Based

on Level of Invasion
Level Clark 68 MSKCC '
All tumor cells above All tumor cells above basement membrane
basement membrane I in situ melanoma)
(in situ melanoma)
II Penetration of tumor cells Superficial penetration of tumor into

into papillary but not subepithelial tissues to depth of 1 mm
reticular dermis or less
III Penetration of tumor cells Superficial penetration of tumor into

to interfacebetween subepithelial tissues between 1 mm and
papillary and reticular 2 mm
dermis
IV Penetration of tumor cells Penetration of tumor cells beyond 2 mm

into reticular dermis but not into subcutaneous fat
Penetration of tumor cells Penetration of tumor cells into

into subcutaneous fat subcutaneous fat
'Memorial Sloan-Kertering Cancer Center

ma. 70 Patients with no metastases to regional lymph nodes in the groin have
a better than 50 per cent five-year survival rate. With metastases to the
groin nodes, survival is less than 15 per eent at five years. Pelvic lymph
nodes are rarely involved in the absence of groin node metastases and if
involved produce virtually no five-year survivals. The gross five-year sur-
vival rate from melanoma of the vulva is less than 40 per cent, and the
ten-year survival rate is less than 30 per cent.
Patients with occult metastases to the groin nodes probably have a better
prognosis than those with clinically positive groin node involvement.
Twenty-five to 50 per cent of patients develop groin node metastases fol-
lowing therapy only of the primary lesions, suggesting a high incidence of
occult metastases at the time of diagnosis.
Treatment
SURGERY. The fact that nevi on die vulva are uncommon and invariably
junctional suggests that they should undergo prophylactic removal by total
excision with a wide margin of normal skin. Minimal acceptable therapy for
malignant melanoma of the vulva is radical vulvectomy with in continuity
bilateral removal of inguinal and femoral lymph nodes. This is required
because of the frequent presence of in-transit metastases and the demon-
strated propensity to bilateral node metastases. As clitoral involvement is
common, the removal of pelvic lymph nodes should be considered in such
cases and performed in all cases in which groin nodes are involved. Care
should be taken to ensure disease-free margins, especially at the junction of
the urethra and vaginal mucosa.
Radiation. Malignant melanoma of the vulva traditionally has been
viewed as being radioresistant. In the absence of clinically apparent metas-
tases, however, radiation therapy has produced up to a 70 per cent five-year
survival rate in other sites. This decreases to less than 30 per cent if metas-
tases are present. Radiation is poorly tolerated by the tissues of the vulva,
but should nevertheless include 10 to 15 cm of normal skin surrounding
the lesion. Palliative radiation therapy has produced about a 50 per cent
response rate with 2000 to 3000 rad in patients with pain secondary to skel-
etal metastases or central nervous system symptoms caused by brain metas-
tases.
Chemotherapy. Survival from malignant melanoma of the vulva in pa-
tients with disseminated disease is less than 5 per cent at five years. Tran-
sient responses are seen with alkylating agents (15 to 20 per cent), vinca
alkaloids (20 per cent), procarbazine (25 per cent), DTIC (25 to 35 per
cent), and the nitrosoureas. Combination chemotherapy usually includes a
vinca alkaloid and DTIC. Women tend to respond more often than men to
chemotherapy of disseminated melanoma and have a longer median surviv-
al if they do respond.
Immunotherapy. Spontaneous regression of melanoma is known. Cuta-
neous hypersensitivity to melanoma cells, antibodies to cell surface and
cytoplasmic antigens, and lymphocyte cytotoxicity to melanoma cells have
been demonstrated. Immunotherapeutic approaches have included the in-

jection oftumor cells from each of a pair of melanoma patients into the
opposite member of the pair and the transfusion thereby of activated lym-
phocytes from the recipient to the donor. This technique has produced a 20
71
per cent response rate in selected patients. Bacillus Calmette-Guerin and
MER methanol extraction residue of BCG) injected into cutaneous le-
(the
sions has resulted in regression of up to 90 per cent of injected lesions if
the patient is able to demonstrate a delayed hypersensitivity response to
DNCB and is able to react to tuberculin after BCG therapy 72 Combinations of
chemotherapy and immunotherapy are now under investigation.
PAGET'S DISEASE
Natural History
Paget's disease of the vulva seen more often than is reported. The
is
disease is regarded as a distinctive form of intraepithelial carcinoma and

causes pruritis with secondary excoriation and bleeding. 73 The characteris-
tic lesion is velvety red with raised, irregular margins. Histologically, the
thickened epithelium is infiltrated with mucin-containing Paget's cells,
which are thought to arise from adjacent glandular structures. Often, the
grossly normal surrounding skin is also involved.
Patients with Paget's disease of the vulva appear to be at risk to develop
unrelated secondary primary neoplasms. Following treatment of their dis-
ease, the physician must be alert not only to the potential for local recur-
rence but also to a second primary tumor. The lower genital tract, skin, and
gastrointestinal tract are affected most frequently.
Treatment
SURGERY. Paget's disease of the vulva can be considered as two distinct

entities for therapeutic purposes. 74 In
75 per cent of patients, the abnormal-
ity is confined to the epidermis, whereas in the remaining 25 per cent of
patients, an underlying invasive adenocarcinoma is present. Occasionally,
the distinction as to which type of Paget's disease is present cannot be
made on clinical grounds. For this reason, a radical vulvectomy is recom-
mended as the primary treatment for all patients with Paget's disease of the
vulva. A wider margin of the normal-appearing skin than is required for
squamous carcinoma should be taken. If no underlying invasive adenocarci-
noma is found on histologic examination of the vulvectomy specimen, sub-
sequent management is directed toward the identification of local recurrent
disease. When a coexisting adenocarcinoma is present, the role of bilateral
inguinal and femoral node dissection deserves consideration. In the ab-
sence of clinically suspicious groin nodes, this procedure is of prognostic
importance but has not been demonstrated to improve survival. Similarly,
the therapeutic value of lymphadenectomy in patients with palpable groin
node metastases questionable. 78 Death in these patients is usually sec-

is
ondary to disseminated disease. In any patient with a suspected invasive

adenocarcinoma, a thorough investigation is required to determine if metas-
tatic disease is present prior to the performance of a radical vulvectomy. A
less radical procedure designed to achieve local control might be indicated
if metastases are demonstrated.
Chemotherapy. Despite attempts to ensure tumor-free margins at the
time of excision, Paget's disease of the vulva is associated with a high rate
of local recurrence. As a result, many patients have been subjected to mul-
tiple wide local excisions following a radical vulvectomy. At the UCLA Me-
dical Center, seven patients with recurrent Paget's disease of the vulva fol-
lowing radical vulvectomy have been treated with topical bleomycin
ointment. 76 Of this group, four patients experienced a complete response to
therapy, and one of these has responded completely to the treatment of a
subsequent recurrence. Studies are in progress to further assess the role of
topical chemotherapy in the treatment of recurrent Paget's disease of the
vulva. 70
Radiation. No information is available to assess the benefit of radiation
therapy in the treatment of Paget's disease. Isolated patients have respond-
ed to radiation therapy for local recurrent disease. The treatment of intraep-
ithelial disease with radiation therapy is not warranted. In the presence of
an underlying invasive adenocarcinoma its use is unproved.
BASAL CELL CARCINOMA

Basal cell carcinoma of the vulva occurs most often in elderly, white pa-
tients. The anterior labium majus is the most common site. Pruritis or a
mass is often present for long periods prior to diagnosis. The etiology of
these lesions is unclear; however, prior irradiation to the vulva has been
reported in some patients. As with basal cell tumors originating in extra-
genital sites, the tumor is locally invasive but does not metastasize, and
treatment is directed toward wide, deep local excision of the lesion with
care to ensure tumor-free margins. Unlike squamous cell carcinoma, this
tumor appears to be unifocal, and radical vulvectomy is not required. 77
SARCOMA
Sarcoma of the vulva is a rare lesion that is usually seen in young women
and accounts for approximately 1 per cent of tumors of the vulva. Less than
200 cases of primary sarcoma of the vulva have been reported. Leiomyosar-
coma is most frequent, whereas rhabdomyosarcoma, neurofibrosarcoma, fi-
brosarcoma, myxosarcoma, and epithelioid sarcoma also occur. 78
A rational approach to the therapy of these tumors must take into account
the tendency of sarcomas to recur locally and to metastasize both by hema-
togenous and lymphatic pathways. A wide radical vulvectomy with care to
ensure tumor-free margins, together with bilateral inguinal and femoral
11 Gynecologic Neopla- 16~
lymphadenectomy, has been shown to be successful in the prevention ol

local recurrence and to produce occasional long-term survival even in the
presence of metastases to the groin nodes. 7y The advantages of adjunctive
chemotherapy for patients at risk to develop recurrent disease currently are
under study. Various combinations of chemotherapeutic agents have been
reported to be successful in the short-term control of disseminated, recur-
rent sarcoma of the vulva.
ADENOCARCINOMA OF
BARTHOLIN S GLAND
Adenocarcinoma of Bartholin's gland is extremely rare. It occurs primar-
ily in older women but has been reported in patients as young as 14
years." The criteria for diagnosis of this tumor include correct anatomic
position, location of the tumor deep in the labium, and the presence of
glandular elements. Patterns of spread are thought to be similar to those of
invasive squamous cell carcinoma; however, too tew xi>t to permit a
definitive statement as to the natural history and biologic behavior of
these tumors. The diagnosis often is made late in the course of the di
and these tumors are associated with a high frequency ot regional and dis-
tant lymph node metastases. This relates to the deep location of Bartholin's
gland as well as to a rich bed of lymphatic vessels draining directly to the
pelvic lymph nodes as well as to those in the groin.
important for the physician to recognize that inflammation of Bartho-
It is
lin'sgland is uncommon after the fourth decade of life and virtually unre-
ported in postmenopausal women. Swelling in the Bartholin's gland area in
this group of patients should lead to biopsy. Because ot the location of
Bartholin's glands deep in the vulvar tissues and because of the lymphatic-
drainage to the pelvic lymph nodes, a radical vulvectomy together with
inguinal and pelvic lymphadeneetomy probably constitute the minimal ac-
ceptable therapy. Survival data are difficult to interpret because of the few
cases, but they suggest that if diagnosed early, this tumor is potentially
curable."' Patients with mett to groin or pelvic lymph nodes rarely
survive five yean

Squamous carcinoma of the vulva, although not preventable, is
cell
theoretically detectable at an early stage.A concerted effort toward patient
education is required if these early lesions are to be brought to the atten-
tion of the physician. The education of the practicing physician will avoid
frequent delays in diagnosis. Any lesion or thickening of the vulva requires
biopsy and histologic interpretation prior to the institution of any therapy
such as topical creams. If these educational efforts are successful, patients
with carcinoma of the vulva will undergo definitive therapy at a time when
it is most likelv to be curative.
The place of wide local excision and topical chemotherapy in the treat-
ment of intraepithelial carcinoma of the vulva requires further study. Many
affected patients areyoung and would benefit from efforts designed to min-
imize the physical and psychosexual problems associated with total vulvec-
tomy. Such studies must be designed carefully to ensure that cure is not
sacrificed in favor of a better cosmetic result. Preliminary studies of pa-
tients with recurrent, intraepithelial Paget' s disease surest that local che-
motherapy can obviate the need for multiple wide local excisions.
The morbidity associated with radical vulvectomy and groin node dis-
section continues to direct our attention toward criteria that will permit
individualized therapy. 82 Although an in continuity dissection is required
for patients with malignant melanoma because of the presence of in-transit
metastases, it has been shown that patients with early squamous cell carci-
noma of the vulva can be treated by the use of separate incisions for the
groin and vulva dissections. Decreased morbidity has not been accompa-
nied by an increase in local recurrence in this patient group. Reconstruc-
tion of large defects following removal of advanced carcinoma of the vulva
has been accomplished in selected patients with the use of myocutaneous
flaps.
The place of radiation therapy in the management of patients with squa-
mous cell carcinoma of the vulva deserves further investigation. The ability
of external beam therapy to eradicate microscopic metastases in the groin
nodes should be studied. Documentation of the ability of whole pelvis ir-
radiation to sterilize tumor in the pelvic lymphatics is required. A combina-
tion of radiation therapy and extended operation for advanced disease war-
rants our continued attention.
Section 4
Cancer of the Vagina
INTRODUCTION
Primary carcinoma of the vagina accounts for only 1 to 2 per cent of gy-
necologic malignancies. Although extension to the vagina from a tumor of
the cervix or vulva is seen frequently, tumors involving both vagina and
cervix are classified as cervical cancers, and those involving vagina and
vulva are considered neoplasms of the vulva. Over 90 per cent of vaginal
cancers are of the epidermoid variety, and most of the remainder are ade-
nocarcinomas. Although about 200 new cases of adenocarcinoma of the va-
gina have been reported in the past eight years in conjunction with expo-
sure in utero to synthetic, nonsteroidal estrogens, the overall incidence has
not risen, and this remains an uncommon disease. 83 Primary sarcoma and
melanoma of the vagina are so infrequent that they do not warrant separate
discussion.
Carcinoma of the vagina should be readily detectable on the basis of its
accessibility to direct examination and the early onset of symptoms. In
spite of these features, the disease is associated with a generally poor prog-
nosis because of frequent spread to regional lymph nodes and adjacent vis-
cera. 84 This is attributed to the anatomy of the vagina as a thin-walled struc-
ture richly supplied with lymphatic vessels and the fact that the vaginal
mucosa and its surrounding areolar tissue offer no effective barrier against
local spread to the adjacent bladder or rectum, or both.
Etiology
Intraepithelial Squamous Carcinoma. As with carcinoma of the

cervix and vulva, invasive epidermoid carcinoma of the vagina is associated
with precursor lesions in the form of dysplasia and carcinoma in situ. Un-
like carcinoma of the cervix, however, the natural history of this continuum
as it applies to the vagina is poorly understood. The factors that influence
dysplasia of the vagina to progress to intraepithelial and invasive carcinoma
and the time required for progression from intraepithelial to invasive can-
cer are not known. The frequent association of cancer of the vagina with a
previous history of carcinoma in situ or invasive cancer of the cervix sug-
gests that the vagina is involved in a field change resulting from exposure
to a carcinogen that is common to both the cervix and vagina.
56, 85
A possi-
ble viral etiology in the genesis of epidermoid carcinoma of the vagina is
suggested by the presence of circulating antibodies to herpes simplex, type
II virus in some women with this disease.
ADENOCARCINOMA. During the 1940s, many physicians prescribed syn-
thetic, nonsteroidal estrogens (diethylstilbestrol) to pregnant women with
histories of prior abortion, diabetes, or toxemia of pregnancy. In 1971, a
link was reported between maternal DES therapy during pregnancy and
the occurrence of clear cell adenocarcinoma of the vagina in female off-
spring exposed to this drug in utero. 86 In all cases of malignancy for which
precise information is available, the drug was initiated before the eigh-
teenth week of gestation. As little as 1.5 mg of DES administered daily
throughout pregnancy has been associated with subsequent cancer in fe-
male offspring.
The number of pregnant women treated with DES or chemically related
compounds during pregnancy has been estimated at about 2 million, but
only 200 cases of adenocarcinoma of the vagina have been reported in the
female offspring of these women. The risk of adenocarcinoma in an ex-
posed female under 30 years of age appears to be minimal in view of the
large exposed population and the low incidence of the disease reported.
Because women have developed adenocarcinoma of the vagina without ex-
posure in utero to synthetic, nonsteroidal estrogens, other factors must play
a role in the etiology of these tumors.
NATURAL HISTORY
Invasive squamous and adenocarcinoma of the vagina have distinctive

features, as shown in Table 11-10. They both tend to involve the upper
and middle one third of the vagina most often. A location on the posterior
wall is most common, followed by anterior wall lesions. Because these
areas can be obscured by the blades of a vaginal speculum, the vagina must
be carefully inspected and palpated in any woman with abnormal bleeding
or an atypical cytologic smear. The symptoms
associated with cancer of the
vagina are similar to those associated with carcinoma of the cervix. Vaginal
bleeding or discharge, or both, are the most frequent symptoms reported by
our patients. Bladder discomfort and frequency of urination are more com-
mon in patients with vaginal tumors than in those with cancer of the cervix
because the location of these tumors can irritate the base of the bladder
and urethra at an early stage.
Most vaginal adenocarcinomas in DES-exposed females are associated
with vaginal adenosis —
the presence of glandular epithelium in the va-
gina. Benign adenosis is found histologically in over 97 per cent of women
with vaginal clear cell adenocarcinoma whether or not a history of DES
exposure in utero is confirmed. Vaginal adenosis occurs in more than one
third of the women exposed during the first four months of gestation but is
rare in unexposed women. Other abnormalities such as transverse vaginal
and cervical ridges are also associated with intrauterine exposure to DES.
Adenosis often can be detected by the presence of metaplastic squamous
cells and columnar cells on a cytologic smear from vaginal wall scrap-
ings. 87,88 Although patients with vaginal adenosis are usually asymptomatic,
TABLE 11-10. Comparison of Adenocarcinoma and

Squamous Carcinoma of the Vagina
Adenocarcinoma Squamous Carcinoma
Mean age at diagnosis (years) 20 to 40 45 to 65
Coexisting adenosis -H- —
In utero exposure to synthetic

nonsteroidal estrogen ++ —
Prior in situ or invasive

cancer of the cervix — +
Preceded by dysplasia and
in situ carcinoma of the vagina — ++
Prior radiation to the vagina — ±
Cytology aids in diagnosis + -l-l-
Frequent presenting symptoms Bleeding, Bleeding,

discharge discharge
on occasion the columnar epithelium on the surface of the vagina produces

a watery discharge. No patient yet has demonstrated a transition from be-
nign to malignant glandular epithelium while under observation for a histo-
ry of in utero exposure to DES.
The diagnosis of dysplasia or intraepithelial carcinoma of the vagina is
suspected on the basis of an abnormal cytologic smear and is confirmed by
appropriate biopsies. Symptoms are usually absent at this stage, but a va-
ginal discharge or irritation occasionally is present. No specific area of the
vagina appears at increased risk for the development of dysplasia, and the
disease is often multifocal, as is the case with carcinoma of the vulva. A
careful colposcopic examination and the use of vital dyes such as toluidine
blue and Lugol's solution assist in the localization of potentially abnormal
areas. 56 A biopsy of these areas is required to confirm the presence and
severity of the dysplastic or neoplastic process; however, on occasion the
area that is responsible for the abnormal cytologic smear cannot be local-
ized.
Clinical Staging
The staging of invasive carcinoma of the vagina has been established by

the International Federation of Gynecology and Obstetrics, as shown in
Table 11-11. This system takes into account the tendency of these tumors
to invade surrounding structures progressively, but it ignores the factors of
tumor volume within a given stage and location in the vagina as it relates
to lymphatic spread. The lymphatics of the vagina are found in the mucosa
and submucosa and are continuous throughout the entire organ. Despite
this continuity, the lymphatic drainage of cancer of the vagina follows a
pattern based on the specific region of the vagina involved in the malignant
process. 89 Lymphatic channels in the upper posterior vagina pass through
the rectal septum and uterosacral ligaments to terminate in the rectal
nodes. Those from the upper anterior vagina traverse the cardinal ligaments
TABLE 11-11. Staging Classification for Vaginal

Cancer (FIGO Nomenclature)
Stage Carcinoma in situ; intraepithelial carcinoma.
Stage I The carcinoma is limited to the vaginal wall.
Stage II The carcinoma has involved the subvaginal tissue hut has not
extended to the pelvic wall.
Stage III The carcinoma has extended to the pelvic wall.
Stage IV The carcinoma has extended beyond the true pelvis or has
involved the mucosa of the bladder or rectum. Bullous edema
as such does not permit a case to be allotted to Stage IV.
Stage I\ d Spread of the growth to adjacent organs.
Stage IVb Spread to distant organs.

to reach the internal and external iliac nodes, whereas those from the lower
vagina follow the vaginal artery and turn posteriorly to the inferior gluteal
nodes. In addition, a distal vaginal lymphatic network communicates with
that of the vestibule and drains to the regional nodes in the femoral trian-
gle. All portions of the vagina have lateral lymphatic trunks that travel to
the pelvic floor, the superior gluteal region, and occasionally to the com-
mon iliac nodes.
Prognosis
The prognosis
of a patient with carcinoma of the vagina relates to the
tumor volume and risk of lymphatic metastases, which are both reflected in
the stage of the primary tumor. Unfortunately, clinical staging of vaginal
carcinoma is less reliable than with other pelvic malignancies. Courtial 90
recognized three stages of carcinoma of the vagina.. His system allotted
those tumors cqnfined to the vagina to stage I, those with more extensive
involvement of vagina and paravaginal tissues to stage II, and those with
invasion into bladder, urethra, or rectum or those associated with palpable
pelvic lymph node metastases to stage III. Using this system, and combin-
ing data from various sources, five-year relapse-free survival rates of 69 per
cent for stage I disease, 45 per cent for stage II disease, and 8 per cent for
stage III disease are obtained. Applying the FIGO staging system, Frick et
91
a/. reported a 55 per cent rate of survival in patients with stage I disease, a 31
per cent rate of survival in patients with stage II disease, and no survivors
in patients with stage III and stage IV disease.
TREATMENT
Intraepithelial Squamous Carcinoma
Patients who have undergone hysterectomy any reason should be ad-

for
vised of the continued need for annual pelvic examination and cytologic
smear of the vagina. This is especially true in patients with a history of
carcinoma in situ or invasive epidermoid carcinoma of the lower genital
tract, since an increased tendency to the development of vaginal dysplasia
and intraepithelial carcinoma in these women has been demonstrated. Pa-
tients in whom a cytologic smear of the vagina is productive of dysplastic
cells require investigation to localize and further define the abnormality.
The colposcope is ideally suited to this purpose and, when used in con-
junction with vital stains of the vagina, often permits the lesion to be iden-
tified and biopsied for histologic interpretation. 56 The treatment of intraepi-
thelial neoplasia of the vagina that is suspected on the basis of a cytologic
smear must not be undertaken until an invasive lesion has been ruled out
by directed biopsy.
The of the vagina can be ac-

effective treatment of carcinoma in situ
complished by radiation therapy in the form of intravaginal radium or ce-
sium, total vaginectomy, or the application of topical chemotherapeutic
agents. Radiation often is associated with a marked decrease in vaginal
function due to loss of vaginal caliber and elasticity. Total vaginectomy re-
quires construction of a neovagina, most often by the use of a free split-
thickness skin graft obtained from the thigh of the patient. At the UCLA
Medical Center, 13 patients have been treated with topical 5-fluorouracil
cream. All patients had abnormal cytologic smears with colposcopically
directed biopsies that identified dysplasia or carcinoma in situ in the ab-
sence of invasive cancer. The cream was applied twice daily for 10 to 14
days with care to ensure that the normal skin of the vulva was protected by
a barrier ointment. All patients noted intense burning and soreness in the
vagina. Cytologic smears obtained 3 months following treatment were nor-
mal in all patients; however, two patients developed a recurrence of their
intraepithelial neoplasia at 11 and 14 months following therapy. These pa-
tients have been successfully retreated with topical 5-fluorouracil cream.
DES Exposure
asymptomatic girls with known or suspected exposure to DES in

All
utero should receive a thorough pelvic examination at menarche or age 14.
Younger girls should be examined if they develop abnormal bleeding or
discharge. Whenever exposure is probable and symptoms are present, in-
vestigation is imperative regardless of the age of the patient. Inspection
and palpation of the entire vagina, cytologic smear of the cervix and vagina,
and staining of the cervical and vaginal epithelium with vital dye should be
performed. Abnormal areas that are nodular, indurated, or hemorrhagic
must be biopsied. For the very young patient with symptoms, anesthesia is
often necessary to permit examination. Colposcopy is a useful adjunct to
this examination but is not essential.
The patient who is exposed to DES in utero should be followed regular-
ly. After a normal initial examination that includes a negative cytologic smear,
no nodularity, and negative biopsy results if performed, an annual pelvic
examination with cytologic smears and staining with vital dye is adequate.
If abnormalities are noted during the initial examination, the frequency of
follow-up visits should be based on the severity of the findings. Cauteriza-
tion, cryosurgery, or excision can be performed if changes such as squa-
mous dysplasia are found on biopsy. The optimal management of asymp-
tomatic vagina] adenosis has not been defined, and observation probably is
sufficient. At the present time, no case has been reported in which vaginal
adenosis has progressed to cancer under direct observation. Extensive
adenosis of the vaginal epithelium that is associated with a bothersome,
watery discharge can be managed with topical cream that is designed to
acidify the vagina and promote squamous metaplasia of the columnar epi-
thelium.
474 II / Treatment ok Sim ( ii i< Neoplasms
Invasive Carcinoma
Patients with invasive squamous cell carcinoma or adenocarcinoma of the

vagina require thorough investigation to define the extent of their disease.
Pretreatment evaluation should include a complete blood count, urinalysis,
blood urea nitrogen and serum creatinine determinations, and tests of hepatic
function. Chest roentgenogram, intravenous pyelogram, and barium enema
should be performed. Cystoscopy and sigmoidoscopy are important to rule
out direct extension into the bladder or rectum. Lymphangiography has not
been shown to predict the status of the pelvic and periaortic lymph nodes ac-
curately. Of eight patients with adenocarcinoma of the vagina who were treat-
ed at the UCLA Medical Center, lymphangiogram reflected the status of
these lymph nodes at the time of their operative removal in only 3 pa-
9-
tients.
Radiation therapy and radical pelvic operation have both been advocated
in the primary treatment of invasive carcinoma of the vagina, and both have
been reported to produce cures. 83,85 Optimal therapy of any patient should
be based on a treatment plan that takes into account the age of the patient,
her childbearing status, the desire for preservation of vaginal function, and
the extent of disease. Pretreatment operations designed to assess the extent
of the primary tumor and the status of the pelvic and periaortic lymph
nodes have been performed at the UCLA Medical Center through an extra-
peritoneal approach designed for the operative staging of patients with can-
cer of the cervix. 93 Applying this technique to patients with cancer of the
vagina has allowed treatment to be modified in accordance with the find-
ings at operation. This is especially important in young women with clear-
cell adenocarcinoma of the vagina in whom the preservation of menstrual
and reproductive function potentially can be achieved by transposition of
the ovaries from the field to be irradiated and combining the modalities of
surgery and radiation therapy to produce cure with minimal sacrifice of nor-
mal organs. 94
Patients with small, well-differentiated stage I lesions with no demon-
strable metastases to the pelvic or periaortic lymph nodes can be managed
by a primary operative approach consisting of radical removal of the vagina.
The placement of a split-thickness skin graft at the time of vaginectomy
facilitates follow-up examination and restores the patient to a functional
status with minimal delay. 95 Patients with large, poorly differentiated pri-
mary tumors and those in whom lymph node metastases are demonstrated
should be treated with a combination of external and intravaginal radiation
that is tailored to the extent of disease. Five thousand rad delivered over
five weeks to the whole pelvis through parallel opposed ports is well toler-
ated by most patients. An additional 1000 rad boost of external radiation
can be delivered to a site of known pelvic lymph node involvement.
Periaortic irradiation has been delivered without undue morbidity in doses
up to 4500 rad over four to five weeks in patients with metastases to com-
mon iliac or periaortic lymph nodes. The use of an extraperitoneal ap-
proach to the pelvic lymph nodes at the time of operative staging has been
shown to avoid the increased morbidity of the transperitoneal approach

when combined with postoperative external radiation therapy. 96
Additional radiation may be delivered to the site of the primary tumor by
the use of an intravaginal tandem and ovoids, a mold fitted to the individu-
al patient, or implant techniques utilizing radioactive iodine seeds. The
risk of vesicovaginal or rectovaginal fistula, or both, is increased with

higher doses to the primary tumor. Radiation occasionally must be com-
bined with subsequent radical pelvic operation in the form of partial or
total pelvic exenteration and total removal of the vagina.
Most recurrences of squamous cell carcinoma of the vagina occur within
three years following treatment of the primary tumor. Occasionally, the re-
currence is confined to the central pelvis, permitting further operative ther-
apy; however, more often it is in the form of regional or distant disease,
which requires systemic therapy. Adenocarcinoma of the vagina, particular-
ly the clear cell variety, is associated with later recurrences. These patients
usually present with regional and distant disease' and rarely are candidates
for additional local therapy.
Systemic chemotherapy in the treatment of disseminated squamous cell
carcinoma of the vagina has involved the use of most available agents with
few objective responses. Bleomycin, a drug that has been shown effective
!,T
in squamous cell lesions of the head and neck and cervix, has been tried in
patients with squamous carcinoma of the vagina and has produced occa-
sional responses. Recurrent adenocarcinoma of the vagina generally has
been treated with a progestational agent and a combination of cytotoxic
drugs. 9S Effective control of pulmonary metastases has been obtained in
two cases using a combination of radiation therapy and dactinomycin.
Tumor regression has been observed after the administration of 5-
fluorouracil, methotrexate, cyclophosphamide, vincristine, and prednisone
in another patient whose tumor had previously been unresponsive to other
combinations of chemotherapeutic agents.

The useof topical chemotherapeutic agents in the treatment of intraepi-
thelialcarcinoma of the vagina has been encouraging. The disappearance of
the lesion has been noted in most patients so treated, and occasional recur-
rence has been managed successfully by treatment.
The natural history of vaginal adenosis and the true incidence of adeno-
carcinoma arising in patients exposed to DES in utero require definition.
The tendency for metaplastic transformation of vaginal adenosis to be asso-
ciated with an increasing incidence of dysplasia and in situ epidermoid
carcinoma of the vagina requires further study. Preliminary reports have
suggested that this might occur as more women who were exposed to DES
in utero are identified.
The treatment
of invasive carcinoma of the vagina should be based on a
knowledge of the precise extent of the lesion. Continued efforts at pretreat-
ment evaluation of the pelvic and periaortic lymph nodes will help to de-
fine the natural history of this disease and permit a rational approach to
therapy. As more institutions report their treatment results, a better under-
standing of the optimal use of radiation and radical pelvic surgery also will
improve survival. Efforts aimed at vaginal reconstruction should continue,
since psychosexual rehabilitation is an important aspect of the management
of this disease. The place of ovarian conservation to preserve both men-
strual and reproductive capability should be defined in young women with
clear cell adenocarcinoma.
Section 5
Cervical Carcinoma
INTRODUCTION
During the past 30 years there has been a. 53 per cent reduction in the
American women from 19 to 9 deaths
mortality rate from cervical cancer in
per 100,000 women per year. During this time interval, cervical cancer has
fallenfrom the leading cause of death from malignant disease to the sixth
most common cause. This decline in mortality rate resulted in part from
advances in radiation therapy techniques, the use of megavoltage equip-
ment, and improved support of patients undergoing radical pelvic surgery.
The five-year survival rate reported for patients with invasive cervical can-
cer diagnosed between 1940 and 1949 was 47 per cent, whereas for women
diagnosed from 1965 to 1969 it was 56 per cent. The major impact on the
disease, however, has resulted from the widespread use of Papanicolaou
smears obtained from the cervix in screening asymptomatic women. This
technique permits the identification of patients with cervical dysplasia or
carcinoma in situ who are at high risk to develop invasive cancer. These
patients then can be treated with simple and often noninvasive measures.
The impact of this diagnostic test has led to a 58 per cent reduction in the
incidence of cervical cancer since the mid 1940s. In the Second National
Cancer Survey of 1947, shortly after Papanicolaou reported his initial stud-
ies, the number of cases of carcinoma in situ of the cervix was believed too
small to warrant a category separate from invasive cancer. In the Third Na-
tional Cancer Survey of 1969 to 1970, 80 per cent of newly diagnosed carci-
noma of the cervix were preinvasive. Despite the usefulness of the Papani-
colaou smear, the American Cancer Society reports that only 53 per cent of
women over 20 years of age have ever had it performed, and despite the
reduced mortality rate from cancer of the cervix uteri, nearly 8000 Ameri-
can women still die each year from this disease.
ll Gynecologic Neoplasms 477
Groups of women who are at increased risk to develop cervical cancer

and its precursors include those with a history of early marriage, first preg-
nane) at a young age, sexual activity early in adolescence, multiple sexual
partners, and prior venereal infections. The common denominator among
the epidemiologic factors of early, frequent coital exposure to multiple part-
ners suggests venereal transmission." The agent implicated most frequent-
ly is herpes simplex virus, type II (HSV II). 100
Support for the oncogenic effects of herpes viruses in humans includes a
carcinogenic role in many naturally occurring animal tumors and their pro-
duction of neoplastic transformation of cells in tissue cultures and experi-
mental animals. Although women with positive serologic test results for
HSV II often do not develop cervical cancer or its precursors, the risk is
increased six- to sevenfold over those women with negative test results.
Approximately 15 per cent of women with recent acute genital herpes in-
fections also have cervical dysplasia or carcinoma in situ on cervical biop-
sy The frequency of positive serologic test results for HSV II increases
.
with progression from cervical dysplasia to invasive carcinoma and is sig-

nificantly higher in these patients than in matched controls. Similarly, HSV
II-related antigens have been found in exfoliated tumor cells from most
patients studied with cervical cancer but not from the cells of controls with-
out cervical neoplasia. " Current investigation into the role of HSV II in
1 1
cervical cancer includes prospective studies of women with proven genital

herpes and attempts to produce cervical neoplasia in experimental animals.
Biology
The mucosa of the cervix consists of columnar epithelium located primar-

ily endocervical canal and squamous epithelium usually found on
in the
the exocervix. The transformation zone between these two cell types con-
sists of columnar epithelium undergoing squamous metaplasia. The meta-
plastic process is accelerated in utero, at puberty, and at the time of first
pregnancy, and declines in the perimenopausal and postmenopausal
period. Coppleson et al. in have suggested that the periods of most active
metaplasia provide the greatest risk for neoplastic transformation if a suit-
able inciting agent is present. The end result of squamous metaplasia is the
slowly progressive movement of the transformation zone centripetally on
the cervix and then into the cervical canal.
Eighty to 90 per cent of cervical carcinomas are of the squamous cell
variety and originate in metaplastic squamous epithelium. The initial event
seems to be one of atypical metaplasia usually occurring in a single locus.
Richart 103 has provided evidence that 95 per cent of squamous carcinomas
begin as a single cell event. The remaining 5 per cent of patients with squam-
ous cancer of the cervix exhibit broad field changes often involving multiple
organs in the genital tract, including cervix, vagina, and vulva. Ten to 20 per
cent of patients with cervical cancer have an adenocarcinoma that develops
from columnar epithelium. Little is known of the natural history of this dis-
ease, and recognized precursors usually are not detectable with the Papani-
colaou smear.
Atypical squamous metaplasia can progress to cervical intraepithelial
neoplasia (CIN). This generic term designates the spectrum of intraepithelial
disease that antedates invasive cervical cancer and implies that the premalig-
nant stages form a continuum rather than consist of distinct pathologic enti-
ties. The disorders within that continuum include the dysplasias and car-
cinoma in situ and have in common a progressive increase in disorderliness

in the epithelial maturation process and the degree of cytologic pleomorph-
ism. Three subclassifications of CIN are defined as follows: grade 1, mild and
mild to moderate dysplasia; grade 2, moderate and moderate to severe
dysplasia; and grade 3, severe dysplasia and carcinoma in situ.
The biologic significance and natural history of CIN is not well defined.
Cervical intraepithelial neoplasia can progress to invasive cancer, remain
static for indefinite periods, or disappear. The course of CIN presumably
relates to the immunobiologic response of the host to the abnormally develop-
ing cells and to the modifications of that response with local medications,
Most studies that evaluate the risk of progression
cervical biopsy, or cautery.
tomore advanced grades of CIN or to invasive cancer indicate that the process
frequently regresses without definitive therapy. A representative study by
Hall and Walton 104 found progression to carcinoma in situ in only 12 per cent
of 206 women with dysplasia followed from 1 to 14 years. Progression to car-
cinoma in situ was most frequent in patients with severe dysplasia, occurring
in 29 per cent of these patients. In this report 75 to 80 per cent of patients
studied were diagnosed by cervical conization, whereas 20 to 25 per cent
were diagnosed with multiple punch biopsies. Since the diagnosis of CIN
was made by operative means, the frequent regression is not surprising. In
many instances, the entire lesion could have been excised and in others
incomplete removal might have altered the host response to the neoplastic
process. Because biopsy often alters the disease process, Richart and Barron 105
followed 557 patients with CIN excluding carcinoma in situ using cytology
alone until it became normal or suggested progression to carcinoma in situ.
In this study, the median time for progression to carcinoma in situ was 86
months from mild dysplasia, 38 months from moderate dysplasia, and 12
months from severe dysplasia.
The presence of carcinoma in situ was documented by biopsy in all in-
stances. Nearly 90 per cent of patients with mild dysplasia had progressed
to carcinoma in situ within ten years, suggesting that the natural history of
dysplasia that is not modified by operation or other cervical trauma is one
of progression to carcinoma in situ in most instances. Carcinoma in situ can
persist indefinitely or can progress to invasive carcinoma. An estimate of
the duration of carcinoma in situ in women whose disease progresses to
invasive cancer is three to ten years based on data obtained from Papani-
colaou smear screening programs in British Columbia, Canada, and Bar-
bados, West Indies. 106 The Third National Cancer Survey report found the
mean age of women with carcinoma in situ to be 15.6 years younger than
for invasive cancer, showing the slowly progressive nature of this disease.
The biologic behavior of invasive cervical cancer is more predictable.

Once cancer extends beneath the basement membrane of the squamous ep-
ithelium, the measurable growth of the tumor is accelerated. The most
common modality of spread is by direct extension to adjacent structures
including the vagina, parametrium, bladder, and rectum. Tumor emboliza-
tion to regional lymph nodes occurs most frequently with large tumor mass,
advanced stage of disease, and possibly with increasing anaplasia. Metas-
tases to the external iliac and obturator lymph nodes accounted for over 40
107
per cent of metastases in 744 patients with lymphatic spread. Hypogastric
lymph nodes account for an additional 15 to 20 per cent of metastases. Me-
tastases to the common iliac and periaortic lymph nodes seem to occur se-
condarily from the external iliac and hypogastric areas. Approximately 40
per cent of patients with lymph node metastases who were studied at
UCLA had involvement of the primary node groups only, whereas 60 per
cent of patients with metastases had both primary and secondary node
group involvement. 93 No patient studied at UCLA has been found to have
involvement of common iliac or periaortic lymph nodes in the absence of
metastases to pelvic lymph nodes. Distant metastases by the hematogenous
route have been reported infrequently and usually are associated with ex-
tensive pelvic tumors. The most common sites of hematogenous spread are
the lung, liver, and bone.
NATURAL HISTORY
Classification
Ninety-eight per cent of malignant neoplasms of the cervix are carcino-

mas, and 2 per cent arc sarcomas. The relative incidence of carcinomas is
changing. 108 Squamous cell carcinomas accounted for approximately 95 per
cent of cervical cancers 30 years ago, with 5 per cent of tumors listed as
adenocarcinomas. More recent studies have found less than 80 per cent of
malignant cervical neoplasms to be squamous cell tumors. This changing
incidence results in large part from an absolute decline in new squamous
cell cancers because of widespread screening for CIN. There has been no
such decline in adenocarcinomas of the cervix, since screening measures
infrequently detect premalignant glandular changes in the cervix. There-
fore, there has been a relative increase in the incidence of adenocarcino-
mas, accounting for 25 per cent of cervical cancers in some recent series. 34
There has been increasing interest in clear cell adenocarcinomas of the
cervix and vagina in young women frequently associated with intrauterine
exposure to synthetic, nonsteroidal estrogens. By 1977, 120 such tumors
had been reported in the cervix, representing 36 per cent of tumors asso-
ciated with transplacental exposure to these drugs. Two thirds of these pa-
tients had documented exposure to nonsteroidal estrogens and an addition-
al 10 per cent of patients were exposed to unidentified drugs that were
prescribed for high-risk pregnancies.

Women with CIN are usually asymptomatic, and the most specific and
sensitive screening test is the Papanicolaou smear. The reliability of this
test in detecting CIN is approximately 90 to 95 per cent. False-negative
tests are seen when the underlying process is obscured by intense inflam-
mation or when the transformation zone is not sampled adequately. This
area is especially difficult to evaluate in postmenopausal women in whom
the transformation zone is located high in the endocervical canal. The test
is less sensitive in detecting invasive cancer, since necrosis and intense
inflammation often accompany this diagnosis. False-negative Papanicolaou

smears have been reported in 15 to 20 per cent of patients with invasive
cancer. In addition to predicting the presence or absence of malignancy,
experienced cytopathologists are often able to accurately predict the grade
of CIN in those patients with atypical smears.
Patients with abnormal Papanicolaou smears that are suspicious for CIN
or invasive cancer must undergo cervical biopsy prior to treatment. If a
visible lesion is not present, the usual biopsy procedure is cervical coniza-
tion. This procedure will provide an accurate diagnosis and is usually ther-
apeutic in cases of CIN, since the entire transformation zone is removed
easily. Because of the cost and risks of this operative procedure, which
include hemorrhage, cervical incompetence, stenosis, and infertility, many
physicians use colposcopy to aid in the evaluation of patients with abnor-
mal smears. Using this technique with a wide range of magnifications from
2 to 32 times enables the examiner to identify and biopsy abnormalities
that are otherwise not visible. Characteristic findings include thickened,
whitish irregular epithelium and vascular changes termed mosaicism, punc-
tation, and atypical vessels. 102 If the lesion is seen in its entirety, and the
biopsy findings are consistent with the degree of atypia suspected on cy-
tologic grounds, therapy can be planned without the need for conization.
These criteria are met in 70 to 80 per cent of patients with abnormal Pa-
panicolaou smears.
Women with invasive cervical cancer often present with complaints of
bleeding or discharge. Because most women with invasive cancer are still
menstruating, tumor-associated bleeding often is not recognized as abnor-
mal, and delays in examination and diagnosis often result. Some women
present initially widi signs and symptoms of advanced disease including
pain resulting from perineural involvement or tumor invading adjacent
bone, leg edema secondary to lymphatic blockage, or uremia from bilateral
obstruction. Since most women with invasive cancer have a visible lesion
on the cervix, appropriate biopsies are obtained easily. Any visible lesion
should be biopsied even in the absence of an atypical Papanicolaou smear,
in order to avoid unnecessary delays in diagnosis. If a lesion is not visible
in a patient with an abnormal Papanicolaou smear, the colposcope will en-
able appropriate biopsies in most patients, and conization of the cervix will
provide the diagnosis if the colposcopic examination is unsatisfactory.
Staging
staging system for cervical cancer adopted by the International Fed-

The
eration of Gynecology and Obstetrics, effective July 1, 1974, is shown in
Table 11-12. 109 Confusion exists for the subdivisions of stage I carcinomas
because the terms microinvasive carcinoma and early stromal invasion
110
(stage la) are not standardized. Quantitative histologic criteria for stage la
cervical cancer adopted by different institutions include maximal invasion
that is either 3 or 5 mm below the surface epithelium, basement mem-
brane, or deepest endocervical glands. Qualitative definitions used by
others include a low risk of lymphatic metastases, absence of lymphatic-like
space involvement, and absence of confluent tongues of invasive tumor
across a broad area. The purpose of subdividing carcinomas confined to the
cervix into microinvasive and frankly invasive cancer is to identify a subset
of invasive tumors whose biologic activity resembles carcinoma in situ. The
criteria used at UCLA Medical Center that appear to serve that purpose
best include invasion less than 3 mm below the basement membrane, ab-
TABLE 11-12. Staging of Carcinoma of the Cervix Uteri
Stage Carcinoma in situ; intraepithelial carcinoma.
Stage I The carcinoma is strictly confined to the cen i\ (extension to the corpns
should he disregarded I,
Stage la Microinvasive carcinoma (early stromal invasion).
Stage lb All other cases ot stage I; occult cancer should he marked "occ."
Stage II The carcinoma extends beyond the cervix hut has not extended to the
pelvic wall. The carcinoma involves the vagina hut not as far as
the lower third.
Stage I la No obvious parametria] involvement
Stage lib Obvious parametral involvement.
Stage III The carcinoma has extended to the pelvic side wall. On rectal
examination, there is no cancer-free space between the tumor and
the pelvic wall. The tumor involves the lower third of the vagina. All
cases with a hydronephrosis or nonfunctioning kidney are included.
Stage Ilia No extension to the pelvic wall.
Stage Illb Extension to the pelvic wall and/or hydronephrosis or nonfunctioning

kidney.
Stage IV The carcinoma has extended beyond the true pelvis or has clinically
involved the mucosa of the bladder or rectum. A bullous edema as
such does not permit a case to be allotted to stage IV.
Stage IVa Spread of the growth to adjacent organs.
Stage IYb Spread to distant organs.

482 II / Treatmeni of Specifn Neoplasms
sence of vascular invasion, and no confluent tongues of invasive tumor.

Using this definition, the risk of lymph node metastases approaches zero." 1
Pretreatment evaluation for proper staging of all patients with invasive

cervical cancer should include chest roentgenogram, intravenous pyelo-
gram, barium enema, cystoscopy, sigmoidoscopy, and blood urea nitrogen
and serum creatinine determinations. In addition, medical evaluation
should include postprandial blood glucose levels, liver function tests, com-
plete blood count, urinalysis, and electrocardiogram. If bone pain or abnor-
mal liver function tests exist, appropriate scans and x-rays should be ob-
tained to rule out metastases. After completion of these tests, all patients
should be staged at a conference attended by gynecologic oncologists and
radiation therapists.
Prognosis
Thebest prognostic indicator on clinical evaluation in cervical cancer is

the stage of disease. The five-year survival rate for all stages of disease and
the ten-year survival for stage I disease from 105 contributing institutions
worldwide are shown in Table 11-13. 2 Interestingly, the cure rates are
'
equal or superior to those for endometrial cancer for each stage, but the
overall cure rateis significantly less. This difference results from the high
percentage of advanced tumors of cervical origin contrasted with 74 per

cent of endometrial tumors that are confined to the uterine fundus at diag-
nosis.
The progressive decrease in survival with advancing stage of disease cor-
relates closely with the incidence of lymph node metastases. By combining
data from 31 series, Plentl and Friedman 107 reported lymph node metas-
tases in 15.4 per cent of3391 women with stage I disease, 28.6 per cent of
2952 women
with stage II disease, and 47 per cent of 217 women with
stage III disease. The importance of this relationship lies in the inherently
poor prognosis of patients with lymph node metastases. A total of 118 pa-
tients with stage lb cervical carcinoma underwent radiation therapy in con-
junction with pelvic lymphadenectomy at the City of Hope National Medi-
cal Center between 1956 and 1968. 112 The overall five-year survival rate
was compared with 93.6 per cent of 98 patients with negative lymph node
TABLE 11-13. Distribution and Survival by Stage:

World Statistics(1959-1968) (105 Contributing Institutions)
Alive at 5 Years Alive at 10 Years

No. of Cases Reported
(Patients Diagnosed (Patients Diagnosed
1964-1969) 1959-1963)
I 34,266(28.5%) 14,348/17,833 (80.5%) 10,457/14,738 (71.0%)

II 44,578 (37.0%) 12,916/21,845(59.1%)
III 35,518(29.5%) 5,565/16,959(32.8%)
IV 5,979 ( 5.0%) 202/2,866 ( 7.0%)
TOTAL 120,341 33,031/59,503 (55.5%)

li Gynecologic Neoplasms 483
involvement. Few series report five-year relapse-free survival rates in ex-

cess of 40 per cent for this group of patients, regardless of the stage of
disease. Therefore, there has been great enthusiasm for identifying patients
with lymph node metastases because the poor prognosis in these women
indicates the need to modify therapy. Bipedal lymphangiography permits
excellent visualization of the external iliac, common iliac, and periaortic
lymph nodes and in some instances can provide unequivocal evidence of
lymph node metastases. 113 Unfortunately, negative and suspicious lymphan-
giograms correlate poorly with histologic findings following operative eval-
uation. In 65 patients who underwent lymphangiography followed by pel-
vic and periaortic lymphadenectomy at UCLA Medical Center, the
'
9
radiographic interpretation was correct in only 78 per cent of patients.
5
Disappointment in lymphangiography as a useful diagnostic tool has led

to the pretreatment operative evaluation that includes pelvic and periaortic
lymphadenectomy of main patients who are identified as being at high risk
114
for metastases. Although this approach by the standard transperitoneal
route has been useful in identifying patients with metastases and in permit-
ting the modification of therapy tailored to the extent of disease, unaccept-
able morbidity and mortality from intestinal complications following post-
operative radiation therapy has limited the applicability of this technique.
Recently, an extraperitoneal operative approach was developed at UCLA
and is associated with minimal risk of bowel complications even when fol-
lowed by extended field radiation therapy. H!
Another important prognosticator for lymph node metastases and survival
is tumor volume. Although this factor frequently relates to the stage of dis-
ease, there is a wide range of tumor sizes within each stage. Of 240 pa-
tients with stage lb or stage Ila carcinoma of the cervix, Piver and Chung
115
found lymph node metastases in 21 per cent of 132 patients with tumors up
to 3 cm and in 40 per cent of 108 patients with tumors greater than 3 cm.
There was no significant difference in the risk of lymph node metastases
between the two stages studied when corrected for tumor volume. The
five-year survival rate excluding patients who died of intercurrent disease
was 80.4 per cent in stage lb disease and 53.2 per cent in stage Ila disease.
When subdivided by tumor volume, the differences in survival between
the two stages were less dramatic. Five-year relapse-free survival rates for
patients with smaller lesions were 88.5 per cent in stage lb disease and 75
per cent in stage Ila disease, whereas patients with a bulkier tumor mass
had five-year survival rates of 65.4 per cent in stage lb disease and 39.3 per
cent in stage Ila disease. Thus, although stage per se is an important prog-
nostic factor in cervical cancer, tumor volume within a given stage can in-
fluence survival. In addition to the increased risk of regional spread, tumor
volume also relates to the risk of central recurrences following radiation
therapy. 116 This finding has necessitated the modification of therapy in
some patients with bulky central disease to include radiation combined
with extrafascial hysterectomy instead of radiation or radical hysterectomy
alone.
The histologic appearance of a cervical carcinoma is of less prognostic-
importance than that of tumors arising in die endometrium or ovary. A few
484 II / Treatment Of Specific Neoplasms
studies separate cervical cancers by their columnar or squamous cell origin

and then subdivide these groups by stage of disease. Pertinent data suggest
that the distribution of stages at the time of diagnosis and the survival for
each stage are similar for tumors of both histologic types.' 07 " 7 The five-
year survival rate for adenocarcinoma in collected series is 70.4 per cent in
stage I disease, 52.9 per cent in stage II disease, and 23.6 per cent in stage
III disease, whereas comparable data for epidermoid carcinoma from the
same studies showed cure rates of 74.7 per cent in stage I disease, 53.7 per
cent in stage II disease, and 35.3 per cent in stage III disease.
The prognostic importance of the histologic appearance of squamous cell
cancers is unclear. Reagan and Ng have divided squamous tumors into
those that consist primarily of large cells, small cells, or keratinizing cells.
The latter group is closer in size to the larger cells. Of these three groups,
small cell tumors seemed to have the poorest prognosis, large cell tumors
the best prognosis, and keratinizing tumors an intermediate prognosis. 108
Other studies indicate little influence of tumor differentiation on prognosis.
Poorly differentiated epidermoid tumors are more often advanced than
well-differentiated tumors; however, within each stage the survival is simi-
117
lar.
Although not included in the staging system, endometrial extension ap-

pears to worsen the prognosis. In a study by Perez et al. lls the five-year
survival rate fell from 85 to 50 per cent in stage I disease and from 70 to 45
per cent in stage II disease if endometrial curettage findings demonstrated
extension to the uterir\e fundus. When endometrial extension is present,
both the risk of lymph node metastases and central recurrence following
radiation are increased. 116 Positive findings from uterine curettage are often
difficult to interpret because they can represent contamination from tumor
within the endocervix. Therefore, curettage is not performed routinely in
the evaluation of patients with cervical cancer.
Occasionally, invasive carcinoma of the cervix is found after a simple
hysterectomy. When this occurs, gross residual disease or a delay in insti-
tuting radiation therapy worsens the prognosis dramatically. If microscopic
invasion only is present or if the surgical margins of the hysterectomy spec-
imen are free of tumor and if radiation therapy is delivered promptly, the
survival rate approaches that seen with radical operation or irradiation. 119
TREATMENT
The management of patients with cervical cancer is determined primarily
by the stage of disease. Preinvasive cancer (stage 0) is best managed with
operation, early invasive cancer (stage I and stage Ha) is managed well
with either radical operation or radiation therapy, and advanced local disease
(stage lib to stage IVa) is treated best with radiation therapy, whereas dis-
tant disease (stage IVb) is often treated with both radiation therapy and
chemotherapy. In some patients with large tumor volume or poor response
to radiation therapy, combined treatment including operation and radiation
is indicated. Recurrent disease confined to the pelvis can be managed sue-
with extended operation

jsfully or, if preceded by operation, can be man-
aged with radiation therapy.
Carcinoma In Situ (Stage 0)
The usual treatment of carcinoma hysterectomy either by the

in situ is a
abdominal or vaginal route. When the lesion extends eccentrically on the
cervix or onto the vagina, a vaginal cuff is often removed. It is unclear
whether or not the removal of a vaginal cuff in these patients influences the
120
risk of recurrent carcinoma in situ. Data by Creasman and Rutledge on 861
patients with carcinoma in situ treated by either hysterectomy or hysterecto-
my with vagina] cuff removal suggest that the more extended operation
does not decrease this risk; however, their data do not evaluate the lesion
size and indications for vaginal cuff removal. Because main women with
carcinoma in situ desire to bear children, less invasive measures are
often employed. Long-term follow-up of patients treated by cervical coniza-
tion indicate that the risk of recurrent carcinoma in situ and subsequent
invasive carcinoma is no greater than for women undergoing hysterectomy
when the surgical margins of the specimen are free of CIN. 121 Because the
risks of complications following conization might include hemorrhage, in-
fertility, cervical stenosis, or incompetence, some investigators have treated
patients with focal carcinoma in situ using cryotherapy or laser beam.
Long-term prospective follow-up of such patients does not exist, and there-
fore this management should be viewed as investigative at present
Stage la Disease
When minimal invasion is present, within the framework of criteria just

defined, the prognosis, the risk of lymph node metastases, and the manage-
ment are similar to those of carcinoma in situ; however, when confluent
tongues of tumor, vascular invasion, or tumor extension 3 to 5 mm
below
the basement membrane is seen, the risk of central recurrence and occult
lymph node spread is increased. Therefore, treatment should be more ex-
tensive, employing a modified radical hysterectomy and pelvic lymphaden-
ectomy. The technique of the modified radical hysterectomy includes re-
moval of approximately half of the parametrium, the uterosacral ligaments,
and the upper one third of the vagina. 122 The operation is less extensive
than the radical hysterectomy described by Wertheim and modified by
Meigs for stage lb or stage Ila disease and is associated with little risk of
bowel or urinary tract fistula, while ensuring wide clearance of a microinva-
sive cancer. This operation also has limited applicability in managing
small, centrally recurrent cancers following radiation therapy.
Stage lb Disease
Occult pelvic lymph node metastases occur in approximately 15 per cent

of women with stage lb cancer. Therefore, effective treatment must be
486 II / Treatmeni oi Specifh Neoplasms
TABLE 11-14. Comparison of Survival Following Various

Treatment Regimens for Stage I Carcinoma of Cervix
Path \ s Sklected
i
Survival RT° Surgery t For RT or Surgery
5-Yeai 1265/1640(77.1%) 480/594(80.8%) 12603/15599(80.8

10-Year 520/822 (63.3%) 526/708(74.3%) 9411/13208(71.3
"14 institutions-all patients treated with radiotherap) (RT).

t At least 90 per cent of patients underwent initial surgery.
| Three (enters included.
5 Four centers included.
directed toward these lymph nodes in addition to the cervix, surrounding

parametrium, and vagina. Optimal management can include operation, radi-
ation therapy, or a combination of both modalities. The choice is deter-
mined by the patient's age, medical status, and tumor volume.
The surgical management of stage lb disease consists of radical hysterec-
tomy and bilateral pelvic lymphadenectomy. Using
approach, the para-
this
metria are resected to the pelvic side walls, the uterosacral ligaments are
transected at their pelvic attachments, the uterine vessels are ligated at
their origin, the upper one third to one half of the vagina with paracolpium
is removed, and the pelvic lymph nodes are freed from the surrounding
\csscls. -- The extensive dissection of the bladder base and the ureters
1
from their tunnels within the cardinal ligaments and ligation of a portion of
the blood supply to the distal ureters subject approximately 2 to 3 per cent
of patients to vesicovaginal or ureterovaginal fistula formation. All patients
develop transient bladder dysfunction, sometimes requiring continuous
catheter drainage for two months or longer.
Major advantages of operation over radiation include the preservation
of ovarian function in young women, obviating the risk of exogenous
estrogens and reducing the risk of post-treatment sexual dysfunction.
Ovarian function can be preserved, since ovarian metastases rarely are seen
in early cervical cancer, and these tumors are not hormonally dependent.
In addition, intraoperative findings provide important prognostic informa-
tion and can help to identify patients in whom more intensive therapy in-
cluding adjuvant radiation might be indicated. Delayed complications of
radiation, including colitis, enteritis, and cystitis, are also avoided. Because
intracavitary radiation cannot be delivered safely to patients with pelvic
infections, operation is also the treatment of choice for these women. The
five-year survival rate in 594 patients with stage lb disease who were treat-
ed in three centers in which almost all such patients are managed surgi-
cally was 80.8 per cent (Table 11-14). This figure compares with a 77.1 per
cent five-year survival rate in 1640 patients who were treated in 14 institu-
tions in which all such patients were managed with radiation therapy. 21
The management of patients with stage lb disease using radiation thera-
p\ provides effective treatment of the primary tumor and areas at risk for
occult metastases or extension. Treatment consists of both intracavitary
therapy in the uterus, endocervical canal, and vaginal fornices usually —
11 Gynecologic Neoplasms -*^7
Carcinoma in-situ Stage M
Desires further No further Extrafascial total abdominal

chikfbearina, chikjbearing Hysterectomy or modified radical
Hysterectomy with lymphadenectomy
Conization or Vaginal
cryotherapy e'ectomyor
total abdominal
hysterectomy
FICl'RE 11-6.Treatment of cervical

^ Stage IB and IIA
\^
Carcinoma Carcinoma in situ and Stag
, II,. and II W
Radical nyster-
,
Bilateral pelvic
Intracavitary therapy
(
^! S^?r
6000-8000 rad
r
™i
to Pt A'
1500- 2000 rad to Pt
l
B"
verin9
in 2 insertions
ljCptl*lliwi.*wj
Ml
External whole pelvis RT
14000-3000 rad in 4-5 weeks)
I
if buky central disease
I
extrafascial simple hysterectomy
8*12 weeks following radiation therapy
aeo'vd 2 am lo*w»qt and 2 en eaphofad »o '** e«r«*«ol cervical o».
<3**<3 5 cm lateral 3r*i 2 c-> eepholod fa Hie ea*en*ai cervical at.
employing radium or cesium — and

teletherapy to the whole pelvis (Fig.
11-6). The intracavitary therapy can deliver curative doses of radiation to
the primary tumor while sparing nearby structures. When the tumor is 1<
than 1 cm in diameter, the risk of lymph node metastases is small, and
-3
therefore intracavitary therapy alone is often curative. The dose-sparing 1
effect occurs because the source of radiation is packed against the tumor
and away from the rectum and bladder and because the dose delivered per
unit of time varies inversely as the square of the distance from the source
of radiation. For example, the bladder and rectum packed 3 cm from a
source of intracavitary radium would receive only 11 per cent ot the dosage
of radiation delivered to a tumor located 1 cm from that source.
The sequence of the two radiotherapeutic modalities is often determined
by tumor volume, patient age, and vaginal caliber. Bulkier tumors ol at
least 4 cm in diameter are treated initially with external beam therapy to
the pelvis in order to reduce tumor volume. Older patients with smaller
tumors often are treated initially with intracavitary therapy, since vaginal
narrowing following external therapy might not permit optimal placement
of applicators. Metastases to the pelvic lymph nodes must be suspected in
patients with stage lb disease and are best treated by radiation therapy.
Radiation therapy is also the preferred treatment in patients with medical
conditions that could make extensive pelvic surgery hazardous. It is also
recommended for patients with bulkier tumors, because good surgical mar-
gins are difficult to achiev e, and there is an increased risk of lymph node
metastases
Complications of radiation therapy include sexual dysfunction, injury to
large bowel, small bowel, and urinary tract, loss of ovarian function, and
vaginal vault necrosis. Sexual dysfunction results from vaginal narrowing,
loss ol lubrication, and perhaps the change in endocrine milieu associated
with ablation of ovarian function. Injun to the large bowel can include
proctitis or rectovaginal fistula if is not packed away from the

the rectum
intracavitary treatment source, or enteritis excessive doses of external ir-
if
radiation are delivered to the small bowel. The latter complication can re-
sult if loops of intestine are fixed in the pelvis from prior surgery or pelvic
infection or if extended ports are used to treat lymph node metastases fol-
lowing lymphadenectomy by the transperitoneal route. Vesicovaginal fis-
tula can result from excessive doses of radiation to the bladder base from
the intracavitary treatment, and hemorrhagic cystitis can occur if the total
dose of irradiation to die bladder exceeds 6000 rad. The incidence of fis-
tulas and damage to the bowel and bladder is less than 5 per cent but these
complications can be life threatening.
Several clinical situations are best managed by combining radiation with
surgery. In some patients with endophytic tumors arising within the endo-
cervix, local extension can be confined to the cervix and lower uterine seg-
ment, producing marked expansion of these structures —
the barrel-shaped
lesion. These patients and those with bulky exophytic tumors are managed
initially with x-ray therapy to the whole pelvis. In many instances, tumor
shrinkage is insufficient to permit curative radiation with subsequent intra-
cavitary therapy, and centrally recurrent disease following treatment can
often result. These patients should undergo extrafascial hysterectomy six to
ten weeks following completion of radiation. 124 Other situations associated
with an increased risk of central recurrence, thereby necessitating hysterec-
tomy following radiation therapy, include endometrial extension and in-
complete radiation therapy. 116
Physicians performing radical hysterectomy with pelvic lymphadenec-
tomy should do the lymph node dissection initially and evaluate the speci-
men histologically by frozen section to help rule out metastases. If metas-
tases are present, the operation should be abandoned, and radiation therapy
should be carried out. If lymph node metastases are detected postopera-
tively, subsequent external radiation therapy should be delivered, as will be
described.
Stages II and III
When a cervical tumor extends only upper vagina, and the tumor is
to the
less than 4 cm in diameter, treatment can be effected either by radical hys-
terectomy with pelvic lymphadenectomy or by radiation therapy. When the
tumor is larger or extends to the parametria, radiation therapy is preferred
because adequate surgical margins cannot be ensured, and the risk of
lymph node metastases is excessive (Fig. 11-7). Because of this increased
risk and the attendant poorer prognosis with larger tumors and more ad-
vanced stage, pretreatment exploration including bilateral pelvic and
periaortic lymphadenectomy is often performed. When lymph node metas-
tases are found, radiation treatment is modified. The dosage of radiation is
boosted on the involved side, and the radiation ports are extended to in-
clude lymphatics one chain above the extent of documented disease. 125
Whereas the usual pelvic ports measure 15 x 15 cm and extend to the bot-
Stage MB- 1MB

(Less Bulky tumors)- - Bulky tumors
4500-5000 rad external 5500-6000 rad external

Whole pelvis radiation therapy in 4-5 weeks Whole pelvis radiation therapy in 6 weeks
I
Intracavitary therapy If good tumor shrinkage
3000-6000 mg hr in 1 or 2 insertions
providing
3000-5000 rad to Pt A and
1000-2000 rad to Pt B Intracavitary therapy
(Approx 3000 mg hr providing 3000 rad Pt A
.Stage IVA
< 1000 rad Pt Bl in one insertion
External whole pelvis Pelvic exenteration Stage I VB

RT 5000 rad - can add if tumor not fixed .. ,nnn_cnnn,^ .„ î pelvisr -.
. „ u •«
„.„ ., ., . . ,. . .. 1) 3O0O-50O0rad to whole i
to palliate
2000 rad to smaller ports pelvic sidewall
to v .,„.. . (^j.
bleeding or infected tumor
\~.
if good initial response
2) Chemotherapy
Pelvic exenteration if
partial response and

tumor not fixed to pelvic
sidewall
FIGURE 11-7. Treatment of cervical carcinoma (stages lib through IVb).
torn of the fifthlumbar vertebral body, the ports are extended to the level
of the aortic bifurcation (body of the fourth lumbar vertebra) with pelvic
lymph node metastases, and the level of the diaphragm (the twelfth thorac-
126
ic vertebra) with common iliac or aortic lymph node metastases.
For small tumors, therapy is mainly with an intracavitary system, with
supplementary therapy to the whole pelvis or parametrium for occult lymph
node metastases. Progressively larger tumors are treated with increasing
quantities of external irradiation and lesser quantities of intracavitary therapy.
Stage IV
Tumors extending bladder or rectum can be cured infrequently

to the
with aggressive radiation therapy sometimes combined with surgery. Exter-
nal radiation (5000 rad) is delivered to the whole pelvis, and if there is
good response, 1000 rad can be given through 10x 10 cm ports and another
1000 rad through 8x8 cm ports for a total dose of 7000 rad. Pelvic exentera-
tion should then be considered if central disease persists three months fol-
lowing completion of therapy. Because radiation therapy alone rarely cures
these advanced tumors, a primary exenteration should be considered if dis-
ease is not fixed to the pelvic side walls.
Disseminated disease is treated for palliation with radiation and chemo-
therapy. Radiation is delivered to the whole pelvis to palliate an infected
bleeding tumor. Although many antitumor agents have been used for wide-
spread disease, the objective response rates to any drug or combination of
drugs are often as low as 10 to 25 per cent. The most useful agent is bleo-
490 II / Treatment of Specifii Neoplasms
mycin, which is most efficacious when delivered by continuous intravenous

infusion. A combination of bleomycin and mitomycin-C has been reported
to produce a 93 per cent objective response rate and an 80 per cent com-
plete, temporary response rate in 15 patients in a recent report. 127 This
study is being repeated at UCLA Medical Center to further evaluate this
combination of drugs.
Pelvic Exenteration
Cervical cancer that persists three to six months following therapy or re-
current cancer that is detected after a longer interval when confined to the
pelvis can be managed by pelvic exenteration. The diagnosis is suspected
if the cervix remains bulky or nodular, tumor mass develops following
if a
initial response, if a Papanicolaou smear is abnormal more than three
months following treatment, or if symptomatology suggesting tumor growth
occurs. Diagnosis usually can be made by cervical biopsy or fractional
curettage of the uterus; however, on occasion abdominal exploration is
needed to confirm the diagnosis. The evaluation of patients with document-
ed or suspected recurrence should include those studies performed in the
initial evaluation of patients with untreated carcinoma. As in untreated pa-
tients, the pelvic examination is most important, since tumor nodularity that
is palpated on the pelvic side wall is associated with little likelihood of
cure, and if documented at operation, an indication to abandon a con-
it is
templated exenteration. Similarly, an abnormal IVP, especially when show-

ing ureteral obstruction, is associated with a high likelihood of tumor on
the pelvic side wall and little likelihood of cure.
tumor
Patients widi in the cervix, vagina, or parametrium following prior
therapy should be evaluated for operation usually consisting of a total pel-
vic exenteration. The operation
involves the removal of bladder, rectum,
vagina, uterus, ovaries, fallopian tubes, and all other tissues within the true
pelvis. Initial steps in the operation include exploration for intraperitoneal
spread, multiple biopsies of the pelvic side walls, and periaortic lympha-
denectomy. Tumor in any of these areas is associated with little chance for
cure and, when found, operation should be abandoned. When operation is
performed, colostomy usually utilizes the transverse or sigmoid colon. A
segment of small intestine or colon is used for a urinary conduit. Less ex-
tensive surgery can be employed in patients with smaller tumors, including
a modified radical hysterectomy in patients with tumors that are apparently
confined to the cervix and are less than 3 cm in diameter; anterior exentera-
tion in patients with lesions not encroaching upon the rectum, uterosacral
ligaments, or pararectal areas; and posterior exenteration with tumor con-
fined to the cervix, posterior vagina, and rectum. Patients rarely are cured if
leg edema, sciatic pain, and ureteral obstruction are present at the time of
surgery. Pelvic exenteration rarely should be carried out in patients who
are more than 65 years old or with impaired pulmonary function,
in those
serious cardiac disease, massive obesity, or emotional instability.
When exenteration is entertained, sophisticated preoperative and postop-
erative support is required. The physician must prepare the patient emo-
tionally as well as medically. Intraoperative efforts should be directed to-
128
ward the prevention of disability and complications. Early postoperative
attention paid to massive fluid shifts, infection, and bleeding. These pa-
is
tients benefit by total parenteral nutrition because protein sparing facili-

tates wound healing and convalescence following ultraradical surgery. Al-
though patients rarely die intraoperatively or in the early postoperative
period, convalescence often takes six months or longer; therefore, this
operation should be undertaken only if there is a reasonable expectation of
cure.
Major morbidity and mortality following exenteration result from bowel
complications, which usually occur several months following operation.
Newer techniques being utilized to prevent small bowel obstruction and
fistulasinclude repair of the pelvic floor using either a sling of omentum or
peritoneal graft. Partial closure of the defect in the pelvic floor by anas-
tomosing sigmoid colon to a 2 cm rectal stump can obviate these bowel
complications while permitting subsequent colostomy closure in some pa-
129
tients with tumors that do not extend to the distal rectum.

Advances in past decades have included improved operative and radio-
therapeutic techniques and better support of patients undergoing extensive
pelvic operations. Prospects for the future include the wider use of pre-
treatment operative staging, permitting treatment of disease in which extent
is known, adjunctive and adjuvant immunotherapy or chemotherapy with
radiation, and improved patient rehabilitation. Nonspecific immunotherapy

using Corynebacterium parvum conjunction with radiation therapy is
in
currently under investigation by the Gynecologic Oncology Group in pa-
tients with advanced cervical cancer. Similar efforts using hydroxyurea as a
radiation sensitizer have demonstrated improved survival in women with
advanced cervical tumors. 130 Better patient rehabilitation and prevention of
disability can result from improved counseling and development of opera-
tive techniques sexual function and eliminate stomas following
to restore
ultraradical surgery. 95 The most important prospect for the future, however,
resides in the potential for wider acceptance of mass screening using the
Papanicolaou smear among the nearly 50 per cent of women in this country
who have never had the procedure performed.
Section 6
Ovarian Cancer
INTRODUCTION
Epidemiology
Cancer of the ovary accounts for 5 per cent of malignant tumors in

women. About 17,000 new cases were diagnosed in 1975. Although it is
less prevalent than carcinoma of the uterus or cervix, the incidence of
ovarian cancer is increasing. It is now the most common cause of death
from a reproductive tract tumor, and more than 11,000 women will die of
this disease in 1979. 181, m
The prevalence per 100,000 women ranges from
3.3 in the South African Indian to 16.6 in the native Hawaiian. The disease
is uncommon in eastern countries such as Japan but is frequent both in
white women and in women of developed western nations.

The five-year survival rate of less than 25 per cent is identical to that
achieved 30 years ago. The inability to define a population at risk, the ab-
sence of specific early symptoms, and the lack of an accurate screening tool
account for these unfavorable statistics. Over 70 per cent of patients have
disease that has spread beyond the ovaries at the time of diagnosis.
Etiology
The cause of ovarian carcinoma is unknown. In the absence of a precise

etiology, correlates have been established with a variety of patient charac-
teristics. A history of benign ovarian pathology, endometriosis, thyroid dys-
function, and carcinomas of the breast, endometrium, fallopian tube, and
colon have been noted in women with ovarian malignancy. " Prior hys- 1
terectomy, radiation therapy, and viral infections in childhood do not in-

crease the likelihood of ovarian cancer.
Although a study of 1000 twins failed to identify a genetic predisposition
to ovarian cancer, six families have been described in which 18 cases of
epithelial ovarian carcinoma occurred. 134 An increased incidence of breast
cancer and multiple primary tumors also existed in these families. A genet-
ic predisposition to granulosa-cell tumors has been suggested in patients
with the Peutz-Jeghers syndrome.
Biology
Carcinoma of the ovary can spread by direct extension, peritoneal im-

plantation, lymphatic dissemination, and hematogenous metastases. These
pathways are interrelated at various stages of the disease, but the precise
[ 1 Gynecologic Neoplasms 493
sequence is not known. Direct extension to adjacent fallopian tubes, broad
ligament, uterus, cul-de-sac, and loops of small and large intestine can
occur early or be absent in the face of widespread intraperitoneal implants.
Peritoneal surfaces are involved by direct extension, implantation of free
tumor cells, and through the subserous lymphatics. Retrograde lymphatic
extension can account for spread to the uterus and opposite ovary. The
transport of free tumor cells through the tubal lumen, endometrium, and
endocervix to the vagina can produce abnormal vaginal cytologic smears in
women with ovarian carcinoma.
Metastases to distant organs occur by transperitoneal spread, through
lymphatics to the iliac, lumbar, mesenteric, and retroperitoneal nodes as
well as by the hematogenous pathway. Over 75 per cent of women who die
of ovarian carcinoma have metastases to the periaortic nodes at autopsy;
however, the time and route of lymphatic spread in the course of their
disease is unknown. Autopsies demonstrate mediastinal and supraclavicular
lymph node metastases up
50 per cent of ovarian cancer patients,
in to
whereas axillary and inguinal lymph nodes are affected in 30 to 40 per
cent. 135
The role of the omentum in the lymphatic drainage of the peritoneal cav-
ity is controversial. Lymphatic channels have been identified
in the areolar
tissue of the omentum but account only a small fraction of the fluid
for
absorbed from the peritoneal cavity. The clearance of inert particles by the
omental lymphatics is considerably slower than by those in the diaphragm.
Omentectomy does not affect the turnover rate of fluid from the peritoneal
cavity in the absence of tumor.
Most patients who die of ovarian carcinoma have disease that is outside
the pelvis but is confined to the abdominal cavity. An extremely large
tumor burden is not incompatible with several months of relatively com-
fortable survival. Death from starvation, anemia, and infection usually fol-
lows multiple episodes of intestinal obstruction, and is preceded by nausea,
vomiting, anorexia, and profound weight loss.
NATURAL HISTORY
Ovarian tumors are commonly classified according to their histologies,

with subgroups based on whether the origin of the tumor is in the germinal
epidielium, gonadal stroma, or germ cells (Table 11-15). Common epitheli-
al tumors include the serous, mucinous, endometrioid, and clear cell varie-
ties. Tumors of the gonadal stroma are classified by cell type rather than by
functional status with regard to the production of estrogenic or androgenic
hormones. Tumors of germ cell origin include the dysgerminoma, endoder-
mal sinus tumor, teratoma, and choriocarcinoma. In spite of this complex
classification, there remain a number of tumors that cannot be categorized.
These include lipid cell tumors, gonadoblastomas, nonspecific soft-tissue
sarcomas, and those with unrecognizable histologic features.
494 II / Treatmeni oi Specifk Neoplasms
TABLE 11-15. Histologic Classification of Ovarian Tumors
Common Epithelial Tumors

Serous Tumors
Benign
cystadenoma and papillary cystadenoma

surface papilloma
adenofibroma and cystadenofibroma
Of borderline malignancy (carcinomas of low malignant potential)
cystadenoma and papillary cystadenoma

surface papilloma
Malignant
adenocarcinoma, papillary adenocarcinoma, and papillary cystadenocarcinoma

surface papillary carcinoma
malignant adenofibroma and cystadenofibroma
Mucinous Tumors
Benign
c>stadenoma
Of borderline malignancy (carcinoma of low malignant potential)
cystadenoma
Malignant
adenocarcinoma and cystadenocarcinoma

Endometrioid Tumors
Benign
adenoma and cystadenoma

Of borderline malignancy (carcinoma of low malignant potential)
adenoma and cystadenoma

Malignant
carcinoma
adenocarcinoma
adenoacanthoma
endometrioid stromal sarcomas
mesodermal (mullerian) mixed tumors, homologous and heterologous
Table continued on opposite pane.

TABLE 11-15. Histologic Classification of Ovarian Tumors (Continued)
Clear Cell Tumors
Benign : adenofibroma
Of borderline malignancy (carcinoma of low malignant potential |
Malignant : carcinoma and adenocarcinoma
Brenner Tumors
Benign
Of borderline malignancy (proliferating)
Malignant
Mixed Epithelial Tumors
Benign
Of borderline malignancy
Malignant
Undifferentiated Carcinoma
Unclassified Epithelial Tumors
Sex Cord (Gonadal Stromal) Tumors
Granulosa-Stromal Cell Tumor
Granulosa cell tumor
Tumor in the thecoma-fibroma group
thecoma
fibroma
unclassified
Androblastomas; Sertoli-Leydig Cell Tumor
Well differentiated
tubular androblastoma; Sertoli cell tumor (tubular adenoma of Pick)

tubular androblastoma with lipid storage; Sertoli cell tumor with lipid storage
(folliculoma lipidique of Lecene)
Sertoli-Leydig cell tumor (tubular adenoma with Leydig cells)
Leydig cell tumor; hilus cell tumor
Of intermediate differentiation
Poorly differentiated isarcomatoid)
With heterologous elements
Gv nandroblastoma
Unclassified
Lipid (Lipoid) Cell Tumors
Tabic continued on following pane.

TABLE 11-15. Histologic Classification of Ovarian Tumors (Continued
Germ Cell Tumors

Dysgerminoma
Endudermal Sinus Tumor
Embryonal Carcinoma
Polyembryoma
Choriocarcinoma
Teratomas
Immature
Mature
solid
cystic
dermoid cyst (mature cystic teratoma)
dermoid cyst with malignant transformation
Monodermal and highly specialized
struma ovarii
carcinoid
struma ovarii and carcinoid
others
Mixed Forms
GONADOBLASTOMA
Pure
Mixed with Dysgerminoma or Other Form of Germ Cell Tumor
Soft Tissue Tumors not Specific to Ovary
Unclassified Tumors
Secondary (Metastatic) Tumors
For each of the common epithelial neoplasias, the critical distinction in-
volves the separation of benign from malignant tumors. However, some
tumors can have characteristics suggestive of malignancy, such as abundant
epithelial proliferation, detached clusters of cells, increased mitotic activity,
and atypical nuclei absence of stromal invasion and metastases. The
in the
malignant potential of these tumors is less than would be expected, and
they are referred to as carcinomas of low malignant potential or borderline
malignancies.
Most patients with early ovarian carcinomas are asymptomatic. Although

several investigators have suggested an association with menstrual irregu-
Unity, change in urinary and bowel function, and a vague feeling of pelvic
and abdominal discomfort, these symptoms are rarely of sufficient intensity
to prompt the patient to consult a physician. On occasion, the physician
rails to perform a pelvic examination on the basis of a low index of suspi-
cion.
The and symptoms of ovarian carcinoma invariably are asso-
classic signs
ciated with advanced disease. Patients who complain of increased abdomi-
nal girth, weight loss, nausea, and vomiting rarely present a problem in
diagnosis, but they reflect an inability to detect this disease at a time when
therapy is be curative.
likely to
The management of asymptomatic women in whom a pelvic mass is
found on routine examination is of concern. The presence of a fixed, nodu-
lar, solid ovarian tumor confers on the physician the responsibility to ride
out ovarian cancer by operative removal of the mass. Women in the re-
productive age group who are found to have a small, tender, cystic enlarge-
ment of the ovary can be observed over the course of a menstrual cycle.
Persistence or growth of the cyst is an indication for its removal.
In addition to a history and general physical examination, a cytologic
smear of the cervix should be performed, together with a complete blood
count, urinalysis, blood urea nitrogen and serum creatinine determinations,
and tests of hepatic function. A chest roentgenogram identifies metastases
to die pleura or lung parenchyma. Intravenous pyelogram and barium
enema detect tumors that invade or displace the urinary or lower intestinal
tract and aid in the identification and preservation of these structures at
operation. Sigmoidoscopy, cytoscopy, and contrast studies of the stomach
and small intestine should be performed if symptoms are present.
Lymphangiography in the investigation of women with suspected ovarian
carcinoma probably is not warranted. In addition to a high rate of false-
positive and false-negative studies, a large number of patients who sub-
sequently are found not to have a malignant tumor would undergo this pro-
cedure. Similarly, the diagnostic role of peritoneoscopy in these patients is
open to debate. Its use presupposes that the gross appearance of the ovary
can predict its histology. An incisional biopsy of the ovary through the
scope could provide access for malignant cells to disseminate throughout
the abdominal cavity. Most patients require laparotomy for definitive diag-
nosis.
Staging
The modified staging for ovarian carcinoma adopted by the International

Federation of Gynecology and Obstetrics in January, 1975 is based on find-
ings at abdominal exploration (Table 11-16). This furnishes an accurate
grouping of patients with similar prognoses, provided the physician con-
ducts a meticulous preoperative and intraoperative search for metastases
and records all information required to place a patient in a particular stage
and substage.
Abnormal supraclavicular, axillary, or inguinal nodes require biopsy. The
presence of a pleural effusion necessitates thoracentesis to obtain fluid for
cytologic examination. Abdominal exploration begins with the cytologic
49H II / Treatment of Specific Neoplasms
TABLE 11-16. Staging Classification" (FIGO Nomenclature)
Stage I Growth limited to the ovaries.
Stage la Growth limited to one ovary; no ascites.
Stage Iai No tumor on the external surface; capsule intact
Stage Iaii Tumor present on the external surface, or capsule(s) ruptured, or both.
Stage lb Growth limited to both ovaries; no ascites.
Stage Ibi No tumor on the external surface; capsule intact.
Stage Ibii Tumor present on the external surface, or capsule(s ) ruptured, or both.
Stage Ic Tumor either stage la or stage lb, but with ascites! present or with
positive peritoneal washings.
Stage II Growth involving one or both ovaries with pelvic extension.
Stage Ha Extension and/or metastases to the uterus and/or tubes.
Stage lib Extension to other pelvic tissues.
Stage He Tumor either stage Ha or stage lib, but with ascites f present or with
positive peritoneal washings.
Stage III Growth involving one or both ovaries with intraperitoneal metastases
outside the pelvis, or positive retroperitoneal node involvement,
or both. Tumor limited to the true pelvis with histologically proven
malignant extension to small bowel or omentum.
Stage [V Growth involving one or both ovaries with distant metastases. If pleural
effusion is present there must be positive cytologic findings to allot a
case to stage IV. Parenchymal liver metastasis equals stage IV.
Special
Category Unexplored cases that are thought to be ovarian carcinoma.
'Staging is based on findings at clinical examination and surgical exploration. The final histologic findings
(and cytologic when available) after surgery are to be considered in the staging.
f Ascites is a peritoneal effusion that, in the opinion of the surgeon, is pathologic, or clearly exceeds normal
amounts, or both.
evaluation of any ascitic fluid. If no ascites is present, separate washings

are taken from the pelvis, the paracolic gutters, and the undersurface of the
diaphragm. The omentum, diaphragm, liver, and retroperitoneal pelvic and
periaortic lymph nodes are inspected and palpated, and any suspicious area
is biopsied. An examination of the colon, stomach, and pancreas is per-
formed to exclude these organs as the site of a primary cancer that has
metastasized to the ovaries. An accurate assessment of prognosis and appro-
priate adjunctive treatment demand a systematic and thorough approach to
patients with ovarian carcinoma at the time of the initial laparotomy. 136
Prognosis
Decreased survival has been shown for each increase in stage and sub-
stage of disease. The volume of residual tumor, histologic cell type, cellular
grade, and nuclear grade also affect prognosis but are not included in the
currently accepted staging system.
The revision of the FIGO staging of ovarian carcinoma subdivides stage
la and stage lb according to theabsence or presence of extracapsular ex-
crescences or intraoperative rupture of the tumor, or both. Support for this
change comes from studies that indicate a five-year survival rate of 90 per
cent for patients with intracystic disease, 68 per cent for those with excres-
cences, and 56 per cent for those in whom cyst rupture occurred at opera-
137
tion. Stage Ic has been expanded to include patients with positive cy-
tologic findings of peritoneal washings in the absence of ascites. The addi-
tion of stage lie identifies patients with malignant ascites or peritoneal
washings. At present, stage IV disease includes patients with malignant
pleural effusion or parenchymal liver metastases. Studies at the UCLA
Medical Center are attempting to determine if survival differences exist for
patients with parenchymal lung and liver disease when compared with
those with disease that has spread only to the pleura or capsule of the liver.
Although most reports of survival statistics for patients with ovarian carci-
noma emphasize the importance of the stage of disease, several studies in-
dicate that initial stagingis often in error. The inappropriate use of a trans-
verse, lower abdominal incision in women

with suspected ovarian cancer
precludes accurate evaluation of the diaphragm, liver, paracolic gutters,
omentum, gastrointestinal tract, and periaortic lymph nodes. The failure to
assess and document the extent of disease is undoubtedly responsible for
main- treatment failures that occur in patients who are presumed to have
tumor confined to the pelvis. Although subsequent re-evaluation, which in-
cludes lymphangiography or peritoneoscopy, has, on occasion, identified
patients with more advanced disease than initially suspected, this does not
obviate the requirement for accurate staging at initial laparotomy. 138 Treat-
ment can be modified on the basis of additional findings, but the initial
stage of disease may not be changed for purposes of reporting results.
The common epithelial tumors account for more than 85 per cent of
ovarian cancers. Although similar patterns of spread have been demonstrat-
ed for serous, mucinous, endometrioid, clear cell, and undifferentiated
tumors, the mucinous and endometrioid varieties tend to present at an ear-
lier stage and are associated with a more favorable prognosis.
Histologic and nuclear grading might be better determinants of prognosis
than the cell type. Broder's classification grades malignant tumors based on
the percentage of cells that are undifferentiated. The nuclei of the tumor
cells can be graded according to the classification of Black and Speer,
which characterizes their size, shape, and chromatin patterns. Stromal eval-
uation as described for breast cancer has been adapted by Sommers to
ovarian carcinoma (Table 11—17). Survival has been shown by several in-
vestigators to correlate with differentiation of the tumor, regularity of the
nucleus, and the presence of the inflammatory cells in the surrounding stro-
ma. 139 These features tend to worsen with advanced stage but appear to be
of less prognostic importance than stage for a given patient.
The amount of tumor that is amenable to resection at laparotomy corre-
lates with survival. Patients in whom all gross disease is removed have a
better prognosis than those who undergo incomplete resection or biopsy.
When no residual tumor mass exceeds a diameter of 2 cm (optimal disease),
.500 II / Treatment of Sp» ii n Neoplasms
TABLE 11-17. Grading of Epithelial Ovarian Cancer
Histologic Grade" Nuclear Grade Stromal Beacti<>\ •
(Broder's Classification) (Black and Speer) (Sommers)
I Highly differentiated None

1 Enlarged, irregular
nuclei with chromatin
clumping and prominent
nucleoli
II Moderately differentiated 1 Minimal

2 Intermediate degree of
differentiation
III Moderately undifferentiated 2 Moderate

3 Similar in size and
appearance to normal
ovarian tissue and to
each other
IV Highly undifferentiated 3 Marked
"Based on an evaluation of up to 13 dependent cytologic characteristics.

tBased on the number of lymphocytes, plasma cells, and polymorphonuclear leukocytes present in the
stroma and around small veins.
a better response rate to subsequent chemotherapy or radiation therapy

exists than when a larger mass remains (suboptimal disease). Survival also
appears to correlate with the size of the largest residual tumor mass. 140
TREATMENT
Epithelial Ovarian Tumors
SURGERY. Operation in patients with suspected epithelial ovarian carci-

noma is performed through a vertical incision. The peritoneal cavity en- is
tered with caution because loops of small intestine can adhere to the an-
terior parietal peritoneum. The ideal operation is a total hysterectomy with
bilateral salpingo-oophorectomy. The role of omentectomy remains contro-
versial but is advocated at the UCLA Medical Center both for its prognostic
importance and in the belief that subsequent ascites secondary to an omen-
tal tumor mass can be prevented. In patients whose tumor extensively in-
volves the posterior cul-de-sac, consideration should be given to a supracer-

vical hysterectomy. This preserves the cervix as a natural barrier to the
growth of pelvic tumor through the apex of the vagina.
Requirements for the conservative operation of unilateral salpingo-
oophorectomy in a young woman of low parity include stage Iai disease, a
well-differentiated or borderline mucinous, endometrioid, or clear cell his-
tology, an otherwise normal pelvis, negative peritoneal washings, no inva-
sion of capsule or lymphatics, negative biopsy results of contralateral ovary
and omentum, close follow-up, and excision of the remaining ovary at the
completion of childbearing. 141
Since more than two thirds of patients will be found to have advanced
disease at the time of their initial operation, judgment is often required as
to the extent of tumor reduction to be performed. In general, operation
should include the removal of all visible tumor. A
segmental resection of
the small or large intestine is justified to accomplish this but otherwise is
not undertaken. When the tumor obstructs multiple areas of small intestine.
enteroenterostomy or enterocolostomy should be performed without resec-
tion.
In patients with apparent stage I and periaortic
or stage II disease, pelvic
lymph nodes should be palpated and biopsied if enlarged. Omental biopsy
and careful examination of the liver and diaphragm are also critical in these
patients, as inaccurate staging can result in suboptimal adjunctive therapy
and a further reduction in survival. 141
Because main patients will require postoperative intestinal decompres-
sion, consideration should be given to a tube gastrostomy to obviate the
need prolonged nasogastric intubation. Closure of the abdominal wound
for
is performed with ureat care to avoid inclusion of any loops of intestine.
Patients with ovarian carcinoma often require intensive postoperative

care that includes maintenance of adequate pulmonary function, prevention
of infection, restoration of fluid and electrolyte balance, and hyperalimenta-
tion. Hyperalimentation by peripheral vein is performed at the UCLA Med-
ical Center and uses 10 per cent dextrose in a balanced salt solution, pro-
tein hydrolysate. and a lipid emulsion. The morbidity associated with an
indwelling central venous catheter is eliminated by this technique, and ca-
loric and nitrogen requirements are maintained in patients whose disease
or treatment often necessitates prolonged periods of starvation. 141
Radiation Therapy. Contemporary radiation techniques that are ap-
plied to the treatment of patients with ovarian carcinoma include high-
eners> external beam therapy and the instillation of radioactive colloids.
.
Factors that are important in external radiotherapy include the energy of

the beam, calculation of appropriate tumor dose, fractionation scheme, field
shape, and field distribution. An appropriate treatment plan combines a
high enough dose applied to a large enough field to produce both a maxi-
mal cancericidal effect and minimal damage to normal tissues. Whole pel-
vic irradiation has been administered in doses of 5000 to 6000 rad deliv-
ered at the rate of 800 to 1000 rad per week. Periaortic fields receive 4000
to 5000 rad in four to five weeks. Treatment of the whole abdomen can be
accomplished with either a stationary field or a moving strip technique, 144
but it is of limited effectiveness because die kidneys and liver require
shielding at a dose of approximately 2000 rad. The moving strip technique
divides the abdominal cavity into multiple horizontal segments. The lowest
strip is irradiated for two days, after which the field is increased by one
strip every two days until four strips are encompassed. The four-strip field is
moved up one strip every two days until the last strip is reached. The field
is then reduced by one strip every two days. Each strip thus receives treat-
ment for eight days by the photon beam and for an additional four days by
the. penumbra. This provides a tumor dose of 2600 to 2800 rad over two
weeks with greater radiobiologic effect than is achieved with a stationary
field. An additional boost of 2000 rad is then delivered to a whole pelvic

field. The success of the moving strip technique depends on the physical
characteristics of the beam to be used with special reference to its proper-
ties of divergence and width of the penumbra. The penumbra of the photon
beam produced by a cobalt unit generally is wide enough to permit a ho-
mogeneous dose distribution. The higher energy linear accelerator has a
reduced penumbra that can lead to inhomogeneity and preclude
its use in
this technique.
Radiation therapy of patients with ovarian carcinoma produces acute gas-
trointestinal and hematopoietic side effects, of which diarrhea is the most
common. Extended field therapy also can produce nausea and vomiting,
and occasional patients require cessation of therapy and admission to the
hospital for correction of dehydration and fluid and electrolyte abnormali-
ties. Although a transient reduction in circulating polymorphonuclear leu-
kocytes and platelets is observed in virtually all patients undergoing radia-
tion therapy, the extended fields required in patients with ovarian cancer
can potentially compromise the bone marrow and substantially reduce tol-
erance to subsequently administered chemotherapy. The most common
long-term complication is radiation enteritis, which occurs in about 30 per
cent of patients who receive 5000 to 6000 rad. Radiation nephritis and hep-
atitis, potentially lethal complications, rarely follow appropriate shielding
of kidneys and liver from doses above 2000 rad.

Since the indications for radiation therapy of patients with ovarian carci-
noma have not been standardized, the ability to interpret available survival
data unclear in many reports whether radiation was admin-
is difficult. It is
istered with a curative or palliative intent. Improved survival of patients

with stage I ovarian carcinoma who receive radiation therapy is difficult to
demonstrate. In many of these patients radiation is directed only to the
pelvis; however, inadequate documentation of disease outside the pelvis in
some of these women could account for their failure to respond to treat-
ment. Extended field therapy of patients with stage I carcinoma includes
the periaortic region or the whole abdomen, and this type of therapy awaits
critical evaluation.
1!m 32
Intraperitoneal colloidal gold ( Au) and phosphorus (
P) have been uti-
145,146
lized in selected patients with stage I disease. Radioactive gold, with
an emission of 90 per cent beta particles and 10 per cent gamma radiation,
has a half-life of 2.7 days and a maximal penetration of the beta particles of
3.8 mm. Radioactive phosphorus, with a half-life of 14.2 days, is a 100 per
cent beta emitter and has a similar maximal, penetrance. Significant radia-
tion with these colloids is confined to the superficial layers of the peritone-
um and small aggregates of malignant cells. Several nonrandomized studies
demonstrate an increase in the rate of survival when compared with histor-
ic controls, as well as a decrease in the subsequent incidence of malignant
ascites. Complications that include pooling of the colloid with injury to the
small intestine are greatly increased with the addition of external radiother-
apy. Radiation precautions need to be observed only with 198 Au because of
the gamma radiation emitted. Prospective randomized studies by the Gyne-
cologic Oncology Group are designed to critically assess the role of these
colloids in the treatment of early ovarian carcinoma.The small numbers of

patients with stage I disease and the favorable outcome of many after
operation alone necessitate a large number of entries to the study who are
then observed for a minimum of five years to establish any therapeutic ben-
efit.
Patients more advanced diseases have been treated by whole pelvis

w ith
(Stage II) or whole abdominal (Stage III) external radiotherapy. Preliminary

data suggest that the size of the largest aggregate of tumor cells that re-
mains after operation the response rate. Patients with tumors
is critical to
greater than 2 cm in diameter, ascites, or tumor on the surfaces of the liver
and kidneys have a less favorable response to radiation administered sub-
sequently.
Radiation therapy has been used to palliate patients with widespread
ovarian tumor. Biliary tract obstruction, obstructive uropathy, and gastroin-
testinal hemorrhage or obstruction have occasionally been relieved with
4000 to 5000 rad of external therapy delivered to a small field.
Chemotherapy. Ovarian cancer is among the more responsive of solid
tumors to chemotherapy. This responsiveness is related to the initial stage
of disease, residual disease after operation, the drug used, prior irradiation,
and prior chemotherapy. Extensive experience has accumulated with alky-
lating agents in the treatment of advanced ovarian cancer. No single al-
kylating agent appears to have particular advantages over any other, and
this class of chemotherapeutic drugs produces initial response rates of 20 to
60 per cent. Similarly, no dose or schedule has demonstrated superiority.
Daily oral doses, an oral loading dose followed by daily oral maintenance,
and intermittent oral and intravenous doses have been utilized. Virtually all
investigators report an increase in survival for patients who respond to an
alkylating agent when compared with those who do not respond. Collected
series demonstrate a median survival rate among responders of 17 to 20
months and a 5-year survival rate of 10 to 15 per cent compared with a
median survival of 6 to 13 months and no long-term survivors among nonre-
14s
sponders. 147,
The response
of patients with advanced disease to alkylating agents sug-
might have a role as adjuvants to operation and radio-
gests that these drugs
therapy in women with localized tumor. A prospective study of patients
with completely resected stage I ovarian carcinoma is underway comparing
no further treatment, pelvic irradiation, or melphalan. To date, fewer re-
currences have been noted in the melphalan-treated group, although no sig-
nificant difference exists among the three groups. Once resistance to an al-
kylating agent occurs, a secondary response rarely is achieved by the ad-
ministration of a different alkylating agent.
Many
other drugs have been tested as first-line chemotherapy of epitheli-
al ovarian cancer. 149
Of these, the antitumor antimetabolite 5-fluorouracil
has been studied most extensively and has a response rate of about 30 per
cent. Hexamethylmelamine does not share cross resistance with the al-
kylating agents and has activity both as a and second-line drug. Meth-
first-
otrexate, alone and in combination with alkylating agents, produces a re-

sponse rate of up to 25 per cent. Doxorubicin, an antitumor antibiotic,
504 II / Treatmkvi oi Specific Neoplasms
appears to produce a response equal to that of the alkylating agents when

used as a first-line drug; however, the duration of response achieved with
doxorubicin is no better than that seen with melphalan, and the drug pro-
duces severe toxicities in the form of alopecia, nausea, vomiting, stomatitis,
and cardiomyopathy. Cisplatin, a nephrotoxic heavy metal compound, has
achieved responses in up to 30 per cent of patients with epithelial ovarian
cancer that was resistant to an alkylating agent. Most responses to this drug
are partial rather than complete, however, and often are maintained for
only three to four months. 150
The variety of agents with different mechanisms of action and toxicities
that produce responses in epithelial ovarian cancer has led to clinical
trials of drug combinations. The combination of dactinomycin, 5-
fluorouracil, and cyclophosphamide has a response rate comparable to
that of alkylating agents; however, the toxicities of these drugs exceed
those of the alkylating agents. 151 At present, the Gynecologic Oncology
Group is comparing melphalan, doxorubicin, and cyclophosphamide with
melphalan and hexamethylmelamine in women with disease that ranges
from suboptimal stage III and stage IV to recurrent epithelial ovarian carci-
noma. Patients with advanced disease have been treated at the National
Cancer Institute with a four-drug combination that includes hexamethyl-
melamine, cyclophosphamide, methotrexate, and 5-fluorouracil (Hexacaf). 152
An increased overall response rate, more complete remissions, and a longer
median survival have been seen when compared with patients who receive
melphalan alone. More severe toxicity also has been encountered. At pres-
ent, no single drug or combination of agents has produced a five-year dis-
ease-free survival rate to exceed that of an alkylating agent. Although an
increased response rate and more complete remissions have been achieved
with cisplatin, cisplatin and doxorubicin, and the four-drug regimen (Hexa-
caf) of the National Cancer Institute, further study is required before any of
these can receive definitive recommendation as the optimal first line of
chemotherapy for epithelial ovarian cancer.
Immunotherapy. Immunotherapy attempts to maintain the immune re-
sponse of the tumor-bearing host to antigens associated with a given neo-
plasm. This requires that antigens exist in and around tumor cells that
identify them as different from normal host cells, that these antigens can
elicit a humoral and cell-mediated immune response, and, further, that
these responses can be beneficially augmented in the cancer patient. The
isolation and characterization of ovarian cancer-associated antigens is the
first step to rational immunotherapy.
A tumor-associated antigen should be specific for the histologic type of
tumor in question and should be present in a large percentage of these
tumors. Evidence for the existence of tumor-associated antigens is valid
predominantly in tumors produced in animals by viral or chemical induc-
tion. Similar antigens in spontaneously occurring human tumors are more
difficult to demonstrate but have been identified in a limited number of
specimens of epithelial ovarian carcinoma. The antigen molecule has been
characterized as an acid glycoprotein with high levels of carboxyl and hy-
droxyl amino acids and low levels of basic and sulfur-containing amino
acid 153
If the antigenicity of ovarian carcinoma

accepted, the clinical appear-
is
ance of the disease suggests an inability of the host to mount an appro-

priate immunologic response. Because this is not always confirmed by tests
of nonspecific immune competence, the measured immune response could
be unrelated to tumor recognition and destruction. Whether the presence of
the ovarian tumor results in a state of immunosuppression in the host or
whether an impaired immunologic status is responsible for the presence of
a tumor remains to be demonstrated.
In the absence of a precise characterization of ovarian cancer-associated
antigens, immunotherapy is empirical in its attempt to increase the host
response to ovarian carcinoma. 154 Three immunotherapeutic approaches
now exist. The first, nonspecific immunotherapy, stimulates the immune
system with adjuvants designed to enhance the response of the patient to
her tumor. The second, active immunotherapy, attempts to increase the im-
munity of the patient to tumor antigens by injection of a tumor cell vaccine.
Finally, passive or adoptive immunotherapy utilizes antisera, immune lym-
phocytes, or subcellular fractions obtained from a host immunized against
the specific tumor antigen.
A variety of materials act as nonspecific stimulators of cell-mediated im-
munity (Table 11-18). Substances that have been utilized most extensively
in patients with ovarian carcinoma include Corynebacterium parvum and
bacillus Calmette-Guerin. 1Vl 1Vi Injection of C. puritan, a gram-positive, an-
-
aerobic rod. activates large numbers of macrophages and increases the an-
tibody response to a variety of antigens. A phase II study designed to deter-
mine the efficacy of adjuvant nonspecific immunotherapy and standard
alkylating agent therapy compares melphalan to melphalan and C. parvum
in women widi optimal stage III epithelial carcinoma of the ovary. Data
have yet to be analyzed with respect to response, progression-free interval,
and survival.
been used extensively in cancer immuno-
Bacillus Calmette-Guerin has
therapy. Despite a large number of clinical trials based on its properties as
an immunopotentiator and macrophage activator, the role of BCG in
ovarian cancer therapy remains to be clarified. The efficacy of BCG vaccine
depends on the strain used, the proportion of viable organisms, the absence
of free soluble antigens, the dose, the route, and the schedule of adminis-
TABLE 11-18. Nonspecific Stimulators of Immunity
Microbiologic Host Biologic

Microorganism^ Products Products Chemicals
Corynebacterium parvum Freund's adjuvant Thymosin Levamisole
Bacillus Calmette-Guerin (BCG) BCG cell skeleton MIF Tilorone
Mycobacterium bovis Klebsiella capsule Tumor necrosis factor Poly I:C
Bordetella pertussis E. coli endotoxin Poly A:U
Vaccinia virus
506 II / Treatment of Spei iik Neoplasms
tration. BCG vaccine is most effective when used in conjunction with or

immediately after tumor reduction 1>\ operation, radiation therapy, or che-
motherapy. Only limited clinical trials of BCG vaccine in the treatment of
ovarian carcinoma have been performed. Small numbers of women with
recurrent or persistent ovarian cancer have received BCG or BCG and
tumor antigen together with multiple drug chemotherapy. 157
Immunization against ovarian carcinoma could be achieved by the tech-
niques listed in Table 11-19. Immunization against oncogenic viruses im-
plies immunoprophylaxis rather than active therapy; however, no virus has
been identified as an etiologic agent in human ovarian cancer. Tumor an-
tigens have been employed in a variety of forms to produce active immun-
ization against cancer cells. Allogeneic and autochthonous cells have been
used. The use of allogeneic cells assumes that related tumors have common
antigens. The use of autochthonous cells implies that additional tumor cells
might provide a greater stimulus for antibody production. Tumor cells used
in a vaccine must be killed or inactivated to prevent growth at the site of
inoculation. Further modification and attenuation by radiation or chemicals
such as mitomycin-C and neuraminidase can increase the antigenicity of
the vaccine.
If immune tolerance (a phenomenon whereby the antigens that are pres-
ent on the surface of the tumor cell are not recognized as foreign and do
not result in antibody production) is the principal reason for failure of the
immune response to protect against the development and progression of
ovarian carcinoma, passive immunization has a rational basis as a method of
ovarian cancer control. However, fear that the antibodies in question might
function in a blocking capacity to enhance tumor growth has limited the
enthusiasm for this concept. Adoptive immunization involves the transfer of
competent cells or cell fractions derived from an immunized donor to a
tumor-bearing recipient. Activated lymphocytes, immune RXA, and transfer
factor have been employed. The use of intact lymphoid cells requires pre-
cise matching of histocompatibility to avoid a graft-versus-host reaction. Au-
tochthonous lymphocytes stimulated in vitro have also been delivered to
patients with ovarian carcinoma. Clinical trials of these methods are in an
early stage of development and do not provide any conclusion as to their
therapeutic effect. 15 "
The most important consideration in the evaluation of an immunothera-
peutic agent iswhether or not increased immunologic reactivity is mean-
ingful in the absence of an antitumor response. No trials have demonstrated
specific antitumor activity of an immunotherapeutic agent against ovarian
carcinoma, and activity against a variety of malignant tumors has been used
as the basis for clinical studies in ovarian cancer. Enhanced immunologic
reactivity of ovarian cancer patients treated with immunotherapy has been
shown. Whether or not this parameter justifies the continued use of poten-
tially toxic substances administered on a somewhat empirical basis remains
to be demonstrated.
Integration of Treatment Modalities. Patients with ovarian carci-
noma require initial operation to confirm the diagnosis, determine the
stage, resect the bulk of disease, and document the size and location of
TABLE 11-19. Methods of Active Immunotherapy
Immunization Against Immunization Against

Oncogenic Virus Cancer Cell"
No virus identified for Autochthonous cells

ovarian carcinoma
Allogeneic cells
Attenuated cells
Soluble tumor antigens
"With or without antigen modification (mitomycin C, neuraminidase I.
residual tumor. Patients who undergo laparotomy with tumor biopsy with
no attempt to resect tumor or document its extent often require a second
exploratory operation prior to the initiation of adjunctive therapy. An occa-
sional patient, unsuitable for operation because of advanced age or coexis-
tent medical problems, is suspected of having ovarian cancer on the basis
of a pelvic or abdominal mass and positive cytologic findings obtained on
paracentesis. These women fall into a special category and are managed by
relief of symptoms and the empirical use of chemotherapy.
The resection of all gross disease improves the prognosis but generally
does not obviate the need Systemic chemotherapy,
for additional treatment.
intraperitoneal radioactive colloids, or external radiotherapy can be select-
ed. Patients who relapse after adjunctive therapy usually have disease in
the upper abdomen or pelvis, or both, and are not candidates for additional
local therapy. Those who fail to respond to chemothorap) are often unsuit-
ed for radiation therapy; however, when radiation therapy has been em-
ployed initially, relapse can occasionally be controlled with systemic drug
therapy. The failure of large tumor aggregates to respond to radiotherapy
and the poor response rates obtained with second-line chemotherapy sug-
gest that re-exploration and further reduction of tumor bulk should be per-
formed prior to retreatment.
Patients often require exploration late in the course of their disease for
relief of intestinal obstruction. When there is a realistic expectation that
survival will exceed several weeks, appropriate diversion should be per-
formed. Careful attention is also required to maintain nutritional support,
restore fluid and electrolyte balance, correct anemia, and prevent secondary
infection. In spite of the precise interaction between the gynecologic on-
cologistand the radiotherapist, a majority of patients with epithelial ovarian
carcinoma die from the complications of their disease.
Germ Cell Tumors
Tumors of genii 3 per cent of ovarian malignan-

cell origin constitute 2 to
Pure genii cell cancers include the immature teratoma, dysgerminoma,
cies.
endodermal sinus tumor, embryonal carcinoma, and choriocarcinoma.
Mixed tumors also occur and generally behave according to their most ma-
lignant component. Careful pathologic evaluation of multiple areas from a
dysgerminoma is required to identify foci of choriocarcinoma or endoder-
mal sinus tumor.
The benign counterpart of the malignant germ cell tumor is the benign
cystic teratoma that is derived from two or more layers of the embryonic
endoderm, mesoderm, and ectoderm. Less than 5 per cent of these tumors
undergo malignant degeneration, usually of a squamous component, and
they are managed by simple removal with conservation of normal ovarian
tissue. Because the benign teratoma is bilateral in 10 to 15 per cent of
patients, the normal-appearing ovary should be carefully inspected. Be-
cause this tumor is common in young women, hysterectomy and bilateral
salpingo-oophorectomy are avoided. 159
The immature teratoma accounts for less than 1 per cent of all ovarian
cancers and tends to occur in children and young women. Incomplete dif-
ferentiation of the embryonic tissue layers is indicative of their malignant
nature. Treatment consists of total hysterectomy, bilateral salpingo-
oophorectomy, omental biopsy, and biopsy of a representative number of
metastatic tumor deposits. Tumor grade correlates more precisely with sur-
vival from these tumors than does stage, and the grade of a metastatic focus
is often more favorable than that of the primary tumor. Clinical stage is
often advanced because of peritoneal implants but can, on occasion, be as-

sociated with a favorable outcome if the histologic appearance of the metas-
tases is benign. If the primary tumor is other than a grade 1 lesion, aggres-
sive adjunctive therapy is indicated. Teratomas are resistant to radiation or
single agent chemotherapy. Treatment consists of multiple agent chemo-
therapy, most commonly with the combination of vincristine, dactinomycin.
and cylophosphamide. 160
As is the case with dysgerminomas and ovarian choriocarcinomas, imma-
ture teratomas produce a hormone that is biologically identical to human
chorionic gonadotropin. Although levels of this glycoprotein have been
shown to parallel the response of these tumors to therapy, the absence of
measurable HCG is not an indication to withhold chemotherapy.
The dysgerminoma accounts for 2 per cent of malignant ovarian tumors.
The mean age at diagnosis is under 20 years, and less than 10 per cent
occur after the age of 30 years. Fifteen to 20 per cent of dysgerminomas are
found in association with pregancy. Patients often present with a mass or
complaints of pelvic and abdominal pain. Unlike epithelial ovarian tumors,
dysgerminoma is frequently unilateral, and about 60 per cent of patients
have stage I disease at the time of initial exploration. Definitive treatment
includes hysterectomy and bilateral salpingo-oophorectomy with documen-
tation of the size and location of any metastatic foci. Frequent metastases
by the lymphatic route necessitate pelvic and periaortic lymph node biopsy
in all patients. Dysgerminoma is extremely radiosensitive, probably on the
basis of a tetraploid DNA content. It is not unexpected that the germ cells
of this tumor have twice the usual complement of DXA, as they are in the
arrested prophase of the first meiotic division. Patients with intraperitoneal
spread receive whole abdominal radiation with a dose of 2500 to 3000 rad
by a stationary 2000 to 2200 rad by the moving strip technique. A

field or
pelvic boost of 1500 to 2000 rad completes the therapy. In those patients
with involvement of the periaortic lymph nodes, an additional 1500 rad are
delivered to this region followed in three weeks by 2500 rad to the medias-
tinal and left supraclavicular lymph nodes.
Indications for conservative operation of unilateral salpingo-
the
oophorectomy to preserve childbearing function include the presence of a
unilateral, encapsulated, pure dysgerminoma with a diameter of less than
10 cm. Negative lymph nodes, a normal lymphangiogram, and absence of
ascites also are required. In patients who are managed according to these
criteria, recurrence is under 25 per cent, and 40 to 70 per cent of patients
who do have recurrences achieve control of their tumor with the subse-
quent administration of radiation therapy. 1*1
Overall survival figures vary from 25 to 90 per cent, with a median time
to recurrence of 12 months. This wide range probably reflects the inclusion
of mixed genu cell tumors, which contain less favorable elements, as dys-
germinomas. When patients with mixed tumors are excluded, the rate of
survival exceeds 80 per cent. Patients who fail radiation therapy delivered
to tolerance occasionally respond to an alkylating agent or a combination of
dactinomycin, 5-fluorouracil, and cyclophosphamide.
Endodermal sinus tumors, embryonal carcinomas, and choriocarcinomas
are extremely rare. They frequently present at an advanced stage and carry
a poor prognosis. The grade of these tumors appears unimportant. They are
often fatal even when confined to the ovary at diagnosis. Endodermal sinus
tumors are uniformly associated with elevated serum levels of alpha feto-
protein, and immunofluorescent techniques have identifed aFP in the cells
of these tumors. This is consistent with their derivation from the human
yolk sac, a known site of aFP synthesis. Although 70 per cent of embryonal
tumors also produce aFP, they also excrete HCG, which has not been iden-
52
tified in tumors of endodermal sinus origin."
Treatment of these extremely malignant ovarian neoplasms consists of
total abdominal hysterectomy, bilateral salpingo-oophorectomy, and reduc-
tion of tumor bulk. Endodermal sinus tumors are radioresistant, but a three-
year survival rate of 10 to 15 per cent has followed treatment with vincris-
tine, dactinomycin, and cyclophosphamide. Embryonal carcinoma has re-
sponded to radiation and a combination of dactinomycin, 5-fluorouracil, and
cyclophosphamide, with 39 per cent of patients alive at five years.
Ovarian choriocarcinoma is not as responsive to chemotherapy as the ges-
tationaltrophoblastic tumors. An occasional survivor has been reported
with the administration of methotrexate, dactinomycin, and an alkylating
agent. 163
Sex Cord (Gonadal Stromal) Tumors
Although tumors of specialized gonadal stroma compose less than 5 per

cent of ovarian neoplasms, they are of interest because of their association
with increased circulating levels of estrogenic and androgenic hormones.
Collected scries indicate hormonal function in 50 to 85 per cent of these

tumors. The cell type does not always correlate with the hormone pro-
duced, and functional classifications have largely been abandoned (Table
11-15).
Other classes of ovarian tumors also can secrete hormones but do so at a
subclinical level. Many women with epithelial ovarian cancer have abnor-
mally cornified vaginal epithelial Elevations of total urinary estrogens
cells.
or pregnanediol, or both, have been described in postmenopausal women
with benign or malignant ovarian tumors. It is theorized that the tumor
cells stimulate the stroma of the ovary to differentiate into cells that are
capable of hormone production. " 4 1
The most common of the gonadal stromal tumors are the granulosa cell
neoplasms, which occur most often between the ages of 40 and 60 years.
Over 50 per cent of women are postmenopausal at diagnosis, and less than
5 per cent are prepubertal. The clinical manifestations of this tumor reflect
both the secretion of estrogen and the age of the patient (Table 11-20).
Fifteen per cent of postmenopausal women have an associated endometrial
carcinoma, and an additional 15 per cent develop endometrial hyperplasia
or polyps.
Eighty-five to 90 per cent of granulosa cell tumors are unilateral. Because
of their frequent presentation at an early stage and a prolonged interval to
recurrence, many investigators have questioned the true malignant poten-
tial of these neoplasms. Recent literature suggests, however, that when
they have spread beyond the ovaries at diagnosis or recurred after initial
therapy, their behavior is similar to that of the epithelial ovarian tumors. 165
The fact that the tumor is often confined to the ovary reflects either a less
rapid rate of growth or the possibility that the associated endocrine mani-
festations bring the patient to the physician earlier in the course of her
disease. Unlike epithelial ovarian cancer, the histology of the granulosa cell
tumor appears to be of little prognostic importance. Complex folliculoid,
pseudoadenomatous, cylindroid, and diffuse patterns have been observed
and do not correlate with stage of disease or outcome.
Many investigators have favored unilateral salpingo-oophorectomy in the
treatment of patients with stage la disease and reserve total hysterectomy
and bilateral salpingo-oophorectomy for those with more advanced tumors.
Recent reports suggest that a more aggressive approach could benefit all
patients with granulosa cell tumors in that conservative operations have
been associated with a tendency to late recurrence. 165 Although radiation
therapy also has been employed in the management of these patients, no
data exist to substantiate its benefit.
Patients who develop a local recurrence or metastases frequently suc-
cumb to their disease. Recurrent granulosa cell cancer appears refractor) to
radiation and single agent chemotherapy but has responded to combina-
tions of chemotherapeutic agents which include dactinomycin, 5-
fluorouracil, and cyclophosphamide.
The Sertoli-Leydig cell tumors are associated with clinical manifestations
of an androgen excess. About 50 per cent of these tumors occur in women
during their reproductive years, and they occasionally are seen in patients
11 Gynecologic Neoplasms oil
TABLE 11-20. Clinical Manifestations of Estrogen-

Producing Ovarian Tumors
Postpcbertal/
Prepubertal Premenopausal Postmenopausal
Pelvic mass Pelvic mass Pelvic mass
Precocious puharche Menorrhagia Postmenopausal bleeding
Precocious menarche Metrorrhagia Breast enlargement

Amenorrhea
under the age of 20 > ears. The tumors are extremely rare, often unilateral,
and infrequently malignant. In the absence of widespread disease, conser-
vative treatment generally has been advocated. Patients with advanced or
recurrent Sertoli-Leydig cell tumors have proved resistant to radiotherapy
and single agent chemotherapy but have responded on occasion to daetin-
omycin, 5-fluorouracil, and cyclophosphamide or vincristine, dactinomycin,
and cyclophosphamide.
Nonspecific Stromal Tumors
Tumors can arise from the fibrous and vascular supporting tissues oi the
ovary and produce fibromas, hemangiomas, and leiomyomas. The fibroma, a
benign connective tissue tumor, accounts for about 20 per cent ot solid
ovarian tumors. On occasion, this tumor can be confused with a malignancy
on the basis of coexisting ascites and right hydrothorax (Meigs' syndrome).
The cause of these fluid accumulations is unknown, and they repress after
conservative operation to remove the fibroma.
Lymphoma and leukemia can, on occasion, present as a primary ovarian
tumor. 188 Although radiation therapy and chemotherapy form the definitive
treatment for these tumors, errors in diagnosis have subjected some pa-
7
tients to inappropriately aggressive operations. 1
'
A definitive diagnosis of
epithelial ovarian cancer must be obtained prior to the performance of any
radical pelvic or abdominal operation.
Fallopian Tube Cancer
Primary fallopian tube cancer accounts for less than 0.5 per cent of all
reproductive tract tumors. Metastases from carcinoma of the ovary or en-
dometrium to the fallopian tube are more common and must be excluded
prior to the diagnosis of a primary tubal cancer. Adenocarcinoma is the
predominant cell type, with rare mixed mesodermal and genu cell tumors
sometimes seen.
The
diagnosis of primary carcinoma of the fallopian tube rarely is made
prior to operation. Pain, bleeding,and a profuse serosanguineous vaginal
discharge are common symptoms and are associated with a pelvic mass sug-
gestive of an ovarian primary tumor. Patients with tubal carcinoma are

slightly older than those with primary ovarian cancer and often are nulli-
parous with a history of pelvic inflammatory disease. The definitive diagno-
sis requires that the main tumor be present in the fallopian tube, that the
ovaries and uterus be normal, and that histologic examination reveal a tran-
sition between benign and malignant cells of the endosalpinx. 168 No recog-
nized staging system for fallopian tube carcinoma exists. In general, the
FIGO system for ovarian carcinoma has been applied.
Treatment includes total hysterectomy, bilateral salpingo-oophorectomy,
and removal of as much tumor as possible. As with ovarian carcinoma, a
careful laparotomy is mandatory to identify patients with disease that has
spread beyond the pelvis to involve the peritoneal surfaces and abdominal
viscera. Advanced and recurrent disease have been managed by radiation
therapy, alkylating agents, 5-fluorouracil, and progestins, with an overall
five-year survival rate of 20 to 30 per cent. When the tumor is confined to
one fallopian tube, the rate of survival approaches 50 per cent. 170
Large gaps exist in the areas of ovarian cancer control and ovarian cancer
research. Cancer control implies the application of all knowledge that is
now available for the treatment of women with ovarian carcinoma. Cancer
research continually expands existing knowledge with particular emphasis
on diagnostic and therapeutic techniques.
Ovarian Cancer Control
The treatment of ovarian carcinoma in a particular patient relates almost

exclusively to the training and expertise of the physician with whom the
patient first establishes contact. The surgeon, able to resect bulky tumor
masses, might be unfamiliar with the role of subsequent radiation or che-
motherapy, or both. Similarly, the radiation therapist and medical oncolo-
gist could be unfamiliar with the role of tumor reduction by operation and
its effect on responsiveness to radiation or chemotherapy. The gynecologic
oncologist, with support from his colleagues in radiation therapy and medi-
cal oncology, attempts to institute a true combined modality approach to
the treatment of these patients. This does not imply that each woman with
ovarian cancer should undergo operation, radiation, and chemotherapy, but
rather that the careful integration of treatment modalities based on an un-
derstanding of the biology and pathophysiology of ovarian tumors is the
path most likely to produce cure or sustained remission. At present, this
approach is confined to cancer treatment centers and major centers of refer-
ral. The comprehensive cancer centers with their outreach programs will
hopefully provide more optimal control of women with ovarian carcinoma.

Ovarian Cancer Research
Advances therapy must await the identification of new cytotoxic drugs

in
that are effective against ovarian cancer. The role of immunotherapy alone
or in combination with chemotherapy also awaits critical analysis. At pres-
ent, major research efforts are under way in the area of early detection. The
location of the ovaries deep in the pelvis often results in their inadequate
assessment by abdominal and vaginal palpation. Obesity, a muscular ab-
dominal wall, and excessive vaginal length or redundancy further reduce
the adequacy of routine pelvic examination as a screening tool for early
ovarian carcinoma. In addition, ovarian cancer is insidious in that it usually
does not produce symptoms until the disease is in an advanced stage. Cure
rates for patients with stage I ovarian cancer have been reported in the
range of 65 to 90 per cent. Most patients, however, present with stage III
and stage IV disease, which have survival rates of 5 to 15 per cent at five
years. Early diagnosis in the absence of any advances in therapeutic tech-
niques could be expected, therefore, to increase survival by 50 to 85 per
cent.
A tumor marker circulating in the plasma or excreted in the urine might
function as an aid to the early diagnosis of ovarian carcinoma. Ideally, a
marker is uniformly present only when the tumor is present and is measur-
able by a sensitive and specific assay. A quantitative assessment of the
marker should correlate with the amount of viable tumor and allow it to
function as an indicator of response to a particular therapy. The disappear-
ance of measurable marker ultimately would signal cure and the need
for
no further treatment.
Research into markers of ovarian carcinoma is in an early stage of devel-
opment. Circulating antigens have been detected in patients with epithelial
ovarian carcinoma; however, cross reactivity with other reproductive tract
tumors has been noted. 171 7/i vitro tests of cell-mediated immunity utilizing
leukocyte migration inhibition, lymphocyte cytotoxicity, and lymphocyte
blastogenic response to autochthonous tumor extract have demonstrated al-
tered levels of these functions in patients with ovarian carcinoma. 172 Other
investigators have utilized the basic premise that certain embryonic genes,
not generally active in normal adults, are activated in patients with ovarian
carcinoma. The resulting ectopic synthesis of enzymes and glycoproteins
constitutes the basis for the search for markers of ovarian carcinoma. The
variable expression of each of these markers in a given patient or a series of
patients suggests that a marker profile is most likely to result in a meaning-
ful clinical application to the early diagnosis of patients with carcinoma of
the ovary.
Regan isoenzyme, a family of enzymes that corresponds to the varieties
of alkaline phosphatase found in the normal term placenta, has been iden-
tified in the serum of patients with malignant ovarian tumor. Enzymes of
immature placental type have been designated
alkaline phosphatase of the
non-Regan and also have been found in patients with ovarian carcinoma. 173
Regan isoenzyme occurs with greatest frequency in ovarian carcinoma but
is also present in patients with uterine and cervical cancer. Human

chorionic gonadotropin, a glycoprotein hormone for which a sensitive and
specific radioimmunoassay exists, has been found in the sera of a high per-
centage of patients with adenocarcinoma of the ovary and also has been
demonstrated in the malignant ascites and pleural effusions of these pa-
tients. Usually the levels of HCG are higher in the effusion than in the
serum, which suggests production of the honnone by the tumor cell. In
some patients, the levels of Regan isoenzyme and HCG rise and fall in a
parallel fashion as the disease progresses or responds to therapy. In others,
however, a rise in one tumor marker is not accompanied by a corresponding
rise in the other. The production of these markers might be controlled by
different genes within the ovarian cancer cell, or the markers could be pro-
duced by different cells.
Integration of Ovarian Cancer Research

and Control
As cytotoxic chemotherapy with alkylating agents has produced responses

in many women with advanced epithelial ovarian cancer, the potential for
these drugs to improve survival in patients with early stage or completely
resected tumors has been investigated. As a result, increased numbers of
patients are free of clinical evidence of tumor after many months of chemo-
therapy. To stop treatment assumes cure and not mere arrest or slow pro-
gression of disease. On occasion, cessation of therapy results in a prompt
recurrence of ovarian cancer, which is then unresponsive to retreatment.
Recent evidence suggests a 21-fold increase in the risk of acute nonlym-
phocytic leukemia for patients with advanced ovarian carcinoma. This rela-
tive risk rises to 36-fold in patients who receive an alkylating agent and is
171-fold for those who survive two years. Comparison with a historic con-
trol group attributes this excess of fatal leukemia to alkylating agent therapy
with a possible enhancing effect by radiation. 174
The need to determine the true status of women with ovarian carcinoma
who are treated with alkylating agents and are in clinical remission is thus
based on the following: (1) unwillingness to stop chemotherapy if a signifi-
cant risk of tumor recurrence exists, and (2) the potential induction of leuke-
mia by alkylating agent therapy in women who no longer require treat-
ment. The "second-look" operation has applicability in this context, and its
indications have been extended to include women in whom a response to
chemotherapy cannot be measured clinically. 175 The operation, performed
through a vertical incision, consists of 30 to 40 biopsies of the pelvic and
abdominal peritoneum, the mesenteries of the small and large intestines,
the retroperitoneal pelvic and periaortic lymph nodes, and any suspicious
foci in the abdominal cavity. Separate cytologic washings are obtained from
the pelvis, the right and left paracolic gutters, and the undersurface of the
diaphragm. Treatment can be stopped with minimal risk of recurrence in
patients who have completed 18 to 24 months of alkylating agent therapy
and are free of tumor at second-look operation. Those who are found to
have residual disease require the continuance of alkylating agent therapy or

introduction to a new program of chemotherapy.
As more women survive two years after the diagnosis of ovarian carcino-
ma, the importance of a second-look operation will be increased. The infor-
mation obtained should improve the early detection of recurrence, docu-
ment cure in patients who no longer require therapy, and prevent
morbidity and mortality secondary- to treatment.
Section 7
Sarcomas of the Uterus
INTRODUCTION
A
group of sarcomas with different biology, histology, and clinical fea-
tures can arise from both the endometrial stroma and myometrium. These
tumors account for 2 to 5 per cent of uterine malignancies, and their in-
cidence has not increased as has that of the endometrial adenocarcinomas.
Because their etiology is unknown, patient characteristics are used to iden-
tify those at risk to develop sarcomas. Patient age ranges from 30 to 85
years, with an average age of 60. Some investigators suggest that these
tumors are more frequent in black women. Although prior pelvic or uterine
irradiation has been implicated in the genesis of uterine sarcomas, a review
of reported cases fails to substantiate this. The triad of obesity, diabetes,
and hypertension that is associated with endometrial adenocarcinoma also
appears frequently in women with uterine sarcoma.
Pathology
Uterine sarcomas can contain both homologous and heterologous ele-

ments. Homologous tumors are composed only of those tissues that are in-
digenous to the uterus, whereas the heterologous types include foreign ele-
ments such as cartilage, striated muscle, or bone. 176 Both can exist in pure
or mixed form, with pure tumors composed of a single cell type and mixed
tumors containing more than one cell type. Another system classifies
uterine sarcomas on the basis of their origin from the endometrium, myo-
metrium, or nonspecific connective tissue such as blood vessels and
nerves 177 (Table 11-21).
Two problems exist in the pathologic interpretation of uterine tumors as
sarcomas. The first is to establish malignant potential, and the second is to
define the predominant cell type. The most important criterion for malignancy
TABLE 11-21. Classification of Uterine Sarcomas
Sarcoma
Homologous
Pure
Leiomyosarcoma
Stroma sarcoma
Endolymphatic stromal myosis
Angiosarcoma
Fibrosarcoma
Mixed
Heterologous
Pure
Rhabdomyosarcoma
Chondrosarcoma
Osteosarcoma
Liposarcoma
Mixed
M 1LIGNANT MIXED MULLERIAN TUMORS

Homologous
Pure
Carcinoma with homologous sarcoma
Mixed
Heterologous
Pure
Carcinoma with heterologous sarcoma
Mixed
Sarcoma, Unclassified
is the mitotic index derived from multiple sections. 178 179 The malignant
-
potential of leiomyosarcomas with greater than ten mitoses per 10 high-

power microscopic fields is clear. Tumors with less than five mitoses per
10 high-power fields are benign. The behavior of tumors with mitotic
counts between five and nine is less certain, however, as some may metas-
tasize after aggressive therapy, whereas others respond completely to oper-
ative removal. The virulence of endometrial stromal sarcoma also is reflect-
ed in the mitotic index; the size of the primary tumor and degree of
encapsulation also are of prognostic importance. 177 Degeneration of a
myoma with associated giant cell formation and cellular pleomorphism
often is difficult to distinguish from a sarcoma. Retrospective reviews of
tumors diagnosed as leiomyosarcoma reveal both benign cellular myomas

and sarcomas of a different cell type. 180 On occasion, sarcomas can be clas-
sified only on the basis of the microscopic appearance of the predominant
cell and are designated spindle cell, round cell, or myxoid sarcoma.
The symptoms of uterine sarcomas relate to their origin from the endo-
metrium or myometrium. Sarcomas of endometrial origin often cause post-
menopausal bleeding, whereas abdominal pain and the presence of a pelvic
or abdominal mass are less frequent. Nonspecific complaints such as vagin-
al discharge, weight loss, and dysuria also occur. Sarcomas of myometrial
origin frequently present as a painful or asymptomatic pelvic mass. Rapid
enlargement of known fibroids in a postmenopausal patient is suggestive of
sarcomatous degeneration. Pain is often associated with a rapidly growing
tumor and should arouse suspicion. The incidence of sarcomatous degen-
eration of a benign leiomyoma is under 2 per cent and does not warrant
182
hysterectomy in all patients with uterine fibroids. 181,
The early diagnosis of uterine sarcomas is often difficult. Patients who
develop postmenopausal bleeding require fractional curettage. On occasion,
a poorly differentiated adenocarcinoma with sarcomatoid features is diffi-
cult to distinguish from a sarcoma. The diagnosis of tumors that arise from
the myometrium usually is made
laparotomy.
at
Noaccepted staging system exists for uterine sarcomas, and the FIGO
staging of endometrial carcinoma is often applied. Those tumors confined
to the fundus are designated as stage I. Stage II, stage III, and stage IV
disease reflect progressive involvement of the cervix, spread to the pelvic
tissues, and distant metastases. Sarcoma spreads by direct extension to in-
volve adjacent tissues, by lymphatic spread to regional and distant lymph
nodes, and by the hematogenous pathway to lung, liver, or bone.
Prognosis
The prognosis of patients with uterine sarcoma relates to cell type, stage,
depth of myometrial penetration, and the presence of lymph node metas-
tases. Patients with endometrial stromal sarcoma —
a pure, homologous
tumor —
appear to have both higher rates of cure and more frequent control
of local disease in the pelvis. Leiomyosarcoma —
a pure homologous tumor
of myometrial origin —
has an unfavorable prognosis because of a tendency
to spread early to distant organs. Tumors that contain heterologous ele-
ments, such as cartilage and striated muscle, are uniformly associated with
a poor prognosis.
Stage correlates both with survival at two years and control of pelvic dis-
ease. It appears, however, that sarcomas are likely to metastasize by the
hematogenous pathway and to involve regional and distant lymphatics at an
earlier stage than are endometrial adenocarcinomas. Of 28 patients with
mixed mesodermal sarcoma or carcinosarcoma, 10 (35.7 per cent) had in-
volvement of pelvic lymph nodes time of hysterectomy. u* Four of

at the
these patients also had metastases to aortic lymph nodes. All patients with
metastases to pelvic or periaortic lymph nodes, or both, had invasion of the
middle or outer third of the myometrium by the primary tumor.
The survival rate of patients with mixed mesodermal sarcoma is reported
at about 50 per cent for stage I disease and 10 per cent for stage II dis-
ease, with virtually no survivors among patients with stage III and stage
IV disease. Difficulty in interpreting survival statistics for other cell types
relates to the use of different staging systems and the small numbers of
patients reported. A
two-year survival rate of 50 to 60 per cent has been
reported for patients with stage I and stage II leiomyosarcoma, with a 60 to
70 per cent survival rate in stage I and stage II endometrial stromal sar-
coma and carcinosarcoma.
TREATMENT
The overall survival figures reported for many patients with these dis-
eases suggest that no single treatment modality is curative. Total hysterec-
tomy and salpingo-oophorectomy is adequate to remove the prima-
bilateral
ry tumor in patients with stage I and stage II disease but often is
ineffective in the prevention of local recurrence.
The high rate of pelvic lymph node involvement suggests that radiation
therapy to the pelvis is required and can be administered prior to or after
hysterectomy. Patients with endometrial stromal sarcoma have benefited
from pelvic irradiation with improved survival and decreased local and re-
gional recurrence. 184 Patients with leiomyosarcoma have not benefited from
pelvic radiotherapy because of a tendency to distant metastases. Isolated
pelvic recurrence is unusual in patients treated by operation and radiation
therapy. Distant disease accounts for about 50 per cent of recurrences,
whereas the other 50 per cent fail on the basis of both regional and distant
disease. 185
Systemic chemotherapy is the logical adjunctive treatment for most pa-
tients with uterine sarcoma. Doxorubicin, dacarbazine, and the combination
of vincristine, dactinomycin, and cyclophosphamide have been of benefit in
selected patients. 186 Ninety per cent of patients who develop recurrence do
so within two years of their diagnosis and initial treatment. 187 Data that
indicate an increase in the two-year survival rate following the administra-
tion of single agent or combination chemotherapy thus are meaningful and
indicate activity against these tumors.
4. Klinefelter HF, Jr, et al.: J Clin En-

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CHAPTER 12
HEAD AND NECK

NEOPLASMS
Section I
Cancer of the Oral Cavity

and Oropharynx
TC Calcaterra G Juillard
INTRODUCTION
Cancers of the oral cavity and oropharynx account for approximately 5
per cent of all cancers in the United States and are responsible for about
7000 deaths annually. As with other head and neck cancers, male cases pre-
dominate.
Many different etiologic factors have been proposed in oral cancers, some
of which seem quite definite. The sun undoubtedly is an important etiolo-
gic factor in lip cancer; the lower lip is most often involved with long-term
sun exposure. Cancer of the floor of the mouth is seen far more frequently
in people who chew snuff than in the general population. Similarly, the
habitual pipe-smoker is prone to cancer of the buccal mucosa. Excessive
smoking and alcohol consumption certainly are related to oral cavity and
oropharyngeal cancers, but it is difficult to assess which of these habits is
more oncogenic, inasmuch as they usually occur together. 1
Some oral cavity cancers, particularly those of the buccal mucosa, arise
from an area of leukoplakia, although, fortunately, this condition does not
usually degenerate into a malignant tumor. Nevertheless, it is important to
correct abrading surfaces on dentures or teeth that give rise to leukoplakia
or superficial ulceration. In cases of cancer of the tongue, an association
with tertiary syphilis was noted when syphilis was prevalent.
522
12 / Head and Neck Neoplasms 523
The and third primary cancers in the oral

rather high incidence of second
cavity is of particular importance. Occasionally, multiple primary cancers
occur in people who do not smoke or drink —
usually older women with
atrophic oral mucosa that is possibly related to deficiencies of iron and ri-
boflavin. Likewise, it has been postulated that alcoholism leads to similar
1
vitamin and mineral deficiencies.
NATURAL HISTORY
Squamous cell (epidermoid) cancer is the most common type of cancer

(90 per cent) arising in die oral cavity and oropharynx. In general, those
cancers originating in the oral cavity are well differentiated, particularly in
the lip and buccal mucosa. Those arising in the oropharynx tend to be less
well differentiated and have a greater propensity for early metastasis. Oral
cavity cancers, which may develop from an area of hyperkeratosis, tend to
be exophytic and well differentiated. Some of these tumors become quite
bulks and develop a warty appearance, and they are termed verrucous can-
cer. They are characterized by nearly normal cellular architecture and rela-
tively late invasion of the underlying musculatures.
The next most prevalent of the other types of cancers that are seen in the
oral cavity and oropharynx is the cancer originating in the numerous nests
of salivary gland tissue that are omnipresent throughout the entire mucosal
lining. 2 The usual site for salivary gland tumors is the palate, and, less fre-
quently, the floor of the mouth and base of the tongue. These tumors vary
in their malignant potential and invasiveness, but, in general, they grow
slowly and have a tendency to recur locally if they are not widely resected
when first treated. Of particular concern is the adenoid cystic carcinoma,
which has a remarkable proclivity for distant extension via the perineural
lymphatics, resulting in a high incidence of local recurrence and lung me-
tastasis.
Lymphomas are likely to be found in the oropharynx that contains Wal-
deyer's ring of lymphoid tissue. Care must be taken during biopsy to avoid
crush artifact of the cells, which makes precise diagnosis difficult. When
lymphomas are localized, an excellent cure rate can be obtained by radia-
tion therapy.
Melanomas are rarely seen in the oral cavity and oropharynx; however,
they may appear as nonpigmented tumors, making diagnosis difficult.
Diagnosis
Although the patient may be aware of symptoms related to an oral cavity

or oropharyngeal cancer, the diagnosis is often delayed for several weeks or
months. Typically, the patient will attribute the symptoms to a slowly re-
solving "fever blister" or "tonsillitis" and fail to seek medical attention.
524 II / Treatment of Specifn Neoplasms
TABLE 12-1. American Joint Committee for Cancer Staging and End-Results
Reporting TNM Classification of Head and Neck Tumors'
T Classification of Oral Cavity and Oropharyngeal Tumors
TX No available information on primary tumor

T, Tumor 2 cm or less in greatest diameter
T, Tumor 2 cm to 4 cm in greatest diameter
T, Tumor exceeding 4 cm in greatest diameter
T 4 Massive tumor greater than 4 cm in diameter with deep invasion into a contiguous struc-
ture such as antrum, pterygoid muscles, root of tongue, or skin of neck
N Classification of All Head and Neck Malignant Neoplasms

(Subgroups a, b, and c Optional)
NX Nodes cannot he assessed

N No clinically positive nodes
N, Single clinically positive homolateral node less than 3 cm in diameter
\'_, Single clinically positive homolateral node 3 to 6 cm in diameter or multiple clinically
positive homolateral node involvement, none over 6 cm in diameter
N 2a Single clinically positive homolateral node 3 to 6 cm in diameter
N 2I> Multiple clinically positive homolateral nodes, none over 6 cm in diameter
N3 Massive homolateral node(s), bilateral nodes, or contralateral node(s)
N 3a Clinically positive homolateral node(s), none over 6 cm in diameter
N 3h Bilateral clinically positive nodes (in this situation, each side of the neck should be
staged separately; e.g., N3b right, N, a left, X,
; ; )
\i, Contralateral clinically positive node(s) only
M Classification of All Head and Neck Malignant Neoplasms
MX Not assessed
Specify sites according to the following notations:
Pulmonary — PUL
Osseous — OSS
Hepatic- HEP
Brain -BRA
Lymph nodes — LYM
Bone marrow — MAR
Pleura- PLE
Skin-SKI
Eye -EYE
Other- OTH
R Postsurgical Treatment Residual Tumor
R No residual tumor
R, Microscopic residual tumor
R, Macroscopic residual tumor— specify
Stage Grouping of Head and Neck Cancer
Stage I T,,N M ,
Stage II T8 N M
, ,
Stage III T3 No, M

,
T, or T, orT3 , N,, M„
Stage IV T4 N orN„ M
,
Any T, N or N 3 M
2 ,
Any T, Any N, M,
Likewise, the first physician consulted will generally carry out a therapeu-
tic trialof antibiotics or gargles that further delays diagnosis. It is therefore
important to refer patients with any persistent throat pain or nonhealing
ulcer to a physician who is capable of performing a thorough head and
neck examination and biopsy of any suspicious lesion.
The examination of the oral cavity and oropharynx requires good illumi-
nation, which is best provided by a head mirror or head light, and is facili-
tated by suction, local anesthesia, and various sized mirrors for systematic
inspection of the anatomic regions of the oral cavity and oropharynx. Manu-
al palpation is extremely important in examining the tongue and the floor of
the mouth to detect indurated tissue that cannot be seen. The use of in-
3
travital staining has assisted in the identification of oral cavity cancers, but
biopsy of sufficient depth to ascertain submucosal extension must also be
performed to confirm the presence of cancer. X-rays of the mandible are
important to determine osseous invasion. After completing the evaluation,
detailed drawings of the cancer should be prepared as a baseline for treat-
ment planning and follow-up.
Staging
The oral cavitydivided into several anatomic regions, each of which

is
gives rise to tumors with similar biologic characteristics and prognostic fac-
tors. These regions are the lips, alveolar ridges, buccal mucosa, retromolar
trigones, floor of the mouth, hard palate, and anterior two thirds of the
tongue. The oropharynx is divided from the oral cavity superiorly by the
junction of the hard and soft palates, laterally by the anterior tonsillar pil-
lars, and inferiorly by the cireumvallate papillae of the tongue. The regions
of the oropharynx are the soft palate and uvula, base ot the tongue (pharyn-
geal or posterior one third), tonsils, and pharyngeal wall. The classification
of the primary tumor is determined by its size (Table 12-1 ). 4 The recom-
mended tumor (T) designation varies from one anatomic region of the head
and neck to another, but the classification of the node (N) and metastasis
(M) categories is applicable to all of the areas of the head and neck. Stage
grouping based on the TNM
stage are also similar throughout, as given in
Table 12-1 .^
CLINICAL FEATURES AND

TREATMENT
Oral Cavity
Lip. Patients with lip cancer usually present with a nonhealing sore on
the lower lip that repeatedly forms a dry crust that bleeds on removal. The
tumor may then develop into a bulky exophytic growth or, less commonly,
an "ulcerative indurated lesion. Associated keratotic lesions may appear on
the remaining area of the lip. Almost 95 per cent of such cancers occur on
526 II / Treatment of Specific. Neoplasms
the lower lip, and these are characteristically more differentiated than
upper lip cancers. The incidence of metastasis ranges from 10 per cent to
15 per cent, especially with tumors of increased size, long duration, and
less differentiation. For midline cancers of the lower lip, the most frequent
site of cervical metastasis is the submental nodes, and for lateral cancers it
is the submandibular nodes. The metastatic incidence of upper lip cancers
approaches 50 per cent, and usually involves the upper deep jugular lymph
node chain.
The treatment of T! and T2 lip cancers can be managed with equal suc-
cess by irradiation or surgery. 5 When irradiation is the selected method, it
is usually delivered by external beam up
6000 rad over five to
to six weeks
or by radioactive implant which delivers 6000 to 7000 rad over five or six
days.
Large lesions are best treated surgically if there is soft tissue destruction
or jaw involvement. Surgery usually consists of a V-incision for small le-
sions or a W-excision with primary closure for larger cancers involving an
area no larger than one third of the lip. A local transposed flap of the oppo-
site lip (Abbe flap or Estlander flap) is often used for somewhat larger le-
sions. For advanced lip cancers either unilateral or bilateral regional cheek
flaps are employed to reconstruct the lip defect. A radical neck dissection is
performed for palpable cervical metastasis, and it is often necessary to re-
move the periosteum or a cortical margin of the mandible to secure ade-
quate tumor clearance. Postoperative radiation is often employed when the
lymph nodes are involved.
The five-year control rate for lower lip cancers is related to the size of
the tumor, but on an average it approaches 90 per cent when there is no
cervical metastasis. However, when cervical metastasis is present, the prog-
nosis is almost reduced by half. Upper lip cancers have a less favorable
prognosis, usually in the range of 50 per cent to 60 per cent.
BUCCAL Mucosa. Tumors of the buccal mucosa, often arising in or asso-
ciated with leukoplakia, 6 are
more frequently exophytic than ulcerative and
sometimes appear as warty outgrowths (verrucous cancer). These tumors
may reach a rather large size before becoming symptomatic, particularly
when they are exophytic. The ulcerative lesions are likely to present earlier
with pain. When there is extension to the posterior buccal surface, trismus
may be present owing to the invasion of the pterygoid muscles. This cancer
is seen in an older age group, more so than those cancers located in all
other regions of the oral cavity; the mean age of those afflicted with these
tumors is in the seventh decade.
Radiation and surgery are equally effective for treatment of early lesions.
For small lesions, peroral cone irradiation or radioactive implants are par-
ticularly effective. If surgery is performed, the buccal defect is usually re-
paired with a dermal graft or a rotational flap from the tongue. Larger
tumors may necessitate the resection of a portion of the mandible or maxil-
lary alveolus. When the tumor extends through the cheek muscles close to
skin, the skin must be excised, after which it is either closed primarily or
repaired with a rotational neck flap.
Metastasis to the submandibular and upper deep cervical nodes tends to

occur when the tumor is advanced. The overall five-year survival rate
ranges between 40 per cent and 50 per cent.
Alveolus and Hard Palate. The discussion of alveolar and hard palate
tumors is combined because cancers in this region demonstrate close ad-
herence to bone, an important consideration in selecting the optimal form
of treatment. Inasmuch as pain is not typical during the early stages, these
tumors are often confused with a dental infection or epulis. Indeed, the
patient may undergo tooth extraction or modification of a denture because
of persistent irritation. These tumors are generally well differentiated and
may be exophytic or ulcerative. Although squamous cell cancer clearly pre-
dominates in tumors of the alveolus, at least half of the hard palate cancers
are of salivary gland origin. Because of the tumor's proximity to bone, bone
involvement is present in most instances, although it may not be con finned
on x-ray studies.
The treatment for these tumors is almost always surgical unless the pa-
tient refuses or has a poor medical status that would substantially increase
operative risk. 7 The surgery removes the tumor en bloc, requiring, at the
least, a marginal mandibulectomy or partial maxillary alveolectomy. Defects
along the mandible may be repaired with a split-thickness dermal graft or
rotational tongue flap. Defects of the maxillary alveolus or hard palate must
be obturated with a prosthesis that is worn like a denture to permit normal
swallowing and speech. The management of cervical lymph nodes requires
a radical neck dissection, and if there is substantial likelihood of metastatic
disease in the neck despite negative clinical findings, prophylactic neck dis-
section or postoperative radiation should be carried out. The five-year control
rate is related to stage, but on the average it is about 50 per cent.
Floor of Mouth and Anterior Tongue. The sites for the majority of
intraoral cancers 8 (excluding the lips) are the tongue and floor of the mouth,
with the tongue being twice as likely to be afflicted. The area usually in-
volved on die tongue is the middle third of the lateral border; the re-
mainder of the lateral borders and ventral surface less commonly give rise
to tumors.
Most cancers of the floor of the mouth arise in the anterior half, in areas
of leukoplakia or erythroplasia; this is not characteristic of tongue cancers.
Histologically, such tumors tend to be moderately differentiated, although
some can be quite differentiated and superficial. Both exophytic and infil-
trative growth patterns are seen —the latter more frequently in the tongue.
Cancers of the tip of the tongue and dorsal surface are quite rare. The
extent of tongue tumors tends to be underestimated because of their "ice-
berg" pattern of growth. It is far more reliable to palpate the underlying
induration than to measure the visible portion. Occasionally, tongue can-
cers appear to be quite superficial, like a patchy desquamation or aphthae.
The symptoms of tongue and floor of the mouth tumors can be negligible
during the early stages, often no more than a slight local irritation. As the
tumor enlarges, particularly if it is ulcerative, frank pain develops, which
may radiate to the ear if it is in the posterior half of the oral cavity. If there
is direct invasion of the lingual nerve, the pain becomes quite severe.
When there is an open ulcer, the patient or his or her family will notice a
foul mouth Deep infiltration into the tongue muscles eventually pro-
odor.
duces abnormalities in speech and an inability to protrude the tongue. If the
submandibular gland duct is invaded, the gland becomes swollen, particu-
larly when eating. Occasionally, a patient presents with a neck mass, and in
such instances the primary site is likely to be a poorly differentiated tumor
in the posterior area of the oral cavity.
Diagnosis must include a biopsy of a viable portion of the tumor, avoid-
ing any necrotic tissue from the center of an ulcer crater. The evaluation
must include careful search for metastatic neck disease, because at least 40
per cent of all tongue cancers present with metastases to the cervical lymph
nodes, and an additional 20 per cent of patients develop this during the
subsequent year. 9 Lymph nodes with anterior lesions are likely to be those
in the submental and submandibular regions; posteriorly located cancers
will first become manifest in the deep cervical chain at the hyoid level.
These tumors are prone to occur with other primary tumors in the oral
cavity, particularly when they arise in areas of leukoplakia and erythropla-
sia.
Treatment varies among institutions, probably because the results of sur-

gery and radiation are comparable. Both modalities used alone are reason-
ably effective with small tumors; however, each is ineffective in cases of
advanced disease, especially when there is cervical metastasis. The treat-
ment should be carefully individualized. For patients with small lesions
who cannot afford a speech impairment, radiation is the treatment of
choice. 10 Conversely, for the same cancer in a chronic alcoholic or a heavy
smoker, or both, radiation is often poorly tolerated, and therefore wide sur-
gical excision is preferred. 11 Surgery is even more valid if the likelihood of
additional oral cancers is suspected, since radiation can usually be adminis-
tered only once and may later be required for a lesion that cannot be effec-
tively excised.
When
tumors are larger than 4 cm or if they have cervical metastasis,
combined therapy is recommended. Radiation may be administered by ex-
ternal beam, intraoral cone, or interstitial implantation. The radiation thera-
pist delivers external beam adequate
irradiation in doses compatible with
wound healing and minimal surgical morbidity and then completes tumori-
cidal radiation with interstitial implantation. The latter technique is partic-
ularly effective when the tumor mass is not lying adjacent to the mandi-
13
ble. 12 Surgical excision ranges from a simple monobloc excision and
primary closure to a composite resection that may include the mandible,
most or of the tongue, and the oropharynx. With these large lesions it is
all
usually necessary to repair the substantial surgical defect with a regional
flap such as a deltopectoral or forehead flap. Obviously, surgery of this
magnitude often interferes with speech and hinders swallowing, especially
when the anterior arch of the mandible is resected, requiring multiple op-
14
erative stages for reconstruction.
In most instances of oral cavity cancers the neck will also have to be
treated. Irradiation appears to be equally as effective in eliminating micro-
12 Head and Neck Neoplasms 529
scopic metastatic disease as radical neck dissection. However, its effective-

ness diminishes rapidly when there is palpable metastatic disease, espe-
cially if the lymph nodes exceed 3 cm; radical neck dissection is employed
when the cervical nodes are larger than 3 cm. Occasionally, radiation may
be employed for the primary tumor, reserving surgery to treat the cervical
metastasis after radiation.
The prognosis varies considerably, depending on the size of the primary
tumor and the presence of regional metastasis. For small (under 2 cm),
well-differentiated tumors of the tongue and floor of the mouth without evi-
dence of metastasis, the five-year survival rate reaches 85 per cent, but for
larger tumors (over 4 cm) with cervical metastasis, this rate is only about
25 per cent.
Oropharynx
Several anatomic regions in the oropharynx have been grouped together

because oropharyngeal tumors are biologically similar and they are treated
similarly. 15 The anatomic regions composing the oropharynx arc the base of
the tongue, tonsillar pillars, retromolar trigone, tonsils, soft palate and
uvula, and lateral and posterior pharyngeal walls extending from the tip of
the epiglottis to the soft palate.
The most common tumor the oropharynx arises from the tonsil; the
in
base of the tongue and palate arc next in frequency. It is unusual, however,
to find any of these tumors confined to a single anatomic site when first
discovered because they grow rather large before becoming obviously
symptomatic. This paucity of symptoms when the tumor is small is proba-
bly related to a less refined sensory nerve distribution than is found in the
oral cavity. Moreover, it is difficult for the patient to visualize or palpate
these sites and thus to discover the tumor.
Oropharyngeal tumors are generally less differentiated histologically than
those in the oral cavity, ranging from moderately differentiated to anaplas-
tic. They are more likely to be ulcerative and infiltrating than exophytic in
gross configuration. The anterior part of the oropharynx sometimes gives

rise to well-differentiated tumors, particularly the anterior tonsillar pillars
and retromolar trigones.
On the whole, the metastatic propensity to regional nodes is significantly
higher in the oropharynx than in the oral cavity. In most regions the meta-
static rate exceeds 50 per cent, and in the base of the tongue it reaches
about 75 per cent. Metastases from small cancers of the tonsil or base of the
tongue are frequent. Typically, the upper deep jugular nodes, such as the
jugulodigastric, are the first to become clinically manifest. Bilateral cervical
metastases can occur, particularly from tumors of the base of the tongue
and the pharyngeal walls. Metastasis to the retropharyngeal nodes portends
a poor prognosis.
As the tumor enlarges and ulcerates, the patient experiences pharyngeal
pain that may sometimes alter in intensity. In fact, when first evaluated,
these tumors are usually considered to be tonsillitis or protracted pharyngi-
tis,and, consequently, the patient is given one or more trials of antibiotic-

therapy. Another common presenting symptom is otalgia; this is referred by
the glossopharyngeal nerve, which has sensory branches to the ear and the
oropharynx. The development of an asymptomatic mass is another frequent
mode of presentation. Even a thorough examination sometimes fails to re-
veal the oropharyngeal tumor; random biopsies ultimately disclose its site.
As the tumor enlarges, it may extend into the retromandibular space, caus-
ing trismus; extension into the base of the tongue can involve the hypoglos-
sal nerve, paralyzing the tongue. When there is an underlying mass without
mucosal ulceration, lymphoma or a tumor of mesenchymal origin must be
suspected.
The treatment of oropharyngeal tumors requires close cooperation be-
tween the surgeon and the radiation therapist. For smaller tumors, radiation
therapy is often the initial treatment of choice. It is usually delivered by
external radiation and is occasionally supplemented by intraoral cone ir-
radiation or,more frequently, by interstitial radiation.
Cervical metastases, even when bilateral and of moderate size, can be
controlled by irradiation alone. Although metastases that are too small to be
palpated can be controlled by radiation doses that produce few sequelae
(i.e., 45005000 rad in 4.5 to 6 weeks), larger masses require higher doses
to
(i.e., 5500 6500 rad in 5.5 to 7 weeks) for frequent control. It has been
to
documented that there is poor correlation between the rate of gross reduc-
tion of oropharyngeal epidermoid carcinomas and ultimate control by radia-
tion therapy. 16 Nevertheless, our personal preference for the treatment of
patients with palpable cervical metastases follows. Radiation therapy is
used and the tumor response completely reassessed when the patient
reaches approximately 5000 rad. If the primary tumor and cervical metas-
tases have responded favorably, the treatment is carried to a tumoricidal
dose range of 6500 to 7000 rad. If substantial tumor remains after the ad-
ministration of 5000 rad, surgical extirpation of the oropharyngeal primary
tumor and the regional cervical lymph nodes is performed. In some cases
with an excellent response at the primary site but persistent adenopathy,
the primary tumor will be given full doses of radiation, but a radical neck
dissection will subsequently be performed if there is biopsy-proven ab-
sence of tumor at the primary site. We realize that this treatment philoso-
phy is controversial, but we have extensive experience with this approach
and consider it optimal contemporary treatment.
Inasmuch as advanced oropharyngeal tumors are not likely to be cured
either by surgery or irradiation alone, 17 planned combinations of these two
modes of therapy are required to maximize the chances for long-term cure.
Composite resection of the oropharyngeal tumor and radical neck dissec-
tion followed by tumoricidal irradiation composes our current preferred
mode of treatment.
Section 2
Nasal Cavity and Paranasal

Sinuses
TC C a lea terra G Juillard
INTRODUCTION
Cancers of the nasal cavity and paranasal sinuses are described in the
same section because of their anatomic proximity, similar biologic charac-
teristics, and common methods of treatment. They constitute about 5 per
cent of all tumors arising from the respirator) tract and approximately 0.5
per cent of all malignancies. 18 As with most head and neck cancers, the
peak incidence occurs in the sixth and seventh decades, and there is a
slight male predominance. The association with tobacco smoking is not as
strong as in other carcinomas of the respiratory tract. There appears to be a
causal relationship between adenocarcinoma of the nasal cavity or sinuses
and certain airborne compounds used in the furniture industry. 19 Exposure
to nickel refinery fumes has also been implicated. 20
NATURAL HISTORY
No widely accepted classification of nasal and sinus malignancies exists,

inasmuch as such tumors are rarely confined to one anatomic area when
first diagnosed. Nasal cavity tumors can sometimes be identified as arising
from the septum or lateral nasal wall. Localized tumors of the maxillary
sinus have been arbitrarily divided into two groups by Ohngren's line,
which is a theoretic plane passing between the medial canthus of the eye
and the angle of the mandible. 21 Tumors occurring below this plane, called
infrastructure tumors, have a more favorable prognosis, whereas those that
develop above this plane, called suprastmcture tumors, have a less favor-
able outlook owing to their proximity to the orbit and cranium. A recent
TNM classification for cancer of the maxillary sinus has been proposed by
the American Joint Committee for Cancer Staging and End Results Report-
ing (Table 12-2).
The type of tumor generally found in the nasal cavity and paranasal si-
nuses the squamous cell carcinoma, representing about 80 per cent of the
is
total.These malignancies are typically intermediate in differentiation, tend-

ing to metastasize late to the cervical lymph node network, particularly
TABLE 12-2. TNM Classification of Maxillary Sinus Cancer
Primary Tumor (T)

TX Tumor that cannot be assessed
T„ No evidence of primary tumor
T, Tumor confined to the antral mucosa of the infrastructure with no bone
erosion or destruction
T, Tumor confined to the suprastructure mucosa without hone destruction or
to the infrastructure with destruction of medial or inferior bony walls
only
Tj More extensive tumor invading skin of cheek, orbit, anterior ethmoid
sinuses, or pterygoid muscle
T, Massive tumor with invasion of cribriform plate, posterior ethmoids,
sphenoid, nasopharynx, pterygoid plates, or base of skull
when they originate in the sinuses. Moreover, distant metastases are quite
rare until late in the course of the disease.
A variety of other kinds of malignant tumors may arise in the nasal fossa
and paranasal sinuses. Olfactory neuroepithelial tumors occur in the upper
portion of the nasal cavity and usually present as polypoid masses that max
be confused with lymphomas or undifferentiated carcinomas. 22 Malignant
melanomas, which are found in the nasal cavity and less often in the sinus-
es, may exhibit a rather unusual, indolent course, with only a slight tenden-
cy to metastasize. 23 The entire spectrum of salivary gland tumors may like-
wise develop in this region inasmuch as nests of salivary gland cells are
found throughout the upper respiratory tract. This biologic growth behavior
generally corresponds to the degree of histologic differentiation of the spe-
cific tumor.
Clinical Features
Tumors in the nasal fossa are typically heralded by unilateral nasal air-
way obstruction and rhinorrhea, which the patient attributes to an infection
or allergy. Occasionally, however, epistaxis or blood streaking of nasal
mucus will arouse suspicion of the presence of a tumor. As the tumor en-
larges, the patient may experience facial pain owing to blocked sinus ostia
and epiphora or dacryocystitis secondary to invasion of the lacrimal drain-
age system.
Among paranasal sinus tumors, those occurring in the maxillary sinus
predominate. Unfortunately, these usually attain a large size before becom-
ing symptomatic. If the drainage of the sinus is impaired, concomitant si-
nusitis is likely to develop. The patient may experience pain or looseness
of the upper molar teeth with progressive tumor growth, followed later by-
distortion of the palate. Fullness over the cheek, particularly when accom-
panied by numbness over the distribution of the intraorbital nerve, strongly
suggests a maxillary sinus cancer. Since the orbit is surrounded on three
sides by paranasal sinuses (maxillary, ethmoid, and frontal), orbital symp-
toms are frequently associated with paranasal sinus cancers. The earliest
sign is simple displacement of the orbital contents away from the involved
sinus, e.g.,upward displacement by a maxillary sinus tumor and lateral dis-

placement by an ethmoid tumor. If the cancer invades the orbital contents,
proptosis, limited ocular motor function, and ultimate blindness can devel-
op. Posterior extension of maxillary sinus tumors is often manifested by
trismus as the pterygoid muscles are invaded. Likewise, posterior and su-
perior extension of ethmoid sinus cancers to the cavernous sinus result in a
number of cranial nerve dysfunctions (cranial nerves I through VI). Frontal
sinus cancers are quite uncommon, typically invading the anterior cranial
fossa before diagnosis. 24 Primary sphenoid sinus cancers, which occur least
frequently, become manifest by affecting the neurovascular structures that
surround the sinus. 25
Because of the paucity of early symptoms, cancers in the nasal fossa and
paranasal sinuses often reach advanced stages before diagnosis. Very often
both the patient and the clinician assume the problem to be an inflamma-
tory one, but when prompt resolution of the presumed infection fails to
occur, the presence of cancer must be considered. Suspicious-appearing tis-
sue in the nasal fossa can be seen through the nares, particularly with ade-
quate topical vasoconstriction of the nasal mucosa. The sinuses can usually
be assessed by radiographic examination including routine sinus views.
The radiographic signs of cancer may be difficult to differentiate from in-
flammation, but suspicion is raised by bone erosion, patchy bone sclerosis,
and a discrete soft-tissue mass, as well as enlargement of the osseous fora-
mina. The anatomic extent of the suspected tumor can be better detailed by
tomography, an important diagnostic tool if surgery is contemplated.
Diagnosis requires histologic confirmation by biopsy; tumors extending
to or arising in the nasal fossa can be readily biopsied through the nares
with topical anesthesia. Maxillary sinus puncture with lavage for cytology is
another method of diagnosis. If transnasal biopsy is not feasible or produc-
tive, it will be necessary to obtain representative tissue by direct sinusot-
omy of the involved sinus, employing various approaches such as the Cald-
well-Luc operation, external ethmoidectomy, or frontal sinusotomy.
TREATMENT
No consensus exists for the optimal treatment of cancers arising in the
nasal cavity or paranasal sinuses. The useof surgery or radiation therapy
alone has been based on the preference of the involved physician.
For cancers limited to the nasal fossa, either method can be highly suc-
cessful, with die choice based on tumor type, location and extent, and de-
anatomic preservation. 253
sire for
During the past two decades, there has been an increased emphasis on
combining both treatment modalities for carcinomas arising in the paranasal
sinuses.
Before a specific treatment plan can be selected, the anatomic extent of
the tumor must be ascertained to determine the feasibility of surgical resec-
tability or the volume of tissue to be irradiated, or both. The computed
axillary tomography (CAT) scan and polytomography have helped to pro-
cure this information. Surgery is not considered worthwhile if there is evi-

dence of extension to the anterior or middle cranial fossa or substantial
involvement of the pterygoid muscles.
The degree of histologic differentiation and the type of tumor modify the
approach to treatment. Poorly differentiated carcinomas and all lymphomas
are generally treated solely with irradiation. Adenocarcinomas, salivary
gland carcinomas, and melanomas are usually treated first by surgery when
there is a likelihood that the tumor can be completely encompassed. In
most of these instances postoperative irradiation will also be employed.
Various treatment plans are followed for epidermoid carcinomas, which
compose the majority of these cancers. Some authors favor preoperative ir-
radiation followed immediately by surgery; 26-28 although
this planned com-
bined therapy maximizes the cure rate, it unnecessarily sacrifices the sinus
or possibly the eye in instances in which irradiation has achieved a cure. At
UCLA Hospital, a modification of planned combined irradiation is often
used, consisting of surgical removal of the alveolar ridge and hard palate
beneath die involved maxillary sinus six to eight weeks after full-dose ir-
radiation. Multiple biopsies of the maxillary and ethmoid sinuses are then
examined by frozen section. If tumor is encountered, a total or extended
maxillectomy is immediately performed. In contrast, if no tumor is found,
the defect is obturated with a prepared prosthesis that is later incorporated
as part of a denture. This palatal opening can then be used for future in-
spection of the sinus cavity to determine if there are any signs of recur-
rence. If the physicians elect to observe the patient only after full-dose
irradiation, it is important to thoroughly re-evaluate this area at frequent
intervals for at least three years.
The type of surgery chosen for nasal and sinus tumors is predicated on
the anatomic extent of the tumor. For tumors occupying the nasal fossa, a
lateral rhinotomy and medial maxillectomy allowing an en bloc resection of
the septum and lateral nasal wall are often employed. 29 Tumors that are
confined to the maxillary sinus are treated by maxillectomy, which may or
may not involve the removal of the sinus roof (orbital floor). Tumors arising
in or extending to the ethmoid sinus usually require the removal of the
orbital contents. The ethmoid roof and cribriform plate can be resected if
tumor closely approximates this area. 30,31 However, tumors are usually con-
sidered inoperable if there is erosion of the pterygoid plates or CAT scan
evidence of involvement of the anterior cranial fossa, sphenoid sinus, or
cavernous sinus. In the latter instances, polytomography will demonstrate
that the cribriform plate is absent, that the crista galli is tilted, or that the
lateral wall of the sphenoid sinus and foramen rotundum is eroded.
The technique of radiation therapy varies according to the type and ex-
tent of the tumor. If it is located in the lower aspect of the maxillary sinus,
the eye can be shielded to avoid late radiation complications. If postopera-
tive radiation is employed, the treatment volume is selected after the surgi-
cal specimen has been analyzed to determine the anatomic margins that are
32
at greatest risk for recurrence.
Close cooperation with a maxillofacial prosthodontist is mandatory for
maximal rehabilitation of these patients. Indeed, all the surgically treated
patients will require some type of obturator to seal the sinus and nasal
fossa from the oral cavity. Although it will sometimes be necessary to resect
the nose or cheek, a prosthesis can be worn to fill the defect and provide
an acceptable appearance. 33
facial
The management of patients with advanced nasal and paranasal sinus
cancer is difficult. In many instances, palliation becomes the therapeutic
goal. Chemotherapy has assumed an increasingly effective role for patients
who suffer from recurrent disease, and it is also being evaluated as an ad-
junctive modality immediately following initial therapy. Recurrent disease
can also be palliated with cryotherapy or local endocavity radiation.
PROGNOSIS
The five-year survival rates for patients with tumors of the nasal fossa and
paranasal sinuses are difficult to summarize because staging is obscure, and
tumor types vary widely. Tumors arising close to the cranial fossa, e.g.,
frontal and sphenoid sinus cancers, have an unfavorable prognosis; indeed,
prolonged survival is rare. Tumors involving or extending to the ethmoid
sinus and orbit have an intermediate prognosis —
with aggressive com-
bined therapy, the five-year survival rate ranges between 30 per cent and
40 per cent. However, tumors that are confined to the nasal fossa and max-
illary sinus cavity have the best prognosis, with the five-year survival rate
ranging between 45 per cent and 55 per cent.
Section 3
Nasopharynx
TC C a lea terra G Juillard
INTRODUCTION
The incidenceof nasopharyngeal cancer varies according to race. In the
United predominantly white population, this site composes ap-
States'
proximately 0.25 per cent to 0.5 per cent of all malignant tumors. 54 The
incidence is much higher in Asian populations, particularly in parts of
southern China, where this tumor has been reported to constitute 50 per
cent of all malignancies. 33 This percentage prevails even when these peo-
ple emigrate to other parts of the world. 36 Nasopharyngeal tumors occur at
an earlier age than do most other head and neck cancers and are not un-
common in the pediatric age group. 37

The occurrence predominates in
males in with a ratio of about 2:1.
all series,
Isolated reports of nasopharyngeal cancer afflicting the same family have

suggested a genetic origin. 38 No specific carcinogens have been identified,
but increased titers of antibody to the Epstein-Barr virus have been demon-
strated in patients with nasopharyngeal cancer, suggesting a possible viral
etiology. 39
NATURAL HISTORY
Inasmuch as most nasopharyngeal tumors are not confined to a specific-

anatomic region of the nasopharynx when first diagnosed, no classification
has been established. A critical factor is whether or not there is evidence of
intracranial extension by the primary tumor. A recent TNM classification
has been proposed by the American Joint Committee for Cancer Staging
and End Results Reporting (Table 12-3).
The nasopharynx, which is part of the respiratory tract, is situated behind
the nasal fossa and below the middle cranial fossa. Its roof principally com-
poses the floor of the sphenoid sinus, and its posterior wall is formed by
the basiocciput. Most tumors of the nasopharynx are believed to arise in
Rosenmuller's fossa, which is immediately superior to the eustachian tube
orifices on the lateral walls. A rich lymphatic system freely communicates
with the lymph nodes of the parapharyngeal space and the upper cervical
region.
The nasopharyngeal mucosa serves a respiratory function, and consists of
ciliated pseudocolumnar epithelium and stratified squamous epithelium.
The carcinomas arising here are chiefly squamous (epithelial) in origin, al-
though, histologically, some may be diffusely infiltrated with lymphocytes
(lymphoepitheliomas), which should not be confused with tumors of lym-
phocytic origin. The differentiation of nasopharyngeal tumors ranges from
moderate to anaplastic. Other tumors arising in the nasopharynx include
salivary gland cancers, lymphomas, sarcomas, and melanomas.
Nasopharyngeal cancer develops insidiously. Initial nasal stuffiness and

excessive nasal mucus discharge are nearly always disregarded. Later, hali-
TABLE 12-3. TNM Classification of Nasopharynx

T, Tumor confined to one site of nasopharynx or no tumor visible
(positive biopsy findings only)
T 2 Tumor involving two sites (both posterosuperiorand lateral walls)
T, Extension of tumor into nasal cavity or oropharynx
T 4 Tumor invasion of skull or cranial nerve involvement, or both
tosis, blood-streaked mucus, and poorly localized headache signify enlarge-

ment of the tumor. Profuse epistaxis is not typical of this tumor.
Frequently, the first clinical indication of nasopharyngeal cancer may be
noted elsewhere, such as fullness in the ear and hearing loss, signifying tumor
involvement of the eustachian tube, or gradual, painless enlargement of an
upper cervical lymph node, indicating metastasis. Severe pain at the base of the
skull, diplopia, and other cranial nerve symptoms point to intracranial exten-
sion of the tumor.
Almost .50 per cent of patients have palpable cervical metastasis at the time of
diagnosis. Characteristically, the enlarged cervical node grows beneath the
upper portion of the sternocleidomastoid muscle or within the posterior cervi-
cal triangle. Although nodal involvement is usually unilateral, there is a
lificant incidence of bilateral metastasis. At times, the nasopharyngeal
tumor may not be readily visible despite repeated examinations of the na-
sopharynx. In instances when a nasopharyngeal cancer is suspected, e.g., in an
occult cervical metastasis, random biopsies of the nasopharynx should be
obtained. Any adult with unilateral serous otitis media should also undergo a
careful nasopharyngeal examination.
Nasopharyngeal cancers tend to gain access to the cranial cavity via the
foramen lacemm. The sixth cranial nerve is usually the first to be affected; the
third, fourth, and fifth cranial nerves become involved later, and there may be
proptosis of the ipsilateral eye. Horner's syndrome develops when the sympa-
thetic nerve fibers around the carotid artery become involved. Distant metas-
tases are likely to occur, particularly to the lung, liver, or bone.
Nasopharyngeal cancer can usually be diagnosed readily, using local anes-
thesia, by transnasal or transoral biopsy. Examination is greatly facilitated by a
rod telescope placed through the mouth or nose. 40 Biopsies can then be
performed under direct vision. The diagnostic work-up, including standard
x-rays or polytomography of the skull base, seeks evidence of bone erosion as
well as an enlargement of the jugular foramen or foramen ovale. If there is any
indication of intracranial extension. CAT scanning is also performed.
TREATMENT
Irradiation to include the nasopharyngeal primary tumor, the retropharyn-
geal lymph nodes, and the bilateral cervical lymph nodes is the treatment of
choice. 41 The treatment include the entire nasopharynx, the posterior
fields
nasal cavity, the posterior ethmoid sinus, the sphenoid sinus, the basiocciput,
the cavernous sinus, and the pterygoid fossa. Dosages to the primary site and
cervical metastases max reach 6500 to 7000 rad in 6.5 to 8 weeks, whereas 4500
to 5000 rad in 5 weeks may be employed for subclinical cervical metastases. If a
palpable mass in the neck persists for two or three months after irradiation with
no evidence of tumor in the nasopharynx, a radical neck dissection may be
indicated. Adjunctive chemotherapy and immunotherapy are experimental.
Recurrent or residual disease is difficult to manage. 42 A second course of
irradiation has been successfully delivered when an interval of several years
had elapsed since the initial radiotherapy. Limited success has been achieved
with cryotherapy and radium packs by fenestrating the palate, hut this method
involves palatal obturation by a dental prosthesis.
Sequelae of Treatment
Because a large volume of normal tissue is irradiated to a high dose, sequelae

are frequent and may result in serious, persistent morbidity. Mucosal dryness
of varying severity follows irradiation of the parotid gland. Dental problems,
related to xerostomia or direct irradiation of the teeth and supporting bone, or
both, may develop. Hearing loss and otitis media may follow changes in the
auditory tube. Infrequent trismus is due to changes in the pterygoid muscles.
The epithelial lining of the external ear canals may become fragile and
susceptible to infection. Irradiation of parts of the hypothalamus and temporal
lobes of the brain and the pituitary gland rarely produces clinically detectable
sequelae. However, radiation myelopathy of the cervical spinal cord and brain
stem has been reported.
PROGNOSIS
The prognosis of nasopharyngeal cancer determined by the extent of the
is
primary lesion, the presence of metastases, and the tumor histology. Tumors
with intracranial extension and skull erosion have the worst prognosis; the
five-year survival rate is generally less than 15 per cent. Cervical metastasis,
which is frequent with this cancer, also reduces the prognosis.
Section 4
Tumors of the Salivary

Glands
TC Calcaterra
INTRODUCTION
Nests of salivary gland cells are normally found throughout the entire upper
aerodigestive tract, making it possible for salivary gland tumors to arise any-
where in this anatomic area. The incidence of these tumors is low, representing
less than 3 per cent of all human tumors; the overall incidence in the general
population is about 1.5 per 100,000. 43
In comparing several large series, no sexual predilection can be consistently

identified, except for eases ofWarthin's tumor, which develops about five times
more frequently in men. As a general rule, benign salivary gland tumors occur
in younger patients, whereas those patients afflicted by malignant tumors are
older.
NATURAL HISTORY
Salivary gland tumors are composed of a complex array of tumor types,

varying ingrowth behavior from indolent to aggressive. Manx of the tumors are
difficult to classify into specificsubgroups, and some overlap histologically.
Acceptable classifications of salivary gland tumors are based on the specific
salivary gland cell that is presumed to have given origin to the neoplasm. The
44
prototype of a salivary gland unit consists of serous or mucous acini that drain to
a duct that is divided sequentially into three different portions lined by
morphologically different epithelial cells, which are termed intercalated,
striated, and excretory. Myoepithelial cells are located around the periphery of
the acini and the intercalated portion of the duct, functioning as contractile
cells to force secretions from the acini and intercalated portion of the duct. The
intercalated cells are undifferentiated, whereas the striated duct cells are well
differentiated.
Using these cell types as progenitors of salivary gland neoplasms, one
hypothesis currently favored is that the excretory duct cells give rise to the
squamous cell and mucoepidermoid carcinomas. 44 The striated duct cells
produce oncocytic tumors, and the intercalated duct cells generate adenocystic
carcinomas. The acinar cells give rise to the acinic cell carcinomas, mixed
tumors, and monomorphic adenomas. Another hypothetic possibility, which is
not based on a dedifferentiation of already highly specialized cells such as the
acinar and striated duct cells, is the "bicellular theory of origin," which
postulates that all neoplasms arise from two undifferentiated cell
salivary gland
types, the excretory duct cell and the intercalated duct cell. 45
Salivary gland tumors, which are also classified by anatomic site of origin, are
divided into two groups —
those of major salivary gland origin and those from
the minor salivary glands. The major salivary glands are the parotid, subman-
dibular, and sublingual; the minor salivary glands are distributed as small nests
throughout the upper aerodigestive tract. About 75 per cent of salivary gland
tumors occur in the parotid gland, 10 per cent occur in the submandibular
gland, and 1 per cent occur in the sublingual gland. The remainder develop in
the minor glands, the most common site being the palate. 46
The relative incidence of malignant tumors increases as the size of the
originating salivary gland decreases; i.e.. the frequency of malignancy in
parotid gland tumors is about 20 per cent, in submandibular gland tumors it is
about 40 per cent to 50 per cent and in lesser salivary gland tumors, the fre-
quency is about 50 per cent to 60 per cent. Fortunately, more than 75 per cent
of these tumors arise in the parotid gland, therein' accounting for the fact that
the majority of all salivary gland tumors are benign.
Diagnosis
The typical presenting complaint of patients with salivary tumors is a

painless mass of variable duration. Although tumors can appear in any portion
of the parotid gland, they usually occur in the posterior half. The lump is often
considered to be an enlarged lymph node, and therefore antibiotic therapy is
generally started. If unattended, salivary gland tumors, particularly the benign
ones, can reach substantial proportions before causing difficulties.
Although partial or complete facial paralysis has been reported in benign
tumors, this feature almost always heralds a malignancy. 47 Other features that
are suggestive of malignancy are hardness and fixation of the tumor to underly-
ing bone or overlying skin. Although pain is not highly diagnostic of malignan-
cy, it raises suspicion because of possible sensory nerve involvement. Cervical
lymph node enlargement suggests malignancy because of the likelihood of
regional node metastasis. However, regional node metastasis is uncommon in
most parotid gland malignancies, and when it does occur, it is usually late in the
course of the disease. The presence of facial paralysis as well as regional node
metastasis portends a very unfavorable prognosis despite aggressive thera-
py-
All patients who are found to have a mass in the region of the major salivary
glands warrant a thorough head and neck examination. When masses occur in
the region of the parotid gland, the scalp should be carefully inspected for skin
lesions, such asmelanoma, because this type of tumor tends to metastasize first
to the paraparotid lymph nodes. The posterior and lateral pharyngeal walls
should be inspected and palpated, since the retropharyngeal space may harbor
a primary tumor presenting laterally in the parotid gland area, mimicking a
parotid gland tumor. Conversely, tumors of the deep lobe of the parotid gland
may extend medially, appearing as a pharyngeal mass. If the mass is located in
the region of the submandibular gland, particular attention should be directed
toward the oral cavity, inasmuch as this area may be the site of a primary cancer
that has metastasized. The submandibular gland duct must be carefully palpat-
ed bimanually to determine the presence of stones. The fixation of the tumor to
the mandible should be assessed, and a determination of the integrity of the
lingular and hypoglossal nerve function must be made.
The role of sialography in the preoperative diagnosis of salivary gland tumors
may be important. 48 In this x-ray study, contrast material is injected into the
ductal system of the parotid or submandibular glands, providing a visual
outline of the ductal architecture. Results of the study often enable the clinician
to determine whether a mass is intrinsic or extrinsic in the region of the parotid
gland or submandibular gland; the latter finding would suggest the presence of
tumor. Moreover, the sialogram may show evidence of malignancy, e.g., abrupt
displacement or incomplete filling of the ducts or puddling or diffusion of the
contrast material into the parenchyma. The appearance of stones or ectasia of
the ductal system suggests inflammatory disease. Sometimes it is necessary to
obtain x-rays of the mandible to determine any osseous erosion.
TABLE 12-4. Primary Tumor (T) Classification of Salivary Gland Carcinomas 4

T No evidence for primary tumor
T, Tumor to 2 cm in diameter, solitary, freely mobile, facial nerve
intact
T, Tumor 2 to 4 cm in diameter, solitary, freely mobile or reduced
mobility or skin fixation, and facial nerve intact"
T3 Tumor 4 to 6 cm in diameter, or multiple nodes, skin ulceration,
deep fixation, or facial nerve dysfunction
T 4
Tumor >6 cm in diameter or involving mandible and adjacent
bone, or both
"Criteria related to facial nerve apply only to parotid gland tumors.
The definitive diagnosisusually accomplished by surgical excision; the

is
complete excision of the tumor with an ample margin of normal salivary gland
tissue also becomes part of the treatment. The surgeon may wish to identify the
tumor type by frozen section examination, or interpretation may await perma-
nent sections. Either method of tumor diagnosis may dictate more surgical
therapy than excisional biopsy. On occasion, needle biopsy may be considered
if the patient is severely ill, if the tumor is unresectable, or if the clinician
strongly suspects a metastatic tumor or lymphoma. As with all needle biopsies,

the specimen is difficult to interpret, and there is a risk of false-negative inter-
pretation.
A staging system for salivary gland tumors has been proposed but not widely
adopted. 4 Nevertheless, it is presented in Table 12-4 for reference pur-
poses.
CLINICAL FEATURES
Benign Tumors
Mixed Tumor (Pleomorphic Adenoma). This most common saliv ary

gland t umor, constituting at least 75 per cent of all benign tumors, is ehar at*~
terized by slow growth, and it usually appears in the superficial lobe of the
parotid gland. The tumor may remain quiescent for several months or years
and then undergo a period of slow growth. Pain is not a frequent symptom,
although a vague pressure sensation may be experienced.
On examination, the mixed tumor is usually solitary, well circumscribed,
sometimes lobulated, and usually mobile. Gross examination shows an encap-
sulated and multilobulated tumor of variable size. Close inspection of the
external surface frequently reveals small excrescences jutting out from the
capsule. On cut section, the tumor surface is variable, depending on the
cellularmake-up.
Although the microscopic appearance is diverse, both epithelial and mes-
enchymal elements must be present for diagnosis. The mesenchymal element
may consist of myxoid, fibroid, or chondroid cellular structures that make up
the stroma. The ratio of epithelial cells to mesenchymal stroma may vary
considerably and probably does not influence the prognosis. 49
Mixed tumors are best treated by wide surgical excision. When treated by
simple enucleation, the recurrence rate has risen as high as 50 percent. Today,
the favored treatment for mixed tumors of the parotid gland is superficial
lobectomy. Although there is no anatomic division of the parotid gland into
lobes, this operation is designed to remove all the parotid gland tissue lateral to
the facial nerve. This constitutes the majority of the gland and the most likely
site for these tumors. The operation requires exposure and careful dissection of
the facial nerve and usually affords ample margins of normal parotid gland
tissue around the tumor. This approach prevents any tumor spillage and
completely encompasses the excrescences or pseudopods that may be on the
outer limits of the tumor.
The same principle applies to the surgical management of mixed tumors that
are located in the deep lobe of the parotid gland or submandibular gland.
Again, a cuff of normal tissue is preserved around the tumor capsule, the only
exception being when the tumor lies directly adjacent to a vital structure, such
as the facial nerve. In such circumstances, it is reasonable to dissect the tumor
carefully from the perineurium. The use of these surgical techniques should
keep the recurrence rate below 2 percent; however, in the event of recurrence
repeated surgical excision is often successful. The sacrifice of the facial nerve
should be considered only if there is evidence of intracranial extension.
Radiation therapy has had limited effectiveness when treating recurrent
tumor. 50
Warthin's Tumor (Papillary Cystadenoma Lymphomatosum). War-
thin's tumor is a lmost exclusively confined to the parotid gland. rfpr^^ nHn ^
between 5 per c ent and 10 per cent of all p arotid gland tumors. Almost without
exception, it is b enign and unlikely to recur atter adequate r emoval. This tumor
develops times more frequently in males than in iemales7 usually in
at least five
the fifth or sixth decade of life. It has the highest incidence of bilateral
occurrence of all salivary gland tumors (in the range of 5 per cent to 10 per
cent).
Warthin's tumor is unique in that it characteristically arises in the inferior
pole of the parotid gland and occasionally originates in the lymph nodes
adjacent to that part of the gland. The genesis of this tumor remains controver-
sial; indeed, in the opinion of some authors it is not a true tumor but is similar to
an autoimmune disorder such as Hashimoto's thyroiditis. 51 The most common-

ly accepted theory is that it arises from heterotopic salivary duct tissue in
paraparotid lymphoid tissue. 52 The tumor is usually soft or even cystic to
palpation, ranging in size from 1 to 6 cm. It tends to be unilocular, encapsulat-
ed, and filled with gray or tan fluid. Microscopically, there is a characteristic-
appearance of intracystic papillary fronds lined by a double layer of cells, an
inner layer of cuboidal darkly staining cells, and an outer layer of tall, co-
lumnar, nonciliated cells.
The tumor is best treated surgically by wide excision, usually requiring
exposure of the facial nerve, and resection of that portion of the superficial lobe
that harbors the tumor. The tumor does not shell out well, and there is always
the risk of spillage and implantation of tumor cells if this approach is attempted.
In the aged or severely ill patient, needle biopsy and observation are reason-
able measures, since this type of tumor grows slowly, and there is essentially no
risk of metastasis.
MONOMORPHIC ADENOMAS. A number of other benign tumors of the sali-

vary glands are generally classified together under the term monomorphic
adenomas, representing 2 per cent or 3 per cent of all salivary gland neo-
plasms. Included in this group are the oncocytomas, consisting of large poly-
gonal eosinophilic cells with granular cytoplasm. Some authors believe that
these lesions may simply represent aggregate hyperplasia of mature cells,
inasmuch as they may be multicentric. 53 Oncocytomas are solid and encapsu-
lated, and they tend to grow slowly. Recurrence is uncommon, and malignant
degeneration is rare.
Other types of monomorphic adenomas have been described that are charac-
terized by a uniform epithelial pattern throughout the tumor without a myx-
omatous stroma that distinguishes them from mixed tumors. They are generally
found among an older age group and follow a benign course. The basal cell
adenoma, the sebaceous adenoma, and the clear cell adenoma are included in
this category. The basal cell adenoma consists of uniform strands or islands of
spindle cells resembling a basal cell carcinoma of the skin. The most difficult
aspect of the diagnosis is to differentiate them from adenoid cystic carcinomas.
Sebaceous adenomas arc composed of lipid-containing cells that are believed
to represent ectopic sebaceous glands in a matrix of lymphoid tissue, not unlike
Warthin's tumor. The clear cell adenoma, which is a rare tumor, consists of
glycogen-rich cells resembling those of its counterpart commonly seen in the
kidney.
Malignant Tumors
Mucoepidermoid TUMOR Mucoepidermoid tumors com-

are the most
mon malignant tumors of the parotid gland, composing annrovimatelv one
th ird of all the salivary gland malignancies 14 M The second most common site
." -
for this tumor is the palate. Although these tumors may develop in patients of
any age, the peak incidence is in the fifth decade. The clinical presentation
varies according to the histologic grade of the tumor, which may range from
well differentiated (low grade) to poorly differentiated (high grade), and the
symptoms range from a slow-growing painless lump to a rapidly expanding
mass that causes trismus and facial paralysis. These variations in differentia-
tion and clinical behavior led to the opinion that the better-differentiated
tumors are benign; however, there have been enough accounts of differenti-
ated tumors infiltrating locally and metastasizing that all grades of this tumor
must be considered in the malignant category.
The tumors are usually circumscribed but poorly encapsulated and thus may
adhere to surrounding structures. Nl icroscopicalK the tumor includes both
,
squamous cells and mucin-secreting cells that are belie ved to arise from the*-'
cmTlal epithelium. In ihe well-differentiated tumor, multiple cystic spaces are
filled with mucin lined by attenuated squamous cells and mucin-secreting
goblet cells. The poorly differentiated tumors mainly show squamous elements
without discrete cyst formation and with only a few acinar or mucinous
cells.
Not surprisingly, the prognosis varies according to the histologic differentia-
tion. The recurrence rate in patients with a well-differentiated tumor is as low
as 10 per cent to 15 per cent, whereas that for poorly differentiated tumors is
about 75 per cent. Initially, the treatment is almost invariably surgical, attempt-
ing to resect the tumor with a wide margin of normal tissue. A radical neck
dissection is considered important by some clinicians for poorly differentiated
tumors, particularly when these tumors arise in the submandibular gland.
Adenoid Cystic Carcinoma. This tumor composes about 4 per cent to 8
per cent of salivary gland tumors, occurring far more frequently in the minor
salivar y glands, and it has been reported in virtually even' part of the upper
aerodigestive tract. 56- 8 Like other salivary gland tumors, it initially presents
"'
as an asymptomatic mass, but b ecause of its proclivity to invo ke nerves, the

symptoms o f pain and numbness frequently follow. I t is typically slow growing,
and survival can be protracted despite the presence of tumor. Distant metas-
tases, particularly to the lung, may be noted many years after the primary tumor
is discovered and are seen more commonly than regional lymph node metasta-
ses.
Adenoid cystic carcinomas vary considerably in size, tending to
be poorly
encapsulated and often exhibiting infiltrative growth into adjacent soft tissue
and bone. The microscopic features of this neoplasm are characteristic in that
the cells are uniform in size with darkly stained nuclei arranged in solid cords
or in a trabecular pattern. The tendency for this tumor to invade along peri-
neural spaces is well known; such perineural extension can sometimes be
noted by concentric enlargement of the osseous foramina of the skull, usually
indicating its unresectability. 59
The overall prognosis for this tumor is unfavorable, although this may not be
reflected in the survival rate at five years. In most series the survival rate shows
a progressive decrease after five years, with some diminishing to only 12 per
cent after 15 years. 56
The analysis of successfully managed patients seems to support aggressive
therapy at the discovery of the tumor, consisting of wide surgical excision that
may necessitate the sacrifice of all or part of the facial nerve, as well as resection
of part of the mandible, temporal bone, or maxilla. Postoperative irradiation
may be useful, particularly when the surgical margins are not ample. 60
Acinic Cell Tumor. This tumor represents 1 per cent to 2 per cent of all
salivary gland tumors and about 10 per cent of the parotid gland malignancies.
It was originally considered to be benign, but long-term series have shown that
there is a 25 per cent incidence of local recurrence and a 10 per cent incidence
62
of distant metastasis. 61,
This tumor characterized by gradual, painless growth, and is often present
is
for several years before receiving medical attention. It typically develops as an

isolated mass in the superficial lobe of the parotid gland. The histologic
configuration appears benign, inasmuch as the predominant granular cells
show minimal pleomorphism. The cell cytoplasm ranges from darkly ba-
sophilic granules to almost clear cells.
Like other slow growing salivary gland malignancies, the five-year survival
rate is about 90 per cent, but continues to diminish significantly with increasing
years. Superficial parotidectomy — totally excising the portion of the parotid
gland that contains the tumor — is the preferred treatment for this entity.
Malignant xMixed Tumor (Carcinoma Arising in Pleomorphic Ade-
noma). Most authorities agree that this type of carcinoma arises from a be-
nign mixed tumor, an opinion based on numerous examples of apparent tran-
63,64
sition to a malignancy within the tumor. It is the epithelial element alone
that undergoes this transition. Clinically, this opinion is supported by the fre-
quent history of suddenly accelerated growth of a dormant mass that had ex-
isted for several years. Likewise, a mixed tumor may have been removed
several years earlier, followed by a rapidly growing recurrence showing a
malignant histology quite different from the original tumor. It has been esti-
mated that between 2 per cent and 5 per cent of all mixed tumors will undergo
this transition, generally in the parotid gland, in which it represents about 7
per cent of the malignancies.
The prognosis is less favorable in the first five years than that for most salivary
gland malignancies; the five-year survival rate is about 50 percent. Metastasis
will occur in about half of patients, frequently to distant sites such as the lung
and the central nervous system.
Miscellaneous Primary Carcinomas. A number of other malignancies
of the salivary gland are seen infrequently, but they seem to have distinguish-
able characteristics that enable separate classification. Most are clinically ma-
lignant, demonstrating rapid growth, frequent recurrence, a nd ultimate death
of the patient. Included inlhis group of tumors are epidermoid carcinoma ,
ll]^)iff<M-f'n f of "^ <-"iiyir.rm-.-i

' ini-1 -irl^n^ M ICJUOma.
These tumors tend to occur in older patients, and rapid growth, harchu
fixation to skin, pain, and facial paralysis indicate malignancy. Grossly, the)
often infiltrate the salivary gland tissue and adjacent structures, even replacing
the entire gland. Thus, the invasion of lymphatics and blood vessels is often
apparent microscopically.
The prognosis for these tumors is bleak; regardless of the type of therapy
employed, the five-year survival rate will be about 25 percent. The prognosis is
even poorer with anaplastic tumors.
TREATMENT
The
successful treatment of salivary gland tumors requires especially close
multidisciplinary communication among the surgeon, the pathologist, and the
radiotherapist. Only during the last two decades has the biologic aggressive-
ness of each type of salivary gland tumor been characterized, thereby enabling
the development of a rational treatment plan for the various kinds of
tumors.
The initial treatment for all primary salivary gland neoplasms is surgical,
employing wide excision whenever possible. In most instances, the extent of
surgical resection is dictated by the tumor type. The various surgical options
must be agreed upon with the patient in advance, so that the surgeon will not be
limited by lack of consent to perform an appropriate operation.
The first step in surgical therapy is careful exposure of the salivary- gland
harboring the tumor. This is followed by wide excision of the tumor mass,
sparing any vital structure adjacent to the tumor unless it has been clearly
infiltrated. Frozen section examination is then carried out to determine the
tumor type. the pathologist is certain that the tumor is benign or of low -grade
If"
malignancy, the excisional biopsy will suffice as adequate therapy. However, if

it proves to be of a higher grade malignancy, it will undoubtedly be necessary to
resect a broader margin of the adjacent tissue.

When dealing with parotid gland malignancies, the reseetion may involve
sacrificing the entire facial nerve, the ascending ramus of the mandible, and
even the temporal bone to provide ample margins around the tumor. Likewise,
if there is possible involvement of the skin, a wide excision should be done and
the defect resurfaced with an advancement neck-chest flap. The upper cervical
node should be routinely examined, and if frozen section reveals malignancy, a
radical neck dissection should be performed. Prophylactic neck dissections are
not routinely performed for most parotid gland malignancies because of the low
frequency of regional metastasis; however, they are frequently a part of a
submandibular gland malignancy resection because of a higher incidence of
associated nodal metastasis.
When the facial nerve or one of its segments has been sacrificed, it has proved
worthwhile to replace the nerve with a sensory nerve, which provides a conduit
for subsequent motor fiber regeneration and achieves satisfactory- facial func-
tion in approximately 9 to 12 months. If the orbital muscles are paralyzed, the
cornea must be preserved by such measures as the frequent instillation of
wetting solutions, eyelid taping, and protective eye coverings.
The role of irradiation remains somewhat uncertain. Certainly it can provide
effective palliation for the patient who has an unresectable tumor or metastasis
to a salivary gland, but, more importantly, there is growing evidence that many
of the malignant tumors can be eradicated if the tumor mass is grossly removed
or at least reduced. 50 In our institution, postoperative tumoricidal irradiation is
advised if there is concern about the adequacy of a surgical margin or if the
tumor is poorly differentiated.
Section 5
Cancer of the Larynx and

Hypopharynx
TC Calcaterra G Juillard
INTRODUCTION
Laryngopharyngeal cancer composes about 2 per cent to 3 per cent of all
cancers diagnosed annually in the United States. The National Cancer Insti-
18
tute has estimated that each year there are about 9500 new cases of laryngeal
cancer, resulting in 3200 deaths. Shumrick65 reported an increasing incidence
that appears to be centered in the industrialized areas of the world.
The onset of laryngeal cancer is highest between the ages of 60 and 65. The »
age-adjusted incidence of laryngeal cancer is approximately 8.1 per 100,000 for

males and 0.9 per 100,000 for females, 18 with no significant differences be-
tween whites and blacks. This higher incidence in males is the case in all areas
of the laryngopharynx, except for the postcricoid region, where there is an
almost total reversal of rates, with females predominating.
No statistically conclusive studies have clearly implicated a specific causal
agent in laryngeal cancer, although the U. S. Surgeon Generals Report on
Smoking and Health showed a strong correlation between heavy smoking and
laryngeal cancer. Certainly, dysplastic changes in the laryngeal epithelium can
be demonstrated in almost all heavy smokers, and the degree of these histologic
66
changes seems to develop in proportion with exposure to tobacco smoke.
Excessive alcohol intake is also frequently associated with laryngeal cancer
and seems to lead to cancers of the supraglottic larynx and hypopharynx. 67
H\ perkeratotic lesions of the vocal cords, such as leukoplakia, are consid-
ered premalignant, and it has been estimated that about 5 per cent of patients
with these lesions will develop an invasive carcinoma. Such lesions are found
in patients who abuse the larynx by excessive, loud talking. The atrophic and
chronic inflammatory changes of the pharyngeal mucous membranes observed
in the Plummer-Vinson syndrome have been associated with cancer in the
postericoid region of the pharynx.
Recent data indicate a correlation between laryngeal cancer and the herpes
virus (HSV). In one series, 95 per cent of laryngeal cancer patients showed
evidence of serum antibodies to HSY-determined proteins, whereas in a
comparable control group only 5 per cent of individuals were seroposi-
68
tive.
548 II / Treatment of Sp» ii i< Neoplasms
NATURAL HISTORY
Anatomic Classification
Cancers of the larynx and hypopharynx are classified according to anatomic-

sites or compartments that relate to the tumors' biologic behavior and progno-
sis. Anatomically, the larynx can be divided into three regions: supraglottic,
glottic, and subglottic (Fig. 12-1). The supraglottis is composed of the lingual
and laryngeal surfaces of the epiglottis, false vocal cords, arytenoid cartilages,
aryepiglottic folds, and ventricle. The glottis includes the true vocal cords,
extending to the inferior limit of the vocalis muscle, which is about 5 mm below
the free margin of the cord, and including the anterior and posterior commis-
sures. The subglottis is the region extending from the lower boundary of the
glottis to the lower margin of the cricoid cartilage.
The hypopharynx extends from a transverse plane through the hyoid bone
corresponding to the pharyngoepiglottic folds to a transverse plane through the
lower border of the cricoid cartilage. It is arbitrarily subdivided into three
areas: the pyriform fossa, the posterior pharyngeal wall, and the retrocricoid re-
gion.
I Supraglottic
*
port
FIGURE 12-1. Schematic illus-

Glottic tration of the three divisions of
port the larynx used for classification
of laryngeal cancer.
Subglottic
port
% r
Pathology
Squamous carcinoma is found in more than 95 per cent of all laryngeal

cell
and hypopharyngeal cancers. Tumors arising from the vocal cords and intrinsic
portions of the larynx tend to be the most differentiated, whereas those
occurring in the hypopharynx are less differentiated. In general, the better-
differentiated cancers are likely to be exophytic with well-defined margins,
whereas those that are poorly differentiated are usually ulcerative and indis-
tinctly circumscribed, with a proclivity for submucosal extension.
Carcinoma in situ characteristically arises from the epithelium of the vocal
cords and is usually accompanied by adjacent areas of hyperkeratosis with
dysplastic changes. Moreover, carcinoma in situ may be grossly indistinguish-
able from the hyperkeratotie lesions appearing as whitish or grey patches on
the vocal cords. Verrucous carcinomas arc warty exophytic lesions, appearing
microscopically like hyperkeratosis with deep rete pegs; however, they invade
the local tissues with continual slow growth and may expand enough to destroy
underlying cartilage.
Sarcomas and adenocarcinomas compose the remainder of the primary
tumors of the larynx. The sarcomas include fibrosarcoma, chondrosarcoma,
rhabdomyosarcoma, and hemangiosarcoma. Occasionally, a squamous cell
carcinoma will have similar microscopic features, and this is called a sarcoma,
spindle-cell carcinoma, or pseudosarcoma. The adenocarcinomas arc generally
presumed to originate in the salivary gland and include such tumors as
adenocystic and mucoepidermoid carcinoma.
Regional cervical metastasis relates to the anatomic site of the tumor and its
differentiation. Highly differentiated tumors, such as verrucous cancer, will
never show metastasis. As the differentiation of the tumor decreases, the rate of
metastasis increases. Tumors of the endolarynx have a much lower rate of
metastasis than those occurring in the hypopharynx. Cancers that are confined
to the glottis have a very low metastatic rate, whereas the rate of metastasis in
the inferior hypopharyngeal cancers may reach 80 per cent. There may be a
long interval between recognition of the primary tumor in the larynx and
pharynx and the recognition of metastasis. The most frequent sites for distant
metastasis are the mediastinum and the lung, with the liver, bone, and brain
being afflicted less often.
Symptoms
Hoarseness is the foremost symptom of laryngeal cancer. The degree of

hoarseness depends on the amount of interference with vocal cord function.
Since the quality of the voice can be affected by small irregularities of the vocal
cord margin, glottic cancers become symptomatic very early. The more distant
the tumor is from the vocal cords, the larger it will grow before it becomes
symptomatic. Supraglottic cancers may cause hoarseness by fixation of the
arytenoid cartilages, but typically the voice remains remarkably clear. Because
invasion of the recurrent nerve paralyzes the vocal cords, infraglottic tumors
tend to produce hoarseness. Characteristically, dyspnea and stridor are later
550 II / Treatment of Spe< hk Neoplasms
symptoms of glottic and infraglottic tumors. These airwa) obstructions are

caused by the sheer bulk of the tumor, which blocks the airway lumen, and are
usually associated with the fixation of one or both vocal cords.
Pain is more characteristic of hypopharx ngeal and supraglottic cancers
because of their tendencies to ulcerative growth patterns. Often the patient first
feels pain in the ear on the side of the tumor. This referred pain arc is
transmitted by the vagus nerve, which has a sensory branch to the tympanic
membrane as well as a sensory distribution to the hypopharynx and supraglot-
tic portion of the larynx. The intensity of the pain may range from a slight
irritation to severe lancinating pain on swallowing.
Dysphagia may stem from the simple mechanical interference of food transit
due to lesions in the postcricoid region or inferior hypopharynx. Generally,
however, difficulty in swallowing is related to mild aspiration, since the
sphincteric actions of the larynx during swallowing are compromised by the
tumor. Significant hemoptysis is uncommon with such tumors, although saliva
may be streaked with blood, particularly in cases of large ulcerative tumors.
The occurrence of an asymptomatic metastatic neck mass is typical of a
pyriform sinus cancer. As with all neck masses of possible metastatic etiology, it
is imperative, whenever possible, to identify the primary cancer and incor-
porate it into die initial treatment plan.
Physical Examination
The inspection and palpation of the larynx are highly important measures,
inasmuch tenderness of the laryngeal cartilage suggests
as irregularity or
cartilage invasion or possible perichondritis. The larynx normally produces a
crepitus on lateral motion across the cervical spine. The absence of this
crepitus suggests a tumor near the cricoid cartilage or metastatic involvement
of the retropharyngeal lymph nodes. Complete palpation of the neck should be
carried out to determine the presence of metastatic adenopathy. Laryngeal and
hypopharyngeal metastases can occur in the anterior cervical triangle opposite
the hyoid bone. Another group of nodes that may be involved, particularly for
intrinsic laryngeal tumors, are those located over the cricothyroid membrane
and anterior trachea.
The examination of the endolarynx is accomplished indirectly with a mirror.
The visible hypopharynx, the base of the tongue, and the larynx are scanned
systematically, with attention directed toward the mobility of the vocal cords,
the visible portion of the subglottic space, the symmetry of the arytenoid
cartilages, and the cricopharyngeal inlet. To permit adequate examination in a
patient with a hyperactive gag response, a local anesthetic spray, such as 2 per
cent lidocaine, may be necessary. Inspection of the larynx, particularly the
region of the anterior commissure, may be facilitated by using a narrow rod lens
system that can be adapted for still and motion photography. 69
Prior to biopsy of a laryngeal or hypopharyngeal lesion, it is often advisable to
perform contrast laryngography. 70 This will provide a permanent record of the
extent of the tumor, which pertinent information for use in the radiation
is
therapy plan. Moreover, contrast laryngography often precisely identifies the

extent of the tumor in certain parts of the larynx and hypopharynx, e.g., the
ventricle, subglottic space, and inferior aspect of the pyrifomi fossa. Inasmuch
as thisis a d> namic study, the mobility of the vocal cords, epiglottis, and
pharyngeal walls can be assessed. The procedures consist of spraying aqueous

propyliodone (Dionosil) into the larynx and hypopharynx after applying topical
anesthesia and injecting atropine intramuscularly. While under fluoroscopy,
the patient is instructed to perform several phonatory maneuvers that cause
distension of the pharynx, abduction and adduction of the glottis, distension of
the ventricle, and so forth. This permits a dynamic study of tumor extent in the
larynx and pharynx — information that is crucial in treatment planning.
X-ray, laminography, and xeroradiography are other means of radiographical-
ly examining the larynx. Laminography is helpful in assessing subglottic
extension of a tumor, particularly in a patient with a compromised airway that
would make contrast laryngography hazardous. Xeroradiography is valuable
in detecting osseous and cartilaginous erosion. Direct laryngoscopy is usually
employed to obtain tissue for diagnosis and then corroborate the findings by
indirect and radiographic studies. This examination may be performed with
either local or general anesthesia. Local anesthesia is accomplished by the
topical application of 4 per cent cocaine to the base of the tongue, pyriform
fossa, and laryngeal vestibule. This is usually supplemented by regional
blockade of the glossopharyngeal and superior laryngeal nerves by directly
injecting 2 per cent lidocaine. 71 General anesthesia is used whenever max-
imum relaxation of the laryngeal muscles is required, such as when vocal cord
stripping or other endoscopic procedures are indicated, e.g., esophagoscopy.
When using general anesthesia, a small endotracheal tube (5.5 to 6.5 Fr) is
placed in the posteriorcommissure for ventilation. The narrowness and flexi-

bility of the tube permit a thorough examination of the entire aerodigestive
tract.
Microscopic examination of biopsy tissue is mandatory before undertaking
any therapeutic measures because main lesions of the larynx and pharynx can
simulate cancer. Granulomatous infections of the larynx, such as tuberculosis,
coccidioidomycosis, and blastomycosis, resemble cancer, although these infec-
tions have a predilection to involve the posterior commissure. Whenever an
infection is suspected, die biopsy tissue should be submitted for culture and
special staining, as well as for routine staining. Papillomas may be solitary and
begin de novo in die adult; however, because of their characteristic microscop-
ic appearance, they are rarely difficult to differentiate from cancer. Chronic
traumatic lesions of the vocal cords, such as contact ulcers, vocal nodules, and
polyps, should be biopsied, particularly if the lesion does not respond to voice
rest and if the patient is a smoker.
Biopsies should be generous and should include the submucosa. A small
superficial biopsy of an exophytic well-differentiated cancer is insufficient for
diagnosis by the pathologist. Indeed, in order to determine histologic invasion,
penetration through the basement membrane must be seen. Sometimes this is
not evident despite numerous deep biopsies of a verrucous carcinoma, and the
diagnosis must be made on the basis of the tumor's gross appearance and
growth pattern.
Detecting residual cancer in the irradiated larynx and pharynx can be
inasmuch as only small nests of tumor may remain after irradiation.

difficult,
The possibility of this situation increases when there is persistent asymmetri-
cal edema or ulceration several months after irradiation. 72 In many instances
multiple sequential biopsies will be necessary to document the presence of
residual cancer. Sometimes the postirradiation course will be indicative of
persistent tumor even if biopsy confirmation is lacking.
Staging
Classification of the primary tumor by the TNM

system is given in Table
12-5 for laryngeal carcinomas and in Table 12-6 for hypopharyngeal carcino-
mas. Classification of the node (N) and metastasis (M) status and the stage
groupings recommended by American Joint Committee for Cancer for Staging
and End-Results Reporting are as given earlier in Table 12-1. 4
TREATMENT
The treatment of carcinoma of the larynx and pharynx has long been con-
troversial, but there is little doubt that radiation therapy and surgery must be
closely integrated. Irradiation may be employed as a primary curative modali-
TABLE 12-5. T Classification of Laryngeal Carcinomas 4
Primary Tumor (T)

Supraglottis
T, Tumor confined to region of origin with normal mobility
T 2 Tumor involves adjacent supraglottic site(s) or glottis without fixation
T :,
Tumor limited to larynx with fixation or extension, or both, to involve postcricoid area,
medial wall of pyriform sinus, or pre-epiglortic space
T, Massive tumor extending beyond the larynx to involve oropharynx, soft tissues of neck,
or destruction of thyroid cartilage
Glottis
T Tumor confined to vocal cord(s) with normal mobility (includes involvement of anterior
or posterior commissures)
T 2 Supraglottic or subglottic extension, or both, of tumor with normal or impaired cord
mobility
T :!
Tumor confined to the larynx with cord fixation
T 4 Massive tumor with thyroid cartilage destruction or extension, or both, beyond the con-
fines of the larynx
Subglottis
T, Tumor confined to the subglottic region
T2 Tumor extension to vocal cords with normal or impaired cord mobility
Tj Tumor confined to larynx with cord fixation
T 4 Massive tumor with cartilage destruction or extension, or both, beyond the confines of
the larynx
TABLE 12-6. T Classification of Hypopharyngeal Carcinomas 4

T, Tumor confined to the site of origin
T, Extension of tumor to adjacent region or site without fixation of hemilarynx
T, Extension of tumor to adjacent region or site with fixation of hemilarynx
T 4 Massive tumor invading bone or soft tissues of neck
ty, as a planned part of combined therapy before or after surgery, or for

palliation. Surgery may also be used to achieve any of these three therapeutic
goals. Although the role of chemotherapy has yet to be completely defined,
recent clinical studies are beginning to show that this modality may be
extremely valuable in eradicating the subclinical tumor population that may
exist after conventional therapy with surgery or irradiation, or both.
The specific type of therapy selected must include several considerations
that are best evaluated in concert by a surgeon, a radiation therapist, and a
chemotherapist. These considerations include the patient's age, occupational
and social needs for precise vocalization, ease of laryngeal and hypopharyn-
geal evaluation, personal habits —
such as smoking and the degree of alcohol
consumption, general health, family support, and a number of other factors.
Ideally, the treatment decision is discussed in an open forum by physicians
who have a special interest in head and neck cancer. A synopsis of the
treatment options is then presented to the patient, who should participate in
the final decision regarding treatment.
Glottic Cancer
Tumors of the glottis tend to be well differentiated and slow growing,

usually arising in the anterior half of the membranous vocal cord. They can
extend anteriorly to the anterior commissure and involve the opposite vocal
cord or they can extend posteriorly to involve the vocal process and arytenoid
cartilages. Extension to the anterior commissure is accompanied by an in-
creased frequency of laryngeal cartilage involvement, whereas posterior ex-
tension can cause invasion of the cricoid lamina. The progressive growth of a
vocal cord cancer inevitably invades the vocalis and thy roary tenoideus mus-
cles, which then limits the mobility of the vocal cord. Fixation of the cord will
result from substantial invasion of these glottic muscles, from the tumor bulk
extending to die thyroid lamina, and from tumor involvement of the recurrent
nerve. 73 Tumor extending more than 1 cm below the glottis often accompanies
the invasion of the cricothyroid membrane and the body of the cricoid car-
tilage.
The lymphatics of the glottis are sparse, and T, cancers have an extremely
low incidence of metastasis (2 per cent). T 2 and T 3 cancers, which extend to
the arytenoid cartilage and subglottis regions, have a metastatic rate of up to
about 13 per cent, and the node most frequently involved is the Delphian
node, which overlies the cricothyroid membrane.
554 II / Treatment of Spe< ii k Neoplasms
Considerable difference of opinion remains regarding the treatment of

carcinoma in situ or microinvasive cancer of the vocal cords. Decortication
(stripping) of the vocal cord under the operation microscope and close obser-
vation to detect any evidence of recurrence are measures that incur the least
morbidity. 74 75 Radiation therapy is also effective in eradicating this tumor.
'
Doyle et al.™ advise complete stripping of the vocal cord, followed one
month later by a biopsy. If there is any evidence of cancer in the biopsy
specimen, irradiation is begun. Miller 77 favors immediate cordectomy via
laryngofissure, whereas DeSanto 78 performs a cordectomy via suspension mi-
crolaryngoscopy.
Radiation therapy is almost universally considered the primary treatment
modality for invasive Tj and selected T 2 cancers of the vocal cord. Small
treatment volumes are employed to minimize injury to the larynx. Doses of
approximately 6500 rad are delivered in 6.5 to 8 weeks. Cure rates using
irradiation for these glottic tumors are approximately 90 per cent, with partial
laryngectomy being reserved for treatment failures.
With extension to the anterior commissure or arytenoid cartilages, the
prognosis worsens for both surgery and irradiation. Some clinicians favor
surgery for these lesions, 79,80 whereas others prefer primary radiation thera-
py,
81
particularly when the cords remain fully mobile. Patients who have
extensive T 2 or T 3 lesions with cordal fixation are generally considered to be
surgical candidates, treated either by vertical hemilaryngectomy (Fig. 12-2)
The extent of partial laryngectomy is tailored to the
or total laryngectomy. 73
anatomic involvement by the tumor. Whenever a partial laryngectomy is
planned, permission for total laryngectomy must be obtained before surgery is
performed. The vertical hemilaryngectomy may include resection of the ary-
tenoid cartilages or the anterior third of the opposite vocal cord, or both.
Confirmation of tumor-free margins is determined at the time of surgery by
frozen-section examination prior to reconstruction and closure.
FIGURE 12-2. Dotted lines indicate

portion of the larynx typically excised
l>> vertical hemilaryngectomy.
-J)
FRONTAL VIEW MIDLINE SAGITTAL VIEW

Cartilage incisions Mucosal incisions outlined
outlined
Thegoals of glottic reconstruction are: (1) to provide a competent sphincter

to prevent aspiration. (2) to reconstruct a tissue ledge for phonation (pseudo-
cord) that will assure a smooth surface for approximation by the opposite vocal
cord, and (3) to provide an adequate channel for respiration. Various recon-
structive procedures have been described for reconstituting the function of
the glottis/- Aspiration can generally be prevented by utilizing tissue bulk in
place of a resected arytenoid cartilage, and an adequate airway can be main-
tained by temporarily placing a keel in the anterior aspect of the larynx when
the anterior portion of the opposite vocal cord has been resected. 8 3 Indeed, if
"
both arytenoid cartilages are preserved, at least the anterior half of both vocal
cords can be resected for an extensive cancer of the anterior commissure. 79 It
is important to emphasize that none of the various modifications of vertical
hemilaryngectomy will provide the same vocal quality as irradiation. Howev-

er, in most instances the voice will be intelligible despite varying degrees of
hoarseness.
When a glottic cancer involves the ventricle (transglottic) or extends below
the level of the cricoid cartilage, total laryngectomy is necessary. Be-
cause transglottic tumors usually involve laryngeal cartilage, partial laryngeal
surgery is inadequate for tumor removal. Resection of a substantial portion of
the cricoid cartilage to attempt partial laryngectomy usually results in perma-
nent subglottic stenosis that is inadequate for respiration. Because the in-
cidence of cervical metastasis ranges from 30 per cent to 50 per cent, treat-
ment of the neck is required —usually radical neck dissection sparing the
spinal accessory nerve if it is completely free of tumor. In addition, the
ipsilateral thyroid lobe is commonly removed because of possible tumor
involvement Postoperative irradiation is employed if the cancer extends
outside the confines of the intrinsic larynx or if several nodes in the radical
neck dissection contain metastatic tumor.
Supraglottic Cancer
Tumors of this type tendto be exophytic and bulky, sometimes obscuring or

hanging down over the vocal cords. 84 Often they invade the pre-epiglottic
space, although there definitely appears to be a compartmentalization or
barrier to downward involvement of the glottis. When the tumor extends
outside the larynx and involves the vallecula epiglottica, tongue base, or
pyriform sinus, it behaves more like a hypopharyngeal cancer.
The treatment of supraglottic cancer is usually surgical, although primary
radiation therapy of T, epiglottic tumors and tumors of the aryepiglottic fold
above the level of the hyoid bone (suprahyoid) has been highly successful. 85
The operation that is generally performed for these cancers is the supraglottic
laryngectomy, 86 which is designed to spare the vocal cords by placing the
inferior plane of the resection through the laryngeal ventricle just above the
vocal cords (Fig. 12-3). This operation may be modified to resect tumors in
different parts of the laryngeal vestibule and hypopharynx. The false vocal
cords, epiglottis, and entire pre-epiglottic space are typically included in the
resection. The resultant defect is closed with a perichondria! flap from the
Supraglottic carcinoma
FIGURE 12-3. Dotted lines indi-

cate portion of larynx usuall) ex-
cised by horizontal supraglottic
laryngectomy.
V*r
FRONTAL VIEW MIDLINE SAGITTAL VIEW
Cartilage incisions Mucosal incisions outlined
outlined
after A Shumnck
thyroid cartilage. Because the incidence of cervical metastasis exceeds 30 per

cent, a radical neck dissection is usually performed concomitantly, sparing the
spinal accessory nerve whenever possible. The patient's primary postopera-
tive handicap —
a tendency toward aspiration because only the glottis re-
mains to protect the airway —
can be minimized by suspending the laryngeal
remnant to the suprahyoid muscles, well under the base of the tongue, which
serves as a ledge to cover the laryngeal inlet. 87
Preoperative or postoperative radiation therapy is frequently employed.
Radiation is particularly valuable in treating contralateral neck metastasis,
which is not infrequent with supraglottic cancers. Supraglottic laryngectomy
after full-dose irradiation is hazardous because of the high incidence of
wound dehiscence and carotid artery rupture due to impaired wound healing
induced by radiation.
The prognosis for supraglottic cancers varies according to the site, size,
gross configuration, and histology. Small (less than 2 cm) tumors involving the
free border of the epiglottis (suprahyoid) have a five-year survival rate that
exceeds 80 per cent. Infiltrative and less well-differentiated tumors (particu-
larly those extending to the thyroid cartilage, base of tongue, and pyriform
sinuses) have a worse prognosis —
in the range of 35 per cent to 50 per
cent.
Subglottic €ancers
These tumors constitute from 5 per cent to 10 per cent of all laryngeal
cancers. 88 They can grow large before becoming symptomatic, inasmuch as
stridor is usually the patient's presenting complaint. There is a relatively high
incidence of paratracheal node metastasis (60 per cent).
The treatment of subglottic cancer is total laryngectomy followed by radia-
tion. It is particularly important that the trachea be transected well below the
tumor because the mucosal lymphatics spread downward. The surgical resec-
tion may he extended to the sixth tracheal ring, including amputation of the
manubrium so that the tracheal stoma can be exteriorized without tension. 89
Both the cervical node dissection and postoperative radiation are directed
toward the paratracheal lymphatics, which are the primary source of recurrent
disease. In selected low subglottic cancers and recurrent tumors at the stoma,
mediastinal resection has been attempted with some success, although the
prognosis remains quite poor. 90
Hypopharyngeal Cancer
Hypopharyngeal tumors usually arise in the pyriform sinuses (tending to be

large when first discovered), or they may be heralded by a metastatic neck
mass. 91 Thelymphatics of the pyriform sinus are profuse, and therefore the
incidence of cervical metastasis, including contralateral metastasis, is quite
high.
Since small lesions are almost never identified, radiation therapy is em-
ployed as an adjunctive modality, and likewise, surgery is rarely used alone
,
as treatment. The choice of surgery varies with the anatomic extent of the
tumor. When the tumor is confined to the lateral or anterior wall of the
pyriform sinus, the glottis can be preserved while resecting almost all of the
pyriform sinus in selected instances. 9 - Since there is a tendency for submuco-
sal extension, surgical margins around the visible tumor must be at least 2 cm
in diameter. When the tumor involves the medial wall of the pyriform sinus
and the arytenoid cartilage, extends to the pyriform sinus apex, or invades the
posterior wall of the pharynx, a total laryngectomy is usually necessary.
Almost all surgery for pyriform sinus cancers involves an ipsilateral cervical
node dissection, including removal of nodes in the retropharyngeal area.
Radiation is used either preoperatively or postoperatively. Postoperative
irradiation is preferable because
can be planned according to the findings
it
of the surgical specimen. If any surgical margins of the specimen are close
to the tumor, irradiation can be boosted to the appropriate area. More-
over, the incidence of wound healing complications is lower with postopera-
tive irradiation.
The prognosis pyriform sinus cancers is generally unfavorable, and the
for
only improved survival statistics have been demonstrated with combined
therapy. 93 The analysis of failures typically shows that the patients developed
distant metastasis or recurrent neck disease.
Hypopharyngeal tumors, which may also occur in the region of the cricoid
cartilage and esophageal inlet, likewise have a poor prognosis because of an
early tendency to spread into the mediastinum via retropharyngeal lymphat-
ics or submucosal extension. Radiation therapy is often employed, but, if used
alone, the number of five-year survivors is quite low (5 per cent to 10 per
cent). Because the circumference of the pharynx is narrow at the cricoid level,
surgical therapy often necessitates resecting most or all of the pharynx in
addition to laryngectomy.
When there is insufficient tissue to reconstitute the pharyngeal lumen, it is
either reconstructed with regional skin Haps or immediately replaced with a

transposed part of the gastrointestinal tract, such as the stomach or colon.
Reconstructing the pharynx with regional skin flaps from the neck or chest is
usually performed in multiple stages, requiring protracted periods of hospital-
ization.
94
The immediate replacement of the pharynx at the time of resection
with a transposed alimentary viscus that is transferred on its own blood supply
can he a formidable operation that incurs significant morbidity and mortality,
but, when successful, it has the advantage of rapidly re-establishing the
ability to swallow. 95 With this type of extensive surgery, it is beneficial to
employ postoperative radiation rather than preoperative irradiation to maxi-
mize healing.
The posterior pharyngeal wall extends from the level of the soft palate to
the arytenoid cartilages. Cancers in this region are difficult to cure even if
they do not grow large. 93 They tend to spread along the prevertebral fascia and
sometimes manifest "skip" areas. Bilateral cervical node metastasis as well as
retropharyngeal node involvement is particularly common. Surgery com-
bined with irradiation is the treatment of choice for these cancers and is
usually performed without sacrificing the larynx. The defect may be repaired
with a dermal graft or neck skin flap. 96 Postoperative irradiation should be
used to control any surgically untreated side of the neck and to sterilize the
area adjacent to the primary tumor. The five-year prognosis for these tumors,
even with combined therapy, is about 5 per cent to 25 per cent.
Section 6
Chemotherapy of Head and

Neck Cancer
Jacob Zighelboim
INTRODUCTION
Chemotherapy, as currently conceived,
primarily indicated for the treat-
is
ment of patients with epidermoid carcinomas of the head and neck region
who have failed other treatment or who are not amenable to surgery or
radiation therapy. Adjuvant chemotherapy programs are being introduced for
patients who have a high risk of developing recurrent tumors following the
completion of "curative" (surgery or radiation) therapy. The rationale for this
approach is derived from the notion that after completion of "curative" thera-
pies, small nests of tumor cells persist and eventually lead to disease recur-
rence.
Recurrent or disseminated head and neck cancer is associated with a dismal
prognosis and poor survivorship. The latter is partly due to the short-term
responses elicited by even the most effective agents. In addition, the potential
effectiveness of therapy is hampered by the debilitated condition of most
patients at the timechemotherapy is initiated.

Most trials that have been conducted to date have included a relatively
small number of patients who were usually affected by a heterogeneous group
of neoplasms. Consequently, a precise analysis of response rates for particu-
lar tumor sites is still unavailable.
Prior surgery or radiation, or both, can compromise the blood supply to the
tumor, significantly affecting patient responsiveness to chemotherapy. 97,98
Performance and nutritional status as well as comorbid conditions are also
important prognosticated of responsiveness to treatment. Main patients who
are considered for chemotherapy are poorly nourished and have a negative
nitrogen balance and subclinical folate deficiency. Attempts to improve the
nutritional status of these patients are therefore of the utmost importance.
Since the advent of intravenous hyperalimentation, vitamins, minerals,
amino acids, and caloric sources can be given parenteral^ in sufficient
amounts to correct negative nitrogen balance and maintain the patient in an
anabolic state. Intravenous hyperalimentation has been used for patients in
whom potential curative surgery or radiation therapy might have been denied
for fear of serious complications secondary to malnourishment. Nutritional
support is also important in patients who are eligible for intensive chemother-
apy, since these patients usually have negative nitrogen balance and limited
possibilities of rapidly improving their nutritional status.
SINGLE AGENT CHEMOTHERAPY

Methotrexate has been studied most extensively. 99 Multiple dosages,
routes, and schedules of administration have been tried in an attempt to
define the optimal method for the administration of this agent (Table 12-7).
Systemic MTX has primarily been used by the intravenous route in a weekly
or biweekly schedule.
MTX that is used in advanced or recurrent head and neck cancer can
produce striking remissions in some patients and an overall tumor response of
40 per cent to 60 per cent. 105 Response rates for patients with carcinoma of the
larynx are in the 30 per cent to 45 per cent range, whereas those for patients
with carcinomas of the hypo- and nasopharynx are much lower (Table 12-8).
The median response duration is short (2 to 2.5 months), with only few
patients responding for more than 6 months. The addition of BCG or BCG and
isoniazid (INH) has not improved response rates or survivorship. 106
In an attempt to increase the therapeutic index and reduce side effects,
high-dose methotrexate administration followed by leucovorin rescue has
been tested. Most reports indicate that response rate, duration of response,
and survival are not improved by this approach. 107 -> 09 The Eastern Cooperative
.560 II / Treatment of Specifk Neoplasms
TABLE 12-7. Effect of Methotrexate Schedule on Patient Responsiveness
NO OF No of Responses
Selected
Dose Schedule Patients CR° >50% Investigator
Weeklt/ or Biweekly Courses

40 to 60 mg/m 2 /IV/wk 23 8 De Palo et al."»>
60 mg/mVIV/wk or
40 mg/m 2 /IV/biwk 35 11 20 Leone et al.
m
25 to 50 mg/rW
102
every 4 to 7 days 27 4 14 Lane et al.
TOTALS 85 15 (20)°° 42 (52)
Monthly Course-,
103
25 mg/day/IV x 5 23 4 Papac et al.
103
15 to 20 mg/day/PO x 5 23 4 Papac et al.
104
0.2 mg/kg/IV/day x 5 10 4 Hellman et al.
TOTALS 56 12 (13)
°CR: complete response

° per cent response rate given in parentheses
Oncology Group (ECOG) recently compared response rate and duration in

patients with advanced head and neck cancer who were treated with metho-
trexate alone, high-dose methotrexate followed by leucovorin, or the latter
plus cyclophosphamide and cytosine arabinoside. An overall objective re-
sponse rate of 24 per cent was obtained with no significant differences among
the three regimens. 110 Buechler et al. ni randomized 23 patients with ad-
vanced disease to receive high-dose methotrexate with leucovorin rescue
alone or with BCG. With drug administration alone, 3 of 12 patients respond-
ed, whereas 2 of 11 patients responded in the BCG group. These reports fail to
demonstrate a therapeutic advantage to the use of these regimens in patients
with advanced disease.
Bleomycin is the second most effective agent, with responses documented
in 112 of 298 patients evaluated (Table 12-9). Ten patients achieved complete
remission with disappearance of detectable tumor, whereas the vast majority
of patients (102 of 298) had partial or minimal responses. The optimal dosage
was 0.25 to 0.5 unit/kg given once or twice weekly. However, responses are
usually short, lasting less than three months. Bleomycin is associated with
minimal or no bone marrow toxicity, making it an ideal drug to use in combi-
nation with odier effective agents.
TARLE 12-8. Responses to Methotrexate as a Function of Tumor Site of Origin
Per Cent NO OF Median Response

Dose Response Patients Duration
Tonsil 50 10 4.5
Alveolar ridge 56 9 2.8
Floor of mouth 50 10 2.0
Larynx 44 9 2.5
Hypopharynx 18 17 2.3
Modified from Bertino JR. et al.: Cancer 36:752, 1975.

TABLE 12-9. Activity of Systemically Administered Single Agents

(Excluding Methotrexate) in Advanced Head and Neck Cancer 99105
No of
Selected >50% c
^c Overall
Drug Patients Becression Besponse Bate
Hydroxyurea 18 7 39
Bleomycin 298 112 38
Cyclophosphamide 77 28 36
Vinblastine 35 10 29
Cisplatin 38 10 26
BCM 12 3 25
Dibromodulcitol 12 3 25
Doxorubicin 34 8 23
5-Fluoronracil 118 18 15
Cisplatin is advanced head and neck cancer

effective in the treatment of
112
(Table 12-9). Wittes et al. treated 26 patients with advanced head and neck
cancer, all of whom had failed radiation therapy and many of whom had
undergone previous surgery or chemotherapy. Of 26 patients, 8 responded —
with complete tumor remission and 6 with partial remission lasting from one
to eight months. Cisplatin causes only mild hone marrow toxicity and there-
fore is an attractive drug to incorporate into combination chemotherapy pro-
grams.
Cyclophosphamide, 5-fluorouracil, hydroxyurea, BCXU, and dibromodulci-
tol have shown effectiveness as single agents (Table 12-9). !,71,;! However,
the duration of response with each of these agents tends to be very short,
casting serious doubt as to their real value in the treatment of advanced head
and neck cancer.
COMBINATION CHEMOTHERAPY
Combination chemotherapy has not been extensively evaluated in head and
neck cancer (Table 12-10). In 1972, the group at the M.D. Anderson Hospital
combined vincristine with bleomycin and reported responses in three of nine
patients who had been previously treated with chemotherapy. 114 A trial with a
TABLE 12-10. Combination Chemotherapy in Head and Neck Cancer
No OF NO WITH
Selected >50%
Drug Combination Patients Regression Investigator
114
Vincristine and bleomvcin 9 3 Livingston et a/.
BACON 35 14 Richman et a/." 5
COBMAM 28 12 Livingston et a/. 116117
COMB 32 11 Livingston et a/." 6
Vincristine, bleomycin, and
methotrexate 21 19 Pouillart and Mathe 118
drug regimen including bleomycin and vincristine in addition to doxorubicin,

CCNU, and mechlorethamine (BACON) was subsequently conducted by the
same institution. 115 Patients were randomized to receive BACON alone or in
combination with BCG given by scarification. The response rate (40 per cent)
and the duration of response were comparable in both groups of patients.
Median survival, however, was only 14 weeks in the chemotherapy group
compared with 30+ weeks in the chemo-immunotherapy group. Thus, non-
specific immunotherapy appeared to prolong patient survival.
The M.D. Anderson group has studied another multiple combination che-
motherapy program identified by the acronym "COBMAM." " " 7 This pro-
1 1
gram combines cyclophosphamide, vincristine, bleomycin, methotrexate,

doxorubicin, and MeCCNU administered in three consecutive phases, each of
which combines two of the drugs just mentioned. This approach was directed
at reducing the development of drug resistance and therapy related morbidity
and mortality. Of 28 patients with no previous chemotherapy, 12 had over 50
per cent tumor reduction (43 per cent response rate) and 5 (18 per cent) had
complete clinical resolution of demonstrable disease. The median response
duration was 25 weeks, clearly longer than that reported with methotrexate
alone or widi other combinations of drugs.
Pouillart and Mathe 118 employed the combination of vincristine, bleomycin,
and methotrexate and obtained 4 complete and 15 partial responses in 21
cases treated; however, responses were short with a median of 2.5 months.
Preasantef a/., 119 using a combination of doxorubicin, BCNU, and cyclophos-
phamide, reported partial responses in 4 of 16 patients with epidermoid
lesions, all of whom had previously received methotrexate.
A setting in which drug combinations are potentially useful is represented
by patients presenting with unresectable tumors. Randolph et al. 120 treated 18
such patients with a combination of cisplatin and bleomycin. DDP was given
in a dosage of 3 mg/kg on day 1, which was repeated on day 22. Bleomycin was
given at a dose of 0.25 unit/kg by rapid IV injection on day 3 followed by the
same dosage by IV continuous infusion from day 3 through day 10. Of 18
patients who were evaluable on day 22, 5 had complete tumor regression and
7 had a greater than 50 per cent tumor reduction. Morbidity was moderately
severe in 5 cases in which a creatinine determination >3.5 mg/dL was
demonstrated, and there was one fatality. Testing the combination of DDP
and doxorubicin, as well as a pilot study combining these with methotrex-
ate and bleomycin, has been initiated.
In summary, combination chemotherapy has resulted in minimal or no
improvement in response rate, length of response, and survival in patients
with advanced head and neck cancer. Further studies to develop effective
agents in optimal concentrations and schedules are clearly indicated.
REGIONAL CHEMOTHERAPY
Regional infusion of chemotherapeutic agents was introduced in 1959. The
objective was to achieve a high concentration of drug at the tumor site, with
the expectation of increased therapeutic effect. Drugs were administered
intra-arterially for variable periods (weeks to months) and in multiple

courses.
The method has been used primarily in patients with tumor that is
regional
no longer responsive or amenable to surgery or radiation therapy; however, it
has also been used preoperatively. The results in either case are controversial.
The reported studies are difficult or impossible to compare because of differ-
ences drugs used, the schedules of administration, the duration of
in the
treatment, and the criteria of response. Methotrexate administered via the
intra-arterial route has demonstrated a 53 per cent response rate in 340
patients so treated. 105 This is similar to the response rates reported with
S) stemic methotrexate; however, the intra-arterial route was far more toxic.
Other antineoplastic agents tested include 5-fluorouracil, cyclophospha-

mide, vinblastine, and dactinomycin. Freckman 12 evaluated the effects of
'
intra-arterial infusion of these drugs singly or in combination for periods of 5

to 14 days, with the cycle repeated at monthly intervals. Out of 169 patients
who were evaluable. 76 (45 per cent) showed objective responses with a mean
response duration of 26 weeks. The median survival was 17 months for re-
sponders compared with 4 months for nonresponders.
The combination of 5-FU and methotrexate was more efficacious than
either drug infused alone. This approach was associated with few complica-
tions, and the drugs were well tolerated. Oberfield ct al. 12i reviewed the
experience that had accumulated at the Lahey Clinic with this form of therapy
and concluded that although useful antitumor effects could be obtained,
serious complications, such as hemorrhage and major vessel embolization,
limited the usefulness and applicability of this therapeutic approach.
ADJUVANT CHEMOTHERAPY
Chemotherapy in Combination with
Radiotherapy
Multiple chemotherapeutic agents have been investigated as adjuvants to

radiation therapy. The rationale for this approach is derived from the notion
that massive tumors are rarely cured by radiation alone. The existence of a
large tumor cell mass, which is usually poorly vascularized and contains high
numbers of hypoxic (i.e., radioresistant) cells, decreases the statistical
chances of damaging all or most of the cells with irradiation. In a randomized,
controlled trial, Gollin et a/. 123 compared the effects of radiotherapy alone
versus radiotherapy plus intravenous 5-FU. For patients with tumors originat-
ing in the oropharynx, median survival was approximately 20 months in both
groups. There have been several studies using intra-arterial 5-FU in combina-
tion with radiotherapy. These studies showed no beneficial effects from the
combined modality, and, although patient selection was nonrandomized, dis-
tribution by disease stage was comparable between the two groups.
A number of uncontrolled, nonrandomized trials have reported beneficial
effects when intravenous methotrexate is given in conjunction with radiother-
564 II / Treatmi vi of Specific Neoplasms
apy 124, \2n y on £ ssen C ( all**-

1-' 7
compared irradiation alone with radiotherapy
plus MTX and found the response rates to be 53 per cent versus 82 per cent
respectively. No
difference, however, was seen in the short-term tumor con-
trol and two-year survival between the two regimens. Kramer 128 reported
beneficial results in patients with T3 and T 4 lesions who were treated with a
variety of MTX schedules preceding the institution of radiation therapy. A
nearly equivalent number of studies involving intra-arterial infusion of meth-
otrexate in conjunction with radiotherapy have been reported. Unfortunately,
these were nonrandomized trials and therefore could not provide definitive
answers. In an effort to firmly establish the role of systemic adjuvant MTX
given in combination with radiation therapy, the Radiation Therapy Oncology
Group (RTOG) is conducting a randomized, controlled study that should
provide definitive information. There is little reason to perform similar stud-
ies using the intra-arterial route, since this approach is associated with high
morbidity and lacks therapeutic advantage.
Berdal 129 combined bleomycin with radiotherapy in 300 patients with head
and neck cancer. Patients received bleomycin, 15 units IM daily, on weeks
one and three and every other day for the second week. Complete regression
was observed in 115 of 212 patients who were followed for at least one year,
and more than 50 per cent tumor shrinkage was reported in another 68 per
cent, making a total response rate of 87 per cent. In patients with small
carcinomas of the larynx (T and T 2 ), the cure rate with this approach was 93
x
per cent. For larger tumors (T and T 4 Ni), a cure rate of 53 per cent was
:J
observed. The side effects were primarily mucositis and transient alopecia.
Chemotherapy in Combination with

Surgery
Data on the effects of adjuvant chemotherapy in patients whose tumors are

130
primarily treated with surgery are limited. Desprez et a/. reported on a
study involving 103 patients with carcinoma of the oral cavity who were initi-
ally treatedwith intra-arterial methotrexate (given for ten days with simultan-
eous administration of leucovorin) and then followed by surgery three to six
weeks later. Twenty-eight patients showed complete disappearance of tumor
and exhibited long-term disease-free survival; however, survivorship for the
75 patients with residual tumor after completion of the intra-arterial infusions
was no better than that for patients treated with surgery alone.
Despite residual tumor, the infusion decreased local inflammation and tu-
mor size, and occasionally made inoperable lesions surgically approachable.
Patients with complete tumor response were previously untreated and had
small exophytic lesions that were limited to the lateral surfaces of the tongue,
gingiva, buccal mucosa, and tonsil. Poor responders included patients with
large ulcerative lesions involving the floor of the mouth, tonsil-palate area,
base of the tongue, and lateral pharynx. Most had received prior radiation
therapy, and some had metastatic disease to the regional lymph nodes.
Taylor et al. ul reported on the use of high-dose methotrexate administration
with leucovorin rescue prior to surgery or radiotherapy, or both, in 17 pa-
tients. Of the 17 patients treated, 10 had no evidence of disease after complet-
ing curative therapy, and 3 of these patients remained without evidence of

disease for periods longer than 21 months.
apparent from reviewing current data that the role of adjuvant chemo-
It is
therapy in the treatment of head and neck cancer requires further evaluation
with properly randomized, controlled trials. In addition, recognition of factors
playing a role in patient responsiveness to therapy may be important in
selecting those patients who might benefit the most from adjuvant therapy.
CONCLUSIONS
Despite growing interest and increasing efforts to develop effective chemo-
therapy or immunotherapy programs, or both, for the treatment of head and
neck cancer, to date such approaches have been of marginal benefit. Our
current policy is that for patients with advanced or recurrent tumors, a trial
with single agent MTX, given IV in a dosage of 40 mg/nr every one to two
weeks, be undertaken. Although MTX-induccd responses are usually short-
lived, they may occasionally last for long periods, which is certainly of sin-
gular benefit for that selected group of patients. The program is usually well
tolerated, with mucositis being the most disturbing complication. For all
other categories of patients, the use of chemo- or immunotherapy is experi-
mental and is to be encouraged only in the context of research programs
aimed at determining the efficacy of such approaches.

The cure of head and neck cancer remains a major challenge for surgeons,
radiation therapists,and medical oncologists. It seems clear that for advances
to occur, increased effectiveness of chemo- and immunotherapy would be
essential. It is becoming evident that combinations of surgery, radiation,
chemo- and immunotherapy given at the time of initial diagnosis, will be the
desired approach in the near future.
To date, immunotherapy has played a minor role in the treatment of these
tumors. Patients with head and neck cancer show severe and protracted
derangements of immunocompetence, which might be instrumental in deter-
mining curability and recurrence rate. A serious and forceful attempt to
control these derangements with hormones (i.e., thymosin) or immunorestora-
tive agents (i.e., levamisole) may prove a highly relevant component of our
efforts to cure and fully eradicate these tumors.
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Chapter 13
NEOPLASMS OF
THE EYE
Section 1
Retinoblastoma
Arthur Rosenbaum Peter Falk
Robert G Parker
INTRODUCTION
Retinoblastoma, which is the most common intraocular tumor in children,
accounts for about 1 per cent of all cancer-related deaths between birth and
age 15 years. Although this cancer is usually recognized within the first two
1
years of life, it has been reported in the newborn and in adults. 2

The reported incidence currently is about 1 per 20,000 live births,' 4 but
there is evidence that the frequency of tumor occurrence may be increas-
4-7
ing. For example, Tarkkanen and Tuovinen" reported a progressive change
in the frequency of recognition of tumor in Finland from 1 per 82,000 live
births in 1919 to 1 per 16,000 live births in 1964. Better diagnosis and report-
ing and more offspring from an ever-increasing number of survivors of this
genetically transmitted cancer at least partially account for this apparently
increasing incidence.

8
Although it has been stated that there is no a high
racial predilection,
incidence of retinoblastoma has been reported from several countries
9 10
(Haiti, Nigeria, Jamaica) where the population is predominantly black. '
8
There is no sex predilection.
569
One of ten patients with newly discovered retinoblastoma lias a blood

11
relative with the tumor. Transmission follows an autosomal dominant pat-
tern of inheritance with about 85 per cent penetrance. Overall, about 35
per cent of cases are thought to be hereditary, with an additional 25 per
cent representing new germinal mutation; 65 per cent are thought to repre-
sent new somatic mutation. 11
Both eyes are involved in 25 per cent to 30 per cent of all patients. How-
ever, the frequency of bilaterality may be as high as 65 per cent in those
with retinoblastoma involving family members. 5 12 Patients with tumor in-
'
volving both eyes have been diagnosed at an earlier age than those with
unilateral involvement (average age of 12 months compared with 24
months). 13 The bilateral involvement can be established at the first exami-
nation in over 80 per cent of patients, whereas an additional 15 per cent are
recognized within 12 months of the initial diagnosis. After tumor is recog-
nized in the first eye, only rarely is there a prolonged interval before tumor
14
is discovered in the second eye.
In counseling potential parents, about 50 per cent of the offspring of pa-

tients with bilateral tumors and a family history of retinoblastoma will be
affected, whereas about 10 per cent of the offspring of those with unilateral
tumors without previous familial involvement will develop tumor. 514 These
unilateral cases are thought to represent germinal mutations for bilateral
disease that are incompletely expressed.
Recently, Knudson 11 proposed a "two hit" hypothesis for developing the
disease. If a germinal mutation has occurred (first hit), another somatic mu-
tation must occur in order for the tumor to become manifest (second hit). In
noninheritable cases, two somatic mutations must occur. Each mutation rate
has been calculated at 2 x 10" 7 per year. Hereditary cases are diagnosed
earlier in life, lending support to Knudson's proposal, since they require
only one postnatal somatic event.
There is a positive association between retinoblastoma and D-group chro-
mosome deletion. 15 Of 45 children with long arm deletion of chromosome
16
13, 13 developed retinoblastoma. All these children were also mentally
retarded, and many had hypertelorism, hypoplasia of the thumbs, skeletal
abnormalities, microphthalmus, coloboma, anterior polar cataracts, and
ptosis. However, it seems that although patients with retinoblastoma and
congenital defects may have demonstrable chromosomal abnormalities,
those with isolated ocular disease do not. 2
The bilateral retinoblastoma survivor has a 500 per cent greater chance of
developing a second cancer than a nontumor subject. The frequency of sec-
ondary tumors in bilateral survivors is 10 per cent, and the tumor may ap-
pear between 1 and 42 years following discovery of retinoblastoma. These
second neoplasms have a fatality rate of 85 per cent, and they usually de-
velop in a field of previous irradiation. However, 19 per cent of these tumors
occur in distant fields, and occasional patients develop second tumors despite
no radiation treatment. Osteogenic sarcoma is the most frequently en-
countered secondary tumor. 1718
13 / Neoplasms of the Eye 571
NATURAL HISTORY
Pathology and Classification
Retinoblastoma probably develops from neuroblasts tissue that forms the

retinal photoreceptors.
19
The tumor may originate in the inner retinal layers
and grow into the vitreous (endophytic) or may originate in the outer retin-
al layers and extend into the subretinal space with consequent detachment
of the retina (exophytic). This growth pattern apparently has no prognostic

significance except that the endophytic type may be easier to diagnose.
Rarely, tumor may thicken the retina without formation of a mass and con-
20
sequently present clinically as "uveitis." The basic retinoblastoma cell is
small and round or polygonal with a relatively large nucleus and little cy-
toplasm.
Rosettes, which are composed of columnar cells in a circular arrangement
around a lumen containing a hyaluronidase-resistant acid mucopolysac-
21
charide, can be identified in most retinoblastomas. "Fleurettes," which
are flower-like arrangements of cell processes in retinoblastoma cells with
photoreceptor differentiation, can be identified occasionally. 18 The clinical
significance of these structures is uncertain, for Ellsworth3 has found no
relationship to prognosis, whereas Tsukahara 22 and Ts'o et al. 19 have claimed
a correlation with a reduced tumor-related mortality, but greater resistance
to radiation.
The frequencies of presenting symptoms and signs, as recorded by Ells-

worth, 23 are white or "cat's eye" reflex —
56 per cent; strabismus — 20 per
cent (esotropia —11 per cent, exotropia — 9 per cent); red, painful eye
with glaucoma —
7 per cent; poor vision — 5 per cent; incidental finding
on routine examination —
3 percent; unilateral mydriasis — 2 percent; het-
erochromia iridis— per cent; hyphema — per cent; "strange expres-
1 1
sion" —
0.5 per cent; nystagmus — 0.5 per cent; white spots on — 0.5 iris
per cent; others, i.e., failure to eat and thrive— These find-
0.5 per cent.
ings, most often leukokoria or strabismus, or both, usually are noted by the
parent, family doctor, or pediatrician and referred to the ophthalmologist
for definitive diagnosis.
Multiple tumors can be identified in 75 per cent of the eyes examined by
indirect ophthalmoscopy with scleral depression. 3 Eighty per cent of these
tumors originate anterior to the equator of the globe. 3 The mean number of
tumors per patient is 4.7, and multiple tumors are now thought to signify a
germinal mutation.
Two characteristic findings of retinoblastoma are vitreous seeding and
flocculent calcification, documented in about 75 per cent of patients on
roentgenographic 24 or ultrasonic exam or computerized tomographic scan.
Although the findings in most patients are characteristic of retinoblastoma,
other conditions, including infections, retinal hemorrhage, and detachment
and vascular malformations, must he differentiated. This requires examina-

tion by personnel who are experienced in the recognition and treatment of
retinoblastoma, which is rare in the usual medical practice.
Elevated urinary excretion of vanillylmandelic acid (VMA) and homovan-
illic acid (HVA) before treatment, followed by decreased post-treatment
5
levels, has been reported by some to be a diagnostic aid,- but this has not
26
been confirmed by others. Lactic acid dehydrogenase, a ubiquitous intra-
cellular enzyme, was first reported as elevated in specimens from paracen-
tesis of the anterior chamber of patients with retinoblastoma by Dias et al.
in 197 1. 27 An elevation two to three times the control value is highly sug-
gestive of retinoblastoma. Ellsworth 3 reported an 8 per cent incidence of
false-negative tests and an occasional false-positive result. Elevated carcino-
embryonic antigen and alpha-fetoprotein (aFP) levels, which drop after
therapy, have been reported. 28 Extrascleral extension of tumor, as well as
29
calcification, may be detected by computerized tomographic scanning. Ul-
trasonography may be helpful in defining tumor when the medium is ob-
scured by cataract or vitreous opacity or the tumor growth pattern is pri-
marily endophytic. The pattern must be distinguished from vitreous
hemorrhage. 29 Retinoblastoma cells have been detected in the aspirate of
30
the anterior chamber of patients presenting with hypopyon or uveitis.
Reese and collaborators 31 and Ellsworth 3 developed a staging system that

correlates the extent and anatomic location of retinoblastoma with preserva-
tion of useful vision following treatment (Table 13-1).
Certain features of the enucleation specimen have prognostic correlation.
When tumor extends to the cut end of the optic nerve (10 to 12 posteri- mm
TABLE 13-1. Staging System for Retinoblastoma
Group I (very favorable)

Solitarytumor smaller than 4 disk diameters at or behind the equator
Multiple tumors, none larger than 4 disk diameters, all at or behind the equator
Group II (favorable)
Solitary tumor, 4 to 10 disk diameters in size, at or behind the equator
Multiple tumors, 4 to 10 disk diameters in size, all behind the equator
Group III (doubtful)

Any lesion anterior to the equator
Solitary tumor larger than 10 disk diameters, behind the equator
Group IV (unfavorable)
Multiple tumors, some larger than 10 disk diameters
Any lesion extending anterior to the ora serrata
Group V (very unfavorable)

Massive tumors involving over one half of the retina
Vitreous seeding
or to the lamina cribrosa sclerae), the mortality rate may be as high as 60 per
cent, whereas this decreases to about 40 per cent if tumor extends beyond
the lamina cribrosa sclerae but not to the end of the cut optic nerve, and to
about 15 per cent if tumor does not extend beyond the lamina cribrosa
sclerae." The involvement of the choroid has been reported in approxi-
mately two thirds of all enucleated eyes 33 and is compatible with survival,
23
although tumor-related mortality increases with the extent of involvement.
The spread of tumor through or beyond the sclera is a dire prognostic
sign.
23
Distant metastases, most frequently to the CNS, skull, long bones,
lung, and lymph nodes, are not consistent with survival using current treat-
ment methods.
TREATMENT
The primary treatment modalities for retinoblastoma are enucleation and
irradiation. Secondary modes of treatment, which include chemotherapy,
photocoagulation, cryotherapy, and cobalt-60 plaques, are almost always
used in conjunction with one of the primary alternatives.
Surgery
Unilateral Cases. Almost all unilateral cases will present only after
they are advanced to the point where a "cat's eye" pupillary reflex or strabis-
mus resulting from tumor in the macular area has occurred. These are usually
group IV or group V in size and location and are treated by enucleation
with an attempt to secure a 12 mm section of optic nerve.
In the past, all unilateral cases were enucleated. Because of encouraging
results from irradiation of retinoblastoma, groups I, II, and III unilateral
cases may be considered for irradiation instead of enucleation. 32 It must be
pointed out that unilateral tumors presenting this small are very uncom-
mon. Also, close follow-up is mandatory. One of the helpful characteristics
of retinoblastoma, as compared with malignant melanoma, is that the oph-
thalmoscopic appearance of response to irradiation is usually present very
soon after treatment. Thus, an examination under anesthesia is performed
six to eight weeks after beginning radiation therapy. If there is not conclu-
sive evidence that the tumor has responded well to irradiation, the eye is
enucleated at that time.
Bilateral Cases. The time-honored approach to bilateral disease has
been to enucleate the eye with the most advanced disease and treat the
remaining eye with irradiation and frequently with chemotherapy if the in-
volved eye has some potentially viable retina remaining. Rarely, both eyes
are completely filled with tumor and both retinas totally destroyed. In
these tragic circumstances bilateral enucleation is indicated.
This principle remains current. However, because of past success with
irradiation, cautious progression toward bilateral irradiation has occurred. If
both eyes have group I, group II, or group III tumors, bilateral irradiation
may be performed with a follow-up assessment two months postirradiation,

witli probable enucleation at that time if one eye lias not responded.
If both eyes have group IV tumors that are symmetrically severe, bilateral
irradiation with probable chemotherapy may be advised if there is at least
one quadrant of retina nninvolved in each eye.'52 Bilateral group V tumors
may also be treated this way if there is potentially good retina remaining in
each eye and if the severity of the tumor is truly symmetrical.
It must be emphasized that some increased risk is being taken in am
treatment other than prompt enucleation. The medical team, together with
the parents, is always struggling with the alternatives of survival versus
blindness, and, at present, each case must be judged individually in this
regard. The prompt response to irradiation makes the risk period about two
months.
Also, the tumor in one eye may be very radiosensitive and the other eye
may demonstrate radioresistance. Although this may be related to patholog-
ic evidence, it is not possible to judge clinically beforehand which eye may
be sensitive. Frequently, the larger tumor may be very sensitive and "melt
away" and the smaller, less threatening tumor may be very resistant and
require additional irradiation or enucleation.
Irradiation
of retinoblastoma to ionizing radiation was observed

The responsiveness
by Hilgartner in 1903. 34 Subsequently, Moore in 1929 35 and Martin and
Reese in 1936 36 reported the destruction of this tumor by radiation therapy.
Although applicators containing radioactive materials, i.e., radium-226
and cobalt-60, have been used successfully, their use alone must be re-
stricted to well-localized tumor. 37 Inasmuch as the entire retina is at risk, 31,38
external beam irradiation has an inherent advantage over local applicators.
Megavoltage radiation teletherapy, with sharp beam margins, makes it
possible to irradiate the entire retinal surface to minimal doses of 4200
to 4500 rad in about four to five weeks, with restriction of the dose to the
lens to about 3 per cent (140 to 150 rad) of the retinal dose. 58
This dose is
well below that expected to induce a cataract. 38, :i9
Cobalt-60 plaques are primarily used to provide a second course of ir-

radiation to a localized area, thus avoiding the ocular and systemic compli-
cations of two courses of external beam irradiation. An isolated tumor that
is larger than 10 disk diameters in an only remaining eye that has not com-
pletely responded to radiation may be considered for this treatment. The

plaque is sutured to the sclera after precise localization of the tumor by
indirect ophthalmoscopy. The plaque remains in place for three to five days
and is then removed. The dosage is calculated so that the tumor apex re-
ceives 3500 to 4500 rad. The dosage at the tumor base may need to be as
high as between 30,000 and 90,000 rad. Ellsworth 25 reports that this scleral
dose is usually well tolerated, but two cases of scleral necrosis have been
reported. 32 In heroic efforts to maintain an only eye, these plaques have
been used two or three times.
Serious complications (i.e., vitreous or retinal hemorrhage 40,41 or the de-

velopment of osteosarcoma) 18 arising in the bones of the orbit have been
reported following irradiation to doses far in excess of what now is consid-
ered necessary for tumor control in excess of 7000 rad). 38,42 Glaucoma
(i.e.,
and keratitis also may follow curative irradiation. 4041 Retardation of growth
of the irradiated bones about the orbit, resulting in enophthalmos, small
orbital entrances, and a narrow interpupillary distance, has been reported
following orthovoltage x-ray treatment. 43 Significant growth retardation of
temporal and orbital bones does not follow megavoltage irradiation to rea-
sonable doses. 44 Inasmuch as the objective of radiation therapy is to pre-
serve while eradicating tumor, treatment-induced complications
vision
must be minimized by well conceived and carefully executed treatment ap-
plication.
A difficult part of radiation treatment is the interpretation of postirradia-
tion ophthalmologic findings. According to Ehlers and Kaae, 45 tumor may
be unchanged in size and surrounded by grayish-white edema for the first
week after irradiation. Small tumors (i.e., less than 6 mm in greatest di-
mension) may completely disappear without trace or may leave only small
white retinal and choroidal scars. Larger tumors may resolve over several
months. Chalk white foci appear until the tumor consists of avascular nod-
ules. White refractile and crystalline fragments may separate into the vitre-
ous and must be distinguished from active tumor seeding. 46 Cysts may de-
velop near the sites of irradiation from applicators.' 7 Vessels may become
attenuated and sclerosed. Choroidal vessels may become clearly visible be-
cause of overlying pigmentary changes in the retina. 45
Chemotherapy
Chemotherapeutic agents have been used as adjuvants to radiation thera-

py and surgery in the treatment of locally extensive tumor and as treatment
of widespread metastases. Triethylene melamine (TEM), a rapidly detox-
ified alkylating agent, has been injected into the ipsilateral carotid artery
early in the course of radiotherapy of patients with locally extensive tumor
(groups IV and V of Ellsworth 3 ). The value of such treatment, which has
substantial morbidity, has not been established 48 and it is currently not
widely used in the United States.
The involvement of the intracranial meninges may be common with lo-
cally extensive tumor. 49 Diagnosis is without enucleation, the
difficult, for
optic nerve cannot be examined, and cytologic examination of the spinal
fluid rarely has been helpful. 50 Clinical remissions have been reported fol-
lowing the intrathecal injection of various drugs, i.e., methotrexate, CCNU,
and cytosine arabinoside coincident with cranial irradiation. 50 The value of
routine use of such regimes for patients with locally extensive tumor has
not been determined.
Adjuvant treatment with vincristine or cyclophosphamide in patients with
locally extensive retinoblastoma has been tried, 51 but long-term results are
not available.
Other Modes of Therapy
Other methods include photocoagulation and cryotherapy.

local treatment
Photocoagulation rarely is used as primary treatment of retinoblastoma, but
it may be effective for small tumors (i.e., less than 5 disk diameters) 2 2 44 ' '
following an incomplete response to irradiation. Ellsworth'5,23 has reported

successful tumor destruction in 79 per cent of this group. Complications of
treatment, i.e., hemorrhage or exudative retinal detachment, are uncom-
mon. Howard and Ellsworth 20 have suggested that resulting breaks in
Bruch's membrane may lead to tumor invasion of the sclera and choroid.
Cryosurgery may also successfully destroy small tumors, i.e., less than 4
to 5 disk diameters, particularly when located anteriorly in the eye. Ells-
worth 3,32 has reported controlling 60 per cent of this group. Complications
are rare when indications for therapy are stringently observed. 3
Results of Treatment
Successful treatment of retinoblastoma is measured not only by patient

survival —
the primary concern —
but also by preservation of useful vision,
which is usually defined as visual acuity ranging from 20/20 to 20/200. 44
Tumor-related deaths are secondary to intracranial spread or hematogenous
metastases, or both, and usually occur within five years of diagnosis. 44 How-
ever, 10 to 15 per cent of these patients may die with metastatic tumor
more than ten years following diagnosis. 3 In Table 13-2, the long-term re-
sults of treatment of 361 patients with bilateral tumor or orbital extension
are listed. All patients were irradiated.

Exciting work under way to further delineate the etiology of retino-
is
blastoma. Evidence is accumulating to implicate some viral role in pro-
ducing the tumor. Adenovirus-12 has induced tumor resembling retinoblas-

toma in hamsters, and feline leukemia virus has produced tumors with
rosette formation in cats. 52,53 DNA polymerase has been discovered in ret-
inoblastoma. This "reverse transcriptase" permits the virus to use RNA for
TABLE 13-2. Results of Treatment

(from Columbia-Presbyterian Medical Center) 23
Number of % Survival of Eye

Group Patients with Useful Vision
I 20 91
II 32 83
III 24 82
IV 32 62
V 74 29
Orbital extension 10 36
the production of DNA in the host cell and has been found in all RNA
55
tumor viruses. 54 -
This is strong indirect evidence to implicate a viral
relationship, but no direct observation of virus particles has been made.
The role of immune mechanisms in retinoblastoma will continue to be
investigated because of the high incidence of spontaneous regression as
compared with other tumors. Cell-mediated immunity has been demon-
strated by Char, et a/. 56,57 in 11 of 14 retinoblastoma patients using in vitro
tissue culture techniques. The same author has also devised a crude mem-
brane extract skin test that has been shown to be positive in retinoblastoma
patients and negative in patients with other tumors. 58 HLA antigens have
been studied in retinoblastoma patients, but results are inconclusive. 58,59
D-locus typing has recently been performed, and one author suggests an
association of spontaneous regression with the presence of the DWII locus.
Oneof the most promising research advances has been the discover) that
retinoblastoma will grow in the anterior chamber of the athymic nude
mouse. 60 This finding may provide new avenues for evaluating both chemo-
therapy and radiation responses of tumors of individual patients as well as
offer a model for evaluation of cytotoxicity of the patient's tumor to his own
humoral and cell-mediated immunologic system.
Section 2
Ocular Malignant Melanoma

Hector L Sulit
INTRODUCTION
Malignant melanoma is the most frequent of the potentially life-
threatening intraocular tumors encountered by ophthalmologists. 61 The in-
cidence of intraocular melanoma in the general population in the United
States and in Europe is about 5 to 7.5 per million per year, but the figure
increases sharply after the age of 50 years to about 21 per million per
year. 62-84 This condition is rarely found in the non-white races.
Ocular malignant melanoma may from the different structures of the
arise
eye. The most common site is the choroid, followed, in decreasing order,
by the body, the iris,
ciliary the conjunctiva, and the skin of the eyelids.
Rarer still are the primary melanomas arising from the cornea and the orbit.
Malignant melanomas may arise from the stromal melanocytes within the
normal tissues of the eye or in congenital or acquired melanocytic lesions
such as benign nevi. The presence of benign-appearing cells at the periph-
ery of a focus of malignant melanoma on histologic sections propagated the
impression that the nevus is the precursor of this tumor. It is rare, however,
to see documented cases of choroidal nevi that become malignant during
years of follow-up.
NATURAL HISTORY
Malignant melanoma of the eyelid skin exhibits the same clinical appear-
ance and biologic behavior as cutaneous melanomas elsewhere. A change
in pigmentation and an increase in growth rate in a previously stable pig-
mented lesion may indicate malignant development, and it should be close-
ly followed or excised for histopathologic confirmation. Pigmented lesions
of the conjunctiva are commonly benign. A nevus may undergo cystic de-
generation that simulates rapid growth. If the nevus is highly suggestive of
malignant change, excision and histopathologic examination of the growth
should be carried out.
In the iris, malignant melanoma may present as a localized or diffuse
pigmented lesion associated with distortion of the pupil, ectropion uveae,
neovascularization, infiltration into the chamber angle structures, with ele-
vation of intraocular pressure, and sector cataract formation at the area of
the lens that is in contact with the iris mass. Malignant melanoma in
the ciliary body may become clinically apparent initially from its extension
into the iris root, the choroid, or the episclera. The lens may be displaced
or develop sector cataract through contact with the ciliary body mass.
Malignant melanoma of the choroid usually appears as an elevated
grayish to brown subretinal mass. Serous retinal detachment adjacent to or
remote from the tumor is a characteristic finding in most cases. Orange pig-
ments may be seen on the tumor surface, representing lipofuscin pigments
released from damaged retinal pigment epithelium and sensory cells.
Tumors of the ciliary body and choroid are visualized with the direct and
indirect ophthalmoscopes, and most can be diagnosed by appearance.'" With
the aid of the biomicroscope and the Goldmann three-mirror contact lens,
the details of the tumor surface and the surrounding structures are
thoroughly studied. Transillumination of the eyeball differentiates a cystic
or bullous lesion from a solid mass. Choroidal melanomas at the posterior
retina are diagnosed early because of the early loss of normal vision. The
fellow eye should be thoroughly examined to ascertain its functional status
and to look for clues that may suggest the nature of a suspicious lesion in
the other eye.
In the past, about 20 per cent of eyes enucleated for suspected choroidal
66,67
malignant melanoma were found to contain benign simulating lesions.
This error has been reduced to less than 3 per cent in most centers because
of the routine use of indirect ophthalmoscopy, contact lens examination,
transillumination, and some ancillary tests that will be discussed presently.
The more common simulating lesions include benign choroidal nevus,
rhegmatogenous retinal detachment, choroidal detachment, subretinal hem-
orrhage associated with disciform retinal degeneration, metastatic tumor,

hemangioma, and chorioretinal inflammatory diseases.
Special diagnostic tests that are helpful in tumor diagnosis include ocular
fundus color photographs and fluorescein angiography, 68,69 ophthalmic A
and B ultrasonographic scans, 70-72 and the radioactive phosphorus (
:!2
P)-
7A
uptake test. 7 '-
Visual field testing is useful in documenting changes in
visual function in different areas of the retina, but it is not specific for
choroidal melanoma. When the lesion is small and doubtful in appearance,
repeated clinical observation and color photography should he done to doc-
ument growth. By demonstrating the vascular patterns within the suspected
lesions, fluorescein angiography is valuable in differentiating a benign from
a malignant chorioretinal mass. Malignant melanoma, with a few excep-
tions, exhibits double circulation, early mottling, and fluorescein leakage
with late staining. A metastatic carcinoma in the choroid, however, can also
give these angiographic characteristics.
Ultrasonography further improves diagnostic accuracy by demonstrating
the internal acoustic properties of the tissues under examination. The A-
scan shows choroidal melanoma as an elevated area with a sharp anterior
border and low internal spike motions in a linear graphic manner. The B-
scan gives a two-dimensional picture of the echo patterns of the tissue en-
countered. Choroidal melanoma is characterized by internal hollowing,
choroidal excavation, and orbital shadowing. Ultrasonography is not reli-
able when the tumor is less than 2 mm
in height.
Radioactive phosphorus is preferentially taken up and concentrated by
rapidly metabolizing tissues, such as malignant melanoma and other types
of tumors. The administration of this substance is recommended as an addi-
tional confirmatory test when the clinical eye examination and the fluores-
cein angiography and ultrasonographic studies are inconclusive. A few
false-positive and false-negative results have been reported with this test,
but in experienced hands the P-uptake test is very helpful. The combined
:!2
use of ultrasonography and the P-uptake test has made it possible to cor-
:!2
"'
rectly diagnose intraocular tumors in eyes with opaque media. 7

A general medical evaluation is mandatory whenever a malignant intra-
ocular tumor is suspected. The discovery of an extraocular metastasis or
primary site and other general health problems may influence treatment
decisions. The medical work-up usually includes a careful history, thorough
physical examination, complete blood count, blood chemistry survey with
liver enzymes, urinalysis, chest x-ray, and liver-spleen radioisotope scan.
The liver is the most common site of metastatic melanoma. The enzyme
gamma glutamyltranspeptidase in the blood is a sensitive indicator of liver
involvement. 76 Metastases from ocular tumors are seldom detected prior to
eye surgery.
Classification and Prognostic Factors
Malignant melanoma of the eyelid skin and the conjunctiva is similar

biologically and histologically to cutaneous melanoma, and the same histo-
~
pathologic classification may apply. 77 7il
In order of increasing malignant po-
TABLE 13-3. Types of Tumor Cells and Prognosis of Uveal Melanoma 80
Mortality Rate
Type Description 5-Year 15-Year

*
Spindle A Spindle-shaped with small flat nucleus; contains 5% 18.8%

nuclear chromatin arranged as a line along the
long axis."
Spindle B Spindle-shaped; larger than spindle A; contains 14% 23%

prominent nucleolus.
Fascicular Spindle B type; cells arranged in ribbons or 14% 23%

pallisades around blood vessels.
Necrotic Difficult to locate or identify because of extensive 51% 60%

necrosis.
Epithelioid Large, well-defined, variably shaped polygonal 69% 72%

epithelioid cells with abundant cytoplasm; nucleus
is single or multiple with prominent nucleoli;
mitotic figures common.
Mixed Spindle and epithelioid cells; most common type. 51% 60%
"The malignant potential of this type of melanoma has been degraded recently after thorough histologic
review of slides from fatal cases revealed the presence of more malignant types of cells mixed with the
spindle type A cells. 83
these are the lentigo maligna melanoma (Hutchinson's freckle with

tential,
melanoma), the superficial spreading melanoma, and the nodular melano-
ma.
The natural history of intraocular melanomas has not yet been defined as
clearly as that of cutaneous melanomas. The differences in the anatomic
structures of the skin and the uveal tract of the eye probably explain why
the melanomas from these two structures do not fit into the same systems of
clinical and histopathologic classifications. Intraocular melanomas are clas-
sified according to Callender's system, 80 which is based on the types of
tumor cells present. This system, outlined in Table 13-3, also offers a
means of predicting the prognosis of a case of uveal melanoma. 81-83
The combined mortality rates of these different types of intraocular mela-
nomas is about 25 per cent during the first 5 years and about 45 per cent in
15 years. The presence of extrascleral extension of the tumor increases mor-
tality. The
prognostic significance of the Callender classification system
holds true for the uveal tract melanomas but not for extrabulbar types. The
mortality rate from melanomas is very low, probably due to early detec-
iris
tion and the predominance of spindle types. The mortality rates from con-
junctival malignant melanoma vary from 20 per cent to 40 per cent in 5
years 81 after excision and are comparable to those of the lower clinical stages
of cutaneous melanoma cited by Moseley et al. in Chapter 16 of this book.
Conjunctival melanomas are rare, and the available series are mostly
small. 79
Different groups of investigators have scrutinized the various clinical and

histopathologic factors that may influence the prognosis of ciliary body and
choroidal malignant melanomas. 82 85 88 The size of the tumor is the single
"
'
most important prognostic factor. Tumors larger than 10 mm in greatest di-

ameter often contain epithelioid cells, more mitotic figures, scleral infiltra-
tion, and breaks through Bruch's membrane —
the factors that worsen prog-
nosis. Studies of tumors smaller than 10 mm in diameter have added other
74 75
factors that may have some prognostic value. Nevertheless, there are
'
some cases that do not follow the course predicted by the classification sys-
tem.
TREATMENT
Malignant Melanoma of the Eyelid Skin
and Conjunctiva
For melanomas of the eyelid skin, wide local excision combined with
incontinuity resection of lymphatics and regional lymph nodes is the treat-
ment recommended." It is estimated that about 30 per cent of patients with
1
malignant melanoma of the skin and the conjunctiva have metastases to the
regional lymphatics.
Malignant melanoma of the conjunctiva is rare, and the treatment has
consisted of surgical management and radiation therapy. Surgical treat-
ments vary from local wide excision to radical exenteration of the orbit.
Reese'51 stated that enucleation alone is not sufficient, and exenteration
done soon after histologic confirmation from the biopsy specimen has given
a 40 per cent five-year cure rate, but only 17 per cent when delayed for
more than a montii. A more conservative approach by radiotherapy has
been reported by Lommatzsch, 89 who used 90 Sr/ 90 Y beta ray applicator in the
treatment of 66 cases of conjunctival melanomas. A daily dose of 1000 rad,
up to a total of 15,000 to 20,000 rad, was given, with 77 per cent of his
cases showing tumor regression or no growth during a 3- to 10-year follow-
up period. The mortality rate in Lommatzsch's series appears lower than
that after surgical management, but this needs confirmation through a well-
controlled clinical study. When metastasis from the conjunctival melanoma
is present in the parotid gland lymph nodes, a radical en bloc dissection of
the orbital contents, parotid gland, and regional lymphatics is recommend-

*»
ed. 61 '
Malignant Melanoma of the Iris and

Ciliary Body
melanomas are usually managed by excision of the

Iris iris sector con-
taining the tumor. 91 Metastases rarely occur preoperatively. There is a risk
of disseminating the tumor cells into the extrabulbar tissues during exci-
sion, so utmost care should be taken to avoid direct manipulation or in-
strument contact with the mass throughout the procedure. When both the
iris and the ciliary body are involved by the tumor, iridocyclectomy is rec-
ommended, provided the mass does not extend more than 2 clock hours in
area.
Malignant Melanoma of the Choroid and

the Ciliary Body
The standard treatment for large melanomas of the choroid and the ciliary
body is enucleation. The fact that early enucleation is beneficial to the sur-
vival of the patient suggested by the observations of multiple investiga-
is
tors
K2, 85, 87, 92
R ecen tly,
it has been suggested that enucleation does not im-
prove survival and perhaps contributes to the increase in mortality rate

"
during the three-year period following surgery. 98 95
The death rate from metastatic disease was lower among a group in
which tumor was observed and followed for several years after diagnosis
rather than immediately removed. It is possible that tumor cells are re-
leased into the blood stream in greater numbers during the handling of the
eyeball for enucleation. One group of investigators developed a "no touch"
technique of enucleation, whereby the eyeball is frozen with liquid nitro-
gen running through a silicon tubing applied around the eye prior to its
excision. 96-97 If the concept is correct, a reduction in mortality from meta-
static melanoma should be seen within the three-year period following enu-
cleation using this technique.
When the choroidal tumor is less than 10 mm
in diameter and less than 3
mm in elevation, especially in a seeing or only remaining eye, conservative
treatment is justified to save the eye after the diagnosis has been con-
firmed. The methods of conservative treatment include irradiation with ra-
dioisotopes encased in plaques or rings that can be sutured on the sclera
over the tumor, proton irradiation with the cyclotron, xenon arc photocoag-
ulation, transcleral diathermy, and local full-thickness eye wall resection.
With radiation treatment, it may take six months to two years or longer
before the success or failure of treatment can be determined. Radiation
probably exerts its effects by obliterating the blood vessels of the tissues
encountered or by inhibiting cell replication, leading to cell death at the
end of its life span.
Choroidal melanoma cells are resistant to conventional external radiation
beam treatments at doses that do not destroy the adjacent normal eye struc-
tures. Stallard 98 and Long et al." have shown that many cases of small
choroidal malignant melanomas may be successfully treated by gamma ir-
radiation from a cobalt-60 source enclosed in a platinum case sutured on
the sclera over the tumor. A dose of 50,000 rad to the tumor base and about
8000 rad to the tumor peak is delivered over two weeks. Cobalt-60 plaques
are not widely used in spite of reported successes because of the serious
side effects on normal tissues, such as scleral necrosis, central retinal vessel
occlusion, optic atrophy, corneal damage, cataract formation, and lacrimal
gland atrophy with a resulting dry eye condition.
Gamma irradiation from radon gas contained in gold seeds that are uni-
formly distributed within a polyethylene tube ring sutured to the sclera
100
has also been successful in the treatment of some choroidal tumors. The
side effects, however, are similar to those from the
(i0
Co plaques.
Less penetrating beta rays emitted from 106 Ru/ ,(Mi Rh in an applicator may
also be successful in some choroidal melanomas. 101 The radiation dose is
100,000 rad to the base and 8000 to 10,000 rad to the peak of the tumor
mass delivered over 8 to 14 days. Proton irradiation with a cyclotron 102 has
been reported recently as another promising way of irradiating the tumor.
The maximum proton radiation effect can be focused precisely at the target
tissue with sparing of the adjacent normal structures of the eye. No surgical
procedure is necessary but the immobilization and alignment process is te-
dious with the present technique.
Photocoagulation with a xenon arc has been used effectively on small
choroidal malignant melanomas. The indications and precise guidelines for
its use have been defined in several reports from patients treated and fol-
lowed over main years. 103-105 The tumor is first completely surrounded by
photocoagulation barrages dining several sessions over a period of several
weeks to cut off its blood supply. This is followed by direct photocoagula-
tion of higher intensities over the tumor mass. A combination of photocoag-
ulation as described and local irradiation from a beta ray source from the
scleral side may be a logical method of treating small choroidal melanomas.
Transcleral diathermy has been used with good results, 40- " l0
but there is
apprehension that the extensive scleral damage created by the burns might
promote extrasclcral extension of remaining viable tumor cells.
Some surgeons advocate the technique of full-thickness excision of the
eye wall containing the melanoma. 106, I0T The tumor is first surrounded with
photocoagulation barrages over several weeks to cut off the choroidal blood
supply. The sclera, choroid, and retina with the tumor is then excised, and
the wall defect is closed with a scleral graft. It is a fairly complicated surgi-
cal procedure in which the chances of seeding tumor cells into the wound
or outside the eyeball are great.
When extrascleral extension is present, radical exenteration is recom-
mended, 61 but mortality from metastatic disease remains high. Chemothera-
py has very limited usefulness in disseminated disease. Dacarbazine gives a
partial response rate of about 20 per cent of patients, 108 but the duration of
benefit is only a few months, and cure is not achieved.

The major unresolved question
in the primary treatment of choroidal
melanomas the role and timing of enucleation. Ideally, a randomized
is
study comparing enucleation with other methods that conserve the eye
should be undertaken.
Treatment most commonly fails because of systemic metastases. Experi-
mental immunotherapy and chemotherapy efforts are ongoing in the hope
of solving the problem.
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phia, WB Saunders Co, 1962. UK 97:445, 1977.
CHAPTER 14
ENDOCRINE
TUMORS
Section 1
Multiple Endocrine
Neoplasia
Charles M Haskell
The endocrine and central nervous systems are closely allied regulators
of the body. Neoplastic disease may involve any component of these two
systems, but contemporary physicians have come to recognize a variety of
families in which multiple tumors may occur in endocrine or neuroendo-
1"5
crine tissues in Three such patterns have been
predictable patterns.
widely accepted, namely, multiple endocrine neoplasia (MEN) type I and
MEN type II, which is subdivided into MEN Ha and MEN lib (Table 14-
1).
MEN I, or Wermer's syndrome, usually presents hypercalcemia. 2

as 1
The parathyroid glands generally contain multiple adenomas, and years

may pass before the pancreatic islet cell tumor or pituitary adenoma be-
comes symptomatic. The Zollinger-Ellison syndrome is frequendy a com-
ponent of MEN
I, and rarely this syndrome may be associated with adrenal
corticaland thyroid adenomas.

MEN Ha (Sipple's syndrome) generally presents as a mass in the neck
that proves to be a bilateral medullary carcinoma of the thyroid. 3, Bilateral
pheochromocytomas and mild hypercalcemia from parathyroid hyperplasia
complete the syndrome, although the latter problems are usually asymp-
tomatic.
586
14 Endocrine Tumors 587
TABLE 14-1. Syndromes of Multiple Endocrine Neoplasia (MEN)
Syndrome MEN I MEN Ha MEN lib
Pituitary adenoma X
Pancreatic islet cell tumor X

± Zollinger-Ellison syndrome
Parathyroid adenoma or hyperplasia X X

Medullar) carcinoma of thyroid X X
Bilateral pheochromocytomas X X
Multiple mucoid neuromas or X

neurofibromas, intestinal ganglio-
heuromatosis, characteristic tacn
and marfanoid habitus
MEN lib a genetic variant of MEN Ha in which medullary carcinoma

is
of the thyroid and pheochromocytomas are not associated with parathyroid

disease, but rather with multiple mucosal neuromas or neurofibromas, in-
testinal ganglioneuromatosis, characteristic facies, and a marfanoid habi-
6,7
tus. This variant is usually diagnosed in childhood because of the muco-
sal neuromatosis and characteristic facies.
MEN I and the two variants of MEN II are inherited as autosomal domi-
nant genes, but the degree of penetrance may vary in different individuals
of the same family. This may be expressed in a family by incomplete or de-
layed expression of the characteristic features in different individuals.
Thus, the physician must be prepared to follow these patients carefully for
life, and, when possible, family members should receive similar careful ob-
8
servation and study. 5 '
The MEN syndromes are possible because of the close relationship be-
tween the nervous and endocrine systems. A concept that further unites
these systems is that of the APUD system, 9 11 an acronym drawn from cer-
"
tain histochemical features that unite peptide hormone-producing tissues

(amine precursor uptake and decarboxylation). This concept is presented in
more detail in the sections on carcinoid tumors and pheochromocytomas,
but suffice it to say at this point that it provides a convenient framework for
visualizing multiple interrelationships between neoplasms producing a
wide range of ectopic peptide substances.
The diagnosis and treatment of the individual tumors that compose the
MEN syndromes are described later in their respective sections. More de-
tailed information may be found in excellent reviews by Keiser et al. 4 and
Wells and Onrjes. 5
Section 2
Parathyroid Carcinoma
E Carmack Holmes
INTRODUCTION
Carcinoma of the parathyroid gland is a rare disease representing 1 to 3
per cent of parathyroid tumors. 12, 13 It occurs equally in both sexes, and
all
the age range is from the first to the seventh decades. 13 Not infrequently,
the histologic criteria for diagnosing parathyroid carcinoma are imprecise;
therefore, only those tumors associated with the increased production of
parathyroid hormone should be placed in this classification. This excludes
many cases reported in the literature that were felt to be parathyroid carci-
noma histologically but lacked the stigmata of hyperparathyroidism. 13
NATURAL HISTORY
Clinical Manifestations and Diagnosis
The carcinoma is characterized by acute

clinical course of parathyroid
and chronic episodes related to the metabolic effects of hyperparathyroid-
ism. Hypercalcemia is invariably present, and secondary to this condition is
a high incidence of bone disease (62 per cent) as well as renal disease,
pancreatitis, and, commonly, a long history of gastrointestinal symptoms,
such as nausea, vomiting, and constipation. Death is almost always due to
the metabolic effects of the tumor and its metastases.
Although there are no pathognomonic features, there are several clinical
findings that may alert the physician to the possibility of parathyroid carci-
noma. These tumors are much more likely to be clinically palpable than
parathyroid adenomas. As many as 50 per cent of the parathyroid carcino-
mas in one review were clinically palpable (Table 14-2). 13
The serum calcium level tends to be considerably higher in patients with
parathyroid carcinoma than in those with hypercalcemia secondary to be-
nign parathyroid tumors. The average serum calcium level in patients with
parathyroid carcinoma is 15.9 mg/dL, whereas that reported in patients with
parathyroid adenomas averages 12 mg/dL. 14 As indicated in Table 14-3,
only 10 per cent of the patients with carcinoma of the parathyroid had
serum calcium levels of less than 13 mg/dL, and 75 per cent had calcium
levels of greater than 14 mg/dL. Hypercalcemia, in the presence of an un-
explained unilateral vocal cord paralysis, suggests the possibility of para-
thyroid carcinoma invading the recurrent laryngeal nerve. Therefore, any
TABLE 14-2. Clinical Manifestations of Parathyroid Carcinoma 13
Number OF
Clinical Feature Patients Per Cent
Hypercalcemia
Calcium >14 mg/dL 34 75
Calcium <13 mg/dL 5 10
Bone disease 34 73
Palpable neck mass 24 52
Renal disease 15 32
Pancreatitis 7 15
Cervical metastases 15 32
Distant metastases 13 21
patient whohas a serum calcium level greater than 14 mg/dL, a palpable

cervical gland, or a recurrent laryngeal nerve palsy should be suspected of
having a malignant parathyroid tumor.
The recurrence of hyperparathyroidism several months following opera-
tion on the parathyroid is highly suggestive of recurrent parathyroid carci-
noma. Multiple adenomata usually make their presence known by persist-
ent calcium elevation and are not likely to cause recurrent symptoms after a
disease-free interval of several months. Recurrent hypercalcemia has been
reported as early as three months and as late as nine years following opera-
tion for parathyroid carcinoma. Since parathyroid carcinomas tend to be
larger than their benign counterparts, it is occasionally possible to diagnose
and localize these tumors by angiography. 15
Operative Findings
Not infrequently, the gross features of the tumor at the time of surgery
are quite characteristic of parathyroid carcinoma. In contrast to the soft,
smooth, reddish-brown appearance of an adenoma, parathyroid carcinomas
have a much harder consistency and are usually surrounded by a dense
fibrous reaction. Unlike adenomas, parathyroid cancers often invade adja-
cent structures, such as skeletal muscle, trachea, recurrent nerve, and thy-
roid. This propensity to adhere to and invade adjacent structures is a key to
the recognition of the malignant nature of the tumor at the time of surgery.
TABLE 14-3. Histologic Criteria for Parathyroid Carcinoma 12

(67 Cases)
Patients
L>K1 I E.K1A
Number Per Cent
Fibrous trabeculae 60 90
Mitotic figures 54 81
Capsular invasion 45 67
Blood vessel invasion 8 12
When these features are present, a presumptive diagnosis of carcinoma

should be made even if the histologic features on frozen section are equi-
vocal.
Histopathology
The principal histologic features that distinguish parathyroid carcinoma

from adenomas are a trabecular pattern with thick, fibrous septa, mitotic
12
figures, and blood vessel invasion (Table 14-3). According to Schantz and
Castleman, the presence of mitoses within parenchymal cells is the single
12
most reliable diagnostic criterion. These authors point out that the presence
of cellular atypia and variation is not a useful criterion for carcinoma identi-
fication in view of the fact that benign adenomas may have variations in
nuclear size, nuclear hyperchromatism, giant cells, and other bizarre nu-
clear features.
not always possible, therefore, to diagnose parathyroid carcinoma by
It is
histologic features alone. As with other endocrine tumors, parathyroid carci-
nomas may be difficult to identify microscopically. With the exception of
direct invasion of surrounding structures, lymph node metastases, or the
presence of mitotic figures, there are no diagnostic histologic features. In
addition, it may be times to differentiate between parathyroid
difficult at
tumors and those of the thyroid and thymus, which may be histologically
similar.
Prognosis
Parathyroid carcinomas tend to be slowly growing tumors with a tenden-

cy for local invasion. The prognosis is quite favorable when the initial sur-
gical treatment is adequate. When the malignant nature of the disease is
not recognized initially, with ensuing inadequate surgical treatment, the
prognosis is almost uniformly poor. However, patients who have a two-year
or greater disease-free interval between the initial surgery and the local
recurrence do have better prognoses than those with recurrence within the
two-year period.
Although patients may survive with clinically apparent disease for many
years, they eventually succumb to the ravages of hyperparathyroidism. A
review of 46 patients with parathyroid carcinoma has indicated an overall
cumulative five-year survival rate of 50 per cent and a ten-year survival rate
of 13 per cent. 13
TREATMENT
Surgery the only curative therapy for carcinoma of the parathyroid.
is
Once the diagnosis has been made, an en block excision is indicated. This
entails skeletonization of the trachea and excision of any skeletal muscle
intimately related to the tumor. If involved, the recurrent laryngeal nerve
14 / Endocrine Tumors 591
should be resected because of the recurrence of disease following attempts

to dissect the tumor from the nerve. If lymph node metastases are present,
complete excision of the nodes in the tracheal-esophageal groove and an
ipsilateral radical neck dissection are indicated. Great care should be taken
to avoid rupturing the capsule of these tumors in view of the high propensity
for local recurrence.
The only opportunity for complete cure occurs at the initial surgical pro-
cedure, and it is imperative that an adequate operation be performed at that
time. Since at least 30 per cent of patients develop a local recurrence fol-
lowing surgical excision, it is imperative that the initial surgical resection
be complete. 13 Most often, unfortunately, the malignant nature of the proc-
ess is not appreciated, and inadequate surgical excision is performed. The
disease is characterized thereafter by local recurrence and ultimately by vis-
cera] dissemination.
When local recurrence occurs following surgical removal, a second opera-
tive procedure is indicated to remove as much tumor as possible. Multiple
excisions of cervical recurrences may, in fact, be indicated for palliation.
However, the survival following a local recurrence in spite of surgical treat-
ment is less than 30 per cent.
Resection of functioning pulmonary metastases should be considered as a
palliative measure to help control hypercalcemia. 13 There is no evidence
that radiation therapy is of any palliative benefit, and there have been no
reports of the successful use of chemotherapeutic agents.
Section 3
Thyroid Gland
Jerome M Hershman William H Blahd

H Earl Gordon
INTRODUCTION
Etiology
Radiation to the thyroid may induce thyroid neoplasms, both benign and
malignant. Calculated rad doses to the thyroid have varied from about 700
rad to 1500 rad in most patients. 1617 Benign neoplasms of the thyroid are
more frequent than carcinoma after radiation. The incidence
five- to tenfold
of benign neoplasms is proportional to the rad dose up to 1200 rad. 18
Doses exceeding 2000 rad probably damage the thyroid to such an extent
that neoplasms are not a consequence. Thyroid carcinoma has resulted from
radiation given to the thymic region of infants, the tonsil and adenoid of
16 19 "
children, and the face of adolescents with acne. The latent period be-
tween the radiation and the recognition of a thyroid neoplasm has most
commonly been 20 to 35 years, 17 but thyroid tumors have been found as
soon as 5 years and as long as 50 years after the radiation treatment. 20
Thyroid cancers that are related to radiation are well-differentiated papil-
lary and follicular carcinomas. Thyroid carcinoma is approximately three
times more common in women than in men, as are most thyroid diseases.
Epidemiology
In Chicago, head and neck radiation was associated with a 6 per cent
incidence of subsequent thyroid carcinoma, 17 whereas in Detroit, the in-
cidence was only 1.5 per cent. 21 Perhaps the method of delivery of the
radiation and other unidentified factors modify the mutagenic effects of thy-
roid radiation. Radioiodine in atomic bomb fallout has been linked with
thyroid carcinoma in Japan 22 and the Marshall Islands. 23 In experimental
animals administration of small doses of radioiodine followed by long-term
administration of goitrogenic chemicals produced neoplasms similar to
human papillary carcinoma. 24
The relationship between endemic goiter and thyroid carcinoma has
been carefully studied. In an endemic
goiter region of Colombia, thyroid
carcinoma was found in 1 per cent of autopsies and was responsible for
death in 0.6 per cent. 25 The incidence of thyroid carcinoma in this region
was fivefold greater than that in New York state. In Switzerland, the use of
iodized salt reduced both the incidence of endemic goiter and the death
rate from thyroid carcinoma. 26 However, the decline in the incidence of
goiter in the United States has not been associated with a reduction of the
incidence of thyroid carcinoma.
Heredity. Medullary thyroid carcinoma, a tumor of the calcitonin-
secreting cells, is a component of multiple endocrine neoplasia, type II, as
are bilateral pheochromocytoma and parathyroid adenomas. Although it is a
hereditary disorder in a large proportion of patients and follows a pattern of
autosomal dominant inheritance, 27 most cases of medullary thyroid carcino-
ma are sporadic rather than familial. Papillary or follicular thyroid carcino-
ma may cluster in families, suggesting hereditary or familial predisposition.
Effect of Thyroid-Stimulating Hormone

(TSH) on Thyroid Tumors
The anterior pituitary hormone, thyroid-stimulating hormone (thyrotro-

pin), stimulates many biosynthetic processes within the thyroid gland and
promotes its growth. The removal of thyrotropin causes involution of the
thyroid.
Papillary and follicular thyroid carcinomas generally possess a lower level
of normal biosynthetic activity. In scans performed with radioiodine, these
tumors usually do not concentrate radioiodine to the same extent as adja-

cent normal thyroid tissue, giving rise to the term cold nodule. This infor-
mation has often been misinterpreted by inferring that hypofunctioning
tumors (in relation to the concentration of radioiodine) are not affected by
thyrotropin. However, recent studies have shown that benign and malig-
nant (differentiated) thyroid tumors have receptors for thyrotropin and that
this hormone increases the adenyl cyclase activity, the cyclic AMP concen-
2829 Growth of the tumor
tration, and the oxidation of glucose by the tumors.
is probably dependent on these processes and is, therefore, influenced by
thyrotropin.
NATURAL HISTORY
Classification
Table 14—4 shows the histopathologic classification and frequency of the

different forms of thyroid carcinoma. The differentiated thyroid cancers, pa-
pillary and follicular, compose 80 per cent of thyroid cancers.
Clinical Features
Thyroid cancer usually presents as a discrete mass in the thyroid. The

onset is insidious, and the tumor is often discovered on routine physical
examination. Sometimes rapid growth of the tumor may call it to the atten-
tion of the patient. Significant enlargement within a period of a few weeks
to a few months suggests a cancer or hemorrhage into a thyroid cyst.
The consistency of malignant tumors varies from firm or even stony to
that of normal thyroid tissue. The lack of movement of the thyroid nodule
with swallowing and fixation of the tumor to adjacent structures indicate
malignancy. Thyroid carcinoma may metastasize to local lymph nodes, to
the contralateral thyroid lobe, and to adjacent cervical structures. In some
patients, there is cervical lymphadenopathy due to metastases, without a
palpable nodule in the thyroid. Distant metastases occur most often in bone
and lung.
Lateral displacement of the trachea and esophagus is more often due to a
large multinodular goiter than to a carcinoma. Vocal cord palsy is strongly
indicative of a cancer involving the homolateral recurrent laryngeal nerve.
TABLE 14-4. Histopathologic Classification of Thyroid Cancer 26
Type Frequency (%)
Papillary (with or without follicular foci) 62

Follicular (note extent of invasion of tumor capsule) 18
Medullary 6
Undifferentiated (anaplastic) 14
Diagnosis
A battery of special diagnostic tests is often employed to determine the

cause of a thyroid nodule. Thyroid scans with radioiodine show the ability
of the nodule to concentrate radioiodine, in comparison with the rest of the
gland. If the nodule concentrates nearly all the radioiodine and is hyper-
functional ("hot"), the lesion is almost certainly not a carcinoma. A recent
study reported the poor discrimination of thyroid scans for making the diag-
nosis of thyroid carcinoma. 30 Nearly all thyroid cancers appear as hypofunc-
tional ("cold") areas if they are large enough. Scans cannot usually detect
lesions smaller than one centimeter. Unfortunately, benign processes such
as cysts, inflammation, colloid goiter, or adenomas are usually "cold" on
the scan, also.
Selective concentration of selenomethionine has been found in thyroid
carcinomas, 31 but the results with this scanning agent have not been as
helpful for diagnosis in other studies.
Ultrasonography is very useful in differentiating cystic nodules from solid
lesions. Thyroid cysts are nearly always benign, but solid or mixed solid
and cystic lesions may be malignant. 32
Fine needle aspiration biopsy is a safe procedure, and cytologic study of
33,34
the aspirated cells has been found to be very useful. With this tech-
nique, the aspiration of fluid permits the diagnosis of thyroid cysts, and the
resulting decompression provides therapy of the cyst. Biopsy with a larger
needle, such as the Vim-Silverman, is also useful 35 but has not been prac-
ticed widely because of the difficulty and possible hazards of this proce-
dure.
X-rays of the neck with soft-tissue technique may disclose psammoma
36
bodies in papillary carcinoma that show up Large,
as fine "grains of rice."
irregular calcifications usually represent calcified degenerative areas in a
multinodular goiter or carcinoma.
Several blood tests may be helpful. Measurements of serum thyroxine
and triiodothyronine concentrations are generally normal; elevated levels
indicate that the thyroid nodule is hyperfunctioning. Low levels of circulat-
ing thyroid hormones and a high serum TSH concentration indicate hypo-
thyroidism and suggest that the thyroid enlargement results from compen-
satory hypertrophy. The measurement of antithyroid antibodies
(antimicrosomal or antithyroglobulin antibodies) will yield diagnostic titers
in about two thirds of patients with nodular goiter caused by chronic lym-
phocytic thyroiditis. Serum thyroglobulin concentrations are elevated in a
high proportion of patients with nodular goiter, regardless of the etiology,
so that this test is not useful in distinguishing benign processes from thy-
roid carcinoma. 37
Serum calcitonin levels are elevated in patients with medullary thyroid
carcinoma; therefore, this blood test is useful in screening patients with
thyroid nodules, although the expected incidence of medullary thyroid car-
cinoma in all thyroid nodules is estimated to be only 0.4 per cent. Screen-
ing with calcitonin may be made more sensitive by using provocative stim-
uli, such as infusion of calcium or pentagastrin. 27
Table 14-5 lists the staging of thyroid cancer by the classification. TNM
In spite of the varied manifestations of thyroid cancer, the rate of growth,
the mode of spread, and the response to therapy are reasonably predictable
for each of the four subgroups. Because of the slow growth of the differen-
tiated types, survival statistics usually reflect a composite of various thera-
peutic approaches that has evolved over the years.
Papillary Adenocarcinoma. The mode of extension of this thyroid
tumor is primarily by way of the lymphatics, with positive lymph node in-
"
volvement present in approximately 40 to 50 per cent of patients. 38 40 In
contrast to malignancy arising in almost all other organs, the presence of
lymph node metastases does not necessarily have an adverse effect on the
outcome of the disease. In fact, some studies now suggest that lymph node
involvement may actually exert a protective effect upon the patient. 41 This
concept, however, demands further study.
It is generally recognized that the prognosis is poorer in patients over the
age of 40 years (Table 14-6). The presence of lesions 5 cm or larger and

extrathyroidal extension of the cancer are additional factors that usually
have an adverse effect on the outcome. In contrast, occult papillary lesions
(1.5 cm or less) are almost invariably curable.
TABLE 14-5. Staging of Thyroid Cancer Utilizing the

TNM Classification
T — Primary Tumor
TX Tumor that cannot be assessed by rules
T„ No available information on primary tumor
T, Mobile tumor
T 4 cm or less in greatest diameter
la
T lb Over 4 cm in greatest diameter

T, Fixed tumor of any size, with or without neurologic involvement
Tv, Lateral position
T lhMidline position
T :) Massive fixation of tumor, any size, with or without neurologic
involvement; fistula
N — Nodal Involvement
NX Nodes cannot be assessed
N No palpable nodes -
N, Palpable mobile node or nodes

\ la Homolateral onlj
\,i, Contralateral only
Ni c Bilateral and/or midline
N 2 Any palpable fixed node
M — Distant Metastasis
MX Not assessed
M No (known) distant metastases
M, Distant metastases present
Specify (site)
'From Manual tor Staging of Cancer (1977) by the American Joint Committee for Cancer Staging and End-
resuks Reporting. (Note: There is currently no satisfactory staging system for thyroid cancer that has been
adopted by the AJC. The above table represents a temporary classification suggested for use by AJC for data
collection.)
596 II / Treatment of Specii k Neoplasms
TABLE 14-6. Survival of Patients with Papillary

Adenocarcinoma by Age Group 40
Age 5 Yrs 10 Yrs
40 yrs or less 98.8% 94.9%

Over 40 yrs 86.6% 72.8%
Follicular Carcinoma. Even though these lesions often appear to be

encapsulated, there is a propensity for vascular invasion. Although the
overall ten-year survival rate is reported at 72 per cent, it decreases to 34
per cent in selected patients who demonstrate a moderate to marked de-
gree of invasion. 40, 42 Spread to regional lymph nodes is rare, compared with
papillary lesions. Distant metastases, when present, are most frequently-
found in the lung and bone.
Medullary Carcinoma. This lesion is much more aggressive than the
differentiated neoplasms. The overall five-year survival rate is about 45 per
cent. 40 In patients without cervical lymph node metastases, the survival
closely approximates the rates for normal subjects of comparable age. 42 Re-
gional lymph node spread is common, but unlike the papillary type, distant
metastases may occur in the lung, liver, and elsewhere.
Anaplastic Carcinoma. These neoplasms are highly lethal regardless
of treatment. Most patients will die of their disease within six to eight
months of diagnosis. 40,42
TREATMENT
Surgery
Surgical therapy is the definitive treatment for thyroid carcinoma. If

operations were performed on all patients with nodular goiter, the inci-
dence of carcinoma would probably be about 4 per cent. This low inci-
dence was found in an autopsy study of thyroid nodules in patients who
had no clinical evidence of thyroid cancer. 43 When patients are carefully
evaluated for surgery by the diagnostic methods described previously in
this chapter, and surgery is restricted to those patients strongly suspected
of having a thyroid carcinoma, the incidence of carcinoma in resected spec-
imens approaches 50 per cent.
The indications for surgical treatment include (1) suspicion of malignancy
by palpation when the nodule is hard, fixed to surrounding structures, or
associated with lymphadenopathy, (2) relatively rapid growth of a thyroid
mass in a euthyroid patient over 40 years old, (3) growth of a thyroid nod-
ule while the patient is on suppressive doses of thyroid hormone, (4) need-
le biospy indicative of thyroid carcinoma, (5) psammoma body calcification
on x-rays, (6) obstructive symptoms, and (7) elevated serum calcitonin lev-
els.
Although there is general agreement that surgical excision is the most

effective primary treatment for thyroid carcinoma, the extent of resection
remains highly controversial. This applies not only to the amount of thyroid
gland that should be resected but also to the management of regional
lymph nodes.
The reasons for a lack of unanimity of opinion in surgical management
are due to the unique characteristics of thyroid carcinoma, compared with
most neoplasms arising in other sites. First, the relatively low incidence of
thyroid carcinoma makes it difficult for any individual or hospital to accu-
mulate a broad experience except for large referral centers. Second, the
slow rate of growth in the vast majority of thyroid cancers dictates that
follow-up must be measured over a time span of 10 to 20 years. Conse-
quently, there is a paucity of prospective studies that compare the merits of
one therapeutic modality with another.
The two major factors that dictate the extent of the operative procedure
are (1) the distribution of the carcinoma within the thyroid gland, and (2)
the histologic type of the neoplasm. Inasmuch as the biologic behavior of
the tumor is influenced so greatly by the second factor, it is useful to con-
sider the surgical approach on the basis of the predominant cell type.
Well-Differentiated Adenocarcinoma (Papillary and Follicu-
lar). Although there are some basic behavioral differences between these
two cell types, there are enough similarities to justify considering them in
one group.
In approaching a single suspicious nodule, a total lobectomy on the af-
fected side is most frequently the biopsy procedure of choice. Exceptions
would be those few small lesions that can be easily removed with a wide
margin of normal tissue. Incisional biopsy or enucleation should never be
done.
been established, a decision must be
After the diagnosis of carcinoma has
made in regard to the extent of thyroid tissue to be removed. This contin-
ues to remain one of the most controversial aspects in the surgical manage-
ment of this disease. Those who favor a total thyroidectomy support their
decision on the high incidence of multicentric foci of carcinoma and the
risk of local recurrence. 44 Many
surgeons favor a lesser resection, usually a
total lobectomy if small and confined to one side of the
the lesion is
gland. 45 The isthmus is often included along with the resected lobe in
order to provide a wider margin of clearance. The proponents of the con-
servative approach support their view with two principal arguments. The
first relates to the recognized risk of permanent hypoparathyroidism and
recurrent laryngeal nerve injury associated with total thyroidectomy. Sec-

ond, while acknowledging the frequency of multicentricity and the poten-
tial risk of local recurrence with the more limited procedures, they argue
that these factors have little bearing on the eventual outcome of the dis-
ease. 38
Recent reports, however, present a challenge to this latter argument. In a
study of the impact of therapy on 576 patients with papillary thyroid carci-
noma, Mazzaferri et al. 39 found that recurrences occurred with more than
twice the frequency following subtotal thyroidectomy, compared with total
thyroidectomy (18.4 per cent and 7.1 per cent, respectively). Also, the pro-
portion of deaths due to thyroid cancer was significantly greater in those
patients treated with a conservative resection.
A reasonable compromise that is gaining support at present is to perform
a near-total thyroidectomy, preserving several grams of thyroid tissue pos-
teriorly on the side of least involvement of carcinoma. "' " 47 !f
In experi- '
;
enced hands, this procedure can be carried out with low morbidity if one
carefully identifies and preserves the recurrent nerve and parathyroid
glands. The remnant of thyroid tissue preserved can then be eradicated
postoperatively with radioactive iodine. The total elimination of all thyroid
tissue carries the additional benefit of enabling one to identify and treat re-
currences and metastases with radioactive iodine. This approach, combin-
ing the use of radioiodine ( 131 I) with surgery, has proved to be a highly
effectivemeans of controlling the disease.
In spite of the recognized risk of total thyroidectomy, this procedure
must be employed in those patients with extensive bilateral carcinoma. In
those instances in which there is extrathyroidal extension of cancer, resec-
tion of adjacent tissues may also be required.
In regard to the management of the regional lymph nodes, there is now
general agreement that prophylactic neck dissections have no value in the
treatment of thyroid cancer. The presence of metastatic cancer, confirmed
at the time of operation, is the indication for the removal of cervical lymph
nodes in this disease. The unique in that the routes of lymphatic
thyroid is
drainage are accessible for examination at the time the primary tumor is
removed. The extent of lymph node dissection to be performed will de-
pend upon the magnitude and extent of node involvement.
Although divergent views prevail in regard to the extent of regional
lymph node dissection, most surgeons have joined the trend toward a more
conservative resection that is limited to the extent of clinical node involve-
ment. Consequently, the standard radical neck dissection should be per-
formed only on those occasional patients in whom the metastatic disease in
the lateral neck cannot be removed with a lesser resection. Even fairly ex-
tensive involvement of lateral cervical nodes can be adequately removed in
most patients with a modified type of neck dissection, resulting in the pres-
ervation of the sternocleidomastoid muscle, the spinal accessory nerve, and,
usually, the internal jugular vein as well. Some surgeons feel that excision
of involved nodes along the internal jugular vein can be done more com-
pletely by removing the vein.
If thepresence of positive node involvement is confined to the anterior
neck in the region of the thyroid, it is reasonable to limit the dissection to
this area. An en block anatomic anterior neck dissection can be undertaken
that is carried superiorly to the level of the thyroid cartilage, laterally to the
and interiorly into the anterior superior mediastinum. The
carotid sheath,
can be readily accomplished through the conventional neck incision.
latter
Care must be taken to encompass the lymphatic tissue along the recurrent
nerves.
Medullary Carcinoma. In view of the high incidence of bilaterality,
48, 49
a total thyroidectomy should be performed. 40, Because of the aggressive
nature of the disease, lymph nodes in the midline compartment of the neck
and internal jugular chain should be routinely biopsied. If these nodes are
positively involved, classic ipsilateral or, if necessary, a bilateral neck dis-
One must be mindful of the possible associa-
section should be carried out.
tion ofpheochromocytoma and parathyroid tumors with this neoplasm. Any
coexistent pheochromocytoma should be removed prior to cervical explora-
tion in order to avoid hypertensive crises during the neck operation.
Anaplastic Carcinoma. These rare tumors grow rapidly and are un-
iformly fatal. Because of local invasion of midline structures, local removal
by total thyroidectomy is recommended but is frequently impossible. Exter-
nal irradiation may provide some degree of palliation.
Radiation
RADIOIODINE. Although the majority of thyroid adenocarcinomas can be

removed surgically, there is often uncertainty as to the completeness of the
resection and the presence of local or distant histologic metastases, despite
the absence of clinically detectable abnormalities. Therefore, radioiodine
131
( I) has been used as adjunctive therapy in the management of thyroid
adenocarcinoma for more than 30 years. There is mounting evidence indi-

cating an increased rate of survival and a decreased tumor recurrence in
patients who have received radioiodine therapy. It would appear to be pru-
dent, therefore, to ablate with radioiodine any residual thyroid tissue that
has not been removed surgically, since the complete ablation of all normal
thyroid tissue usually assures rapid radioiodine uptake in remaining tumor
deposits and tumor metastases.
The efficacy of radioiodine therapy, with rare exception, is directly relat-
ed to tumor uptake and retention. Under appropriate conditions, radioio-
dine uptake has been found in 50 to 80 per cent of adenocarcinomas of the
thyroid. 50 Efficient uptake and response to radioiodine is observed in
tumors that are of the differentiated cell type, such as papillary or follicular,
whereas undifferentiated tumors and Hiirthle cell and medullary carcino-
mas rarely concentrate radioiodine. Effective tumor uptake is approximately
0.5 per cent of the dose per gram with a biologic half-life of approximately
four days. From the administration of 150 millicurie (mCi) ,3, I, a tumor
will receive about 25,000 rad or five times the absorbed dose that can be
delivered by a course of external radiation therapy. Moreover, this dose will be
delivered to every functional metastasis regardless of its size or location in
the body, and tumor tissue will receive several hundred times the radiation
exposure received by the rest of the body.
In addition to the ablation of all normal thyroid tissue, the administration
of thyroid-stimulating hormone may also significantly increase the accumu-
lation of radioiodine in thyroid cancer metastases. This is particularly true
in those patients in whom endogenous TSH levels fail to rise significantly
after thyroid ablation. Since radioiodine uptake by tumor tissue appears to
be closely related to elevated endogenous TSH levels, the measurement of
TSH would appear to be essential for the rational management of thyroid
cancer patients. 51 The administration of TSH, however, is not without com-

plications, since sensitivity reactions may occur in as many as 40 per cent
of patients who receive repeated courses. Controversy also exists as to
whether or not exogenous TSH is significantly additive to the endogenous
TSH levels that follow a prolonged period of withdrawal of thyroid replace-
ment. 52
Once adequate tumor uptake has been assured by radioiodine imaging
may be administered. Doses rang-
studies, therapeutic doses of radioiodine
ing from 100 to 200 mCi 131
depending on the extent of tumor distribution,
I,
are given at intervals of four to six months until no clinical or imaging

evidence of residual thyroid or functioning tumor tissue is demonstrable.
Thryoid hormone replacement therapy with thyroxine (T-4) or desiccated
thyroid is discontinued four weeks before each diagnostic or therapeutic-
dose and is resumed three days after therapy or immediately after comple-
tion of diagnostic studies. Therapy with triiodothyronine (T-3) needs to be
discontinued for only two weeks, because T-3 is cleared from the body
much more rapidly than thyroxine. After total tumor ablation, test doses of
5 mCi 131 I, preceded by TSH stimulation, are given at yearly intervals for five
years, and biennially thereafter to detect recurrence (Table 14-7). 53
In accordance with radiation therapy principles, the maximum amount of
131
I that can be safely administered should be given. The limiting factor is
the possibility of complications from the damaging effects of radioiodine on

normal or vital tissues. Whole-body radiation from usual therapeutic doses
of radioiodine is estimated at 20 to 40 rad. Generally, complications are
minor and rarely interfere with therapeutic endeavors. 54 Transient radiation
thyroiditis may occur, persisting for two to three weeks, and occasionally
swelling of the parotid or submaxillary salivary glands may be observed
shortly after therapy and persist for several days. Bone marrow depression
is uncommon with usual dosage regimens, except when bone metastases
are present. Pulmonary fibrosis has been reported in patients with pulmo-
nary metastases after repeated administration of large therapeutic doses. 55
TABLE 14-7. Diagnostic, Therapeutic, and Follow-up

Procedures Following Tumor Ablation"
A. Diagnostic Procedure after Thyroidectomy

Discontinue thyroid hormone therapy for 4 weeks prior to diagnostic testing if T-4
1.
was used or two weeks if T-3 was used

2. Give 10 units of TSH daily for three days
3. Give 5 mCi l3I I orally 24 hr after last TSH injection
4. Scan neck and body 48 hr after 13, I dose
B. Therapeutic Procedure
1. Repeat steps 1 and 2 of procedure A.
2. Give 100 to 200 mCi 131 I orally 24 hr after last TSH injection
3. Scan neck and body three to five days after 131 I dose
C. Follow-up Procedure
1. Repeat procedure A yearly for five years and every two years thereafter
2. Retreat according to B if functioning metastases are detected

3. Prescribe thyroid hormone replacement therapy after and between 131 I diagnostic
and therapeutic procedures
"After Krishnamurthy GT, and Blahd WH: Cancer 40:195, 1977.

Fifteen cases of leukemia have been reported in the medical literature, an

incidence that is slightly greater than the expected natural incidence. 56 The
majority of such patients had received large total cumulative radioiodine
doses. The transformation of previously differentiated tumors to rapidly
growing anaplastic cancers may occur in a small percentage of patients. 57
Since this is known to occur spontaneously in untreated adenocarcinomas,
there appears to be no evidence to implicate radiation as the cause of
tumor transformation.
Radioiodine imaging is the most sensitive and specific test available for
the early detection of recurrent thyroid cancer. Recurrent lesions are gener-
ally not clinically apparent but are detectable by this procedure. The recur-
rence of tumor following radioiodine ablation of all functioning tumor tis-
sue has been observed in more than 50 per cent of patients who had tumor
metastases and in 25 per cent of patients who did not have metastases. 53
Recurrences have been observed after five to ten years of negative diagnos-
tic studies. In view of the possibility of late recurrence, all patients in
whom total radioiodine ablation has been obtained should be followed by
means of diagnostic imaging studies at one- to two-year intervals to assure
that they remain free of functioning tumor.
Despite 30 years of experience, the therapeutic efficacy of radioiodine in
the management of thyroid cancer remains controversial. There are several
possible explanations for this circumstance. Of primary importance is the
fact that relatively few patients have been treated with radioiodine. Conser-
vative estimates place this figure at approximately 5000. Only a small
number have been followed for a period that is sufficient for evaluation of
long-term therapeutic benefit. This situation exists because of the remark-
able longevity of many thyroid cancer patients. Evaluation is further con-
founded by the multiple and combined forms of adjunctive therapy that
have been employed in most reported series. 54
A number of reports have appeared in recent years that would tend to
support the therapeutic efficacy of radioiodine therapy. 39, 58 62 In a large
"
group of patients with papillary and follicular carcinoma, Varma et «/. 58

observed that surgery combined with radioiodine therapy significantly im-
proved the rate of survival in patients over 40 years of age when compared
with a series of 50 patients who were only surgically treated. They also
observed a 20-fold increase in the death rate when total radioiodine abla-
tion of tumor tissue was not achieved. Using recurrence of cancer as an
index of response, Mazzaferri et a/. 39 observed only a 2.6 per cent recur-
rence rate at five years and no deaths in a group of thyroid cancer patients
who received radioiodine and thyroid hormone therapy postoperatively. In
those patients who received only thyroid hormone postoperatively, the re-
currence rate was 11 per cent, and in those patients who received no post-
operative therapy, the recurrence rate was 20 per cent with a mortality rate
of 12.5 per cent.
In some patients, no therapeutic benefit is obtained with radioiodine
therapy, whereas in others, large and disseminated tumor masses disappear,
and no evidence of recurrence of tumor tissue can be demonstrated after 20
years of follow-up. In view of this variability in response, it is important
602 II / Treatment oe Specific Neoplasms
that radioiodine therapy be used judiciously in the appropriate clinical sit-
uation and for the histologic type of tumor that can he expected to be
clinically responsive.
One may conclude from the foregoing discussion that postoperative ra-
dioiodine ablation therapy is efficacious in the management of patients
with adenocarcinoma of the thyroid. It is also clear that the risk of death
from residual postoperative tumor or the continued spread of inoperable
tumor is considerably greater than the hazards attributed to radioiodine
therapy.
External Radiation. Conventional radiation therapy may be detri-
mental to the success of radioiodine therapy in thyroid adenocarcinomas
and should not precede therapeutic efforts with radioiodine. 63 External ra-
diation therapy in the management of thyroid cancer should be reserved for
anaplastic carcinoma and lymphoma. It is of questionable value in Hurthle
cell and medullary carcinomas. Therapy is best given using high-energy
electrons. 64
Chemotherapy
Thyroid Hormone. There have been no trials of treatment with thy-

roid hormone as primary therapy. Instead, it is used after surgical therapy
and radioiodine. In most instances, the administration of thyroid hormone
is regarded as an adjuvant to prevent recurrence of the tumor. The use of
thyroid hormone to suppress TSH secretion after resection of differentiated

thyroid cancer has been practiced for many years. As noted previously,
thyrotropin is an important growth factor for thyroid follicular cells, and in
a few cases, metastatic thyroid carcinoma has diminished markedly after

treatment with thyroid hormone.
Suppression of pituitary thyrotropin secretion may be achieved with thy-
roid in doses that are only slightly greater than those of customary
hormone
replacement. The preparation of choice is sodium levothyroxine (thyroxine)
because the serum concentrations of thyroxine and triiodothyronine are
more stable in patients treated with thyroxine. About two to six hours after
administration of desiccated thyroid or triiodothyronine, there are large su-
praphysiologic peaks of serum T-3 concentration, which fall to lower levels
over the next 24 hours, thus making therapy with these preparations less
physiologic. The measurement of TSH concentration is not sufficiently sen-
sitive todemonstrate low levels in most TSH radioimmunoassays. For this
reason, the suppression of the TSH response to thyrotropin-releasing hor-
mone (TRH) may be a helpful criterion in the follow-up of patients with
thyroid cancer. 65 - 66
The mean dose of thyroxine to obliterate the TSH increment after TRH
is about 220 /xg in patients with thyroid carcinoma and 175 to 200 fig in
patients with benign goiter. This is only about 25 to 75 fig greater than the
mean replacement dose of thyroxine in adults. The dose should be adjusted
for each patient. Excessive doses of thyroxine, desiccated thyroid, or triio-
dothyronine have been advocated in the past. These should be avoided,
however, because they may produce disturbing symptoms of thyrotoxicosis
and may exert deleterious effects on the heart and cause demineralization of
bones if continued chronically.
DOXORUBICIN". For patients with metastatic undifferentiated thyroid car-
cinoma, medullary carcinoma, or aggressive differentiated carcinoma that is
refractor> to radiotherapy, doxorubicin has been used with some benefit. 67
In a significant proportion of patients, doxorubicin has caused a greater
man 50 per cent reduction in the size of metastases and has produced sub-
jective improvement. Guidelines for the use of this drug are given in Chap-
ter 5.
Section 4
Endocrine Pancreas
Ronald K Tompkins Mayer B Davidson
INTRODUCTION
In general, the behavior of malignant tumors of the endocrine pancreas
mimics that of their benign counterparts, and clinical and laboratory diagnos-
ticprocedures are similar for both. In this section the tumors of alpha-cells
(glucagonomas), beta-cells (insulinomas), and delta-cells (Zollinger-Ellison
tumors, or gastrinomas, "pancreatic cholera," or diarrheogenic tumors, and
somatostatinomas) will be discussed. The incidence of malignant tumors of
the endocrine pancreas ranges from 10 per cent for insulinomas to 50 per cent
for glucagonomas and up 65 per cent for Zollinger-Ellison (Z-E) and
to
diarrheogenic tumors. Tumors of the endocrine pancreas producing multiple
hormones have been described but will not be specifically covered in this
discussion, since their management is very similar to those that will be de-
tailed.
NATURAL HISTORY
Alpha-Cell Tumors (Glucagonomas)
Tumors of the (glucagonomas) have recentiy been de-

alpha-cells
in women than in men, and over 50 per
69
scribed. 68 '
They are more common
cent are malignant, in contrast to the low prevalence of malignancy in insulin-
omas. 70
The "glucagonoma syndrome" is characterized by a very distinctive rash,
weight loss, stomatitis, glossitis, mild diabetes, hypoaminoacidemia, and a
normochromic, normocytic anemia. The cardinal features of the rash (termed

necrolytic, migratory erythema) are erosions and crusting, which tend to be
seen on the buttocks, groin, central parts of the face, and distal aspects of the
lower extremities. Marked erythema with plaques, papules, pustules, and
even bullae is usually present. Fungal and bacterial superinfections, as well
as sparse scalp hair and thin, friable nails, are not uncommon.
The diagnosis is confirmed by markedly elevated fasting plasma levels of
pancreatic glucagon, often in excess of 1000 pg/ml (normal <150 pg/ml). This
hyperglucagonemia is directly responsible for the mild diabetes through its
stimulation of hepatic glucose production via enhanced glycogenolysis and
gluconeogenesis. Increased gluconeogenesis, in which amino acids are con-
verted to glucose, is responsible for the lower amino acid levels. As with
patients harboring insulinomas who have an increased percentage of proin-
sulin, the plasma from patients with glucagonomas contains greater than
normal amounts of a high molecular weight molecule, possibly proglucagon,
which reacts with antisera to pancreatic glucagon. 71, ** Since glucagonomas
can be part of the multiple endocrine neoplasia, type I syndrome, further
appropriate endocrine testing is important.
Beta-Cell Tumors (Insulinomas)
Insulinomas are tumors involving functioning pancreatic beta-cells. They

occur more often in women than in men and are usually diagnosed in the
older age group. Approximately 80 per cent of these patients have single
benign adenomas, 10 per cent have malignant tumors, and the remaining 10
per cent have multiple benign tumors. A large percentage of the latter group
are part of the syndrome of multiple endocrine neoplasia, type I. The tumors
are small, usually < 2 cm in diameter, and are located with equal frequency in
the head, body, and tail of the pancreas. Almost without exception, these
patients present with symptoms of hypoglycemia occurring in the fasting
state. Because the blood glucose may drift down slowly as fasting ensues, the
symptoms of hypoglycemia (tachycardia, nervousness, weakness, circumoral
and extremity tingling, sweating, tremor, and occasional nausea and vomit-
ing), which are due to sympathetic nervous system activity, may be absent or
minimal. Therefore, these patients may present with the more confusing
symptoms of depressed central nervous system function (headache, transient
neurologic syndromes, visual difficulties, mental confusion, personality
changes, and convulsions). Weight gain is common in these patients because
chronic hyperinsulinemia and hypoglycemia lead to excessive caloric intake
and lipogenesis.
To prove that an endocrine gland is overactive and functioning auton-
omously, one must show that it cannot be suppressed normally. The only
physiologic stimulus that inhibits insulin secretion is Therefore, the
fasting.
key to diagnosing an insulinoma is to document an inappropriately high
insulin level for the resulting glucose concentration as the patient fasts.
Although glucose concentrations may drop as low as 30 to 35 mg/dL in normal
patients (especially in women) after a three-day fast, insulin levels also de-
crease considerably.
There are several ways to relate glucose and insulin concentrations during
However, we have found that the simple glucose (mg/dL): insulin
fasting. 7 -
(fxU/ml) ratio is very effective. In normal subjects, this will remain above 2.5
as fasting proceeds, whereas in patients harboring an insulinoma, the ratio
will almost invariably fall below 2.5. 73 After an overnight fast, glucose and
insulin measurements are obtained every 4 to 6 hours for 72 hours or until
symptomatic hypoglycemia occurs. This will happen within 24 hours of start-
ing the fast in two thirds of the patients with insulinoma and in 95 per cent
within 48 hours. Only 5 per cent of patients need three full days of starvation
to manifest hypoglycemia. It should be stressed that high insulin concentra-
tions are not necessary to make the diagnosis. A value of 25 to 40 /xU/ml at a
time when the glucose concentration has fallen to less than 40 mg/dL is
typical. Although stimulator) tests with tolbutamide, leucine, and glucagon
are often employed, false-positive and/or false-negative results are not
uncommon (Table 14-8). Since false-positive leucine tests are relatively un-
usual, this the one we prefer if a stimulatory test is used.
is
The measurement of proinsulin has proved helpful in diagnosing insulin-

omas. Normally, the percentage of proinsulin in the fasting plasma is less than
20 per cent of the total immunoreactive insulin. This may increase from 25 to
75 per cent in many insulinoma patients. 74 76 Malignant tumors are often
"
associated with the highest amounts of proinsulin —

50 to 75 per cent. 7
"'
Arteriography for insulinomas has been found to be approximately 50 per cent

successful in visualizing the tumor. 77 It is of relatively little use in other
islet-cell tumors, however.
Delta-Cell Tumors
Zollinger-Ellison Syndrome, or Gastrinoma. The classic triad of

ulcer diathesis, massive gastric hypersecretion, and pancreatic islet-cell
tumor, which was described in 1955 78 and is known as the Zollinger-Ellison
syndrome, has been expanded. 79 Further experience has shown that these
TABLE 14-8. Laboratory Tests for Insulinoma
Sampling Times Glucose Insulin

Test (Mins) (Mg/dL) (/xU/Ml)
Glucagon 0, 3, 6, 10, 15, 20, Late hypoglycemia >120 M U/ml

1.0 mg IV 25, 30, 60, 90, 120 diagnostic of
insulinoma
Leucine 0, 10, 20, 30, 45, Rapid decrease to >40 fiUlml

150 mg/kg orally 60, 75, 90 <40% of basal
Tolbutamide 0, 5, 10, 20, 30, 60, Failure to return >120 /iU/ml

1.0 gm IV 90, 120, 150, 180 toward fasting
level by 2 to 3 hours
72-hour fast every 4 to 6 hours Glucose: insulin

ratio <2.5
tumors may arise outside the pancreas in the duodenum and that steatorrhea
may be a prominent feature of the illness.
The early diagnosis of these tumors has been facilitated by the physician's
awareness of the condition (over 800 cases now registered) and the develop-
ment of a specific radioimmunoassay for gastrin. In difficult diagnostic cases,
the measurement of plasma gastrin levels following intravenous administra-
tion of calcium or secretin 80 has confirmed the presence of a gastrinoma.
Recent data indicate that secretin is the safest and most reliable provocative
test to use in these cases. 80a Approximately 65 per cent of these tumors are
malignant and have metastasized by the time of operative confirmation of the
disease. For reasons as yet unclear, total gastrectomy may slow down the
course of the disease and cause metastases to regress. 81 Indeed, one of Zol-
linger and Ellison's initial two cases had lymph node metastases at the
operation at which total gastrectomy was performed. The patient underwent
thorough re-exploration during a cholecystectomy ten years later, and no
metastases were found. She was alive and well 23 years after total gastrec-
tomy. 82 In spite of such favorable cases, Fox et al. S3 have analyzed the reported
cases and found that deaths from metastatic tumor are frequent.
Diarrheogenic TUMORS OF THE Pancreas. These tumors produce a
syndrome of massive, watery diarrhea (as distinct from the steatorrhea of Z-E
tumors), leading to hypokalemia and associated with the absence of gastric
hypersecretion. Approximately two thirds of the patients have hypercalcemia
during active diarrhea and one third are found to be hyperglycemic. 84 A
variety of names have been associated with this disease entity, including
Verner-Morrison syndrome,85 syndrome of watery diarrhea with hypokalemic
alkalosis (WDHA), 86 and "pancreatic cholera," a term coined by Dean Sher-
man Mellinkoff of UCLA. 87 The diagnosis is to be suspected in patients
presenting with the classic symptoms in whom other, more common, causes of
diarrhea have been excluded. There is no pathognomonic test as yet, but the
finding in many
of these patients of high levels of vasoactive intestinal poly-
peptide (VIP) in the serum and in tumors has led some to consider this the
88
active hormonal agent and to call these tumors "VIPomas." These tumors
have been reported in approximately 80 patients and 56 per cent of them were
malignant and had metastasized at the time of operation. Untreated or refrac-
tory tumors lead to death from dehydration or renal failure in a few weeks to
months. As in other "APUDomas," these tumors have been reported in sites
other than the pancreas. 88
Somatostatinoma. Three cases of pancreatic islet-cell tumors associated
with diabetes or abnormal glucose tolerance (and in one case hypochlorhydria
and steatorrhea) have been reported. 89 91 In all cases, the tumor of the pancreas
"
contained high levels of somatostatin. It is interesting that two of the tumors

were found during operations for cholecystectomy prompted by symptoms of
abdominal pain. In two of the three cases, liver metastases were found, and
the patients died shortly after operation. Retrospectively, it was felt that in
one patient the tumor had probably been present on x-rays taken eight years
previously. In the patient with the benign tumor, pancreaticoduodenectomy
was performed, and the patient was asymptomatic at follow-up 28 months
92
after operation.
Based uponthis admittedly small experience, it appears that the malignant

potential these tumors is similar (66 per cent) to that of other delta-cell
of*
tumors previously discussed. The action of somatostatin is to inhibit most

other gut hormones, such as insulin, glucagon, and gastrin, as well as growth
hormone. The occurrence of diabetes was the clinical index finding in one of
these patients and was cured by removal of the tumor. It is too early to know
the natural history of these tumors, but their occurrence should be suspected
in the presence of diabetes and an islet-cell tumor.
TREATMENT
Surgery
As is the case in most endocrine tumors, the treatment of choice is complete

surgical extirpation of the lesion, if possible.The malignant endocrine pan-
creatic lesions call for similar surgical approaches, with the exception of Z-E
tumors, which are discussed separately.
Glucagonomas, Insulinomas, Diarrheogenic Tumors, and Somato-
STATINOMAS. In the presence of nodal metastases only, wide excision of the
lesion is indicated. However, with hepatic metastases, unless they are isolat-
ed to one anatomic area of the liver, complete resection is not feasible. In the
case of widespread hepatic metastases, placement of a hepatic artery catheter
by way of the gastroduodenal artery is indicated for postoperative chemother-
apy (see later discussion). In all cases, if "debulking" is technically possible,
it should be done. If complete surgical extirpation does occur, the characteris-
tic rash of glucagonoma will usually improve within several days and clear
rapidly. 95
ZOLLINGER-ELLISON TUMORS. In this lesion, even in the presence of
widespread metastases, radical resection of the target organ (stomach) by total
gastrectomy is associated with long, symptom-free intervals and occasional
regression of metastases. This is one of the relatively few instances in endo-
crine surgery in which a target organ can be removed effectively, and it offers
some insight into the feedback mechanisms that may drive these tumors.
Radiation Therapy
The treatment of metastatic deposits with radiation has not been associated
with significant relief of symptoms. Since most metastatic lesions are in the
liver, treatment with high-voltage radiation carries with it the risk of hepatic
decompensation or failure.
Chemotherapy
GLUCAGONOMA. The relative rarity of this lesion precludes any large

experience with chemotherapy. One case of malignant glucagonoma has been
successfully treated with streptozotocin. 94
Insulinoma. If hyperinsulinemia and hypoglycemia persist after surgical

intervention — because of metastases, incomplete removal of multiple tumors
or hyperplastic tissue, or failure to locate a small tumor — oral diazoxide
(Proglycem) is usually employed to treat the hypoglycemia. This preparation
should not be confused with the intravenous diazoxide (Hyperstat), which is
administered as a bolus to lower dangerously high blood pressure.
Diazoxide is a nondiuretic benzothiadiazine that causes hyperglycemia in
normal subjects and animals. This agent will not affect tumor growth. Diazox-
ide is known to directly inhibit insulin secretion by the beta-cell; 95 to stimu-
late epinephrine production by the adrenal medulla, 95 which may further
block insulin secretion 96 and inhibit peripheral glucose utilization; 97, 9H and to
directly block hepatic glucose production. 99 The usual dose is 100 mg orally
three to four times daily. Side effects may include nausea, sodium retention
(for which a diuretic is added), rash, increased hair growth (hypertrichosis
lanuginosa), unexplained tachycardia, eosinophilia, granulocytopenia, neu-
tropenia, thrombocytopenia, lymphocytosis, and hyperuricemia. Approxi-
mately half the patients will respond to diazoxide. 100 Since oral diazoxide may
be ineffective in an appreciable number of cases, other agents have been tried
for the treatment of hypoglycemia. These include diphenylhydantoin
105
(Dilantin), 101 103 chlorpromazine, 104 and propranolol.
"
Streptozotocin, an experimental antibiotic isolated from Streptomyces

achromogenes, will localize in and destroy normal and neoplastic beta cells.
This intravenously administered agent is the drug of choice in metastatic
insulinoma, since both objective tumor regression and amelioration of hypo-
glycemia are often seen. 106 Its use is discussed in Chapter 5. In view of the
toxicity of this drug, only patients with metastatic and unresectable tumors
should be treated. Approximately 50 per cent of these patients will show
108
objective remission. 100 106 L-asparaginase 107 and doxorubicin
'
have occasion-
ally been effective in patients who are unresponsive to streptozotocin.
Zollinger-Ellison Tumors. To date, the best results with any chemo-
109
therapeutic agent have been reported with the use of streptozotocin. The
recent introduction of the histamine H 2 blocking agent cimetidine carries
with it the hope for long-term effective control of the gastric hypersecretion
effects of these tumors in those patients who are not candidates for total
gastrectomy. 110 The effect of this drug on metastatic lesions from Z-E tumors is
unknown.
DlARRHEOGENlC TUMORS. Streptozotocin has been the only effective che-
motherapeutic agent reported in the treatment of these metastases, and the
111
hepatic arterial route has been recommended. Other agents, such as cortico-
113 114
steroids, 112
nutmeg, and indomethacin (the latter two being prostaglandin
inhibitors), have been used to ameliorate or abolish the diarrhea caused by
persistent hormone production from the metastases of these tumors.
SOMATOSTATINOMA. As yet, there is no reported experience with any
chemotherapeutic agent in these unusual tumors. However, it would appear
from experience with other pancreatic endocrine tumors that streptozotocin
would be a logical choice for trial administration in the patient with metastatic
somatostatinoma.
Immunotherapy
There has been no reported use of immunotherapy in these tumors.

Theincreasing use of radioimmunoassay in the diagnosis of these endo-
crine tumors will enable the suspicious physician to confirm the diagnosis
earlier. Similarly, the coupling of hormonal antibodies with specific tumor
toxins or radioisotopes may aid in more effective eradication of metastatic
tumor deposits. The recent report of somatostatin use in a patient with hy-
perinsulinemia due to nesidioblastosis of the pancreas may herald a trial of
this drug in patients with metastatic insulinomas. 115
Section 5
Carcinoid Tumors
Charles M Haskell Ronald K Tompkins
INTRODUCTION
Carcinoid tumors are found in fewer than 1 per cent of all cancer autopsy
cases, and its approximate incidence is only 1 to 2 per 100,000 population. 110
Despite the rarity of these tumors, their multiple manifestations have fascinat-
ed physicans for decades, and the carcinoid syndrome often proves to be a
dramatic and difficult problem in patient management. The detailed biochem-
ical, endocrinologic, and biologic characteristics of the carcinoid tumors are
beyond the scope of this section, but certain features that are important in
treatment will be summarized. Excellent reviews exist for the reader who is
interested in a more detailed description of these problems. 10, 116, 117
The etiology of carcinoid tumors is unknown. However, the pathogenesis of
the tumor is fairly well understood through studies defining the neuroectoder-
mal origin of cells of the APUD system (amine precursor uptake and decar-
boxylation). 10, n It has been known for more than 60 years that carcinoid
tumors develop in enterochromaffin cells; however, only since the work of
Pearse 9 in the late 1960s has the unifying concept of the APUD system
allowed clarification of the histogenetic basis for carcinoid tumors that occur
in such diverse sites as the lung, 118 119 biliary tree, 120 pancreas, 121 stom-
'
610 II / TREATMENT] OF SPECIFK NEOPLASMS
H H NORMALLY
-0
C-C-COOH 99%
Oct-
^^X^ H NHj CARCINOID AS
littleas +o'A
-> NIACIN 6- PROTEIN
H
NON- HYDROXYLA TED L-TRYPTOPHAN
INDOLE ACIDS TRYPTOPHAN
OR AMINES HYDROXYLASE
1
H H
-C-COOh
^>< N ^ H NH 2
5-HYOROXYTRYPTOPHAN (5HTP)
AROMATIC L- AMINO AC/O DECARBOXYLASE
(IN TUMOR AS WELL AS NORMAL TISSUES)
I
(
H H
s^>k N ^ h N
l
5-MY0R0XYTRYPTAMINE SEROTONIN (5 HT)
/ MONOAMINE OXIDASE
(IN TISSUE, BLOOD 6-
TUMOR)
ALDEHYDE DEHYDROGENASE
PLATELET BINDING
S-HYDROXYTRYPTOPHOL
-COOH
•O-SULFATE ESTER
'txji O-SULFATE O-GLUCURONIDE
CONJUGATE CONJUGATE
S-HYDROXYINOOLE ACETIC ACIO
(S-HIAA)
FIGURE 14-1. Metabolism of tryptophan in a patient with carcinoid syndrome. Heavy

arrows indicate the shunting of tryptophan away from its usual metabolic pathway to form
niacin and protein. Heavy arrows leading from serotonin show the major metabolites of sero-
tonin excreted in the urine sec text for further discussion (From Mclmon KL: In Textbook of
i ).
Endocrinology. Williams RH (ed), Philadelphia, \YB Saunders Co, 1974.)
ach, 122, 123

duodenum, 123,small intestine, colon, rectum, ovary, 125 cervix, 126
124
testis,
127
thymus, 128 kidney, 129 and larynx. 130 This concept also underpins the
rare occurrence of carcinoid tumors in some of the multiple endocrine neopla-
sia syndromes (MEN, types I and II), as well as its association with the ectopic
production of various peptides (ACTH, growth hormone, insulin, gastrin,
10 u
calcitonin, beta MSH, ADH, and vasoactive intestinal peptide).
"
l22, 123, 131
133
Many of the clinical and diagnostic considerations in carcinoid tumors

relate to their syntheses of serotonin and other biologically active materials.
Serotonin synthesis and metabolism play a key role in the understanding of
this disease. 116 The schematic presentation shown in Figure 14-1 emphasizes
the shunting of tryptophan away from its usual metabolic pathway to form
niacin and protein in patients with the carcinoid syndrome. Some gastric and
bronchial tumors lack aromatic L-amino acid decarboxylase and release large
amounts of 5-hydroxytryptophan (5HTP) into the blood. Metabolites in the
urine then include 5HTP, 5-hydroxytryptamine (5HT, serotonin), and less
5-hydroxyindoleacetic acid (5HIAA) than is expected.
NATURAL HISTORY
Classification
Carcinoid tumors are usually small greyish white to yellow nodules fre-
quently encased by intact gut mucosa. 10 116 The primary tumor is almost never
'
larger than 3 cm, and its submucosal location often makes it difficult to locate.
This is in marked contrast to the gross appearance of carcinoid metastases.
Metastatic lesions may be very large or they may be small tumors enmeshed
in an abundant desmoplastic reaction that may mimic the one seen with
retroperitoneal fibrosis. 10,118,117 Indeed, when the desmoplastic reaction in-
volves the mesentery, it may retract, giving a gross appearance likened to
that of a closed umbrella.
Because of differences in the histologic appearance of carcinoid tumors
occurring in different parts of the gut, as well as differences in histochemistry
and the frequency of association with various clinical syndromes, Williams
and Sandler 134 have classified carcinoid tumors as being of foregut, midgut,
and hindgut derivation. Table 14-9 gives some of the characteristics of carcin-
oid tumors that are derived from different embryonic divisions of the gut.
Depending on the site of carcinoid tumors, they may be benign or of very
low metastatic potential or may frequently be associated with widespread
metastases. The appendix is the only site that is almost never associated with
metastatic disease. 110 Criteria for malignancy have been developed, based
primarily on the size of the tumor and its invasiveness. A high frequency of
metastatic spread appears to be associated with tumors greater than 2 cm in
VMi
any location, including the appendix. 10 -
Spread into muscular layers of
i:i:>
-
the intestine or into regional lymph nodes also may be associated with distant
metastasis. 10
TABLE 14-9. Characteristics of Carcinoid Tumors Derived

from Different Embryonic Divisions of the Gut°
Characteristic Foregut Midgut Hindgut
Histologic structure Trabecular pattern Characteristic Atypical;

solid nests of tendency to
cells trabecular
Argentaffin and diazo reactions Usually negative Positive Often negative
Tumor 5-HT Low High Not detected
5-HTP secretion Frequent Rare Not detected
Urinary 5HIAA High High Normal
Metastases into bone Common Unusual Common

(usually osteoblastic) and skin
"Modified from Melmon KL: In Textbook of Endocrinology, 5th ed. Williams RH (ed), Philadelphia, \VB
Saunders, 1974 and Williams ED and Sandler M: Lancet 1:238, 1963.
Clinical Features
Most carcinoid tumors occur

in the gastrointestinal tract, as shown in Table
138
14-10. 137,The clinical course of these tumors is highly variable. The prima-
ry tumor commonly causes no symptoms, and even with extensive local
disease bowel obstruction is uncommon. 10 Primary lesions in the appendix
may cause symptoms of appendicitis, but many are found in patients undergo-
ing incidental appendectomy performed as part of pelvic or abdominal opera-
tions.
The systemic symptoms of the carcinoid syndrome are almost never found
in patients lacking metastatic disease in the liver. 10, 16, m Exceptions include
carcinoid tumors of the ovary or bronchus (Table 14-11). The latter sites
release humoral mediators of the carcinoid syndrome directly into the system-
ic vascular system, whereas gut primary tumors release these mediators into
the portal system. The liver is highly efficient in degrading these materials;
therefore, little, if any, of these vasoactive substances reach the systemic cir-
culation.
There are several variants of the classic carcinoid syndrome, and many
vasoactive materials have been implicated in their genesis. 10,116117,139 The
most common component of these syndromes is flushing of the skin, but
diarrhea, bronchoconstriction, and cardiac lesions may also be seen. Rarely,
myopathy 140, 141 or arthropathy 142 may occur, although the relationship of these
problems to the other manifestations of the carcinoid spectrum is obscure.
Table 14-12 summarizes the major patterns of the carcinoid syndrome; the
"classic" syndrome is that described for tumors arising from the
II6, 117
ileum. 10, Serotonin is well established as the cause of diarrhea in these
patients, and it is also the putative cause of fibrotic changes in the heart and
elsewhere. 10, 116, 117, 139 However, a wide variety of substances may contribute
to the other features of the "carcinoid spectrum." Some of these mediators,
with their usual therapy, are summarized in Table 14-13. 10, 116, 117, 139
A final clinical feature of note with carcinoid tumors is their high association
with other tumors. 143,144 Patients with carcinoid tumors must therefore be
carefully followed for life.
Diagnosis
syndrome usually have the diagnosis

Patients presenting with the carcinoid
confirmed by measuring the 24-hour urinary excretion of 5HIAA. 10, 116, 117 A
value in excess of 9 mg per 24 hours in a person without malabsorption or a
value in excess of 30 mg per 24 hours in cases of malabsorption may be
considered confirmatory. One must remember that certain foods or drugs may
give a false-positive test result (bananas, walnuts, avocados, pineapples,
reserpine- and glycerol guiacolate-containing cough syrups, for example).
Phenothiazines may give a false-negative result.
Patients with gastric or, rarely, bronchial carcinoids may not have diagnos-
118
tic elevations of 5HIAA because of the lack of L-amino acid decarboxylase.
In these patients, confirmation of the diagnosis may require a search for
5-hydroxytryptamine and 5-hydroxytryptophan in the urine by paper chroma-
1 1 Endocrine Tumors 613
TABLE 14-10. Sites of Carcinoid Tumors
Surgical Patients 137 Necropsy 1M

Site (%) (4000 Cases) (%) (201 Cases)
Appendix 45 3
Small bowel 30 76
Rectum 15 1.5
Bronchus 5 9
Colon 5 6
Stomach 3 2.5
Ovary 1
Other 2
TABLE 14-11. Metastatic Behavior of and Syndrome Production by

Carcinoid Tumors
Site Metastasizing (%) \\ nil Syndrome (%)
Colon 60 5
Small bowel 30 7
Bronchus 30 15
Stomach 5
Rectum 15
Ovary 5 50
Appendix 1 Rare
TABLE 14-12. Carcinoid Syndromes by Anatomic Site 10,118 1 " '
Syndrome Bronchus Stomach Ileum
Flush Severe, prolonged Blotchy, often Episodic"

with facial edema continuous (3 to 10 minutes)
Diarrhea Infrequent Less severe Severe
Bronchoconstriction Infrequent Frequent Sporadic, asthma-like

attacks, may be severe
Cardiac lesions Left side Infrequent Right side
Miscellaneous Sudden death Hypotension,

peptic ulcers
"Worse after eating, exertion, alcohol.

614 II / Treatment of Sri < n u Neoplasms
TABLE 14-13. Carcinoid Spectrum 10 n6 - >»• 139
Syndrome Possible Chemical Mediators Treatmi n
Flushing 5-Hydroxytryptamine Adrenocorticosteroids

Bradykinin Phenothiazine
Prostaglandins
Unknown hydroxy fatty acids
Calcitonin
Diarrhea 5-Hydroxytryptamine Cyproheptadine

Methysergide
P-chlorophenylalanine
Fibrotie changes— right 5-Hydroxytr> ptamine Surgery

heart disease
Miscellaneous Catecholamines
Histamine
Kinins
Gastrin
ACTH
Insulin
tography. Wedo not recommend the use of epinephrine as a provocative test

for the carcinoid syndrome because of its potential dangers.
Staging
Since no staging system has been established for carcinoid tumors, we have
proposed one based on the TNM
system, as described in Table 14-14. This
system may be applied to the multiple primary sites at which these tumors
mav arise.
Prognosis
In one series, the average survival rate from the onset of the carcinoid
syndrome was over 8 years, with some patients surviving 10 to 20 plus years
TABLE 14-14. Proposed TNM Staging for Carcinoid Tumors
T„ No primary tumor found

T, Tumor ^ 1 cm in greatest diameter
T 2 Tumor 1.1 to 2 cm in greatest diameter
T ;1
Tumor 2.1 to 3 cm in greatest diameter
T4 Tumor > 3 cm in greatest diameter
N No regional node metastasis
N] Regional node involved
\1„ No metastasis
M, Metastasis present
A Asymptomatic
B Carcinoid syndrome present
TABLE 14-15. Five-Year Survival Rates (%) in Patients with Carcinoid Tumors
Stage
p__
alTfc.
Local Regional Distant
Appendix 99 99 27 99
Bronchus 96 71 11 87
Rectum 92 44 7 83
Small bowel 75 59 19 54
Stomach 93 23 52
Colon 77 65 17 52
with metastatic disease. 145, " However, in another series, patients with well-
,;
documented hepatic or bone metastases, markedly elevated urinary 5HIAA

levels, and the carcinoid syndrome did not survive longer than one year on
the average." 7 The reason for the discrepant results is not clear. Five-year
survival rates from a series of 2837 cases are given in Table 14-15 for refer-
ence purposes 148
TREATMENT
Surgery
Surgical removal of all neoplastic tissue is the preferred therapy for primary
10
tumors. The extent of the surgical resection is dependent upon the location
of the tumor, its size, its anticipated stage, and the general condition of the pa-
tient.
Sites. More specific guidelines for selected sites are as follows:
Appendix. Small appendiceal carcinoids (< 2 cm) are best managed by
simple appendectomy unless the lesion is adjacent to the cecal wall. A rare
larger lesion or one that involves the cecum may require right hemicolectomy
with removal of regional nodes.
Small Bowel. Since about one third of these carcinoids metastasize, en
bloc resection is indicated, including the lymph nodes draining the tumor
plus at least 10 cm of the bowel on either side of the lesion. If the tumor is
within 5 cm of die ileocecal valve, a right hemicolectomy may be necessa-
10
ry.
bowel carcinoid is too extensive for curative resection, one

If the small
should still resect as much of the tumor as possible to reduce tumor bulk or
perform intestinal diversion if there is any obstruction. Every attempt should
be made to remove all visible tumor; if this is not feasible, a subtotal resection
should be attempted. 110 In every case, however, one must remember the
tendency of this tumor to cause fibrosis and to be associated with malabsorp-
tion. The mesenteric vasculature must be protected and the amount of small
bowel resected kept to the minimum necessary to accomplish the debulking
procedure.
Rectum. Tumors smaller than 2 cm may be treated with local resection. If

the tumor is larger or shows other signs of locally aggressive growth, a more
extensive resection is necessary. Above the peritoneal reflection this may be
accomplished by anterior resection and anastomosis. Below the peritoneal
reflection such tumors generally require an abdominoperineal resection. 10
Liver Metastases. Metastatic involvement of the liver is not a contraindi-
cation to the palliative resection of symptomatic primary and metastatic car-
cinoid tumors. If hepatic metastases are limited to a single lobe of the liver,
hepatectomy should be considered. 10,149 151 If hepatic metastases are
"
partial
bilateral, enucleation of these lesions by blunt finger dissection may be
considered, if feasible. 10 152
'
If multiple liver metastases preclude partial hepatectomy or enucleation,

and if the patient demonstrates progressive deterioration, hepatic artery liga-
tion may be considered. 10, 153155 This has been reported to give symptomatic
improvement, but its true place in treating these patients has not yet been
defined. In particular, it is at present unclear whether or not the results justify
the risks of surgery and anesthesia. Hopefully, further study of alternatives to
this approach, such as that employing hepatic artery occlusion by the use of
embolic fragments of gelatin, 156 will obviate the need for the more invasive
procedure.
Cardiac Disease. Endocardial plaques may accompany the carcinoid syn-
drome and result in cardiac failure. 157 Tricuspid valve replacement may be
useful in selected patients in whom due to right-sided congestive
ascites is
heart failure rather than progressive abdominal tumor. 158

Anesthesia Considerations. Patients with the carcinoid syndrome tol-
erate anesthesia poorly. 124, 159161 Careful preoperative assessment and treat-
ment is mandatory, and the anesthetist must be prepared for the potential
intraoperative problems that may occur. In general, the major problems can
be ascribed to either serotonin or kallikrein-bradykinin. 159 Table 14-16 sum-
marizes the pertinent effects of these materials as they relate to anesthesia.
Based on the factors summarized in Table 14-16, the following general
principles of anesthesia for these patients can be enunciated. First, every
effort should be made to avoid factors that precipitate a carcinoid attack.
This includes avoiding nerve blocks, succinylcholine, curare, morphine,
muscle agitation, or prolonged attempts at intubation. Second, it is usually
prudent to premedicate the patient with an antiserotonin agent (such as
cyproheptadine hydrochloride) and in severe cases an antibradykinin agent
(phenothiazine).
Intraoperative therapy should be tailored to the problem. Methotrime-
prazine may be used for serotonin effects. Corticosteroids are generally avoid-
ed except for patients with severe flushing associated with a bronchial carcin-
oid. Hypotension should be treated with methoxamine hydrochloride or
angiotensin; catecholamines and metaraminol should be stringently avoided,
since they may aggravate the carcinoid attack.
It should be clear from this discussion that a thorough understanding of the
physiologic basis for the carcinoid syndrome is required for safe anesthesia in
these patients. The physician responsible for such treatment is encouraged to
review several good references on this subject. 10, 159161
TABLE 14-16. Anesthetic Considerations in the

Carcinoid Syndrome 10 116 159161
- -
Serotonin Effect Bradykinin Effect
Brain Slow awakening from -

anesthesia
Heart Tachycardia; Tachycardia

positive inotropic effect;
cardiac plaques (chronic)
Blood vessels Vasoconstriction; Vasomotor paralysis;

and flow hyperkinesis; hypotension
hypertension
Lung Hyperpnea Bronchoconstriction
Gut Nausea, vomiting, —

diarrhea, cramps
Metabolism Hyperglycemia Bradykinin shock with

acidosis. hypotonicity,
hypovolemia
Skin - Flushing, edema
Treatment Cyproheptadine Phenothiazine preoperatively

preoperatively
Methotrimeprazine Aminophvllin las required for

intraoperativel) as required bronchoconstriction)
Use minimal anesthesia Alpha-blockade (as required for

flushing) (phenox) benzamine;
phentolamine)
At oid morphine Methoxamine or angiotensin

(for hypotension)
Avoid catecholamines,
metaraminol, dopamine
Radiation Therapy
The traditional view has been that radiation therapy is ineffective in treat-
ing carcinoid tumors, save for symptomatic bone metastases. 10 Even with
novel techniques, such as injection of yttrium-90 microspheres into the hepa-
162
tic artery of patients with liver metastases, radiation therapy has not been
widely used. However, this view has been challenged by Gaitan-Gaitan and
coworkers 163 who reported long disease-free survival for five patients with
nonresectable abdominal carcinoid tumors treated with 2500 rad of whole
abdominal radiation therapy given over four to six weeks. We remain skepti-
cal of this approach, but it clearly justifies further study and possible use in
patients who have failed more established therapy.
Chemotherapy
Cytotoxic chemotherapy should be avoided in the early stages of the carcin-

oid tumor. 164 The indolent course of the tumor in many patients, the exacerba-
tion of symptoms that may result from treatment, and the lack of evidence for a
life-prolonging effect of chemotherapy all support this recommendation.
However, cytotoxic chemotherapy appears justifiable in patients with pro-
gressive, symptomatic tumors. Partial responses with single agents have gen-
erally lasted four to six months, but more prolonged palliation has been
achieved in some patients. Table 14-17 summarizes the available agents and
"
178
their approximate response rates. 164
Combination chemotherapy appears to be superior to single agents, as
shown in Table 14-17. The combination of 5-fluorouracil and streptozotocin
has been reported to benefit 38 per cent of a small series of patients treated at
164, 165
the Mayo Clinic and by the Eastern Cooperative Oncology Group. Since
streptozotocin is not toxic for the bone marrow, both drugs can theoretically
be given in full doses, as described in Chapter 5. However, patients with the
carcinoid syndrome should not receive full-dose therapy initially because of
possible precipitation of a carcinoid Moertel 164 therefore recommends
crisis.
starting this drug combination at 50 per cent of full dose for each agent, with
subsequent dose escalation as tolerated. Unfortunately, premedication of
TABLE 14-17. Chemotherapy for Carcinoid Tumors
Partial Response
Treatment No. of Patients No. % References
Single Agents
Streptozotocin 23 7 30 164-169
Alkylating agents 39 9 23 164, 165, 170-173
5-FU 29 6 21 164, 165
MTX 6 1 16 174
Dactinomycin 9 1 11 164
Mitomycin-C 3 - 164
Doxorubicin 1 1 — 175
Dacarbazine 2 2 — 176
Drug Combinations
5-FU + streptozotocin 53 20 38 164, 165
CYC + streptozotocin 45 12 27 165
CYC + MTX 12 7 58 166, 172, 174
D (ADR) + 5-FU 3 2 - 166
Ftorafur + D (ADR) + RCNU 2 - 166
BCNU + streptozotocin 1 - 164
CYC + MTX + D (ADR) 1 - 175
CYC + VCR 1
— 177
CYC + VCR + CCNU 1
— 178
5-FU +BCNU 2 - 164
CYC + MeCCNU 4 — 166
5-FU 2 — 166
'Abbreviations are as follows: 5-FU, 5-Fluorouracil; MTX, methotrexate; CYC, cyclophosphamide; D (ADR),
doxorubicin; VCR, vincristine; BC\T, carmustine; CCNU, lomustine; MeCCNU, semustine.
these patients w ith serotonin antagonists is generally ineffective in prevent-

ing the precipitation of carcinoid symptoms. 184
The chemotherapy by hepatic artery infusion is very controver-
role of
*'»
sial.M" Most oncologists avoid this technique because of the prolonged
hospitalization that often results and because of the complications of the
procedure. We are currently reserving this technique for patients who have
failed systemic chemotherapy and who are candidates for experimental treat-
ment with hepatic artery ligation. In this setting, hepatic artery infusion with
5-fluorouracil appears to be acceptable therapy.
General Care Including Control of

Pharmacologically Active Products
Factors that appear to precipitate carcinoid attacks should be identified and

avoided if possible. Examples may include certain foods, alcohol, or certain
kinds of physical activity. Careful attention to nutrition is important, with

particular attention to the likely development of niacin deficiency. 10, n6, n7
Psychologic factors may also be important.

The physiologic basis for various components of the carcinoid syndrome
has already been given. Serotonin-induced diarrhea should be treated with a
narcotic preparation initially. Diarrhea that is resistant to such measures may
also be treated with the antihistamine cyproheptadine (Periactin), usually
given in a dose of 4 mg three times daily. Resistant cases may respond to
methysergide maleate (Sansert) at doses of 10 to 15 mg per 24 hours. Since
methysergide maleate can cause retroperitoneal fibrosis, its use should be
minimized.
The
control of flushing is more difficult. Antiserotonin agents rarely modify
thisproblem, although phenothiazine or alpha-adrenergic blockage with phe-
noxybenzamine hydrochloride may be useful. Patients with bronchial carcin-
oid and severe flushing may benefit dramatically from corticosteroids. Aspirin
may be useful in the rare patient whose tumor elaborates prostaglandins.
As described in the discussion of anesthesia for patients with carcinoid
tumors, severe hypotension should be treated with angiotensin or methoxa-
mine; catecholamines and metaraminol should be stringently avoided. We are
unaware of any reports on the use of dopamine in these patients, but theoreti-
cally should be avoided. It is also important to avoid monoamine oxidase
it
inhibitors, since they may block the conversion of serotonin to inactive

metabolites. 180
There very little experience with combined modality treatment for car-
is
cinoid tumors, save for die obvious need to combine the medical management
of the carcinoid syndrome any treatment likely to precipitate carcinoid
witii
attacks. The curative mainstay of treatment remains surgical excision, with
other modalities serving palliative goals.
620 II / Treatmivi oj Specifw Neoplasms

A variety of experimental approaches to the control of the carcinoid syn-
drome has been reported, but none of these has been widely accepted.
Examples include the use of parachlorphenylalanine as an inhibitor of sero-
"
tonin synthesis, 181, 182 the use of 5-fluorotryptophan, and hemodialysis.
IH:!
A 1 1
single case report of spontaneous regression of a bronchial carcinoid follow-

ing pregnancy suggests a hormonal role in treatment, but this avenue has not
been pursued. 185 To the best of our knowledge, immunologic approaches to
treatment also remain unexplored.
Section 6
Pheochromocytoma
Ronald K Tompkins Roy T Young
INTRODUCTION
Pheochromocytomas may tumors — most commonly within
arise as single
the adrenal medullary tissue — as bilateral tumors in the adrenal glands, or as
nonmalignant tumors scattered in the adrenal glands and the other catechol-
secreting tissues throughout the body (Table 14-18). 186 In addition, they are
on occasion associated with other endocrine tumors, most notably multiple
endocrine neoplasia, type Ila, which includes medullary carcinoma of the
thyroid, hyperplasia of the parathyroid glands, plus the frequent association of
bilateral adrenal medullary pheochromocytomas. A variant of this syndrome
(MEN lib) replaces parathyroid disease for a marfanoid habitus, a characteris-
tic facies,and intestinal and other mucosal neuromas.
Although the majority of pheochromocytomas occur in adults, about one
fifth of reported cases have been in children. The age incidence of tumor
ranges from 5 months to 82 years, with the peak incidence occurring between
the ages of 20 and 50 years. In children, approximately 30 to 40 per cent are
either bilateral or multiple (Table 14-18).
Approximately 10 per cent of pheochromocytomas in adults are malignant
and are more commonly found in males. In children there is confusion as to
the malignant potential. In a series of 19 patients with MEN II reported at the
Mayo Clinic,4 had metastatic pheochromocytoma, which is roughly twice
187
the usual malignant potential for this tumor. The histology of the primary
tumor may be misleading; hence, proof of malignancy usually rests on defini-
tive evidence of spread to liver, lung, bone, or other nonsympathetic chain
areas. The differentiation between multicentric primary sites and metastatic
sites may occasionally be troublesome.
TABLE 14-18. Pheochromocytoma
Sites Adults (%) Children (9c)
Right or left adrenal 78.3 47.5

Both adrenals 8.7 19.7
Both adrenals and extra-adrenal — 4.0
Extra-adrenal (one site) 5.8 9.2
Organ of Zuckerkandl 3.8 3.8
Multiple other sites 3.4 15.8
NATURAL HISTORY
Classification
compose the adult adrenal medulla and the extra-adrenal nervous

Cells that
S) stem or paraganglia] cells throughout the body arise from or in association
widi embryonic sympathetic ganglia and migrate to their final sites. Migration
commences early in fetal life and continues until the fetus is over 200 mm
long. Poorly differentiated cells called sympathogonia or pheochromoblasts
gradually mature into the more definitive medullary cells. Early in fetal
development, islands of adrenocortical cells are intermixed with nerve cells
and fibers as well as with fetal medullar} cells. The adrenal cortex is em-
bryologically distinct and arises from the urogenital portion of celomic meso-
derm at the fourth to sixth week of fetal development.
The paraganglia are scattered masses of neural crest tissue. They are dis-
tributed symmetrically in the paraxial regions of the trunk and in the vicinity
of the developmental gill arches. The paraganglia, including those that func-
tion as chemoreceptors, are capable of storing catecholamines in dense gran-
ules within their cells. These cells are probably identical with those that come
to rest in the adrenal medulla; hence, the entire chromaffin tissue network is
Functional catecholamine-secreting neo-
in all probability of similar origin.
plasms may arise from any of the paraganglia, either ectopic to or within the
adrenal medulla, and thus may present clinically in the same manner as a
pheochromocytoma. Technical ly. the tumors that arise outside the adrenal
medulla most probably should be called paragangliomas. The term pheochro-
mocytoma is so commonly used, however, that all catechol-secreting tumors
are referred to as such.
An attempt to explain the association of diverse tumors producing endo-
crine substances has focused on the concept of the APUD series of cells, the
name which is derived from the following three characteristics: an Amine
of
content and amine Precursor C/ptake, plus the presence of amino Decarbox-
ylase. The APUD cells are thought to be derived from the primitive neural
crest, which spreads in the embryo to the foregut and its derivatives. The cells
begin with the ability to produce simple amines but evolve to produce a
variety of pohpeptide hormones. The system is common to all vertebrates and
probably represents a peripheral neural endocrine system.
622 II / Treatment oi Specific Neoplasms
The APUD scries are demonstrable by histochemical

characteristics of the
techniques and radioisotope tracer studies. Other characteristics include me-
tachromasia following acid hydrolysis, nonspecific esterase or choline es-
terase activity, high levels of alpha-glycerophosphate metadione reductase,
and specific immunofluorescence demonstration of the presence of a polypep-
tide hormone within the cell. These common characteristics (which occur in a
number of cell types throughout the body, including the parafollicular cells of
the human thyroid, which is the site of origin for medullary carcinoma of the
thyroid) are those necessary to carry out synthesis of low molecular weight
polypeptide hormones. The adrenal medullary cell is somewhat anomalous
within this system in that no known adrenal medullary polypeptide hormones
are usually synthesized. However, reports have shown that ectopic (or paraen-
docrine) polypeptide hormones, such as ACTH and thyrocalcitonin-like poly-
peptides, can be produced from the adrenal medulla.
A family history of thyroid tumors or hyperparathyroidism in any patient with
episodic hypertension or a firm diagnosis of pheochromocytoma, or both, is an
absolute indication to search for the existence of the more general multiple
endocrine adenoma syndrome that is associated with a pheochromocytoma.
Investigation of the entire kindred by means of calcium infusions and assays of
urinary catecholamines should be carried out if MEN II is diagnosed in the
index case.
Clinical Features
The symptoms and signs of pheochromocytoma result from the release of

excessive amounts of catecholamines (epinephrine or norepinephrine, or
both).The wide variety of clinical manifestations induced by these tumors may
appear apparently unrelated because almost any of the organ systems of the
body may be involved (Table 14-19). 188
Hypertension is the most common presenting sign and may follow one of
three patterns: (1) the classic pattern, in which blood pressure is normal
between hypertensive paroxysms, (2) sustained elevation of blood pressure
without paroxysms, resembling essential hypertension, or (3) extreme fluctua-
tions in blood pressure superimposed on a constant elevation of pressure.
Fluctuations in blood pressure probably represent episodes of hormone re-
lease, either epinephrine or norepinephrine.
Paroxysmal symptoms are characterized by severe headaches, profuse sweat-
ing, tachycardia, palpitations, skin pallor, and anxiety. During these episodes,
patients may present with convulsive seizures, cardiac arrhythmias, systolic
blood pressures in excess of 300 mm
of mercury, or extreme blanching of the
face and extremities. On occasion, syncope, nausea, vomiting, angina, or
changes in vision may accompany an attack. Symptoms may persist from a few
minutes to several hours and may occur anywhere from several times a day to
only a few times each year.
On occasion, patients may present with milder symptoms that include
headache, nervousness, palpitations, nausea, weakness, anorexia, flushing,
dizziness, and shortness of breath. These attacks may occur infrequently,
making immediate accurate diagnosis difficult or even impossible. Between
TABLE 14-19. Symptoms and Signs of Pheochromocytoma^
Approximate %
Adult Child
Symptoms
Persistent hypertension 65 92
Paroxysmal hypertension 30 8
Headache 80 81
Sweating 70 68
Palpitation, nervousness 60 34
Pallor of lace 40 27
Tremor 40
Nausea 30 56
Weakness, fatigue 25 27
Weight loss 15 44
Abdominal or chest pain 15 35
Dyspnea 15 16
Visual changes 10 44
Constipation 5 8
Raynaud's phenomenon 5
Convulsions 3 23
Polydipsia, polyuria 25
Puffy, red, cyanotic hands 11
Signs
BMRover+20% 50 83
Fasting hlood glucose over 120 mg/dL 40 40
Glycosuria 10 3
Eye ground changes 30 70
attacks, blood pressure can be normal, and these patients are frequently
classified as "functional." Individuals presenting with such a constellation of
symptoms require careful testing, sometimes repeatedly over long periods, to
definitely exclude the presence of a catechol-producing tumor.
Physical examination of pheochromocytoma patients is most often normal
but may show physiologic findings related to the tumor or to the presence of an
abdominal mass. Most patients are thin. When sustained catechol release is
present, they may appear tremulous, with evidence of excessive sweating.
Tachypnea and tachycardia are also frequently present. Evidence of associated
findings (such as cafe au lait spots in neurofibromatosis, retinal manifestations,
cherry red spots with the von Hippel-Lindau disease or the Sturge-Weber
i.e.,
disease, and retinal vascular abnormalities seen in patients with long-standing

sustained hypertension) can be diagnostic clues. Objectively, attacks are ac-
companied by diagnostic elevations in urine and blood catecholamine lev-
els.
Abdominal palpation, especially if vigorous and in the vicinity of a pheochro-
mocytoma, may precipitate a hypertensive attack. This can be hazardous, and
since biochemical testing is readily available, abdominal massage should be
avoided. Attacks can be precipitated by a variety of stimuli, such as exer-
cise,emotional trauma, physical trauma, increases in intra-abdominal pressure
caused by micturition, sneezing, coughing, and the ingestion of alcohol. Most
important is the recognition of paroxysmal attacks during anesthetic induction,
624 II / Treatment <>i Specific Neoplasms
any operative procedure, or bodily stress. After an attack, a patient frequently

feels extreme weakness.
Laboratory Diagnosis
In the routine evaluation of patients with sustained hypertension a single

determination of vanillylmandelic acid from a 24-hour urine specimen is
probably sufficient to exclude the diagnosis of pheochromocytoma in greater
than 95 per cent of patients When . VM
A analyses give inconclusive results, and
the suspicion of pheochromocytoma is high, i.e., sustained hypertension with
paroxysmal symptoms, catecholamine levels should be assayed.
A few cases of pheochromocytoma have been reported in which
metanephrine-normetanephrine or VMA
excretion has been normal. If a pa-
tient has paroxysmal attacks that suggest a pheochromocytoma, and the 24-hour
output of catechols and metabolites are normal, it may be necessary to measure
norepinephrine and epinephrine levels as expressed in micrograms per hour in
a timed urine specimen begun immediately with an attack. Very rarely, a
pharmacologic provocative agent, such as histamine, must be used to induce
the release of catecholamines from storage granules, but such provocations are
dangerous. Almost without exception, patients whose hypertension is caused
by a pheochromocytoma will have abnormally large amounts of norepineph-
rine or epinephrine, or both, in their plasma and urine. After successful
removal of the tumor, catecholamine levels return to their normal range within
minutes.
Patients with pheochromocytomas seldom have increased urinary excretion
of dopa, dopamine, and homovanillic acid. Previously, it was thought that
abnormally high levels of dopamine or HVA, or both, occurred exclusively with
malignant pheochromocytomas. However, patients with benign tumors have
been described as having high dopamine or HVA excretion (Tables 14-20 and
14-21). 189 The preoperative demonstration of pheochromocytoma has im-
proved remarkably since the advent of ultrasonography and computerized
body scanning. Adrenal tumors as small as 2 cm in diameter are routinely
visualized by the use of a combination of these new techniques. The most
recent information suggests that computerized body scanning will proba-
bly be the most effective means of demonstrating adrenal tumors. 190 Pheochro-
TABLE 14-20. Urinary Excretion* of Catecholamines and

Metabolites from Healthy Individuals of Various Ages
Ace DA HVA NE E VMA

<1 yr 60.9+24.3 < 1000 10.6 ± 3.4 1.3 ± 1.2 569 ± 309
1 to 5 yr 124.1±40.7 <2000 18.8 ± 7.0 3.2 ±2.7 1348 ± 433
6 to 15 yr 169 ± 72.6 <3500 37.4 ± 16.6 4.8 ± 2.4 2373 ± 698
>15 yr 249 ± 74.9 <4500 50.7 ± 15.7 7.1 ±3.3 3192 ± 699
"Measured in /ug/24 lir.

Key to abbreviations:
DA, dopamine; HVA, homovanillic acid; NE, norepinephrine; E, epinephrine; VMA, vanillylmandelic acid.
TABLE 14-21. Clinical Data, Preoperative Urinary Excretion of

Catecholamines and Metabolites, and Tumor Catecholamine Content
of Patients with Pheochromocvtomas 189
Clinical Dat\ Preoperative Urine \\ U YSES Timor Analyses

(pig/24 HR) Ox g/g Tissue)
Blood
Patient Age Sex Pressure DA HVA NE E VMA NE E
IT 10 >T F High 311 376 491 NDt 6580 515.6 20.1

18 13.5 yr M Hi eh 233 - 958 ND 19,400 366.6 ND
19 Adult M HighP" 740 740 494 501 .' 750 1:348.6 1897.4
20 Adult M High 774 1000 306 43.000 6486.3 7221.1
21 Adult F High — — 1289 ND 29.800 1245.5 52.7
22 Adult M High 398 13.280 2 315 ND 49.800 515.9 ND
"P. paroxysmal hypertension
t None detected
Keyto abbreviations: DA. dopamine; HVA, homovanillic acid; NE, norepinephrine; E, epinephrine; VMA,
vanillylmandelic acid.
mocytomas tend to be vascular tumors, and 90 per cent of cases can be

visualized easily by selective aortography.
On rare occasions in extra-adrenal tumors, which tend to be almost exclusive-
ly noradrenaline-producing, venous catheterization of the superior and inferior
vena cava can be a useful aid to tumor localization. The procedure should be
done only when strong evidence exists for a noradrenaline-producing
pheochromocytoma, and all other attempts to visualize the tumor within the
adrenal or abdominal cavity by noninvasive methods have failed to uncover a
mass lesion. In selective venous sampling, the primary diagnostic feature is a
step-up in the measured plasma catechols at the approximate level that coin-
cides with the venous drainage from the tumor.
Staging
There is no established staging system for pheochromocytomas.
Prognosis
In a review at the Mayo Clinic of 138 surgically treated patients with

pheochromocytomas, the operative mortality rate was 2.9 per cent. 191 The
overall recurrence rate for benign and malignant tumors resected was 9.8 per
cent, and the five-year survival rate for patients with malignant tumors was 44
per cent.
TREATMENT
Surgery
The initial approach to pheochromocytoma should be prompt, aggressive,

and surgical. Prior to the planned surgical extirpation of the tumor, patients
should have a symptom-free period, during which blood volume, myocardial

stress, and the emotional consequences of long-standing catechol excess can be
controlled. This can be accomplished through pharmacologic control with
alpha blockers and, at times, beta blockers, which allows for a smoother intra-
and postoperative period.
In the usual case, treatment is begun with an alpha blocker. The most
common orally used agent is phenoxybenzamine. Therapy is initiated at 10 mg
daily with a gradual increase in dosage to approximately 30 to 100 mg daily,
depending on the patient's symptomatic response. In well-blocked individu-
als, almost all the catechol-mediated symptoms and signs are controlled by the
use of this agent. The principal reported toxicity has been mild and transient
sedation. If significant tachycardia continues following the initiation of therapy
with phenoxybenzamine, beta blockers (such as propranolol) may be used to
control the tachycardia. In rare instances, the specific enzyme inhibitor and
experimental agent alpha-methylparatyrosine, which blocks the enzyme tyro-
sine hydroxylase, has been used to control preoperative symptoms. This agent
has also been used in cases of nonoperable metastatic pheochromocytomas.
The anesthetic management of these patients during surgery is aimed at
providing blockage of hypertension during manipulation of the tumor and its
excision, and the reversal of these effects to prevent hypotension after the
tumor has been removed. The initial steps can be managed with phenoxyben-
zamine and propranolol and the latter step with norepinephrine, if necessary.
Prior to pharmacologic blocking, the operative mortality rate was in the range of
20 per cent. 192
Some controversy exists in the literature regarding the continued use of
alpha and beta blockers during the intra-operative period. Although some
anesthesiologists and surgeons favor the continued use of phenoxybenzamine
and propranolol during the intra-operative period, there is a growing number of
anesthesiologists who feel that the drug should be discontinued five days prior
to the planned operative procedure and that the patient's blood pressure can be
controlled intraoperatively by the use of a nitroprusside drip. This latter
method has been reported to be useful in intra-operative localization of the
catechol-secreting tumor, since gentle palpation of the operative site can result
in blood pressure elevations because of catechol release. These hypertensive
episodes can easily be controlled by the use of nitroprusside. In the postopera-
tive period, patients who had therapy with alpha and beta blockers that were
discontinued three to five days prior to the operation have been noted to have
less prolonged anesthetic effects and shorter mean postoperative hospitaliza-
tion times.
In the case of metastatic disease, an attempt should be made to remove all
possible sites of tumor deposits. This type of "debulking" may enable the
patient to survive longer, with subsequent more effective chemotherapy of
lesions that are not resectable. An anterior transabdominal approach is pre-
ferred because of the need to explore the entire abdomen for possible extra-
adrenal sites of tumor. Recurrences should be aggressively treated surgically,
since patient survival rates up to 20 years have been reported after the removal
of such lesions. 191
In those patients who are found to have Sipple's syndrome or MEN II, the
pheochromocytomas should be excised first and later attention should be

given to the thyroid and parathyroid tumors.
Radiation Therapy
Some authors feel that radiation therapy may be of benefit in palliation of

metastatic disease, 193 and there is no doubt that such therapy is indicated for
painful bone metastases from these tumors.
Medical Management of Malignant

Pheochromocytoma
Medical management of malignant pheochromocytoma is reserved for those

cases in which the tumor has metastasized or cannot be located at surgery or
when medical contraindications preclude an exploratory laparotomy. Metastat-
ic pheochromocytoma tends to be a slow-growing tumor, and both the morbidi-
ty and mortality rates of this disease can be directly related to the cardiovascu-
lar complications produced by the prolonged elevated catechol secretion.
Useful anticancer agents for this disease have not been identified, but
long-term symptomatic palliation can be obtained in some patients with the
chronic oral administration of phenoxybenzamine in divided doses of 30 to 100
mg daily. Direct inhibition of catechol synthesis in patients with pheochromo-
cytoma has been achieved with the experimental agent alpha-
methylparatyrosine.

When surgical extirpation is not possible, the development of techniques to
destroy metastatic lesions selectively by occluding their vascular supply with
intra-arterial substances or the development of specific biochemical neu-
tralizers may enable more effective improvement in long-term survival.
Section 7
Adrenal Cortex Neoplasms

Ronald K Tompkins Charles M Haskell
INTRODUCTION
Malignant tumors of the adrenal cortex are rare lesions that are estimated to
afflict only two persons per million population. 194 For this reason, large series
are difficult to assemble, and case reports produce most of the current informa-
tion. This section is a synthesis of salient features from the collected literature
and the personal experiences of the authors.
NATURAL HISTORY
Adrenal cortical carcinomas are highly lethal tumors with postsurgical sur-
low of 8 per cent at one yeartoahighof31 per cent at
vival rates reported from a
five years. 195
The tumors tend to be quite large when discovered, some
weighing as much as 1 kg, suggesting the insidious nature of their growth and
development. Indeed, metastases to lung and liver, as well as lymph node or
bone, or both, are commonly found at initial presentation (Table 14-22).
There is no clear predilection for these tumors to involve one side with more
frequency than the other.
Classification
The adrenal tumors are generally classified as functional or nonfunc-

cortical
tional, depending upon the endocrine status of the patient. In most series,
approximately half the tumors have been functional.
Functional Tumors. Adrenal cortical carcinomas are considered func-
tional if biochemical data show excessive Cortisol production without diurnal
variation that cannot be suppressed by dexamethasone. Patients with this type
of tumor usually have the clinical signs of Cushing's syndrome. From the
reverse perspective, approximately 10 per cent of patients with Cushing's
syndrome have a malignant adrenal tumor as its cause. Excessive produc-
tion by adrenal cortical carcinomas of other hormones, such as aldosterone,
testosterone, or estradiol, maybe associated with Conn's syndrome, virilization
syndromes, or feminization syndromes, respectively (Table 14-23). ,96
In general, because of their endocrinologic manifestations, the functioning
tumors tend to be diagnosed at an earlier stage in their development and are
generally smaller at the time of surgical exploration.
Nonfunctional Tumors. Tumors in this class tend to be quite large at
discovery, have not produced any clinical endocrine syndrome, and do not
contain unusually high amounts of hormones.
The major presenting symptoms in most patients with adrenocortical carci-

noma are abdominal pain, weakness, and weight loss. In most series, physical
TABLE 14-22. Sites of Metastases in

Adrenal Cortical Cancer
Organ Cases (%)
Lungs 60
Liver 53
Lymph Nodes 47
Abdomen 43
Bones 33
Kidneys 20
Brain 10
'Alter llujiar HA et al: Cancer 35:549, 1975

TABLE 14-23. Hormone Production in Adrenal Cortical Cancer 196
Adenomas Carcinomas
Presentation
Cushing's syndrome
Aldosteronism
Adrenogenital
Virilism
Child
—
—
2
—
627
Adult
3
—
—
Child
—
l
—
Adult
—
_
3
Feminization — — — _
Nonfunctioning — 12 — 3
TOTAL PATIENTS 2 21 3 13
signs of abdominal mass, distant lymphadenopathy, hepatomegaly, and leg

edema are common at the time of presentation. In addition, patients with
functioning tumors that are producing excess Cortisol will show the cardinal
features of Cushing's syndrome (central obesity, cutaneous
osteoporo- striae,
sis, hypertension, diabetes, plethora, and hirsutism). Clitoral hypertrophy,
deepening of the voice, receding hair at the temples, and acne indicate the
presence of excessive androgen production. Breast enlargement in men and
children and precocious puberty in young girls are signs of excessive estrogen
production. Primary aldosteronism due to adrenocortical carcinoma is very
rare, but when it occurs the signs of potassium depletion, edema, and hyperten-
sion are present.
In establishing the diagnosis of functional adrenocortical carcinomas, the
usual plasma and urinary measurements of Cortisol, 17-hydroxycorticosteroid,
and 17-ketosteroid levels, as well as testosterone and estradiol levels, are
assessed in basal and dexamethasone-suppressed conditions. The details of
these endocrinologic evaluations are beyond the scope of this discussion, but
the interested reader is referred to a standard reference. 197
Once the suspicion of a functioning or nonfunctioning adrenal tumor has
been and CAT scan of the
raised, specific diagnostic tests, such as ultrasound
retroperitoneal area or arteriography, or both, have proved most reliable in
establishing the presence of suprarenal masses. Metastatic evaluation by
sampling accessible large lymph glands, obtaining chest x-rays, and perform-
ing liver and bone scans is often helpful prior to surgical exploration of the
abdomen and retroperitoneum.
Pathologic proof of malignancy in the resected tumor is, in part, based upon
large size (736.5 gram average) and microscopic features of capsular invasion
and invasion of venous channels. 198 Poorly differentiated tumors present no
problems in diagnosis to the pathologist, and most differentiated tumors can
also be adequately classified. There is, however, no morphologic distinction
between functioning and nonfunctioning tumors.
Staging
Bradley 199 has devised a clinical staging system for adrenocortical tumors,
using the TNM
system (Table 14-24). This schema, with minor modifications,
might serve as a model for all endocrine tumors.
TABLE 14-24. Clinical Staging System for Carcinoma of

the Adrenal Cortex 199
T= Extent of primary tumor

1= <5 cm and confined to adrenal gland
2 = >5 cm but <10 cm or adherence to kidney
3= >10 cm or invasion of surrounding structures including renal vein
M= Presence and type of metastases
= No demonstrable metastases
1 = Regional lymphatics
2= Distant metastases, for example, liver, lung, bone
R= Tissue remaining after resection

= Tumor completely excised
1 = Tumor entered at operation
2= Tumor tissue remaining after resection

D= Degree of histologic differentiation
1 = Differentiated, no capsular or vascular invasion
2 = Moderately undifferentiated, either capsular or vascular invasion
3 = Anaplastic, both capsular and vascular invasion
Stage 1=3 or fewer; for example, T, M„ R„ D,

Stage 2 = 4 and 5; forexample, T2 R! D2 M
Stage 3 = 6 and 7; for example, T M, R, D 2
:i
Stage 4 = 8 or more; for example, T M 2 R2 D :1 :1
TABLE 14-25. Correlation of Clinical Classification of Carcinoma

of Adrenal Cortex and Patient Survival
Patient Survival
No." Tt M R D Total Stage (Months)
1 1 2 3 1 180|
15 2 2 4 2 132
8 3 1 4 2 40
10 2 2 4 2 19
7 3 1 2 6 3 16
11 3 1 2 6 3 14
9 3 1 2 6 3 12
4 3 2 2 7 3 17
12 3 1 3 7 3 19
14 3 2 2 7 3 8
3 3 1 1 2 7 3 7
5 3 2 3 8 4 11
2 3 2 1 3 9 4 10
6 3 2 2 3 10 4 10
"One immediate postoperative death not included in this analysis.

f See Table 14-24 for staging system.
J Living and well
After Bradley EL, III. 199

Prognosis
The prognosis for the patient with either hormone-producing or

nonhormone-producing malignant tumors of the adrenal cortex is very poor. It
is generally found that the metastatic lesions cannot be completely excised or
treated by nonsurgical means. Metastases tend to grow rapidly, and survival is

often measured in months rather than years.
There has been a recognized clinical correlation between tumor size and
196
survival time. Tang and Gray reported that the best clinical outcome in their
series occurred in those patients with small tumors weighing 30 gm or less.
Most, if not all, of these small tumors were in the functional classification, and
their endocrinologic manifestations undoubtedly led to earlier diagnosis and
treatment. Bradley 199 similarly found correlation between the stage of the
malignancy and postsurgical survival (Table 14-25). One patient with stage I
disease was alive and well at 15 years, three patients with stage II disease
survived an average of 5.3 years, seven patients with stage III disease survived
an average of 13.3 months, and three patients with stage IV disease survived
only a mean of 10.3 months. One patient with widespread metastases from an
adrenocortical carcinoma was reported to have been cured by a combination of
200
surgical excision and chemotherapy.
TREATMENT
Surgery
Surgery is the treatment of choice for malignant adrenal tumors, since

nonsurgical therapies are less effective. The operative approach should be an
aggressive one that attempts to remove all visible tumor and metastases as
completely as possible. In a series of 20 untreated patients, the average survival
time was only 2.7 months from the time of diagnosis. 201 The comparison of these
figures with the figures from the patients with disease of most advanced stage
referred to by Bradley 199 indicates that even palliative removal of as much
tumor tissue as possible may have a beneficial effect on survival time.
In preparation for surgery, any preoperative endocrine effects (such as
hypertension, diabetes, and edema) should be controlled as much as possible,
and the use of corticosteroids should be considered if there is a likelihood of
bilateral adrenalectomy. A transabdominal approach through a long midline or,
preferably, a bilateral subcostal (chevron) incision is favored. This approach
allows full examination of the viscera (including the liver) and the retroperiton-
eal area. If metastases are found, as much of the tumor should be removed as
possible. Reports of prolonged survival time and reduced symptoms in patients
who have had repeated excision of metastatic deposits should encourage the
surgeon to take an aggressive approach.
Postoperatively, the patient may require corticosteroids if all adrenal tissue
has been removed. Follow-up of patients with functional tumors should in-
clude periodic reassessment of steroid levels as an indicator of possible recur-
rence or progression of their disease process.
Radiation Therapy
Generally, radiation therapy of recurrent or metastatic lesions has been of

little value. One group has reported, however, that palliative doses of irradia-
tion (1500 to 5100 rad) delivered over two to three weeks resulted in relief of
pain from metastases, healing of osseous lesions, and relief of localized intesti-
nal obstruction. 202 Occasional prolonged local control of unresectable lesions
was obtained.
Chemotherapy
Patients with unresectable or metastatic adrenocortical carcinoma, of both

the functional and nonfunctional types, should be given a trial of treatment
with mitotane. 194, 200> 203 205 The mechanism of action, pharmacology, and clini-
-
cal use of this drug are described in Chapter 5. It appears to be useful in about
half of such cases, and rarely its use may be associated with cure. 200 Mitotane
has also been used in Cushing's syndrome or the ectopic ACTH syndrome; 206
however, we rarely recommend the use of mitotane because surgical treatment
is generally superior, and the drug is not approved for this indication by the US
Food and Drug Administration.

Adrenal carcinomas are rare, and little is known about the usefulness of
cytotoxic chemotherapy. In our own experience we have not seen an objective
response to any drug other than mitotane. Patients who fail mitotane treatment
and who have symptoms due to excessive Cortisol production by their tumors
may be considered for experimental therapy with aminoglutethimide 207 (see
Chapter 5) or metyrapone. 208, 209 We rarely use such therapy, however, since it
does nothing for the underlying disease, and in the case of metyrapone it may
precipitate hypertension and hypokalemia as a result of its potent mineralocor-
ticoid effects.
Integrated Therapy
The mainstay of treatment is surgical excision of the tumor. This may be

useful for the primary tumor and in many cases for local recurrence. The roles of
adjunctive radiation therapy or chemotherapy, or both, are difficult to assess,
and we have tended to withhold such treatment in asymptomatic patients who
lack an elevation of Cortisol that provides a guide to therapy. However, the poor
survival rate of patients with residual tumor who do not receive adjunctive
therapy suggests that our approach may have been excessively conserva-
tive.
194, ,99
We are currently employing both radiotherapy and mitotane treat-
ment in patients with Bradley 199 stages II to IV disease in the hope of improving
their outlooks for disease-free survival. Patients with Bradley stage I tumors are
followed without adjunctive treatment.
Section 8
Pituitary Tumors
Robert W Rand Robert G Parker
INTRODUCTION
Pituitary tumors represent approximately 10 per cent of intracranial tumors.

Pituitaryadenomas usually are found in the 20- to 40-year-old age group. It is
uncommon for them to be detected in children before adolescence, and it is in
this group that malignant pituitary adenomas are most common. If a growth
hormone-producing adenoma develops in a child before closure of the epi-
physes, the individual may develop into a giant.
Etiology of pituitary tumors is the subject of considerable speculation. One
theory is that pituitary cells have been chronically hyperstimulated by releas-
ing factors of the hypothalamus. Another theory is that pituitary adenomas arise
from cells that have developed independent growth characteristics within the
pituitary gland.
Biology
The pituitary gland is composed of anterior and posterior lobes. Rathke's

pouch of the oral cavity is the origin of the anterior lobe with invagination of
ectodermal tissue that becomes located in the sella turcica. The hypothalamus
gives rise to a stalk that has both neural and vascular connections to the
pituitary gland. The anterior lobe of the pituitary gland, under the influence of
releasing and inhibiting factors or hormones of the hypothalamus, synthe-
sizes and secretes a variety of polypeptide and glycoprotein hormones. 210 The
posterior lobe and pituitary stalk contain secretory granules and release pos-
terior pituitary hormones that are synthesized in the supranuclear and para-
ventricular hypothalamic nuclei and are then transported to the posterior
lobe, primarily for storage.
Stimulatory or inhibitory influences control the secretion of the anterior
pituitary gland hormones. The humoral substances, now called releasing
factors or hormones, are produced in the hypothalamus and stimulate or in-
hibit the release of the pituitary hormones of the pituitary gland. Neuro-
secretory cells in various regions of the hypothalamus synthesize these neural
hormones. The neurosecretory cells are affected by endocrine and metabolic
influences from various regions of the body other than the hypothalamus,
resulting in altered neurosecretion of these neural transmitters. Such sub-
stances include, among others, norepinephrine, dopamine, and serotonin.
Anegative feedback mechanism is present. The anterior lobe pituitary

hormone that causes the target gland to produce its specific hormones may be
inhibited by a feedback mechanism from that gland. This mechanism is exerted
at the hypothalamic level and is known to be present for gonadotropin secre-
tion, TSH, and ACTH secretion.
The pituitary gland rests in the protective sella turcica with the sphenoid
sinus interiorly and the diaphragma sellae superiorly. The diaphragma sellae
separates the gland from the optic chiasm, yet allows the subarachnoid space to
be developed — usually anterior to the pituitary through its aperture. Lateral to
the sella turcica are the venous cavernous sinuses. These are traversed by the
internal carotid arteries and in the lateral wall by the oculomotor, trochlear,
abducens, and first division of the trigeminal cranial nerves.
The supply of the pituitary gland is from the superior hypophyseal
arterial
arteries that are derived from each internal carotid artery within the cavernous
sinus. These arteries also send branches to the median eminence of the
hypothalamus. A capillary network is formed by the arterial branches of the
median eminence. Blood traverses down the stalk through the portal veins that
arise from this capillary network to the anterior lobe. Thus, neural hormones
that are produced within the hypothalamus as releasing factors travel to the
target cells in the anterior pituitary gland by way of these portal vessels.
Conversely, the posterior lobe of the pituitary gland is supplied primarily by
branches of the inferior hypophyseal arteries that arise from the internal carotid
arteries.
NATURAL HISTORY
The staining characteristics of the secretory granules found in the anterior

pituitary gland cells in the past. Using light
have been the basis of classification
microscopic techniques, the cells of the anterior pituitary gland have been
classified into chromophobic, acidophilic, or basophilic cells. The latter
two groups possess granules that react strongly with either acid or
cell
basic dyes. More recently, histochemical and immunologic as well as elec-
tron microscopic studies have demonstrated that many cells that were
originally classified as chromophobic cells by light microscopy have some
degree of secretory granules. 211, 212 Therefore, many of these "nonfunctioning"
or "nonsecreting" tumors are actually secretory adenomas that produce hor-
mones. The most common tumors in this group produce prolactin and are now
classified as prolactinomas rather than chromophobe adenomas. In the future,
other subtypes of chromophobe adenomas will be described as the secretory
nature of the granules found in these cells becomes better understood.
In addition, basophilic cells or acidophilic cells are no longer considered a
homogeneous cell population. They have been divided into subgroups de-
pending upon the elaboration of specific hormones. Therefore, by combining
these various techniques, both immunologic and electron microscopic, certain
cell types can be related to the secretion of specific hormones. For example,
growth hormone, which is a peptide structure, arises from acidophilic cells and
has its biologic action with respect to growth of connective tissue, bones,
cartilage, muscle, and so forth. It also has an effect on glucose metabolism.
Growth hormone, when it is secreted in larger than norma] amounts, is usually
associated with adenomas of the acidophilic variety, causing gigantism or
acromegaly. An increase in ACTH
production results in Cushing's syn-
drome. 21 '
Many of the tumors
formerly classified as chromophobe adenomas
have been reclassified as prolactinomas producing galactorrhea and elevated
serum prolactin levels, as in the Forbes-Albright syndrome. 214
Prolactin, which promotes lactation, is a peptide hormone also arising from
the acidophilic cells. Excessive amounts in nonpregnant women cause galac-
torrhea and amenorrhea, which suggest the presence of a prolactinoma of the
anterior lobe of the pituitary gland.
believed that the basophilic cells give rise to the following hormones:
It is
follicle-stimulating hormone (FSH), luteinizing hormone (LH), thyroid stim-

ulating hormone (TSH), and adrenocorticotropic hormone (ACTH).
Craniopharyngiomas are the second most frequent tumors in the intra- and
"'
suprasellar region, constituting some 2 to 4 per cent of all intracranial tumors. 21

In children, they are the third most frequent brain tumor, following medullo-
blastomas and astrocytic tumors. 2 " These tumors are of developmental origin
5
but may not be clinically recognized for main years. The peak incidence is in
the second decade, although patient ages have ranged from infancy to the
seventh decade. 217
Clinical Findings and Diagnosis
Whether the symptoms of a pituitary tumor are neurologic or endocrinologic

depends on the tumor cell type and the predominant direction of growth.
Symptoms and signs of these tumors may be due to hormone secretion by the
tumor or compression neuropraxia or necrosis of the adjacent normal pituitary
tissue, or toboth of these, as well as to compression neuropraxia or necrosis of
neural tissues within the sella turcica or in the suprasellar position — including
the hypothalamus and the optic chiasm. 218
The anterior-posterior diameter of the sella turcica in the adult male or
female is approximately 15 mm, and the vertical diameter is usually about 12
mm. Therefore, an increase beyond these dimensions is suggestive oi a
pituitary tumor. Of more importance, however, is the presence of erosion of the
sella floor or slanting of the floor in the anteroposterior x-ray view, or both,
which is usually well seen in polytomography of the sella turcica. Tumors of
the pituitary may expand and erode the walls of the sella turcica inferiorly
into the sphenoid sinus, where they do little harm except for the risk of cere-
brospinal rhinorrhea. Laterally, however, if they expand into the cavernous
sinuses with the contained vascular and cranial nerve elements, the patient
may show varying elements of a cavernous sinus syndrome.
The optic chiasm, optic nerves, and hypothalamus may be affected by
superior growth of pituitary tumors, which is not uncommon because this
is the path of least resistance to pituitary tumor growth. A non-secretory
chromophobe adenoma may cause visual field deficits, generally progressive

bitemporal hemianopsia, or the first symptoms may be loss of sex hormone

activity, producing amenorrhea in women or decreased libido in men. About
85 per cent of patients with benign nonsecretory chromophobe adenomas
have some degree of visual impairment at the time of diagnosis. Ocular
findings, such as paresis of extraocular movements or optic nerve or optic
chiasm compression, or both, are late signs and symptoms of pituitary tumors
indicating suprasellar extension. Therefore, a clinician is more likely to see
some endocrine dysfunction primary manifestation.
as the
Hypersecretion of a specific hormone will produce a syndrome related to the
hormone's activity. Unfortunately, some of these syndromes are easily recog-
nizable only in their advanced state. Once the clinical findings become more
obvious, many irreversible changes may have developed in patients with
acromegaly or Cushing's syndrome prior to the effective therapeutic destruc-
tion of the tumor.
At least 50 per cent of patients, regardless of whether the pituitary tumor is
secretory or not, have severe headaches, which are usually localized either
behind the eyes or in the bitemporal region. Increased intracranial pressure is a
rare cause of headache in patients with pituitary tumors but will occur if the
tumor produces obstruction of the basal cistern or the aqueduct of Sylvius, or
both, or obliterates the foramen of Monro.
Approximately 55 to 60 per cent of craniopharyngiomas are cystic, whereas
about 15 per cent are solid, and the remaining are combined. 219 These usually
well-encapsulated masses lie above the pituitary, and as they enlarge through
cellular proliferation, fluid formation, and accumulation of debris, pressure is
exerted on adjacent structures such as the optic chiasm, the floor of the third
ventricle, and the pituitary gland. Sometimes these tumors directly invade the
base of the brain. 215
The clinical findings vary with the ages of the patients. In the very young,
elevated intracranial pressure and visual defects are most common. In the
adolescent, retarded growth and sexual immaturity are prominent. In the adult,
endocrine insufficiency and visual defects are prominent, and many have
mental changes varying from memory loss to dementia. 215,219 223
"
On roentgenographic examination of the skull, about 50 per cent of children

and 25 per cent of adults have an enlarged pituitary fossa, and the dorsum sellae
may be shortened. 221 About 80 per cent of children and 40 per cent of adults
have grossly visible supra- or intrasellar calcification. 215 On pneumoencepha-
lography, the floor of the third ventricle may be indented. 215 On computed
tomography (EMI scan), the tumor may be well outlined.
Radiologic Findings. The classic change caused by a pituitary adenoma
is anterior, posterior, or inferior expansion of the sella turcica due to growth of
the tumor.More definitive roentgenographic studies are necessary to differen-
adenomas from carotid aneurysms, intrasellar cysts, or so-called
tiate pituitary
"empty sella syndrome," which also may expand the sella.
Once an abnormal configuration of the sella turcica is identified, and this
would be true in 95 per cent of patients harboring pituitary tumors, specialized
roentgenograms are required. One of the most successful techniques used to
discern the configuration of the sella turcica is coronal and sagittal polytomo-
graphy, which enables one to detect a slope of the sella floor in the presence
of a microadenoma.- 14 This small erosion may justify further tests and ultimate
surgical exploration of the sella turcica, often using the transnasal transsphen-
oidal approach. These microadenomas are generally no larger than 5 or 10 mm,
but careful tomography may very well show the thinning and bulging of the
particular area of the sella turcica.
Calcification is rare in pituitary adenomas. More commonly, it occurs in
craniopharyngiomas and cerebral carotid aneurysms.
CT brain scanning, especially with iodine enhancement, has made it possi-
ble to demonstrate suprasellar extensions regularly. 28* Although CT brain
scanning will eliminate much of the current use of pneumoencephalography,
partial selective pneumoencephalograms occasionally will be required.
Although many clinicians are concerned about the potential risks of carotid
and vertebral-basilar angiography in producing a vascular accident, at UCLA
Hospital this complication has been recognized in less than 0.5 per cent of
patients of all age groups. In order to lessen the risk of reaction to the iodine
compound, or to assist the patient during the diagnostic procedure if adrenal
function is borderline, supplementary cortisone is administered prior to angi-
ography.
The internal carotid study may be limited to the anteroposterior (AP) views
only, because the position of the carotid arteries is the information that is
desired by the surgeon and the radiotherapist. Suprasellar extension of the

adenoma may elevate the A-l segment of the anterior cerebral arteries. More-
over, it is important that the neurosurgeon or radiation therapist know that the
patient's hypopituitary state is not due to an aneurysm that is simulating a
pituitary tumor. The lateral views are important if, on the AP series, arterial
disease, either occlusive or aneurysmal above the site of the carotid artery
siphon, is suspected.
Rarely a basilar aneurysm pointing anteriorly at the site of bifurcation may
penetrate the sella turcica and thus cause it to assume a "balloon" appearance.
The risks of a vertebral-basilar angiogram limited to the lateral view are
sufficiently low to justify this investigation.
The knowledge acquired by carotid angiography assures the neurosurgeon
that the carotid arteries will be out of any direct line of dissection using the
modified Hirsch-Hardy transnasal transsphenoidal approach.
Endocrine Studies. A complete endocrine profile must be obtained on
all patients suspected of harboring a pituitary tumor prior to the time they
undergo diagnostic radiologic tests such as pneumoencephalogram or carotid

angiogram. This is best left to a skilled endocrinologist, but many baseline
studies can be obtained by the general physician or the neurosurgeon.
TREATMENT
For all practical purposes, the treatment of pituitary tumors is the respon-
sibility of neurosurgeons, radiation therapists, ophthalmologists, and endocrin-

ologists. Chemotherapy plays very little, if any, role in treatment, and there are
very; little data on immunotherapy. Ideally, the neurosurgeon and radiation

therapist will carefully coordinate their treatment efforts, although very few
638 II / Treatment of Specif k Neoplasms
controlled studies exist that allow for a precise determination of the role of each
in the management of the individual patient. For this reason, the ensuing
discussion of therapy is in two sections: first, the neurosurgeon's perspective is
given (Rand), followed by the perspective of the radiation oncologist (Parker).

We are not yet ready to provide more definitive, mutually agreed upon
guidelines for integrating these modalities for pituitary tumors.
Surgery
The optimal treatment for individual patients is determined by the particular

syndrome resulting from the pituitary adenoma. Additional factors include the
geometric design of the particular tumor, whether it is strictly limited to the
confines of the sella turcica or has major suprasellar or lateral extensions.
Therefore, from a surgical point of view, no one particular operation should be
considered for every pituitary tumor, but rather a system of operations should
be considered in each case. These operations may use a transnasal or trans-
frontal approach (Fig. 14-2).
Transnasal Transsphenoidal Approach. A historic review of the
transnasal transsphenoidal approach to the pituitary was published by Moseley
et al. in 1978. 225 They reviewed the various operations that have been proposed
rather thoroughly, starting with the first transsphenoidal approach to the
pituitary gland, credited to Koenig in 1898, using a bucconasal approach.
The surgical technique currently employed by Rand and Calcaterra, as
226
described in the article by Moseley et al., 225 is a direct outgrowth of the Hardy
227
modification of a procedure developed by Cushing. Using this procedure the
FIGURE 14-2. Sagittal draw-

ing of the cranium demonstrat-
ing the transnasal and trans-
fronted approaches to the
pituitary gland.
patient placed in a supine position and given a general anesthesia. An

is
endotracheal tube is taped off to the left side of the mouth, and the head is
stabilized. An indwelling intrathecal catheter is placed in the lumbar subarach-
noid space for administration of filtered oxygen in order to define the supra-
sellar extension of the pituitary tumor. The face, nose, and oral cavities are
cleansed with hexachlorophene solution, and the right thigh is prepared with
an antiseptic iodine solution in case a small muscle-fascia graft is needed to seal
a cerebrospinal fluid leak. Under additional local anesthesia which is injected
in the submucus regions of the posterior septum and anterior sphenoid wall,
the anterior septum and premaxilla are approached through a right hemitrans-
fixation incision. The mucoperichondrium is elevated from the entire left
side of the cartilagenous and bony nasal septum. The mucoperiosteum is then
raised from the floor of the nasal fossae, and fibrous attachments of the septum
to the left It is important to preserve the quadrang-
maxillary crest are severed
ular cartilage and its blood supply in order to prevent postoperative deformity
of the nose. The remaining septum beyond this is removed, and pieces are
saved for use in case it is necessary to rebuild the osseous floor of the sella
turcica.
Thenasal fossae do not in themselves provide adequate exposure to the sella
turcica, and therefore an intraoral labia gingival transverse incision is made
and connected to the nasal dissection. The C-ann fluoroscopic image inten-
sifier ispositioned in order to establish the direction of the bivalved nasal
septum retractor. Once the anterior wall of the sphenoid has been removed and
identified, it is essential that a wide enough opening is created so that the
speculum will not be hindered by bony limits. If infection is present within the
sphenoid sinus, the area is cultured and the operation is discontinued until the
sphenoid sinus infection is completely controlled by drainage and appropriate
antibiotics. The floor of the sella turcica is identified and opened in a rectangu-
lar oval manner with small chisels or, if it is quite thick because of acromegaly,
with a high speed diamond drill. The initial opening is then enlarged with an
Angel punch rongeur. The entire anterior surface of the dura within the floor of
the sella turcica is identified.
microadenoma, a vertical incision is made first followed by a
If one suspects a
horizontal incision to the side of the suspected adenoma. Once this adenoma is
identified and removed, and, if necessary, the identification proved by frozen
section, the tumor base of the microadenoma is treated with cryosurgery using
appropriate instrumentation and taking the temperature down to -90° C. This
allows preservation of pituitary tissue on the opposite side. The author has
observed a number of patients who have reconstituted menstrual cycles and
ovulation within four to six weeks and have become pregnant shortly thereaf-
ter.
If one not dealing with a microadenoma, the dura is opened more widely,
is
and the tumor is removed by suction and curettage starting from the anterior
surface and working posteriorly and superiorly in order to try to identify the
normal pituitary gland tissue and to preserve it. The gland may be a solid mass
of yellow, rather firm tissue or may be flattened out and difficult or impossible
to identify. In the latter situation it is difficult to preserve the gland, but in the
former situation this is not so much a surgical problem. The epithelial origin of
the pituitary gland permits the opportunity for regeneration and restoration of
function.
Those tumors that have a rather high suprasellar position are more challeng-
ing tomanage by the transnasal transsphenoidal operations but can be removed
grossly. Then, once again, the lateral, inferior, and anterior walls, as well as the
inferior surface of the diaphragma sellae, can be thoroughly treated with
overlapping necrotizing cryosurgical lesions down to -90° C or more.
226
It is this author's opinion (RR) that absolute alcohol, as used by Hardy, or
229
Zenker's solution, as was used in the past by Ray and more recently by Stern
and Batzdorf, 228 is of little use in destroying pituitary cells. Some of the largest
recurrences of tumors at UCLA Hospital have occurred when only Zenker's
solution was used and radiation was not given postoperatively following a
radical tumor resection by transfrontal craniotomy.
The transnasal transsphenoidal operation has proved to be extremely valu-
able because in essence it is an extracranial procedure, and the convalescence
is generally rapid. The patient has no visible scars because the incisions are
intraoral and intranasal in position. In general, the patients leave the hospital
on the fifth or sixth postoperative day. The possible tendency for cerebrospinal
rhinorrhea during the operation can be prevented by rebuilding the floor of the
sella turcica using the patient's muscle or fat and cartilage from the septum.
Should delayed cerebrospinal rhinorrhea develop, immediate repair should be
undertaken.
Contraindications to the use of the transnasal transsphenoidal approach
include parasellar extension of the tumor or extensive suprasellar tumor
involvement. Under these circumstances the patient is best treated by the
transfrontal approach. This may be combined with a transfrontal transsphen-
oidal approach by drilling away the planum sphenoidale and the anterior
surface of the sella turcica and thus combining the best visualization of both the
and the transnasal transsphenoidal operations. 225 226
transfrontal 229 '
In our series of over 200 patients treated by transnasal transsphenoidal

operation we have had one serious episode of meningitis, from which the
patient recovered but subsequently died of a hemorrhage in the occipital lobe
of unexplained origin. A second patient had a minor degree of meningitis.
Several patients had delayed cerebrospinal fluid rhinorrhea, which cleared
either with multiple lumbar punctures or by re-exploring and sealing the
opening. Diabetes insipidus is not common because great care is taken to avoid
damage to the pituitary stalk. In addition, this operation has allowed the
preservation of normal pituitary function because it is easier to discern the
more yellow, firm pituitary tissue from tumor tissue.
Transfrontal Transsphenoidal Operation. The transfrontal opera-
229
tion, as developed by Frazier, is a classic approach. The patient is generally
in a supine position but will occasionally be in a prone position using the
Sheldon-Pudenz face-up procedure. The disadvantage of this latter procedure
is that there has to be more frontal lobe retraction on the brain and also there is
the disadvantage of hyperextension of the neck. Consequently, the supine

position seems to be the more easily acceptable position, and a satisfactory
operative exposure of the pituitary region and the optic chiasm can be obtained
using appropriate dehydrating agents such as mannitol, furosemide, and dex-
amethasone.
If the optic chiasm is found to be prefixed, as it will be in about 5 to 10 per cent

230
of cases, possible to resort to the technique described by Rand,
it is which
was originally used by Freshwater, for normal hypophysis namely, the —
transfrontal transsphenoidal approach drilling away the planum sphenoidale
and the anterior wall of the sella turcica and yet at the same time preserving the
dura mater, diaphragma sellae, and mucous membrane of the sphenoid sinus,
thus avoiding an immediate or delayed cerebrospinal rhinorrhea.
The specific indications for such a transfrontal procedure include the pres-
ence of parasellar extension or marked suprasellar extension of the pituitary
tumor which would make it relatively inaccessible to the transsphenoidal ap-
proach. In addition, it is opinion (RR) that if there is a progressive
this author's
is probably advisable to be sure
serious loss of vision, the transfrontal approach
that small knuckles of tumor are not left beneath the optic nerve resulting in
continued visual problems. There seems to be very little indication for die use
of the transfrontal operation in tumors that are strictly confined to the sella
turcica without hypopituitarism or loss of vision.
The most undesirable side effects of transfrontal operations include the
possible permanent production of hypopituitarism and often a serious degree
of diabetes insipidus. In addition, there may be some softening of the frontal
lobe with unilateral anosmia resulting in an undesirable deficit. Occasionally,
optic nerve damage microscope and stricdy
will occur, but in using the surgical
adhering to the surgical principle of not touching or manipulating the optic
chiasm or nerve in any way, this has not been a problem in this author's ex-
perience.
Postoperative subdural or epidural hemorrhages are obviously more apt to
occur here than in a transnasal transsphenoidal procedure. It is interesting that
the infection rate in the transfrontal operation is no lower than in the transnasal
transsphenoidal operation. Therefore, a lowered risk of infection is not a
specific indication for the transfrontal craniotomy procedure.
CRYOHYPOPHYSECTOMY. Stereotaxic eryohypophysectomy was intro-
duced in 1962 by Rand231-*83 as a substitute for radioactive yttrium-90 hypophy-
sectomy, because it offered an equal chance of total destruction of an intrasellar
pituitary tumor and yet, at the same time, avoided the late ill effects of the
yttrium-90 — specifically, extraocular palsies and cerebrospinal rhinorrhea in
15 per cent of patients treated.
It was soon learned that the depth to which the temperature needed to be
taken to cause destruction of pituitary tumors was somewhere in the range of

- 130° C to — 180° C. Consequently, this author chose to freeze at the lowest
temperature possible, making overlapping cryogenic lesions bilaterally from
the midline. The exact position of the cryoprobe within the intrasellar tumor
depended upon the lateral growth of the tumor. This could readily be es-
tablished with anterior-posterior angiograms and could be particularly well
done by the use of cavernous sinus venograms. The problem with the latter was
that at times, when the tumor actually invaded the cavernous sinus, one could
not identify an anatomic landmark on that particular side. In order to obtain the
best clinical results, the deep freezing technique was limited to occupy
primarily the anterior two thirds of the enlarged sellae, which had a rather
regular "balloon" shape.
This technique of stereotaxic eryohypophysectomy has also been success-
642 II / Treatment of Speclfr Neoplasms
fully employed in metastatic breast and prostate cancer, even as an outpatient

procedure, when palliative results arc desired.-"
With respect to primary pituitary tumors, and especially in acromegaly in
which stereotaxic cryohypophysectomy has been used extensively (Fig. 14-3),
15-year follow-up periods have now shown that these secretory tumors can be
completely destroyed without evidence of recurrence, either clinically or by
laboratory radioimmunoassay tests.
The one technical drawback of stereotaxic cryohypophysectomy is the cost of
the cryosurgical equipment, which ranges up
$15,000 for the cryosurgical
to
Dewar instrument and suitable cryoprobes, with additional costs for the
stereotaxic instrument.
Another problem is the proper anesthesia. It is quite important in using
stereotaxic cryohypophysectomy to keep the patient relatively alert during the
time of the freezing in order to be absolutely positive that vision and extrao-
cular muscle function are being preserved. In 10 per cent of patients, there will
be beginning amaurosis or a change in visual fields or in the extraocular
function. Occasionally, a combination of these reversible deficits will be
present. Permanent loss of neural function will not occur if the cryosurgical
freezing is discontinued immediately, because the nerves are only cooled to a
FIGURE 14-3. A, Woman with moderate acromegalic features of face and hands prior to
stereotactic cryosurgical destruction of the intrasellar acidophilic adenoma. B, Several months
following successful tumor destruction, the acromegalic characteristics of the face and hands
had virtually vanished, and growth hormone levels were less than 5 ng/ml. The patient remains
well ten years after the operation, without recurrence of the tumor. Growth hormone levels
remain below 5 ng/ml; therefore, postoperative radiation was not required. Substitute hormone
therapy was not needed because the pituitary gland was preserved.
temperature of to 15° C, and recovery is total. However, if one persists in the

freezing, a rather disastrous result will occur with permanent neural loss. In
over 250 patients treated by this cryosurgical technique for metastatic cancer,
diabetic retinopathy, and pituitary tumors, no permanent extraocular or optic
nerve palsy has been produced in this author's series.
The great benefit of the procedure is that surgical trauma is minimal. The
cryoprobes are passed simply through the nasal passages, and twist drill holes
are made in the floor of the sella turcica, which are readily sealed by using
sterile silicone plugs impregnated with some barium sulfate or tantalum
powder to make them radiopaque for placement under television fluoro-
scopy.
An intriguing concept in the future treatment of pituitary tumors is the
possibility of injecting ferrosilicone with high hysteresis characteristics into
the sella turcica and then subjecting this mass to a special high-intensity
electromagnetic field producing heat that can be controlled. This con-
cept, inwhich iron rod pellets were placed into the normal pituitary gland to
produce hypophysectomy by localized hyperthermia, has been employed in a
limited manner in the past in the United States. However, the pellet design
would not be suitable for the treatment of tumors because it would be neces-
sary to distribute iron into the various crevices of the sella turcica in order to
have uniform heating. This could be accomplished using ferrosilicone placed
in silicone balloons, which would take the shape of the enlarged sella turcica.
Once vulcanization takes place, the mass does not move. It has been shown in
animals, using this technique, that temperatures can be taken to a high of 90°
C. Therefore, this is one additional technique that could be used to destroy
any residual tumor and therefore avoid the need tor postoperative radiation. It
allows the sella turcica to be reheated in cast evidence appears that the tumor
1
was not completely destroyed initially and is recurring. This would avoid
either further radiation or a second operation.
In summary, one could perform a stereotaxic cryohypophysectomy and then
seal the twist drill holes with premade ferrosilicone plugs, which can be heated
at a future time if tumor recurrence is suspected or gland destruction was
incomplete. Another technique is to place the ferrosilicone material in the
sella turcica in a uniform manner during the time of transsphenoidal opera-
tion, and this can later be used for heating.
Detailed results of stereotaxic cryohypophysectomy for acromegalic pa-
tients have been recently published by DiTullio and Rand. 235 The remark-
able aspect of this treatment is the rapidity with which the symptoms dis-
appear, not only the overt enlargement of the hands, feet, and coarseness of
the face but also cardiac size, and there is a return of abnormal glucose
tolerance tests to a normal range. The severe headaches of which these patients
frequently complain usually abate markedly.
Although it is indeed true that it is difficult to identify and preserve normal
pituitary tissue by stereotaxic cryosurgery because the procedure is done using
an indirect x-ray technique, it has been possible in a series of patients to
preserve the pituitary gland and its function sufficiently so that many have had
complete relief of acromegaly and yet do not require substitute hormone
therapy after surgery.
Postoperative Hormone Management. When pituitary tumors or ef-

forts to cure them through surgical treatment cause hypopituitarism, hormone
replacement is not particularly difficult. It is well tolerated as long as the
patient understands the need for the therapy, particularly the necessity' of
having to take some form of cortisone on a regular basis.
The four hormones basically required to overcome the deficiencies include
some form of thyroid, cortisone, male or female sex hormone, and growth hor-
mone. Occasionally, vasopressin is needed and is given intramuscularly as
Pitressin tannate in oil or as lypressin, a nasal spray, to control the polyuria
and polydipsia. Alternatively, a long-acting synthetic analog, DDAVP (desa-
mino-d-arginine vasopressin), may be used as a nasal spray.
With respect to a TSH deficiency, Synthroid (levothyroxine, 0.1 to 0.2 mg
daily) produces a euthyroid state. This can be determined by evaluating for the
presence of clinical hypothyroidism and by serum T4. It is important to give the
patient thyroid to avoid the hypothyroid state.
When ACTH is lost, the adrenals are unable to produce Cortisol, and re-
placement therapy is necessary. This author prefers to use prednisone, 5 mg
in the morning and 2.5 mg in the afternoon, increasing the dose during times of
stress. Other forms of glucocorticoid are equally satisfactory. Without corti-
sone, the patient does not have a sense of well-being, and the blood pressure is
usually low. In addition, the patient may actually go into shock and die if it is
not given on a regular basis. All our patients are warned that if they develop a
gastrointestinal upset and are not able to take the oral cortisone, they must
take a parenteral preparation, such as hydrocortisone sodium succinate,
during that period of time.
The male and female sex hormones are quite important in terms of improv-
ing libido and maintaining normal secondary sexual characteristics. The un-
fortunate problem is that the oral preparation for males is not as satisfactory as
that for females, although methyltestosterone, 5 to 50 mg daily, or testosterone
enanthate, 100 to 400 mg intramuscularly every two to four weeks, does help.
The parenteral preparation is more effective. Fortunately, in females, ethinyl
estradiol, in the amount of 0.01 to 0.1 mg daily, or diethylstilbestrol, 0.5 to
2 mg daily given orally and produces very satisfactory results.
cyclically,
Growth hormone is somewhat difficult to obtain, but it is useful in individuals
with unfused epiphyses who are less than 5 feet tall, and one needs to try to
overcome growth failure in children. Under these circumstances, human
growth hormone is given subcutaneously in the amount of 2 to 5 IU three
times weekly.
Bromocriptine and L-dopa are capable of suppressing prolactin and growth
hormone synthesis. Bromocriptine has also been reported to reduce pituitary
size in some patients with prolactinomas and acromegaly. 282 Further study is
needed to place these observations in perspective, but the potential value of
drug therapy for these tumors is promising.
Radiation Therapy
Pituitary Adenomas. Following the first report of the successful x-ray

treatment of a pituitary adenoma by Beclere in 1909, 236 radiation therapy
became established as a major, and often preferable, primary treatment for most
patients with suspected pituitary adenomas. This was based on a high level of
clinical diagnostic accuracy and clinically measured control of at least three of
every four patients irradiated, with no treatment-induced mortality and in-
frequent treatment-induced morbidity in contrast to a substantial morbidity
and mortality related to the alternative surgical treatment.
Controversy regarding treatment developed early and continues. In a 1942
statement, Dyke and Davidoff 237 noted, "There is some tendency on the part of
radiotherapists and neurological surgeons to show preference for their own
238
type of therapy." In 1932, dishing predicted that "so far as concerns
radiotherapeusis, at least in the case of chromophobe adenomas, it is safe to say
it will comebe discarded." Yet, in 1939, based on a follow-up study of 338
to
239
pituitary adenomas treated surgically by dishing, Henderson observed that
in that group with chromophobe adenomas, 45 of 107 patients (42 per cent)
remained free of recurrence for five years following surgery only, whereas 59 of
80 patients (79 per cent) remained tumor free when surgery was followed by
radiation therapy. Henderson's conclusion that "prophylactic x-ray treatment
given within a month or two of operation delays and, probably in many cases,
completely inhibits any recurrence of tumor growth" continues to be disre-
garded by many physicians today, with tragic consequences. In a recent report
Sheline 240 documented that in a group of 140 patients treated for chromophobe
adenomas for the first time, at ten years the absolute tumor control rates were 71
per cent following radiation therapy alone, 79 per cent following surgical
decompression plus irradiation, and 9 per cent following surgery alone.
In addition to being very effective in permanently clinically controlling most
pituitary adenomas without treatment-related mortality and with negligible
morbidity, external beam photon irradiation does not usually destroy the re-
maining normally functioning pituitary cells. 241 Thus, pretreatment function
can be retained. When pituitary dysfunction does occur it tends to be delayed
as long as 5 to 20 years, and it may be a subtle finding. 242- 243 This advantage of
preserving existing pituitary function is disregarded by those advocates of
"complete" pituitary destruction, whether by surgery or special high-dose
radiation techniques.
Visual field defects, even of substantial extent, can be reversed or at least
arrested by conventional external photon beam radiation therapy. Correa and
Lampe 244 reported a return to normal visual fields in 11 of 55 patients (20 per
cent) and an improvementin 22 of 55 patients (40 per cent) using orthovol-
tage x-rays. In Sheline's study, 240 for those eyes having a deficit of one half or
less of the visual field, 36 per cent returned to normal, 32 per cent improved,
32 per cent did not change, and none got worse within one year of primary
irradiation. These results are comparable to those of primary surgery. Colby et
245
a/. documented that following conventional radiation therapy alone, 28 of
34 patients (82.4 per cent) with visual impairment of less than 33 per cent
(Group I) had improved or stationary vision, whereas of those 21 patients with
more than 66 per cent visual impairment (Group III), 5 of 21 patients (23.8 per
cent) improved to Group II (33 to 66 per cent visual impairment) and 6 of 21
patients (28.6 per cent) improved to Group I (less than 33 per cent impairment).
Chamlin 246 studied the long-term effects of radiation therapy on visual acuity
and concluded that failure to improve cannot be judged for up to six months
following irradiation, and maximum improvement may not occur for two to
three years. Therefore, when rapid loss of visual fields can be documented or
646 II / Treatment of Sim ( n i< Neoplasms
there is substantial visual lossmaking even temporary further loss undesirable,

the slow response to conventional radiation therapy dictates immediate surgi-
cal decompression to save vision.
Good responses following conventional external beam irradiation of
clinical
patients with acromegaly or gigantism have been observed by nearly all
radiation oncologists and have been reported by several. In a 1961 report,
Sheline et al. 247 noted improvement in 13 of 17 patients with acromegaly
receiving calculated doses in excess of 3500 rad delivered in a single four- to
six-week course, as measured by reversal of skeletal changes, visceral hyper-
trophy, evidence of hypermetabolism, decreased carbohydrate tolerance, and
elevated blood serum phosphorus levels. In 1962, Correa and Lampe 244 noted
favorable clinical results in 19 of 29 patients with acromegaly treated with
orthovoltage x-rays.
When the radioimmunoassay of growth hormone became available 248 as a
more sensitive indicator of the activity of pituitary adenomas producing acro-
megaly or gigantism, conventional radiation therapy was disparaged by
many 249 251 because elevated growth hormone levels were detected following
"
irradiation. Rapid post-treatment fall of elevated growth hormone levels was

arbitrarily considered to be a measure of effective treatment even though
pretreatment elevation may have existed for years. This led to an enthusiasm
for different treatment methods that had more complications and ultimately
were no more effective and often caused hypopituitarism.
Lawrence et al. 252 measured normal or near normal basal serum growth
hormone levels in 22 of 28 patients (78 percent) at various intervals following
conventional radiation therapy for their acromegaly. In a study of 17 patients
with acromegaly conventionally irradiated prior to 1965, Sheline and Wara 253
found normal fasting growth hormone (FGH) levels (< 7.5 ng/ml) in 13 of them.
Two of the remaining four patients had early postirradiation surgery, whereas
in the other two patients radiation therapy clearly failed to reduce the FGH to
normal levels. In a compilation of more recent data from several sources,
Sheline and Wara 253 documented that for patients with FGH levels < 45 ng/ml
prior to irradiation, post-treatment levels of < 10 ng/ml were reached in 7 of 19
patients at 12 months, 10 of 17 patients at 18 months, 14 of 17 patients at 24
months, and 16 of 16 patients at 36 months. For patients with pretreatment
FGH levels of > 50 ng/ml, radiation therapy was less effective (as was surgery),
with post-treatment levels of < 10 ng/ml reached in 5 of 10 patients at 12
months, 5 of 9 patients at 18 months, 5 of 9 patients at 29 months, and 5 of 7
patients at 36 months.
Sheline and Wara,253 as well as Lawrence et al'lh2 and Roth et <//., concluded
2r>4
that (1) conventional radiation therapy is as effective in the primary control of

acromegaly as any other form of therapy, (2) properly administered radiation
therapy is followed by minimal morbidity, (3) the length of time for control may
vary up to at least two years, and (4) conventional radiation therapy may be
effective for the acromegalic patient who has failed to respond to surgery. It
should be noted that some still favor more intensive treatment than convention-
al external beam irradiation primarily to cause more rapid and perhaps more
substantial reduction of plasma growth hormone levels.
Cushing's syndrome, clinically characterized by hypertension, obesity,
plethora, asthenia, moon facies, diabetes mellitus, osteoporosis, violaceous

striae, and virilism female and feminization in the male, is the body's
in die
response to hyperadrenocorticism of multiple etiologies. A frequent cause
is pituitary adenoma, which may be basophilic, chromophobic, or mixed with
conventional staining under light microscopy. Pituitary irradiation has been

reported as effective in many patients despite the uncertain etiology. Sosman 255
reviewed the literature up to 1949 and found 9 cures among the 16 improved in
236
a total group of 42 patients irradiated. In a 1952 review, Johnson reported that
about 25 per cent of patients treated got a useful response. In 1961, Soffer et
s7
al.'- reported complete clinical remissions in 7 of 14 patients receiving only
pituitary irradiation in doses ranging from 3800 to 4000 rad delivered in 39 to 52
days. At this point in time, improved therapeutic performance will await
improved diagnostic accuracy rather than refinement of therapeutic meth-
ods.
Pituitary adenomas may be successfully treated by megavoltage teletherapy
photon beams from a high-energy accelerator (linear accelerator betatron) or an
isotope source (cobalt-60), by high intensity radiations such as protons, alpha
particles, or other heavy ions, or by direct implantation of radiation sources
such as yttrium-90, a beta emitter.
Megavoltage external beam radiation therapy, which has the advantage of
widespread availability, is highly effective in permanently controlling pitu-
itary adenomas with negligible morbidity when limited to total doses of 4500 to
5000 rad delivered in daily (five fractions per week) increments for 4.5 to 6
weeks. In Sheline et ai/s*40, 247 25:i extensive experience, as well as others', not
'
a single death or major complication could be attributed to radiation therapy

used in this conventional way. Reports of brain necrosis, 2 8 optic nerve dam-
"'
age, 257 26 ° and the development of neoplasms 261- 262 are anecdotal from among
the thousands of patients irradiated and in nearly all instances have occurred in
patients not irradiated conventional ly. Such complications can usually be
traced to one or more of the following: doses in excess of 5000 rad, 868 use of daily
increments in excess of 220 to 250 rad, 260, 26! irregular or interrupted patterns of
application, 247 or irradiation of unusually large volumes. 283 Also, it is of interest
that complications of treatment have been most frequent in patients treated for
Cushing's syndrome. 263
The disadvantages of conventional radiation therapy include slow tumor
responsiveness precluding rapid reversal of loss of vision or rapid reduction of
elevated growth hormone levels to normal values, as well as the inconvenience
of prolonged treatment often distant from home.
Biologic causes of radiotherapeutic failure include intratumor cysts, present
in 10 to 40 per cent of patients, 264, 26:> hemorrhage, and large tumor masses,
which also are more be cystic. Formerly, diagnostic errors included
likely to
unrecognized craniopharyngiomas and aneurysms.
The major technical cause of radiotherapeutic failure is low dosage second-
ary to inaccuracy of delivery or the lack of conviction of the physician. In the
past, this was compounded by the use of multiple interrupted courses that
further reduced the biologic equivalent dose, while contributing to unnecessa-
263, 266
ry sequelae. 247,
"Heavy" particles (heavy compared with the weight of the electron),
whether charged or uncharged, have an ability to produce ionization in tissue

that is much more dense than that produced by megavoltage photons. 267
Also, in contrast to the continuing decrease of dose with increasing depth in
tissue of photons, the dose from heavy particles actually increases near the
end of their paths in tissue (Bragg peak). 268 Thus, pituitary tumors and the
normal pituitary gland itself can be destroyed by carefully directed heavy ion
beams without serious damage to surrounding structures. In the irradiation of
pituitary adenomas, there is no advantage over conventional megavoltage
photon irradiation, except for earlier and possibly more substantial reduction of
elevated growth hormone levels. This may be accomplished at the price of the
destruction of remaining normal functional pituitary gland, with consequent
panhypopituitarism. Such pituitary ablation may be desirable in the treatment
of widespread breast cancer or severe diabetic retinopathy. At this time, heavy
particle irradiation of the pituitary remains investigational. 265 266'
Interstitial implantation of the pituitary for treatment of adenomas and for

functional ablation has been tried using a variety of methods and radioactive
materials including radon seeds, gold- 198, colloidal radioactive chromic phos-
phate, and yttrium-90. Problems common to all methods and materials are the
initial placement and maintenance of the radioactive sources, so that the
pituitary gland and its tumors can be uniformly irradiated to high doses.
Complications, including rhinorrhea, meningitis, optic nerve damage, and
diabetes insipidus, 269 when added to frequent nonhomogeneous and inade-
quate irradiation, have resulted in little clinical use of these methods.
In summary, conventional megavoltage beam radiation therapy of pituitary
adenomas is as effective and less morbid than any other treatment method
currently available. Such use has been continually challenged since first
reported by Beclere in 1909. 236
Surgery of any form has the advantage of producing rapid, although usually
incomplete, tumor removal. When vision is threatened by the suprasellar
extension of an adenoma with pressure on the optic chiasm, this advantage is
critically important. Likewise, elevated levels of growth hormone can be re-
duced more rapidly by surgical removal of the neoplasm, although the clinical
advantage may be difficult to measure, particularly if there is resultant treat-
ment-related morbidity. Surgery also has advantages in the treatment of large
tumors, many of which are cystic and less responsive to irradiation. Improve-
ments in neurosurgery have, for practical purposes, eliminated operative
mortality, which was formerly in the range of 30 to 40 per cent, 215 and serious
morbidity and thus have made preirradiation identification of nearly all pitu-
itary adenomas reasonable. This diagnostic accuracy has become increasingly
important as effective high-dose irradiation techniques have been developed
for the curative treatment of craniopharyngiomas. These must be differentiated
from pituitary adenomas, which should be irradiated to lower doses with
consequent less morbidity. However, it is important to emphasize that surgery
alone is not adequate treatment for most gross pituitary adenomas. 215,240,253
Craniopharyngiomas. The variability of the clinical course of cranio-
pharyngiomas makes assessment of treatment difficult, and controversy about
such treatment persists. Although surgical removal would seem reasonable for
these often slowly enlarging, usually cystic tumors, total excision is difficult
and probably impossible. 215 221 Hoff and Patterson 222 claimed complete exci-
'
sion in only 2 of 16 patients. Kahn et al. 270 recorded tumor regrowth after
apparent complete excision, which was possible in only 32 per cent of their
patients, and claimed good to excellent results in only 21 per cent of the
children surgically treated. Bartlett 271 stated that total excision of a crani-
opharyngioma is impossible and accomplished radical excision in only 6 per
cent of his patients. Kempe 272 emphasized that the tumor capsule may be
attached to the hypothalamus, with consequent risks of infarction when remov-
al isattempted surgically.
However, with the introduction of ACTH and cortisone in 1950, Matson and
Crigler 273 pioneered attempts at total (radical) removal of carniopharyngiomas
274
in children. In a 1975 review, tumor had not recurred clinically in 53 per cent
of the patients. Hoffman and associates 275 recently reported that between 1950
and 1975 they completely excised the tumor in 17 of 23 attempts from a group of
48 children. Fifteen of these 17 patients with completely excised tumors
remained alive 1 to 12 years postsurgery without the need for additional
treatment. Vision improved in ten. There were two operative catastrophes,
with one death. Fourteen patients developed diabetes insipidus, 11 needed
cortisone replacement therapy, 13 needed thyroid replacement, and 4 received
sex hormones. Hoffman et a/. 275 consequently recommended complete exci-
sion, reserving radiation therapy for incompletely excised tumors or recur-
rence of symptoms or signs indicating tumor regrowth.
Total excision of craniopharyngiomas seems more difficult in adults, 278
possibly secondary to adhesions formed in response to prolonged, intermittent
leakage of cerebrospinal fluid.
Carpentered air" suggested the value of radiation therapy in 1937. In 1961,
Kramer et al. 27S reported the results of high-dose radiation therapy (7000 rad in
seven weeks for adults and 5500 rad in six weeks for children) following mini-
mal surgical intervention. Often consecutively diagnosed patients, nine lived
over five years after treatment without evidence of tumor recurrence or brain
damage. All six of the children irradiated were well 13 to 15 years following
treatment. This policy of conservative surgery followed by radical radiation
therapy has been continued at the Royal Marsden Hospital, London, for over 25
years, 215 where between 1950 and 1971, 107 of 112 newly diagnosed patients
received radiation therapy. Radical excision was attempted in only 14 and
accomplished in only 3 of the 99 patients in whom primary surgery was used. At
ten years post-treatment, 74 per cent of the children and 60 per cent of the
adults were alive. Of 51 patients more recently irradiated using 6 MV x-rays, 89
per cent of the children and 81 per cent of the adults were alive ten years
following treatment. At two years postirradiation, 90 per cent had no significant
neurologic or mental disability, and 83 per cent had useful vision. 215, 279 These,
and comparable reports of others, 280,281 document that modern radical radiation
therapy is at least as effective and less morbid than radical surgery, while being
applicable to nearly all patients.
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CHAPTER 15
NEOPLASMS OF
THE
MUSCULOSKELETAL
SYSTEM
Section 1
Osteosarcoma
Frederick R Eilber Thomas Weisenburger
INTRODUCTION
Osteosarcoma is a rare primary tumor of bone made up of malignant cells
that produce osteoid. The American Cancer Society estimates that approxi-
mately 2000 to 2200 cases of this tumor occur in the United States per
year. Males are affected 2:1 over females.
1
Osteogenic sarcoma occurs primarily in two age groups — the first being
between the ages of 10 and 20 years and the second being between the
ages of 45 and 50 years. 2 Tumors that occur in the older age group tend to
be associated with Paget's disease. However, since only 9 to 10 per cent of
those with polyostotic Paget's disease develop osteosarcoma, the second
peak in incidence is minimal. 3
The most common site for the appearance of osteogenic sarcoma is in the
metaphyseal end of long bones of the extremity. Although osteosarcoma can
occur' in any bone, the distal femur is the most common site, followed by
the proximal tibia and the proximal humerus. Greater than 80 per cent of
655
lesions occur in these locations. 2 Prognosis appears to he somewhat better

with the more distal lesions; tumors that are more proximal, such as those
in the ilium or vertebra, have a worse prognosis.
Etiology
Although there is no known etiology for osteogenic sarcoma, several fac-

tors may be related to its occurrence. First, there is a rapid growth rate
around the time of puberty. These tumors tend to occur in those areas of
the long bones that are responsible for major growth, i.e., the distal femur
and proximal tibia. However, there is no clinical evidence to show that
they are responsive to hormonal manipulation or that the tumor cells have
hormone receptors.
Studies have shown that high-dose radiation therapy has resulted in os-
4
teosarcoma. However, the majority of these reports involved patients who
had received greater than 10,000 rad of radiation.
In animal tumor models it has been possible to isolate a virus as the
"
etiologic agent for certain types of osteosarcoma. 3 7 Also, chemical carcin-
ogens such as methylcholanthrene, for example, were found to induce os-
teosarcoma in laboratory animals. Numerous attempts to find an oncogenic
virus in human osteosarcoma have been largely unsuccessful, although
some reports have described virus-like particles in human osteosarcoma
8
cells grown in tissue culture.
A history of traumaalmost always elicited from patients with osteosar-
is
coma. The usual explanation for this is that the tumor was pre-existing and
that a minor degree of trauma produced symptoms because of the underly-
ing weakness of the bone. However, it raises the possibility that trauma
may be an inciting factor for an abnonnal reparative process, which results
in osteosarcoma. Several large studies of people at high risk for repeated
trauma have shown no evidence of a higher incidence of osteosarcoma, so
most physicians have rejected this hypothesis.
The only known premalignant lesion is long-standing Paget's disease of
bone. About 10 per cent of patients with polyostotic Paget's disease and 3
2,3
to 5 per cent with monostotic Paget's disease develop this lesion. The
reason for this is unknown.
NATURAL HISTORY
Osteosarcoma can be divided into four major types. The first is central or
osteosarcoma ordinaire. This lesion is classified by malignant cells produc-
ing osteoid. Varying degrees of chondroblastic and osteoblastic differentiat-
tion have been described. Whether the tumor is osteoblastic or chondro-
blastic does not appear to influence the prognosis. 2
A second type of osteogenic sarcoma is telangiectatic sarcoma. This ex-
15 / Neoplasms of the Musculoskeletal System 657
tremely rare tumor was found in only 25 of 1000 cases reviewed at the
Mayo Clinic. 9 Radiologically, its characteristics are of a purely lytic lesion.
Histologically, this tumor has cystic spaces containing blood, is lined with
anaplastic cells, and contains The most common presenta-
lace-like osteoid.
tions of osteosarcoma are in the distal femur and humerus, and patients
often present with pathologic fractures. From the review of the Mayo Clin-
ic experience, it appears that this tumor has a worse prognosis than central
osteosarcoma, since 23 of the 25 patients with such a histologic and clinical
picture died of metastasis.
Osteosarcoma in the juxtacortical region can be divided into two types,
parosteal and periosteal. Parosteal osteosarcoma is distinguished by a lobu-
lated blastic lesion and is most commonly found in the posterior distal
femur. Females have a slightly higher incidence than males, and this tumor
occurs most often in the third decade of life. 10 Histologically, it is heavily
ossified and tends to be a low-grade tumor with very few mitotic figures.
The prognosis is distinctly more favorable than for centralosteosarcoma,
and it has a five-year survival rate of 80 per cent. The other juxtacortical
tumor is the periosteal osteosarcoma. Again, the Mayo Clinic found only 23
cases of this type of tumor." It commonly presents in a distal femur or tibia
of patients in the second decade of life. Histologically, it contains predom-
inantly malignant cartilage, with no intramedullary extension of the tumor
histologically. The prognosis appears to be better than for central osteosar-
coma, and a five-year survival rate of 60 per cent has been reported.
The natural history of osteogenic sarcoma is progressive local tumor
growth that extends out of the intramedullary cavity of the bone to involve
the adjacent soft tissues. Radiographically, the tumor presents as a combi-
nation of blastic and lytic lesions of bone. Periosteal reaction is common,
leading to a triangular space beneath the uplifted periosteal edge (Cod-
man's triangle), and the periosteum is characteristically interrupted show-
ing a sunburst or onion peel appearance. Destruction of the cortex is a
common, if not universal, finding.
Metastases to the regional nodes and direct invasion of blood vessels or

major nerve structures are rare. However, the majority of patients succumb
to distant metastatic disease.
12
Several autopsy studies have shown that in
70 per cent of the patients who died, the only evidence of metastasis was
in the lung. 13
An additional peculiarity of this tumor is its tendency to me-
tastasize to the subpleura of the lung. Therefore, presentation with sponta-
neous pneumo- or hemothorax is not an uncommon indication of metastatic
disease.
Most patients with osteosarcoma complain of pain and swelling of the

extremity at presentation. These symptoms vary in their duration from
weeks to months. Pathologic fracture is a rare occurrence in central osteo-
sarcoma, whereas patients with telangiectatic osteosarcoma have pathologic
fractures approximately 30 per cent of the time. 9 Laboratory evaluation
shows marked elevation of the alkaline phosphatase level in approximately

50 per cent of patients.
A definite diagnosis of osteosarcoma requires a biopsy. Although needle
biopsy has been used for the diagnosis of this tumor, the best biopsy is
incisional. This method assures the pathologist ample tissue to evaluate the
malignant cells producing osteoid. It must be emphasized that one must be
extremely careful in making this diagnosis when there is a history of recent
fracture. Histologic examination of a reparative process in a fracture can be
confused with osteosarcoma. Also, the diagnosis of a soft-tissue mass and a
recent history of trauma can be confused because myositis ossificans can
also mimic osteosarcoma.
Once an open biopsy has been performed, a staging evaluation must be
done. This includes chest x-ray and whole lung tomography. Numerous
studies indicate that whole lung tomography can elicit lesions not previous-
ly noticed on routine x-rays. 14 A CAT scan of the chest may also be consid-
ered, as it may have greater capacity for detecting tumors in the subpleural
locations. This technique is currently under evaluation. A bone survey and
bone scan are performed because there are rare instances of multicentric
primary osteosarcomas. Routine complete blood count and blood chemis-
tries, including alkaline phosphatase measurement, complete the staging
evaluation.
There is no currently accepted clinicopathologic staging system of osteo-

sarcoma. Before the advent of effective chemotherapy, approximately 50
per cent of patients with osteogenic sarcoma died within one year of diag-
nosis with a median time to metastasis of four months. 12 During the second
year, an additional 50 per cent of those surviving one year developed pul-
monary metastases and died. Thus, the overall survival rate from amputa-
tion alone was approximately 25 per cent. A review from the Mayo Clinic
suggests that the survival rate has increased to nearly 35 per cent in pa-
tients by amputation during the last decade. 15 However, results
treated
from the Memorial Hospital 12 and Roswell Park Memorial Hospital 16 have
not shown this improvement, with overall five-year survival rates in this
group of patients remaining at 20 per cent.
TREATMENT
Surgery
The classic surgical treatment for osteogenic sarcoma is amputation, al-

though controversies still exist concerning the optimal level. Most surgeons
recommend amputation one joint above the primary tumor in order to re-
move the entire bone in which the tumor arose. The rationale for amputa-
tion one joint above the location of the primary tumor is based on the re-
ports of Enneking and Kagan, 17 who described "skip" areas within the
intramedullary canal at some distance from the primary site. Since several
histologic studies suggest that "skipping" occurs in less than 6 per cent of
patients, the rationale for amputation one joint above the tumor may be
questioned.
The Mayo Clinic has done transmedullary amputations, in which the fre-
2
quency of local recurrence over the years has been extremely small. Early
attempts to perform en bloc excision of tumor with cadaver allograft re-
placement of the diseased bone were largely unsuccessful because most of
the patients died of disseminated disease.
The surgical treatment of metastatic osteosarcoma may involve pulmona-
ry resection. The rationale for resection was provided by autopsy studies
that showed that the metastatic disease was confined to the lungs in more
than 70 per cent of the cases. In addition, control of the primary tumor is
usually possible, and because this tumor tends to metastasize to the sub-
pleura] location, wedge resections rather than pneumonectomy can be
done. Therefore, this is an ideal tumor to attack by surgical resection.
Retrospective studies by Morton et al. u revealed that if the tumor dou-
bling time was greater than 60 days, surgical resection resulted in a 50 per
cent long-term survival rate. However, if the tumor doubled more rapidly
(i.e., TDT < 60 days), the survival rate was not significantly increased by
pulmonary resection. 19
Radiation Therapy
High-dose radiation therapy to the primary bone tumor has been em-
ployed in the past but is rarely used now. Cade 20 showed that approximate-
ly 8000 to 10,000 rad had to be delivered to the extremity to produce his-
tologic evidence of tumor cell destruction. Several large trials of
preoperative radiation therapy in the 8000 to 10,000 rad range and sub-
sequent amputation have been reported. 21,22 The main rationale for this
procedure was to save amputation in patients who subsequently developed
pulmonary metastases. Radiation therapy to unresectable lesions has result-
ed in significant relief of pain, even though for curative intent the success
rate has been minimal.
Since the natural history of osteosarcoma is such that most patients die
from pulmonary metastases, there have been trials of adjuvant whole lung
irradiation immediately following amputation. The dose range has been
1500 to 2000 rad, but a randomized preoperative trial by the Mayo Clinic
showed no benefit. 23 Although pulmonary irradiation has probably failed
because of the inadequate doses employed, higher doses are impossible
because of pulmonary intolerance.
Chemotherapy
The primary treatment for metastatic osteosarcoma is chemotherapy. Al-

though numerous chemotherapeutic agents have been used in the past with
minimal benefit, important advances in chemotherapy have been made

since 1972. Two new approaches that were effective against metastatic os-
teosarcoma were found almost simultaneously. The first was the use of doxo-
rubicin, which is usually given at a dose of 45 mg/m- IV on each of two
consecutive days. Cortes et al. 24 have described an objective response rate
for doxorubicin of about 35 per cent for metastatic disease. The second
advance was the combined use of vincristine and high-dose methotrexate
followed by leucovorin rescue. The methotrexate is usually administered at
200 mg/kg of body weight and is preceded by vincristine at a dosage of 1.5
mg/m 2 The methotrexate is given by infusion over four to six hours after
.
hydration and alkalization of the urine. Leucovorin rescue is usually begun

four to six hours following the infusion. Jaffe et al. 25 reported a 35 per cent
response rate for metastatic disease with this regimen given every three
weeks and a response rate of 80 per cent when it is given weekly. Further
details of this approach are given in Chapter 5.
Since 1972, many clinical trials have employed combinations of the active
chemotherapeutic agents immediately following amputation. The prelimi-
nary results of several of these studies have been reported, and follow-up
data continue to show that approximately 50 per cent of patients remain
26 37
"
continually disease free following the amputation (Table 15-1). This ap-
proach requires a highly skilled treatment team and is generally employed
only in investigational centers.
Immunotherapy
There have been several trials of adjuvant immunotherapy for osteosar-

coma. The major trials have employed BCG alone or in combination with
tumor cell vaccine.
The studies of Eilber et al. 38 and Marcove et al. 39 failed to show statisti-
cal benefit for patients treated with immunotherapy immediately following
operation for osteosarcoma. Neither recurrence nor survival rates were af-
fected by this modality. 40 Other immunotherapy studies performed with
41
transfer factor have yielded some very encouraging preliminary results.
All these studies involved small numbers of patients and were done before
active chemotherapeutic agents were found. By and large, the use of im-
munotherapy for this disease has been restricted to combinations of chemo-
immunotherapy rather than immunotherapy as the sole adjuvant treatment.
We consider all these approaches to be experimental.
Limb Salvage
There are several being conducted in the United States to deter-
trials
mine if limb salvage is possible for patients with osteosarcoma. Employing
known active agents, the trial of Morton et al 37 includes intra-arterial doxo-

rubicin (over three consecutive days), rapid fraction radiation (3500 rad),
and en bloc excision of the involved bone followed by a cadaver allograft.
Results to date have been equal to those of amputation as primary treat-
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ment. Postoperatively, these patients receive adjuvant chemotherapy with

doxorubicin and high-dose methotrexate. Tumor cell destruction is marked
in this group of patients in that approximately 80 per cent of the cells in
each specimen are necrotic at the time of operation as a result of the preop-
erative therapy.
Rosen et al. 42
have treated approximately 50 patients with preoperative
cyclical doxorubicin, high-dose methotrexate and cyclophosphamide, radi-
cal en bloc removal of the affected bone and surrounding soft tissue, and
replacement of the involved bone with a metallic endoprosthesis. Again,
their results show a remarkably low local recurrence rate and an overall
disease-free rate equal to other studies that employed amputation.
SUMMARY
Osteogenic sarcoma is a rare malignant bone tumor occurring most often
in the extremities of teenage males. Primary therapy for this disease is sur-
gical removal of the tumor either by amputation or en block excision. Dis-
eased bone can be replaced with metallic or cadaver allografts. Chemother-
apy plays a major role in the treatment of this tumor. Doxorubicin and
high-dose methotrexate have been found to be highly effective for the treat-
ment of metastatic disease. The results of numerous trials have suggested
that adjuvant chemotherapy following surgical removal of the primary
tumor is extremely beneficial. Three- to four-year survival rates of 50 to 60
per cent have been achieved in several large studies. Whether these results
represent a delay in the appearance of metastases or an actual cure can be
answered only by additional time for follow-up studies.
Section 2
Ewin^s Sarcoma
Thomas Weisenburger Frederick R Eilber
INTRODUCTION
In 1921, Ewing described a tumor of bone composed of small round cells
with a microscopic appearance, clinical course, and response to radiation
therapy different from osteosarcoma. 43 This tumor, which he originally
called, "diffuse endothelioma of bone," composes approximately 10 per cent
of all malignant bone tumors and 1.5 per cent of all malignant neoplasms in
children under 15 years of age. 44
The incidence begins to rise at age five years and appears to peak in the
late teens. The male to female ratio is equal until age 16 years, at which
time the incidence drops in females and continues to rise in males until the
third decade of life. 44 It is an uncommon tumor before age fixe years and after
age 30 years and is said to be less frequent in blacks than in whites. 45 No
etiology has been established for Ewing's sarcoma.
NATURAL HISTORY
Ewing's sarcoma can occur in almost any bone, but it tends to involve
46
the pelvic girdle or long bones of the legs more frequently. Any portion of
the bone can be involved, but the tumor commonly occurs in the diaphysis,
and it rarely crosses the epiphyseal plate. Pain is the most common pres-
enting symptom, occurring in almost 90 per cent of patients, along with a
soft-tissue mass (in approximately 60 per cent of patients), and fever (in
approximately 50 per cent of patients). 47 The tumor may simulate osteomye-
litis, since it is frequently associated with leukocytosis and malaise. In con-
trast to osteosarcoma, pathologic fractures are infrequent.

The differential diagnosis of Ewing's sarcoma includes all small round
cell tumors involving bone, such as metastatic neuroblastoma, metastatic
rhabdomyosarcoma, small round cell osteosarcoma, and lymphoma. Gener-
alized lymphadenopathy or hepatosplenomegaly would make a lymphoma
more likely, as would nervous system involvement. An IVP in addition to
urinary catecholamine levels should be obtained to exclude neuroblastoma.
A hemogram and bone marrow examination may help distinguish the
ly mphoma-leukemia group from Ewing's sarcoma, although the latter is one
of the few solid tumors that may be detected in the marrow prior to radio-
graphic evidence of metastases. 48
Radiographically, Ewing's sarcoma presents with laminated periosteal
elevation and mottled rarefaction of the underlying bone (onion skin ap-
pearance), 49 although this is not a constant feature. 48
Definitive diagnosis is established by biopsy of the lesion. Care should
be taken to ensure that the cortical bone is not weakened, that there is a
reasonable amount of underlying connective tissue, and that the biopsy scar
will be in the treatment field if radiation therapy is anticipated. 50
Of the 229 cases reviewed by Pritchard et a/., 47 35, or 15 per cent, pre-
sented with metastatic disease. Approximately 80 to 90 per cent of patients
who present with nonmetastatic Ewing's sarcoma and who receive treat-
ment only to the primary tumor may be expected to develop metastatic
disease. Skeletal metastases are most commonly followed by lung and lym-
phatic metastases. 47 Central nervous system metastases are not common. It
has been reported that adjuvant chemotherapy increases the risk of metas-
tases to the nervous system. 51 52 This is not well documented, and most
-
observers have noted no change in the metastatic pattern with the use of
48, 53
systemic therapy. 47,
There is currently no staging classification for Ewing's sarcoma. Young

patients or those who present with weight loss, weakness, leukocytosis, or
elevated sedimentation rate have a poorer prognosis than those who are
older and asymptomatic. 47, 54 55 Survival also appears to depend on the loca-
'
tion of the primary lesion, with the best survival for distal extremity lesions
and decreasing survival for proximal extremity and truncal lesions. 55,56 Le-
sions of the pelvis have somewhat higher local failure rates in some
series 57, 58 but not in others, 56 and they also tend to metastasize more fre-
quently than at other sites. 55,56 The local failures for pelvic lesions may
relate to unappreciated lymph node or soft-tissue extension that is not in-
cluded in the treated volume or lower radiation doses because of decreased
tolerance of the pelvic viscera.
As expected, those patients with metastatic disease at presentation have
the poorest prognosis, although there have been cases of patients surviving
five years — some disease free — following aggressive radiation therapy
and chemotherapy. 47, 59 This illustrates that cure should be attempted in all
patients, no matter how bleak the prognosis appears. Although the clinical
course of those patients not cured of their disease is usually rapid, with
death occurring within 24 months of diagnosis, there appears to be a small
group who present with a more indolent course characterized by a longer
latent period to the development of metastases and longer survival with
59 " 61
disease. 48,
TREATMENT
Because of the propensity of Ewing's sarcoma to disseminate, it is neces-
sary that initial presumed micrometastatic
therapy include treatment of the
deposits in addition to treatment of the primary tumor. Since the tumor
arises in the bone marrow cavity, 62 this usually includes the entire bone as
well as possible sites of distant metastases.
Surgery
For lesions of the and small bones of the hands or

ribs, clavicle, fibula,
feet, at which points excision minimal functional impairment,
will cause
surgery is often the recommended treatment. 47 For large lesions in these
sites, preoperative radiation or chemotherapy may be used to reduce the
bulk of the tumor and make surgery technically feasible. Although some
physicians have advocated radical surgical excision for most of these tumors,
claiming improved survival, 47 others have noted no improvement in results
for patients treated surgically. 60, 61
Radiation Therapy
The radioresponsiveness of Ewing's sarcoma was noted in the original

description of this entity in 1921, 43 and since that time, radiation has been
the mainstay of treatment for the primary lesion. Evaluation of the early
literature to obtain dose response data is difficult because the treatment
techniques using orthovoltage were not standardized, and the fields did not
always include the entire marrow cavity. Also, some non-Ewing's cases
were sometimes included, and none of these patients received concurrent
chemotherapy. Subsequent studies using megavoltage radiation equipment
and no chemotherapy suggested that the radiation dose should be in the
range of 4000 to 6000 rad to the entire bone; 63 these doses yielded local
control rates of 50 to 70 per cent. The higher doses appear to give better
local control, although the dose response curve appears to flatten somewhat
53 64
at doses above 5000 rad. -
The addition of three radiation-enhancing drugs —

doxorubicin, dactin-
omycin, and high-dose cyclophosphamide —during the last decade appears
58, 65, 66
to have improved local control rates to 80 to 90 per cent, but this has
been associated with increased morbidity from the radiation, specifically
severe fibrosis. 58,
,!?
Tumor in the medullary shaft at a distance from the
primary site consists of relatively few cells and would, therefore, require
lower doses to achieve control. Accordingly, when vincristine, dactinomy-
cin (actinomycin-D), and cyclophosphamide (VAC) chemotherapy, with or
without doxorubicin, is used, the initial ports should include the entire
bone up to a dose of only 4000 to 4400 rad in 4 to 4.5 weeks. At that time,
the fields should be reduced to include the primary site plus a generous
margin for an additional 1000 to 1500 rad, with perhaps a boost of 500 to
1000 rad with a field encompassing only the remaining tumor mass. 50
The functional results using this "shrinking field technique" are general-
ly quite good; however, impaired function may occur when tumors require
very large radiation fields because of extensive soft-tissue extension or
when radiation therapy is used in very young patients with growing bones,
leading to arrested bone growth. The majority of patients reported to have
functional impairment have not received shrinking field therapy, 58, 68 which
emphasizes the necessity of carefully applied radiation techniques.
Total body irradiation has been attempted to treat micrometastatic dis-
ease, 56 but the survival results are no better than with chemotherapy, and
there is greater morbidity. The Intergroup Ewing's Tumor Study is current-
ly evaluating the use of bilateral whole lung irradiation along with radia-
tion to the primary site and multidrug chemotherapy. The preliminary re-
sults of this study suggest that the appearance of metastases is at least
delayed in those patients. 69
Chemotherapy
Chemotherapeutic agents that are effective for Ewing's sarcoma include

cyclophosphamide,63,70 dactinomycin,71 vincristine,72 doxorubicin,73 BCNU, 74
and mithramycin, 7 with response rates of 40 to 60 per cent in patients with

"'
metastatic disease. The most effective combination appears to be vincristine,

dactinomycin, cyclophosphamide, and doxorubicin. Using this combination,
Rosen et al. 7i reported initially that all 12 of their patients, including 2 with
metastatic Ewing's sarcoma, were alive without disease at 10 to 37 months.
In a later series, 16 of 20 similarly treated patients (3 with metastases at diag-
nosis) were free of disease at a median 36-month follow-np.'
i4
The Intergronp Ewing's Tumor Study is currently investigating the effi-

cacy of adding doxorubicin to VAC in nonmetastatic Ewing's sarcoma pa-
tients, both with respect to local control and survival. 66 We recommend that
patients with this disease be entered into that study if possible. If this is
not feasible but the facilities for combination chemotherapy and radiation
therapy are available, the regimen of chemotherapy described by Rosen et
58
al. is recommended. This involves the prolonged use of intermittent
cycles of chemotherapy, as shown in Figure 15-1. The interval between

doses of chemotherapy is maintained at a maximum of two weeks from the
first day of the beginning of one drug course to the first day of the next
drug course. Delays in chemotherapy are allowed only when mucositis is

persistent or bone marrow depression is substantial (WBC < 2000 or plate-
let count < 100,000). Rosen et al. 58 recommend that after the first two
cycles of treatment, one of the two three-day courses of doxorubicin be
deleted so that the total cumulative doxorubicin dose from eight complete
cycles of treatment is limited to 600 mg/m 2 or less. In view of the high risk
of cardiac toxicity from such a dose of doxorubicin (see Chapter 5), we
favor limiting the total cumulative dose of this drug in this setting to 450
mg/m 2 .
DRUG DOSE
Radiation DACTINOMYCIN (AMD) 450gammo/M MV <
i 1
i
ADRIAMYCIN (ADR) 20mg/M2|V
VINCRISTINE (VCR) 15-2 0mg/M 2 IV
L...J CYCLOPHOSPHAMIDE(CP 1200mg/M 2 IV
Cycles
I
T
± \-
n m --wt
AMD ADR ADR VCR
tttt it it *pf
I I
CP CP
t I III * 5
5
Months
FIGURE 15-1. Memorial Sloan Kettering Cancer Center protocol T-2 for the treatment of
Ewing's sarcoma. (From Rosen G, et al.: Cancer 41:888, 1978.) See text for details of drug ad-
ministration.
SUMMARY AND PROSPECTS FOR

THE FUTURE
Combination chemotherapy and radiation of the primary tumor site for
Ewing's sarcoma offers the best chance of tumor control at the present
time. Local control is not always achieved, however, and since survival is
increased by controlling systemic micrometastatic disease, the risk of local
recurrence may increase. The question of whether or not limited surgery in
combination with chemotherapy and lowered doses of radiation will de-
crease this risk remains to be answered. Optimizing the schedules of the
available chemotherapeutic agents, in addition to seeking more effective
agents, will be necessary to provide further increases in survival for this
once almost uniformly fatal disease.
Section 3
Soft-Tissue Sarcomas
Frederick R Eilber Thomas Weisenburger
INTRODUCTION
Malignant tumors of the soft parts compose less than 1 per cent of all
malignancies diagnosed annually. According to the American Cancer Soci-
ety there are approximately 5000 new cases diagnosed per year, and 2500
persons die of these tumors annually.
Soft-tissue sarcomas can occur in any age group; however, the peak in-
cidence is in childhood, with the second most common age group between
approximately 45 and 50 years. 76 The majority of the childhood tumors are
rhabdomyosarcomas or undifferentiated tumors primarily arising in the
head and neck area. The incidence of soft-tissue tumors in adults tends to
be highest in the extremities; the retroperitoneum is affected less often,
and the head and neck is the least affected area. The sex incidence is ap-
proximately equal among males and females.
It appears from all available evidence that these tumors develop de novo
and not by dedifferentiation from pre-existing lesions. A possible exception

may be in von Recklinghausen's disease in which approximately 10 to 12
per cent of patients with multiple benign neurofibromas develop neurofi-
brosarcoma. 77, 78 There are reported cases of malignant soft-tissue tumors
developing in injured tissues, 79 such as those arising from granulating
wounds or burn scars and those following radiation injury. 80 In addition,
these tumors have been reported in patients with chronic lymphedematous

extremities (principally those occurring following mastectomy), as well as
in casesof chronic congenital lymphangiosareomas. 8184 However, it must be
emphasized that the development of sarcomas in pre-existing lesions is ex-
tremely uncommon.
NATURAL HISTORY
Classification and Histopathology
The terminology malignant tumors of the soft parts is complicated and

for
confusing. At the present time, there are at least 55 different types of soft-
tissue sarcomas. However, this extremely varied histologic spectrum may
be simplified, since it appears that all these tumors are derived from the
mesenchymal and neural crest tissue. Stout 85 and Stout and Lattes 86
cells
have classified these tumors according to their cells of origin; the common-
ly recognized types with their frequencies and prognoses are given in
Table 15-2. It should be noted that certain portions of a single tumor may
be well differentiated, whereas other portions may be totally undifferentiat-
ed, making classification according to the primary cell of origin difficult
when only small tissue samples are available. Furthermore, it also appears
that these tumors have a potential for dedifferentiating into any of the soft-
tissue elements, i.e., fat, blood vessels, nerves, muscles, and connective tis-
sue.
Electron microscopy may occasionally be useful in clarifying the primary
cell of origin for a soft-tissue sarcoma. This usually involves the identifica-
tion of neurofibrils or cross-striations, leading to the classification of these
tumors as neurosarcomas or rhabdomyosarcomas, respectively.
clear from several histologic studies of soft-tissue sarcomas that there
It is
is no true tumor capsule even though these tumors appear to be grossly

encapsulated. This "pseudo capsule" consists of compressed normal sur-
rounding cells that have been invaded by microscopic malignant cells. 87
TABLE 15-2. Frequency of Adult Soft-Tissue

Sarcoma and Prognosis' M
Five-Year
Histology Frequency Survival Rate"
Liposarcoma 25% 50 to eo r ;
Fibrosarcoma 22% 70%

Rhabdomyosarcoma 12% 25%
Malignant fibrous histiocytoma 10% 30%
Undifferentiated 10% 20%
Synovial cell S' f 35%
Leiomyosarcoma 7% 30%
Neurofibrosarcoma 5% 4(Kr
"The five-year survival rate is based on surgical resection alone in extremity sarcomas.
Clinical Features
The malignant soft-tissue tumors often present as very large local masses.
Growth is relatively slow in the majority of cases, and they very seldom
cause early symptoms. These tumors are often only appreciated when the
mass is very large. If contiguous areas, such as nerve or vascular structures,
are compressed, the major symptoms are paresthesia, lymphedema, or ve-
nous engorgement. However, direct invasion of nerve and blood vessels
occurs in less than 10 per cent of the cases, 88 and most of the symptoms can
be related to a mass effect with compression of normal structures.
These tumors tend to spread in a three-dimensional fashion, but the
greatest microscopic extension tends to occur along fascial planesup to 6 to
7 cm beyond all gross disease. 89,90 Metastases to regional lymph nodes are
extremely uncommon with the exception of rhabdomyosarcoma and syn-
ovial cell sarcomas, 91 both of which metastasize to regional nodes in ap-
proximately 10 to 15 per cent of patients.
The primary metastatic site for the majority of these tumors is the lungs.
Approximately 80 per cent of patients who die from soft-tissue sarcomas do
so with either an uncontrolled primary or metastatic disease confined to the
lungs, or both. 92 The remaining 20 per cent of patients have metastases to
the liver, bone, soft tissue, and, rarely, to the central nervous system.
Diagnosis
When a patient presents with a soft-tissue tumor that may be a sarcoma

(very large, firm mass), whether it is increasing in size rapidly or more
slowly, the clinician should consider a biopsy. Careful consideration of the
types of biopsy incisions that are available is mandatory, because in order
to perform an adequate surgical resection for subsequent control of the
tumor, this prior biopsy site must be incorporated within the field of the
definitive operation.
Clinicopathologic Staging and Prognosis
The prognosis for patients with soft-tissue sarcomas is a function both of

histopathology and the anatomic extent of disease. Owing to the rarity of
these tumors, the problems in making an accurate histologic diagnosis, and
the lack of a widely accepted system for assessing prognosis, the American
Joint Committee for Stagingand End Results Reporting organized a task
force to study this problem. This committee evaluated the end results of
surgical therapy in 1215 cases from 13 institutions treated since 1968. 93 It
soon became clear that there was a marked disagreement among the pathol-
ogists regarding the tissue of origin of many tumor specimens; however, it
became apparent that the tissue of origin was less important in prognosis
than was the grade of the tumor (mitotic figures per high-powered field).
Moreover, it was reasonably easy to standardize a reproducible system for
assessing the grade of the tumor. Therefore, a staging system was devel-
oped based on the TNM system, with the addition of a "G," which repre-
93, 94
sents grade (Table 15-3).
After classifying the tumors and evaluating the outcome of all cases by
the surgical procedures, it was possible to stage these sarcomas as clin-
icopathologic stage through stage IV (Table 15-4). Stage I tumors have an

I
80 to 90 per cent ten-year survival rate, stage II tumors have a 60 per cent
survival rate, stage III tumors have a 25 per cent survival rate, and stage IV
tumors have a 3 per cent survival rate. It can be concluded that clinicopath-
ologic staging is useful and reproducible. It should be emphasized that this
system obviates the necessity for exact histologic classification of the
tumors and substitutes a more objective evaluation of the number of mi-
toses per high-powered field, the only exception being that by definition
rhabdomyosarcomas and synovial cell sarcomas are grade 2 tumors.
TABLE 15-3. TNM Classification for Soft-Tissue Sarcomas 94
Primary Tumor (T)
TX Minimum requirements cannot be met

T„ No demonstrable tumor
T, Tumor less than 5 cm in diameter
T-, Tumor 5 cm or greater in diameter
T, Tumor that grossly invades bone, major vessel, or major nerve
Nodal Involvement (N)
NX Minimum requirements cannot be met

N No histologically verified metastases to lymph nodes
N, Histologically verified regional lymph node metastasis
Distant Metastasis (M)
MX Not assessed
Specify sites according to the following notations:
Pulmonary = PUL
Osseous = OSS
Hepatic = HEP
Brain = BRA
Lymph
nodes = LYM
Bone
marrow = MAR
Pleura = PLE
Skin = SKI
Eye = EYE
Other = OTH
Tumor Grade (G)
G, Well differentiated
G 2 Moderately well differentiated
G 3 to G 4 Poorly to very poorly differentiated
TABLE 15-4. Stage Grouping for Soft-Tissue Sarcomas 94
Stage I
[a: G„T„ N„, M„
Grade 1 tumor less than 5 cm in diameter with no regional lymph node or

distant metastases
lb: C,,T,, N0) M„

Grade 1 tumor 5 em or greater in diameter with no regional lymph node or
distant metastases
Stage II
[la: G,,T,, \„, M„

distant metastases
lib: G,.T,. N M„ ,
Grade 2 tumor 5 cm or greater in diameter with no regional lymph node or

distant metastases
Stage III
Ilia: G„ T„ N., M,

distant metastases
[lib: G„T„ N 0J Mo
Grade 3 tumor 5 cm or greater in diameter with no regional lymph node or

distant metastases
Ilk: Any G.T, orT,, N„ M„
Tumor of any histologic grade or size (no invasion) with regional lymph node metastases
but without distant metastases
Stage IV
IVa: Any G, T„ Any N, M„
Tumor of any histologic grade or malignancy that grossly invades bone, major vessels, or
major nerves with or without regional lymph node metastases but without
distant metastases
IYb: Any G, Any T, Any N, M,
Tumor with distant metastases

TREATMENT
Surgery
Surgical Procedures. The surgical excision of soft-tissue sarcomas is

the initial treatment of choice, the goal being complete eradication of the
tumor. In order to accomplish this, the surgeon must consider all potential
avenues of tumor spread in a three-dimensional view. The possible micro-
scopic extension of the tumor from 10 cm or more along the fascial planes
must also be taken into consideration.
Local Excision. Local excision of gross tumor with a narrow margin of
less than 1 cm surrounding the tumor cannot be classified as complete exci-
sion. A 90 per cent local recurrence rate has occurred in patients treated
with such narrow excisions. 87 Failure is directly related to the mistaken
impression that these tumors are surrounded by a true anatomic capsule. 95
Muscle Group Excision. Well-differentiated tumors arising in a muscle
group or fascial planes can be treated successfully if excision includes the
entire soft-tissue part from origin to insertion and encompasses the adjacent
fascial planes. 96For example, when a tumor arises in the sartorius muscle
of the thigh, an operation that completely encompasses the sartorius from
origin to insertion plus the adjacent fascial planes of the adductor and qua-
driceps mechanism is appropriate. Regional lymph node dissection is
usually not performed unless lymph nodes are clinically involved.
Amputation. Amputative procedures are necessary for tumors that are
deep-seated, that involve multiple fascial planes, major blood vessels, or
nerves, or that invade a bone directly. 90 The techniques for amputation are
well known, and the decision for level is derived from the pattern of tumor
spread. Above the knee (AK) amputations are usually perfonned for tumors
below the knee, whereas below the knee (BK) amputations are reserved for
more distal tumors in the leg or foot. Hip disarticulations are perfonned for
proximally placed tumors when the origin of the muscle can be removed
with this operation. Interscapular thoracic amputations or hemipelvectomy
may be required for those tumors that are proximally placed in order to
remove muscles completely from origin to insertion as well as the associat-
ed structures.
Results of Surgery. Depending on the location of soft-tissue sarco-
mas, various results can be expected from surgical procedures.
Retroperitoneal Sarcomas. The surgical treatment of retroperitoneal sar-
comas is often difficult and usually results in failure. The principles for
excision of tumors in the extremities are also valid for tumors arising in the
retroperitoneal area. Complete excision of the tumor from origin to inser-
tion is usually not possible. Additionally, these tumors often involve major
blood vessels and have direct extension into adjacent organs. However, a
wide surgical excision is still the accepted means of therapy, and the best
results have been achieved in those tumors in which at least a 3-cm margin
could be achieved.
Head and Neck Sarcomas. Malignant sarcomas of the head and neck,
although rare, present additional problems for complete surgical extirpa-
tion. As with the retroperitoneum, complete en bloc excision of these
tumors seldom possible, the reasons being the very narrow anatomic
is
limits of the spaces of the head and neck and interrelated fascial planes.
Additionally, the cosmetic deformity that results from massive resections in
this area often makes aggressive surgical therapy in the head and neck area
unacceptable. The local recurrence rates in the head and neck area, even
with radical excisions, are 60 to 70 per cent, re-emphasizing the fact that a
wide surgical excision and adequate surgical margin are not possible in the
majority of these cases. 97
Summary of Surgical Principles. Complete surgical excision of
well-differentiated small tumors has been highly successful, with a recur-
rence rate of less than 10 per cent and an overall survival rate of nearly 80
per cent. This is true in the retroperitoneal area, the extremities, and the
head and neck areas. However, the local recurrence rate is much higher for
larger tumors in all locations. Additionally, proximally located tumors and
those with many mitoses have a very high recurrence rate despite radical
surgical procedures.
Radiation Therapy
Radiation therapy used alone is of marginal value in the treatment of this

group of tumors. When used alone as the primary mode of therapy, it re-
sults in local recurrence rates of 80 to 85 per cent and survival rates of less
than 10 per cent. 98 100 Suit et al. 101 and Lindberg 102 have examined the role
"
of modern radiation therapy as an adjunct to surgical excision for soft-tissue

sarcomas. Patients with primary tumors located distal to the elbow or the
knee who had been treated by complete excision of all gross tumor with at
least a 1-cm margin were given high-dose postoperative radiation therapy
in the range of 5000 to 6000 rad. With this combination the local recurrence
rate for patients with extremity sarcomas was less than 10 per cent, whereas
the predicted local recurrence rate with surgery alone was considered to be
about 60 per cent. These results appear to be equal to those achieved with
muscle group excision and radical amputation. When treating the more
proximally placed tumors (thigh, arm, head, or neck), these authors found
the local control rate was much less and local recurrences were found in 35
to 40 per cent of cases. This combination therapy has not been efficacious
for tumors located in the retroperitoneum because of the dose limitations in
irradiating the intra-abdominal structures.
The rationale for high-dose radiation therapy to the involved extremity
was based on the hypothesis that even though the gross tumors were ra-
dioresistant, the microscopic disease that was still present following local
excision was not. High-dose radiation to the tumor bed has been highly ef-
fective.
Complete amputative surgery or muscle group excision has resulted in
approximately 90 per cent local control of these tumors. For patients with
primary tumors of the forearm or calf, complete excision followed by post-
operative radiation therapy appears to be a reasonable alternative to ampu-
tative surgery. The advantage of maintaining a potentially functional ex-
tremity makes the latter choice attractive to most patients.
Chemotherapy
Although soft-tissue sarcomas have a history of extreme resistance to che-

motherapeutic drugs, several new agents have been used effectively. Dox-
orubicin induces beneficial responses in approximately 30 to 40 per cent of
patients with disseminated disease. 103 Combination chemotherapy with Cy-
VADIC (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and da-
carbazine [imidazole carboxamide]), as originally described by Gottlieb et
a/.,
104
leads to an even higher response rate (Table 15-5). A combination of
doxorubicin with high-dose methotrexate administration, as discussed pre-
viously for osteosarcoma, has also been of value. 36 The most dramatic re-
sults of chemotherapy have been those achieved by vincristine, dactinomy-
cin, and cyclophosphamide in childhood rhabdomyosarcomas, in which the
response rate approaches 90 per cent even with disseminated disease
(Table 15-5). 105 106-
Additional routes of chemotherapy administration have also been studied.

Original studies by Haskell et al. 107 and DiPietro et al. l0S suggested that
doxorubicin by the intra-arterial route may be more effective than the sys-
temic route in selected patients, because a high concentration of the drug
can be achieved in a local area.
Reports from Stehlin 109 indicate that isolated limb perfusion with dactin-
omycin can be used effectively for selected patients to destroy tumor in an
extremity. The addition of hyperthermia to such perfusions may further
augment the activity of dactinomycin. 110 However, the head, neck, and ret-
roperitoneum are seldom amenable to this type of treatment because of
anatomic limitations.
Morton et al. 37 and Eilber et al. 111 112 have described preoperative treat-
'
ment of patients with large soft-tissue sarcomas of extremities employing

intra-arterial doxorubicin and rapid-fraction radiation followed by complete
en bloc excision. The local recurrence rate in this series was less than 5 per
cent, and although the follow-up has thus far been only 24 months, these
TABLE 15-5. Chemotherapeutic Combinations

Sarcoma
for Soft-Tissue
Agents Dose Frequency
VAC 105, l06
Vincristine 2 mg/m 2 IV Q wk x 12
Dactinomycin 0.015 mg/kg/day IV x 5 Q 3 months x 5 to 6
Cyclophosphamide 2.5 mg/kg/day PO Startday 42 and
continue 2 years
CyVADIC 104
Cyclophosphamide 500 mg/m 2 -day 1 IV Repeat
Vincristine" 1mg/m 2 — days 1 and 5 IV Q 22 da> s
Doxorubicin 50mg/m 2 -dav 1 IV

Dacarbazine 250 mg/m 2 -day 1 -» 5 IV
"The maximum single dose of vincristine in both regimens is 2 nig.

results are encouraging. They are also consistent with a possible synergism
of doxorubicin and radiation therapy.
This is most appropriately considered as a function of the anatomic re-

gion of involvement.
EXTREMITY TUMORS. Since the majority of extremity tumors in children
are rhabdomyosarcomas, the most appropriate means of therapy appears to
be initiation of chemotherapy with VAC, complete surgical excision if —
possible —
and postoperative radiation therapy with continued cycling on
chemotherapy.
In adults with extremity tumors, several factors must be taken into con-
sideration. Localized tumors that are well differentiated can be adequately
excised by radical en bloc excision. Clinicopathologic stage I and stage II do
not appear to require local or systemic postoperative adjuvant therapy with
either radiation therapy or chemotherapy, since local recurrence rates are less
than 10 per cent and survival rates are very high. However, in patients with
clinicopathologic stage III or stage IV tumors, or those that are well differenti-
ated but proximally placed at a point at which adequate excision cannot be
achieved, additional therapy following surgical procedures seems warranted.
Although local recurrence is a major problem, it is the distant metastatic
spread that is the major detenninant of patient survival in these tumors.
Control of these metastases requires some form of systemically active thera-
py. Of the two types available to date — i.e., chemotherapy and immuno-
therapy —the best results have been achieved with adjuvant chemothera-
py. Several studies are now under way in the United States and elsewhere
to test the efficacy of the various kinds of combination chemotherapy.
These studies almost always include a regimen like CyVADIC. Although
the results have been encouraging, it is too early to determine definitely
whether or not these combinations will reduce the frequency of distant
metastatic spread.
Head and Neck Tumors. For those patients with head and neck sar-
comas, the appropriate method of therapy is yet to be defined. Clearly, in
childhood head and neck sarcomas primary treatment with VAC chemo-
therapy combined with radiation therapy following adequate biopsy is the
treatment of choice. Radical surgical resection is required infrequently.
Retroperitoneal Sarcomas. Complete radical excision of retroperi-
toneal sarcomas should be carried out in all cases when technically possi-
ble, regardless of the histopathologic grade. This requires aggressive surgi-
cal therapy and in many instances resection of major blood vessels, such as
the vena cava and aorta, in order to achieve an adequate tissue margin.
Radiation therapy does not seem to be applicable in these areas, since the
5000 to 6000 rad dose range required for the extremities and head and neck
tumors is not possible in the abdomen at the present time without signifi-
cant morbidity to the adjacent bowel, kidney, and liver. In these cases it
would seem reasonable to try intra-arterial doxorubicin, if there is a feeding
vessel, or systemic chemotherapy.

There are few tumors that better illustrate the potential value of mul-
timodality treatment than do the soft-tissue and bone sareomas. The next
decade should provide further guidelines to such combined treatment, as
well as guidelines to better techniques of reconstruction and rehabilitation.
ReterenceS (Asterisk indicates key references)
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and Coventry MB: y Bone 27. Sutow WW
and Martin RG: In Cancer
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Deinhardt F. et al: J Med Primatol ma: Interim report of the South-
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14. Neifeld JP, et al: Cancer 39:383, mas: 5 vear report. Proc ASCO
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in Man, Terry WD
and Windhorst D 17.265. 1976
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1973. ASCO 18:326, 1977.
CHAPTER 16
MELANOMA
H Stephens Moseley Frederick R Eilber
Donald L Morton
INTRODUCTION
Melanoma is a cancer with an increasing worldwide incidence and is
now more common than Hodgkin's disease and primary brain tumors. In
1976, there were nine new cases per 100,000 persons in the United States.
1
Australia has the highest reported incidence of melanoma in the world,

with approximately 17 new cases for every 100,000 persons each year. In
Canada, the rate of increase in melanoma is greater than any other tumor
except for male lung cancer. An examination of possible reasons for the
increased incidence demonstrates two patterns that may reflect a trend.
First, the incidence of melanoma appears to be proportionally greater in
younger persons than in people over age 65 years, and second, an increase
in certain sites of melanoma has also been noted. There has been a slight
increase in the prevalence of melanoma around the head and face but not
nearly as marked as the increase on the legs of females and the trunk of
males.- It appears that the change is greatest at those sites at which sun
exposure has increased, resulting from a change in clothing styles and re-
creational habits.
Although the etiology of melanoma is unknown, sunlight and in partic- —
ular ultraviolet light —
has been implicated as a factor. In whites, an in-
16 / Melanoma 679
crease in both the incidence and death rate of melanoma has been correlat-
"
ed with decreasing latitude. 3 6 This increased incidence has been noted

particularly in fairer skinned people of Celtic extraction. A
markedly lower
incidence of melanoma has been demonstrated in other races and in more
"
darkly pigmented whites. 7 9 However, there are several arguments against
the sunlight hypothesis. The most important of these is that the distribution
of melanomas is vastly different from other actinic-induced neoplasms.
Basal and squamous cell carcinomas, for example, occur most commonly on
the head, neck, forearm, and dorsum of the hand. Melanomas are more
common in regions of the body that have never been exposed to sunlight.
If melanomas were totally actinic-related, one would expect that with in-
creasing age, the incidence of primary melanomas would increase. This
does not appear be the case. 10
to
Certain families appear to have a high incidence of melanoma. In the
Queensland experience, the incidence of familial melanoma was approxi-
mately 11 per cent, and the probability of developing the disease was four
times the expected incidence for a person with a family history of melano-
ma. 11 A high incidence of multiple primary' melanomas, ranging from 11 to
27 per cent, with an earlier age at onset has also been noted in familial
"
14
cases. 11
The genetic mechanism for the transmission of the tendency to develop
melanoma is not known but has been attributed to an autosomal dominant
gene with incomplete penetrance. 13, 15, 16 It has also been suggested that the
genetic transmission is polygenic from an undetermined number of alleles
at separate loci, perhaps influenced by a cytoplasmic component.
11, 12, 14
To
date, no relationship between exposure to airborne or work-related carcin-
ogens has been established. 17, 18
The possible role of trauma in the etiology of melanoma is controversial.
Some patients will give a history of recent trauma, which they associate
with the growth of a lesion. Other patients state that a mole was irritated by
various belts and straps. In Bantu blacks there has been a high incidence of
melanoma of the soles in people who go barefoot as opposed to those who
wear shoes. In a study of American blacks, no such factor could be substan-
tiated. 19 Although the role of trauma remains unknown, it is possible that in
certain instances it may be a factor in stimulating an active growth phase of
pre-existing melanoma.
NATURAL HISTORY
The classic clinical signs of melanoma are darkening color, recent en-
largement, developing nodularity, pruritus, ulceration, and bleeding. These
features all too often apply to a melanoma that has invaded deeply into the
dermis and reflect an advanced tumor. More subtle signs, such as irregular
or angular border and variegated color with shades of pink, red, white, and
blue are frequently seen in early melanomas, particularly of the superficial
spreading type. 20, 21 The articles by Mihm et al. 21 and Kopf et al. 22 contain
excellent descriptions of these changes illustrated with color photographs.
Classification
The American Joint Committee for Cancer Staging and End Results Re-
porting accepts 11 different forms of extraocular melanoma occurring in
humans (Table 16-1). 2:i - 4 Of these, lentigo maligna melanoma, superficial
spreading melanoma, and nodular melanoma constitute 80 to 85 per cent of
21 22 - 25
the total. -
Lentigo Maligna Melanoma (LMM). This type of melanoma arises

from lentigo maligna or melanotic freckle of Hutchinson. constitutes LMM
about 10 per cent of all primary cutaneous melanomas and is found most
commonly in elderly persons (median age of 70 years) on chronically sun-
exposed areas of the face, neck, and dorsum of the hand. This lesion has no
sex predilection and often appears as a large (3 to 4 cm), irregular tan to
dark brownish black lesion with a flat surface. Areas of hypopigmentation
representing regressivephenomena may be present.
Superficial Spreading Melanoma (SSM). This is the most common
form of cutaneous melanoma, making up 70 per cent of all melanomas. It
has a peak incidence in the fifth decade of life but is common throughout
adulthood. The occurrence of SSM is more common in males than in fe-
males around the head, neck, and trunk, but it is more common in females
on the extremities —
particularly the lower extremities. In both sexes, the
most common site is the back where 30 per cent of SSM are found.
SSM tends to be somewhat less irregular in outline than LMM, although
it often has notched borders. These lesions are characteristically multicol-
ored with shades of tan, brown, black, red, and white. Early in their devel-
opment, they may be barely palpable. These melanomas may have long
periods of growth, from one to five years or longer, before invasion.
Nodular Malignant Melanoma (NM). Nodular melanoma composes
10 to 15 per cent of all cutaneous melanomas. With a median age of onset
at 49 years, NM
tends to have the earliest occurrence of the three types.
There is no true sex predilection, but it most commonly occurs on the trunk
of men. Nodular melanoma lesions are typically dark blue to black but may
be amelanotic. They are characterized by an almost complete absence of
intraepidermal growth and are associated with rapid vertical invasion of the
TABLE 16-1. Classification of Extraocular Melanoma'
1. Superficial spreading melanoma

2. Lentigo maligna melanoma
3. Malignant melanoma with an unclassified radial growth phase
4. Nodular melanoma
5. Malignant melanoma arising in a giant hairy nevus
6. Volar-suhungual melanoma
7. Oral, vaginal, and anal mucous membrane melanoma
8. Malignant melanoma without demonstrable primary lesion
9. Malignant melanoma arising in a blue nevus
10. Malignant melanoma arising in a visceral site
11. Other malignant melanomas such as those in childhood and those arising in dermal nevi
"Adapted from The American Joint Committee for Cancer Staging and End Results Reporting,
1976 and Clark WH, et al.: Semin Oncol 2:83, 1975.
16 / Melanoma 681
dermis. The history of duration of such lesions is typically from a few

months totwo years. The differential features of the common types of mela-
noma summarized in Table 16-2.
are
Less Common Types of Melanoma. Of the less common types of cu-
taneous melanoma, volar and subungual melanomas constitute 2 to 3 per
cent of the total. Their occurrence is almost equally divided between the
hands and the feet, with the most common sites being under the nail of the
thumb and the great toe. Although melanomas are uncommon in blacks,
subungual melanomas in this race compose 15 to 20 per cent of the total
distribution. These lesions may have long periods of growth and are fre-
quently misdiagnosed as fungi, hematomas, and ingrown nails. 22,24,26 Gib-
son et al. 27 reported that two thirds of these cases had some form of minor
surgical procedure performed before melanoma was suspected.
The congenital nevi represent hamartomatous tissue of neural crest ori-
gin. Melanoma arising in congenital nevi is uncommon, but it occurs most
frequently in the first five years of life, with most cases developing in ex-
tensive nevi. 28 29 Congenital nevi are most easily followed with the aid of
'
serialphotographs.
The cellular blue nevus is a benign lesion occurring commonly in the
sacrococcygeal area. These lesions have been reported to metastasize to
regional lymph nodes and may pose significant diagnostic and therapeutic
problems. In such situations, these lesions should be regarded and treated
as malignant, since melanoma arising in blue nevi has been reported. 30, 31
Developmental Biology
Regarding the natural history of melanoma, there is a great deal of con-

troversy as to whether or not the neoplasm arises from acquired pigmented
nevi or from pre-existing malignant melanocytes. Originally, it was as-
sumed that the majority of melanomas arose from areas of increased junc-
tional activity, and certain nevi were considered to be premalignant. How-
ever, histologic and clinical evidence suggest that it is exceptional for a
melanoma to arise in a pre-existing nevus. 24
Melanomas usually have two distinctive growth phases radial and ver- —
tical. During the period of the radial growth phase, the melanoma spreads
out either above or just below the basal lamina. This initial phase of growth
is rarely associated with metastasis, and in certain types of melanoma, such
as SSM or LMM, it may last for many The prolonged radial growth
years.
phase helps create the controversy over whether a melanoma arises from a
pre-existing lesion or de novo. Eventually the vertical growth phase begins,
a process known as intralesional transformation, and this phase may give
rise to cell populations commonly associated with metastatic disease.
Diagnosis
BIOPSY. The biopsy of a suspicious nevus is the first surgical consider-

ation for melanoma. An excisional biopsy that includes a small amount of
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16 / Melanoma 683
subcutaneous tissue is the preferred method because it removes the

totally
lesion and allows accurate microstaging of the entire specimen. For lesions
that are larger than 2 cm or for large lesions on the face, an incisional
biopsy may be indicated. Concern that an incisional biopsy through a mela-
noma might worsen the prognosis has not been verified.''- An incisional biopsy
should be performed through that portion of the lesion that appears most
irregular or nodular. It should also include a portion of adjacent normal
skin. Shave biopsies, although they are usually adequate to make a diagno-
sis, are condemned because they do not permit accurate microstaging. Bi-
opsy techniques have been well illustrated by Harris and Gumport. 33

Work-up Prior to Therapy. Once a diagnosis is made, work-up is
usually straightforward. A complete physical examination looking for in-
transit metastases, regional lymph node involvement, other primary mela-
nomas, and distant metastases should be undertaken. Multiple primary mel-
anomas occur in 4 to 5 per cent of all melanoma patients, and the majority
are usually diagnosed within one year of the original diagnosis. 34 The biop-
sy specimen should be microstaged. Patients at UCLA preoperatively re-
ceive a chest x-ray, complete blood count, and liver function studies. Pre-
operative liver, brain, and bone scans in patients with stage I disease who
do not have clinical or laboratory evidence of metastases are rarely positive
and are not usually indicated. 35
Clinical Staging
Melanomas usually are clinically staged by either the method of the In-
ternational Union Against Cancer or the MD Anderson Hospital (Table
16-3). Throughout this discussion stage I melanoma will denote a lesion
confined to the primary site, stage II will indicate regional lymph node
involvement, and stage III will imply disseminated disease.
In 1953, Allen and Spitz 31 first attempted to predict the biologic behavior
of melanoma by histologic staging of the primary. Since then, several sys-
tems have been devised, but the methods of Clark et al. u and Breslow 36
have been used most frequently. In the Clark system, the primary melano-
ma is histologically classified according to its microanatomic level of inva-
sion of the dermis (Fig. 16-1). Clark's original observations suggested that
progressive invasion through the deeper levels of the dermis was associat-
ed with an increasingly poorer diagnosis.
A level I melanoma is considered to be equivalent to "in situ" melanoma
and lies in the epidermis above an intact basal lamina. The natural history
of level I melanoma is not completely known. Clark's level I is often de-
scribed as AMH or "atypical melanocytic hyperplasia." This lesion is
thought to have no malignant potential because there are no known blood
vessels or lymphatics above the basal lamina. For this reason, many pathol-
ogists use the term AMH to avoid possible overtreatment by surgeons.
More appropriately, it protects the patient from the emotional trauma of a
diagnosis of cancer and from occupational and insurance problems associat-
ed with such a diagnosis.
TABLE 16-3. Staging in Melanoma

IUCC Classification \id Anderson Classification
Stage I Primary with satellites St. me Superficial melanoma

within 5 cm of primar)
Stage I No metastases — primary only

Stage II Involvement lymph node la Intact primary
draining basin with or II) Primar) localh excised
without in-transit metastases Ic Multiple primary melanoma
Stage III Disseminated melanoma Stage II Local recurrence of metastases

All melanotic lesions within
3 cm ot primary site
Stage III Regional metastases

(>3 cm from primar)
Ilia In-transit metastases
Illh Regional lymph nodes
1 1 lab Intradermal and regional
lymph nodes
7
Stage IV Distant metastases
IVa Cutaneous
IVb Visceral
IVc Lymph nodes
IVac Combinations of above
Once the melanoma has penetrated the basal lamina into the papillary
dermis, it is classified as level II. As the melanoma continues to invade and
spread along the papillary-reticular interface, it is classified as level III. A
level IV melanoma represents invasion into the reticular dermis, and level
V is penetration into the underlying subcutaneous fat.
LEVELS:
Epidermis
'
— Basal lamina
Papillary dermis
Reticular dermis
Subcutaneous fat
FIGURE 16-1. Diagram of Clark's levels of invasion. Depth of invasion is measured verti-
cally from the basal lamina. (In Plastic Surgery: A Concise Guide to Clinical Practice. Grabb WC
tech. Boston, Little. Broun 6 Co., 1968.)
16 / Melanoma 685
Breslow38 devised a system in which the actual depth of invasion from

the basal lamina was quantitated using an ocular micrometer. It appears
that lesions measuring greater than 1.7 mm in thickness have a high meta-
static potential, whereas lesions with less than 0.76 mm invasion have a very
low metastatic potential. Clark's levels and depths of invasion are frequent-
ly used together to give complementary information for classifying melano-
mas. Obviously neither technique is totally independent of the other, but it
is helpful to consider them separately because of the variations in skin
thickness in different parts of the body. For example, a melanoma arising in

the skin of the face or the ear could be a deep level but have a shallow
depth of invasion. Conversely, on the back, a lesion could be well over a
millimeter in thickness and still be intermediate Clark's level. In a mul-
tifactorial study of prognostic factors in melanoma, it appeared that the
depth of invasion was a more important variable prognostic-ally than
level —
a finding also suggested by the studies of Balch et al.* and Wan-
1
ebo et al. 38
Prognosis
Manyparameters have been reported to influence survival, such as age,

sex, anatomic location, size and type of primary, level, depth, and status of
regional lymph nodes. The Queensland data and others have found that
females have a better prognosis than do males. 10, 39, 40 Premenopausal fe-
males are reported to have a much better rate of survival than those who
are postmenopausal. An age-related trend was noted in males, but it was
not nearly so marked as in females. Both male and female patients with
melanomas of the extremities have an improved survival rate over those
with melanoma of the head and neck. Patients with melanomas of the
trunk, particularly the back, have the worst rate of survival. 10
In the last ten years the use of microstaging — combining level and
depth with the presence or absence of regional lymph nodes — makes up
the most important parameters influencing survival. Clark's 25 levels have
been shown to give prognostic information regarding both the probability
of regional lymph node metastases and survival, as illustrated in Table
16-4. Cady et a/. 41 reported survival at six years in a retrospective study of
176 patients and found overall survival for level II to be 86 per cent, level
III and level IV to be 67 per cent, and level V to be 11 per cent. 41 At ten
years, Wanebo et al. 38 reported 100 per cent survival in clinical stage I
patients with level II melanoma of an extremity. Patients with level III and
level IV had a 77 per cent and 57 per cent survival rate, respectively, but
only one of six patients (17 per cent) with level V was alive. 38
The depth of invasion offers prognostic information that is similar to
level. In several series, the five-year survival rate for lesions less than 0.5
mm was 100 per cent, whereas patients with thick lesions (greater than 3
mm) had less than a 30 per cent five-year survival rate. 36 38 Wanebo et al. 3S
"
proposed a rule of thumb that stated that the five-year mortality rate was
approximately ten times the measured depth of invasion in millimeters.
Although level and depth are important, the status of the regional lymph
TABLE 16-4. Clark's Levels and Five-Year Survival
Lym ph Node
Level Metastases W anebo Et Al. ° 38
Das Gupta t
4
II + 100 100
- 100 100
III + 91 91
— 100 97
IV + 33 32
- 82 91
V + 29
— 100
'Retrospective study, clinical staê I extremity melanoma.

tProspective stuck, all body sites. Number of level V patients small.
nodes is perhaps a better indicator of ultimate survival.An NCI study

found of level or depth, the five-year survival rate in pa-
that, irrespective
tients with negative node involvement was 73 per cent, 55 per cent with
one to three positively involved nodes, and only 26 per cent when four or
more nodes were involved. 40
TREATMENT
Surgery
Primary Melanoma. The only effective therapy for primary melanoma

at present is surgical resection. Because melanomas are notorious for early
lymphatic spread beyond their clinically detectable borders, the treatment
of choice is radical wide excision. The rationale for wide excision is based
upon the work of Sampson-Handley 42 who excised a 5-cm margin of grossly
normal tissue around a primary melanoma. Although the original width of
wide excision was empiric, Cochran 43 described antigenic changes, and
Wang 44 demonstrated melanocytic activation up to 4 cm away from a prima-
ry tumor in areas of skin that appeared normal. Recently, Balch et al. 37 and
Breslow and Macht 45 have suggested that a width less than 5 cm does not in-
fluence prognosis in level II and level III melanomas of low and
intermediate depth. Clearly, in the head and neck region, a 5-cm margin is
not possible and a 2. 5-cm minimum margin is used. The incidence of local
recurrence using this measurement has been reported to be only 4 per
cent, which is similar to local recurrences in other sites. 46 However, on the
scalp a 5- to 6-cm radius around the primary is recommended. 47
The depth of incision is equally important. Since lymphatics are not
thought to penetrate fascia, the depth of the incision should include this
layer to avoid cutting across possible tumor in deep subcutaneous lymphat-
16 / Melanoma 687
48
ics. The anatomic layer that helps to ensure an
fascia provides a definite
adequate depth of excision. A secondary benefit is that skin grafts appear to
take better on exposed muscle than on fascia.
Split-thickness skin grafts provide adequate coverage of the wide exci-
sion site. On the trunk it is often possible to close wounds primarily using
advancement flap techniques, even with a 10-cm total defect. At UCLA, we
have seen no differences in local recurrence rates between grafting and
primary closure when a 5-cm wide excision was used. 49 However, if a re-
currence develops in a wound primarily closed, the entire previous surgical
dissection site should be considered contaminated. Rotational and cross ex-
tremity flaps are contraindicated in the initial management of primary mela^
noma.
Since subcutaneous tissue and fascia are nonexistent in the subungual
-areas, appropriate treatment for melanoma in these locations usually in-
volves amputation at the level of the distal interphalangeal joint. For exten-
sive lesions, amputation of an entire digit may be necessary.
Even though the actual width of primary excision is being debated, it
seems unlikely that smaller margins will improve therapeutic results. Since
any form of local recurrence following excision of a primary is all too often
eventually associated with disseminated disease, the most conservative
therapy for primary melanoma is the wider excision. 50
REGIONAL LymphadenectOMY. For the patient with clinically suspi-
cious or pathologically proven metastases to regional lymph nodes, regional
lymphadenectomy is indicated. A major controversy exists over whether
early lymph node dissection in patients with clinically negative lymph
node involvement offers any therapeutic advantage over later dissection
after the patient has obvious nodal metastases. Some recent data help to
resolve the controversy. Veronesi et a/., 51 in a prospective randomized
World Health Organization study of stage I melanoma of the distal extremi-
ties, found that elective lymph node dissection did not statistically improve
prognosis when patients could be followed at three-month intervals. How-
ever, in that study, patients with level IV melanoma who were treated by
wide excision and elective regional node dissection had a 12 per cent bet-
ter survival rate at five years than did patients with level IV melanoma and
therapeutic dissections. For patients with level III melanomas, there was also
a slight survival advantage in favor of early dissection. A preliminary report
from a Mayo Clinic Study that included truncal melanomas also failed to
show a significant difference between elective and therapeutic dissect-
ions. 52
These studies suggestthat routine elective lymphadenectomy for melano-
ma probably not efficacious. However, by stratifying melanoma patients
is
by level and depth of invasion, subgroups of patients who have a high

probability of regional lymph node metastases can be identified. Holmes et
53
a/. found that patients with level III melanoma had a 29 per cent in-
cidence of positive node involvement. Level IV was associated with a 42
per cent incidence of positive node involvement and level V with a 58 per
cent incidence (Table 16-5).
A prospective study by Das Gupta, 54 in which regional lymph node dis-
TABLE 16-5. Regional Lymph Node Involvement by Clark's Levels 53
Clark's Level
II-III IV \
Number of patients 112 78 12

Clinically positive node involvement 15% 24% 50%
Pathologically positive node involvement

Total no. (+) nodes 29% 42% 5895
Occult metastases 18% 27% 32%
sections were contiguous with primary melanoma operations to evaluate

the prognostic influence of Clark's levels, found a 41 per cent, 74 per cent,
and an 89 per cent incidence of pathologically positive node involvement
for Clark's levels III, IV, and V, respectively. This study has the highest
percentage of occult metastasis yet described and very high five-year sur-
vival rates. Cady et al. 41 found that the number of involved lymph nodes
also influenced survival. Patients with only a single involved node had a
poorer, but not statistically significant, five-year survival rate than patients
with negative nodes.
Although patients who have occult positive node involvement may not
have a statistically significant improved survival rate over those with palpa-
ble disease, it is clear that a regional lymphadenectomy is the only avail-
able staging procedure. Patients with pathologically negative lymph node
involvement have a 70 to 95 per cent five-year survival rate, whereas at
least 50 per cent of patients with melanoma metastatic to regional lymph
nodes have disseminated disease within three years of their surgical proce-
dure. 10, 38 40 51 Staging helps select patients who might benefit from adju-
' '
vant therapy.
One facet of the node dissection controversy concerns the ambiguous
lymphatic drainage associated with truncal melanomas near the midline or
beltline that may drain to more than one lymph node group. Injection of
the primary site with a radioactive colloid of gold 198 Au) has been shown to
(
demonstrate accurately the route of lymphatic drainage. 53 The procedure

does not indicate nodal metastases, but in a series of 77 patients, no one
developed metastases in an area that did not absorb the gold colloid. Pri-
maries arising in the face, forehead, eyelids, and anterior ear drain through
parotid lymph nodes, and when a lymphadenectomy is indicated it should
include a superficial parotidectomy. 36
Another facet of the controversy concerns the morbidity associated with
lymphadenectomy. Although morbidity from axillary and radical neck dis-
sections seems to be minimal, complications from inguinal node dissections
can be as high as 40 to 60 per cent. 57,58 Holmes et a/. 33 described a method
of groin dissection that reduced the morbidity associated with inguinal lym-
phadenectomy to about 10 per cent. Their technique involved routinely
removing only inguinal lymph nodes. The iliohypogastric nodes were dis-
sected only if the inguinal nodes were involved with melanoma.
16 / Melanoma 689
The current practice at UCLA is to perform lymph node dissections on

all patients with clinically suspicious or pathologically positive regional
nodes. Elective node dissections are advocated for all patients with Clark's
level IV and level V melanoma and for selected level III patients with a
depth of invasion greater than 0.65 mm. This depth of invasion was chosen
after several patients with lesions between 0.65 and 0.76 mm developed
regional node metastases.
Palliative Surgery. Surgical procedures are generally not indicated
for the treatment of disseminated melanoma, but there are occasional, highly
selective indications in which surgery can offer relief of symptoms and im-
provement in quality of life. Melanoma frequently metastasizes to the gastro-
intestinal tract, which may produce bleeding, obstruction, or intussusception.
Patients with nonterminal disease having significant GI symptoms may often
be symptomatically palliated by resection of those metastatic lesions.
It is not uncommon for melanoma of an extremity to produce massive
subcutaneous and intracutaneous metastases with little or no evidence of

distant dissemination. Such patients may be benefited by a regional hy-
perthermic perfusion. Amputations usually are not done for such conditions
but may be indicated in selected instances.
A single melanoma metastasis to the lung without evidence of other pul-
monary or involvement is uncommon. An occasional patient may
visceral
be found with a pulmonary metastasis and no other evidence of disease
after a careful metastatic work-up and frequent observation. If the tumor
doubling time is greater than 40 days, consideration should be given to
surgical resection. 59 Cahan 60 reported 19 patients who had excision of mela-
noma metastases to lung. Of 12 patients operated upon, at five-year follow-
up only 4 were still alive, and all had only a single metastasis.
Solitary brain metastases are equally infrequent. In such cases neurosur-
gical resection followed by whole brain irradiation has occasionally pro-
longed survival for several years. Since there are occasional long-term sur-
vivors from radiation therapy alone, it is difficult to decide what role
neurosurgical decompression plays in this group of patients. Patients with
superficial solitary lesions in noncritical areas of the brain would seem to
be the best candidates.
Radiation Therapy
Melanomas are traditionally classified as radioresistant tumors, although

this is isnot strictly true. Radiotherapy has been attempted in stage I mela-
noma but is not recommended. Its principal use is in stage III disease for
palliation of brain metastases. In selected instances radiotherapy is used as

an adjuvant after surgery in which clear margins could not be obtained and
22, 61
for palliation after failure of surgery and chemotherapy.
Chemotherapy
Treatment of Advanced Disease. Chemotherapy for melanoma has

not been nearly as rewarding as for other solid tumors, such as carcinomas
of the breast and sarcomas. Luce 82,83 reviewed the literature on active
agents in melanoma, which are summarized in Table 16-6. DTIC has had
the most extensive trials of any single agent, with a reported objective re-
sponse rate of 25 per cent based on 806 reported cases. Currently, DTIC is
considered to be the single agent of choice in the treatment of melanoma.
Trials of other drugs with activity against melanoma, such as the nitro-
soureas, vincristine and cyclophosphamide in combination with DTIC,
have been investigated by several oncology groups. Combination trials with
these multiple agents have not demonstrated significant therapeutic advan-
tage over the use of DTIC alone. 64
"
67
Several observations suggest that melanomas may be influenced by hor-

mones. Melanomas rarely appear before puberty, and women have a better
prognosis than men. 10 Exacerbation of melanoma has appeared in certain
instances with pregnancy, and positive estrogen receptors were reported in
16 of 35 patients in a NCI study. 68, 69 Although most attempts at endocrine
manipulation have been unsuccessful, occasional responses have been
70-72
reported. At present, the role of hormonal manipulation, if any, in the
management of melanoma has yet to be defined.
Adjuvant Chemotherapy. Patients with metastases to regional lymph
nodes are at high risk for developing systemic metastases and eventually
dying from melanoma. In an effort to benefit these patients, postoperative
adjuvant trials have been initiated throughout the world during the past
several years. Although DTIC is currectly considered to be the drug of
choice in treating disseminated melanoma, adjuvant trials in patients with
stage II melanoma demonstrated no improvement in survival using DTIC
compared with surgery alone. 73
Regional Perfusion. Hyperthermic chemotherapeutic regional perfu-
74
sion was first reported in 1958 for control of locally recurrent disease. The
technique involves isolating the blood supply to a limb and inserting arteri-
al and venous catheters. A tourniquet is applied, and the limb is perfused
using a cardiac bypass pump and an oxygenator. The blood is usually heated
to no more than 104° F and drugs such as melphalan or dactinomycin are
77
infused. Stehlin et al.,75 McBride, 76 and Krementz and Ryan found benefit
from this technique in controlling locally recurrent or in-transit melanoma.
Results from a NCI study comparing heated and unheated melphalan implied
TABLE 16-6. Chemotherapeutic Agents Active in Melanoma
Drug % Response Drug % Response
Doxorubicin Hydroxyurea 12
Cytarabine 11 Mechlorethamine 5
BCNU 18 Melphalan 9
Bleomycin 10 6-Mercaptopurine 7
CCNU 8 Methotrexate 10
Cyclophosphamide 22 Mitomycin-C 16
Dactinomycin 17 Procarbazine 28
DTIC 25 Vincristine 20
5-Fluorouracil 4 Vinblastine 20
"Modified from Luce JK: Cancer 30:1604, 1972 and Luce JK: Semin Oncol 2:179, 1975.
16 / Melanoma 691
longer survival in the heat plus melphalan group. 75 Studies comparing heat
alone with heat plus drugs have yet to be done.
There is some controversy over the efficacy of hyperthermic perfusion in
patients with stage I and stage II disease, but a randomized study compar-
ing perfusion with surgery alone has yet to be done. The proponents of
perfusion claim a 2 to 3 per cent local and in-transit recurrence rate follow-
ing perfusion, which in their series is an improvement. 75 77, 78 Other groups
'
have reported only 4 per cent local recurrences with wide excision and
regional node dissections. 51,53 54 It is doubtful that perfusion in the latter
'
groups would significantly improve therapeutic responsiveness.
Immunotherapy
Melanoma has been known spontaneously. Although it is unu-

to regress
phenomena in primary mel-
sual for metastatic lesions to regress, regressive
anomas are not uncommon. Approximately 4 per cent of patients present
with metastatic melanoma to regional lymph nodes for which a primary can
never be found, suggesting complete regression of the primary. 79 Attempts
have been made to augment that response using various immunostimula-
tive agents.
BCG and BCG plus a tumor cell vaccine have been under intense inves-
tigation by Morton's group at UCLA. 8082 In a preliminary postoperative trial,
BCG appeared to delay the time to recurrence significantly and to prolong
survival when compared with surgical resection alone. Gutterman et a/. 83
also have shown an apparent reduction of disease recurrence in patients
treated with BCG immunotherapy. Trials from the World Health Or-
ganization indicated benefit from immunotherapy. 84 However, Pinsky et
a/.
85
found no benefit from BCG treatment. Preliminary results from a post-
operative adjuvant prospective randomized controlled trial at UCLA com-
paring no further treatment with adjuvant immunotherapy with BCG and
BCG plus tumor cell vaccine suggest no delay in time to recurrence in
immunotherapy patients compared with controls, but survival was improved
in patients receiving BCG. 86 At the present time, the use of adjuvant immu-
notherapy in patients with melanoma remains experimental.
Surgical excision is the cornerstone of treatment for melanoma. Other

modalities may also be required for the individual patient, and the best
integration of these modalities is often controversial. However, as a guide,
we have summarized our current approach to management at UCLA in Fig-
ures 16-2 and 16-3.

It is easy to predict that when better cytotoxic and immunostimulative
agents are available, treatment results will improve. At present, there are
692 II / Treatment of Spk< ii k Neoplasms
SUSPICIOUS NEVUS
I
Excisional Biopsy
(Incisional (or large nevi, cosmesis)
I
Diagnosis Melanoma Confirmed
I
Level II or III, < 0.65 mm Level III > 0.65 mm
Level IV, V
I
Clinically Negative Nodes
I
FIGURE 16-2. Management
Wide Excision Radical Wide Excision of Stage I and static II mela-
I Clinically
+ nomas
^Regional Lymph Node Dissection
Follow -Positive
(Gold scan as necessary)
Nodes
4
~~1
Pathologically Pathologically
Positive Nodes Negative Nodes
I I
Follow Follow
+
Consider Adjuvant
Experimental Trial
no highly effective single or combination cytotoxic agents for melanoma. Al-

though adjuvant chemotherapy is attractive, it is not realistically effective
in most tumor systems until the therapeutic responsiveness in disseminated
disease is at least 50 per cent. Immunotherapy is most effective with a
tumor burden that is low. Stage II patients who are clinically without dis-
ease may already have a tumor burden greater than 10 6 cells, which may or
may not be effectively controlled with presently available immunostimula-
tive agents. The search for improved cytotoxic and immune-stimulative
agents is continuing, but at this time no promising advances have been
made.
RECURRENCE SUSPECTED
I
— Metastatic work-up —
Consider Intra-
reexcision lesional
BCGor
Hyperthermic
topical
perfusion
DNCB
FIGURE 16-3. Management of stage HI melanomas.

16 / Melanoma 693
There is a means currently available that would be highly effective and

implemented with relatively little cost. Cutaneous melanoma, unlike vis-
ceral solid tumors, can be detected at very early stages. Based upon the
assumption that early level and depth melanomas metastasize infrequently
and are associated with a good prognosis, one would predict that a public
health and community education program could be highly successful, espe-
cially when coupled with a physician education program into the biology of
melanoma and the most effective treatment methods. Because the warning
signs of melanoma may be extremely subtle, it is recommended that all
nevi brought to the attention of a physician warrant biopsy with a patholog-
ic review by an experienced dermopathologist.
Australia, which has the highest incidence of melanoma of any country in

the world, is the model on which this thesis is based. It would appear that
melanoma in Australia is either biologically less malignant, or, more likely,
public and physician awareness has reduced the mortality. A carefully
planned public health and education program could offer the greatest im-
pact on melanoma statistics in the United States through the 1980s.
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297:627, 1977. therapy with BCG in treatment of
52. Sim FH, etai: Cancer 41:948, 1978. regional-lymph-node metastases of
*53. Holmes EC, et al.: A rational approach malignant melanoma. N Engl J Med
to the surgical management of mela- 294:237, 1976.
noma. Ann Surg 186:481, 1977. 82. Eilber FR, et al: Am J Surg 132:476,
*54. Das Gupta TK: Results of treatment of 1976.
269 patients with primary cutaneous *83. Gutterman JU, et al: Postoperative
melanoma. Ann Surg 186:201, 1977. immunotherapy for recurrent malig-
55. Robinson DS, et al.: Surg Forum nant melanoma: an updated report.
28:147, 1977. In Immunotherapy of Cancer, Pres-
56. Storm FK, et al.: Am J Surg 134: 115, ent Status of Trials in Man. Terry
1977. WD and Windhorst D (eds), New
57. Papachristou D and Fortner JG: Ann York, Raven Press, p. 35, 1978.
Surg 185:13, 1977. 84. Beretta G: In Immunotherapy of Can-
58. Polk HC, Current Topics in
et al.: In cer, Present Status of Trials in Man.
Surgical Research. New York, Aca- Terry WD and Windhorst D (eds),
demic Press, Inc., p. 121. 1969. New York, Raven Press, p. 65 1978.
59. Morton DL, et al.: Ann Surg 178:360, 85. Pinskey CM, et al.: In Immunothera-
1973. py of Cancer, Present Status of
60. Cahan WG: Ann Surg 178:703, 1973. Trials in Man. Terry WDand Wind-
61. Luce JK, et al.: In Cancer Medicine, horst D (eds), New York, Raven
Philadelphia, Lea & Febiger, p. Press, p. 27, 1978.
1823, 1973. 86. Morton DL: Unpublished data.
62. Luce JK: Cancer 30:1604, 1972.
CHAPTER 17
SKIN CANCER
Richard A S trick
INTRODUCTION
Cancer is more common in the skin than in any other organ of the body.
Accurate statistics are not available for nonmelanoma skin cancers, since
they are usually diagnosed and treated as outpatient procedures in private
offices and clinics and are not reported to health authorities. However, it has
been conservatively estimated that 300,000 new cases of nonmelanoma skin
cancer occur in the United States annually, which is approximately one third
of the total annual new cancer cases occurring in all organ systems. 1
The overwhelming majority of skin malignancies are either basal cell carci-
noma (BCC) or squamous cell carcinoma (SCC). This chapter is confined to
the consideration of these entities, focusing primarily on diagnosis and treat-
ment. Melanoma and mycosis fungoides are discussed elsewhere in this
book.
Many sources provide discussions of the diagnosis and management of the
infrequently encountered cutaneous neoplasms, as well as more detailed
discussions of etiology and epidemiology of BCC and SCC; a particularly
useful reference is one edited by Andrade et al. %
Epidemiology
The incidence of both BCC

and SCC is higher in men than in women,
except when they occur on the lower legs. This probably represents differ-
ences in exposure to various etiologic factors, including actinic radiation.
The incidence of BCC and SCC is highest in those who have fair skin, light
eyes, and light hair; those who have been exposed to the most sunlight; and
those who tend to sunburn easily. 3 It is highest in whites, especially those
with fair complexions. The rates are much lower for Orientals and lower still
for blacks. In white populations, BCC is much more common than SCC,
whereas in dark-skinned races, SCC predominates.
The probability of developing multiple primary BCCs and SCCs is high.
The chances of developing a second primary has been estimated by MacDon-
695
aid 4 to be almost 50 per cent in men and

over 30 per cent in women, with an
incidence rate 140 times that of first primaries. Spoor et al* have estimated
that 80 per cent of patients with x ray-induced tumors develop multiple
lesions. Bergstresser and Halprin 6 estimated that in individuals with one BCC
or-one SCC, a new or recurrent skin cancer occurred within 18 months 22 to
50 per cent of the time. Other studies have shown the probability of develop-
ing a second primary to be closer to 20 per cent.
Etiology
The etiology of skin cancer is multifactorial. Actinic radiation, ionizing

radiation, chemical carcinogens, burns, scars, ulcerations, and predisposing
genetic disorders may each have a contributing causal role. 7-10 Most of the
evidence suggesting such roles is based on epidemiologic data.
The evidence for the carcinogenicity of sun exposure falls under five main
headings: (1) over 90 per cent of skin cancers occur on parts of the body that
are exposed to the sun; (2) these skin cancers are seen more commonly in
those who receive more sun exposure either occupationally or recreationally;
(3) the amount of pigmentary protection from sunlight varies inversely with
the incidence and prevalence of skin cancers; (4) the geographic latitude and
levels of ultraviolet light correspond to the incidence and prevalence of skin
cancer; and (5) ultraviolet light has been shown to cause tumors in the skin of
experimental animals.
Actinic keratoses (solar keratoses, senile keratoses) are somewhat hyper-
keratotic lesions arisingon exposed skin that frequently shows other effects of
actinic damage. These lesions, which are found on the exposed areas of the
head and neck and dorsal hands and forearms, are considered to be precan-
cerous, since SCC may arise from them. No accurate figures exist for the
incidence of this malignant transformation. However, in the series of Mont-
gomery and Dorffel in 1932, " 40 patients who had multiple actinic keratoses
had nine SCCs and one BCC that were believed to have arisen from actinic
keratoses. The incidence of the transformation of any given lesion to frank
carcinoma is probably low, since patients are frequently seen who have
literally hundreds of these lesions and develop few or no cancers as well as
many other patients who have a smaller number of actinic keratoses and never
develop such degeneration.
There are two groups of skin cancers that are induced by x-radiation. The
first affects people who work with x-rays, such as physicians, dentists, and
technicians, and the second includes patients who are treated with x-rays for a
variety of benign skin lesions. 12 Tumors arising in areas of x-ray damage tend
to be multiple 5 and tend to ulcerate more frequently than other SCCs and
BCCs."
Conway and Hugo 14 reviewed 126 cases of x-radiation dermatitis collected
over a 31-year period. They found only three cases of SCC arising in the 63
patients treated for malignant conditions occurring 8 to 25 years after therapy.
There was also a group of 63 patients who developed x-radiation dermatitis
following treatment for a variety of benign conditions including acne, hirsut-
ism, psoriasis, keratosis, hemangioma, benign ulcers, and accidental expo-
17 / Skin Cancer 697
sure. Of these patients, 23 (38 per cent) developed a total of 60 carcinomas,

including 36 BCCs and 24 SCCs from 1.5 to 43 years later, with a mean of 26.5
years. SCC developed five years sooner than BCC on the average. These
lesions tended to develop in the areas of the greatest radiation damage.
In the series of Cannon et «/., 15 22 per cent of 165 patients who had x-
radiation dermatitis from treatment of benign conditions developed skin can-
cers. These included 14 BCCs, all of which were on the face, and 22 SCCs.
Martin et (d. a reviewed their experiences over 40 years of treating skin
cancers of the head and neck and found they had treated 368 patients believed
to have developed such tumors secondary to x-radiation given as therapy for
benign conditions. The most common treated condition was acne in both
sexes, and the most common condition treated in women was facial hirsutism.
Because of the large number of patients in the latter category, women out-
numbered men 3 to 1 in this series. Two thirds of the lesions were BCCs, and
the remainder were SCCs. They developed a mean of 21 years after therapy.
The mean age of onset was ten years younger than that of skin cancer in
individuals who had not received x-radiation, and the mortality rate was 10
per cent.
It was originally thought that only SCC developed from x-ray exposure, but
this is probably because the early peak of cases included mainly those who
received exposure on their extremities, and SCC is the predominant lesion in
such locations. BCC predominates on the face in most series in which the
x-radiation is given for treatment of benign conditions. Skin cancer is ap-
parently not as common following therapy for malignant conditions. This is
due to many factors, including the long intervals required before the develop-
ment of tumors, the fact that patients treated for malignancy may not survive
their underlying disease, the different doses and fractionation delivered to the
skin, and the relatively young age of many of the patients treated for benign
conditions.
Chronic arsenic exposure causes cancer in the skin and also in other organs.
Such exposure may occur from contaminated drinking water, pesticides, her-
bicides, and medications such as Fowler's solution, which was used in the
past to treat psoriasis and other conditions. After a long latent period, kera-
toses appear on the palms and soles. Later, multiple BCCs and SCCs develop
on the fingers and toes and on exposed parts of the body. The superficial
variety of BCC is often seen on the trunk. A more recently described iatrogen-
ic cause of SCC is the variety occurring in long-standing lichenoid eruptions
of the palms caused by quinacrine hydrochloride therapy. 16
In 1775, Sir Percival Pott 17 first noted the development of scrotal SCC in
chimney sweeps secondary to exposure to soot. Although the exposure to
various products of combustion and distillation of coal, shale, and petroleum
continued to cause SCCs predominantly and some BCCs for the next century
and a half after this discovery, such industrial exposure now seems to be an
infrequent cause of skin cancer. 18
Skin cancer develops in a variety of conditions that lead to chronic damage
of the skin or scarring. Although Marmelzat's 19 review of tumors occurring in
vaccination scars showed a greater incidence of BCC than SCC, most series
reporting skin cancer occurring in areas of trauma and in scars reveal mainly
SCCs. 20 Carcinomas arising in a variety of thermal and electric burns are well
known. They include such culturally induced lesions as the kangri cancers of
India and the kairo cancers of Japan, which result from burns acquired from
wearing various containers of hot coals next to the body for warmth. The kang
cancers of China, which are burns from sleeping on heated beds, and SCC
arising in erythema ab igne, which is a form of chronic dermatitis arising in
those who rely on open fires for heat, also are in this category. It is also well
known that skin cancers arise in fistulous tracts, stasis ulcers, osteomyelitic
sinuses, and amputation stumps.
There are syndromes that genetically predispose affected individuals to the
development of multiple skin cancers. Patients with xeroderma pigmentosum
are deficient in several enzymes that are required to repair DNA damage from
ultraviolet light. Patients with the basal cell nevus syndrome develop multi-
ple BCCs, even on the palms and soles, in association with abnormalities of
the skeletal and other systems. In this condition the BCCs arise from lesions
that in the initial stage clinically resemble nevocellular nevi (moles).
BCC and SCC are being discovered with increasing frequency in patients
who are immunosuppressed for various reasons including renal transplanta-
"
tion and methotrexate therapy for psoriasis. 21 25 In renal transplant patients the
risk of developing skin cancer is more than 35 times higher than expected for
SCC and more than 7 times higher for SCC and BCC combined. 25
NATURAL HISTORY
Classification
The histologic features of BCC and SCC are shown in Table 17-1. The most
common clinical type of BCC is the noduloulcerative or "rodent ulcer" form.
Itfrequently occurs on the head and neck and has a predilection for parts of
the body exposed to the sun. It characteristically presents as a well-defined
nodule that often has a rolled pearly or translucent border with telangiectases
running across it and a central dell that is often ulcerated. This clinical form
corresponds to four different histologic types. 26 One is the solid type, which
shows tumor masses of uniform basalioma cells that have large nuclei and
not much cytoplasm, lack intercellular bridges, and more than 90 per cent of
the time show connection to the epidermis. The cells at the edges of the tumor
masses are lined up like the logs in the wall of a stockade, and this is called
"peripheral palisading." There is an arti factual retraction of the tumor masses
from the fibrous tissue stroma that proliferates with it. The keratotic his-
tologic type differs by having large whorled masses of keratin called "horn
cysts" distributed through the tumor. The cystic type differs from the solid
type by having cystic spaces in the tumor. The fourth histologic type cor-
responding to the noduloulcerative type is the adenoid variety, which shows
tubular gland-like structures within the tumor.
The pigmented clinical and histologic types are distinctive because they
have melanin pigment deposited in them, which may make them clinically
indistinguishable from nodular melanoma.
TABLE 17-1. Differential Clinical and Histologic Features of

Basal Cell Carcinoma and Squamous Cell Carcinoma
Clinical Characteristic Histologic Histologic

Type Features Type Characteristics 26
Nodulo- Usually on head and neck. Solid Masses of basophilic cells.

ulcerative Rolled pearly or translucent Larue nuclei and little cyto-
BCC border. Telangiectasis on plasm. Peripheral palisading
surface. Central cell ul- and retraction connected to
ceration. epidermis. Lack of inter-
cellular bridges.
Keratotic Features of solid type. Masses
of keratin: "horn cysts."
Cj stic Features of solid type. Cystic
spaces in tumor.
Adenoid Features of solid type. Tubular
gland-like structures.
Superficial Usually on trunk or ex- Superficial Buds of small groups of baso-
BCC tremities. Tends to be multi- philic cells from the epi-
ple. May be large. dermis into the superficial
Erythematous macule with dermis.
slight scaling on surface.
Mimics main benign
conditions.
Pigmented Features of above types. Pigmented Features of above types.
BCC Black or brown pigmenta- Melanin deposition.
tion. May suggest mela-
noma. Usually in brown-
eyed people.
Morphea-like Usually on bead. Fibrotic, Morphea-like Fine strands of basophilic cells
BCC ivory appearance. Borders embedded in dense fibrous
difficult to define. stroma.
Telangiectasis.
Squamous cell May occur anywhere, but SCC Masses of cells invading into
carcinoma usually on damaged skin. the dermis that vary from
Nonhealing ulcerations well differentiated to ana-
with indurated border. plastic.
The superficial or multicentric type of basal cell carcinoma is most often

seen on the trunk, and frequently there are multiple lesions. It presents as a
slowly enlarging erythematous macule that has slight scaling on the surface. It
often lacks the characteristic findings of rolled borders, thready telangiectases,
and ulceration, which often results in misdiagnosis as a wide variety of benign
dermatoses, unless one has a particular awareness of this lesion. These lesions
may attain sizes of several centimeters in diameter, largely because they are
asymptomatic and because the diagnosis is often not suspected early in their
course. Histologically, these tumors show budding of small groups of tumor
cells attached to the epidermis extending only into the most superficial por-
tion of the dermis.
A less common type of BCC is the morphea-like fibrosing or sclerosing
variety. This tumor is usually encountered on the face and has borders that are
particularly difficult to define. It has a fibrotic ivory or white appearance and
often telangiectases across the surface. Histologically, it shows only fine
strands of basalioma cells embedded in a dense fibrous stroma, which ac-
counts for its resemblance to a scarring rather than a neoplastic process.
An unusual variety of BCC is the fibroepithelioma, which is usually seen as a

single or multiple pink sessile or pedunculated papule on the lower back or
abdomen. Another distinctive type is the slowly enlarging pore, which resem-
bles a chicken pox scar and often has telangiectases at the edges.
Squamous cell carcinoma may occur anywhere on the skin or mucous
membranes, but rarely arises from normal-appearing skin. This chapter deals
only with those SCCs arising on the skin proper, excluding those on the lips,
vulva, penis, and anus. As discussed earlier, SCC most frequently arises in
areas of actinic damage in whites.
Actinic keratoses may be considered carcinoma in situ. Clini-
biologically
cally, they are well-circumscribed macules with a rough, scaly surface that at
times may be thickened. They vary in color. Although they are often shades of
red and brown, they may also be the color of the surrounding skin, gray, or
black. They are usually several millimeters in diameter but vary from a
pinpoint to several centimeters in size. The smaller lesions may often be more
easily palpated than visualized. Crusting, thickening, and ulceration are signs
that should raise suspicion of transformation to SCC or BCC.
SCCs are usually ulcerations with an indurated border. They may often be
indistinguishable clinically from BCC and may be differentiated only by
biopsy. There is also a variety called verrucous carcinoma that tends to be a
fungating type of tumor. It is usually well differentiated and although it may
invade deeply, it usually metastasizes only very late in its course, if at all. 26 On
microscopic sections, squamous cell tumors show masses of tumor cells invad-
ing from the epidermis to the dermis, which vary from well differentiated to
markedly anaplastic. The more differentiated variety tends toward keratiniza-
tion and has structures called horn pearls, which consist of concentric layers
of keratin and squamous cells.
Diagnosis
Physicians who are trained in the treatment of skin cancer generally have a
high index of suspicion for these lesions. However, it has recently been
shown that even experienced practicing dermatologists make errors in diag-
nosing BCC as often as 25 per cent of the time. 27 This fact particularly
emphasizes the need for biopsy prior to institution of definitive care. In the
case of small lesions, an excisional biopsy with a margin of normal tissue is the
procedure of choice.
Basal Cell Carcinoma. There is no accepted staging system in general

use for BCC. This is easily explained by the particularly low rate of metastasis
of this tumor. In a study from Australia (where BCC is particularly common),
which was conducted on information obtained from doctors' offices and hospi-
28
tals, the rate of metastasis was found to be 0.0028 per cent.
The low metastatic potential of these tumors can be further demonstrated.
Of the millions of BCCs occurring in the past 80 years, only 93 cases with
metastases, beginning with Beadles' 29 case in 1894, had been reported at the
time of the review of Mikhail et al. in 1977. Of these cases, only 78 met the
30
criteria established by Lattes and Kessler31 for metastatic BCC. These criteria
include the presence of a primary skin tumor, metastasis to a different site —
not by direct extension, similar histology of both primary and metastatic
lesions, and no squamous cell component to the tumor.
Data from the study of Mikhail et al. 30 in reviewing these 78 cases are
summarized as follows: Eighty-five per cent of the primary lesions were on
the head and neck, which corresponds closely to the anatomic distribution of
BCC in general. 32"34 Metastases occurred 1 to 45 years after the appearance of
primary lesions, with the average being 11 years. Most patients with metastat-
ic lesions had lymph node involvement (60 per cent), followed by lung (29 per
cent), and bone (28 per cent). Rare metastases were found to liver, spleen,
pancreas, peritoneum, diaphragm, pericardium, kidney, adrenal, and skin.
Metastasis to multiple sites occurred in 29 per cent of the patients. The primary
tumors tended to be long-standing, large, ulcerated, and locally invasive. In
addition, they were resistant to treatment. This is evidenced in that 90 per
cent of the tumors were treated by at least one procedure prior to metastasis,
and 60 per cent were subjected to both surgical procedures and radiation
therapy prior to dissemination. Over 80 per cent had been treated with
extensive and repeated surgical excision. The average time of survival follow-
ing metastasis to internal organs other than lymph nodes was about ten
months, with only 2 of 40 such patients having undergone successful treat-
ment.
Usually mortality from BCC is secondary to intracranial extensions of a
particularly locally aggressive tumor rather than to metastases. 34 There can
also be considerable morbidity involved from destruction of local structures,
such as the eye, ear, and nose by these tumors. However, it must be empha-
sized that the vast majority of BCCs pose no threat to life and have high cure
rates with a variety of therapeutic modalities.
Squamous Cell Carcinoma. The American Joint Committee for Cancer
Staging and End Results Reporting has proposed a staging system based upon
the TNM classification s> stem, 35
but this is not used to a great extent at
present for either BCC or SCC. Broders' 3,i system of grading SCC on the basis
of the proportion of differentiating cells is still being used. Grades are defined
as follows: grade 1 —
more than 75 per cent of the cells differentiating, grade
2— 50 to 75 per cent of the cells differentiating, grade 3 — 25 to 50 per cent
of the cells differentiating, and grade 4 — less than 25 per cent of the cells
differentiating. However, the degree of atypicality of the cells and the depth
of penetration of the tumor are also important factors to consider when grad-
ing this tumor. 28 Lever and Schaumberg-Lever 26 also consider actinic kera-
toses to be SCC grade V2, since they show anaplasia even though there is no
invasion.
The overall rate of metastasis in cutaneous SCC has been estimated to be
about 2 per cent, as determined from a series of almost 7000 patients based on
hospital cases recorded in the California Tumor Registry. 37 However, this
figure included only those cases in which metastasis had already occurred by
the time the patient came to medical attention. About 90 per cent of patients
in this series had metastasis to local lymph nodes only, but 54.5 per cent of the
patients with such local spread died of their skin disease in the first five years,
and 62.5 per cent of those with more distant metastases died of their skin
disease in thesame time span. It was not only neglected lesions that tended to
metastasize, since over two thirds of the lesions had been noted less than one
year before metastases were found.
In a series of SCC
developing in burn scars, Novick et a/. 38 found the rate of
metastasis to be 32.6 per cent. The mortality rates were particularly high in
those who did develop metastasis, with 15 out of 16 patients dying of their dis-
ease.
A retrospective study by Lund 39 on SCC treated in offices of dermatologists
found 12 cases of metastasis out of 1000 lesions, a rate of 1.2 per cent.
Although the majority of these SCCs were believed to have arisen from actinic
damage, only five of the metastases arose from exposed skin. In this study, the
characteristics of metastasizing SCC were felt to be the following: etiology
odier than actinic injury, large size (smallest was 1.3 cm in diameter), abun-
dant cells with extensive invasion, and a tendency to be histologically undif-
ferentiated.
In a series of 601 SCCs in 411 patients, Katz et al. 7 found that about 4 per
cent of the lesions were metastatic at the time of presentation to the physician,
and an additional 2.6 per cent metastasized later. There are many studies in
the literature that show rates of metastasis of approximately 15 to 35 per cent
for SCC not arising from actinic damage, as shown by the examples in Table
17-2.
In summary, SCC arising in actinically damaged skin rarely metastasizes.
Those lesions arising on normal skin or other pre-existing lesions tend to be
more aggressive, and, although metastases are usually confined initially to
local nodes, metastatic SCCs are often fatal.
TREATMENT OF ACTINIC
KERATOSES
Since actinic keratoses result from exposure to sunlight, they are theoreti-
cally entirely preventable. Prophylactic measures instituted early in life,
TABLE 17-2. Metastatic Rates for Squamous Cell Carcinoma

Excluding Those Arising From Actinic Damage
Author Underlying Etiology % Metastatic
Glass et al.
40
Lower extremity, variety of lesions 15
Graham and Helwig41 Lower extremity, variety of lesions 18
Martin et al." Radiodermatitis 20
Hueper42 Radiodermatitis 26
Sedlin and Fleming-' Osteomyelitic sinuses 31
Arons et al.** Scar tissue 32
Novick et al. 38 Burn scars 34.8
Glass et al.*° Lower extremity, normal skin 60
including avoidance of sun exposure or the use of protective measures, such

as sunscreens and clothing in fair-skinned individuals, would prevent these
lesions. Once a patient has developed lesions, these measures should be
stressed in the hope of preventing further damage.
Actinic keratosis rarely exhibits malignant biologic behavior, even on trans-
formation to SCC; therefore, treatment modalities should be chosen that
present little morbidity for the patient. Since these lesions are noninvasive
and entirely contained within the epidermis, the utilization of treatment
methods that limit destruction to the epidermis should eradicate the lesion,
leaving minimal or no scarring.
Surgical procedures that utilize excision of the full thickness of the skin and
closure with sutures are rarely necessary for actinic keratosis, unless there is
concern that the lesion may actually be a SCC and it is small enough and
located so that excisional biopsy will give an excellent cosmetic result. The
disadvantages include increased treatment time and cost and postoperative
scarring.
Curettage, in which the abnormal tissue is scraped away and the base is
then lightly electrodesiccated or treated with chemical cauterants such as
Monsel's solution or aluminum chloride for hemostasis, may be used. This
procedure is generally curative and often leaves imperceptible scarring, but it
may leave a white area that sharply contrasts with surrounding actinically
damaged skin, which may be telangiectatic.
Radiation therapy not indicated for actinic keratosis and, in fact, may be
is
contraindicated. 45 However, it may be utilized in SCC complicating actinic

keratosis.
Cryosurgery using liquid nitrogen is effective, reliable, rapid, cosmetically
excellent, and inexpensive, with no anesthesia necessary for treating actinic
keratosis. It may be done by applying the liquid nitrogen to the lesion with a
cotton swab, a copper disc, or in the form of a spray. It should only be ap-
plied long enough to freeze the surface of the skin, since the lesions are
superficial. It is better to repeat the treatment two to four weeks later, if
necessary, than to freeze too deeply the first time and cause discomfort and
scarring. Contrast with surrounding telangiectases of actinic skin is the only
cosmetic blemish, if any. Individual lesions may be treated rapidly with "dip
stick" methods, but the faster freeze (3 to 5 seconds) of the spray unit is
particularly advantageous for treating patients with dozens of lesions. Any
lesion that is indurated, inflamed or ulcerated, or unresponsive to cryotherapy
as described should be suspected of being a frank carcinoma and should be
biopsied.
Topical therapy with 5-fluorouracil may be used effectively in treating wide-
spread actinic keratoses. 46- 47 It is usually used in a 1 per cent solution or cream
on the face and up to 5 per cent concentrations on the arms applied twice daily
by the patient Ribbing it in with the fingertips. Care must be taken around the
eyes, but individual lesions may be treated in the periorbital skin. One must
also avoid applying large amounts of medication in areas such as the na-
solabial fold and corners of the mouth and nose. After application, the hands
should be washed. Patients should be advised that sunlight will accelerate the
reaction and, therefore, sun exposure during therapy must be carefully moni-
704 II / Treatment of Spe< iik Neoplasms
tored. Usually,erythema begins three to seven days after treatment is begun.

This generally progresses to scaling, erosion, and tenderness, and may result
in painful denuded areas.
There is a selectivity for the areas of actinic keratosis, so that normal skin is
not visibly affected other than for the reaction in what would otherwise be
clinically inapparent actinic keratoses. This brisk inflammatory response can
be used to judge the length of the treatment course, which is usually from two
to six weeks on the face and often longer on the arms. If there is difficulty in
obtaining an adequate response on the arms, the preparation may be applied
under occlusion with a plastic pliable film. 4 " Any keratosis that is unrespon-
sive may be treated with other modalities. Repeat courses of 5-FU may be
given at later dates. Healing takes place in about two weeks after completion
of therapy and the application of a topical steroid during this time may reduce
the reaction more quickly. When re-epithelialization is complete, there is
usually no resultant scarring, although pigmentary changes occasionally
occur. Systemic toxicity from absorption through the skin has not been report-
ed. 48
Although therapy with 5-FU advantage of treating widespread
offers the
lesions, including incipient ones, at the same time and gives excellent
results, the short-range cosmetic effect approximates the appearance of raw
hamburger and, along with the associated discomfort, provides the major
disadvantage to the regimen. This may lead to poor patient compliance in
completing adequate therapy. 49 It has been shown in a bilateral comparison
study that high-potency topical steroids applied 10 to 15 minutes after applica-
tion of 5-FU solution resulted in no differences in the resolution rate or rate of
appearance of new actinic keratoses, but markedly diminished the associated
inflammation. 50 This observation provides an argument against the theory that
5-FU acts mainly by causing an inflammatory reaction in the manner that
trichloroacetic acid, bichloroacetic acid, and liquid phenol did in treating these
lesions in the past. The mechanism of action of 5-FU is probably through the
blockage of DNA synthesis by inhibition of thymidylate synthetase, resulting
in metabolic disruption and cell death in the dividing cells of actinic kera-
toses. 51 The inflammation then results from the death of these cells. There has
been recent evidence that 5-FU may occasionally cause a delayed hypersensi-
tivity reaction, 52, 53 and it has been suggested that the mechanism of action may
be immunologic. 54 Both the inability to induce contact dermatitis to 5-FU using
maximization procedures 55 and the excellent therapeutic response in those
patients who do not become sensitized to the drug provide strong evidence for
a chemotherapeutic rather than an immunotherapeutic primary' mechanism of
action for topical 5-FU.
TREATMENT OF BASAL CELL

AND SQUAMOUS CELL
CARCINOMAS
Conventional means of treating both BCC and SCC
include surgical exci-
sion, curettage and desiccation, radiation therapy, cryotherapy, and chemosur-
gery. In certain circumstances, chemotherapy and immunotherapy may be

appropriate. The most important goal of treatment is the cure of disease. The
preservation of cosmesis and function are important secondary considerations.
For the vast majority of BCCs and SCCs, any of the five generally accepted
modalities is likely to produce a cure when performed by someone who is
expert in its use. Therefore, the decision as to which modality should be used in
a specific patient is often made on the basis of criteria other than cure rates.
Certain tumors may be particularly difficult to treat because of anatomic-
location, histologic type (e.g., morphea-like BCC), subclinical extension, and
recurrence. It is particularly important to cure these more difficult lesions,
since failure to do so may result in loss of vital structures or even death.
The cure rates between studies, and even with different modalities within
the same study, are not truly comparable. Patients are not randomized prior to
choosing a particular modality but rather are preselected by the characteristics
of the tumor and by the expertise and prejudices of the physician in relation to a
particular modality. For example, those cases treated by chemosurgical tech-
niques are specially selected for their challenging nature. Techniques may
vary from one study to the next and even within a particular study in which
multiple physicians are involved. Some of the studies are derived from the
experience with difficult cases selected for referral, whereas in others the data
were generated from private offices. It is striking that with expert therapy using
a variety of modalities, the cure rates are quite high, and therefore, any
physician and any treatment modality has a high standard to match.
Those BCCs and SCCs that do recur are much more difficult to cure.
Whichever method is selected, patients must be followed closely over many
years for signs of recurrent tumors and for development of new primaries,
although recurrences usually appear in the first three years. Table 17-3 com-
pares median cure rates for the five conventional methods of therapy. The
median rather than the mean was felt to be a more meaningful statistic, since
the studies from which these tables were generated have only roughly compa-
rable figures.
TABLE 17-3. Median Per Cent Cure Rates for Basal Cell C, arcinoma and
Squamous Cell Carcinoma
Median
Type of Tumor Method Cure Rate
Basal cell carcinoma Surgery 95.2
Curettage and electrodesiccation 96.0
Radiation 94.0
Cryosurgery 97.8
Chemosurgei)
Fixed tissue 99.3
Fresh tissue 97.0
Squamous cell carcinoma Surgery 93.2
Curettage and electrodesiccation 98.0
Radiation 94.5
Cryosurgery 95.5°
Chemosurgery
Fixed tissue 100.0°
Fresh tissue 94.4°
"One series only.

706 II / Treatment of Specify Neoplasms
Surgery
In general, surgical techniques for treating BCCs and SCCs involve excising
the lesion, including a margin of several millimeters beyond what is clinically
felt to be the extent of the tumor. For very small (0.5 cm or less) BCCs with very
clearly defined edges, this margin may be as little as 3 mm, 58 but for lesions that
are larger and have margins clinically or are SCCs, larger margins
less distinct
(5 to 10 mm) are advised. These borders may be checked for clearance using
57
frozen sections if there are particular doubts about clearing the lesion and using
permanent sections in other cases. The incision includes the full thickness of
the skin down subcutaneous fat. Wounds are usually closed by primary
into the
suturing, although they may be allowed to heal by secondary' intention (gran-
ulation) with good cosmetic results at times. Larger lesions may be closed by a
wide variety of local and distant flaps or grafts. However, it is important not to
hide residual tumor beneath skin flaps or full-thickness grafts.
Biopsies should precede any large or potentially disfiguring surgery. Howev-
er, if the lesion is small and easily removed, an excisional biopsy may be
performed and may be both the definitive therapy and the pathologic confirma-
tion of diagnosis.
usually helpful to carefully mark the planned excision lines prior to
It is
distortion of the tissues by local anesthesia. Careful inspection and palpation

are often necessary to properly delineate the extent of tumor and to best plan
the lines of incision. Whenever possible, these lines should follow the natural
skin lines.
The surgical removal of BCC and SCC has several advantages. All except the
largest or most invasive lesions may be treated under
local anesthesia on an
outpatient basis. Healing generally rapid, the rate of infection is low,
is
cosmetic results are usually good to excellent, all histologic types may be
treated, and the specimen may be checked for clearance of tumor at the
margins, giving further assurance that the patient has been adequately treated.
Frozen sections may be done at the time of operation, but their accuracy in
cutaneous lesions is not as high as in other areas, 58 and they are not available to
most dermatologists.
If the pathology specimen shows extension of SCC to the margins of the
excision, a repeat procedure should be performed to eliminate the residual
tumor. In BCC, there is some controversy over whether or not this should be
done promptly, as opposed to performing further treatment only when recur-
rence is actually found clinically. In a study of nearly 1200 BCCs by Gooding et
59
a/., in which the surgeon felt the lesions had been cleared at the time of
operation, 66 showed marginal extension on histologic review. Without further
therapy only about one third actually recurred clinically. Of these, 41 per cent
were on the nose, with the cheek and the nasolabial fold being the next most
commmon sites. All the recurrent lesions in this study were cured either by
repeat operations or by radiation therapy once recurrence became clinically
apparent. If all patients showing marginal extension histologically would have
been retreated, two thirds of them would apparently have been receiving
further treatment unnecessarily. Shanoff et a/. !4 found a recurrence rate of
about 30 per cent in lesions that the pathologist said either had narrow mar-
gins or contained tumor in the margins.
therefore difficult to give a general recommendation; rather, procedures

It is
for individual cases must be determined on their own merits. However, it must
be kept in mind that it is more difficult to cure recurrent lesions than it is to cure
primary ones (see Table 17-4). Lesions covered by full-thickness grafts or by
flaps may recur as deep nodules and may remain hidden for a long time.
Therefore, in these types of wound repair, one must be assured that the tumor
has been cleared by a wide margin, and it has been advised that recurrent
tumors should not be immediately covered with full-thickness grafts or
flaps."
Table 17-4 shows cure rates for various studies using surgery for BCC and
SCC, and Table 17-5 summarizes indications, advantages, and disadvantages
for this method.
Curettage and Desiccation
Curettage and electrodesiccation (C and D) can be used for either BCC or

SCC, although it is more commonly employed in the fonner. This method takes
advantage of the difference in feel of the neoplastic tissue and its relative
TABLE 17-4. Cure Rates for Surgical Treatment of Basal Cell Carcinoma
and Squamous Cell Carcinoma
Author \l MBER OF Years % Without

Lesions Follow-up Recurrence
Basal Cell Carcinoma

Shanoffef al. (1967)" 550 1-15 91.0
Gliosci et al. (1967)61 103 2-5+ 91.2
Williamson and Jackson (1962) 62 63 3 91.5
Bart et al. (1978)56 468 5 93.2
63
Freeman ct al. (1964 62 3 93.5
Taylor and Barisoni (1973)64 535 v2 94.8
Battle et al. (I960)65 197 3 94.9
Knox et al. (1967)66 119 5 95.0
Ferrara (196()) BT 47 5 95.5
Menu et al. (1971)68 344 Varied 96.2
Hayes (1962) 69 179 1-13 96.6
Lauritzen et al. (1965)70 2900 10 96.6
Nevrkla and Newton (1974)71 35 1-10 97.0
Eberhard (1947) 72 49 3 98.0
Rintala (1971) 73 204 5 98.0
Macomber et al. (1959) 74 162 5 98.1
Median Cure Rate (BCC) 95.2

Eberhard (1947)72 28 3 89.0
Gliosci et (1967)61
al. 22 2-5+ 90.1
Freeman et al. (1964)63 58 3 93.1
Macomber et al. (1959) 74 44 5 93.2
Knox et al. (1967)66 81 5 93.8
Ferrara (I960)67 24 5 95.5
Median Cure Rate (SCC) 93.2

TABLE 17-5. Indications, Advantages, and Disadvantages of

Surgical Treatment of Basal Cell Carcinoma and
Median cure rates

BCC 95.2%
SCC 93.2%
Size and depth of tumor May he used for tumors of all sizes and depths, although less
suitable for lesions including bone or cartilage.
Histologic types Useful for all (including morpheadike BCC). May be "overtreat-
ment" for superficial BCC.
Checking margins Margins may be checked for clearance on frozen or permanent
sections.
Use in recurrent tumors Significantly lower cure rates than chemosurgery. Wide margins
needed.
Location Not suitable for large numbers of lesions in one area. Sacrifices
more normal tissue than other methods so may be less suited
for lesions located on or near eyes, ears, tip of nose, nasal alae,
fingers, penis. Cure rates often lower for periorbital, ear, nasal
alae lesions. Reasons include margins too narrow in attempt to
preserve function and appearance and subclinical extension
spreads along or into cartilage or bone and is missed; therefore,
frozen sections at times are useful for these lesions.
Patient characteristics Useful for all ages. Less suitable for patients on anticoagulants
or who have other bleeding problems. Less suitable in certain
areas for keloid formers.
Convenience Usually performed under local anesthesia. Rapid healing time
with little morbidity. Time for procedure longer than some
other methods. Expense greater than some other methods and
if done in hospital may be most expensive. Usually more than
one visit required (biopsy, excision, suture removal).
friability compared with the tough normal cutis. Normal skin is not damaged
when firmly scraped with a sharp curette, whereas most epidermal tumors are
easily removed with this instrument.
This technique is done as a clean, but not necessarily sterile, procedure.
After infiltrating the lesion with a local anesthetic, the bulk of the tumor is
curetted and may be sent for histologic verification of diagnosis, especially if no
previous biopsy was performed. Information as to clearance of tumor is not
available from such a specimen. Subsequently, the base and edges of the
resulting cavity are vigorously scraped with a small curette exploring for any
pseudopods of tumor. The base and edges are then electrodesiccated to a
distance of 2 to 4 mm
into normal-appearing tissue. The tissue thus charred is
vigorously curetted as before in a search for any extension of tumor, usually
using a small, fresh curette. The rim and base are again electrodesiccated.
Many physicians repeat this procedure a third time. 7 -77 The resulting eschar-
"'
covered wound heals in three to six weeks, depending upon the size and lo-
cation, eventually leaving a white, flat scar in most cases.
There is some controversy concerning the performance of a biopsy prior to
this procedure. If there is any doubt as to the diagnosis (especially for large
lesions) or if a critical cosmetic area is involved, the biopsy should probably
be done prior to treatment. Ifapunch biopsy or incisional biopsy is performed,
it may be advisable to avoid going through the entire thickness of the skin
into the subcutaneous tissue. Otherwise, if one is curetting at a later time,

the curette falls into this pit, and the feel of the subcutaneous fat cannot
easily be distinguished from the friability of BCC or SCC. If a shave biopsy is
initially performed removing the entire exophytic portion of the tumor, the
definitive procedure should be performed prior to complete healing of the
biopsy site; otherwise, it may prove difficult at the time of therapy to find the
site of residual tumor. If no biopsy was done prior to curettage and desiccation,
the curettage specimens should be sent for histopathologic diagnosis.
In general, cosmetic results are surprisingly good in curettage and desicca-
tion. Ferrara
67
found a higher percentage of excellent cosmetic results with C
and D than with surgery or radiation. Occasionally, hypertrophic scar, which
usually resolves spontaneously, follows the procedure. If it fails to resolve
within three months, corticosteroid injections into the scar generally produce
satisfactory flattening." Rarely, a true keloid will form, the therapy for which is
variably successful.
Curettage and desiccation is particularly superior to surgery or radiation in
the treatment of large lesions of the superficial type of BCC. The superficial
nature of the lesion allows their removal in entirety by this method, with
excellent cosmetic results; however, scalpel surgery and closure requires
either very long scars or utilization of flaps or grafts and may represent
overtreatment for such lesions. 7 Radiation therapy tends to leave cosmetically
'
unacceptable scars on the trunk and extremities. 7579

The morphea type of BCC is not suitable for treatment with C and D because
the dense sclerotic stroma does not allow differentiation of the tumor from the
surrounding cutis by feel with a curette. Sweet 78 noted recurrence within three
years in six of seven of these tumors that were treated with this technique.
Recurrent tumors that contain dense fibrotic scar are also more difficult to treat
with this method. In addition, lesions that penetrate into fat, cartilage, or bone
also pose problems in removing the entire tumor with a curette. Lesions that
penetrate deeply into the nasolabial fold or the forehead and large lesions
involving the eyelid or the nasovestibular area max also be more difficult to
treat with this method. 62
Although C and D is simple, proper technique is vital, as can be seen from
Table 17-6. Those who use a single curettage and electrodesiccation have
recurrence rates that are twice as high as those who repeat the procedures. In
the study by Williamson and Jackson, 62 the staff dermatologist achieved a cure
rate of 97.4 per cent, although he handled the most difficult cases, whereas
those cases treated by residents had a cure rate of 89.2 per cent. In the study by
Kopf et al., s0 the clinic patients treated by the less experienced physicians had
a cure rate of 84.3 per cent, but the practicing physicians achieved a cure rate
of 96.2 per cent.
When BCC and SCC reappear following C and D, they tend to recur in the
margin because of the lack of aggressiveness of the operator or because the
lesion was morpheaform. 75 When recurrences do occur they appear early.
Simpson 81 found that two thirds occur in the first two years after treatment.
Recurrences are easily detected because, with this method, they are usually
located on the surface of the scar.
7/0 II / Treatment of Specific Neoplasms
TABLE 17-6. Cure Rates for Curettage and Desiccation of

Number of Years % Without

Author Lesions Follow-up Recuhrem I

Kopfetal. (1977r° 688 1-5 84.3°
Sweet (1963) 78 244 5 87.71
Williamson and Jackson (1962)62 148 3 89.2°
Whelan and Deckers (1973)82 123 2-7 93.5
Menu (1971)68
et al. 967 Varied 93.5
Ferrara (I960)67 55 5 94.9
Tromovitch (1965)83 75 5 96.0
ShanoffetaJ. (1967)34 618 1-15 96.0
Kopfef al. (1977) 80 210 1-5 96.2}
Knox et al. (I960)84 56 5 96. 4 §
Williamson and Jackson (1962) 62 76 3 97.4}
Freeman et al. (1964)63 117 5 97.5
Knox et al. (1967) 66 315 5 98.7

Ferrara (i960)67 27 5 94.9
Tromovitch (1965)83 29 5 97.1
Knox et al. (I960)84 34 5 96.6
Honeycutt and Tansen (1973)85 281 5 98.9
Freeman et al. (1964)63 244 3 99.2
Knox etal. (1967)66 213 5 99.5
"Cases performed by residents only.

fC and D not repeated.
{Cases performed by staff dermatologist
§A1I recurrences by one physician who did not repeat C and D.
Table 17-7 summarizes indications, advantages, and disadvantages of C

and D in treating BCC and SCC.
Radiation Therapy
BCC and SCC are moderately radiosensitive tumors. Cure rates are compa-
rable to those of other standard modalities, as can be seen in Table 17-8.
Radiotherapy is currently used less frequently in treating BCC or SCC than
most of the other standard modalities, largely because it requires special
skills, expensive equipment, and multiple patient visits.
There are numerous effective radiation treatment regimens for BCC and
SCC. They range mainly from 3000 to 6000 rad using x-rays of varying penetra-
tion fractionation ranges, generally from 5 to 15 treatments over one to four
weeks, although some physicians use fewer fractions. The treatment failures
that occur with radiation generally result from an underestimation of the size
of the tumor or an underdosage. 89
Usually, young patients with BCC or SCC are better treated with modalities
other than radiation, since the cosmetic deterioration results with time follow-
ing this therapy. After many years, altered skin color, atrophy, and telangiec-
17 / Skin Cam eb 111
TABLE 17-7. Indications, Advantages, and Disadvantages of Curettage

and Electrodesiccation Treatment of Basal Cell Carcinoma
Median cure rates

BCC 96.0%
sec 98.0%
Size and depth of tumor Not suitable for lesions invading fat, cartilage, hone. Less
suitahle for very large tumors because of prolonged healing,
except superficial BCCs. which are ideal even if huge.
Histologic types Not suitahle for morphea-like BCC. Useful for all others
(especially good for superficial BCCs).
Checking margins Curettage specimen not suitahle to check margins but method
excellent for removing lesions with hidden pseudopods of
tumor in dermis.
Use in recurrent tumors Cure rates low. \ot suitahle if sclerotic scar present. Tends
to be tissue sparing, so may he useful near vital structures,
although surgical reconstruction occasionally required. Less
suitable for eyelid margins, canthi, nasal alae, nasal tip,
penis. Useful for multiple lesions in one area.
Patient characteristics Useful for all ages. Electrocoagulation may cause problems
for patients with cardiac pacemakers. Less suitahle in
certain areas for keloid formers.
Convenience Local anesthesia. Healing time usually three to six weeks,

depending on and location. Time for procedure short,
size
so multiple ones can he done at one visit. Economical.
Definitive diagnosis and treatment may he accomplished
in one v sit without necessity of returning for suture removal.
j
No need for sterile technique and may he done in nursing

homes if electrocautery is available or portable unit is used.
No need for postoperative pain medication or dressings.
Cosmetic results Usually good to excellent; usually heals with white atrophic
scar; improves with time. Occasional hypertrophic scars,
keloids, or contractures.
tases develop in treated areas. Patients with blond hair and blue eyes are
90
more susceptible to these changes. This is usually not a significant problem
in those who are elderly at the time of treatment, since these changes occur
insidiously over many years.
Radiation is a particularly useful treatment for lesions at sites in which
destruction of tissue undesirable for functional or cosmetic reasons. It may
is
be useful for either BCC or SCCinvolving the eyelids, the alae nasi, the tip of
the nose, or the ear. Small lesions particularly can often be treated more easily
by other means with good results. Larger lesions may do quite well with
radiation, although reconstructive surgery may rarely be required. Lesions on
the trunk and lower extremities are responsive to radiation but often heal with
poor cosmetic results. There may even be residual nonmalignant ulcerations
after several years.
There has been controversy over the efficacy of treatment of morphea-type
BCC with radiation. It has been stated that x-ray therapy does not produce
adequate cure rates in these tumors, 91 94 but in a series of eight such tumors up
"
to 3.5 cm in diameter, seven were cured. 95 The other tumor recurred at the
edge of the field, and it was believed to be a geographic "miss" due to
utilization of margins that were too narrow. However, the authors felt the
cosmetic results were inferior to what is usually expected from radiation and
to what would be expected from other means.
Although tumors that arise secondary to previous radiation therapy are
generally still curable by radiation, many authors feel such therapy is con-
traindicated for these lesions. 13-15 Table 17-9 summarizes the indications,
advantages, and disadvantages of x-ray therapy for BCC and SCC.
Cryosurgery
Cryosurgery involves the destruction of tumor by the use of cold tempera-

tures. In order to accomplish this, it is necessary to attain a temperature of at
least -25° C in the entire tumor. The alterations produced in cells, tissues,
and blood vessels due to this rapid change in temperature produce irrevers-
ible destruction of the cells. The cold temperature forms an ice ball in the
tissue; the cells that survive later die from anoxemia produced by the vascular
thrombosis when the small vessels are frozen. These effects are enhanced by
application of a double freeze-thaw cycle.
The only agent currently available that provides these conditions is liquid
nitrogen. A variety of instrumentation is available to deliver this substance to
the tissues effectively as a spray or as a direct probe, but cotton or metal
applicators are generally not useful for treating any but the most superficial
malignancies. 96
It is necessary to be sure that sufficiently low temperatures are achieved in
all portions of the tumor to destroy it. The most precise way to determine the
temperature at a specific site in the tissue is to measure it with a thermocouple

and cryometer. The ice ball is colder at the center (which is the point of
TABLE 17-8. Cure Rates for Radiation Therapy of Basal Cell Carcinoma
Number Years % Without

Author of Lesions Follow-up Recurrence

Stall et al. (1964)*'
1
276 1/2-12 89.5

Del Reâto (1949) 87 101 3 91.0
Barter al. (1970) 79 500 5 92.0
Shigematsu et al. (1966) s8 831 5 93.3
Ferrara(1960)KT 33 5 94.0
Nevrkla and Newton (1974) 7 '
129 1-10 94.0
Eberhard (1947) 72 333 3 95.0
Williamson and [ackson (1962) fi2
24 3 95.8
Menn et al. (1971 i
liN
566 Varied 95.8
Knox et al. (1967)"" 97 5 95.9
Median Cure Rate (8CC) 94.0

Knox et al. (1967)
fi6
74 5 93.2
Ferrara (I960)67 17 5 94.0
Stoll et al. (1964r 62 1 2-12 94.5
Eberhard (1947) 7 - 97 3 96.0
Honeycutt and Jansen (1973) HS 18 5 100.0
TABLE 17-9. Indications, Advantages, and Disadvantages of X-ray

Therapy of Basal Cell Carcinoma and Squamous Cell Carcinoma
Median cure rates

BCC 94.0
SCC 94.5
Size and depth of tumor Suitable for all.
Histologic types Suitable for all, but less useful for morphea-like BCC.
Checking margins No specimen available; relies on clinical judgment for limits

of tumor and additional margin of normal tissues.
Use in recurrent tumors Significantly lower cure rates than chemosurgery.
Location Especially useful on or near vital structures such as eyelid

margins, canthi, nasal tip, nasal alae, ears. Less suited
for lesions on trunk.
Patient characteristics Avoid in younger individuals, since the radiated tissues

deteriorate in time. Useful in keloid formers, bleeders,
those who refuse surgery. Avoid in those tumors that arose
from prior radiation.
Convenience No anesthesia needed. Multiple visits needed. Relatively

expensive.
Cosmetic results Initially good to excellent, but deteriorates over the years.
Tissue sparing may be especially useful in critical areas.
contact with the liquid nitrogen) than it is at the periphery, so one must be
sure that sufficiently low temperatures are reached at the edges of the tumor
as well as at the center.
An estimate of the depth of tumor
is necessary in order to determine where
to place the thermocouple to measure the temperature. Zacarian 96 found that

96 per cent of BCCs were limited to a depth of 3 mm below the skin surface.
Ebbehoj 97 found 11.5 per cent of skin cancers extending deeper than 5 mm,
but the majority of the deeper lesions were SCCs. Therefore, for all but the
particularly large tumors, freezing to -25° C at a depth of 5 mm below the
surface is certainly sufficient to destroy the entire tumor.
If a thermocouple is necessary to use local anesthesia prior to
used, it is
insertion; in other instances anesthesia is optional. A margin 4 to 5 mm

beyond the clinically apparent edge of the tumor is drawn on the skin. The
liquid nitrogen spray or probe is then delivered to the center of the tumor.
Intermittent freezing for a few seconds, followed by a short pause and repeti-
tion of the process, avoids the situation of more rapid extension of the ice front
on the surface than takes place at the depth of the tumor. After the entire
tumor has been completely frozen, it is allowed to thaw, and then a second
freeze is performed. It has been shown that a single freeze cures only two
thirds of tumors, which is not an acceptable figure. 98 However, the utilization
of a double freeze-thaw cycle achieves cure rates for BCC comparable to other
modalities, as may be seen in Table 17-10.
The length of time of the freeze varies with the size of the tumor, but for
tumors up to 1 cm in diameter, 1 to 1.5 minutes is generally sufficient. Large
tumors may require up to two minutes, and very thick lesions may require
even longer. The thaw time is usually 1.5 to 2 times the freeze time. 96
A method for estimating the temperature at a given depth without the use of
thermocouples is suggested by Torre. 102 It involves estimation of the tempera-
ture of a given depth by the spread of the ice ball on the surface. It has been
found that the depth of freeze is roughly 1.3 times the lateral spread of the
freeze. There is a gradient of temperature within the ice ball that ranges from
0° C to - 160° C. The -25° C isotherm, which is required for treating BCC and
SCC, usually is approximately one half to one third the radius of the ice ball.
Therefore, an ice ball having a 5-mm radius on the surface with a temperature
of 0° C at the edge will be roughly 0° C at 6.5 mm
below the surface. The
— 25° C isotherm will be about 3 to 4 mm
below the surface. Relating this back
to the depth data presented earlier, approximately 96 per cent of BCCs can be
frozen to the appropriate depth by generating such an ice ball that extends 5
mm beyond the limits of the tumor on the surface. Larger BCCs and SCCs
require a greater and more extensive freeze. The spray may be limited to the
desired area by the utilization of truncated neoprene cones of the appropriate
size or by trimming polystyrene plastic to the appropriate size. The freeze and
thaw times should be accurately measured, and the utilization of two freeze-
thaw cycles is mandatory. The area frozen should extend far enough to in-
clude a halo of nonnal tissue around the tumor, so that the ice ball is large
enough to encompass the entire tumor within the —25° C isotherm. The
TABLE 17-10. Cure Rates for Cryosurgical Treatment of

Number Years % Without

Author of Lesions Follow-up Recurrence

Torre (1973P 800 1-5 97.0
100
McLean et al. (1978) 177 2-8 97.7
Zacarian (197 2331 3-10 (80%) 97.8
Fraunfelder rf al. (19* 101 1 98.0
Woolridge et al. (1975)"" 364 2 98.6

Woolridge et al. (1975) 101 133 95.5
TABLE 17-11. Indications, Advantages, and Disadvantages of Cryosurgery

of Basal Cell Carcinoma and Squamous Cell Carcinoma
Median cure rates

BCC 97.8%
SCC 95.5% (one stud) '
Size and depth of tumor Suitahle for all. For very exophytic lesions, it is helpful to
reduce hulk of tissue first with scalpel or curette. Very large
lesions should he done in stages.
Histologic types Suitahle for all. hut less useful for morphea-like BCC.
Checking margins No specimen available; relies on clinical judgment for limits

of tumor and additional margin of normal tissue.
Use in recurrent tumors Limited data available.
Location Useful for lesions on or near vital structures such as eyelid

margins, canthi, nasal tip, nasal alae, ears, especially those
lesions over or invading into cartilage or near lacrimal ap-
paratus. Useful for multiple lesions in one area. Scalp lesions
have relatively low cure rates. Lower extremity lesions heal
especially slowly. Care is required to avoid freezing nerves,
which results in neuropathy.
Patient characteristics Useful for all ages. Useful for keloid formers, hleeders, those
who refuse surgery. Avoid in patients with cryoglobulinemia
or cold urticaria.
Convenience Local or no anesthesia necessary, but may be painful first 24

hours. Healing time prolonged; four-eight weeks. Time
for procedure is short, so multiple lesions can be done in one
visit. Economical. Treatment may be accomplished in one
visit. No need for sterile technique.
Cosmetic results Usually good to excellent. Occasional hypertrophic scar,

hyperpigmentation, hypopigmentation. Keloids do not occur.
adequacy of freeze can be assured by measuring the halo thaw time. This is
the time it takes the normal rim of the tissue to thaw. As soon as the first point
of the tumor returns to normal color, the halo thaw time ends. This time
should be at least one minute for each freeze-thaw cycle. If it is not at least
one minute, a third freeze-thaw cycle should be performed. 102
In certain areas, there is no need to measure or estimate depth of freeze.
Tumors overlying the alae nasi and ears can be frozen straight through to the
opposing surface, certainly ensuring adequate depth of freeze without necro-
sis of cartilage. Areas such as the forehead, temple, and bridge of the nose may
be frozen until the skin is adherent to the periosteum.

In freezing areas around the eye, a polystyrene plastic shield may be used
to protect the eye. If lid lesions are being treated, a plastic lid retractor may be
used. Shields and instruments made of metal conduct cold and therefore
should not be used for such protection. The lacrimal duct is not damaged
permanently after being frozen, although it may temporarily be blocked. 96
Freezing lesions around the eyes often results in periorbital edema, and
treating forehead lesions may lead to bilateral edema.
BCCs and SCCs treated with cryosurgery usually heal within a month on
the face but may take considerably longer in other locations, especially the
lower legs.
Lesions that have particularly indistinct borders are less suitable for cryo-
surgical treatment, since there is no way to ensure that the entire tumor is
being treated adequately unless a large surrounding area of normal skin is also
treated. Therefore, morphea-like BCC usually is not best treated by this meth-
od; however, a combined technique of curettage, to delineate the extent of
tumors with difficult to delineate borders (except the morphea-like tumors,
which are not easily curetted), followed by cryosurgery has been utilized with
success. 103 It is particularly helpful for invasive BCCs that on curettage are
found to extend into underlying cartilage. Table 17-11 lists the advantages
and disadvantages of cryosurgery.
Chemosurgery
Chemosurgery is a technique pioneered by Mohs 104

in the 1930s that in-
volves carefully controlled microscopic monitoring in the excision of skin
cancers. It originally referred only to a method of fixing the tissues chemically
in situ followed by surgical removal with microscopic examination of the
lesion. This is now referred to as the "fixed-tissue technique" in contrast to
the more recently developed "fresh-tissue technique," in which the tissues
are not chemically treated in situ but rather frozen specimens are used.
Until the 1950s, Mohs began his chemosurgery with the application of a
However, it was found that steps were saved
zinc chloride fixative paste.
when the main bulk of the tumor was removed initially with a scalpel or
curette with the patient under local anesthesia. Hemostasis can then be
achieved with the application of such agents as dichloroacetic acid prior to the
17 Skin Cancer 7/7
application of the zinc chloride fixative paste. This fixative kills the cells but
preserves the architecture of the tissue. Within hours, or a day later, thin
horizontal layers of tissue 1 to 3 mm
thick are removed from the base and sides
of the defect. These are carefully mapped according to the location from
which they came.
Owing to the effects of the fixative there is no bleeding, making it easy to
mark the surface with agents such as merbromin or laundry blue in carefully
mapping the sections removed from the corresponding location. The tissues
are firm and easy to handle, since they have been fixed in situ. Bone is also
fixed with this technique and after decalcification may be prepared in the
same manner as other specimens. Horizontal frozen sections are then made
from the undersurface and edges of each specimen. If tumor is detected in any
portion of the specimen, the mapping can be utilized to determine where that
portion had been situated. Successive stages of fixation, removal, and exami-
nation need to be carried out only on those areas where tumor is still present
until a tumor-free plane is reached. Zinc chloride paste that is present in the
edges of the wound at the end of the procedure is sloughed several days
later, providing additional margins of tissue destruction.
In the Mohs' chemosurgery fresh-tissue technique, thin sections are re-
moved without fixation by the zinc chloride paste in situ. The excised tissue is
carefullymapped to delineate the corresponding location within the defect
and sectioned on a crv ostat. In both techniques the key is the careful mapping
of the horizontal sections of tissue, which are meticulously examined for
residual tumor. This preserves normal tissue while assuring that the entire
tumor is removed, since the excision is carried out in stages until tumor-free
planes are achieved, and these additional stages are performed only where
residual tumor is found.
The fixed-tissue technique may have better results for very large BCCs and
SCCs, especially those that invade bone or cartilage. 104 It also may be prefera-
ble in treating deeply invasive SCC of the penis because it makes hemostasis
in the noncontracting vascular spaces of erectile tissue more easily attain-
able. 105
The fresh-tissue technique has several advantages over the fixed-tissue
method. avoids the discomfort from the application of the zinc chloride
It
paste, making the
injection of the local anesthetic the only uncomfortable
aspect. It is suitable for use around the eyes and even for the intraorbital
extensions without the danger of fixative damaging the eye. 105 Since there is
no extra margin of tissue destroyed by the paste, a small extra saving of normal
tissue is achieved, which can be of significance when important structures are
affected. 104 Since there is no need
wait for the fixation of the tissue before
to
proceeding with the successive stage, most patients who undergo the fresh-
tissue method have the procedure completed in a single visit, whereas suc-
cessive visits may be necessary to complete the procedure when the fixed-
tissue technique is used. 104
Usually, with either technique the wounds are allowed to heal by granula-
tion, and often the cosmetic results are good to excellent, comparing favorably
71H II / Treatment of Specific Neoplasms
TABLE 17-12. Cure Rates for Chemosurgical (Mohs') Treatment of

\i A1BER Years W H IIOL |
Author of Lesions Follow- i p Recurrence

Fixed-tissue technique
Robins and Albom (1975) 108 183 5 97.3

Mohs (1978)"' 5 9351 5+ 99.3
Morgenstern and Leeper (1964)'"'' 213 1-7 100.0
Fresh-tissue technique
Robins and Albom (1975) 10 * 89 5 97.0

Tromovitch and Stegeman (1974)"° 102 3-8 97.0
Mohs (1978) 103 196 5+ 98.1
Median Cure Rate (BCC) Fixed-tissue technique 99.3

Fresh-tissue technique 97.0
Mohs (1978) 103

Fixed-tissue technique 3302 5+ 94.4
Fresh-tissue technique 18 5+ 100.0
'Includes 1387 recurrent lesions. Cure rate for primary lesions only is 99.8%.
with a graft or flap technique. A definitive cosmetic repair may be done six
months to a year after the procedure in those patients whose cosmetic results
are not optimal. This delay allows an observation period to detect early signs
of recurrence prior to hiding any residual tumor under normal tissue. Howev-
er, since the recurrence rate is so low with chemosurgery because of the
excellent microscopic control, it has been suggested that all lesions, except
those that are particularly widespread, deep, or difficult to ablate, can actually
be surgically repaired immediately following the use of the fresh-tissue sur-
gery if this would be advantageous for the patient. 106, 107
Mohs' chemosurgery offers the advantage of relative assurance that the
entire tumor is removed coupled with the minimal sacrifice of normal tissue.
This makes it suitable therapy for the cure of the more difficult lesions and
also for tumors located near structures that are functionally critical cosmetic-
ally. Although series utilizing either of the two types of chemosurgery gener-
ally have selected the most difficult BCCs and SCCs, the highest cure rates
are consistently shown (Table 17-12).
Large, deeply infiltrating lesions, tumors involving the periorbital region,
fingers, or penis, and those spreading along perichondral or periosteal planes
are particularly suitable for this method. Tumors in which it is particularly
difficult to clinically determine borders, such as morpheaform BCCs, also
lend themselves quite well to chemosurgery. In a study of 72 BCCs treated by
chemosurgery, the clinically apparent margins of the tumor were compared
with the actual margins found with microscopic control. 57 The mean increase
in the radius by including the subclinical extension was nearly 1 cm if the

tumor was any of the following: recurrent; larger than 2 cm in diameter;
morpheaform; located on the forehead, scalp, or temple; or had been present
longer than five years. For this selected group of tumors that were treated by
chemosurgery, tumors that were primary, less than 2 cm in diameter, solid
type on histologic examination, located on the nose or lips, and present less
than one year, subclinical extension was considerably less.
One of the most important indications for using one of the chemosurgical
techniques is treating recurrent tumors. Rather than dealing with a difference
in cure rate of just a few percentage points, the cure rate for recurrent lesions
is markedly superior to that of other modalities (Table 17-13). Another indica-
tion for chemosurgery is determining the adequacy of curettage and desicca-

tion in lesions that the operator has doubts as to the adequacy of the removal.
A series of 30 patients whose physicians questioned whether or not the tumor
had been entirely removed with C and D because it was wider or deeper than
expected were treated with chemosurgery within two weeks of C and D, and 6
were found to have residual tumor, which was eliminated with the "chemo-
check."
Mohs, in his personal series, includes patients with some of the most
difficult to treat and far advanced BCCs and SCCs who were referred from all
over the world. His cure rates are impressive. For almost 8000 such primary
TABLE 17-13. Cure Rates for Recurrent Basal Cell Carcinoma
Number of % Without
Method/Author Lesions Years Followed Further Recurrence
Electrodesiccation and
Curettage
Mennef al. (1971) 68 56 1-5+ 41

Kopf etal. (197 57 1-5 51
Sweet (1963) 78 33 5 87.9
Excisional Surgery
Menu et al. (1971) 68 28 1-5- 60

Haves (1962)69 181 1-20 72.9
Kopf et al. (1977) 80 20 1-5 80
Taylor and Barisoni (1973) 64 282 1/2-3+ 80.9
Radiation Therapy
Mennef al. (1971)68 11 1-5+ 73

Kopf et al. (1971)80 18 1-5 89
Chemosurgery
Robins and Albom

(fixed) (1975) 108 117 5 95.2
Mohs (fixed) (1978) 105 1387 5+ 96.8
Mohs (fresh) (1978) 105 97 5 97.0
BCCs, he has had technique

a cure rate of 99.8 per cent with the fixed-tissue
after a follow-up of at least five years.For nearly 1400 recurrent BCCs, his
five-year follow-up figures show a 96.8 per cent cure rate, and for all BCCs it is
99.3 per cent. For SCCs followed for at least five years, many of which were
far advanced, his figures are 94.4 per cent without recurrence.
The major disadvantages of Mohs' technique include the relatively few
people expert in its use, the time involved, and the relatively high expense. It
offers little advantage in the management of routine BCC and SCC. It is,
however, uniquely suited for treatment of those BCCs and SCCs that are
recurrent, morphealike, extensive, infiltrating, involve vital areas, or are oth-
erwise particularly difficult to treat. Table 17-14 summarizes indications,
advantages, and disadvantages of Mohs' chemosurgery.
Topical Chemotherapy
A variety of topical chemotherapeutic agents have been administered ex-

111, 112
perimentally in the treatment of skin cancers, but the current approval
TABLE 17-14. Indications, Advantages, and Disadvantages of

Chemosurgical Treatment of Basal Cell Carcinoma and
Median cure rates

BCC Fixed tissue technique — 99.3%
Fresh tissue technique — 97.0%
SCC Fixed tissue technique — 94.4%°

Fresh tissue technique— 100%°
Histologic types Suitable for all.
Checking margins Meticulously checked in three dimensions; therefore, optimal

method for lesions that have indistinct clinical margins or
invade hone or cartilage.
Use in recurrent lesions Cure rates are markedly superior to all other methods in
recurrent tumors.
Location Especially useful on or near vital structures because it is both

tissue sparing and gives best assurance of clearance of tumor.
Patient characteristics No limitations.
Convenience Done under local anesthesia. Long time for procedure.

Relatively expensive. Healing time comparable to those
with C and
D, but for large lesions not immediately repaired,
it may be
prolonged. May require secondary repair. Few
physicians are trained in its use.
Cosmetic results In those not repaired at a

second procedure, comparable to
C andD. In those repaired, comparable to surgical manage-
ment, although minimum amount of tissue necessary to cure
tumors has been removed.
"One study only.

for such usage is limited to 5 per cent 5-fluorouracil exclusively for the
histologic category of superficial BCC. This agent is effective in the treatment
of actinic keratoses, as discussed earlier.
The approval of 5-FU for use in superficial BCCs is based on a 93 per cent
cure rate in 113 lesions that were proved histologically to be of this type." " 5 l
This method results in no systemic toxicity, little or no scarring, and rapid

healing. 115 However, conventional means are still recommended whenever
practical for these lesions because cure rates are near 100 per cent for superfi-
cial BCCs.
Although no approval for use of 5-FU in therapy of other kinds of BCC or
SCC 103 such BCCs and 15 SCCs treated successfully has
exists, a series of
already been referred to Mohs and reported by him. 116 It is of special concern
that many of these lesions were covered by entirely normal skin, although
they all showed evidence of widespread invasive tumor. This indicates a
tendency of such inappropriate use of 5-FU to conceal foci of invasive BCC
and SCC and therefore to delay proper treatment further.
There is evidence that 5-FU in higher concentration may be effective for
some noduloulcerative BCCs. In a series with a three-year follow-up, 56 per
cent of 32 patients showed no recurrence. 115 Treatment utilized 20 per cent
5-FU under occlusion. Another series recommended application of 20 per
cent strengths for a period of months for such lesions and showed a high
percentage of tumor regression, 117 but the length of follow-up averaged less
than one year, so little can be said of cure rates.
Therefore, at this time, topical chemotherapy is restricted to use of 5-FU in
5 per cent strength as an alternative therapy for superficial BCCs and in
higher strengths on an investigational basis for noduloulcerative BCCs. It
definitely should not be used as therapy for recurrent lesions. 115, 116 It is hoped
that in the future, by utilizing different agents, various strengths of 5-FU,
better penetrating vehicles, or combinations of agents, chemotherapy will
ultimately offer cure rates as high as conventional methods.
Immunotherapy
Immunotherapy is becoming useful as a tool for treating skin cancers. At

this point, its use is restricted to a few centers for carefully selected patients.
Itinvolves sensitizing an individual to a particular antigen and then eliciting a
delayed hypersensitivity inflammatory reaction at the desired local site,
usually by topical application of this chemical.
Patients who have xeroderma pigmentosum, the nevoid basal cell syn-
drome, chronic arsenic exposure, extensive chronic radiation dermatitis, or
long-term exposure to excessive actinic radiation may have large numbers of
skin cancers. The large area of the body surface involved may make surgical
excision, curettage and desiccation, cryosurgery, or radiation therapy a diffi-
cult and disfiguring undertaking. It is in such patients that topical immuno-
therapy has biggest role.
its
It was first noted more than a decade ago that the induction of a cutaneous
delayed hypersensitivity reaction resulted in the elimination of multiple

superficial BCCs. 118 The epidermal neoplasms are selectively more sensitive
to agents such as dinitrochlorobenzene, triethylene-immino-benzoquinone

(TEIB), mechlorethamine, purified protein derivative of tuberculin (PPD),
streptokinase-streptodornase, and Candida extract than is normal skin. This
feature allows one to use a weaker strength for treatment than the lowest
concentration causing an inflammatory response on normal skin, as deter-
mined by patch testing. The medication can then be applied to the entire
affected area rather than just to the visible tumor without causing a marked
reaction, except in the clinically apparent tumor and in microscopic foci of
involvement by malignant and premalignant cells. Therefore, small lesions
may be recognized and treated earlier in their courses than would ordinarily
be possible. Such allergic contact dermatitis reactions have been utilized with
cure rates generally between 60 and 90 per cent for basal cell carcino-
ma n8-i22
Immunotherapy can also be used prophylactic-ally for patients who develop
a vast number of cutaneous neoplasms. Studies in three xeroderma pigmen-
tosum patients, in whom one side was treated by conventional therapy and the
other side was treated with intermittent courses of DNCB in an attempt to
prevent new tumors, showed 177 new tumors on the control sides of the three
patientsand only 10 on the sides receiving DNCB immunoprophylaxis in the
course of one year. 119, 120 Patients with other conditions resulting in multiple
epidermal neoplasms have also had remarkably reduced rates of new tumor
120
formation. 119 '
Combinations of two or more agents inducing a cell-mediated immune

response and combinations of a chemotherapeutic agent such as 5-FU plus
such an agent may be more effective than single agent therapy. 119, 12 ° This
observation has theoretic as well as practical implications. A delayed hyper-
sensitivity reaction can be elicited to a combination of two antigens in concen-
when either is given alone. The selective
trations that fail to elicit the reaction
response upon application to the tumors may be the result of the adjuvant
effect of adding an additional antigenic agent to weak tumor antigens, result-
ing in a delayed hypersensitivity reaction.
Another possible mechanism is that the delayed hypersensitivity reaction
causes the specifically sensitized lymphocytes to accumulate at the sites of the
application of the sensitizing agent. These cells release lymphokines, which
cause inflammation locally, and since the tumor cells are multiplying more
123
actively than normal cells, they may be more vulnerable to destruction. In
any case, the lack of scarring associated with this process provides argument
against a simple chemical or physical injury being the mechanism of action.
SUMMARY
BCC and SCC are curable the vast majority of the time using surgical
excision,C and D, x-ray therapy, cryosurgery, or chemosurgery. However,
these lesions should not be regarded too lightly, since they are capable of
producing significant morbidity and occasional mortality if they are long
neglected or improperly treated. When a particularly aggressive tumor is

encountered, the mode of therapy should be tailored to the characteristics of
the particular patient and lesion.
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CHAPTER 18
NEOPLASMS OF
THE NERVOUS
SYSTEM
Ulrich Batzdorf
Thomas H Weisenburger
Section 1
Brain
INTRODUCTION
Although previous reports gave lower figures, tumors of the central ner-
vous system — including meningeal tumors —
are now believed to repre-
sent 9 per cent of all primary tumors and to account for 1.2 per cent of all
'
autopsied deaths. 2 Primary tumors of the central nervous system are rela-
1
tively more common at an early age and are estimated to account for 12 to
18 per cent of cancers in children, second only to leukemia as a cause of
death. 3,4 These figures underline the significance of the problem of primary
central nervous system neoplasia.
At present, the treatment of malignant CNS tumors is, in general, still
less than satisfactory and represents a major challenge to surgeons, radia-
tion therapists, chemotherapists, immunologists, and others concerned with
cancer therapy. Of even greater importance to the physician are the many
difficult questions posed by the cancer patient with metastases involving
the brain or spinal cord. Not only are these tumors encountered more fre-
quently in a general oncology practice than are primary brain tumors, but
the management of individual patients may require particularly keen judg-
ment.
726
18 / Neoplasms of the Nervous System 727
Epidemiology
At the present time there are no known epidemiologic factors clearly re-
lated to gliomas or other types of central nervous system neoplasms. In-
cidence figures differ depending on the population studied. In one study,
the average annual incidence rate for all primary brain tumors was estimat-
ed at 12.6 per 100,000 population, 5 of which approximately 28 per cent
were gliomas. These figures, based on an analysis of the Rochester, Minne-
sota population, represent combined autopsy and clinical statistics and are
higher than in some other studies. 6 The finding of meningiomas, the most
common type of previously undiagnosed brain tumor encountered at post-
mortem examination, probably explains both the higher overall incidence
6,
rate of tumors and a lower relative percentage of gliomas in that study.
Several surveys have described the preponderance of tumors of the astro-
cytoma series among males and of meningiomas among females. 56 The
higher incidence of gliomas in males seems to apply equally to adult and
pediatric age groups in a ratio of 3:2. Incidence curves for gliomas show a
peak in the second 5 years of life and again between ages 45 and 64 years,
after which the incidence declines. 4 Well-differentiated astrocytomas ap-
pear to be more common in a younger age group, whereas malignant astro-
cytomas and glioblastomas occur more frequently in older patients. 7
It has also been noted that the incidence of gliomas is higher among
North American whites, whereas meningiomas, pituitary adenomas, and

nerve sheath tumors are more common among North American blacks. 8,9
The frequency with which the various tumors are encountered is given in
Tables 18-1 and 18-2.
The epidemiology of metastatic lesions relates to the primary tumor type.
The incidence rate for metastatic tumors of the nervous system is estimated
at 11.1 per 100,000 population, with such tumors representing 41 per cent
of CNS neoplasms in a combined clinical and autopsy survey. 5, 10
Etiology
To date, the cause of spontaneously occurring CNS tumors remains un-

known. As in the case of other malignant tumors, different etiologic factors
have been considered. In a thorough review, Bigner and Pegram 11 conclude
TABLE 18-1. Frequency of Intracranial Gliomas (All Ages) 020
Glioblastomas 55.0%
Astrocytomas 20.5%
Ependymomas 6.0%
Medullohlastomas 6.0%
Oligodendrogliomas 5.0%
Choroid plexus papillomas 2.0%
Colloid cysts 2.0%
"From Koos WT and Miller MH: Intracranial Tumors of Infants and Children. St. Louis,
The CV Mosby Co, 1971.
TABLE 18-2. Frequency of Brain Tumors

in Infancy and Childhood -
Spongioblastomas, including 21.7%

cerebellar astrocj tomas
Medulloblastomas 18.9%
Astrocytomas 10.1%
Ependymomas 8.7%
Glioblastomas 4.6%
"From Koos W'T and Miller MH: Intracranial Tumors of Infants and Children. St. Louis,
The CV Mosby Co, 1971.
that at this time there no unequivocal evidence for either a virus or virus
is
genome to be associated with human brain tumors in a cause and effect

relationship. Several leads are being followed, and intensive study in this
area is under way. 12 Gliomas have been reported in association with im-
munodeficiency states. 13
Radiation exposure has also been cited as a possible etiologic factor.
Studies of children irradiated for tinea capitis 14 and of atomic bomb survivors 15
suggest that children may be particularly sensitive to the effects of radiation
with respect to CNS neoplasia. However, the importance of the time factor
required for the neoplastic effect to become manifest is well recognized
and makes analysis of data difficult.
Underlying endocrine influences may be important, since it appears that
in both males and females the incidence decreases coincident with de-
creasing sex hormone levels. 4
Various chemical carcinogens have been considered, as they have for
other malignant tumors. 16 At present the evidence for such factors is largely
anecdotal. There has been no follow-up to former studies to suggest an
increased incidence of brain tumors among rubber and plastic workers. 17
The possibility of a hereditary role in the occurrence of CNS tumors re-
mains questionable. One study showed no evidence of a hereditary factor
when the incidence did not appear to be higher among relatives of glio-
blastoma patients. 18 Other studies suggest a familial trend, particularly in as-
sociation with dysraphic conditions. 19 There is a much clearer association of
malignant brain tumors with the phakomatoses, particularly neurofibroma-
tosis and tuberous sclerosis. 20 Families with a high incidence of CNS
tumors have been reported. A higher incidence of malignant CNS tumors
in association with certain blood groups has been called into question, 21 but
in general has not been substantiated. 22
Biology
Primary Tumors. The biology of primary tumors of the brain and spi-
nal cord cannot be discussed without reference to their histologic classifica-
tion. In a broad sense, neuroepithelial tumors derived from the three major
glial cell types range from those made up of very well-differentiated cells
to highly anaplastic tumors in which the basic cell type is difficult to recog-
nize. Astrocytomas, oligodendrogliomas, and ependymomas all exist in such

a range of tumor variants.
The mitotic index of glioblastomas is surprisingly low, and kinetic stud-
ies have shown that more than 50 per cent of the tumor cell population is
in the nonproliferative (G ) phase. 23 The picture is further complicated by
the fact that glial tumors are often not homogeneous with respect to either
the degree of cell differentiation or the predominant cell type. It can be
stated, however, that the degree of malignancy of primary CNS tumors is
never less than that of the most anaplastic portion of the tumor. This is an
important consideration when the physician is asked to make a statement
regarding tumor prognosis on the basis of a needle biopsy, since this limit-
ed technique could introduce a sampling error.
Glial tumors grow primarily by contiguity, infiltrating the surrounding
brain or cord parenchyma as they extend. Highly anaplastic tumors may
grow so rapidly that excessive demands are placed on the regional blood
and oxygen supply, resulting in regional tissue necrosis within the tumor.
Glioblastomas may produce a substance stimulating proliferation of neo-
24
plastic vessels within the neoplasm. Hemorrhage into tumors has been
considered to occur more frequently than is seen clinically. Significant
hemorrhage is encountered, particularly in association with oligodendro-
gliomas, 25 pituitary adenomas, 28 and in association with melanomas and
choriocarcinomas. 27- 28
In addition to growth by direct contiguous extension, primary tumors
may extend within the CNS by implanting beneath the leptomeninges or
the ependyma and by forming perineuronal and perivascular aggregates of
tumor cells beyond the margins of the main tumor mass. These formations,
known as Scherer's secondary structures, are seen only in association with
primary CNS tumors and may be indicative of early anaplasia. 2, 20 Tumor
cells also seem capable of growing along heavily myelinated structures,
such as the corpus callosum, expanding into another mass beyond the re-
strictive confines of the myelinated structure.*9, *n This gives rise to the
characteristic appearance of so-called butterfly lesions of the cerebral hemi-
spheres. Approximately 2.5 per cent of gliomas show evidence of multicen-
31
tric origin.
It would appear that all primary
tumors CNS —
but most commonly me-
dulloblastomas, pineal cell tumors and germinomas, and fourth ventricle
ependymomas, as well as papillomas of choroid plexus are capable of —
shedding cells into the CSF, which can then be detected by cytologic ex-
amination. Retinoblastomas (see Chapter 13) share this property. Perhaps
only the histologically most benign tumors do not seed into the CSF in this
manner. Secondary tumor implants within the spinal subarachnoid space
are, however, very uncommon except for the group of tumors just listed. 32, 33
Metastasis of primary malignant brain tumors outside the CNS is even
more uncommon, although sporadic reports of such cases have appeared in
37
the literature. 34
"
As is the case with tumors of other organ systems, the presence of a pri-
mary^ brain tumor is accompanied by changes in the host's immune system.
Careful studies of patients with malignant gliomas have shown that there is
TABLE 18-3. Source of Metastatic Tumors to the Brain
\i i ROLOGY NEUBOSl K(.ERY AlTOPS^

Statistics Statistic s Statistic s
Tumor 456 Patients 2037 Patients 1067 Cases
Lung 40.0% 36.0% 34.0%

Breast 21.0% 14.0% 22.0%
1
1> pernephroma 7.5% 8.0% 6.0%
Melanoma 4.5% 5.0% 5.5%
GI tract 9.0% 6.0% 8.5%
Thyroid 1.0% 2.0% 2.0%
Female genitalia 4.0% 3.0% 4.5%
Male genitalia 1.0% 0.5% 1.0%
Prostate 1.0% 0.5% 2.0%
Face- 1.5% 2.0% 2.0%
Other carcinomas 2.0% 2.0% 5.0%
Sarcomas 2.0% 1.0% 3.0%
Unknown primary 5.5% 20.0% 4.5%
'From Penzholz H: Acta Neuwchir (Suppl) 16:1, 1968.
a decreased number of circulating lymphocytes, particularly de- T cells,

creased histogenesis of lymphocytes, and depressed skin test reactivity to
common antigens. 38 41 A glioma-associated antigen has been postulated on
"
the basis of some investigations, 42, 43 whereas other studies point to the
presence of a meningioma-associated antigen. 44, 45 There is some evidence
for the presence of glioma-specific antibodies or antigen-antibody com-
plexes, and the possibility exists that there are circulating blocking factors
that impair the cytotoxic response to the tumor. 46
Metastatic Tumors. Metastatic tumors to the brain can arise from any
primary neoplasm capable of hematogenous dissemination. The frequency
with which different primary tumors are represented in one series is indi-
cated in Table 18-3. Metastatic tumors probably appear with equal fre-
quency among men and women. Recent surveys fail to substantiate that
one hemisphere is more likely to be involved than the other. 47
Certain primary neoplasms, in particular carcinoma of the breast and lym-
phomas, tend to give rise to diffuse leptomeningeal carcinomatosis. 48 Dural
invasion also is most common for metastatic tumors arising from the
breast. 47 Solitary brain metastases originate most commonly from the breast
or hypernephroma primaries. 47
Although metastatic carcinomas may be in contact with the subarachnoid
space or the ventricular system, thereby allowing tumor cells to be recov-
ered in the cerebrospinal fluid, the majority of such freely floating cells in
the CSF rarely, if ever, give rise to subarachnoid implants over the spinal
cord or cauda equina. 33 Sarcomatous tumors, by contrast, may give rise to
such meningeal metastases. 49
NATURAL HISTORY
Classification
Table 18^4 gives the classification of primary tumors of the CNS as rec-
ommended by the World Health Organization for universal adoption. 50
Malignant or anaplastic tumors are found in even' category. However, in
view of the potentially lethal character, even of histologically more benign
intracerebral tumors, histology cannot be the sole prognostic criterion (see
also Prognosis section). The reader is referred to standard textbooks for a
2,2 "
detailed discussion of the pathology of these tumors.
There are many varieties of brain tumor, some of which are quite rare.
Only the more common intraparenchymatous tumors will be discussed
here.
Clinical Features
In the case of well-differentiated tumors, there may be little, if any, rec-

ognizable effect on the function of the infiltrated neural tissue. In time,
however, tumors may be expected to produce symptoms by one or more
all
of the following mechanisms: (1) increased intracranial pressure, which

may be due to the tumor mass, pcritumoral edema, and obstruction of CSF
pathways; (2) local biochemical changes, which may act to depolarize
neurons within or adjacent to the tumor, thereby triggering seizure activity;
(3) local destruction of brain tissue resulting in neurologic deficits; (4)
stretching, distortion, or compression of surrounding neural structures
(cranial nerves), which are themselves not infiltrated by tumor; (5) remote
effects on other organ systems due to the alteration of neuroendocrine func-
tion or elaboration of active substances by the tumor; and (6) stretching of
the dura and stretching or distortion of the basal arteries composing the
circle of Willis.
Intracranial pressure may be
elevated as a result of the tumor mass itself,
but sometimes the mass effect of peritumoral edema may be as great or
greater than that of the tumor nodule. Cerebral edema certainly is a major
contributing factor to the increased intracranial pressure. The magnitude of
peritumoral edema is particularly great in the more rapidly growing neo-
plasms and in the case of metastatic tumors. 2 Intracranial pressure may also
be elevated because the tumor and surrounding edema obstruct the ventric-
ular system. This would most commonly occur at or near the interventric-
ular foramen, at the narrow third ventricle and the aqueduct of Sylvius, or
near the outlet foramina of the fourth ventricle. Increased intracranial pres-
sure gives rise to rather nonspecific symptoms and signs, including head-
ache, nausea and vomiting, papilledema, and, in young children, spreading
of cranial sutures.
The irritative action that tumor or edema may exert upon the involved
brain can lead to seizures, which may be focal or generalized. Rarely, a
TABLE 18-4. Outline of the WHOHistologic Classification of Tumors
of the Central Nervous System 50
I. Tumors of neuroepithelial tissue
A. Astrocytic tumors
1. Astrocytoma
a. Fibrillar)
b. Protoplasmic
c. Gemistocyte
2. Pilocytic astrocytoma
3. Subependymal giant cell astrocytoma
(ventricular tumor of tuberous sclerosis)
Astroblastoma
4.
5. Anaplastic (malignant) astrocytoma
B. Oligodendroglial tumors
1. Oligodendroglioma
Mixed oligoastrocytoma
2.
Anaplastic (malignant) oligodendroglioma
3.
C. Ependymal and choroid plexus tumors
1. Ependymoma
Variants:
a. Myxopapillaryependymoma
b. ependymoma
Papillary
c. Subependymoma
2. Anaplastic (malignant) ependymoma

3. Choroid plexus papilloma
Anaplastic (malignant) choroid plexus papilloma
4.
D. Pineal cell tumors
1. Pineocytoma (pinealcytoma)
2. Pineoblastoma (pinealblastoma)
E. Neuronal tumors
1. Gangliocytoma
2. Ganglioglioma
3. Ganglioneuroblastoma
4. Anaplastic (malignant) gangliocytoma and ganglioglioma
5. Neuroblastoma
F. Poorly differentiated and embryonal tumors
1. Glioblastoma
Variants:
a. Glioblastoma with sarcomatous component (mixed glioblastoma and sarcoma)
b. Giant cell glioblastoma
2. Medulloblastoma
Variants:
a. Desmoplastic
b. Medullomyoblastoma
3. Medulloepithelioma
4. Primitive polar spongioblastoma
5. Gliomatosis cerebri
II. Tumors of nerve sheath cells
A. Neurilemoma (schwannoma, neurinoma)

B. Anaplastic (malignant) neurilemoma (schwannoma, neurinoma)
C. Neurofibroma
D. Anaplastic (malignant) neurofibroma (neurofibrosarcoma, neurogenic sarcoma)
III. Tumors of meningeal and related tissues
A. Meningioma
1. Meningothelioma (endotheliomatous, syncytial, arachnotheliomatous)
2. Fibrous (fibroblastic)
3. Transitional (mixed)
4. Psammomatous
5. Angiomatous
6. Hemangioblastic
7. Hemangiopericvtic
8. Papillary
9. Anaplastic (malignant) meningioma
732
TABLE 18-4. Outline of the WHO
Histologic Classification of
50
Tumors
of the Central Nervous System (Continued)
B. Meningeal sarcomas
1. Fibrosarcoma
2. Polymorphic cell sarcoma

3. Primary meningeal sareomatosis
C. Xanthomatous tumors
1. Fibroxanthoma
2. Xanthosarcoma (malignant fibroxanthoma)
D. Primary melanotic tumors

1. Melanoma
2. Meningeal melanomatosis
E. Others
IV. Primary malignant lymphomas

V. Tumors of blood vessel origin
A. Hemangioblastoma (capillary hemangioblastoma)
B. Monstrocellular sarcoma
VI. Germ cell tumors
A. Cerminoma
B. Embryonal carcinoma
C. Choriocarcinoma
D. Teratoma
VII. Other mal formative tumors and tumor-like lesions

A. Craniopharyngioma
B. Rathke's cleft cyst
C. Epidermoid c\ st
D. Dermoid cyst
E. Colloid cyst of the third ventricle
F. Enterogenous cyst
G. Other cysts
H. Lipoma
I. Choristoma (pituicytoma, granular cell "myoblastoma")
J. Hypothalamic neuronal hamartoma
K. Nasal glial heterotopia (nasal glioma)
VIII. Vascular malformations
A. Capillary telangiectasia
B. Cavernous angioma
C. Arteriovenous malformation
D. Venous malformation
E. Sturge-Weber disease (cerebrofacial or cerebrotrigeminal)
IX. Tumors of the anterior pituitary
A. Pituitary adenomas
1. Acidophil
2. Basophil (mucoid cell)
3. Mixed acidophil-basophil
4. Chromophobe
B. Pituitary adenocarcinoma
X. Local extensions from regional tumors
A. Glomus jugulare tumor (chemodectoma, paraganglioma)

B. Chordoma
C. Chondroma
D. Chondrosarcoma
E. Olfactory neuroblastoma (esthesioneuroblastoma)
F. Adenoid cystic carcinoma (cylindroma)
G. Others
XI. Metastatic tumors
XII. Unclassified tumors
733
prolonged state of seizure activity — status epileptieus — may develop,

which could have a fatal outcome if it is not or cannot he adequately treat-
ed.
Local destruction of brain tissue may also he the result of tumor or peri-
tumoral edema, or both, and can cause the loss of neural function appro-
priate to the area of brain involved. The resulting clinical picture can be
very variable and may include disturbances of motor, speech, sensory, visu-
al, or intellectual function or personality changes. Cranial nerves often are
stretched or distorted by tumor so as to interfere in their function. The

from such cranial nerve deficit can be of localizing
clinical picture resulting
value, although stretching of the most frequently involved nerve the ab- —
ducens —is nonspecific and often does not aid the anatomic localization of
the tumor.
Intracranial tumors may remote effects if they impinge upon
also exhibit
or involve neuroendocrine structures such as the hypothalamus or pituitary
gland.
Mechanisms of Death
The most common cause of death from brain tumors is a herniation syn-
drome resulting from increased mass effect. In the case of cerebral hemi-
sphere lesions, medial-temporal lobe herniation commonly results in me-
dial displacement of the uncus of the temporal lobe, producing
compression and stretching of the brain stem. Posterior fossa tumors may
compress the lower brain stem directly or produce herniation of the cere-
bellar tonsils with medullary compression. In all these situations, coma and
respiratory arrest will ensue. Not infrequently, the compressive effect on
the brain stem is somewhat more gradual, and the patient first becomes
comatose. During this time there is, of course, a great risk of aspiration and
pneumonia. Some patients die as a result of uncontrolled seizure activity.
Diagnosis
The evaluation of a patient with a suspected solitary intracerebral lesion

should begin with a careful history and general physical examination. Gra-
dual rather than abrupt onset and a relentless progression of neurologic
symptoms and signs suggest a neoplastic rather than a vascular lesion.
Rapid progression of clinical abnormalities suggests the presence of a more
malignant lesion or neoplastic involvement with considerable associated
perifocal edema.
Today, the first neurodiagnostic procedure performed will frequently be
a computerized axial tomography scan, and the question of dealing with a
single versus multiple lesions is quickly resolved. 51, 52 Since up to 50 per
cent of metastatic lesions to the brain may be solitary, 47,53 however, a rea-
sonable effort must be undertaken to exclude a primary malignancy else-
where in all patients suspected of having a malignant brain tumor. This
would obviously include a chest x-ray and such other organ system inves-
considered appropriate. An electroencephalogram (EEG) is

titrations as are
another useful screening study. Although CAT scans have largely replaced
isotope scans, the latter are still helpful in clarifying the occasional diag-
nostic problem. 54
The complete diagnostic evaluation should not overlook the value of
plain radiographs of the skull. 55 They may disclose valuable information
concerning sites of bone destruction or osteoblastic activity, pathologic cal-
cification, and abnormalities of the orbits or paranasal sinuses, some of
which may not be seen on CAT scans. Erosion of the sella is a nonspecific
change seen in the presence of elevated intracranial pressure. Several
weeks are required for these sellar changes to become evident. Provided
the pineal gland is calcified, displacement of this structure should always
be sought.
Special neurodiagnostic studies will be required in almost every instance
before surgical therapy can be considered but may be deferred or avoided
in patients with multiple cerebral metastases by CAT scan criteria or in
patients who are clearly not candidates for surgical therapy. Angiography is
of great value in further localizing a tumor with respect to brain surface
vascular landmarks. 56 Cerebral angiography is also most valuable in iden-
tifying the vascular supply and drainage of a tumor, and the nature of the
vascular tumor stain itself can be a helpful diagnostic feature. Selective
arteriography is helpful in identifying the contribution of the external caro-
tid system to the tumor vascular supply.
Air encephalography, although performed less frequently since the ad-
vent of CAT scanning, is still of great value in further defining the anatom-
ic localization of tumors, particularly those in proximity to the ventricular
system and those at the base of the brain. 58 Because of the unavoidable
effect on the intracranial mass dynamics, which may be delicately balanced
in the presence of one or more intracranial lesions, air encephalography has
greater inherent risks, particularly when intracranial pressure is already in-
creased. A neurosurgeon should therefore be consulted prior to the perfor-
mance of this procedure in a patient suspected of harboring a tumor. The
use of ventricular puncture (ventriculography) rather than lumbar puncture
for the introduction of air and the administration of corticosteroids in appro-
priate dosage (see later discussion) at least 24 hours, and preferably longer,
before the study is performed help to reduce the risks. Equipment for ven-
tricular aspiration by means of a twist drill should be available in the radi-
ology suite, so that intracranial pressure can be reduced in an emergency.
In many instances, it is essential to have an operating room immediately
available for definitive surgical therapy. Positive contrast material may be
used conjunction with ventriculography.
in
A diagnostic lumbar puncture can be undertaken safely if there is no
evidence of a mass lesion with increased intracranial pressure. Examination
of the cerebrospinal fluid (CSF) may show an increase in the overall
number of cells, and tumor cells may be present. The routine cell count
may record tumor cells simply as "mononuclear" cells. A specific cytologic
examination should be undertaken and may be a most helpful diagnostic
study. 57 This is particularly true in situations in which the diagnosis of
meningeal carcinomatosis or of a nodular metastasis in contact with CSF is

under consideration. Cerebrospinal fluid protein levels are commonly ele-
vated in the presence of an intracranial tumor, and brain sugar values may
be low.
Staging
Criteria for staging of malignant tumors of the brain have been defined in
58
the Manual for Staging of Cancer. These criteria incorporate factors of
histology, anatomic extent, and completeness of tumor resection. Staging of
central nervous system tumors is not widely practiced at this time. Sys-
tematized recording of data, such as outlined in the manual, would proba-
bly aid in the analysis of tumor therapy records.
Prognosis
Primary CNS Tumors. Factors affecting the prognosis of patients with

primary brain tumors have been incorporated into the staging criteria and
TNM classification just discussed. 58 They include type of neoplasm, his-
tologic grade, ranging from well differentiated to very poorly differentiated,
anatomic sites involved, tumor size, invasion or encroachment on the ven-
tricular system and extension across the midline to invade the opposite
hemisphere, or extension to the opposite side of the tentorium cerebelli.
Although all these factors are significant with respect to prognosis, it
must be recognized that the variety of primary tumors and the differences
in their biologic behavior make it difficult to apply these factors rigidly to
all tumors in order to formulate a prognosis. It is therefore necessary to
elaborate to some degree on the criteria listed. For instance, even the most
differentiated cerebral glioma, if not totally resectable as is true of most,
may ultimately lead to the death of the host by virtue of its mass effect. Yet
juvenile cerebellar astrocytomas form an exceptional group, and cures of
this type of tumor are not uncommon. 59 Proximity to the brain stem, CSF
obstruction, and seeding must be emphasized in considering the prognosis
of a patient with medulloblastoma as compared with glioblastoma.
In addition to the prognostic factors just presented, one must consider
the following in approaching the question of tumor prognosis: (1) cystic
versus solid nature of the tumor; (2) vascularity of the tumor; (3) limitations
on resectability imposed by lateralization of the tumor, i.e., speech-
dominant hemisphere, or localization of the tumor within the deep struc-
tures of the brain precluding resection, i.e., basal ganglia or thalamus; (4)
radiosensitivity of the tumor — medulloblastomas (which are often difficult
to resect totally), pineal tumors, and ependymomas are among the most sen-
sitive to x-ray therapy; (5) quality of survival, reflecting many aspects of
function including motor and intellectual function —
rough quantitation
using Karnofsky 60 ratings has proved useful in assessing these factors —and
age of the patient at the time of diagnosis, has also been found to be an
important feature; (6) obstruction of CSF pathways necessitating a shunting
procedure; and (7) dissemination of the tumor within the subarachnoid

space or, rarely, outside the central nervous system.
Metastatic Tumors Involving the CNS. The prognosis for survival
of patients with metastatic lesions involving the CXS requires consider-
ation of some different factors than those that apply to primary tumors. Key
considerations are the nature of the tumor of origin, how well it is con-
trolled, and how extensively it has spread. Factors that apply specifically to
CNS involvement include (1) the number and size of metastatic foci and
how they affect cerebral mass dynamics; (2) the extent of peritumoral
edema and its responsiveness to pharmacologic agents, i.e.. corticosteroids.
as well as the patient's ability to tolerate such therapy; (3) resectability of a
solitary tumor focus and the rare possibility of local recurrence at the site of
the metastatic tumor resection; and (4) radiosensitivity of the (primary)
tumor and availability of unexplored routes of chemotherapy.
In a large series, 47 up to 18 per cent of patients who underwent surgical
resection of a metastatic brain tumor survived more than one year; survival
figures for patients with metastatic hypernephroma are considerably better
than those with bronchogenic tumors or melanoma. 47 ' •*•
TREATMENT
Steroids
Before discussing specific modalities of brain tumor therapy, it is impor-

tant to note that certain measures may be very useful as adjuncts both to
operative and nonoperative therapy 6S M From a practical point of view, cor-
'
ticosteroids are most commonly employed for the treatment of increased

intracranial pressure and for the reduction of cerebral edema that surrounds
brain tumors.
Steroids may be administered orally, intramuscularly, or intravenously,
depending on the patient's condition. The response to steroid therapy often
becomes apparent within 6 to 12 hours, although the full benefits may not
be realized for several days. The possibility that large-dose steroid admin-
istration may have a direct suppressive effect on tumor growth has been
considered and is being further evaluated. 69
When dexamethasone is used, the usual adult dose is 10 mg initially and
4 mg every six hours subsequently. A maintenance dose of 2 mg even six
hours may be sufficient for long-term therapy. It has been demonstrated,
however, that increasing the dose to significantly higher levels may be very
useful in selected tumor patients. 66 In children, the dosage is reduced ac-
cordingly. 67 If methylprednisolone is used, the initial dose is 120 mg fol-
lowed by 20 mg every six hours.
Although the precise role of steroids in producing gastric ulceration is
still being debated, it is probably advisable to protect patients receiving
steroids with oral antacid medication. 68,69 Comatose patients and patients
on respirators seem to be particularly at risk for serious gastric bleeding. 70
In situations that are acutely life threatening because of intracranial pres-
sure, the use of intravenous osmotic diuretics, such as 30 per cent urea or
20 per cent mannitol at a dose of 1 to 1.5 gm/kg, may be most helpful.
Although their action is brief and temporary, osmotic diuretics in this situa-
tion may provide some margin of safety for the patient while further con-
sultation is being obtained and diagnostic studies are carried out. Osmotic
diuretics may be administered simultaneously with corticosteroids.
Anticonvulsants
Some
physicians prefer to start all patients with a demonstrated cerebral
hemisphere tumor on anticonvulsant medication whether or not they have
actually had a seizure. The risk of brain herniation due to seizure activity
measure.
justifies this
Phenytoin, 300 mg daily, an excellent anticonvulsant. Phenobarbital,
is
up to 60 mg every six hours, may

also be used, either in place of phenytoin
or concurrently. Blood levels of these drugs should be checked in 10 to 14
days to ascertain that therapeutic levels have been reached. Phenytoin and
phenobarbital may affect the action and metabolism of corticosteroids. K4
The reader is referred to a standard textbook of pharmacology for details of
drug administration and therapeutic drug levels. 71
Surgery
Although one would like to think in terms of a potential surgical cure,

total elimination of primary intraparenchymatous tumors by surgery alone
is extremely rare. In dealing with these tumors of the brain, the aims of
surgical therapy include (1) establishing a histologic diagnosis, (2) reducing

intracranial pressure by removing as much tumor as possible without de-
vastating the patient neurologically, and (3) gaining time, so that the patient
may benefit from x-ray therapy and chemotherapy, thereby extending life
expectancy.
The planning of surgical therapy depends on the individual tumor. The
factors discussed under prognosis are weighed before and, to some extent,
during the course of the operation in order to determine the procedure best
"
suited for a particular case. 72 75 There is a variety of surgical procedures that
can be carried out. These include the following:
1. Needle biopsy with frozen-section identification of tumor tissue. In most

instances only permanent sections should be relied upon to make a firm
diagnosis. This procedure is indicated only for lesions that are not suit-
able for more extensive resection. 76
2. Internal decompression. This procedure aims at reducing the tumor bulk

without attempting to cleave the tumor from the surrounding brain tis T
sue. This limited resection is indicated when it is important to preserve
functioning cerebral tissue in a critical area. Drainage of a tumor cyst
and excision of some or all of a mural nodule may also be regarded as
examples of this approach.
3. Enucleation of the tumor. This approach applies to some gliomas that

give the appearance of being well demarcated from the surrounding
brain. Ependymomas are particularly likely to present in this manner at
the time of operation, but it must be conceded that microscopic exten-
sions of these tumors almost always exist (see section on Biology). Occa-
sionally,even a glioblastoma will appear on the surface as if demarcated,
with of just one or a few distinct cortical gyri. These tumors
infiltration
usually extend deeply from their base beyond the area of grossly abnor-
mal tissue, however, and experience has shown that such seemingly
"total" resections are best regarded as subtotal. In contrast, metastatic
brain tumors lend themselves well to enucleation. Since they displace
brain tissue as well as invade it, they may be regarded as demarcated,
but presumed residual microscopic foci of tumor in the area of resection
dictate additional therapy.
4. Internal decompression or subtotal removal with resection of normal

brain tissue is performed in order to gain space for future tumor expan-
sion, such as when tumor involves the frontal, temporal, or occipital
lobes. If the tumor is pole of a lobe, a formal lobectomy,
confined to the
carried out through healthy tissue, can be considered. When the malig-
nant high-grade tumor is very small, such a procedure provides a very
slim chance of a cure or long-term survival. 77 Microscopic rests and diffi-
culty in recognizing the extent of tumor are common sources of further
tumor growth. Frequently, the tumor is deeply situated, and a pole am-
putation is carried out through a portion of the tumor with the aim of
providing room for the tumor to expand. This results in a temporary re-
prieve during which time it is hoped that chemotherapy and radiation
therapy will become effective.
5. Very rarely, subtotal hemispherectomy has been performed for radical

tumor resection, particularly in younger patients. 29 Even this approach
has not been curative, however, and has largely been abandoned in
favor of more aggressive radiation and chemotherapy.
6. Shunting procedures, with or without simultaneous operations on the

tumor (procedures 1 through 4), aim to reduce intracranial pressure by
diverting the CSF when the tumor has already obstructed, or is likely to
obstruct, CSF pathways. Such considerations apply particularly to infil-
tratingneoplasms involving the third or fourth ventricle, subependymal
gliomas, pineal tumors, and large gliomas of the optic nerves, optic
chiasm, or hypothalamus. Some complications of shunting in the pres-
ence of tumor are discussed in the section on medulloblastomas.
The reader is referred to additional texts for the technical aspects of brain
tumor surgery, which are beyond the scope of this chapter. 75, 78 In general,
surgical therapy alone has been most successful in the treatment of cystic
astrocytomas of the cerebellar hemispheres and hemangioblastomas of the
cerebellum. In combination with radiation therapy, surgery has proved
most, successful in the treatment of ependymomas and pineal tumors. In
almost all other primary intracerebral tumors, surgery in combination with
adjunctive forms of therapy has been palliative only. 78
Surgical treatment of metastatic tumors may be considered when there is
a solitary brain lesion in the absence of systemic metastases, provided the

patient's overall condition sufficiently good to permit a major operation
is
under general anesthesia. 79 Computerized axial tomography is of great help

in evaluating patients for the presence of cerebral metastatic lesions. 80
Resection is not recommended if the lesion is located so centrally that its
removal would be associated with major neurologic deficit. 81 Location of

the tumor exactly in the speech area also is considered a contraindication
by many surgeons. Prolonged immunosuppression and bone marrow deple-
tion must be regarded as negative factors in considering a patient for opera-
tive therapy, which consists of excision of the metastatic nodule. The best
long-term results have been achieved in metastatic lesions arising from the
kidney and breast, whereas the benefits of surgery have generally been
least with metastases arising from the lung or melanoma.
The one-year survival rate following surgery is approximately 20 to 25
per cent. Survival beyond two years was approximately 12 per cent in one
series. 47,62,82 The presence of multiple cerebral metastases is usually re-
garded as a contraindication to surgical therapy, although a more aggressive
approach to such lesions has been suggested when surgery in combination
with yet-untried chemotherapy and radiation therapy gives promise of ex-
tended life expectancy of at least 6 to 12 months. 83 Anticipated improve-
ment in the quality of life, rather than the prospect of a total tumor cure,
should be a major consideration in deciding whether or not surgery should
be performed for cerebral metastases.
Needless to say, surgery performed upon patients with increased intra-
cranial pressure requires special precautions prior to operation, during the
induction and maintenance of anesthesia, and with respect to the surgical
procedure itself. 75,84 In the case of deeply situated tumors, which by angio-
graphic criteria are very vascular and clinically manifest the characteristics
of a malignant glioma, one would probably wish to avoid the risks of sur-
gery and would proceed directly to some other form of therapy. The same
considerations would apply to a deeply situated solitary lesion presumed to
be metastatic. Knowing the exact histology of a tumor in this situation is a
matter of little significance.
Nonoperative therapy of even solitary lesions, as advocated by Posner85
in his recent report, has gained followers. This must, however, be weighed
against the occasional report of tumor cure following surgical extirpation of
a cerebral metastasis 86, 87 and collected series that show a higher early mor-
tality rate among nonoperated patients. 47,62 Posner85 himself noted that, be-
tween 200 days and 2 years, there were more survivors among the operated
group. Randomized studies are needed to answer this question.
Posner and Shapiro 82 recommend surgical extirpation of a solitary metas-
tasis if a patient relapses after an initial course of radiation therapy. They
also recognize that tumors of uncertain diagnoses and those that are unre-
sponsive to steroids and radiation therapy merit consideration for surgical
therapy.
Most current data of the primary malignant
results of surgical therapy of
brain tumors include postoperative radiation therapy. The average one-year
survival rate for malignant gliomas treated with surgery alone is 10.6 per
88
cent, a figure significantly improved to 32.3 per cent by radiation therapy.
Therefore, except when the primary tumor is considered to be radioresis-
tant, patientsshould receive postoperative radiation therapy.
82
They may
also be considered for chemotherapy, although there is little evidence of
beneficial results.
Radiation Therapy
Previous evaluation of the success of radiation therapy for CNS tumors

might be misleading because, until recently, no randomized clinical trials
had compared patients who were systematically and vigorously treated by
this mode of treatment with untreated controls. Also, main series utilized
ortho voltage equipment, which limited the ability to deliver tumoricidal
doses to a sufficient volume. Additionally, anatomic information concerning
the tumor volume critical to treatment planning was sometimes inadequate.
Despite these difficulties, however, radiation has become an established
modality, at times curative and often palliative, in the management of CNS
tumors.
Most malignant tumors of the central nervous system are responsive to
radiation, varying from the more sensitive medulloblastoma and pineal
gland tumors to the less sensitive, well-differentiated astrocytoma. Unfortu-
nately, by the time most tumors are discovered, they have infiltrated deeply
into the brain and are not completely resectable. The infiltrative nature of
the tumors requires that a generous volume be radiated in order to include
the entire tumor. In 1960,Concannon et al. m studied a series of patients
with high-grade malignant gliomas, whose treatment was planned using
small fields (average 8 x 10 cm) and who died prior to or during therapy.
They found that, in the majority of cases, the entire tumor was not included
in the radiated field. They therefore recommended that the entire brain be
included treatment field.
in the
The necessity to include relatively large volumes requires exposing nor-
mal structures to doses close to tolerance levels. The range of tolerance
varies from the brain stem, which is most sensitive (tolerance dose 4500 rad
in five weeks) through the more resistant motor cortex (6000 rad in six
weeks) the most resistant frontal cortex (6000 to 7000 rad in seven
to
weeks). These tolerance doses are volume dependent (less tolerance with
larger volumes) and fractionation dependent (less tolerance with fewer
dose fractions or shorter overall treatment times).
Radiation therapy is used in a number of instances for brain tumor. It
may be combined with surgery following incomplete resection as in glio-
mas. Because the treatment of the various CNS tumors depends on the spe-
cific histologic type, radiation therapy is usually given following a surgical
procedure that had been indicated for establishing the diagnosis, evaluating
the location and extent of disease, and providing decompression. Radiation
is used as the primary therapy following biopsy only, as in medulloblas-
toma, or it may be used when biopsy is not indicated and the diagnosis is
based on clinical evidence of tumor, as in brain stem gliomas.
742 H / Treatment of Specific Neoplasms
High-grade Gliomas. For high-grade gliomas the radiation fields must

encompass the whole brain, and the doses must be substantial —
4500 to
5000 rad (with a boost to the known tumor volume to 5500 to 6000 rad) to
6000 rad. The best results in a randomized trial comparing the available
treatment modalities have been reported by the Brain Tumor Study Group
(BTSG) 90 when combining maximum feasible surgical resection with a ni-
trosourea and postoperative radiation to 6000 rad in 6 to 7 weeks (median
survival 51 weeks).
Grade 1 and Grade 2 Astrocytomas. For these tumors, radiation
therapy increases the five-year survival rate when there has been incom-
plete surgical resection, as reported by Leibel et al. 50 (grade 1 —25 per
cent without radiation, 58 per cent with radiation; grade 2 — per cent
without radiation, 25 per cent with radiation). They reported no increase in
survival with the addition of radiation therapy in those patients whose
tumors were completely resected. However, as already noted, the infiltra-
tive nature of these tumors makes complete excision, except perhaps in
polar lesions, extremely difficult. It appears that doses in the range of 4500
to 5500 rad are required to obtain this increase in survival.
Oligodendrogliomas. These are infrequent tumors that usually have
a protracted clinical course. There is no indication that postoperative radia-
tion following complete resection increases the rate of survival. However,
there is evidence that following incomplete excision, which is often the
case, postoperative radiation (5000 rad in 45 to 50 days) improves the five-
year survival rate. 91
Ependymomas. These tumors arise from the ependymal cells and sub-
ependymal glial plate that line the ventricles, central canal of the spinal
cord, and ventriculus terminalis of the conus medullaris. Ependymal
tumors may extend into the cerebral hemisphere and may also occur in the
filum terminale.
The location of these tumors often precludes complete surgical removal.
However, they are quite responsive to radiation and should receive 4500
rad in five to six weeks to generous fields following incomplete resection. 92
As noted previously, ependymomas tend to "seed" within the spinal sub-
arachnoid space. Consideration has been given in the past to radiation of the
craniospinal axis, especially for anaplastic ependymomas, as well as for pa-
tients with positive CSF cytologic findings and for those with posterior
fossa tumors. However, the increased morbidity of this aggressive treatment
and the relative infrequency of metastases to the spinal canal (10 to 30 per
cent) mitigate against routine treatment of the entire CNS axis.
MEDULLOBLASTOMAS. Medulloblastomas have the greatest tendency of
any CNS tumor to form intracranial or intraspinal metastases and therefore
require vigorous systematic treatment of the entire neuroaxis with radiation
following subtotal removal and decompression. Many clinicians continue to
regard the prognosis of patients with medulloblastomas as nearly hopeless,
despite evidence that it is a radioresponsive and even radiocurable disease.
Several recent series report ten-year survival rates of 25 to 40 per cent,
with doses in the range of 5000 to 5500 rad to the posterior fossa and 3500
to 4000 rad to the whole brain and spinal axis. 93 94 Great care must be taken
'
in matching these fields to ensure inclusion of all the subarachnoid space

without overlapping the fields and risking necrosis.
Intrathecal radioactive gold has been used to treat tumor implants in the
subarachnoid space, with encouraging results in a small number of pa-
tients. 95 Newer techniques to promote better distribution of the isotope ap-
pear to avoid "hot spots," which have caused injury to the Cauda equina in
earlier cases. However, because of the problem of distribution of the iso-
tope and the complexity of the method compared with external beam radia-
tion, this technique has not become widely accepted in the primary man-
agement of medulloblastoma.
Brain Stem and Midbrain Tumors. These tumors are difficult to eval-
uate. They can rarely be biopsied. At autopsy the majority are gliomas, and
tumors were never histologically confirmed in those who survived therapy.
However, radiation therapy is indicated on the basis of a clinical diagnosis
of these tumors, using doses of approximately 5000 to 6000 rad in seven to
6-98
eight weeks. Survival at fixe years has ranged from 16 to 40 per cent.
5'
PINEAL Gland TUMORS. Pinealomas are radioresponsive tumors that

often present with signs and symptoms of obstruction of the aqueduct of
Sylvius. Following shunting, which can produce dramatic improvement in
the presence of obstruction, radiation therapy to the entire ventricular sys-
tem, using doses in the range of 4500 to 5500 rad in five to six weeks, is
recommended. 99, ltM) Seeding to the spinal subarachnoid space may occur,
but, as in the case of ependymomas, is not frequent enough to warrant
routine prophylactic treatment of the spinal canal.
Metastases. Metastases to the brain occur in 12 to 14 per cent of pa-
tients with cancer. Primary tumors that metastasize to the brain most fre-
quently are melanoma, and lung, breast, kidney, and thyroid cancer. The
metastases are multiple approximately two thirds of the time, with the excep-
tion of melanoma, which is almost always multiple, and hypernephroma,
which more commonly presents as a solitary lesion.
The expectancy of patients with untreated brain metastases is four to
life
six weeks. The goal in management therefore should be to provide ade-
quate palliation in the shortest time possible. Recently, Hendrickson 101 re-
ported the data from the Radiation Therapy Oncology Group on the treat-
ment of brain metastases and stated that the treatment schedules, consisting
of 2000 rad in one week, 3000 rad in two weeks, 4000 rad in three weeks,
and 4000 rad in four weeks to the whole brain, relieved symptoms in about
two thirds of the patients. He noted more prompt and prolonged relief in
those patients who received the higher doses in shorter schedules. The
addition of steroids seemed to shorten the response time to radiation but
did not increase the overall response rate or its duration. The median sur-
vival in the RTOG study for patients with minimal or absent neurologic
findings was six months. Those who required hospitalization or nursing
care at home had shorter median survivals (one to four months). The one-
year survival rate was 15 per cent.
Our treatment policy is to give 3000 rad in 2 weeks to patients with
widespread disseminated disease and 4000 to 4500 rad in 4.5 weeks, with a
1000-rad boost to any dominant lesions, in those patients with minimal
symptoms and no systemic disease or disease that is being controlled with

chemotherapy.
Radiation therapy has been applied to various neoplasms of and around the
nervous system including chordomas when incompletely resected, 102, 103 optic
nerve gliomas,"" and meningiomas when progressive and unresectable, "' 1
often with beneficial effects. The interested reader is referred to more detailed
59, 98, 101
information.
Chemotherapy
As noted in the Prognosis section, difficulties are encountered in arriving at a

precise evaluation of response to any type of therapy in the management of
brain tumors. These difficulties are accentuated in the case of chemothera-
106
py.
The criteria of drug selection that apply to other tumor systems require some
modification with respect to the nervous system. fundamental to select a
It is
drug that has a high differential between tumoricidal activity and nonspecific
cytotoxicity for the same organ, as well as one that has an acceptable level of
systemic toxicity. However, certain peculiarities of brain tumors make the
following drug properties very important: 107 (1) the ability to pass the blood-
brain barrier, (2) high lipid solubility, low ionization, and small molecular size,
(3) minimal capability for inducing either peritumoral or diffuse cerebral
edema, and (4) the ability to stimulate transformation of tumor cells from the
nonproliferative phase into the active phases of the cell cycle.
The earlier experience with brain tumor chemotherapy, using methionine
sulfoxide, mechlorethamine, triethylenethiophosphoramide, methotrexate,
and vinca alkaloids, 108 has given way to the following four modern develop-
ments: (1) the introduction of nitrosourea derivatives into brain tumor chemo-
therapy in 1970 by Walker and Hurwitz 109 and Wilson et a/. 110 —
these com-
pounds satisfy at least three and possibly all four of the necessary criteria; (2)
the use of multiple agents in combinations of chemotherapy and radiation
therapy for brain tumor management; (3) the application of (controlled) large-
scale prospective studies to the evaluation of adjunctive brain tumor therapy;
and (4) the development of a group of drugs that has no direct tumoricidal
activity but enhances the effect of radiation therapy. The general problems of
toxicity of systemic chemotherapy are discussed in Chapter 4.
The first reports of clinical trials with carmustine showed that intermittent
intensive therapy of gliomas, including ependymomas, gave encouraging
results in phase 2 studies, with a patient response rate of nearly 50 per
cent. 109, u0 A dose of 80 mg/m 2 given daily for three successive days, was
,
recognized as optimal, with bone marrow toxicity at acceptable levels. Treat-

ment was repeated every six to eight weeks, depending on marrow recovery.
The theoretic potential of combining carmustine, a cell cycle-nonspecific
agent, with vincristine, a cell cycle-specific agent, led to a clinical trial of these
two drugs, but the results were not as good as with carmustine alone. 111
Lomustine was introduced into brain tumor therapy shortly after carmus-
tine, 112, u3 and phase 2 studies showed a comparable, but perhaps slightly
lower, response rate of glioblastoma patients to this agent. With both carmus-
B Neoplasms of the Nervous System 745
tine and lomustine, an interval of two to four weeks was required before a
clinical response was evident Marrow toxicity was comparable to that of
canmistine and was the dose-limiting factor. Semustine also showed similar
114
levels of antitumor activity and toxicity.
Further phase 3 clinical trials of the nitrosourea drugs have been carried out
and are in progress under the direction of the Brain Tumor Study Group
sponsored by the National Cancer Institute. These carefully controlled and
randomized prospective studies confirmed a therapeutic benefit for carmus-
115 n*
tine, further enhanced by radiation therapy. -
The median survival of
untreated control patients was 17 weeks, compared with 25 weeks for those
treated with canmistine, 38 weeks for patients treated with radiation therapy
only, and 41 weeks for patients treated with both canmistine and radiation
therapy. The most recent figures from this study show a further increase in
median survival time to 51 weeks for glioblastoma patients treated with
radiation and chemotherapy. Patients in the study received 6000 rad through
bilateral opposing ports over six to eight weeks.*' Comparison studies between
semustine and canmistine are still in progress. A British study 117 reports an
overall favorable response rate of 40 per cent with the nitrosoun
The randomized studies of lareer numbers of patients carried out by the
BTSG probably will serve to provide the most accurate data in v iew of the large
number of variables inherent in the patient population, but it should be
recognized that several other studies have been undertaken suggesting that
the nitrosourea compounds may have no significant effect on either the dura-
tion or the quality of patient survival beyond that attributable to radiation
therapy. 11H1 -° The BTSG approach did demonstrate its value in the past by
pointing out that mithramycin conferred no advantage in terms of patient
survival when administered to patients with brain tumors. 121
Several other agents have also been used in recent years for brain tumor
chemotherapy. Of these, procarbazine is the most promising for the treatment
of glioblastomas on the basis of phase 2 studies. 111 Administered atadose of 150
mg/m- for 30 days with a 30-day rest period between courses of therapy, 14 of 27
patients composing a mixed group including those with glioblastomas, malig-
nant astrocytomas and other gliomas, a^ well as medulloblastomas and one with
metastatic tumor, responded favorably with an overall response rate of 52 per
cent. Bone marrow depression was at acceptable levels. - Hydroxyurea, in
1 5
combination with radiation therapy, also showed promising results in a small

randomized study, with improvement in survival time of patients with malig-
nant glial tumors from 9 to 14 months. 124 Favorable reports using other
agents, 125, 12fi notably epipodophyllotoxin, 127 have also appeared. It is hoped
thatrandomized studies will clarify their usefulness.
Different combinations of chemotherapeutic agents have been tested for the
treatment of malignant glioma ready noted, 111 the combination of car-
mustine with vincristine has not confened an adv antage in one study, but other
12H
investigators feel it is beneficial. Only additional experience with larger
numbers of patients will resolve this question. Another combination regimen
that has produced favorable responses is procarbazine, lomustine, and vincris-
tine. 123
At the present time, evidence suggests the optimal treatment to be a combi-
nation of surgery, early postoperative radiation therapy (see earlier discussion),

and cammstine or semnstine in the management of glioblastomas, malignant
astrocytomas, and ependymomas. Mednllohlastomas will be discussed sepa-
rately. It is hoped and prospective studies
that further large-scale controlled
will clarify the usefulness of these agents, as well as the more complex
combination chemotherapy programs. In addition to the BTSG, other chemo-
therapy protocols are in progress 129 and should be examined for significant data
in the future. Although such multi-institutional studies introduce their own
problems, in the absence of a single dramatic curative agent, the large number
of variables to be considered in a brain tumor population can only be resolved
by large-scale investigations.
Histologic abnormalities have been described at autopsy in areas of
brain not containing tumor among some patients who underwent combined
radiation and chemotherapy. 130 These changes were more likely to be present
in patients with a longer survival time. Radiation therapy alone and carmustine
alone apparently were also able to provoke these changes.
At present, there is no clear evidence that chemotherapy benefits patients
with low-grade (grade 1 and grade 2) gliomas, well-differentiated oligoden-
drogliomas, or any of the histologically benign tumors. No reports have ap-
peared dealing with cerebral sarcomas and the rare malignant meningiomas.
The subject of brain tumor chemotherapy is covered in detail in an excellent
'
monograph. 1 51
MEDULLOBLASTOMAS. This highly malignant posterior fossa tumor of chil-

dren represents several unusual features and merits separate consideration.
Medulloblastomas are not totally resectable by surgical means, and patients
often present with life-threatening increased intracranial pressure due to
obstruction of the fourth ventricle. For this reason, preoperative shunting of
cerebrospinal fluid has recently been practiced. The same tendency to dispers-
al of tumor cells that results in subarachnoid implants of medulloblastoma has
also produced a significant incidence of peritoneal metastases. In one recent

series, 132 4 of 44 patients developed peritoneal spread with no evidence of local
tumor recurrence. These patients had received total neuraxis radiation therapy,
but this did not prevent escape and implantation of viable tumor cells. The
advisability of shunting these patients is therefore under serious question at
this time. This mode of spread makes the adjunctive use of chemotherapy in
addition to radiation therapy of greater value.
Several chemotherapeutic agents have been employed in treating medullo-
blastoma, with varying evidences of remission. 117, 133 Vincristine, the nitro-
soureas, procarbazine, epipodophyllotoxin, and methotrexate have all been
reported beneficial in selected patients. 126 133 The combination of vincristine
'
and lomustine is currently being evaluated in a randomized prospective study

by the Children's Cancer Study Group of the National Cancer Institute
(CCSG). Early encouraging results using this combination together with a
single course of intrathecal methotrexate have been reported, and this combi-
nation is undergoing further evaluation by the International Society of Pediat-
ricOncology. 117
Total neuraxis radiation therapy should be carried out soon after surgery,
irrespective of the choice of chemotherapeutic agent or agents. Radiation
therapy is discussed in a preceding section of this chapter.
Metastatic Tumors. Chemotherapy of metastatic tumors to the brain is

generally considered under the topic of systemic chemotherapy administered
for the control of regional and disseminated neoplasia, as discussed elsewhere
in this volume. The results to date have not been impressive. 82
It must be emphasized, however, that the optimal properties for chemothera-
peutic agents employed in primary brain tumor chemotherapy, i.e., lipid

solubility, penetration of the blood-brain barrier, and so forth, apply equally to
tumors originating elsewhere in the body. The conclusion of a recent survey,
therefore, that the mortality from melanoma today is primarily due to intracran-
'
ial metastases is not surprising.

14
Cure of a metastatic choriocarcinoma to the
1
brain has been reported by a combination of surgery, radiation therapy, and

multiple agent chemotherapy. 86 Chemotherapy with radiation therapy should
be considered in certain nonsurgical problems requiring tumor palliation, for
example multiple intracranial metastases and metastatic lymphomas and leu-
kemias (see Chapters 21 and 22).
Immunotherapy
Immunotherapy of brain tumors has been attempted by several investigators

but has been unsuccessful to date. The most recent and innovative approach of
injecting the tumor with autologous lymphocytes is still in the experimental
stage. 135
Section 2
Spinal Cord
INTRODUCTION
Spinal cord tumors, both primary and metastatic, are less common than
cerebral tumors in a ratio of 1:7 to 1:10, depending on the nature of the
hospital population studied. 136
Nothing is known about the etiology of these tumors, and the same con-
siderations that were cited with respect tumors apply. An associa-
to brain
tion of primary spinal tumors, often multiple, with central von Recklinghau-
sen's disease is recognized.
The epidemiology of spinal cord tumors has not been studied separately
from that of central nervous system tumors. 10 Considerations applicable to

metastatic tumors are those that relate to individual tumor type
The original primary site of metastatic tumors has been analyzed in various
series. 137 Findings depend to a considerable extent on the nature of the hospi-
tal population studied and the particular areas of interest within the field of
oncology that are emphasized.
Biology
Extramedullary intradural tumors are most commonly either the benign

neurilemomas (schwannomas) or meningiomas. Primary intraspinal tumors,
corresponding to the tumor categories in Table 18-5, are more frequently of
a less malignant nature than corresponding tumors of the brain. Thus,
ependymomas, both those occurring in the cord and those that arise in the
filum terminale, are generally well differentiated. These tumors expand the
cord in growing and, like extramedullary tumors, ultimately block the cir-
culation of cerebrospinal fluid, compartmentalizing the fluid below the
level of the tumor. Owing to selective resorption of water, there is a pro-
gressive increase in protein concentration of fluid below the level of the
tumor, reaching very high levels if there is a complete subarachnoid block.
Spinal cord tumors produce their neurologic symptoms by compression of
myelinated tracts and anterior horn cells and possibly by vascular mechan-
isms. 138 Occlusion and thrombosis of extradural veins may occur.
NATURAL HISTORY
Classification
Spinal tumors are commonly classified both by location and by histologic

nature (Tables 18-5 to 18-7). Extramedullary tumors displace rather than
invade neural tissue. However, extradural metastatic tumors usually spare
the dura mater, which appears to act as a barrier to tumor extension.
Histologically, spinal cord tumors represent several of the tumor catego-
ries listed in the classification of CNS tumors (Table 18-4). Most common
among these are neurilemomas (schwannomas), meningiomas, and gliomas,
but many other varieties of tumors are also encountered in small numbers.
TABLE 18-5. Frequency of Primary Intraspinal Tumors in a

Series of 1322 Cases at Mayo Clinic 136
Schwannomas 29.0%
Meningiomas 25.5%
Gliomas, including extramedullary 22.0%
Sarcomas 11.9%
Vascular tumors 6.2%
Chordomas 4.0%
Epidermoid and other tumors 1.4%
Neoplasms of the Nervous System 749
TABLE 18-6. Frequency of Primary Intraspinal

Intramedullary Gliomas 136
Ependymomas 63.0 r r
Astrocytomas 24. Y?
iles 1 and 2)
r
Glioblastomas 7.5 r
(astrocytomas grades 3 and 4)

Oligodendrogliomas 3.0%
Other tumors 2.0%
Metastatic tumors of the spine also may be classified with respect to their
anatomic location (Tables 18-8 and 18-9). Strict separation of these catego-
ries is not always possible, however. It is not uncommon for tumors involv-
ing the vertebral bodies to extend into the epidural space, at which point
they may form a carpet constricting the spinal cord. Another form of meta-
static tumor to be considered is that developing from the seeding of primary
brain tumors. The most common examples of such tumors are seen in rela-
tion to medulloblastomas, retinoblastomas, pineal gland tumors, and epen-
dymomas. The multifocal nature of these secondary deposits creates special
problems with respect to their therapy.
The clinical manifestations of spinal cord tumors include local spinal

pain, which usually precedes progressive neurologic deficit. Pain may be
relatively diffuse over the involved area of the spine, but it often has a
radicular component as well when one or more nerve roots are compressed,
stretched, or infiltrated by the tumor. Radicular pain is encountered in the
extremities or may be perceived as a band-like pain in dermatomal distribu-
tion over the trunk. Neurologic manifestations include motor and sensory
deficit as well as loss of sphincter control. Sphincter problems are more
commonly encountered as an early sign when the tumor is intramedullary.
Acute urinary retention in a patient known to have cancer should always
arouse the suspicion of spinal cord or Cauda equina compression.
The diagnosis of spinal cord tumors is made both by clinical examination
and by radiologic techniques. The clinical examination should place special
TABLE 18-7. Classification of Spinal Tumors 138
By Levels By Location
Cord Extramedullar 71 r r
Cervical Extradural
Thoracic Intradural
Lumbar
Intramedullary 29 r?
Cauda Equina
Lumbar sacral
TABLE 18-8. Metastatic Spinal Tumors with

Potential Neurologic Complications
Metastases to vertebrae
Osteoblastic
Osteolytic with or without vertebral
collapse
Epidural metastases
By extension from vertebrae
By extension from paravertebral tumor
Hematogenous
Subarachnoid ("meningeal") dissemination
Intramedullary nodular foci
emphasis on motor and reflex evaluation of the extremities, on the presence

of a sensory level, and on intactness of sacral cutaneous reflexes and
sphincter tone.
Motor weakness may develop asymmetrically, although the severe cord
compression deficit tends to become symmetric. Unsteadiness is occasion-
ally seen before weakness. Deep tendon reflexes are usually hyperactive,
plantar responses become extensor responses, and superficial abdominal re-
flexes disappear. Patients with diffuse meningeal involvement of the Cauda
equina or of individual nerve roots often show loss of deep tendon reflexes
in association with pain and weakness. Sensory deficit tends to ascend,
reaching a "level" as cord involvement becomes more complete.
Slowly growing spinal tumors may produce erosive changes of the verte-
bral spine, which often are apparent on plain roentgenograms or on tomo-
graphic views of the spine as a scalloping distortion of the vertebral body
outline, thinning of a pedicle, or enlargement of a nerve root foramen.
More rapidly growing metastatic lesions of the spine may show partial or
complete collapse of vertebral bodies, sometimes with angulation of the
spine. Osteolytic and osteoblastic changes are seen in less advanced situa-
tions. Tomography is also helpful in demonstrating more clearly paraverte-
bral soft-tissue masses, which may accompany a variety of spinal tumors,
including schwannomas, neuroblastomas, and chordomas, as well as meta-
static lesions.
TABLE 18-9. Primary Sites of Metastatic Spinal Tumors 1
Origin No. of Cases Per Cent
Carcinomas
Breast 15 19.2
Lung 14 17.9
Prostate 7 9.0
Colon and rectum 6 7.7
Kidney 5 6.4
Unknown 11 14.1
Sarcoma 6 7.7
Melanoma 4 5.2
Others 10 12.8
Total 78 100.0
Isotope scanning is a very helpful diagnostic tool for early identification

of vertebral metastases, often capable of identifying the lesions long before
roentgenography. 139, 14 °
Contrast myelography is most useful in confirming the diagnosis and
demonstrating the precise level of spinal involvement. 141 Positive contrast
media include iophendylate and metrizamide (Amipaque). The latter, re-
cently released for general use in the United States, is water soluble and has
the advantage of not requiring removal at the conclusion of the radiologic ex-
amination. This is a consideration of particular importance when a total
myelographic block is demonstrated, and precipitous changes in the CSF
pressure would hazard impaction of the tumor against the spinal cord. In
certain special instances, including in patients with a known iodine sensi-
tivity, air oroxygen may be used as the contrast medium in combination
with tomographic examination technique to demonstrate spinal tumors.
Myelography distinguishes cord tumors from non-neoplastic conditions,
such as transverse myelopathy and radiation myelitis. The latter in particu-
lar may merit consideration in cancer patients whose neurologic deficit
would correlate with an irradiated segment of cord. Posner 142 also cites the
rare occurrence of spinal epidural hematomas in patients with depressed
platelet counts. Such lesions could closely mimic metastatic tumor, both
clinically and on myelography. Body scanning is also being found useful in
the diagnosis of spinal tumors.
Cerebrospinal fluid protein is often elevated in the presence of an in-
traspinal tumor. When a complete subarachnoid block exists, the protein
level may reach several gm/dL.
Staging
The Manual for Staging of Cancer58 does not provide a staging guide for
spinal tumors.
Prognosis
The prognosis of must be considered from two points of

spinal tumors
view, i.e., with respect to restoration or preservation of neural function and
with regard to local tumor control and survival.
The time course over which cord compression develops is most impor-
tant with respect to the prognosis for recovery or stabilization of neurologic
function. Impaired spinal cord function duecompressive lesion shows
to a
a surprising potential for recovery after surgery if the tumor was growing
slowly. Examples of this are encountered with meningiomas, neurilemomas
(schwannomas), and some intraparenchymatous tumors. By contrast, recov-
ery of neurologic function following decompressive surgery of a metastatic
spinal tumor is often very disappointing; the loss of neurologic function
due to such lesions often develops precipitously over the course of a few
days or even hours. The prognosis for recovery is inversely proportional to
the severity of the deficit at the time of therapy and the duration of neuro-
logic symptoms. 138 143 '
Total tumor removal is generally possible in most spinal neurilemomas

and meningiomas. Recurrences may, however, develop from residual tumor
foci if total removal was not or could not be accomplished. Primary intra-
parenchymatous tumors may or may not lend themselves to total removal
by surgery. Total removal is often possible for intraspinal ependymomas,
but is rarely accomplished in the instance of astrocytomas. 138, 143 Ependymo-
mas may recur, although usually after a long period of time, if initial remov-
al was not total. Primary malignant gliomas of the spinal cord have a poor
prognosis for survival; most patients live less than two years after combined
surgery and radiation therapy. 144
Metastatic spinal tumors are practically never totally resectable. There is.
of course, also a great likelihood that other metastatic foci are present else-
where in the body, so that palliation rather than cure becomes the primary
aim of therapy.
Death from spinal cord tumors usually occurs by one of two mechanisms.
High cervical cord tumors (at or above the C-4 level) may produce respira-
tory embarrassment, whereas tumors situated more distally not infrequently
lead to chronic urinary tract disease.
TREATMENT
Surgery
The initial treatment of primary spinal tumors is always surgical. Ad-

vances in surgical technique, in particular the use of bipolar coagulation
and microsurgery, have made the removal of primary tumors safer for the
patient and have permitted more complete resection of these lesions. Astro-
cytomas and ependymomas often have a considerable longitudinal extent
within the spinal cord, requiring meticulous intraspinal surgery. 138 Astrocy-
tomas are more difficult to remove because they are less clearly demarcated
from surrounding cord tissue than are ependymomas. Malignant glial
tumors of the cord are rare, and their diffuse intraspinal growth prevents
any extensive removal. 136, 144 Ependymomas are highly radiosensitive, but
the advisability of routine postoperative radiation is controversial at this
time. 98, 138, 145 It is clearly justified, however, in partially resectable infiltrat-
ing ependymomas of the cauda equina.
Initial treatment of metastatic tumors of the spinal cord is also often sur-
gical, although the specific circumstances must be carefully considered be-
fore any treatment is planned. A distinction must be made between meta-
static foci associated with neurologic impairment and those that are either
totally asymptomatic, having been diagnosed only by routine scanning or
other radiologic techniques, or are manifested merely by pain. 137 When
there is no neurologic involvement or when spinal and root pain is the
major symptom, radiation or chemotherapy, or both, may be preferred forms
of therapy. Pain due to metastatic spinal involvement may respond to brac-
ing, particularly when further adjunctive therapy can then be implemented.
It is questionable whether or not myelography is routinely indicated in all
these patients. When pain is present and not associated with bony involve-
ment, myelography may be helpful in early diagnosis of tumor encroach-
ment on the dural sac. This situation occurs more commonly in lymphomas
than in other tumors. When neurologic impairment is present, myelography
should be carried out immediately.
The physician must distinguish whether cord involvement is the result of
vertebral collapse, with bone protruding into the spinal canal, a vascular
occlusive phenomenon produced by tumor, or due to epidural tumor,
which is the most common form of spinal involvement. Vertebral collapse
produces mechanical bony compression of the cord that cannot be expected
to improve with treatment other than mechanical decompression. However,
the hazards of further distortion of the spine following removal of ligamen-
tous support and posterior laminectomy must be carefully considered. Oc-
casionally, such patients become candidates for a spinal stabilization proce-
"
dure, using methyl methacrylate or other techniques. 146 149
Spinal epidural metastases are the most common form of spinal metastat-
ic disease. The treatment plan must take into consideration the extent of
neurologic impairment and the nature of the primary neoplasm. Patients
who have little neurologic impairment have a better immediate prognosis.
Those who are already paraplegic have a very poor prognosis for significant
recovery irrespective of the treatment employed. The longer the neurologic
deficit has been present, the worse the prognosis for recovery. However,
Barron et a/. 150 pointed out that surgical results were better, even in para-
plegic patients, if the condition was gradual in onset and further noted that
patients with spastic paraplegia did better than those with flaccid paraple-
gia. Therefore, early recognition of metastatic involvement of the spine be-
comes of paramount importance as does establishment of the presence of
cord compression. Active therapy should be initiated as soon as there is
evidence of any neurologic impairment. The progression of neurologic defi-
cit is often very rapid, and hours may make a significant difference in the
outcome of therapy.
Most neurosurgeons prefer the certainty of immediate surgical spinal
cord decompression once the diagnosis of epidural tumor or cord compres-
sion is made. This is particularly true when spinal cord dysfunction is par-
tial, i.e., when there is much to be gained by preventing further progres-
sion. Decompressive laminectomy for metastatic disease in the face of total

paraplegia, particularly ifpresent for many hours, is probably futile. Surgi-
cal decompression of metastatic disease should be followed by radiation
therapy. Posner, 151 in a small nonrandomized series of patients, showed that
the results of surgical therapy followed by radiation therapy and radiation
therapy alone were comparable. Although he did take into account the ra-
diosensitivity of the tumor, it is difficult to tell whether or not sufficient
consideration was given to the rate of progression of neurologic symptoms
prior to therapy in his comparison study. The completeness of the myelo-
graphic block also may be an important variable. As mentioned previously,
neurologic deficit may progress very rapidly, and existing deficit frequently
is not reversible. The suggestion by Posner 151 that surgical decompression
is indicated if the patient deteriorates over a 48- to 72-hour period of radia-

754 II / Treatment oi Specific Neoplasms
tion therapy is Any evidence of

therefore fraught with considerable danger.
deterioration while the patient undergoing radiation therapy should be
is
considered an indication for immediate decompressive surgery. This im-

plies that patients who are treated nonoperatively must be followed ex-
tremely closely by a competent examiner. 152
The benefits of surgery for metastatic disease not only are due to tumor
removal but are also the result of the bony decompression afforded by la-
minectomy. Patients with solitary spinal metastases of slowly growing
tumors may occasionally be candidates for radical tumor excision involving
resection of portions of the spinal column and subsequent stabilization. 149
Pain relief may be very gratifying following decompression of a spinal me-
tastasis. 150
Radiation Therapy
The infrequent occurrence of primary intraspinal tumors and the variety

make a precise definition of the indications for
of factors affecting prognosis
the use of radiation therapy difficult. However, several studies indicate that
postoperative radiation therapy is probably beneficial. 98 136, 153 Bouchard 98
'
combination of surgery and adequate postoperative radiation

states that the
(5000 rad in 6.5 to 8 weeks) appears to prolong survival and restore normal
function of the cord in 50 to 60 per cent of these patients.
Postoperative radiation may be indicated in ependymomas that have
been completely resected. However, for partially resected infiltrating epen-
dymomas and malignant glial tumors, vigorous radiation in the dose men-
tioned to an adequate field outlined at surgery would provide the best
chance for local control at minimal risk of radiation myelopathy.
Most of the early literature on the management of epidural metastases
reports combined treatment with laminectomy and radiation to be optimal.
Caution was expressed concerning the use of radiation therapy alone, be-
cause of the possibility of early deterioration, thought to be due to "radia-
tion edema." However, Rubin et a/. 154 feeling that the deterioration in
these patients may be due to lack of tumor response instead, treated a small
series of 12 patients by means of radiation therapy with large initial frac-
tions, followed by more standard fraction sizes (400 rad times three, then
150 to 200 rad per fraction to a total dose of 2500 to 4000 rad). Nine of the
patients improved without laminectomy. The three who did not respond
had been paraplegic prior to therapy. They concluded that for very radio-
sensitive tumors, such as lymphomas and neuroblastomas, high initial daily
close therapy should be uniformly effective. For moderately sensitive
tumors, such as breast and lung cancer, the same schedule was recom-
mended if the neurologic deficit was stable, with laminectomy reserved for
patients showing progression of symptoms. Radioresistant metastatic spinal
neoplasms, such as those arising from the prostate and teratocarcinoma,
would not be expected to respond quickly and, therefore, surgical decom-
pression is recommended.
Cobb et a/. 152 reported a series of 44 patients with myelopathy secondary
to metastatic epidural breast cancer, 26 initially treated with laminectomy
and 18 with radiation. They concluded that patients with

initially treated
radiosensitive neoplasms, such as breast carcinoma, may reasonably be
treated with radiation without laminectomy if they do not show a rapidly
progressive myelopathy. They also emphasized that patients so treated
must be followed very closely, with operative intervention at the earliest
sign of progression of symptoms.
Local recurrence or persistence of disease remains the most common
cause of failure in the treatment of CNS tumors with radiation. The use of
metronidazol as a radiosensitizer 153 to increase the radiation effect on hy-
poxic tumor cells has been reported in the treatment of glioblastoma with
encouraging, but preliminary, results. 158 The BTSG is currently studying
the use of misonidazole (Ro 7-0582), a related electron-affinic compound.
Therapy using neutrons has recently been reported for the treatment of
malignant gliomas. 157, 138 These particles are more densely ionizing than
photons and therefore less dependent on oxygen for their effect. Of 36 pa-
tients with glioblastoma treated with neutrons alone and neutrons plus pho-
tons by Laramore et a/., 158 15 were autopsied and showed no viable tumor
at death. In all but 1 of the 15 cases, the bulk of the tumor had been re-
placed by a localized mass of coagulative necrosis. Unfortunately, the sur-
vival of this group of patients was not statistically different from published
data using photons alone.
Chemotherapy
The experience with chemotherapeutic management of spinal cord

tumors has been extremely limited. Extrapolating from the treatment of
brain tumors, one may presume that ependymomas would respond to the
nitrosoureas and that spinal glioblastomas may be somewhat responsive.
Chemotherapy would be considered for patients with multiple intraspinal
subarachnoid seedling lesions, as well as for patients with metastatic spinal
tumors.
Immunotherapy
There has been no reported experience with immunotherapy of primary

spinal cord tumors. Immunotherapy of metastatic tumors is discussed in the
various chapters dealing with individual primary tumors.

A
breakthrough in the treatment of malignant brain tumors does not ap-
pear imminent. Progress, however, can be anticipated in several areas. The
major advances in diagnosis that came about as a result of computerized
axial tomography can be expected to be extended as the power of resolu-
tion of the scans is improved. Advances in surgical technique, per se, can-
not be expected to alter the outlook for patients with malignant gliomas,
but adjunctive techniques currently under investigation, such as immuno-

therapy, the use of radiosensitizing chemicals, or hyperthermia, may prove
useful. The agents used
present for chemotherapy represent a tremen-
at
dous advance over the drugs that were available ten years ago, but they
have provided no decisive cure. Much effort is being expended to develop
newer drugs and carrier agents that will reach CNS tumors more specifically.
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CHAPTER 19
CHILDHOOD
SOLID TUMORS
Eric W Fonkalsrud Stephen A Feig
Section 1
Neuroblastoma
INTRODUCTION
Except leukemia and brain tumors, neuroblastoma is the most
for acute
common malignancy in children, and in the first four years of life it is the
leading cause of cancer mortality. Every year more than 300 children die
from it, and the incidence of clinical neuroblastoma has been established
1
at approximately 1 in 10,000 births.

Neuroblastoma is primarily a disease of infancy and early childhood; ap-
proximately one third of all patients are younger than one year of age at the
time of diagnosis. More than 80 per cent of cases are recognized by the age
of five years. 2 The prognosis is better for patients younger than one year or
older than six years of age at the time of initial diagnosis. There is no
demonstrated association of neuroblastoma with developmental defects.
Although an understanding of the pathophysiology and immunology of
this embryonal neoplasm has increased substantially during the past sever-
al years, it has been disappointing that following the use of new therapeu-
tic drugs and new multidisciplinary approaches, the overall survival rate of
patients has not improved.
760 II / Treatment of Specifm Neoplasms
Despite the factneuroblastoma is one of the most malignant of

that
human cancers, itshows the highest rate of spontaneous regression.
also
This phenomenon, which is not related to the extent of dissemination, is
observed almost exclusively in patients who are less than one year of age.
NATURAL HISTORY
Clinical Features
Neuroblastoma may originate in any area of the body in which there are
elements of sympathetic nervous tissue arising from neural crest ectoderm.
The recognition of the wide distribution of primitive sympathetic neuro-
blasts in the embryo helps to explain the widely variable clinical behavior
of this tumor. Approximately two thirds arise in the abdomen, primarily in
the adrenal medulla; the remainder develop in the mediastinum or sympa-
thetic ganglia (Table 19-1). 3
The most common presenting feature is the presence of a recently recog-
nized asymptomatic abdominal mass. The mass is usually the primary adre-
nal tumor; however, in children up to the age of one year, it may be an
enlarged liver filled with metastatic tumor. The common initial manifesta-
tions of neuroblastoma in children beyond infancy include (1) the presence
of a mass representing the primary or metastatic distribution, usually in
lymph nodes; (2) neurologic signs, such as weakness in an extremity, limp-
ness, or paralysis; (3) pain, usually in the bone or joints; and (4) orbital
signs, such as ecchymosis and proptosis (Fig. 19-1). Less frequent and less
specific symptoms that may be apparent include weight loss, nonspecific
anemia without leukopenia, fever, lymphadenopathy, diarrhea, and hyper-
tension. Opsoclonic hyperkinetic multidirectional eye movements and lo-
calized or systemic jerking motions have been reported in occasional pa-
tients with neuroblastoma. Except for the orbital signs associated with an
abdominal mass, no particular constellation of findings occurs with suffi-
cient frequency to constitute a pathognomonic syndrome.
Neonatal neuroblastoma is often accompanied by extensive metastases to
the liver, the bone marrow, or the subcutaneous tissue with the characteris-
tic blue nodules that blanch on pressure. The primary tumor in this age
TABLE 19-1. Site of Primary Neuroblastoma 3
Location Per Cent of Patients
Abdomen 65.6
Chest 16.7
Pelvis 3.3
Neck 3.3
Intraspinal 3.3
Head 2.2
Unknown 5.6
100.0
FIGURE 19-1. Ecchymoses of

the upper eyelids associated with bi-
lateral periorbital metastases from
neuroblastoma.
group often originates in the chest. The paraspinal neuroblastoma, usually

originating in a sympathetic ganglion in the chest, frequently extends
through the neural foramina into the epidural space as a "dumbbell"-
shaped mass. Children with this condition usually develop paraparesis or
paraplegia, which in an otherwise healthy child should strongly suggest the
presence of neuroblastoma.
Diagnosis
Once the diagnosis of neuroblastoma is suspected, a sequence of studies

should be undertaken. In the majority of cases, either adrenal or extra-
adrenal abdominal neuroblastomas will be demonstrated on intravenous
pyelogram as masses displacing the kidney downward and the upper pole
outward without distorting the calyceal system (Fig. 19-2). Finely stippled
calcification in the mass is apparent in approximately one third of cases but
is not considered diagnostic. Abdominal ultrasonographs will show a solid
mass that is separate from the kidney, although it may be closely attached.
These neural crest tumors produce neuroactive catecholamines and other
neurosecretory substances. The 24-hour urinary excretion of \ anilK lmande-
lic acid is elevated several times above normal in as many as 80 per cent of
patients with neuroblastoma. 4 When combined with the measurement of

homovanillic acid, using a bidirectional paper chromatographic technique,
over 95 per cent of patients with neuroblastoma may be detected. 5 The
results of the VMA determination may not be available for a few days, and
consequently therapy may be initiated before this information is available.
The value of the simplified urine dipstick technique for measurement of
FIGURE 19-2. A, Aneuroblastoma arising from the left adrenal gland. Abdominal roent-
genogram shows ((deification iti the tumor. H, Intravenous pyelogram indicates displacement
but not distortion of the calyceal system of the left kidney.
VMA remains to VMA excretion have

be proved. 6 Serial measurements of
been particularly valuable in following a patient's response to therapy and
monitoring tumor recurrence. Urinary cystathionine levels have also been
found to be elevated in patients with neuroblastoma, although this is nei-
ther a reliable early sign of the tumor nor a method for determining the
degree of malignancy. 7
Despite a significant correlation between lymphocyte infiltration of the
tumor and survival, no correlation exists between the number of lympho-
cytes circulating in the blood and the survival of the patient. 8
Bone marrow aspiration is performed as one of the initial studies in most
patients with suspected neuroblastoma, and the findings are positive in ap-
proximately 50 per cent of patients at the time of diagnosis. Although the
presence of tumor cell "rosettes" is diagnostic, it is more common to find
clumps of extrinsic-appearing cells in the marrow. Bone marrow involve-
ment generally portends a poor prognosis, although several such patients,
particularly those younger than one year, have been cured of the tumor.
Conversely, bone involvement, as demonstrated on radiographic skeletal
survey, indicates an unfavorable outcome in most patients, regardless of
therapy.
Pathology
Of all human malignancies, neuroblastoma remains the most enigmatic.

The cells that ultimately form the sympathetic ganglia, dorsal root ganglia,
adrenal medulla, organ of Zuckerkandl, and melanocytes are all derived
embryologically from the neural crest and have the potential to form
neuroblastoma. There is great variation in the histopathologic picture from
19 Childhood Solid Tumors 763
tumor to tumor as well as within the same tumor. 9 At one end of the spec-
trum are undifferentiated cells that are very difficult to distinguish from
small cell sarcoma and at the other end are tumors consisting solely of ma-
ture cell types. Between these two extremes, varying degrees of differentia-
tion may be exhibited.
Beckwith and Martin 10 have developed a histopathologic grading for
neuroblastomas (Table 19-2). Both these authors and a survey by the
Surgical Section of the American Academy of Pediatrics 11 have demon-
strated a direct correlation between the degree of histologic differentiation
and survival. Approximately 30 per cent of patients having well-
differentiated or moderate ly differentiated tumor survived two years with-
out evidence of disease, compared with only 9 per cent for those with poor-
ly differentiated tumor.
Ganglioneuromas, which are usually encapsulated, represent the benign
end of the neuroblastoma spectrum. They may produce elevations in uri-
nary catecholamine excretion similar to those seen with undifferentiated
neuroblastoma. Considerable controversy exists regarding the spontaneous
maturation of neuroblastoma into ganglioneuroma. In a review of 66 cases
of neuroblastoma, Greenfield and Shelley 12 found 11 cases with complete
maturation to benign ganglioneuroma. Almost all the reported transformed
tumors have been found in a paravertebral position or in some other extra-
adrenal location. In support of this concept, it has been shown that imma-
ture neuroblastoma cells have the potential of differentiating ganglion
15
cells. Furthermore, a "nerve growth factor" (XGF) has been isolated that
selectively stimulates the growth of sympathetic and embryonic spinal sen-
son ganglia. 14 However, attempts to induce neuroblastoma maturation by
the administration of XGF have thus far been unsuccessful.
Beckwith and Perrm 15 first called attention to the in situ neuroblastoma
of infancy, in which neuroblastoma cells are present in otherwise normal
adrenal glands of infants who are dying from other causes. The incidence
of in situ neuroblastomas was 1 in 259 autopsies among infants less than
three months of age. Strikingly, however, these lesions were not found in
any infants older than three months. These authors suggested that the 40-
fold increase in the autopsy incidence of neuroblastoma compared with the
clinical incidence of the tumor indicates that involution or maturation of
the tumor occurs spontaneously in most infants.
TABLE 19-2. Histopathologic Grading for Neuroblastomas
Grade Differentiation
I Predominantly differentiated
(over oO^r differentiated elements)
II Predominantly undifferentiated
to 50' "r differentiated elements)
III Slightly differentiated

(less than 5% differentiated elements)
IV Undifferentiated
(no recognizable neurogene-
764 II / Tre.vimkvi Of SPECIFIC Neoplasms
Clinical Staging
a staging scheme for neuroblastoma that

Evans and associates 16 proposed
describes the extent of the disease present without reference to resectabi-
lity (Table 19-3). This method is widely used to compare the outcome with
various methods of therapy. In general, the more localized the disease, the
better the prognosis, but patients with stage IV-S disease have a favorable
prognosis despite the presence of disseminated disease. The site of the pri-
mary tumor is prognostically significant; extra-adrenal tumors, particularly
those arising in the chest and pelvis, have an especially good prognosis. In
contrast, the presence of bony metastases apparent on x-ray is of grave
prognostic importance.
Age is also prognostically significant. Children younger than one year
have a relatively favorable prognosis, even when mestastatic disease (usual-
ly stage IV-S) is present at diagnosis. However, age and stage are indepen-
dent prognostic variables.
The American Joint Committee for Cancer Staging has proposed a stag-
ing system based upon the TNMclassification system. 17 This system, not
now widely used, does not recognize the unusual biologic behavior of the
Evans IV-S category or the effect of primary site on prognoses. Indeed, the
clinical utility of the standard TNM staging system when dealing with this
unique tumor remains to be validated.
TREATMENT
The therapy for neuroblastoma must involve a multidisciplinary team ap-
proach, since close cooperation between the surgeon, chemotherapist, and
radiation oncologist is mandatory for providing optimal patient care.
Surgery
Removal of the primary tumor within 24 to 48 hours after neuroblastoma

is first suspected is the preferred initial method of treatment for most pa-
TABLE 19-3. Staging of Neuroblastoma
Stage Neuroblastoma in situ.
Stage I Tumor confined to the organ or structure of origin.

Stage II Tumor extending in continuity beyond the organ or structure of
origin but not crossing the midline. Regional lymph nodes on
the homolateral side may be involved.
Stage III Tumor extending in continuity beyond the midline. Regional
lymph nodes may be involved bilaterally.
Stage IV Remote disease involving skeleton, visceral organs, soft tissues,
or distant lymph nodes, lungs, or brain.
Stage IV-S Patients who would otherwise be stage I or stage II but who have
metastatic disease confined to one or more of the following
sites: liver, skin, or bone marrow, but without radiographic
evidence of skeletal disease.
tients, even the presence of metastases. Well-eonfined lesions with adja-

in
cent nodal tissue should be resected whenever feasible, although in the
majority of patients with abdominal tumors, complete excision is not possi-
ble because of extension to contiguous vital structures. Physicians generally
favor removing as much bulk from the primary tumor as possible in order
to minimize the amount of residual tumor to be treated by radiation and
chemotherapy. The ipsilateral kidney must often be removed because of its
close adherence to the tumor.
In patients with suspected metastasis, the extent of tumor involvement
should be carefully ascertained, and liver biopsy should be performed. The
contralateral adrenal is occasionally involved and should be inspected.
Metal clips placed around the margin of the tumor facilitate subsequent ra-
diotherapy.
In patients with stage III and stage IV disease who have tumors that are
not resectable, a "second-look" operation with attempted resection or even
debulking of the tumor mass following five to six months of radiation and
chemotherapy in those cases evidencing remission has been recommended
by the Children's Cancer Study Group. However, the efficacy of this ap-
proach is unproved, and the prudence of "second-look" surgery is question-
able. Moreover, surgery or anesthesia, or both, may impair the immuno-
competence of the patient, allowing rapid recurrence and regrowth of
tumor. Tumors that extend into the epidural space must be treated as surgi-
cal emergencies, usually requiring a combined posterior neurosurgical and
transthoracic approach, generally as separate operations.
Radiation Therapy
Postoperative radiation is indicated for stage I neuroblastoma in the rare

patient in whom resection has been incomplete, but it is also recommend-
ed for all patients with stage II and stage III disease in an attempt to con-
trol residual local tumor. Radiation is also given to the primary tumor site
in stage IV disease. Perez et <i/. ,s reported a two-year survival rate of 55 per
cent in a heterogeneous group of 22 patients who underwent abdominal
exploration without resection and then received radiation. Although the
series is small, these authors recorded a two-year survival rate of 32 per
cent for patients older than two years of age as opposed to 83 per cent for
those younger than two years, and 100 per cent for the 9 patients who had
primary tumors in the thoracic area as opposed to 41 per cent for the 23
patients with abdominal primary tumors. These results do not differ from
those reported more recently concerning patients who have received com-
bined chemotherapy, surgery, and irradiation.
The boundaries of fields to be radiated are designated to encompass the
volume of the tumor bed as outlined by clips placed at the time of opera-
tion. The tumor dose that is recommended for postoperative treatment of
neuroblastoma is 2500 to 3000 rad; most therapists advocate reducing the
tumor dose to 1500 to 2000 rad for patients who are younger than two years
and increasing it to 3500 to 4000 rad for patients who are older than five v ears
20
of age. 19 -
766 II / Treatmivi of Specifh Neoplasms
In patients having stage IV-S neuroblastoma with liver involvement, radi-

ation to the liver with as little as 1000 rad, in addition to standard treatment
of the primary site, has been reported to be curative. 8 However, the current
view is that these patients, who are almost invariably younger than one
year of age, should receive minimal, if any, radiation and chemotherapy
after excision of the primary tumor, since the prognosis is very good regard-
less of therapy.
For palliation in widespread metastatic disease, e.g., bone, doses in the
range of 1000 to 2000 rad to the involved sites may be effective in relieving
local symptoms.
Chemotherapy
The failure of new chemotherapeutic agents and combinations of treat-

ment modalities to substantially alter the ultimate outcome of this tumor
has been a major disappointment. Nevertheless, drugs (e.g., vincristine, cy-
clophosphamide, meehlorethamine, daunomycin, doxorubicin, and dimethyl-
triazenoimidazolecarboxamide 21 22 ) appear to effect transient tumor regres-
'
sion. Cyclophosphamide in high doses (10 mg/kg/day for seven to ten days
in monthly courses or single doses of 600 to 1800 mg/m 2/month), with or
without other agents, has been the preferred drug.
An aggressive investigational approach to the management of patients
with disseminated disease is generally advised. The efficacy of chemothera-
py for localized disease is questionable and if the tumor has been totally
resected, many oncologists might omit adjuvant chemotherapy. Even in the
presence of widespread disease, spontaneous regression is common in pa-
tients less than one year of age, and chemotherapy is usually not given
unless progression is observed.
Transient responses may be expected in as many as 50 per cent of pa-

tients who are treated with aggressive chemotherapy, but nonresponders
usually traverse a rapid downhill course. Unfortunately, even responding
patients typically become resistant to chemotherapy within 6 to 18 months,
and extensive recurrent disease ultimately leads to their demise. 25
The evaluation of response to therapy requires close attention to the ini-
tial prognosis of the patients entered in a study. Factors such as staging and
tumor morphology must be considered, but the unusual biology of neuro-

blastoma and the high frequency of spontaneous regression of advanced
tumors in children presenting before the age of one year or in children
with stage IV-S disease must also be considered. Moreover, short-term sur-
vival statistics must be questioned because, in contrast to the course of
Wilms' tumor, very late recurrences have been reported. 23

Maturation-inducing Agents
In 1963, Bodian 24 reported the favorable effect of vitamin B 12 in patients

with neuroblastoma — the rationale for its use being the hope that it might
provide a stimulus or factor required for the conversion of neuroblastoma to

ganglioneuroma, the more benign form of this tumor. Subsequent studies
have failed to confirm Bodian's observation, 25 but the search for maturation-
inducing agents continues.
Cyclic nucleotides may play an important role in the differentiation and
maturation of neuroblastoma. 26 The study of this phenomenon has led to
the suggestion of a therapeutic potential for drugs that may influence cyclic
nucleotide levels and receptors. In particular, sodium butyrate, dibutyryl
cAMP, and papaverine have been shown to produce differentiation of
neuroblastoma cells in vitro," and clinical trials are now in progress.
Immunology
Host immune responses have been postulated as an explanation for the

spontaneous regression and clinical progression of neuroblastoma. Blocking
antibodies may arise in patients with large tumor masses and allow more
rapid tumor growth. 28 Cell-mediated and antibody-mediated cytotoxicities
have been postulated as host mechanisms of tumor control. 29 It is hoped
that the ability to grow neuroblastoma cell lines in continuous culture will
allow the identification of tumor-specific antigens that may be useful in the
development of specific immunotherapy. Further delineation of the host
immune response to surgery, radiation, and chemotherapy may make it pos-
sible to improve methods of immune enhancement/
50
Tumor Models
Human neuroblastoma cell lines have been developed and characterized
according to their biologic features. The in vitro aspects of these cell lines
appear to correlate closely with their behavior in vivo.* 1,32 Improved under-
standing of cell-cycle kinetics may enable a more rational approach to de-
vising new therapeutic regimens. Analyses of human tumors transplanted to
nude mice will provide an intermediate experimental model for the evalua-
tion of new agents and chemotherapeutic schedules."
Section 2
Wilms' Tumor
INTRODUCTION
Wilms' tumor (nephroblastoma) is one of the most common malignant
solid tumors of childhood, excluding those arising in the central nervous
system. occurs with approximately the same frequency as neuroblastoma.

It
Approximately 1 child in 10,000 will develop a Wilms' tumor, and about

500 new patients are diagnosed in the United States every year. Approxi-
mately 62 per cent of patients are diagnosed between one and four years of
age, although reported cases have ranged from early infancy to late adoles-
cence. 34 Males are affected slightly more often than females. Whereas
Wilms' tumor occurs with equal frequency on both sides, approximately 7
per cent of patients develop bilateral tumors.
The etiology of Wilms' tumor has not been defined. An increased fre-
quency of this malignancy has been reported in patients with congenital
sporadic aniridia, 35 hemihypertrophy or focal gigantism, 36 neurofibromato-
37
sis and anomalies of the genitourinary system, mental retardation, and mi-
crocephaly. Familial cases are rare; however, linear transmission 38 and
the concurrence of this tumor in occasional siblings and identical twins 39
probably reflect an inherited predisposition that may become more appar-
ent as greater numbers of patients survive to reproductive age.
NATURAL HISTORY
Pathology
The typical Wilms' tumor is a sizeable discrete mass that displaces adja-
cent organs but rarely extends into them. The tumor largely replaces the
kidney in which it arises and is confined by a capsule that is partly fibrous
and partly composed of compressed renal tissue. It is whitish gray and oc-
casionally contains cystic or hemorrhagic areas that may be seen on cut
section. Although the tumor remains encapsulated for a period, local inva-
sion into the renal parenchyma and perinephric tissue has occurred in ap-
proximately 80 per cent of children at the time of diagnosis, and regional
lymph nodes are involved in approximately 30 per cent. Vascular invasion
is the primary determinant of systemic metastases, the most common sites
being the lung, liver, and retroperitoneal area (Table 19-4). 40 The degree of
differentiation of a given tumor may vary quite widely from one part of a
tumor to another. Metastases may have a greater degree of mesenchymal
differentiation and less tubular and glomerular differentiation than primary
tumors. 40 Although the histogenesis of the Wilms' tumor is controversial,
most authorities ascribe the histologic heterogeneity of this tumor to a bi-
phasic differentiation of the metanephrogenic blastema into both epithelial
and mesenchymal elements. The mesenchymal tissue gives rise to fibrous
and adipose tissue, blood vessels, and smooth and striated muscle that may
be present in the tumor. Tubular or glomerular differentiation of the tumor
is often seen and is believed to be induced by collecting tubules arising
from a diverticulum of the Wolffian duct. 41 However, recent observations of

neural tissue in Wilms' tumor do not conform to this hypothesis. 42
Congenital mesoblastic nephroma, often called fetal renal hamartoma, is
a solid tumor of the kidney that is usually noted at birth or shortly thereaf-
43
ter. Although Wilms' tumors occasionally occur in children younger than
TABLE 19-4. Sites of Wilms' Tumor Metastases 40
Location No. of Patients
Lunu 43
Liver 23
Retroperitoneum 18
Peritoneum 17
Mediastinum 16
Pleura 10
Contralateral kidnev 9
Diaphragm 8
Adrenal 6
Bone 6
Pancreas 4
Subcutaneous 3
Brain _
Ovary :
Items l
Spermatic cord l
six months, the majority of solid renal tumors in this age group are benign
hamartomas, consisting primarily of fibroblastic tissue without malignant
epithelial components. Foci of cystic or dysplastic tubules, or both, are
always present. The tumor is believed to be histogenetically related to
Wilms' tumor, but it is a benign lesion, and the prognosis for long survival
is excellent following nephrectomy alone.
The most common initial manifestation of a Wilms tumor is the presence

of a large, asymptomatic, unilateral upper abdominal mass, generally dis-
covered incidentally by a parent or physician. The tumor is solid, discrete,
nontender, and usually fixed to the posterior abdomen. Other malignant
tumors that may present in this manner include neuroblastoma, rhabdomyo-
sarcoma, and hepatic tumors. The solid nature of the mass may occasionally
be difficult to determine clinically, and therefore cystic lesions must be con-
sidered in the differential diagnosis. Benign cystic abdominal masses in
children include multicystic or hydronephrotic kidneys and mesenteric,
choledochal, and duplication cysl
Wilms' tumors usually enlarge rapidly shortly before detection; although
they are believed to be embryonal in origin, they apparently remain dor-
mant until their doubling rate increases sharply before detection. The pres-
ence of hypertension (due to the secretion of renin by the tumor 44 ), erythro-
cytosis (due to the secretion of erythropoietin by the tumor 45 ), and vague
symptoms of abdominal pain, fever, and weight loss should arouse diagnos-
tic suspicion. However, excessive palpation of the mass should be avoided,
since it may dislodge malignant cells and cause hemorrhage.
Readily available diagnostic studies will establish the diagnosis of W ilms'
7
tumor in most patients. Routine urinalysis is frequently normal, but 15 to

20 per cent of patients have hematuria —
especially older children. Chest
770 II / Treatment OF Sim( imc Neoplasms
x-rays should be part of the routine diagnostic work-up. Approximately 10

per cent of patients, particularly older ones, have roentgenographic evi-
dence of pulmonary metastases at the time of diagnosis according to data
compiled by the National Wilms' Tumor Study (NVVTS). Our own clinical
experience indicates that more than 30 per cent of children have metastas( ts
when tumor is first diagnosed.
Plain abdominal roentgenograms usually disclose the displacement of
bowel gas shadows away from the tumor. In contrast to neuroblastoma, cal-
cification in a Wilms' tumor is unusual. Intravenous pyelography charac-
teristically shows distortion and splaying of the calyces of the involved kid-
ney (Fig. 19-3), although, occasionally, renal excretory function may be
completely absent. Prior to the removal of the affected kidney, clear visual-
ization of the contralateral kidney is essential to rule out the existence of
bilateral tumors and to assure that the uninvolved kidney is normal.
Contrast studies of the inferior vena cava may be useful to demonstrate
extension of the tumor into the renal vein and blockage of the inferior vena
cava. Such a study can be performed simultaneously with the pyelogram by
injecting the contrast material through the saphenous vein in the lower leg.
Abdominal ultrasonography is helpful in demonstrating a solid mass contig-
uous with the ipsilateral kidney.
General baseline laboratory studies are usually normal preoperatively but
may be extremely helpful in following the patient through the postopera-
tive period and subsequent therapeutic course. Thus, the initial work-up
should include a complete blood count, serum creatinine and electrolyte
levels, and liver function tests. Serum renin and erythropoietin levels may
be elevated. In contrast to neuroblastoma, urine catecholamine metabolites
(especially VMA and HVA) are not significantly elevated. Bone marrow as-
FIGURE 19-3. A, Wilms' tumor involving the left kidney. The tumor mass distorts the ealy-
eeal system and displacesthe kidney inferiority. B, Inferior venacavogram revealing lateral dis-
placement of the inferior vena cava to the right (arrows).
piration and metastatic bone surveys (or bone scans) are not usually per-
formed unless the possibility of neuroblastoma is considered likely. Selec-
tive renal arteriography is not performed unless some unusual feature of
the tumor requires clarification. Over 95 per cent of Wilms' tumors will be
correctly diagnosed with the studies recommended.
Early studies of the NWTS group employed a staging classification

based upon extent of disease at diagnosis. 46 The original classification cor-
related well with prognosis, except that patients with regional node in-
volvement did poorly, and patients with limited tumor spillage during sur-
gery did somewhat better than expected. The system was therefore
changed in 1978 (Table 19-5). Prognostic categories are identified as
"group" in the original system and as "stage" in the revised classification
of 1978. Yet another staging system has been recommended by the AJC, 17
but we do not recommend its use.
Beckwith and Palmer 47 recently proposed a histologic classification of
Wilms' tumor based upon the extent of anaplasia and sarcomatous changes
that appear to correlate closely with an unfavorable outcome. These features,
observed in 10 to 15 per cent of patients, do not seem to correlate with patient
age and portend a mortality rate of greater than 50 per cent despite aggressive
therapy. The predominant favorable pathologic pattern has an overall mor-
tality rate of less than 10 per cent; however, mortality is greater in older
children.
TREATMENT
The principal modalities of treatment for Wilms' tumor are surgery, che-
motherapy, and irradiation in combination; rarely is one used alone. The
TABLE 19-5. Staging of Wilms' Tumor- 1978

Stage I Tumor limited to kidney and complete!) excised. Renal capsule
intact and not ruptured during removal.
Stage II Tumor extends beyond the kidney hut is completely excised.
There isregional extension of the tumor by penetration
through the renal capsule into perirenal soft tissues. Vessels
outside the kidney may he involved, the tumor may have been
biopsied, or minimal local spillage of tumor confined to the
flank may have occurred.
Stage III Tumor not completely resected but residual nonhematogenous

tumor is confined to the abdomen. One or more of the follow-
ing max occur: regional node inxolxement, diffuse peritoneal
contamination by the tumor, peritoneal implants present,
gross or microscopic extension of tumor beyond the surgical
margins.
Stage IV Hematogenous metastases present (see Table 19-4)

Stage V Bilateral renal inxolxement.
772 II / Treatment of Specific Neoplasm
coordinated efforts of surgeons, chemotherapists, and radiation therapists

are essential to obtain the optimal outcome for the patient.
Surgery
Within 24 to 48 hours after hospital admission, transabdominal nephrec-

tomy is carried out as the primary treatment, regardless of the presence of
metastases. A upper abdominal incision generally provides
large transverse
satisfactory exposure and allows good evaluation of the contralateral kid-
ney. The overlying colon, which is usually splayed over the surface of the
tumor but is rarely involved, is dissected free and reflected medially.
The tumor is mobilized from the retroperitoneal tissues, with care taken
to compress or manipulate the mass as little as possible. The pedicle is
exposed as early in the dissection as feasible, and the artery (often small in
comparison to the vein) is ligated and divided. In large tumors extending
across the midline, caution must be exercised to avoid injuring the closely
approximated contralateral renal pedicle. The vein is mobilized over a 2-cm
distance and to its junction with the vena cava when feasible. The vein is
carefully inspected for tumor thrombus, which has been present in over 15
per cent of cases in our experience. If no tumor is evident, the vein is
ligated and divided; however, if tumor is seen within the renal vein or the
vena cava, or both, the vena cava is temporarily occluded 2 to 3 cm above
and below the entrance of the renal vein, and the lumbar veins are tempo-
rarily clipped. A thin wedge of the vena cava, including the renal vein
orifice, is then excised, and the enclosed tumor is removed. Since the
tumor rarely adheres to the intimal surface of the vena cava, it is repaired
with a continuous suture. The ureter is divided close to the bladder. The
perinephric fat and the periaortic lymph nodes, both superior and inferior
to the renal pedicle, are removed with the tumor. The efficacy of routine
para-aortic node dissection is under investigation but has not been estab-
lished. The adrenal gland is often removed with the specimen, although
occasionally it may be left in the patient when it is not closely attached.
Metal clips are placed around the margin of the resected tumor bed and on
the ovaries to serve as markers. Broad-spectrum antibiotics are usually
given for three to four days. A wound drain is used for 48 hours until it is
apparent that bleeding has ceased.
In patients with bilateral tumors, one kidney typically has a much larger
tumor than the other. The side with the smaller tumor usually involves
either the lower or upper pole, with the remainder of the kidney providing
the patient's entire renal function. Although for many years bilateral
nephrectomy with subsequent renal allotransplantation was recommended
as the treatment of choice, the long-term survival rate had been dismal.
The current preferred treatment is complete resection of the more exten-
sively involved kidney and heminephrectomy for the smaller tumor. This is
occasionally facilitated by temporary removal of the kidney with reanas-
tomosis of the renal vessels to the iliac vessels ("workbench" surgery) in
difficult cases. The tumor in the partially involved kidney is usually much
less malignant than that in the primarily affected kidney, and recurrence is
uncommon in this area.
According to NWTS experience, pulmonary metastases are present in ap-

proximately 10 per cent of patients with Wilms' tumor at the time of initial
diagnosis and appear in another 20 per cent within the ensuing 18
months. 48 Although a metastasis may appear to be solitary on chest roent-
genogram, it is likely that multiple additional metastases, too small to be
detected, are also present. Consequently, surgical resection of a pulmonary
metastasis is deferred for a period of at least six months after the primary
tumor has been removed and systemic chemotherapy as well as radiation of
both lungs and the tumor bed has been administered. If a solitary pulmo-
nary metastasis remains after six months of therapy without appearance of
new metastases in a patient who has no other evidence of active tumor,
wedge resection or pulmonary lobectomy may be advisable. Hepatic resec-
tion for metastatic Wilms' tumor is rarely indicated.
Radiation Therapy
The work of Gross and Neuhauser 49 in 1950 demonstrated that early sur-
gery and routine postoperative radiation to the renal fossa in patients over
one year of age with Wilms' tumor doubled the survival rate from 21 to 43
per cent. Although this was in the prechemotherapy era, the value of radia-
tion therapy in Wilms' tumor was established. The goal for managing such
patients has been to define the indications for and sequence of surgery,
radiation, and chemotherapy to achieve maximum survival with minimum
acceptable morbidity.
A randomized trial to evaluate preoperative versus postoperative radia-
tion has demonstrated no difference in survival or recurrence-free survival
between groups. Some investigators who advocate preoperative radiation
combined with chemotherapy believe that this regimen facilitates surgical
removal and reduces the incidence of surgical spillage. 50 However, the fre-
quency of surgical complications is higher when surgery is performed after
radiation therapy. Moreover, 4 per cent of the patients diagnosed preopera-
tively as having Wilms' tumor were found to have benign conditions at
surgery. For these reasons, and because information obtained at surgery
concerning the pattern of intra-abdominal involvement is useful in the
planning of treatment, we favor postoperative radiation. However, if serious
technical difficulties are anticipated at surgery because of a massive tumor
volume, preoperative radiation should be considered.
The first National Wilms' Tumor Study 46 evaluated the usefulness of post-
operative radiation in group I patients and found that for patients over two
years of age there was a statistically significant increase in the two-year
relapse-free survival rate between irradiated and nonirradiated patients (77
per cent versus 55 per cent). For patients in group I who were younger
than two years, the relapse-free survival rate at two years was equivalent
(90 per cent versus 88 per cent), suggesting that for this particular subset of
patients, radiation is not necessary. Group I patients who are two years of
age and older, and group II, group III, and group IV patients (of all ages)
benefit from postoperative radiation to the tumor bed. The doses of radia-
tion are adjusted for age, as shown in Table 19-6.
In order to reduce the incidence and severity of scoliosis that is second-
TABLE 19-6. Age-adjusted Radiation Dose
Vci Timor Dose (Rad)
Birtli to 18mo 1800-2400

19 mo to 30 mo 2400-3000
31 mo to 40 mo 3000-3500
41 mo or more 3500-4000
ary to growth retardation, the medial portion of the field should include the
entire width of the vertebral bodies. Meticulous care must be taken to
avoid radiating the opposite kidney. The lateral margin is blocked to pre-
vent a tangential incidence on the lateral abdominal wall. Superior and in-
ferior margins are determined by the clips around the tumor bed placed at
surgery. If significant spillage of tumor has occurred at surgery, the entire
abdomen is radiated, taking care to block the femoral heads, to a dose of
1500 to 2000 rad, at which time the field size is reduced to encompass the
tumor bed. Radiation is continued to the appropriate dose.
When pulmonary metastases are present at the time of diagnosis (stage
IV), both lungs are treated in contiguity with the tumor bed until a dose
of 1200 to 1400 rad is achieved, even though only one lung may show
metastases on x-ray. The field is then reduced to include the tumor bed
alone, and radiation is continued until the appropriate dose is reached.
When there is residual disease in the lungs, which can be encompassed by
limited fields, it is boosted with an additional 1000 to 1500 rad. If pulmona-
ry metastases develop subsequent to initial therapy to the primary tumor,
the guidelines for pulmonary radiation already given are used.
In cases of bilateral tumors, both renal fossae are radiated to recommend-
ed doses, except that the dose to the remaining kidney is limited by careful
blocking to 1500 rad.
The sequelae from radiation are related to the age of the patient, the
volume and tissue radiated, and the dose given. 51 Inasmuch as scoliosis can
result from asymmetric growth of the vertebral bodies or unilateral fibrosis
of the paraspinous muscles, or both, prompt institution of physical therapy
at the first sign of scoliosis is recommended. Complications in soft tissue
(radiation hepatitis, pneumonitis, pericarditis, and nephritis) occurred in 29
of 359 patients (8 per cent) in the NWTS-1, resulting in three treatment-
related deaths. These data emphasize the fact that extreme caution to mini-
mize the complications of therapy must be exercised by the surgeon, radia-
tion oncologist, and pediatric oncologist in treating Wilms' tumor.
Chemotherapy
The efficacy of chemotherapy in the management of Wilms' tumor has

been well demonstrated. The NWTS has shown the particular effectiveness
of combined therapy using both vincristine and dactinomycin in patients
with regional spread of disease (Table 19-7). 46 At recommended drug dos-
TABLE 19-7. The Effect of Chemotherapy on

Group II and Group III Wilms' Tumor"
Actuarial
Relapse-free Actuarial
Agent 2-Year Survival 2-Year Survival
Dactinomycin 67%
Vincristine 55% 72%
Dactinomycin and vincristine 81% 86%
'Data derived from \\VTS. All patients were also treated with surgery and radiation therapy. 14
ages, toxicity is usually mild and well tolerated, although occasional pa-
tients may show significant marrow depression when dactinomycin and ra-
diation therapy are used concurrently in the early phase of treatment.

The present recommended schedule for the treatment of Wilms' tumor,
regardless of stage (but excluding stage I patients), is depicted in Figure
19-4. It should be recognized that these recommendations reflect the best
available treatment but that as new studies are completed improved regi-
mens will evolve.
Virtually all metastatic disease occurs within 18 months of the initial
diagnosis, and chemotherapy is usually terminated at 15 months. The over-
all survival rate of patients with Wilms' tumor is greater than 80 per cent,
even in stage IV and stage V patients. The vast majority of recurrent dis-
ease is found with unfavorable histologic findings. 17 Although re-
in patients
lapses are usually highly resistant to therapy, some favorable results with
doxorubicin have been reported. 5 - In fact, very preliminary results of NWTS
II suggest that the addition of doxorubicin may improve the disease-free
survival of patients with unfavorable histologic findings and of patients with
stage II and stage III disease. 53 The recommended dose of doxorubicin is
20 mg/m 2 IV daily for three days, at 6 weeks, 4.5 months, 7.5 months, and
13.5 months.
RADIO
SURG
VCR I I I I I II II I I I I
DACT
~i
— ———— —
i
-/h
v-\ i i i r"~\ r"-\
—r~"-\— v~"~\
—r"~\—
DAY 17 19 21-28 35 42 49 56 85 89 169 173 253 257 337 351421425
WEEK 4-5 6 7 8 9 13 14 25 26 37 38 51 52 63 64
FIGURE 19-4. Therapy of Wilms' tumor. RADIO, radiation therapy, as outlined in text;
SURG, surgery, as outlined in text; VCR. vincristine, 1.5 mg I m*— maximum dose, 2 mg, to be
given on days 8, 15, 22, 29. 36. 43. 50, 57. 85. 89. 169. 173. 253. 257. 337. 341. 421. and 425);
DACT, dactinomycin, 15 u,glkglday for 5 consecutive days— maximum dose. 0.5 mg, given
on days 1 through 5.36 through 40. 85 through 89, 169 through 173,253 through 257,337 through
341, and 421 through 425. In addition, patients icith stage II or stage HI disease or an unfavor-
able histologic appearance receive doxorubicin in a dose of 20 mg/m2 IV daily times 3, at six
weeks, 4.5 months, 7.5 months. 10.5 months, and 13.5 months.

NWTS-1 provided a model for interdisciplinary interinstitutional coopera-
tive study and brought about a major improvement in the overall survival
rate of children with Wilms' tumor. 46 It demonstrated the utility of radiation
therapy in all stages of disease and also showed that combined adjuvant
chemotherapy with vincristine and dactinomycin was superior to either
agent used alone.
Recently initiated, NWTS-2 will address different problems. The patients
with the best prognosis, usually the youngest ones, are also most suscepti-
ble to the damaging side-effects of therapy. One major objective of NWTS-2
is to determine whether or not chemotherapy, now being recommended,
can be reduced in group I patients. A second objective is to determine

whether or not advanced disease can be more effectively managed by in-
tensified adjuvant chemotherapy. Genetic, epidemiologic, and pathologic
features will be further defined and correlated with the outcome of therapy
in an effort to clarify front-end prognostic indicators and the need for ag-
gressive adjuvant therapy.
Miller RW, et al.: Am J Dis Child

1. 18. Perez CA, et al.: Radiologij 88:750,
115:253, 1968. 1967.
*2. Pochedly C: Neuroblastoma. Littleton, 19. Stella JG, et al.: Am J Roentgenol
Ma, PSG Pub Co, Inc, 1976. 108:324, 1970.
3. Priebe CJ, Jr and Clatworthy HW, Jr: 20. Tefft M and Wittenborg MH: JAMA
Arch Surg 95:538, 1967. 205:159, 1968.
4. Gitlovv SE, et al.: In Neuroblastoma. 21. Gasparini M, et al.: Cancer Che-
Pochedly C (ed), Littleton, Ma, PSG mother Rep 58:365, 1974.
Pub Co, Inc, p. 115, 1976. *22. Liekin S, et al.: The impact of chemo-
5. Williams CM and Greer M: JAMA therapy on advanced neuroblastoma.
1 83: 836, 1963. Survival of patients diagnosed in
6. Leonard AS, et al.: J Pediatr Surg 1956, 1962, and 1966-68 in Chil-
7:528, 1972. dren's Cancer Study Group A. J Pe-
7. Studnitz W: Acta Paediatr Stand diatr 84:131, 1974.
59:80, 1970. 23. Konrad PN, et al.: J Pediatr 82:80,
8. Lauder I and Aherne A: Br J Cancer 1973.
26:321, 1972. 24. Bodian M: Arch Dis Child 38:606,
9. Finklestein JZ and Gilchrist GS: Calif 1963.
Med 116:27, 1972. 25. Sawitsky A and Desposito F: J Pediatr
10. Beckwith JB and Martin RF: J Pediatr 67:99, 1965.
Surg 3:106, 1968. 26. Prasad KN, et al: J Natl Cancer Inst
11. Surgical Fellows of the American 57:619, 1976.
Academy of Pediatrics: J Pediatr 27. Helson L, et al. In Progress in Chemo-
Surg 3:191, 1968. therapy. Daikos GK (ed), Athens,
12. Greenfield LJ and Shelley WM: J Natl Greece, Hellenic Society of Chemo-
Cancer Inst 35:215, 1965. therapy, 3:966, 1973.
13. Burdman J A, et al.: J Natl Cancer 28. Hellstrom I, et al.: hit J Cancer 6:172,
Inst 32:165, 1964. 1970.
14. Varon S: J Pediatr Surg 3:120, 1968. 29. Bvfield JE, et al.: Nature 264:783,
15. Beckwith JB and Perrin EV: J Am 1976.
Pathol 43:1089, 1963. *30. Chung HS, et al.: Abnormalities of the
16. Evans AE, et al: Cancer 38:655, 1976. immune system in children with
*17. The American Joint Committee for neuroblastoma related to the neo-
Cancer Staging and End Results Re- plasm and chemotherapy. J Pediatr
porting. Manual for Staging of Can- 90:548, 1977.
cer. American Joint Committee, Chi- 31. Schlesinger HR, et al.: Cancer Res
cago, 111, p. 163, 1978. 36:3094, 1976.
32. Seeger RC, et al: Cancer Res 37:1364, 42. Kuo T: Cancer 39:1105, 1977.
1977. 43. Bolande RP, et al.: Pediatrics 40:272,
33. Siege! MM. ct al.: Proc Am Assoc 1967.
Cancer Res 19:152, 1978. 44. Mitchell JD, et al: Arch Dis Child
34. Jones PG and Campbell PE: Tumors 45:376, 1970.
of Infancy and Childhood. Oxford, 45. Shalet MF, et al: J Pediatr 70:615,
Blackwell Scientific Publications. 1967.
Ltd, p. 491, 1976. *46. D'Angio GJ, et al.: Treatment of
35. Fraumeni JF, Jr and Glass AG: JAMA Wilms' tumor, results of the national
206:825, 1968. Wilms' tumor study. Cancer 38:633,
36. Fraumeni JF, Jr, et al.: Pediatrics 1976.
40:886, 1967. 47. Beckwith IB and Palmer NF: Cancer
37. Stay EJ and Vawter G: Cancer 47:1937. 1978.
39:2550, 1977. 48. Bond JV and Martin EC: Clin Radiol
38. Brown WT, et al.: Surgery 72:756, 27:191, 1976.
1972. 49. Gross RE and Neuhauser EBD: Pedi-
39. Knudson AG, Jr: Cancer 35:1022, atrics 6:843, 1950.
1975. 50. Lemerle J, et al.: Cancer 38:647, 1976.
40. Bannavan GA, et al: Cancer 27:812, 51. Tefft M: Int / Radiat Oncol Biol Phys
1971. 2:455, 1977.
*41. Canale VC and Muecke EC: Wilms' 52. Tan CE, et al:Cancer 32:9, 1973.
tumor —
A clinical review. CA 53. D'Angio CT. et al.: Proc Am Soc Clin
24:66, 1974. Oncol 20:309, 1979.
CHAPTER 20
MISCELLANEOUS
SOLID TUMORS
Section 1
Mediastinal Tumors
Donald G Mulder Henry Fee
Harvey A Gilbert
INTRODUCTION
The mediastinum may be the site of both primary and metastatic tumors.
This section deals with selected tumors that have their origin within the
mediastinum and excludes all esophageal, vascular, lymphomatous, and en-
docrine organ lesions, since these are discussed elsewhere.
Approximately 75 per cent of all mediastinal tumors are benign, and sur-
gical removal is usually curative. With some exceptions, the prognosis is
1
poor for the remaining 25 per cent of patients with malignant tumors.
Because of the predilection of most tumors to be found in certain regions
(Table 20-1), it is helpful to arbitrarily divide the mediastinum — which
consists of that part of the thorax between the two pleural cavities laterally,
the thoracic outlet superiorly, and the diaphragm inferiorly —
into anterior,
middle, and posterior compartments (Fig. 20-1). The location may also be
an important contributing factor to the signs and symptoms produced by
these space-occupying masses, even though in many instances the tumor
may be discovered incidentally on chest x-ray.
This section emphasizes those tumors of the anterior mediastinum that
are most likely to be seen by the clinician, namely, thymomas and germ
cell tumors. Lymphomas (middle mediastinum) are discussed in Chapters
778
20 / Miscellaneous Solid Tumors 779
TABLE 20-1. Usual Location of Mediastinal Neoplasms'
Mediastinal Compartment Primary Neoplasms
Anterior Thymoma
Germ cell tumors
Benign teratoma
Seminoma
Embryonal cell carcinoma
Malignant teratoma
Choriocarcinoma
Endodermal sinus (yolk sac)
Middle Lymphoma
Posterior Neurogenic tumors
Miscellaneous tumors
°A wide variety of other lesions may occur in these locations. 2
24 and 25. Neurogenic tumors (posterior mediastinum) are discussed only

briefly, since they are relatively rare.
In addition to the routine diagnostic studies, certain special procedures,
such as angiography, arteriography, sonography, tomography, and computed
tomography, may be uniquely helpful in the discovery of mediastinal
tumors. The procedure used depends on the type and location of the le-
sion; therefore, the value of each will be discussed in relation to the specif-
ic tumor.
FIGURE 20-1. Normal lateral

chest x-ray indicating the anatomic
compartments of the mediastinum.
ANTERIOR MEDIASTINUM—
THYMOMAS
Thymomas compose 20 25 per cent of all mediastinal tumors 1,2 and are
to
found with equal frequency in males and females. Although they may occur
in ectopic locations, virtually all are located in the superior portion of the
anterior mediastinum —
the area normally occupied by the thymus gland.
They are the most common neoplasms found in the anterior mediastinum
in adults and occur rarely in individuals less than 20 years of age. 1,3,
Natural History
Classification. Because the thymoma is composed of the two types of

cells that make up the normal thymus gland — lymphocytes
and epithelial
cells — tumor is often called a lymphoepithelioma. Those that contain
this
predominantly lymphocytic cells may be confused with lymphosarcoma or
Hodgkin's disease, whereas those with predominantly epithelial cells may
suggest a primary carcinoma. In most instances, however, thymomas are
classified into either lymphocytic or epithelial types.
More important is the determination as to whether the thymoma is be-
nign or malignant. Fortunately, 65 to 70 per cent are well encapsulated and
contained within the thymus, whereas 30 to 35 per cent are locally inva-
sive. 1,5 The gross appearance at the time of operation is a more reliable
means of determining whether the tumor is benign or malignant than is the
histologic picture. In contrast to most malignant tumors, thymomas rarely
produce distant metastases, but rather invade contiguous structures such as
the pericardium, pleura and lung, the innominate vein and superior vena
cava, and occasionally the sternum.
Clinical Presentation. Most patients with benign thymomas are
asymptomatic, the exception being those with associated myasthenia gravis.
By contrast, the invasive thymoma commonly causes symptoms, either be-
cause of the direct involvement of mediastinal structures with tumor or
from the resulting secondary inflammatory process. Chest pain and cough
are seen most frequently, whereas dyspnea and superior vena cava syn-
drome from tumor invasion or compression are less common.
Patient age is related to the frequency of symptoms. Collected series of
mediastinal masses indicate that the infant or child is more prone to have
symptoms than is the adult. 3, 7 This appears to be due to extrinsic pres-
fi -
sure of the mass on adjacent structures such as the trachea, esophagus, and
vena cava, rather than the histology of the lesion, since in several series,
the 30 to 55 per cent incidence of malignancy seen in infants and children
7 9 "
is comparable to that seen in adults.
The most common symptoms noted in patients with thymic tumors are
those of myasthenia gravis. This autoimmune disorder of neuromuscular
transmission is found in 40 to 60 per cent of patients with either benign or
invasive thymomas. Muscle weakness and easy fatigability may be of a gen-
eral nature or involve the ocular or oropharyngeal region exclusively. Since
20 Miscellaneous Solid Tumors 781
these symptoms may be subtle, careful questioning of all patients with thy-
mic tumors to detect unrecognized myasthenia gravis is important, espe-
cially before contemplating an operative procedure. The presence of this
associated disease in patients with suggestive symptoms can be document-
ed readily by their responses to anticholinesterase medication. The admin-
istration of edrophonium chloride (Tensilon), a fast-acting anticholines-
terase drug, will be followed by immediate improvement in muscle
strength and symptoms if myasthenia gravis is present.
In addition to myasthenia gravis, other rare conditions such as red blood
12
cell agenesis,
10
acquired agammaglobulinemia, 11 and Cushing's syndrome
have been associated with thymoma. Since some of these occur frequently
with thymoma, the Mayo Clinic group has suggested that the spectrum of
diseases associated with thymoma may represent a distinct syndrome,
13
rather than a series of coincidental diseases. Specifically, in a review of
598 patients with thymoma, they found that 71 per cent suffered from a
variety of immune disorders, and of this group 44 per cent had myasthenia
gravis, 21 per cent had various cytopenias, 17 per cent had cancer, 6 per
cent had hypogammaglobulinemia, 5 per cent had polymyositis, and 2 per
cent had systemic lupus erythematosus.
Diagnostic Studies. Characteristically, benign thymomas arc detected
on routine chest x-ray — frequently best seen on the lateral film, unless the
mass projects toward either pulmonary hilus. Lateral chest tomograms
should be obtained on patients suspected of having anterior mediastinal
tumor on routine x-rays. They should also be performed on every patient
with myasthenia gravis, because 15 to 30 per cent of such patients have an
unsuspected thymoma. Special studies are not essential when the tumor is
classic in its location and appearance, as shown in Figure 20-2.
Computer assisted tomography has added an additional unique diagnostic
dimension, particularly in those instances in which conventional tomo-
grams are equivocal. The use of the CT scan is especially helpful in inva-
sive thymoma, and information as to the extent of the lesion and the feasi-
bility of surgical extirpation may be obtained. 14
In special circumstances in which there is a question of tumor invasion
or compression of the superior vena cava, innominate vein, or the heart,
angiography is indicated. However, this is not performed routinely. Past
techniques, such as pneumomediastinography, are no longer used because
of the associated morbidity with this relatively invasive technique and,
more importantly, its failure to provide reliable information.
The role of cervical mediastinoscopy or limited parasternal exploration
for biopsy only is more difficult to define. As mentioned previously, the
determination of malignancy in thymic tumors is best established by the
invasiveness of the lesion as seen at operation, rather than on its histologic
characteristics. Thus, a limited procedure for biopsy only is not recom-
mended in patients strongly suspected of having a potentially resectable
thymoma. In contrast, on the basis of clinical findings or findings on the CT
scan, those individuals who are likely to have a large and probably nonre-
sectable tumor — either thymoma or teratoma — might be spaced a major
unrewarding operative procedure.
7H2 II / Treatment of Specific. Neoplasms
FIGURE 20-2. Lateral chest radio-

graph showing a large, lobulated,
discrete mass in the riglit anterior
mediastinum— classic appearance for
a thymoma.
Staging. There is no established staging system for thymomas. The key

factors inplanning therapy relate to whether or not the tumor is locally
invasive and whether it was completely or incompletely excised.
PROGNOSIS. The outlook for patients with thymoma depends upon
whether the tumor is benign or invasive. A second factor is the presence
and severity of associated myasthenia gravis. Resection of benign thymoma
in the absence of myasthenia gravis is virtually curative. 15
Little information is available concerning the possibility of developing
myasthenia gravis after excision of a thymoma. Total thymectomy, rather
than just excision of the thymoma, is recommended in the hope of lessen-
ing that likelihood. In the patient with a benign thymoma and myasthenia
the patient's response to the my-
gravis, the limiting factor for the future is
asthenia gravis following operation. Approximately 54 per cent of males

and 75 per cent of females have a remission of their myasthenia gravis or
improve following operation, and in many instances this is sustained. 16
The generally unfavorable prognosis of patients with invasive thymoma
is reflected in the experience of the Mayo Clinic. 17 Only 12.5 per cent in
their series were long-term survivors, with death being attributable to local
invasion of mediastinal structures. This finding is in keeping with the expe-
rience of others. 15, ,8
In the past, when a patient exhibited myasthenia gravis in addition to an
invasive thymoma, the prognosis was even more grim. In these cases, the
lethal complication of local invasion of vital structures was added to the
problem of respiratory insufficiency.
Treatment
SURGERY. Surgical excision is the preferred treatment of any thymoma

regardless of size, since it is not known whether benign tumors may later
undergo malignant change. Small lesions are readily resected, whereas the
advanced and invasive tumors pose significant technical problems with in-
creased likelihood of local recurrence.
Whether the tumor is benign or malignant, and even in the absence of
myasthenia gravis, the entire thymus is removed along with the thymoma.
There are two reasons for this: (1) The risk of leaving a small undetected
thymoma in another portion of the gland or the subsequent development of
a new lesion such as this may be avoided, and (2) since there is such a
high incidence of myasthenia gravis in these patients, complete removal
of the thymus might lessen the chance of developing this disease at a later
date.
The perioperative management of myasthenic patients undergoing sur-
gery for thymic tumor is extremely important, and close cooperation among
the neurologist, anesthesiologist, surgeon, and radiotherapist, who are
knowledgeable in this disease, is essential. Endotracheal intubation is ac-
complished without paralyzing agents because of the exquisite sensitivity
of these patients to curare-type drugs. A median sternotomy incision is
used in all patients, and, if feasible, the entire thymus, including the tumor,
is completely excised along with any contiguous structures it may have in-
vaded. In myasthenic patients with invasive tumors involving the pleura

and pericardium and encroaching on the phrenic nerve, it is preferable to
avoid injury or sacrifice of the phrenic nerve. The ventilatory impairment
secondary to nerve sacrifice may be disastrous in such a patient, and reli-
ance on radiation therapy to control residual disease in that location is pref-
erable. Questionable tumor margins are marked with metallic clips to per-
mit accurate limited-field radiation therapy.
When postoperative complications occur, they are almost invariably pul-
monary- in nature. Chest splinting due to pain and transient worsening of
the myasthenia gravis are common causes of hypoventilation. This, along
with the inability to raise secretions, may lead to atelectasis and acute re-
spiratory difficulty. Controlled ventilation through a nasotracheal tube dur-
ing the first 24 to 48 hours postoperatively prevents further muscle fatigue,
as well as providing ready access for the aspiration of secretions. Gradual
weaning of the patient from the respirator is accomplished by the use of
intermittent mandatory ventilation progressing to spontaneous T-tube
breathing while monitoring serial arterial blood gases and ventilatory capa-
bility.
No anticholinesterase drugs are given for the first 24 to 48 hours because
of the increased sensitivity of many patients to the medication. The routine
resumption of the preoperative dose of anticholinesterase drugs might pro-
duce toxicity, the symptoms of which may be similar to inadequate medica-
tion. Cautious resumption of medication at a reduced level two or three
days postoperatively may be necessary and advisable. By careful attention
to the respiratory tract, tracheostomy can be avoided in most patients.
Radiation Therapy. Patients with complete encapsulation and total

removal of their thymomas have almost no local recurrences of tumor and
require no irradiation for local control. Those with thymoma in whom in-
19
vasion is discovered at surgery, but who have total gross removal, re-
first
quire 5000 rad20 over about five weeks to large fields extending from the
sternal notch to below the surgical clips and extending laterally to include
the medial pleural reflections. This radiation may be given with wedged
21
fields and should deliver less than 4000 rad to the spinal cord. Patients
who have postresectional residual tumor or who presented with compres-
sive symptoms 22 probably require greater than 6000 rad given over six to
eight weeks for a high degree of long-term local control.*
Chemotherapy. There is a paucity of data on the role of chemotherapy
23
in treating thymomas. Doxorubicin and cisplatin appear to be active
agents, as are the alkylating agents. However, their proper roles as single
agents or in combination have not been defined. This would appear to be a
fertile area for a cooperative group study.
Integration of Treatment Modalities. Goldman et al. 24 reported a
group of 19 patients with invasive thymoma and myasthenia gravis treated
and followed at UCLA for 20 years. All patients received anticholinesterase
drugs, but there were no long-term survivors in the three patients who re-
ceived this as the only form of therapy. The remaining patients received
some combination of steroids and/or radiation and/or cytotoxic agents, with
an overall five-year survival rate of 69 per cent, and a ten-year survival rate
of 26 per cent. We therefore recommend that high-dosage alternate-day
prednisone and radiation therapy to the tumor mass should be started
seven to ten days after operation. Anticholinesterases should be kept to a
minimum and eliminated as quickly as possible. If there is evidence of
tumor recurrence, additional local radiation to the tumor or cytotoxic agents
(usually cyclophosphamide) may be given.
For those patients with invasive thymoma who do not have myasthenia
gravis, radiation therapy is the most commonly employed adjunctive thera-
py. There have been advocates of preoperative radiation to thymic tumors,
the rationale being that this might sufficiently reduce the size of otherwise
nonresectable lesions to make extirpation possible. 25 However, initial ex-
ploration and resection of the tumor followed by radiation therapy for obvi-
ous or questionable residual tumor is currently the common practice. It
seems likely that the addition of the newer cytotoxic agents may have a
role, but inadequate experience is available at this time to support such a
recommendation
GERM CELL TUMORS OF THE

ANTERIOR MEDIASTINUM
An interesting group of tumors is found in the anterior mediastinum that
is composed of multiple tissues foreign to that location. Numerous classifi-
"Fayos JF, personal communication.

cations of these tumors have been suggested, depending on the author's

"
concept of their histogenesis and the predominant histologic features. 26 29
A reasonable presumption is tumors arise from a common
that all these
germ cell and can, therefore, be categorized as germ cell tumors. The di-
rection and extent to which differentiation occurs then results in tumors
that fall into one of three general categories: (1) benign teratoma, (2) semi-
noma, and (3) embryonal carcinoma, which may give rise to the subdivi-
sions of malignant teratoma, choriocarcinoma, or endodermal sinus (yolk-
sac) tumor.
Because of the presence of multiple germ layers and the pluripotential
nature of these tumors, the classifications used by various authors in report-
ing such tumors have varied widely. The inconsistency in terminology is
unimportant as far as the benign teratoma is concerned, since there seems
to be reasonable agreement on the histology and behavior of this tumor. It
is quite confusing, however, when malignant tumors are involved, since
some reports classify these lesions according to the predominant cell type
present. 1,30 Consequently, it is difficult to determine precisely the frequen-
cy with which certain of the tumors are seen, the age and sex distribution,
and so forth. It is fortunate that these factors appear to be relatively unim-
portant. Of considerable importance, however, is the determination of ma-
lignancy and the predominant cell type, since both the therapy selected
and the prognosis relate importantly to those determinations.
An additional indication of malignancy is the detection of serum or urine
levels of alpha-fetoprotein, or beta-human chorionic gonadotropin (/3HCG).
These glycoproteins are secreted by the malignant component of the tumor,
and their presence may assist in both diagnosis and preoperative classifica-
tion. Specifically, /3HCG is secreted only by syneytiotrophoblastie cells,
and alpha-fetoprotein is secreted by germinal cells derived from the en-
dodermal sinus (yolk sac). 31 Thus, an isolated elevation of /3HCG suggests a
choriocarcinoma, an isolated alpha-fetoprotein elevation suggests an endo-
dermal sinus tumor, and when both substances are present, embryonal cell
carcinoma is suggested. 31
When present, symptoms of extrinsic compression and local invasion of
mediastinal structures will be common to most of the malignant lesions, as
will the methods used for establishing the diagnosis. Since benign and ma-
lignant teratomas have many similarities, they will be considered together,
whereas the unique features of the other germ cell tumors will be indivi-
dually emphasized.
Teratomas
Teratomas compose approximately per cent of all mediastinal

10
1,30
tumors. In fact, the mediastinum is second only to the gonad (ovary or
testis) as the primary location of teratomas in adults, and in children it is
the neoplasm found most frequently in the anterior mediastinum. 32
Radiographically, teratomas appear as a dense, rounded mass with dis-
tinct borders. Calcification, which frequently appears as a capsular shell, 33
can be seen in roentgenograms in approximately 50 to 75 per cent of cases,
and occasionally teeth, which are pathognomonic, can be identified. Al-

though calcification is by no means an absolute indicator, it has been found
four times more frequently in benign lesions than in malignant teratomas.
Benign teratomas do not secrete either /3HCG or alpha-fetoprotein."
Characteristically, the benign lesions tend to be cystic and multiloculated,
whereas the malignant tumors tend to be solid. In the mediastinum, the
larger the tumor the more likely it is to be malignant. This is in striking
contrast to the sacrococcygeal teratomas, in which the larger lesions tend to
be benign. 34
Most of the patients are adolescents or young adults when the diagnosis
is made, at which time the majority are symptomatic. Anterior chest pain is
the most common symptom, whereas cough, dyspnea, and fever also may
be present. Symptoms are more likely to exist with malignant teratomas,
which, fortunately, compose only 20 per cent of all teratomas. An exception
to this occurs in infants and young children, in whom the presence of even
a small mass in the limited confines of the small chest causes symptoms
from extrinsic pressure on vital structures, especially the tracheobronchial
tree.
The treatment for benign teratomas is surgical excision — hopefully prior
to the development of complications. The risk of operation is minimal, and
cure is virtually assured. In contrast to the good results following resection
of benign lesions, the results of surgical treatment alone for the malignant
variety (malignant teratoma and embryonal carcinoma) are uniformly dis-
mal. 1, 18,35 Even so, extirpation of the tumor along with contiguous struc-
tures that have been invaded (pericardium, lung, and so on) may be of
palliative value. When local or distant metastases preclude such an ap-
proach, diagnostic biopsy is indicated to determine the histologic charac-
teristics of the particular tumor as a guide to the choice of appropriate radi-
ation therapy or chemotherapy, or both.
In patients with primary embryonal carcinoma of the mediastinum, ir-
radiation is of palliative value only when used by itself. 36 We prefer to
recommend multiagent chemotherapy afterwhich is continued
biopsy,
until maximum tumor response occurs. The choice of chemotherapy is the
same as that used for the histologically analogous germ cell tumor of the
testis, as discussed in Chapter 10. In some patients, radiation therapy may
be employed either before or after "second look" resectional surgery. The
added localization of the tumor bed that is accomplished by radiation thera-
py after the placement of silver clips during such surgery allows minimal
radiation doses to adjacent normal tissues.
Endodermal Sinus (Yolk Sac) Tumors and

Choriocarcinoma
The endodermal sinus, or yolk sac, tumor is a highly malignant form of

embryonal cell carcinoma, as is choriocarcinoma. Each of these tumors
occurs almost exclusively in males during the second and third decade of
life, although they have been reported in children. 33 Symptoms of cough,
dyspnea, and chest pain are invariably present, at which time a large an-
terior mediastinal mass is seen. It is not possible to radiographically dif-

ferentiate endodermal sinus tumor from choriocarcinoma or malignant tera-
toma unless calcification happens to be present in the latter.
The diagnosis of choriocarcinoma can be suggested by the detection of
31,37
chorionic gonadotropin in the blood or urine. Gynecomastia and testicu-
lar atrophy are noted in over half the patients. Distant metastases are al-
ready present in most cases by the time the diagnosis is made. In most
instances, because of the extent of the disease when the patient seeks me-
dical care, surgical removal of the entire tumor is impractical, and such
attempts are ill-advised. Rather, a limited thoracotomy for biopsy and his-
tologic confirmation of diagnosis is indicated. Unfortunately, the
the
choriocarcinomas are seldom responsive to radiation or chemotherapy, but
monitoring urinary chorionic gonadotropin levels can be used as a guide to
the effectiveness of such treatment. A rapidly fatal course in virtually all
patients is predictable, despite the use of any of the current adjunctive

modalities of treatment.
The endodermal sinus tumor has a similar clinical presentation. The
diagnosis should be suspected if alpha-fetoprotein can be detected. As with
choriocarcinomas, the tumor is usually large and involves contiguous struc-
tures by the time it is discovered. Surgical therapy alone is often inade-
quate, and most authors consider this tumor to have a grim prognosis.
Hopefully, the advances in chemotherapy for testicular germ cell tumors
described in Chapter 10 will prove of equal value for the analogous tumors
in the mediastinum.
Seminomas
Seminomas occur more frequently than either choriocarcinomas or en-

dodermal sinus tumors. They are found most commonly in the same patient
population of young males between 20 and 30 years of age. Symptoms,
when present, relate to extrinsic compression of adjacent structures by the
mass, giving rise to retrosternal chest pain, cough and occasional hoarse-
ness, and the vena cava! syndrome. 38 The anterior mediastinal mass seen on
chest roentgenogram is nonspecific, and, as with most tumors, the diagnosis
is established at the time of biopsy or excision.
Complete surgical excision of a completely encapsulated seminoma of
the mediastinum may be curative. 38 However, surgical treatment alone is
rarely employed because of the high curative potential of radiation therapy.
The seminoma has the most favorable prognosis of the malignant germ cell
tumors, due to the marked sensitivity of the tumor to radiation therapy.
Radiation is usually delivered in a dose of 3000 rad over three weeks
using generous ports to include the entire tumor volume. 38,39 Patients ex-
periencing a compromised removal of their seminoma or patients present-
ing with tumors requiring a highly morbid surgical procedure should re-
ceive 4000 to 4500 rad in four to five weeks to a wide peritumoral volume
(see Thymoma). 36, 40 If elevated alpha-fetoprotein or /3HCG levels persist,
post-treatment chemotherapy may be indicated.
The five-year survival rate following radiation therapy, even in the ab-
sence of excision of the tumor, ranges from 50 to 90 per cent. 35- 41_4:f In a
collected review of over 100 patients treated principally by operation and
radiation, Silverman and Sabiston 2 found an overall five-year survival rate
of 58 per cent. This is probably a more accurate estimate of the prognosis
for all patients with this tumor but may be less optimistic than is actually
the case in those patients who are treated before distant metastases have
occurred.
MIDDLE MEDIASTINUM
Lymphomas
Lymphomas are discussed in Chapters 24 and 25.
POSTERIOR MEDIASTINUM
The posterior mediastinum contains the esophagus, lymph nodes, thorac-
ic duct, spinal cord, vertebral column, descending aorta,
and sympathetic
and peripheral nerves. Each of these structures may develop a lesion that
presents as a posterior mediastinal mass. However, neurogenic tumors com-
pose the vast majority of these lesions and will be the focus of attention in
this section. Tumors and cysts of the other structures occur much less com-
monly and will not be discussed here. It should be noted that from one
fourth to one third of all mediastinal tumors are malignant, and thus careful
diagnostic evaluation is mandatory, and surgical intervention is usually in-
dicated.
Neurogenic tumors are the most common
tumors of the mediastinum, and
in a recent collective series including 1000 patients they composed 24 per
cent of the entire group. 44 The malignant neurogenic tumors usually occur
in childhood but, fortunately, are less common than the benign tumors. 32
The frequency of malignancy has been reported to be between 10 and 20
per cent. 2 The majority of these tumors arise from intercostal and sympa-
thetic nerves, but a few arise from the vagus or phrenic nerve. 1
These tumors may be divided into two groups, depending on their ori-
gin —nerve sheath and nerve cells. Tumors of nerve sheath or fiber origin
are either neurofibromas, neurilemomas, or neuroblastomas. These usually
arise from differentiated Schwann cells.
Neurofibroma
This benign tumor contains all the nerve components (axons, sheath
cells, and connective tissue) and seldom undergoes malignant degenera-
tion. Frequently, the lesion is noted on an incidental chest x-ray in an
asymptomatic patient. Occasionally, symptoms of nerve entrapment, para-
plegia, or osteoarthropathy may be present. The sex distribution is equal,
1
FIGURE 20-3. Lateral chest

x-ruy of a neurofibroma. Note the
narrow base and acute angle that
the tumor forms with the medias-
tinal silhouette.
and the tumor has been described in all age groups. It is occasionally asso-
ciated with von Recklinghausen's neurofibromatosis but is usually a local-
ized solitary tumor of the posterior mediastinum. On radiograph, it appears
to have a narrow base and usually forms an acute angle with the mediastin-
um (Fig. 20-3). Grossly, the tumor is well encapsulated, and histologically
it is composed of a random arrangement of spindle-shaped cells. It occa-
sionally has a dumbbell configuration, in which case staged resection, with

removal of the spinal portion first, has been recommended. The prognosis
1
after surgical removal of benign neurogenic tumors is excellent, even if

incompletely removed, making adjuvant treatment unnecessary.
1
Neurilemoma (Schwannoma)
This tumor arises from sheath cells, and it is the most common neurogen-
ic tumor. Microscopically, it appears as an organized arrangement of elon-
gated fusiform cells 44 or a loose reticular pattern. 2 Rare cases undergo ma-
lignant degeneration. Most patients are asymptomatic, but a few note vague
back pain or mild osteoarthropathy. 2 The tumors are usually encapsulated
and solitary, although a recent review reported seven cases in which a sec-
ond simultaneous primary was found in close proximity. Radiographically,
1
calcification may be seen and indicates tumor necrosis only, not malignan-
cy. Dumbbell growth has been described, and, as in neurofibromas, it is
2
recommended that the resection be staged with the spinal portion removed
first. Treated surgically, patients with these tumors have an excellent prog-
nosis, and local recurrence is very uncommon. As in neurofibromas, no ad-

juvant treatment is recommended, even in the case of incomplete surgical

excision.
Neurosarcoma (Malignant Schwannoma)
This tumor has microscopic similarities to both neurofibroma and neurile-

moma and may represent the malignant degeneration of these tumors. They
usually occur in the older population. Clinically, patients with these tumors
present with pain or symptoms referable to invasion of adjacent structures.
This neoplasm has been associated with hypoglycemia secondary to elevat-
ed plasma insulin levels, 2 and blood glucose levels have been documented
45
to return to normal after resection. Grossly, these tumors have a pseudo-
capsule but are closely adherent to adjacent structures and invade quite
readily. Complete surgical excision is difficult, and recurrence is the rule.
Patients with recurrent disease may be treated using the guidelines for soft-
tissue sarcomas given in Chapter 15.
Ganglioneuroma
This isbenign tumor of nerve cell origin. It originates from the sympa-
a
thetic chain and thus is located in the paravertebral sulcus. This is the most
common type of neurogenic tumor in children 44 and is usually asymptoma-
tic, but it may present with hypertension secondary to catecholamine pro-
duction or with diarrhea and abdominal distention. 2 The radiograph usually

demonstrates a broad-based tumor with an obtuse angle at the tumor me-
diastinal interface. Complete surgical excision is usually easily accom-
plished, and recurrences are rare, although occasionally the tumor does ex-
tend through an intervertebral foramen making complete excision difficult. 9
Neuroblastoma
This tumor is discussed in Chapter 19.
Ganglioneuroblastoma
Ganglioneuroblastoma contains immature sympathetic nerve tissue and

mature ganglion cells. Its biologic nature lies between the always-benign
ganglioneuroma and the highly malignant neuroblastoma. These tumors are
usually extrathoracic but can be found in the posterior mediastinum. VMA
levels have been elevated in some patients with this disease. This tumor
has an excellent prognosis if completely excised but can present with dis-
seminated disease. Although ganglioneuroblastoma is found rarely in the
adult, the prognosis is extremely poor when it does occur. Radiation and
chemotherapy are felt to be helpful adjuncts to incomplete surgical exci-
sion.
Neural Crest Tumors (Pheochromocytoma,

Paraganglioma, Chemodectoma, and
Aortic Body Tumor)
These tumors arise from the chemoreceptor apparatus and are often hor-
monally active, in which case elevated urinary catecholamine levels and
systemic hypertension can usually be demonstrated. Less than 1 per cent of
all pheochromocytomas occur in the mediastinum and are usually found in
the paravertebral region (see Chapter 14). The paragangliomas, which are
extremely rare in the mediastinum, occur near the aortic arch but may also
be found in the posterior mediastinum. Although these tumors often appear
to be malignant microscopically, only 3 per cent actually demonstrate frank
invasion or distant metastasis. 44 Surgical excision is the treatment of choice
for all neural crest tumors. These neoplasms are radioresistant, and no che-
motherapeutic adjuvant treatment has been demonstrated to be helpful.
Reduplication Cysts
BRONCHOGENIC. Microscopically, these cysts are lined with ciliated co-

lumnar epithelium and contain mucous glands and cartilage. There may be
a demonstrable lumen between cyst and bronchial tree, but usually these
are connected by fibrous adhesions. X-rays demonstrate a sharply circum-
scribed, round to oval mass in the midposterior mediastinum, usually di-
rectly behind the carina. These cysts can produce symptoms referable to
bronchial compression if they are large or an abscess if they communicate
with the bronchial tree. Usually, however, they are asymptomatic and diag-
nosed incidentally by chest x-ray. The frequent association of these cysts
with cervical and thoracic vertebral anomalies has been noted. Malignant
degeneration has never been reported, 44 and surgical excision, which is eas-
ilyaccomplished, constitutes definitive treatment.
ENTEROGENIC. These cysts are lined with stratified squamous epitheli-
um with fibromuscular walls. Rarely, they contain gastric or small intestinal
mucosa. The structures are usually closely associated with the esophagus,
1
possibly even communicating with its lumen, and on occasion have been
found within the esophageal wall. Vertebral anomalies are commonly asso-
ciated with these cysts. Symptoms may be related to infection, esophageal
compression, ulceration, bleeding, or perforation. 44 Malignant degeneration
has not been described, but surgical excision is indicated to establish the
diagnosis and to avoid the unusual but serious complications already men-
tioned.
Miscellaneous Tumors
Mesenchymal. These rare mediastinal tumors of connective tissue in-

clude lipoma, liposarcoma, fibroma, fibrosarcoma, myxoma, and mesothelio-
ma. They account for about 7 per cent of primary mediastinal tumors and
cysts. 2 Fifty-five per cent of these neoplasms are malignant and behave
much as they do anywhere else in the body. Lipoma is the most common
1
of the mesenchymal tumors of the mediastinum. It may be found in any

compartment but is usually in the anterior mediastinum, specifically the
right cardiophrenic angle. Posterior mediastinal lipomas resemble neuro-
genic tumors and require surgical excision to establish the diagnosis. Radia-
tion and chemotherapy are helpful adjuncts to surgery in the treatment of
malignant varieties, but long-term prognosis remains poor.
Carcinoma. Undifferentiated or squamous cell carcinoma of the me-
diastinum is not rare, composing up to 11 per cent of primary mediastinal
lesions in some series." These tumors are typically anterosuperior in loca-
tion but may occur posteriorly. Although speculation as to the origin of
these tumors has included the thymus, lymph nodes, and lung, many are
found independent of these structures, and their origin remains unknown.
1,33
Prognosis is universally fatal, with radiation and chemotherapy offering
very little palliation.
Chordoma. Originating from embryonic notochord, this tumor demon-
strates chords of polygonal and vacuolated cells separated by homogeneous
mucin matrix. Most chordomas are intracranial or sacrococcygeal, but a few
are vertebral. Those occurring in a thoracic vertebra may present with cord
compression, or they may be noted on chest x-rays.
as incidental findings
Osteoblastic or lytic activity can be demonstrated, and often the mass con-
tains calcification. 46 These tumors are slowly invasive, and 10 per cent will
demonstrate distant metastasis. Surgical excision and radiation therapy have
achieved long-term survival rates; however, local recurrence is the rule.
Because the tumor is relatively radiosensitive, large doses of 5000 to 6000
46
rad in five to six weeks are recommended. In a single case report, dramatic-
improvement of symptoms secondary to a recurrent cervical chordoma fol-
lowed administration of vincristine. This may indicate a possible place for
chemotherapy in the management of this tumor. 47
Section 2
Vascular Tumors
Herbert I Machleder
INTRODUCTION
Although benign tumors and malformations of vascular origin occur with
great frequency in the catalogue of human pathology, malignant tumors of
demonstrably vascular origin are paradoxically quite uncommon. These
tumors are presumed to arise de novo, since malignant evolution from a
benign vascular neoplasm has rarely been established, despite abundant

opportunities for long-term surveillance. Several carcinogens have, howev-
er, been convincingly implicated in the genesis of malignant vascular neo-
plasms. Of historic interest is the angiosarcoma associated with exposure to
the early angiographic material Thorotrast.
43
More recently, hepatic angio-
sarcoma has been described with increasing frequency following prolonged
polyvinyl chloride exposure. 48, 49 The cause of most vascular neoplasms is
nevertheless obscure, although Kaposi's sarcoma and lymphangiosarcoma
have a characteristic propensity for development in unique clinical settings
that respectively suggest an environmental and iatrogenic component to eti-
ology.
Progress in clarifying the biologic characteristics of this rare group of
tumors has been retarded by difficulties in taxonomy and precise classifica-
tion. Although angiosarcoma has been used as a generic tenn to encompass
all malignant tumors of vascular origin, subdivisions based on histologic
differentiation of the predominant cell of origin have gained favor as a

more useful, accurate, and clinically valuable characterization. This has led
to the subclassifications of hemangiopericytoma, hemangioendothelioma,
Kaposi's sarcoma, lymphangiosarcoma, and malignant glomus tumors. Of the
malignant glomus tumors, only those of the carotid body will be discussed.
There is a disparity between the histologic characterization of these
tumors as benign or malignant and their ultimate biologic behavior. It is of
prime importance to recognize that the prediction of biologic behavior
based on histologic appearance alone can be hazardous in these tumors. A
tumor characterized as benign by the usual histologic criteria may, by its
subsequent biologic behavior, exhibit malignant characteristics, such as re-
currence, extensive local invasion, and metastatic spread. This problem is
particularly characteristic in the histologic grading of hemangiopericytomas.
HEMANGIOPERICYTOMA -
MALIGNANT HEMANGIOPERICYTOMA
This tumor arises from the normally occurring pericyte that is usually
identified on the external surface of vascular capillaries. The characteristic
axially disposed cytoplasmic processes are usually identifiable only by spe-
cial silver staining.Although in many instances the malignant hemangio-
pericytoma resembles the benign perithelioma or glomus tumor, there is
generally less evidence of differentiation, and assessment by electron mi-
croscopy indicates an absence in the malignant tumors of the usual smooth
muscle elements that occur in their benign counterparts. Histologically,
these tumors are very cellular with typically less stroma than fibrosarcomas.
Unfortunately, histologic assessment alone is notoriously inaccurate in
grading the malignant potential of hemangiopericytoma, with many well-
differentiated, cytologically mature, benign-appearing tumors being
synchronously associated with proven metastases. The gross appearance of
the tumor may also suggest a benign process, since these tumors tend to
have a circumscribed appearance. However, this is due to the compression
of surrounding fibroareolar stromal tissue rather than true tumor encapsula-
tion. In this instance, histologic examination reveals invasion of the sur-
rounding stromal tissue by pseudopods of sarcomatous tissue.
In general, the biologic behavior of malignant hemangiopericytomas
tends to imitate the fibrosarcomas, encompassing a wide variation in growth
rate from extremely rapidly proliferating and metastasizing tumors to those
characterized by very slow indolent growth. Despite the intimate relation-
ship of these tumors to the vascular system, the tendency toward hematoge-
nous metastatic spread seems no greater than that of other soft-tissue sar-
comas. Metastatic spread occurs in 10 to 15 per cent of cases, as culled
from the literature, and approximately 25 per cent of cases develop local
recurrence after wide local excision. It is evident, therefore, that the malig-
nant nature of these tumors must always be suspected despite the histolo-
gic appearance of benignity. When the tumor has unmistakably malignant
cytologic characteristics, however, there is a roughly 50 per cent incidence
of subsequent metastatic spread. 50
The peak incidence of clinical identification of these tumors is in the
third to the sixth decade with no sexual or racial predilection. The tumors
occur most commonly in the extremities, with the thigh predominating as a
site for primary location.
As a group, the angiosarcomas, including hemangiopericytomas, should

be staged as described for other soft-tissue sarcomas in Chapter 15. Since
these tumors are rare, prognostic groupings are difficult to define; however,
in general, the malignant form of hemangiopericytoma has a five-year sur-
vival rate of about 10 per cent with a three-year survival rate between 15
and 20 per cent.
Treatment
SURGERY. The mainstay of therapy is complete surgical excision of the

primary tumor if at all possible. The impressive vascularity of these tumors
combined with the potential for intraoperative dissemination have posed
formidable technical problems. Several recent innovations, however, have
reduced the operative risk considerably and have led to successful reports
of management and control of large and locally invasive tumors.
Superficially located tumors can be evaluated noninvasively, prior to op-
erative intervention, by use of the Doppler Flow Meter (Fig. 20-4). This
method enables a fairly accurate assessment of the major arterial and ve-
nous supply, so that vascular control can usually be accomplished before
extirpation. Endovascular techniques have dramatically changed the safety
of surgical treatment for the more deeply situated tumors, particularly the
large retroperitoneal angiosarcomas that attain great size and often present
Miscellaneous Solid Tumors 795
FIGURE 20-4. Doppler ultrasound flow meter used for transcutaneous assessmt nt of major
ular tupplv in tuperficiaUu disposed angiosarcoma
the specter of exsanguinating hemorrhage even following simple attempt at

incisional biopsy. Following angiographic characterization ot the tumor, the
major feeding vessels can be cannulated and emholized with thromhogenic
material, such as an absorbable gelatin sponge (Gelfbam) soaked in throm-
bin or the ferro-magnetic silicone approach developed by Rand (Figs. 20-5
and 20-61 A succinct description of this technique and its usefulness has
been provided by Smith and his coworkers. 51
Radiation Therapy. This tumor is commonly considered "radioresis-
tant," based on older studies using low-energy treatment techniques. A re-
port from Memorial Hospital in New York suggests that this view may be
inappropriate, since 90 per cent of a group of patients with advanced he-
mangiopericytomas responded to radiation therapy, and more than half of
the responding patients enjoyed complete tumor regression. 5 - The dose re-
quired for such benefit would appear to be in the range of at least 5000 rad
in five weeks to ports designed to cover the tumor bed with a wide margin.
CHEMOTHERAPY. The most useful single agent for the treatment of ma-
lignant angiosarcomas is doxorubicin, with a response rate of about 44 per
5-5
cent based on a cumulative search of the literature. Scattered case reports
suggest that dactinomycin-containing combination regimens may also be
useful. 54 58 Based on this spectrum of activity, one should probably utilize
"
combination chemotherapy as described for other soft-tissue sarcomas (see

Chapter 15) when chemotherapy is indicated.
Integration of Treatment Modalities. Given the renewed interest
in chemotherapy and radiation therapy for the treatment of sarcomas, plus
FIGURE 20-5. Angiogram of large

retroperitoneal pelvic hemangioperi-
cytoma.
FIGURE 20-6. Same tumor as in

Figure 20-5 after endovascular em-
bolization prior to resection.
the highly malignant nature of many hemangiopericytomas, combined mo-

dality therapy should probably be employed in patients thought to have a
malignant variant of this tumor. General guidelines for such an approach to
the soft-tissue sarcomas are given in Chapter 15.
HEMANGIOENDOTHELIOMA-
MALIGNANT HEMANGIOENDOTHELIOMA
The hemangioendothelioma and its malignant counterpart are derived

from the vascular endothelial cell and manifest a biologic behavior that cor-
relates well with the histologic grade. The malignant tumors characteristi-
cally show evidence of rapid cell division, endovascular invasion, and loss
of histologic differentiation. In the most anaplastic variants there may be
loss of formation of the distinguishing vascular clefts, without which accu-
rate assignment of the tumor to vascular origin becomes difficult. Biologic
behavior and histologic appearance run in parallel, with one end of the
spectrum being well-differentiated, clinically benign lesions or tumors
characterized by modest differentiation and a clinical course often de-
scribed as "low-grade malignancy," with a typically attenuated course of
indolent growth and eventual invasion and metastatic spread. At the other
pole are frankly undifferentiated tumors with sparse hemangioendothelial
elements that have a characteristically aggressive malignant clinical course.
Grossly, these tumors are soft with a lack of compressibility giving them
,
a characteristically indurated conformation. When close to the skin and sub-

cutaneous tissue, there is an ecchymotic appearance with occasional satel-
lite nodules evident. As with a hemangiopericytoma, the mass max be
somewhat circumscribed but rarely encapsulated. Although there is gener-

ally compression of surrounding fibrous stromal tissue, this is usually
breached by invading tumor cells and again undoubtedly accounts for the
high rate of local recurrence following enucleation. Metastasis occurs in
about 10 to 15 per cent of reported cases, and the routes of spread are quite
similar to those of the hemangiopericytoma.
Staging should follow the guidelines described for hemangiopericytomas.

The prognosis of hemangioendotheliomas is similar to that of hemangio-
pericytomas for a given stage and grade of lesion.
Treatment
The principles and choice of treatment are as described previously for

hemangiopericytomas. As a generality, the therapy of these tumors has
been most successful when wide local resection has been followed by radi-
52
ation therapy.
KAPOSI'S SARCOMA
An angiosarcoma with peculiar distinguishing characteristics was de-

scribed in 1872 by Kaposi and retains the designation of Kaposi's sarcoma.
This is not only by virtue of primacy but also because of the relatively
obscure cytologic origin of this tumor and the attendant problems of cell
type classification. 57 The tumor has a definite racial predilection, occurring
uncommonly in whites and when it does occur, it is almost always confined to
males in that race (94 per cent), predominantly in the skin of the lower extrem-
ities. The disease has a particular predilection for black Africans, more specifi-
Bantu tribes. It has recently been described in Arctic
cally those of the
Eskimos and may indeed be more widespread than earlier reports sug-
gest.
In the earliest stages, red macules or papules may develop, followed by
relatively rapid spread along the course of the superficial veins,which in
the lower extremities leads to venous thrombosis and ankle edema. Purpura
and pruritus are typical, with pain and tenderness being very common. The
brownish discoloration of hemochromatosis gradually develops with the
progressive deposition of hemosiderin in macrophages. These characteris-
tics maylead the clinician to think that he or she is dealing with manifesta-
tions of the postphlebitic syndrome accompanied by chronic venous hyper-
tension and venous stasis. This similarity necessitates biopsy and histologic
verification of all unusually indolent venous ulcers that continue to pro-
gress, despite the administration of what would ordinarily be adequate ther-
apy for the less severe condition.
There is no established staging system for Kaposi's sarcoma; however,

three clinical patterns of the disease are recognized that have some prog-
nostic value. 58 the disease tends to remain localized,
The nodular form of
and long survival is nearly always seen. Locally aggressive Kaposi's sar-
coma has a worse prognosis; many of these patients develop subsequent
lymph node or bone involvement, and in a series from Africa, the three-
year survival rate with this form was 64 per cent. 58 Patients with general-
ized Kaposi's sarcoma have the most aggressive and lethal form of the dis-
ease; in an African series there were no survivors at three years with this
form of disease. 58
Treatment
Nodular forms of Kaposi's sarcoma are generally treated by wide local

resection. More extensive local disease may require the addition of radia-
59 60
tion therapy, or even radiation therapy as a sole modality. This tumor
'
tends to be very radiosensitive. Indeed, in a small series from San Francis-

co, local control was achieved in all patients treated with 2000 or more rad
over two weeks.' 9
Generalized forms of Kaposi's sarcoma are treated with chemotherapy.
Vinblastine as a single agent appears to be especially useful, 61 but other
agents are also active including BCNU, bleomycin, vincristine, and dactin-
omycin. 62 The variety of active agents bodes well for programs of combina-
tion chemotherapy, although this is an unexplored approach to treatment.
LYMPHANGIOSARCOMA
Only one malignancy of lymphatic vascular origin has been character-
ized in the literature, the lymphangiosarcoma. This tumor arises most com-
monly in long-standing lymph stasis and lymphedema. The particular oc-
currence in postmastectomy lymphedema was first reported by Stewart and
Treves in 1948 63 (Stewart-Treves syndrome), since which time over 200
cases have appeared in the medical literature. 64
The lesion is often first recognized as an ecchymotic area in the arm of
the patient with postmastectomy lymphedema, from as early as 5 years to as
late as 25 years following radical mastectomy. The ecchymotic area usually
becomes ulcerated, and satellite lesions develop. The histologic appearance
shows typically malignant endothelial cells in the stroma, which is charac-
teristically that of chronic lymphedema composed of proliferating lymphat-
ics and lymphocyte infiltration.
Metastatic spread is common, and therapy
to this time has been singular-
ly unsuccessful. Radical forequarter amputation and radiation therapy are
often followed by stump recurrence, or the appearance of pulmonary metas-
tases, usually evident within a year of diagnosis. The five-year survival rate
reported in the literature ranges from 5 to 10 per cent. Palliation and a few
long-term survivors have been reported after radiation therapy. Responsive-
ness has been noted to cyclophosphamide, although long-term survival has
still not been reported following this therapy.
CAROTID BODY TUMORS

Tumors of the carotid body are of perivascular origin, invariably develop-
ing in the thick adventitial tissue of the intersection of internal and external
carotid arteries at the carotid bulb. These tumors are characterized by slow
FIGURE 20-7. Angiogram of

carotid body tumor showing "clear
area" of adventitial plane in which
dissection can be accomplished.
preserving carotid vessels.
indolent growth progressing to late local invasion and occasional late met-
astatic spread.
The intimate relationship of this tumor to the carotid bifurcation, with a
tendency for local pressure rather than invasion to result in palsy of the
hypoglossal and superior laryngeal nerves, as well as Horner's syndrome
from compression of the sympathetic trunk and superior stellate ganglion,
has led to extirpation of the tumor and accompanying blood vessels. The
very high incidence of hemiplegia and mortality after this procedure was
probably unwarranted, since there is an overall incidence of local recur-
rence of less than 10 per cent and a less than 5 per cent incidence of met-
astatic spread. Whengraded histologically, however, a large proportion, and
in some cases as many
as 50 per cent, of the tumors would be characterized
as malignant by these criteria alone. This certainly is not borne out by an
overall surveillance of the biologic characteristics of this tumor. Problems
of local recurrence and metastatic spread have generally been confined to
tumors that have attained large size at the time of initial therapy.
Although the necessity for angiography has been questioned in the litera-
ture, this technique does verify the nature of the tumor and the patency of
the internal and external carotid vessels. In general, there is a relatively
avascular subadventitial plane through which the vast majority of these
tumors can be removed without sacrifice of either branch of the common
carotid artery. This so-called clear area is quite evident in the accompany-
ing angiogram (Fig. 20-7). The assessment of internal and external carotid
artery integrity can be made noninvasively by the Doppler ophthalmic test
or by oculopneumoplethysmography. 50, M
Recognition of the mentioned characteristics has led to a dramatic change
in the therapy of these tumors, with morbidity and mortality exceedingly

rare and no concomitant increase in local recurrence or metastatic
66, 67
spread. In the occasional case of local invasion, the placement of an
indwelling carotid shunt and grafting with an autogenous saphenous vein
should provide proper reconstitution after carotid artery resection. Cerebral
protection can be provided by either an indwelling internal carotid or ex-
ternal carotid shunt. 68
•1. \V\ chulisAR. et al.: Surgical treatment 22. Weissberg D and Goldberg M: Ann
of mediastinal tumors A 40-year— Thorac Surg 16:141. 1973.
experience. J Thorac Cardiovasc 23. Boston B: Cancer 38:49, 1976.
Surg 62:379, 1971. *24. Goldman AJ, et al.: Myasthenia gravis
*2. Silverman \A and Sabiston DC, Jr: and invasive thymoma: a 20-year ex-
Primary tumors and cysts of the me- perience. Neurology 25:1021, 1975.
diastinum. Curr Probl Cancer 2:1, 25. Keynes G: Lancet 1:1197. 1954.
1977. 26. Friedman NB: Cancer 4:265. 1951.
3. Heimburger IL and Battersby JS: J 27 Schlumberger HG: Arch Pathol
Thorac Cardiovasc Surg 50:92, 41 :398, 1946.
1965. 28. Teilum G: Cancer 12:1092. 1959.
4. Bergh \P. et al.: Ann Thorac Surg 29. Willis, RA: Pathology of Tumors. Wo-
25:91, 1978. burn, Mass. Butterworths Pub, Inc, p.
5. Braitman H. et al.: Arch Surg 703:14. 984, 1960.
1971. 30. Rubush JL. et al.: J Thorac Cardiovasc
6. Whittaker LD and Lynn HB: Surg Surg 65:216, 1973.
Clin North Am 53:893, 1973. 31. Kurman RJ. et al.: Cancer 40:2136,
7. Pokomy WJ and Sherman OJr / 1977
Thorac Cardiovasc Surg 68:869, 32. Vaughan, VC, III. et al.: Nelson Text-
1974. book of Pediatrics. 11th ed. Philadel-
8. HaJler JA, et al.: J Thorac Cardiovasc phia. \VB Saunders Co, 1^7 l ).
Surg 58:385, 1969. 33. LeRoux BT: Thorax 15:333, 1960.

9. Grosfeld JL, et al.: Ann Thorac Stin: 34. Came\ JA, et al: J Pediatr Surg 7:271.
i2:179. 1971. 1972.
10. Field EO, et al.: Br J Haematol 35. Cox JD: Cancer 36:1162, 1975.
15:101, 1968. 36. Martini N, et al.: Cancer 33:763, 1974.
11. Mac- Lean LD. et al.: Surgery 40:1010, 37. Fine G. et al.: Am J Med 32:776, 1962.
1956. Besznyak I. et al.:} Thorac Cardiovasc
12. Scholz DA and Bahn RC: Mayo Clin Surg 65:930, 1973.
Proc 34:433, 1959. 39. It/ DC and Buscemi MF: J Urol
13. Souadjian JY. et al.: Arch Intern Med 105:271. 1971.
134:374, 1974. 40. Bagshaw MA. et al.: Am J Roentgenol
14. Mink JH. et al.: Am J Roentgenol Rad Ther Xucl Med 205:86, 1969.
130:239, 1978. 41. Schantz A, et al.: Cancer 30:1189, 1972.
"15. Wilkins EW, et al.: Cases of thymoma 42. Maier JG, et al.: J Urol 99:72, 1968.
at the Massachusetts General Hospi- 43. Quinlan MF and Scopa ]: Aust \Z J
tal. J Thorac Cardiovasc Surg Med 6:329. 1976.
52:322. 1966. 44. Oldham HN Jr: Ann Thorac Surg 11:
16. Mulder DG, et al.: Am J Surg 128:202, 246, 1971.
1974. 45. Rossman EM: Arch Intern Med 104:
'17. Bematz PE, et al.: Thymoma: factors 604, 1959.
influencing prognosis. Surg Clin 46. Wang CC and James AE Jr: Cancer 22:
Am 53:885, 1973.
North [62. l
l
)68.
18. Cohn LH and Grimes OF: Surg Gyne- 47. Razis DY. et al.:] Med 5:274. 1974.
col Obstet 131:206. 1970. *48. Brady J, et al.: Angiosarcoma of the
10. Salver WR
and Eggleston JC: Cancer liver: an epidemiologic survey. J
37:229. 1976. Natl Cancer Inst 59:1383, 1977.
20. Penn CPH and Hope-Stone HF: Br J 49. Editorial: Br Med J 2:134, 1976.
Surg 59:533. 1972. 50. Machleder HI and Barker WF: Arch
21. Marks RD, et al.: Cancer 41:117, 1978. Surg 112:944, 1977.
802 II / Treatment of Spe< iih Neoplasms
*51. Smith RB, et al.: Preoperative vascular 61. Tucker SB and \\ inkelmann KK: Arch
embolization as an adjunct to suc- Dermatol iJ2:958, 1976.
cessful resection of large retroperi- 62. Vogel CL, et al.: Cancer Chemother
toneal hemangiopericytoma. J Urol Rep 57:325, 1973.
115:206, 197d. 63. Stewart FW and Treves N: Cancer
52. Mira JG, et al.: Cancer 39:1254, 1977. 2:64, 1948.
53. Gottlieb JA, et al.: Cancer Chemother "64. HerrmannJB: Lymphangiosarcoma of
Rep (Part 3) 6:271, 1975. the chronically edematous extremity.
54. Cohen Y, et al.: Oncology 26:180, Surg Gynecol Ohstet 121: 1107,
1972. 1965.
55. Bredt AB and Serpiek AA: Cancer 65. Machleder HI: Angiology 24:374,
24:266, 1969. 1973.
56. Ortega JA, et al.: Cancer 27:730, 1971. 66. Chambers RG and Mahonev WD: Am
57. Braun-Faleo O, et al.: Virchows Arch J Surg 116:554, 1968.
(Pathol Anat) 369:215, 1976. "67. Shamblin WR, et al.: Carotid body
58. Templeton AC and Bhana D: J Natl tumor (chemodectoma): Clinicopath-
Cancer Inst 55:1301, 1975. ologic analysis of ninetv cases. Am J
59. Mann SG: Am J Roentgenol Racl Ther Surg 122:732, 1971.
Nucl Med 121:793, 1974. 68. Machleder HI and Barker WF: J Car-
60. Duncan |Tk: Clin Radiol 28:503, diovasc Surg (Special Issue):506,
1977. 1976.
CHAPTER 21
ACUTE LEUKEMIA
Jacob Zighelboim Robert P Gale
INTRODUCTION
Acute leukemia encompasses a heterogenous group of hematologic neo-
plasms that originate from the malignant transformation of stem cells or
precursor cells undergoing myeloid or lymphoid differentiation. The infil-
tration of blood-forming tissues, lymph nodes, spleen, central nervous sys-
tem, and other organs by leukemic cells causes the clinical manifestations
that characterize these disorders. The processes encompassed by the term
acute leukemia have been divided into two groups on the basis of morpho-
logic, cytochemical, immunologic, and therapeutic differences. These
groups are acute lymphoblastic leukemia (ALL) and acute myelogenous
leukemia (AML).
To avoid unnecessary repetition, features common to both these process-
es (i.e., etiology, epidemiology, and biology) are discussed jointly. Howev-
er, the clinical, diagnostic, and therapeutic features of the two groups are
discussed separately.
21 / Acute Leukemia 803
Etiology
Genetic Factors. The cause of acute leukemia is unknown in most

instances. Heredity plays a role in some cases. 1,2 Acute leukemia has been
reported to occur with increased frequency in identical twins, particularly
if the onset of disease is before the age of ten years. In certain high-risk
families, the incidence of AML in genetically nonidentical siblings may be

two to four times higher than normal.
Acute leukemia occurs with increased frequency in a spectrum of con-
genital disorders, including Down's syndrome (trisomy 21), Bloom's syn-
drome, Klinefelter's syndrome, Fanconi's anemia, osteogenesis imperfecta,
and the Wiskott-Aldrich syndrome. In Down's syndrome, the relative risk
of developing acute leukemia may be increased as much as five to ten
times, and the leukemia is usually myeloid despite the young age of these
patients. 3 Fifty per cent of patients with Bloom's syndrome and up to 25
per cent of those with Fanconi's anemia may develop AML. Cells from
these patients show increased chromosomal breaks in vitro, and their fibro-
4,5
blasts show increased susceptibility to SV40 transformation. The relation-
ship between these findings and the development of acute leukemia is un-
clear. Other diseases that are associated with abnormal DNA repair
mechanisms, such as xeroderma pigmentosum, are not associated with an
increased risk of developing AML.
Several forms of congenital leukemia, i.e., cases present at birth or within
the first year of life, have been reported, including AML, ALL, and chronic
myelogenous leukemia. Conditions associated with congenital leukemia in-
clude trisomy 21, trisomy 13-15, absent radii, the Ellis-van Creveld syn-
drome, patent ductus arteriosus, the Klippel-Feil syndrome, atrial and ven-
tricular septal defects, and the Bonnevie-Ullrich syndrome. 6, Some cases
of congenital leukemia, particularly those associated with trisomy 21, re-
solve without specific therapy.
RADIATION. The leukemogenic effect of ionizing radiation has been
well established. Survivors of the atomic bomb have experienced an in-
creased incidence of all types of leukemia, and an increased risk of acute
leukemia, particularly AML, has been reported in medical personnel and
patients exposed to excess radiation. Radiation has been shown to cause
breaks in double-stranded DNA and to induce the replication of oncogenic
viruses. This is particularly true of C-type RNA viruses (retroviruses), some
of which are associated with murine and primate leukemias. 8,
CHExMlCALS and Drugs. Chemicals, particularly hydrocarbons, have
been associated with acute leukemia in animals and humans. There is con-
vincing evidence of a relationship between benzene exposure and AML in
humans. A small proportion of workers exposed to benzene for five years or
more develop a marrow failure syndrome that may occasionally terminate
in AML. 10 Erythro leukemia is particularly common following benzene ex-
posure, but all subtypes have been reported. Chloramphenicol and phenyl-
butazone have likewise been implicated, but the data are less convincing.
Chemicals and drugs associated with a heightened risk of AML tend to
be toxic to hematopoietic stem cells and tend to cause chromosome breaks
similar to the effects of ionizing radiation. This association is strengthened
by increasing reports of AML in patients with neoplastic and immunologic

disease with cytotoxic and
treated immunosuppressive drugs or radia-
tion. Although AML may develop in the natural history of related neo-
11-13
plasms, such as multiple myeloma or Hodgkin's disease, the increased in-

cidence (3 to 400 times) in patients with breast and lung carcinomas and in
immunosuppressed patients with non-neoplastic diseases is noteworthy. Al-
kylating agents, procarbazine, and the nitrosoureas are the drugs most fre-
quently implicated.
Viruses. A direct relationship between RNA viruses and leukemia has
been demonstrated in animals, and C-type RNA leukemia viruses have
been found in mice, rats, fowl, cats, cattle, sheep, and subhuman primates.
Recently, several studies have suggested that virus-related leukemia can
occur in cats despite the inability to detect either virus or virus-directed
reverse transcriptase in affected animals. Leukemogenic RNA viruses iso-
lated from different species are remarkably similar. These viruses contain
reverse transcriptase (an RNA-directed DNA polymerase), have similar
primer requirements, and show molecular homology to varying degrees.
Considerable research has been directed toward detecting a leukemogen-
ic virus in patients with acute leukemia. 14, 15 Despite several intriguing ob-
servations, including the reported recovery of C-type RNA viruses in sever-
al cases, there is no convincing evidence of a viral etiology of acute
leukemia in humans.
Epidemiology
The question of leukemia clustering has been of concern in recent years.

Eight cases of ALL or stem cell leukemia were reported in Niles, Illinois
between 1957 and 1960. 1H This represented a 15- to 20-fold increase in the
expected incidence in neighboring towns. Similar clusterings have been
reported in other communities. When reported "clusters" are examined
with newer statistical techniques, the degree of clustering becomes less
apparent. Equally interesting are the so-called leukemia houses, in which
leukemia occurs in successive occupants of the same house. 17 It should be
strongly emphasized that these observations do not imply that acute leuke-
mia is contagious in nature. In fact, all evidence to date points in the oppo-
site direction. Despite the existence of several hundred documented cases
of leukemia during pregnancy, only two cases in the offspring have been
reported. 18 Furthermore, the incidence of leukemia does not increase
among marital partners of affected subjects.
The incidence of acute leukemia is five to seven cases per 100,000 peo-
ple per year. 19 ALL is the most common type of acute leukemia in children,
whereas AML is most common in adults. The peak incidence for ALL
occurs between the ages of four and five years, whereas the peak incidence
for AML occurs during the fifth and sixth decades. ALL and AML occur
with equal frequency in both sexes. 20 One exception is T cell ALL (a sub-
type of ALL in which leukemic blasts have surface characteristics of T
cells), which occurs more frequently in males, with a ratio of 5 to l. 21
Biology
The pathophysiology of the leukemic process is still unclear. The hypoth-

esis that is most accepted describes a clone of leukemic cells that probably
develops from a single cell mutation. This clone usually has a longer gener-
ation time than normal marrow cells, 22 but produces few, if any, endstage
cells. Consequently, despite a slow doubling time, leukemic cells infiltrate
bone marrow, lymph nodes, spleen, and other organs and tissues.
The leukemic cell population can be divided into a proliferative compart-
ment, composed of larger cells with several nucleoli, and a nonproliferative
compartment, composed of smaller blast cells with few (usually one) nu-
cleoli.
The
nonproliferating cells can remain in phase G, for 10 to 20 days and
sometimes for even longer periods. 2,1 These "resting" cells appear to be
morphologically viable and metabolically active in terms of continued RNA
and protein synthesis. Some have the potential to resume rapid prolifera-
tion once the tumor cell mass has been reduced by treatment. Rosen et al. 24
provided experimental support by demonstrating that small, dormant AKR
leukemic lymphoblasts, after transplantation into normal AKR mice, prolif-
erate and cause death at about the same time as do large, actively proli-
ferating leukemic cells. Clearly, nonproliferating cells are resting cells that
are capable of DNA synthesis and division. The corollary is that to cure
this disease, all leukemic cells must be eradicated.
At the time the patient is first seen, leukemic tissue has occupied a large
segment of the bone marrow, having displaced or inhibited normal hemato-
poietic elements. Although the production of red blood cells, granulocytes,
and platelets is markedly decreased, the proliferative rate of normal hema-
topoietic precursors is not slower than that of leukemic cells. This indicates
that depressed hematopoiesis must result from the inhibition of normal
stem cell differentiation and maturation by the leukemic process.
Section 1
Acute Lymphoblastic
Leukemia
INTRODUCTION
Acute lymphoblastic leukemia is a hematologic neoplasm characterized
by the accumulation of immature lymphoid cells in bone marrow and the
impairment of stem cell function. Normal hematopoiesis is decreased with
resultant development of anemia, granulocytopenia, and thrombocytopenia.
S06 II / Treatment of Specific Neoplasms
Clinically, it presents as an infiltrative disorder involving primarily bone
marrow, blood, spleen, and lymph nodes. Recently, it has become evident
that the term ALL encompasses a heterogenous group of disorders with
distinct clinical, immunologic, and biochemical features.
NATURAL HISTORY
Leukemic lymphoblasts have a broad range of morphologic appearances.

The lymphoblasts of an individual patient can be morphologically homoge-
nous, as in childhood ALL, or heterogenous, as in the adult form of the
disease. On rare occasions, lymphoblasts present as a monomorphic cell
population resembling Burkitt's lymphoma cells. On the basis of these ob-
servations, Bennett et al. 25 subdivided undifferentiated nonmyeloid blast
cell leukemias into three morphologic groups: L, lymphoblasts, which are
small and homogenous (includes most cases of childhood ALL), L, lymph-
oblasts, which are heterogenous (includes most cases of adult ALL), and
L lymphoblasts, which are homogenous and have the cytomorphologic
:J
appearance of Burkitt's lymphoma cells. Morphologic analysis alone does

not provide sufficient information for the critical evaluation of undifferen-
tiated blasts. Some cases currently identified as lymphoblastic leukemia
may prove to involve cells of different origin when more sophisticated
techniques are applied.
ALL can be further subdivided on the basis of the surface characteristics
of the neoplastic cells. At present, three subtypes of ALL are identified —
—
T cell, B cell, and null cell ALL 26 27 according to whether the leukemic'
lymphoblasts have surface characteristics of T cells (form rosettes with

sheep erythrocytes), B cells (surface membrane immunoglobulin, comple-
ment, or Fc receptors), or neither of these (Table 21-1).
Most workers agree that 75 to 85 per cent of patients belong to the null
cell subtype. 28 Previously, identification of null cell ALL was based on neg-
ative findings, i.e., lack of surface markers for T and B cells. This technique
has been replaced by a positive definition based on lymphoblast reactivity
TABLE 21-1. Classification of ALL by Membrane Phenotype
Reactivity with
Surface Antimll Cell
Markers Classification Morphology ALL Sera
Absent vi ii
Null cell
II ui
ALL f
<
Childhood
, . ,
L, (75% cases)
Positive (72%)
[Adult L 2 (68% cases)
T cell T cell ALL Variable L, + L2 Negative
B B ALL urki "' sT yP e Negative

cell cell (?
[ Lymphosarcoma L2 , rarely L!
with specific rabbit antinull cell sera. 29, 30 The antigen or antigens detected
by these sera are absent from fetal and adult lymphocytes, and from T and B
cell leukemias. This antigen is expressed in 50 per cent of adult patients and
more than 70 per cent of affected children, allowing for the subclassification of
null cell ALL into antigen (+) and antigen (— ). The biologic significance of
this subclassification is still unclear.
T cell encompasses between 15 and 20 per cent of all cases of ALL.
ALL
31
This form of leukemia has distinct clinical and cytochemical features.
Usually, >50 per cent of lymphoblasts form rosettes with sheep erythro-
cytes (E rosettes), with a range of 28 to 91 per cent. By contrast, E rosette-
forming cells compose ^ 10 per cent of the blast cells in patients with the
null cell subtype. 31
In some cases, T cell-specific antisera react with non-E
rosetting blast cells. This indicates that some cases classified as null cell
ALL may indeed represent leukemias involving T cells that are lacking
surface receptors for sheep erythrocytes.
B cell ALL is rarely seen and probably represents the leukemic form of
poorly differentiated lymphocytic lymphomas. Two morphologic types are
recognized —
the Burkitt's type and the lymphosarcoma type. The former is
more common in children and young adults and probably corresponds to
the advanced stage of the so-called non-African sporadic or nonendemic
Burkitt's lymphoma. 32 Cells of the lymphosarcoma type, which are usually
seen in patients who are older than 50 years of age, are often extremely
undifferentiated by morphologic criteria.
Clinical Features
The onset of leukemia usually subtle, with gradual presentation of pal-

is
lor, anorexia, irritability, and malaise. Low-grade fever is often present and
may alternate with intermittent periods of marked temperature elevation.

Infection is the primary' cause of elevated temperature. Frequently, howev-
er, cannot be firmly documented in patients presenting with
infection
fever. Petechiae and ecchymoses are common, and occasionally bleeding
involving mucous membranes is found at diagnosis.
Most patients with ALL have symptoms for less than three months before
diagnosis. 33 Typical laboratory features include leukocytosis with immature
cells or blasts, anemia, granulocytopenia, thrombocytopenia, and bone mar-
row packed with poorly differentiated blast cells. The peripheral leukocyte
count varies between 1 and 400 X 10 9 /L (1,000-400,000/mm 3 ). Approximately
half the patients present with pancytopenia and no circulating blasts. Patients
with T cell ALL tend to present with higher white blood cell counts. 31 Leu-
kostasis due to intravascular clumping of leukemic cells may occur in patients
with blast counts in excess of 100 X 10 9 /L. This leads to tissue hypoperfusion
and occlusion of small blood vessels. In addition, perivascular infiltration of
the meninges is common in these circumstances and may account for the
poor prognosis associated with high blast counts. 34
Bone marrow infiltration by leukemic blasts results in alterations of nor-
mal hematopoietic activity. Anemia occurs in more than 90 per cent of pa-
tients and is generally normocytic and normochromic, although macrocyto-
sis, poikilocytosis, and polychromatophilia may also be present.

Normoblasts are in the bone marrow, and morphologically ab-
reduced
normal erythroid elements are frequently seen. There is evidence that
erythropoietin production is normal 35 and that the anemia may be due to a
decrease in the stem cell compartment available for erythroid differentia-
tion. 36 Thrombocytopenia occurs at some time during the course of the ill-
ness in most patients with ALL and is thought to result from a decreased
number of megakaryocytes in bone marrow. In some cases, splenic seques-
tration of platelets may be contributory. Granulocytopenia likewise occurs
in most patients and seems to result from a reduced number of bone mar-
row precursors undergoing myeloid differentiation.
Lymph node and splenic enlargement are frequent in ALL. The nodes
are usually firm, nontender, and diffusely involved. Uncommonly, medias-
tinal lymph nodes can be markedly enlarged. In T cell ALL, an anterior
mediastinal mass is demonstrated in two thirds of patients at diagnosis,
whereas only 6.7 per cent (9/134) of patients with null cell ALL present
this finding. 31
Neurologic manifestations of ALL result primarily from meningeal in-
volvement by the leukemic process or hemorrhage secondary to thrombo-
cytopenia, or both. Meningeal leukemia begins in the arachnoid space and
occasionally spreads into the brain parenchyma. 37 Early symptoms of men-
ingeal leukemia include headache and nausea. Increased intracranial pres-
sure may lead to papilledema, convulsions, cranial nerve palsies, and sepa-
ration of the cranial suture lines in children. In addition to the meninges,
the CNS parenchyma may be directly infiltrated by leukemic cells. The
examination of cerebrospinal fluid characteristically shows low sugar levels,
elevated protein levels, and leukemic cells on the cytocentrifuge or nucleo-
pore filter preparations.
Bone pain occurs in 40 to 50 per cent of children with ALL. Roentgeno-
graphic changes include transverse bands of decreased density at the ends
of the metaphysis, osteolytic lesions, subperiosteal new bone formation,
and, rarely, osteosclerotic lesions. 38 Histologically, one may see thinning of
trabeculae and periosteal infiltration with leukemic cells. The mechanism
of bone destruction is unknown. Crowding and pressure alone are insuffi-
cient to explain the findings. Likewise, the mechanism responsible for
bone pain obscure. Joint pains are also frequently described. The clinical
is
picture may simulate rheumatoid arthritis or rheumatic fever. 39 These find-

ings may be associated with infiltration of the synovia or involvement of
bone adjacent to the joint.
Genitourinary manifestations include hematuria, cystitis, pyelonephritis,
priapism, and renal failure. Microscopic foci of leukemic cells in the kidney
are frequently found. 40 Infiltration of sufficient magnitude to produce renal
enlargement and impairment of renal function are relatively uncommon.
Testicular involvement in ALL is common and may occur even when the
patient is in hematologic remission. 41
Infections are common at the time of diagnosis and are usually present at
the time of death. Infectious complications may be of bacterial, viral, fun-
gal, or protozoal origin and are a major cause of death in lymphoblastic
leukemia. 42 Infections may be due to common bacterial pathogens (i.e.,

4:i
gram-negative microorganisms, pneumococcus, staphylococcus) or oppor-

tunistic pathogens like Listeria, Candida, Aspergillus, Pneumocystis carin-
44
ii, or viruses. At the time of diagnosis or during the course of remission
induction, patients are frequently affected by bacterial infections, most of
which present as septicemia without localized findings. During mainte-
nance, however, most infectious complications are of viral origin or involve
opportunistic pathogenic microorganisms. 44
ALL causes marked impairment in host antimicrobial defense mechan-
isms. The most important abnormality is the reduction in the number of
phagocytic leukocytes as a result of the underlying disease process or che-
motherapy, or both. Both neutrophils and monocytes may be reduced in
number. Even when normal numbers are present, their mobilization to
fight off infection may be impaired by adrenal glucocorticoids, and their
microbicidal activity may be abnormal as a consequence of the disease
process or the effects of therapy.'"'
Diagnosis
The clinical and laboratory features of ALL are nonpathognomonic, and

thus are of limited diagnostic value. The most common symptoms
at diag-
nosis are weakness, bleeding, tendency to bruise easily, pallor, anorexia,
nausea, and vomiting. Lymphadenopathy, hepatosplenomegaly, and pur-
pura are the most common physical findings. Laboratory features include
anemia, granulocytopenia and thrombocytopenia, elevation of LDH levels,
hyperuricemia, abnormal liver function tests, and, occasionally, elevations
in BUN levels.
In patients presenting with leukocyte counts higher than 5 X 10 9 /L (5,000/
mm 3
), leukemic blast cells are usuallyfound in peripheral blood smears. In
contrast, patients presenting with leukopenia must undergo examination of a
bone marrow sample to make the diagnosis. Typically, the marrow aspirate
shows hypercellularity, obliteration of fat spaces, and marked reduction in
normal hematopoietic elements. Marrow spaces are infiltrated by leukemic
blast cells that, in the majority of cases, can be properly identified by their
morphologic and cytochemical features.
Morphologically, leukemic lymphoblasts vary in size and have a high
nuclear-cytoplasmic ratio, 1 to 2 nucleoli, and no Auer bodies in their cy-
toplasms. Furthermore, erythroblasts make up less than 50 per cent of bone
marrow cells. 4
Mathe and associates 46 identified five morphologic types of ALL, which
they designated as (1) microlymphoblastic, (2) prolymphocyte, (3) macro-
lymphoblastic, (4) prolymphoblastic, and (5) immunoblastic. After review-
ing 345 bone marrow slides, Flandrin et al. 47 were unable to distinguish
the five types of ALL. Clearly, further studies are necessary to determine
whether or not this cytomorphologic classification is of diagnostic and prog-
nostic significance.
ALL blast cells are peroxidase-, Sudan black-, and alpha-naphthyl-AS-D-
chloroacetate esterase-negative. The periodic acid-Schiff (PAS) reaction,
which cytoplasmic glycogen, is positive in over 90 per cent of

stains
cases. 4849 lymphoblasts show coarse granules or blocks of
Usually, the
PAS-positive material in the cytoplasm.
It has been suggested that nuclear arylsulfatase stains are useful for the
diagnosis of ALL. 50 This enzyme, however, is not specific for ALL, since
blast cells obtained from well-characterized cases of can show posi- AML
tive staining.
Acid phosphatase is a useful cytochemical marker for T cell ALL. In a
double blind study, 1 of 51 patients with null cell ALL had a positive reac-
tion. In contrast, all (8/8) patients with T cell ALL had a positive reaction.
The acid phosphatase reaction can be particularly useful in the identifica-
tion of ALL patients with lymphoblasts lacking surface receptors for sheep
erythrocytes.
Chromosome analysis of leukemic lymphoblasts reveals no characteristic
karyotypes. Approximately 50 per cent of cases show aneuploidy or pseudo-
diploidy at diagnosis, 51, 52 with many having a hyperdiploid chromosome
number. The more frequent abnormalities occur in chromosome groups C,
D, E, and G. 5:! These groups of chromosomes may contain genes that are
concerned with the regulation of white blood cell production or differentia-
tion.
Leukemic lymphoblasts have distinct biochemical features that can be
helpful in their identification. Reverse transcriptase (an RNA-dependent
DNA polymerase) is an enzyme found in ALL blasts that could serve as a
marker for leukemic cells, once sensitive methods for its intracellular iden-
tification are developed. Similarly, terminal deoxynucleotidyltransferase
(TdT) has been found in increased concentrations in the peripheral blood
and bone marrow of the majority of patients with ALL at the time of initial
presentation and during relapse. 54 55 In contrast, bone marrow and periph-
-
eral blood TdT levels are normal during remission.

55
Prognostic Factors
The natural history of ALL has been modified, so that 50 per cent of
affected children enjoy long-term survival. For the remaining 50 per cent,
relapse and death are still inevitable. The latter group might benefit from
new therapeutic approaches. Knowledge of prognostic factors in acute leu-
kemia may contribute to the identification and selection of these
patients.
Age represents the best defined and consistent patient characteristic with
prognostic significance. The best survival has been reported for patients
between the ages of three and 10 years. 56 The white blood cell count at the
time of diagnosis has been consistently associated with response rate and
patient survival. Decreased response rate and shortened survival have been
reported for patients presenting with a WBC greater than 100 x lO^L
(100,000/mm 3 As response rates to chemotherapy have improved, the WBC
).
has lost part of its prognostic significance. 57

The height of the been identified as important in prognos-
platelet count has
ticating survival in children and adults with acute leukemia. 57 Patients with
low platelet counts (25 x lOVL (25,000/mm 3 )) have poor prognoses, whereas
21 Acute Leukemia 811
those with platelet counts equal to or higher than 100 X 10VL (100, 000/ 3
mm
)
have favorable prognoses.

T cell ALL has a poorer prognosis than null cell ALL. The former has
been described as an aggressive disease with shorter remission duration
and survival time. 58
Hemoglobin concentration, organomegaly, degree of bone marrow infil-
cytochemical features may have prognostic significance in ALL.

tration, or
The data supporting these conclusions, however, are controversial and, to
date, inconclusive.
TREATMENT
At the time of diagnosis, the leukemic mass ranges between 10" and 10
13
cells, depending on patient size and extent of disease.' If we assume 10

9 12
leukemic cells to be present, a 13-decade reduction is necessary for com-

plete disease eradication. By contrast, to achieve bone marrow remission, a
smaller cell reduction, i.e., two to three decades, is required. Consequent-
ly, more than 10 viable leukemic cells might be present after bone marrow
9
remission and be clinically nondetectable.

Following a two- to three-decade reduction, seven to ten doublings
would restoretumor cell mass to its original volume. After a two-decade
reduction, assuming a doubling time of 5 days, the tumor cell mass would
return to its original volume in 35 days. These observations strongly sup-
port the need for the continuation of therapy after bone marrow remission
has been achieved.
Principles of Chemotherapy
There are three phases to the treatment of ALL, which require separate
consideration. Remission induction represents the and most important
first
phase and is directed toward the rapid restoration of bone marrow and
body functions. The first eight weeks of treatment are of fundamental im-
portance for remission duration and survival. If therapy is suboptimal dur-
ing this time, important opportunities might be lost, and subsequent at-
tempts at disease control could result in failure. The second phase of
therapy involves the use of continuation chemotherapy to prolong remis-
sion duration. This phase aims to control the disease in the bone marrow
(maintenance chemotherapy) and in extramedullar} sites, particularly the
central nervous system (CXS prophylaxis). Maintenance chemotherapy
should be continued for long periods, since early cessation leads to relapse
within a few months. The final phase of the program involves the decision
for cessation of therapy.
Remission Induction. The immediate goal of remission induction che-
motherapy is the prompt reduction of the leukemic cell mass and the res-
toration of normal hematopoiesis. A secondary goal is to reduce this mass to
the smallest fraction possible in anticipation that disease behavior will be
influenced by the body's tumor burden. The criteria for remission status are
TABLE 21-2. Remission Induction Rates Achieved with Prednisone

in Combination with Other Effective Agents
Drug No. Patients Treated % Remission
Vincristine >200 82-92
6-Mercaptopurine 107 48
Daunomycin 44 81
Methotrexate (oral) 100 50
Methotrexate (IV) 14 100
fairly well established and include (1) Mj marrow, i.e., <5 per cent lympho-
blasts, (2) the absence of lymphoblasts in peripheral blood and the pres-
ence of more than 0.5 X 10 9 granulocytes/L and 75 x 10 9 platelets/ L, and (3)
the absence of physical findings attributable to ALL.
In childhood ALL, prednisone, in combination with vincristine or other
effective agents, induces complete remission in >80 per cent of untreated
patients (Table 21-2). 60 Remission rates are increased to>90 per cent when
either L-asparaginase or daunomycin are added to the former two
agents. 61 2 The addition of a fourth agent to these regimens has resulted in
'-
small increments in remission rates, but drug-induced toxicity and morbidi-

ty clearly increased (Table 21-3).
The remission induction regimen that is employed influences the propor-
tion of patients remaining in complete remission. 63 Clearly, the use of two-
drug regimens results in greater numbers of relapses than does that of
three-drug regimens. This observation suggests that the number of leu-
kemic cells killed by remission induction therapy is an important determin-
ant in disease control. Accordingly, a three-drug combination, including
vincristine, prednisone, and L-asparaginase or daunomycin, should be used
as the regimen of choice for remission induction.
With most programs, complete remission is achieved within four weeks,
with only 5 to 10 per cent of patients showing persistent blast cells in the
bone marrow by that time. Some of these patients might benefit from two
TARLE 21-3. Remission Induction Rates Using Three- and

Four-Drug Combinations
Drug No. of Patients Treated % Remission
Prednisone, vincristine, >100 97

and L-asparaginase
Prednisone, vincristine, >100 94-98

and daunomycin
Prednisone, vincristine,
6-mercaptopurine, and 35 88-94
methotrexate
to four extra weeks of treatment with the same or alternate drugs. Failure to
achieve remission can be primarily attributed to the development of drug
resistance, severe infections, CNS leukemia, or a combination of these.
Remissions induced with prednisone alone are usually brief (median du-
64
ration two to three months), whereas with combination regimens, unmain-
65
tained remissions may sometimes last more than one year. These results
are still inferior to those obtained with programs that include maintenance
therapy and support the rationale for using the latter in current chemother-
apy programs.
Intensification or Consolidation. Data derived from the murine L1210
leukemia model indicate that disease curability is dependent upon the de-
gree of reduction of the malignant cell population at the beginning of thera-
66
py. Consequently, following remission induction, a period of intense ther-
apy designed to further reduce the leukemic cell mass was included in
several studies. 67
unclear at this time whether or not intensification or consolidation
It is
therapy prolongs remission or increases the number of patients achieving

therapy-free survival. Most consolidation regimens were evaluated at a time
when the significance of CNS prophylaxis was not fully appreciated and
maintenance regimens were less aggressive. Consolidation of remission has
also been attempted by administering x-irradiation to extramedullary sites
recognized as leukemia sanctuaries. Limited numbers of patients have re-
ceived consolidation radiation therapy to liver, kidney, 68 thymus, and
spleen, 69 none of which has influenced the outcome of the disease.
Central Nervous System Prophylaxis. In the early 1960s, a fundamental
obstacle in the control of ALL was the development of central nervous sys-
tem leukemia in patients who otherwise remained in bone marrow remis-
sion. Complete remission was terminated by primary CNS relapse in 33 to
67 per cent of patients not receiving specific CNS therapy. 60 Consequently,
prevention of CNS leukemia became indispensable and resulted in the in-
corporation of CNS prophylaxis in the treatment of ALL.
The rationale for prophylactic therapy was based on the hypothesis that
CNS infiltration by leukemic cells had already occurred by the time the
disease was diagnosed and that these cells were sequestered in an area
beyond the reach of drugs commonly used for remission induction. At some
later time these cells would begin to grow and produce symptomatic CNS
leukemia. This hypothesis is supported by the chromosomal analysis of leu-
kemic blasts from bone marrow and spinal fluid, which demonstrates that
meningeal leukemia is indeed a metastatic manifestation of the disease. 70
Histopathologic evaluation of meningeal leukemia provides the rationale
for not using intrathecal chemotherapy alone. Studies of drug distribution
after intrathecal injection indicate that leukemic infiltrates involving the peri-
vascular arachnoid are not adequately exposed to the injected drugs, thus
serving as potential foci from which meningeal relapse might occur. In con-
firmation, Jacquillet et al. 71 noted a 33 per cent primary meningeal relapse de-
spite repeated instillations of intrathecal methotrexate.
Currently, the most frequently employed fonn of CNS prophylaxis com-
bines cranial irradiation with intrathecal methotrexate. This combination
814 II / Treatment of Spe< uk Neoplasms
has reduced the incidence of meningeal leukemia from more than 40 per
cent to less than 8 per cent. 72 These observations were confirmed in a study
conducted by the Medical Research Council, which demonstrated that only
1 of 75 patients receiving prophylactic CNS therapy relapsed with menin-
75
geal disease. Intrathecal and high-dose intravenous methotrexate given
throughout a period of continuation chemotherapy have been proposed as
alternative methods of CNS prophylaxis. Further follow-up is required be-
fore meaningful efficacy and toxicity evaluations can be made.
Complications associated with either prophylaxis or treatment of CNS
leukemia include chemical arachnoiditis, transient paralysis, transverse
74
myelitis, and encephalopathy. There are indications that neurotoxicity as-
sociated with intrathecal methotrexate may be secondary to prolonged ex-
posure to high drug concentrations. 75
Cranial irradiation can affect CNS toxicity of chemotherapeutic agents
given at a later time. 76 Supposedly, the irradiation alters the blood-brain
barrier, changing vascular permeability and allowing for larger amounts of
drug to come in contact with the brain parenchyma. Patients treated with
large doses of intravenous methotrexate after a course of cranial irradiation
have an increased risk of developing leukoencephalopathy. This association
may hold true for other drugs as well.
Continuation Therapy. Initial approaches to continuation therapy
consisted of the administration of single agent chemotherapy. Methotrexate
and 6-mercaptopurine were the agents most commonly used. 60 The effec-
tiveness of this approach was severely hampered by the development of
resistant leukemia that rapidly led to disease recurrence. As experience
grew, results improved steadily with the use of regimens combining single
agents given at dosages close to their maximum biologic tolerance. The St.
Jude Children's Research Hospital conducted a study in which patients
were randomized into four distinct continuation therapy arms. 77 Patients in
the first ami received methotrexate alone, those in the second arm received
6-mercaptopurine and methotrexate, those in the third arm had cyclophos-
phamide added to the first two drugs, and those in the fourth arm had cyto-
sine arabinoside added to the other three drugs. As expected, the four-drug
regimen caused a greater degree of immunosuppression (involving T and
B lymphocytes) and was associated with a higher incidence of Pneumocys-
tis carinii pneumonia. The overall relapse rate for the second, third, and
fourth groups was equivalent. By extrapolation, it might be concluded that

a combination of 6-MP and methotrexate is adequate for maintenance thera-
py ALL.
in
Cessation of Therapy. The optimal duration of maintenance chemo-
therapy is unknown. Lonsdale et al.™ using single-agent maintenance che-
motherapy, demonstrated that patients who were treated for two to six
months after remission induction had shorter remissions than those receiv-
ing continuous therapy until relapse. For patients in their initial complete
remission, the question arises concerning when, if ever, therapy should be
discontinued. In the absence of adequate means for determining the pres-
ence of residual leukemia, no objective means are known to determine at
what point therapy can be safely stopped.
An analysis of the course of 132 patients whose maintenance therapy was

discontinued after 2.5 to 3 years revealed a relapse rate of 16 per cent. 79 Of
those patients who relapsed, six had not received specific CNS therapy,
indicating its importance in remission duration. The likelihood of relapse
after the discontinuation of maintenance therapy is greater during the first
>ear. A pertinent question currently under investigation is whether or not
maintenance therapy given for more than three years significantly reduces
the likelihood of relapse.
Treatment of High-Risk ALL

Although this group is considered under one heading, it is highly he-
terogenous and requires the use of varied and individualized therapeutic-
approaches. Included in this category are patients with T cell ALL, CNS
leukemia at diagnosis, a white blood cell count greater than 50 x 10 9 /L,
and failure to achieve remission after four weeks of induction therapy.
In a study reported by Simone et td., n the stratification of patients into
different chemotherapy arms according to risk factors did not improve the
results that had been obtained using more conventional approaches. It is
hypothesized that these patients readily develop drug resistance, which ex-
plains their failure to respond to conventional treatment, making the identi-
fication of the mechanisms leading to drug resistance essential before sub-
stantial improvement can be expected.
Treatment of Recurrent Disease
Leukemia may recur either in the bone marrow or in an extramedullary

site. If the bone marrow and blood are involved, the time of relapse is of
prognostic importance. Among patients relapsing during therapy, the possi-

bility of a long-term second remission is small. With a three-drug combina-
tion that includes vincristine, prednisone, and L-asparaginase or daunomy-
cin, second remissions can be achieved in approximately three quarters of
patients. These remissions, however, are of short duration (about 60 days),
and subsequent relapse is almost inevitable. 81 If, in contrast, relapse occurs
after the discontinuation of therapy, retreatment is more successful, and re-
mission induction rates of about 95 per cent can be achieved with a regi-
men combining prednisone, vincristine, and doxorubicin. 82 The second re-
mission in this category of patients is usually longer, with some patients
reaching the point at which maintenance therapy can be discontinued. For
patients who are refractory to these drugs, combinations of cytosine arabin-
oside with 6-thioguanine or L-asparaginase have been reported to be effec-
tive in over half of those treated. 83 However, remission durations were brief,
morbidity was severe from drug-induced neutropenia, and allergic reactions
were common.
CXS leukemia, the most common site of extramedullary relapse, is pri-
marily seen in patients who received no CNS prophylaxis (see previous
section in this chapter on CXS prophylaxis). Intrathecal methotrexate is the
standard therapy for CNS leukemia. The dosage commonly used is

12 mg/nr given weekly for six doses. If leukemic cells persist in the spinal
fluid, additional doses are given until spinal fluid samples are free of leu-
kemic cells. If progressive pleocytosis or an increase in protein concentra-
tion occurs, intrathecal methotrexate is discontinued, and radiotherapy to
the cranial-spinal axis is instituted. Usually, doses of 1500 to 2400 rad over
a two- to six-week period are given, depending on factors such as age, focal
neurologic signs, and patient tolerance.
After CNS leukemia has developed, it has a tendency to recur. Kinetic
studies in three patients with CNS leukemia clearly indicate that a large
portion of the leukemic cells in the CNS are dormant and may remain viable for
long periods without initiating DNA synthesis. 84 The presence of resting
leukemic cells in the CNS is an important obstacle to eradicating CNS disease.
The median symptom-free interval for successful treatment of CNS leukemia is
about 90 days. 85 Early recurrence tends to be more frequent in patients with
high spinal fluid blast counts. Because of the high recurrence rate, maintenance
therapy is recommended. Intrathecal methotrexate, given at a dose of 12 mg/m 2
every six weeks, can significantly prolong the disease-free interval. For pa-
tients who are resistant to methotrexate and radiation therapy, cytosine arabin-
oside is the next drug of choice. The doses used have varied between 5 and 100
mg/m 2 and response
, has lasted for about one month.
Testicular relapse has increased in frequency as patients with ALL survive
for longer periods of time. In a large number of cases, testicular relapse has
occurred after the cessation of maintenance therapy. The treatment of choice is
x-irradiation to the affected testicle. Bilateral irradiation is not indicated,
particularly for patients with unilateral involvement confirmed by biopsy.
Relapse in other sites is frequently seen in this patient population, justifying
the additional administration of a reinduction type of chemotherapy program as
a preventive or delaying measure.
Treatment of Adult ALL

Remission rates and survival times in adult patients with ALL (> 15 years old)
are significantly less than for children with the same disease. Remission
induction rates have ranged between 50 and 90 per cent, with most studies
reporting remission rates of 65 to 80 per cent. 86, 87 Clarkson et a/. 88 treated adults
and children with an intensive, multiple drug chemotherapy program (L-2
protocol) and achieved 78 per cent and 99 per cent remission rates, respec-
tively. A combination of vincristine and prednisone induced complete remis-
sions in 50 per cent of treated patients, whereas the addition of daunomycin
increased the remission rate to 75 percent. The median remission duration for
adult patients with 10 to 12 months, with the exception of patients who
ALL is
are treated according to the L-2 protocol who have a median remission of 2
years and a median survival of 33 months.
Analysis of therapeutic results with current programs reveals that the majori-
ty of patients will have relapsed by three years. In consequence, new and better
chemotherapy programs are required. Clarkson and his collaborators devel-
oped a new program (L-10 protocol), which approaches the toxicity limits that
can be safely tolerated by adults. It is too early to determine whether or not
long-term results will be superior to those obtained with other programs.
It is unclear why adult ALL is less responsive to chemotherapy than is
childhood ALL. One possibility is that the disease originates from the malig-
nant transformation of a primitive undifferentiated cell with distinct biochem-
ical and biologic features, one of which is the rapid acquisition of resistance to
drugs commonly employed in the treatment of childhood disease.
Immunotherapy
Remission rates and survival have dramatically improved in children with

ALL. Nonetheless, 50 per cent of patients are still relapsing and dying of their
disease during the initial five years following remission. To improve the
outcome of ALL, several forms of immunotherapy have been investigated
(Table 21-4).
The first immunotherapy was reported by Mathe and coworkers in
trial
1969. 89 Children with ALL

remission were treated for two years with
in
combination chemotherapy and were then randomized to receive immunother-
apy or no further therapy. Eight patients received BCG by scarification, five
patients received subcutaneous injections of allogeneic irradiated leukemic
cells, seven patients received a combination of both forms of immunotherapy,
and ten patients received no therapy at all. All patients in the untreated group
had relapsed by 130 days postrandomization, whereas half the patients receiv-
ing immunotherapy were still in remission. Furthermore, 1000 days after
randomization 45 per cent of the immunotherapy patients remained in remis-
sion. These patients were not stratified according to prognostic parameters
currently identified for ALL, and therefore the results may not be representa-
tive.
TABLE 21-4. Results of Immunotherapy in ALL

Method of BCG
Immunotherapy Administration Results Referinc £s
Allogeneic Cells -+- BCG

89
French group Scarification Prolonged remission Mathe et a/.
and survival
EORTC Scarification No effect Otten 90
NTH Heaf gun No effect Poplack"
BCG
Glaxo strain Heaf gun No effect Kay"
Tice strain Tine multiple No effect Heyn et al.

93
puncture
Pasteur strain Heaf gun No effect Ekert et al**

The British Medical Research Council conducted a study designed to test

Mathe's observations. 95 Their results demonstrated that maintenance thera-
py with BCG did not prolong remission duration. It should be emphasized,
however, that the chemotherapy and BCG strain (Glaxo Lab) employed in this
study were different from those used by Mathe. Furthermore, specific immu-
notherapy with allogeneic leukemia cells was not employed. 95
Andrien et a/. 96 reported no difference in the relapse rate or the death rate for
patients receiving either maintenance chemotherapy or maintenance immuno-
therapy with BCG and allogeneic irradiated leukemic cells. Randomization
into the maintenance arm was performed after completion of one year of
consolidation therapy, and therefore these results may reflect the effects of the
latter rather than the effectiveness of the immunotherapy program.
Poplack 91 investigated the effectiveness of BCG and nonirradiated allogen-
eic leukemia cells given immediately following remission induction. Immuno-
therapy was given intermittently for periods of two months interspersed
between four-month cycles of chemotherapy. No significant difference in
relapse rate or remission duration was seen, with 59 per cent of patients from
both groups remaining in remission after 30 months.
During the last ten years, there have been dramatic improvements in the
treatment of childhood ALL. Several groups using combination chemotherapy
and CNS prophylaxis have had as many as 80 per cent of their patients in
complete remission at five years without any form of immunotherapy. These
important developments raise serious doubts as to whether immunotherapy,
as understood today, has any role in the treatment of this disease.
Complications of Therapy
Drug-induced myelosuppression or immunosuppression, or both, frequent-

lyoccur in patients with ALL. Combination chemotherapy produces lympho-
penia that involves T and B cell populations. After chemotherapy is discontin-
ued, B cells reach normal levels within 2 to 3 months, whereas it takes T cells
approximately 12 months. If a severe infection develops during remission,
myelosuppressive therapy should be stopped until the infection is properly
controlled. If, in contrast, the patient is in relapse, antileukemic therapy should
be continued because granulocyte recovery will not occur unless the leukemic
process is controlled.
During the administration of chemotherapy, various complications may
develop (see Chapter 4 for detailed information on toxic side effects of chemo-
therapy). Growth is somewhat retarded. However, once therapy is discontin-
ued, catch-up growth is the rule, and most patients eventually attain normal
height and weight.
Mucous membrane and gastrointestinal tract ulcerations that are seen in
association with methotrexate therapy are well controlled by the adjustment of
drug dosage. Cystitis, hematuria, and contracted bladder can occur in pa-
tients receiving cyclophosphamide. If hemorrhagic cystitis develops, the
drug should be stopped immediately and restarted only after the microscopic
hematuria has cleared. Sterility might be associated with cyclophosphamide
therapy and spinal irradiation.
Cranial or craniospinal irradiation has been associated with multiple side
effects, including somnolence and low-grade fever. Furthermore, interference
with brain growth has also been reported.
Intrathecal administration of methotrexate or ara-C results in headaches,
vomiting, meningism, and febrile reactions. On some occasions, convulsions
and dementia have been described. 97 The effects of therapy on neuropsycholo-
gic development have become most important as increasing numbers of chil-
dren are achieving long-term disease-free survival. Initial results indicate no
impairment 98 Further studies are, however, required to elucidate this very
important aspect of the treatment of ALL.

Considerable progress has been made in the treatment of childhood ALL.
Remission induction is achieved in more than 80 per cent of cases using
combination chemotherapy regimens that include vincristine and prednisone.
Central nervous system prophylaxis is essential to permit long-term disease-
free survival and should be used in every patient entering bone marrow
remission. Maintenance therapy using a combination of methotrexate and
6-mercaptopurine or the latter plus cyclophosphamide results in a median
remission of 4.5 to 5 years. A large proportion of these children may actually be
cured. Today, with ten-year follow-up data, we can estimate that patients who
are disease-free five years after remission induction have a < 10 per cent risk of
developing recurrent disease.
The disease, however, is far from conquered. Fifty per cent of children in
remission have recurrence during the initial five years. Of those, few will
achieve long-lasting second remissions. An important goal, therefore, is to
increase the percentage of patients remaining disease free. To accomplish this,
a better understanding of prognostic factors and biologic properties of the
leukemic cells is essential. Ideally, future therapy would be tailored and
individualized according to prognostic factors. Stratification of patients accord-
ing to prognostic categories based on cell surface markers is already under way.
Patients with null cell ALL have excellent prognoses, whereas those with T
cell ALL have the worst prognoses. It is quite likely that the latter group
encompasses many of the patients who develop recurrent disease and fail
current chemotherapy programs. This latter group may indeed benefit from
more aggressive chemotherapy.
Efforts should equally be invested into developing accurate methods for
detecting residual leukemia. This would be extremely useful in determining
the length of maintenance therapy and furthermore would provide accurate
guidance as to when therapy can be safely discontinued.
Section 2
Acute Myelogenous Leukemia

INTRODUCTION
Acute myelogenous leukemia is a hematologic neoplasm characterized by
the accumulation of immature myeloid elements in the bone marrow. Be-
cause of a common stem cell origin, other hematopoietic cells, including
monocyte-macrophages, red blood cells, and megakaryocytes, are frequent-
ly involved.
The term AMLencompasses a spectrum of diseases that may involve ei-
ther a single cell line, as in acute myeloblastic or monocytic leukemia, or
several cell lines, as in acute myelomonocytic leukemia or erythroleukemia.
These three subgroups are discussed together, making special reference to
features of diagnostic or therapeutic import.
NATURAL HISTORY
Classification
Acute myelogenous leukemia can be classified on the basis of the degree

of differentiation and maturation. 99, 10 ° Those leukemias with granulocytic
differentiation include a group showing no maturation (Mi), maturation to
or beyond the promyelocyte stage (M 2 ), and a variant with hypergranular
promyelocytes and Auer bodies, which are abnormal primary granules
characteristic of leukemic myeloblasts (M 3 ). Acute leukemias with monocy-
tic differentiation include a heterogenous group with myeloid and monocy-
tic features — myelomonocytic
leukemia (M 4 ), and a "pure" form — mono-
cytic leukemia (M 5 ). The final variant, erythroleukemia (M 6 ), shows
prominent involvement of immature erythroid precursors.
Clinical Features
The hematologic features of AML result from the "crowding out" of nor-
mal hematopoiesis, involvement of other cell lines in the neoplastic proc-
ess, and indirect effects of leukemia on normal cells. Approximately 20 per
cent of patients have symptoms of anemia that precede the diagnosis of
AML by weeks or months. It is usually of modest severity, although some
patients present with a hemoglobin concentration/dL of 5 gm or less. The
anemia of AML is usually normocytic and normochromic, and poikilocyto-
sis is common. The pathogenesis of the anemia is complex and involves
decreased production and increased destruction of red blood cells second-
an leukemic involvement of red blood cell precursors. 101 The latter is

to
particularly evident in erythroleukemia (MJ and in patients with a preced-
ing history of sideroblastic anemia, refractory anemia with excess blasts
(RAEB) or "preleukemia.' 99100 Iron deficiency may develop secondary to
bleeding or nutritional deficiencies.
Bleeding is a common feature in patients with AML. It may be mild, as
in patients with petechiae of the skin or mucous membranes, or severe, as
in patients with gastrointestinal genitourinary, or central nervous system
hemorrhage. Bleeding has two major causes —
thrombocytopenia and coag-
ulation abnormalities. Twenty to 50 per cent of patients with AML present
with thrombocytopenia. This is related to decreased platelet production as
well as to increased consumption resulting from infection, hypersplenism,
and, rarely, disseminated intravascular coagulation (DIC). Megakaryocytes
may occasionally be involved in the leukemic process, resulting in abnor-
mal platelet production. Coagulation abnormalities —
including hypofibrin-
ogenemia, abnormalities of factors V and VII, increased fibrin degradation
products, and circulating anticoagulants —
occur in a variable proportion of
patients with AML. Disseminated intravascular coagulation is frequent in
patients with acute promyelocyte leukemia (M3 ) and is related to the re-
lease of a protein with factor YH-Iike activity from the leukemic promyelo-
cytes. 1"- IW
Infection is a common feature of AML, the incidence of which is in-
versely related to the level of circulating neutrophils. 104 Normal neutrophils
are usually decreased because of direct involvement of the myeloid stem
cell by the leukemic process. Additionally, neutrophils from patients in re-
mission may not function normally, further compromising host defenses.
Common types of infections include gingivitis, stomatitis, cellulitis, perirec-
talabscesses, pneumonia, urinary tract infection, and septicemia. Bacterial
infections are common, but fungal infections occur in treated patients, as do
viral and protozoal infections. Staphylococcus, Pseudomonas, Escherichia
co/i, and Klebsiella are frequent pathogens.
Diagnosis
Physical Findings. Physical findings in patients with AML from

result
the infiltration of normal tissues by leukemic cells. The most important site
of leukemic infiltration is the bone marrow, which may lead to bone or
joint pain from increased intramedullary pressure or periosteal involve-
ment. Hepatomegaly, splenomegaly, and lymph node enlargement have
been reported in 10 to 60 per cent of patients with AML and are more
common in younger patients. Renal abnormalities may develop from infil-
tration, obstruction of the ureters by enlarged nodes, uric acid nephropathy,
or from infectious or hemorrhagic complications. Gastrointestinal symptoms
of distention, early satiety, and obstipation may result from organomegaly
or from direct leukemic infiltration.
Central nervous system leukemia may present with features of increased
intracranial pressure, including headache, papilledema, diplopia, or cranial
II / Treatment of Spfj q u Neoplasms
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nerve palsies. This usually due to meningeal infiltration. Leukemic in-

is
volvement of the heart and lung is uncommon. Patients with acute monocy-
tic leukemia (M-, typically develop skin or gingival infiltration.
)
Laboratory Features. In most instances, the diagnosis of AML

de-
pends upon the demonstration of malignant cells in the bone marrow. Rare-
ly, the diagnosis may be made on the basis of extramedullary tissue in-
volvement.
Except for Auer bodies (abnormal primary granules) that are found in less
than 10 per cent of cases, there are no pathognomonic features of AML.
The morphologic and histochemical features that distinguish AML from
ALL are detailed in Table 21-5. AML cells tend to be larger, have a lower
nuclear-cytoplasmie ratio, and have discrete nuclear chromatin and multi-
ple prominent nucleoli. Bilobed nuclei (pseudo-Pelger-Huet nuclear abnor-
mality) may be present. Histochemical stains for myeloperoxidase, alpha-
naphthyl-AS-D-chloroacetate esterase, and Sudan black are helpful in dis-
tinguishing AML from ALL. The results from these stains may be negative,
however, owing to the immaturity of the cells, and a negative result does
not exclude the diagnosis of AML. Esterase staining may be used to distin-
guish myeloid from monocytic leukemia, since the latter has a fluoride-
inhibitable esterase not present in the myeloid variant Erythroblasts from
patients with erythroleukemia tM typically stain with periodic acid-Schiff
t; )
(PAS) reagent.
The morphologic features of AML may be indistinguishable from the
blastic phase of chronic myelogenous leukemia, but chromosome analysis
will usually reveal the absence of the Philadelphia (Ph chromosome.
1
)
Prognostic Factors
Because of the substantial morbidity and mortality associated with induc-

tion therapy, it is important to identify patients who are most likely to ben-
efit from treatment. Age, performance status, morphologic diagnosis, pre-
treatment myeloblast and platelet counts, and pretreatment fever, infection,

or hemorrhage seem to have prognostic importance. 105, ,06 Almost all these
points are controversial. For example, age was a significant prognostic fac-
tor in recent Medical Research Council trials, with 55 per cent of patients
less than 30 years old achieving complete remission, compared with 21 per
cent of those over 60 years achieving complete remission. In contrast, re-
cent trials of intensive induction chemotherapy show no age-related differ-
ences in response rates.
Several investigators have attempted to correlate pretreatment cytokinetic
parameters —including mitotic index, labeling index, and growth frac-
tion —with the outcome of therapy. 107 To date, cytokinetic data seem to be
of limited value in predicting response to chemotherapy, and the applica-
tion of cytokinetic principles, including cell synchronization, requires fur-
ther investigation.
In vitro growth of hematopoietic cells has also been used to predict clini-
108, 109
cal responsiveness. Several cell growth classification systems have
been proposed. These generally divide patients into those without evi-
dence of leukemic growth (with or without residual normal Jiemato-

cell
poiesis), those with abortive colony formation or clusters, and those with
both clusters and colony formation with an abnormal colony-cluster ratio.
The last two groups are believed to represent different patterns of leukemic
cell growth. In most studies reported there has been a significant correla-
tion between the in vitro growth pattern and the response to chemothera-
py. Results are preliminary, however, and it is difficult to compare data
from different centers.
TREATMENT
Chemotherapy
Remission Induction. The initial therapeutic goal in AML is to induce

remission. The usual strategy is to reduce the leukemic cell mass rapidly
with intensive chemotherapy. Complete remission is defined as less than 5
per cent myeloblasts in the bone marrow, normalization of hemoglobin,
granulocyte, and platelet counts, resolution of organomegaly, and return to
a normal performance status.
Drugs active in AML are indicated in Table 21-6. Cytosine arabinoside
is a pyrimidine analogue that inhibits DNA synthesis by competitive inhi-
bition of DNA polymerase. 110
Complete response rates of 20 to 40 per cent
have been reported with doses of 100 to 200 mg/m 2/day by continuous in-
travenous infusion or by 8 to 12 hourly intravenous injections for five to
seven days. The combination of ara-C and 6-thioguanine may produce a
slightly higher remission rate, ranging from 20 to 50 per cent in several
large series. 111 115 Studies from
"
MD
Anderson Hospital and the Southwest
Oncology Group have evaluated the combinations of ara-C, vincristine, and
prednisone with or without cyclophosphamide (COAP and OAP). 114 Results
with these regimens are comparable to those obtained with ara-C and thio-
guanine.
Daunomycin, a cell cycle phase-nonspecific agent, is a highly effective
drug in the treatment of AML. This agent, at a dose of 40 to 60 mg/m 2 /day
for one to three days, produced complete remissions in 30 to 50 per cent of
patients. 116 118 The response rate of a combination of ara-C and daunomycin
'
given over five days was 40 to 50 per cent, which is comparable to results
TABLE 21-6. Drugs Active in Acute Myelogenous Leukemia
Drug % Complete Remissions
Thiopurines (6-MP, 6-TG) 10
Cytosine arabinoside (ara-C) 20-35
Daunomycin 25-50
5-Azacytidine 15-30
TABLE 21-7. Combination Chemotherapy in Acute Myelogenous Leukemia
Drug % Complete Remissions
Ara-C + 6-TG 25-40
Ara-C + Daunomycin 30-50
Ara-C + Daunomycin ± 6-TG (5 days) 30-50
Ara-C ± Daunomycin ± 6-TG (7 days) 50-80
with daunomycin alone, or a combination of ara-C, 6-thioguanine, and dau-

nomycin given over five days. 118 120 A summary of selected remission induc-
"
tion schedules is given in Table 21-7.

Further advances in AML therapy occurred with the development of more
intensive induction regimens. These programs usually include ara-C and 6-
thioguanine given for seven days at a dose of 100 to 200 mg/m 2 /day, and dau-
nomycin, given on either the first three or last three days at a dose of 45 to 60
mg/m 2 /day. Several groups reported 60 to 86 per cent complete remissions
with no substantial differences seen when daunomycin was given at the be-
ginning or the end of the schedule (or when doxorubicin was substituted for
"
daunomycin). 112, 121 126
Numerous experimental drugs have been evaluated in patients who fail
to achieve remission with standard agents including nitrosoureas, the ara-C
analogues 5-azacytidine and cyclocytidine, cisplatin, rubidazone, epipodo-
phylotoxin (VP 16-213), L-asparaginase, high-dose methotrexate with leu-
covorin rescue, neocarcinostatin, and guanazole. Results have been disap-
pointing, with complete remission rates of less than 25 per cent in most
instances.
In summary, most patients with AML
will achieve a hematologic remission
following intensive induction chemotherapy. We generally employ 1 to 3
cycles of the TAD regimen developed at UCLA. 122 This includes 100 mg/m 2
6-TG orally and 100 mg/m 2 ara-C intravenously every 12 hours for 7 days, plus
60 mg/m 2 daunomycin intravenously on days 5, 6 and 7. The remission rates
with TAD and similar regimens developed elsewhere are comparable to those
currently achieved in the adult form of ALL and representadvance
a major
over the past 20 years, when less than 10 per cent of patients achieved
remissions.
Consolidation and Maintenance Chemotherapy. Once complete
remission is achieved, the next therapeutic objective is to prolong its dura-
tion. Consolidation and maintenance chemotherapy are primarily directed
toward reducing the leukemic cell mass further, thereby preventing the
emergence of recurrent disease.
There are few reported controlled trials of maintenance chemotherapy,
and the data indicate only a modest prolongation of remission at best. 127 128 '
It is clear, however, that patients who do not receive maintenance chemo-
therapy usually relapse within six months. In general, drugs are given as
one- to seven-day pulses with two- to three-week intervals between cycles.

The median remission duration is approximately one year in most series
and frequently is less than six months.
Central Nervous System Leukemia. The incidence of CNS leuke-
mia in patients with AML appears to be increasing. Autopsy studies indi-
cate a 6 to 21 per cent prevalence of meningeal leukemia, and one pros-
pective clinical trial revealed a high incidence of asymptomatic CXS
leukemia. 129 131 A 10 per cent incidence is not uncommon at most centers.
"
This apparent increase in recent years may relate to increased survival of

patients with AML. Cranial irradiation, intrathecal methotrexate, or intra-
thecal ara-C are effective in preventing and treating meningeal leukemia. Un-
fortunately, the median remission duration has not been prolonged by CXS
prophylaxis, suggesting that this probably is not a biologically important
leukemic "sanctuary."
Patients who develop meningeal leukemia are treated with radiation (2400
rad) and intrathecal ara-C (100 mg) or methotrexate, or both. Systemic, high-
dose methotrexate with leucovorin rescue may also be effective but has not
been adequately evaluated.
Intensive Chemotherapy. Intensification therapy refers to the admin-
istration of intensive drug therapy to patients in remission with the objec-
tive of eradicating residual leukemic cells. 132, 133 In one series, intensifica-
tion therapy administered one year following remission resulted in a
ralapse rate of approximately 55 per cent, most occurring within the first
year following intensification. Although intensification therapy may be of
value in AML, it cannot be routinely recommended, since its therapeutic
value is still undetermined.
Quality of Life and Cost. There has been an increasing trend to-
ward using more intensive chemotherapy programs for the treatment of pa-
tients with AML. This has been associated with a substantial increase in
therapy-associated morbidity and mortality, particularly in older patients.
Some argue that the objective of current therapy is to achieve hematologic
remission rather than to improve the quality or quantity of life.
Results from University College Hospital (UCH) suggest improved sur-
vival in older patients when relatively nonaggressive chemotherapy is
used. 134 Although this approach should be considered in some patients, the
achievement of hematologic remission is a clear prerequisite for prolonged
survival. In the UCH study, only 2 of 51 patients survived > 2 years, and all
young patients died before 1.5 years. This compares unfavorably with recent
results from intensive chemotherapy, in which 50 to 80 per cent of patients,
including those >45 years of age, achieved remission. Furthermore, at some
centers up to 20 per cent of patients treated with intensive chemotherapy
may remain in remission longer than two years.
Although intensive chemotherapy may compromise the quality of life,
this is balanced by the increased proportion of patients who will achieve
prolonged disease-free survival. Optimal therapy for an individual patient
will depend on the patient's objectives, potential complicating factors, and
the setting in which therapy is undertaken. If the patient favors attempts to
achieve remission, and support facilities are adequate, intensive induction

therapy is appropriate.
The treatment of AML is expensive. The cost for the average patient with
a survival of 12 months has been estimated at $38,000.
1;55
Others have es-
timated a cost of $25,000 to $30,000 for remission induction chemotherapy,
exclusive of professional costs. Our own experience, combined with the
increasing costs of hospitalization, places the cost at more than $50,000 for
one year of therapy. Although these costs are considerable, they are not out
of accord with comparably complex clinical therapies, including one year of
hemodialysis ($30,000), kidney transplantation ($20,000), and treatment of
respiratory distress syndrome ($50,000 to $60,000).
Immunotherapy
Immunotherapy has been used to prolong remissions in patients with

AML. Two approaches have been studied: (1) nonspecific stimulation with
immune adjuvants, such as bacillus Calmette-Guerin, Corynebacterium
parvum, or a methanol extract residue of BCG (MER), and (2) attempts at
specific immunization with leukemic cells. Frequently, these approaches
are combined. Table 21-8 summarizes the results obtained in several re-
cent trials. With the exception of one trial with neuraminidase-treated allo-
geneic leukemic cells, most trials have failed to show an increase in remis-
™" 141
sion duration. 1
Several important points emerge from the studies indicated in Table

21-8. First, although there may be an increase in remission duration in
some patients receiving immunotherapy, the median remission duration is
still brief. In several trials, notably the Southeastern Cancer Study Group
and the Mt. Sinai studies, the remission duration of immunotherapy-treated

patients, although superior to randomized controls, is not superior to results
obtained with optimal chemotherapy. Finally, immunotherapy may have a
TABLE 21-8. Immunotherapy in Acute Myelogenous Leukemia
Chemo- Immunotherapy Median Medi \\

Center 1
AltM therapy - Remission Survival
BCG C Parvum Cells
BARTS 1 + _ _ _ 28 39
2 + + - - 49 73
MDA 1 + _ _ 60 74+
2 + + - - 72+ 85+
3 + + - + 40 -
Mt. SINAI 1 + — _ _ 20 54
2 + - - + 60+ 95+
SEC 1 _ + _ _ 32 101
2 + — - - 31 48
3 - - - - 26 -
UCLA 1 + _ _ _ 49 90
2 + - + + 126 96+
favorable effect on postrelapse survival and frequency of second remis-

142
sion. Since virtually all patients with recurrent leukemia will die of resis-
is a limited achievement.
tant disease, this increase in postrelapse survival
At present, there is no convincing evidence that immunotherapy has an
important role in the treatment of AML. Nevertheless, the evidence that
chemotherapy prolongs remissions is likewise lacking, so that immunologic
approaches deserve further consideration.
Bone Marrow Transplantation
Reports from two centers indicate a 15 to 20 per cent two-year disease-

free survival in recipients of allogeneic grafts who had failed conventional
therapy. 143, 144 This probably compares favorably with results obtained from
other approaches. A greater than 30 per cent four-year disease-free survival
rate has been reported in identical twins. Whether or not these survival
figures can be improved by earlier transplantation or the development of
more effective pretransplant conditioning regimens is currently under in-
vestigation. Because of the poor survival of AML patients following initial
relapse, transplantation at that time in patients who have an HLA-identical
sibling is a potential consideration.
Several centers are currently performing marrow grafts for patients in

their initial remission. Although preliminary data are encouraging, it is pre-
mature to recommend this approach.
Preleukemia, Smoldering Leukemia,

Therapy-linked Leukemia
The therapy of three subcategories of AML —

preleukemia, smoldering
leukemia, and therapy-linked leukemia —
deserves special consideration.
Preleukemia generally occurs in older patients. The marrow is usually hy-
percellular and dys plastic, and although the percentage of myeloblasts is
frequently increased, the diagnosis of AMLcannot be established with cer-
tainty. Most patients eventually develop typical AML. Patients with preleu-
kemia respond poorly to intensive chemotherapy and should receive sup-
portive therapy until there is evidence of progressive disease.
In smoldering leukemia, the diagnosis of AML can be established with
relative certainty, but the disease remains dormant for weeks to months.
Therapy should be withheld until disease progression occurs. The response
rate in therapy-linked AML has been disappointing, with less than 10 per
cent of patients achieving complete remission. The median survival is less
than three months in most series. 145 148 Nevertheless, most physicians feel
"
that these patients should be treated if their primary disease has been eradi-
cated.

Worthwhile progress has been made in the therapy of AML. With inten-
sive induction chemotherapy, over 70 per cent of patients achieve a hema-
tologic remission lasting from nine to 18 months. Chemotherapy and immu-
notherapy given during remission may prolong it, but their effects are
minimal. Nevertheless, 20 per cent of patients with AML will remain in
remission two years after diagnosis, and some may become long-term sur-
vivors.
Future efforts should be directed toward prolonging remission by im-
proving maintenance programs. Attempts should be made to improve the
detection and eradication of residual leukemia. Further understanding of
normal and leukemic cell growth may provide insight into novel therapeu-
149
tic approaches, e.g., the inhibition of leukemia growth with chalones and
manipulations to favor maturation of leukemic cells. Newer therapeutic
approaches, such as bone marrow transplantation, for patients in remission
deserve further evaluation.
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CHAPTER 22
CHRONIC
LEUKEMIA
H Phillip Koeffler David W Golde
Section 1
Chronic Myelogenous
Leukemia
INTRODUCTION
Chronic myelogenous leukemia (CML) is an acquired clonal disorder in-
volving the hematopoietic stem cell and is associated with a prominent ex-
pansion of the granulocyte compartment. 3 The etiology of this disease is
"
1
unknown, although there is an increased incidence following exposure to

ionizing radiation. 4 Chronic myelogenous leukemia can present at any age,
but the incidence increases steadily throughout life. constitutes about CML
15 to 20 per cent of all adult leukemias.
In the usual form of CML, the Philadelphia (Ph found
1
) chromosome is
in the dividing marrow cells. The Ph chromosome generally arises on the

1
basis of a balanced translocation from the long arm of chromosome No. 22

to chromosome No. 9 (22q", 9q + ). There are a number of cytogenetic
22 / Chronic Leukemia 833
TABLE 22-1. A Classification of Chronic Myelogenous Leukemia (CML)
Clinical and Cytogenetic Variants

Typical CML (Ph'-positive)
Atypical CML (Ph'-negative)
Juvenile CML (Ph'-negative)
Morphologic Variants (Ph 1
Chromosome Variable)
Chronic eosinophilic leukemia
Chronic basophilic leukemia
variants. The common clinically identified classes of CML are listed in

Table 22-1.
About 10 per cent of patients with CML lack the Ph chromosome. These 1
patients are usually older, have a lower leukocyte count, respond poorly to
therapy, and have a shorter survival time than patients with the Ph chro- 1
mosome. 5 7 Juvenile CML is a Ph'-negative form of the disease, which has

"
its peak incidence at age one to two years. These patients usually have a
marked elevation of fetal hemoglobin. The response to therapy is poor, and

survival from the time of diagnosis is generally less than one year. 8,
Because CML affects the pluripotent hematopoietic stem cell, it is not
surprising that an unusual cell type will predominate occasionally. This
may explain the rare appearance of chronic eosinophilic leukemia 10 and
chronic basophilic leukemia. " 12
NATURAL HISTORY
Frequent presenting symptoms of patients with CML are fatigue, weight
loss, and abdominal fullness, and occasionally easy bruising or bleeding
may be seen. The diagnosis of CML is usually established easily because
of the frequent constellation of splenomegaly, leukocytosis with absolute
increase of basophils and eosinophils, a low leukocyte alkaline phosphatase
level, and the presence of the Philadelphia chromosome.
At the time of diagnosis, the leukocyte count is usually near 200 x 10 9 /L,
the platelet count is 400 x 10 VL, and the hemoglobin concentration is about
!
10 gm/dL. A spectrum of granulocytic forms is present in the peripheral

blood. A direct relationship exists between the height of the leukocyte count
and the percentage of immature cells in the peripheral blood at diagnosis. 13 A
small proportion of patients have a 50- to 70-day cyclic oscillation of their
leukocyte and platelet counts, 14 l5 which can occasionally cause confusion
'
in therapy.
The bone marrow shows granulocytic and often megakaryocyte hyperpla-
sia. Differential counts reveal an orderly granulocytic maturation. Marrow
myelofibrosis, although rare at diagnosis, occurs in 30 to 40 per cent of
patients during the course of disease. 16
The diagnosis of CML
is aided by two tests: the cytogenetic analysis of
the hematopoietic cells and the determination of the leukocyte alkaline

phosphatase level. The bone marrow contains the Ph^-chromosomal abnor-
mality in nearly 90 per cent of patients with CML. 5 The leukocyte alkaline
phosphatase (LAP) level is decreased or absent in the neutrophils of pa-

tients with CML at the time of diagnosis. With infection, inflammation, sec-
ondary malignancy, or peripheral blood remission as a consequence of che-
motherapy, the LAP can rise to normal or high levels. 17 19
"
Occasionally, inflammatory or malignant disease can produce a leuke-

moid reaction with leukocytosis, immature circulating granulocytes, hyper-
plasia of the bone marrow, and slight hepatosplenomegaly. Patients with a
leukemoid reaction will not have a Philadelphia chromosome and usually
will not have a low LAP level or absolute basophilia in the peripheral
blood.
Within a mean of three years after diagnosis, the relatively benign chron-
icphase gives way to a period of difficult management that ends in either bone
marrow failure or a phase known as "blast crisis." Blast crisis is characterized
by rising blast counts in the peripheral blood, increasing anemia and thrombo-
20
cytopenia, and lack of response to therapy. During this period, extramedul-
lary myeloblast tumors can develop, especially in bone, lymph nodes, or skin.
21
Blast crisis is frequently preceded by the evolution of cell lines with addi-
22 23 "
tional chromosomal abnormalities. Most patients go through at least a
six-month period during which inexplicable malaise, fever, increasing
splenomegaly, progressive anemia, basophilia, thrombocytosis, and leuko-
cytosis that is refractory to previously effective chemotherapy may be pres-
ent. 20 -
24
The two major morphologic subgroups of blast crisis are the myeloblasts
and lymphoblastic types. In most cases, the blast cells are similar to those
of acute myelogenous leukemia. 25,26 In about one third of cases, however,
the cells have a lymphoblastoid morphology and contain a DNA-
27 " 29
synthesizing enzyme known as terminal deoxynucleotidyltransferase.
This enzyme is often found in acute lymphoblastic leukemia cells.
TREATMENT
Chemotherapy in the Chronic Phase
objective of treatment in the chronic phase of disease is to maintain

The
the patient in a symptom-free condition without incurring complications
from therapy. Since symptoms of the disease parallel the peripheral blood
granulocyte count, therapy should be designed to maintain the white blood
cell count below 50 X lu^/L.
BUSULFAN. Although many drugs chronic phase of
are active in the
30
CML, busulfan is the drug of choice. In one comparative trial, busulfan
produced partial or complete peripheral blood remissions in 75 per cent of
patients as compared with 50 per cent of patients treated with cyclophos-
phamide. 31 Likewise, the drug has been shown be more effective in dis-
to
ease control than 6-mercaptopurine, chlorambucil, 33 and splenic irradia-
32
tion. 34 Dibromomannitol, an alkylating agent, appears to have no advantage

over busulfan. 33
Busulfan is given in a single daily oral dose of 2 to 4 mg in combination

with allopnrinol, with weekly blood counts being obtained. The decrease
in granulocytes is a good indicator of therapeutic effect. The white blood
cell count usually begins to fall after two to three weeks of starting therapy.
If no change in the white blood cell count has occurred by that time, the
dose can be increased to 4 to 6 mg. Once the white blood cell count begins
to decrease, it falls exponentially. Because of the unpredictability of busul-
fan, the drug should be discontinued when the white blood cell count is
about 20 x 10 9/L because the white blood cell number can continue to
decrease for as long as one month after the cessation of therapy. 36
When the white blood cell count is normalized, there are usually only
rare immature blood cells seen in the blood. Anemia is frequently correct-
ed, and thrombocytosis is reduced in two thirds of patients with remission
induction. The spleen size usually decreases in parallel with the decrease
in the white blood cell count. The low leukocyte alkaline phosphatase
level will occasionally rise to normal with remission. 17 Although the periph-
eral blood reverts to normal with therapy, the bone marrow will still mani-
fest some granulocytic hyperplasia, and the Philadelphia chromosome con-
tinues to be present. Therefore, although the peripheral blood counts are
normalized, a true hematologic remission is not achieved.
Survival does not appear to be affected if the patient is placed on mainte-
nance busulfan or if the drug is not reinstituted until the leukocyte count
has risen to about 50 x 10 9 /L. It is important that busulfan therapy be indi-
vidualized. We prefer to stop the drug when the WBC 9
is 20 x 10 /L. Blood
counts should be obtained at regular intervals. The period of no-drug thera-

py is variable but averages around three to five months. When the leuko-
cyte count rises to 50 x 10 9/L, the patient usually becomes symptomatic,
and the drug is reinstituted. The patient can generally achieve repeated
peripheral blood remissions and does not become refractory to busulfan
until he or she enters the accelerated or blast phase of the disease.
Busulfan can also be given as maintenance therapy at a dose 2 to 4 mg
daily to keep the WBC in the range of 15 to 20 x lO^L. Maintenance thera-
py requires more frequent patient visits to monitor the WBC and platelet
count and to adjust the drug dosage. This form of therapy does not appear
to be more efficacious than the intermittent schedule.
A small group of patients has been treated with pulse high-dose busul-
fan. 37 The oral dose ranged between 50 to 200 mg even- 15 to 29 weeks. No
clinical toxicities were recorded. More experience with this regimen is re-
quired before it can be recommended.
The complications that can develop in patients receiving busulfan (in-
cluding pulmonary fibrosis, increased skin pigmentation, and a syndrome
resembling Addison's disease) are discussed in Chapter 5. Dose-related
myelosuppression is the major toxicity of busulfan. Some patients' hemato-
poietic precursors appear to be unusually sensitive to the drug, and marrow
aplasia develops at relatively low doses of busulfan. 38, 39
Pregnancy does not appear to have an adverse effect on the course of
CML. 40 42 However, 10 to 20 per cent of pregnant women with
"
CML de-
liver prematurely with resultant fetal mortality. Busulfan can probably be
given relatively safely after the first trimester of pregnancy.
Hydroxyurea. Hydroxyurea can rapidly lower the WBC

and platelet
count in CML. When given in oral doses ranging from 20 to 50 mg/kg
43 " 45
daily, the patient's WBC may return to normal in one to two weeks. The
drug dosage is decreased by one third to one half of the initial dose when
the WBC reaches 20 x lO^L. A maintenance dose of approximately 20 mg/kg
daily is given because leukocyte counts begin to rise almost as soon as the
drug is discontinued. Hydroxyurea is a very effective agent. Its main side
effects are marrow suppression, skin rashes, and gastrointestinal into-
lerance.
DlBROMOMANNlTOL. This alkylating agent is effective in CML but
offers no advantages over busulfan. The daily oral dose is usually 250 mg,
which is decreased to 250 mg every two to three days. The leukocyte count
begins to decrease after 7 to 14 days of therapy, and about 60 to 80 per cent
of patients have normalization of their WBC in 3 months. 35 46, 47 This is '
compared with the usual 85 to 90 per cent response rate for busulfan. 35 In
one cooperative study, the median survival of CML patients who received
dibromomannitol was 43.3 months, 47 which is comparable to that achieved
with busulfan. 48 When the drug is given in doses greater than 5 mg/kg
daily, severe granulocytopenia and thrombocytopenia can develop.
Other Drugs. Many other drugs are useful during the chronic phase
of CML, such as 6-mercaptopurine, 32 6-thioguanine, 49 melphalan, daunomy-
cin, mechlorethamine, and cyclophosphamide.
6-Mercaptopurine can control the disease. 32 The usual dose is 2.5 mg/kg
daily. The dose is decreased by one third if allopurinol is used at the same
time. The drug should be discontinued when the WBC is 10 x 10 /L. Plate-
9
let counts must be followed because thrombocytopenia may occur.
Chemotherapy in Blast Crisis
With the onset of blast crisis, the disease becomes resistant to conven-
tional therapy employed during the chronic phase of CML. Chemothera-
peutic regimens that are useful in the treatment of acute myelogenous leu-
kemia have been tried in patients in blast crisis, but they are not very
effective (Table 22-2).
To achieve acomplete remission in AML with the potential for pro-
longed survival, chemotherapy must be given until there is almost com-
plete bone marrow aplasia. If the blast crisis of CML appears to be myelo-
blastic, chemotherapy should also be given to the point of marrow aplasia.
Usually no more than three cycles of chemotherapy are required to produce
aplasia. The time required for marrow regeneration is quite variable, and
many patients die during this period because of infections and hemorrhage.
A major advance in the treatment of blastic crisis is the use of vincristine
"
and prednisone for remission induction. 51 53 Vincristine sulfate, 2 mg, is
given intravenously each week. Prednisone, 60 mg/m 2 is given orally daily.
,
At least two to three courses of vincristine should be given before the pa-
tient is judged as refractory to this therapy. About 30 per cent of patients in
blast crisis have lymphoid morphology, 25, 26 and about 50 per cent of these
58
patients will respond to vincristine and prednisone. A recent report dem-
22 Chronic Leukemia 837
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onstrates that the presence of the enzyme terminal deoxynucleotidyltrans-

ferase in the blast cells is a characteristic of a subset of blastic CML pa-
tients who are more likely to respond to vincristine and prednisone
induction therapy. Blast cells that are predominantly hypodiploid also ap-
pear to be more responsive to vincristine and prednisone. 51 52 '
In summary, patients whose have lymphoid morphology, TdT,

blast cells
or a hypodiploid karyotype have a better chance to respond to vincristine-
prednisone induction therapy. Those who do not respond may still re-
spond to a second combination of intensive chemotherapy. If remission is
achieved, the marrow morphology and karyotype revert back to the chronic-
phase of Ph^positive CML.
The best way to maintain a remission in CML blast crisis is not known.
For patients with lymphoid blast cells, oral methotrexate, 15 to 20 mg/m 2
twice weekly, or oral hydroxyurea, 20 to 30 mg/kg as a single daily dose, may
be effective.' 2 Monthly doses of vincristine (modified to minimize neurotoxic
effects), with or without prednisone, appear to be essential for prolonged re-
mission maintenance. The median survival for responders is around eight to
ten months after blast crisis as compared with two to three months for non-
responders.
With increasing survival in blast crisis, meningeal leukemia is becoming
more frequent. In one series, more than 40 per cent of patients who
achieved a complete remission developed meningeal leukemia. 59 The major
neurologic findings are symptoms of increased intracranial pressure and oc-
casionally cranial and peripheral nerve deficits. Treatment is either with
twice weekly intrathecal injections of cytosine arabinoside (100 mg) or with
methotrexate (12 to 15 mg/m 2 ) with or without leucovorin rescue (12 to 15
mg/m 2 daily) given orally or parenterally beginning 24 hours after the in-
stillation of intrathecal MTX
and continuing for 48 hours. 59 Either drug is
given until the spinal fluid pleocytosis clears. This is followed with weekly
maintenance therapy, after which twice monthly and then monthly mainte-
nance therapy is instituted. Cranial irradiation (2400 rad) should be given,
especially when cranial nerve deficits are present. Cytosine arabinoside or
methotrexate therapy often eliminates neurologic symptoms, and occasion-
ally no evidence of meningeal leukemia is found at postmortem examina-
tion. The CNS
therapy has not been defined.
role of prophylactic
Other extramedullary such as skin, bones, or
sites of blast transformation,
lymph nodes, are usually radiosensitive and can be controlled with radio-
therapy. 21
Some patients have an abrupt onset of blastic transformation of CML
with a rapidly rising white blood cell count. When the blast count ap-
proaches 100 x 10 9 /L, the patient can develop cerebrovascular leukostasis.
This potentially fatal complication requires the acute reduction of the blast
count. A daily dose of either 50 to 75 mg/kg hydroxyurea or cytosine arabin-
oside (2 to 4 mg/kg every 12 hours) may be effective. Before therapy, the
patient must be well hydrated, the urine must be alkalinized, and allo-
purinol must be started to prevent uric acid nephropathy.
Irradiation
Splenic Irradiation. Before the era of chemotherapy, splenic irradia-

60,61
tion was used extensively to treat CML. The dose of radiation varied
but generally totaled between 600 and 1000 rad delivered in daily dose
fractions of 25 to 200 rad. Radiation treatment controls the leukocytosis and
splenomegaly. Control is variable but usually lasts several months initial-
8
ly. * With progression, the patient's disease becomes more resistant to
splenic irradiation and eventually becomes totally refractory to this mode of

therapy.
Splenic irradiation as the sole therapy for CML is inferior to busul-
fan.34.63 j n a controlled trial, busulfan therapy resulted in maintenance of

higher hemoglobulin levels and produced increased survival. 34 The median
survival in the drug-treated group was 170 weeks as compared with 120
weeks for die irradiated patients. Splenic irradiation may be effective for
patients who have entered the accelerated period of their disease and have
become refractory to chemotherapy.
Radioactive Phosphorus. Radioactive phosphorus 32 P) localizes in
(
marrow cells, killing hematopoietic progenitors, thereby lowering the white

blood This form of therapy is often useful for older patients and
cell count.
those who cannot be seen at regular intervals. Radioactive phosphorus may
be given in conjunction with other modes of therapy. 84
Extracorporeal Irradiation of the Blood. An arteriovenous
shunt allows peripheral blood cells to flow through a radiation source. 65
This procedure is inconvenient for the patient and only temporarily lowers
granulocyte counts. It has very little application today.
Splenectomy
The indications splenectomy are not clearly defined. During the

for
chronic phase it improves neither response to chemotherapy nor survival,
but it does eliminate the morbidity of massive splenomegaly and improves
response to platelet transfusion. 66 Splenectomy is effective in alleviating ab-
dominal discomfort and decreasing thrombocytopenia and transfusion re-
quirements due to hypersplenism. 87
The role of splenectomy in the management of CML is controversial. An
operative mortality rate of at least 25 per cent was reported prior to 1967. 68
Deaths were usually due to bleeding, infection, anesthesia complications,
and occasionally thrombosis. Since that time, the operative mortality rate
has decreased to about 3 per cent when the procedure is performed by an
experienced surgeon. 66,69 71 A higher operative mortality' rate occurs in older
"
patients, in the blastic phase of the disease, and in the presence of a mas-
sive infarcted spleen that is adherent to the peritoneum. 72
The total experience suggests that because of improvements in surgical
technique and pre- and postoperative management, splenectomy is a feas-
ible procedure for the management of symptoms of Hypersplenism. Surviv-

al, however, is not dramatically different from nonsplenectomized pa-
tients. 66 -
70 - 71
Leukapheresis
"
Several investigators 73 75 have tried to control the chronic phase of CML
with the removal of peripheral white blood cells by intensive leukaphere-
sis. This technique is performed by continuous flow centrifugation or nylon
fiber filtration to remove adherent granulocytes. Although results have dif-

fered, the white blood cell count usually can be reduced only for short
periods; the spleen occasionally reduces in size but the bone marrow does
not revert to normal. The technique is time consuming and expensive, and red
blood cells and platelets are lost during the procedure. Leukapheresis does
not have an advantage over conventional therapy.
Immunotherapy
Few trials of immunotherapy for CML

have been conducted. One study
reported using intradermal injections of BCG and cultured lymphoid cells
derived from two patients with myelogenous leukemia, which produced in-
creased survival. 76 Adequate controls were lacking. Until results of more
immunotherapy trials are published, this form of therapy should be viewed
as unproved.
SURVIVAL
The median survival of CML patients in most series is from 36 to 44
48, 63, 77
months. 34, Effective chemotherapy produces hematologic and clinical
48
benefit and prolongs survival. 34, Patients treated with busulfan or a com-
parable drug have mortality rates of 5 to 10 per cent during the first year
after diagnosis. 48 The mortality rate increases during the second year, and
thereafter it is approximately 26 per cent per year.
Patients who present in blast crisis or have Ph'-negative or juvenile CML
CML have poor prognoses. Survival is usually less than a year with juve-
nile CML, and response to therapy, including busulfan, has been disap-
pointing. 8,9
With good management, most CML symptom free until
patients are the
accelerated or blastic period of their disease. The median survival in
this
latter phase is usually two months if a patient does not achieve a remission.
Approximately 25 to 30 per cent of patients in the blast phase will achieve
a remission, and survival in these patients lasts an average of 8 to 12 months.
22 I Chronic Leukemia 841

There are a number of cases reported in which patients have had long
survival after finding that they had both Ph'-positive and Ph'-negative
bone marrow cells. 38, 78 80 This chromosomal mosaicism was frequently asso-
"
ciated with busulfan-induced aplasia during the chronic phase of the dis-
ease. Some investigators, therefore, have turned their attention to aggres-
sive therapy in the early chronic phase. One such program includes
intensive therapy with cytosine arabinoside, 6-thioguanine, L-asparaginase,
vincristine,and splenectomy. 81 A transient conversion to a mosaicism of
Ph'-negative and Ph'-positive cells was achieved in 5 to 21 patients. Be-
cause most patients are nearly asymptomatic during the chronic phase of
CML, more investigation is needed before life-threatening chemotherapy
can be recommended during this stage.
During the blast phase of CML, bone marrow transplantation from an
identical twin isan effective therapy. 82 Allogeneic marrow transplantation
is highly experimental.
Another approach under investigation is autologous marrow transplanta-

tion. 83,84 Bone marrow is cryopreserved during the chronic phase of CML.
When blast crisis develops, intensive chemotherapy is given to produce
bone marrow aplasia and eradicate the new malignant clone. The cryopre-
served autologous marrow cells are thawed and infused into the patient to
repopulate the marrow and re-establish the chronic phase of disease. Au-
tologous marrow transplantation is also very experimental and should be
attempted only at a few medical centers.
Section 2
Chronic Lymphocytic
Leukemia
INTRODUCTION
In chronic lymphocytic leukemia (CLL), increased numbers of morpholo-
gically normal lymphocytes circulate in the peripheral blood and infiltrate
the bone marrow and other organs. The disease is rare in persons younger
than 30 years of age, and most affected patients are older than 60 years.
Males outnumber females 2:1 to 3:1. It is the most common form of chronic
leukemia in whites, whereas it is rarely found in Orientals.
The etiology of CLL is unknown. Unlike many of the other leukemias,
irradiation appears to play no role in the development of this disease. A
familial tendency has been demonstrated, hut no pattern of inheritance is
present to suggest a genetic predisposition. 85 Patients with immune defi-

ciency states, such as ataxia telangiectasia and the Wiscott-Aldrich syn-
drome, have an increased incidence of CLL. m!
NATURAL HISTORY
Chronic lymphocytic leukemia is discovered as an incidental finding in
about 25 per cent of patients. Some patients seek attention because of
symptoms of anemia or because of enlarged lymph nodes. The spleen is
only moderately enlarged, and the liver is slightly enlarged in about 50 per
cent of patients. Uric acid levels are usually normal.
The total white blood cell count at diagnosis usually ranges from 15 x
10 9 /L to 200 X 10 9 /L, with 70 to 95 per cent lymphocytes. Unlike chronic
myelogenous leukemia, the level of the white blood cell count does not
consistently correlate with symptomatic disease. Lymphocyte counts of
greater than 100 x 10 9/L frequently are tolerated without unusual symp-
toms. The bone marrow shows heavy infiltration with small, well-
differentiated lymphocytes. The red blood cell and platelet counts are gen-
erally slightlyreduced at diagnosis.
Approximately 10 to 20 per cent of patients with CLL develop a Coombs'
test-positive immune hemolytic anemia. 87 These patients have numerous
spherocytes and polychromatophilic macrocytes on the blood smear, elevat-
ed reticulocyte counts, and erythroid hyperplasia in the bone marrow. The
antibody is usually of the warm-reacting IgG class.
In 95 per cent of CLL cases the cells have a monoclonal surface immuno-
globulin, most commonly IgM with or without IgD. 88 90 About 5 per cent of
"
patients have a prominent monoclonal immunoglobulin (usually IgM) in

their serum. The CLL cells possess a receptor for the Fc portion of IgG,
and complement receptors are variably present. 91, 92
Hypogammaglobulinemia is present in 50 to 75 per cent of patients and
becomes more severe as the disease advances. 93,94 The impairment of im-
munity predisposes the patient to infections. Infection accounts for nearly
50 per cent of deaths of patients with CLL. 95, 96
Classification
The variants of CLL include classic CLL, T cell CLL, and chronic pro-
lymphocyte leukemia. Patients with T cell CLL have been described as
having lymphocytes of CLL morphology but possessing T lymphocyte cell
markers. 97 These patients usually have massive splenomegaly, minimal
lymph node involvement, and a tendency for skin involvement.
The CLL variant, prolymphocytic leukemia, is rarely found in individuals
younger than the age of 60 years. 98, " The spleen is often massive, whereas
the lymph nodes are usually not greatly enlarged. The cells are larger than
regular lymphocytes, with a prominent nucleolus and coarsely condensed
'22 I Chronic Leukemia
843
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53
chromatin. The absolute lymphocyte count tends to be very high, usually

above 200 x 10 9 /L at diagnosis.
Differential Diagnosis
An adult with CLL has prominent lymphocytosis on repeated blood cell

counts over several monthly examinations. The morphology and cytochem-
istry of the leukemic lymphocytes are similar to normal cells.
Other diseases can usually be excluded by clinical findings, morphology,
cytochemistry, and immunologic studies (Table 22-3). The following sec-
tions include examples of some of these diseases.
Reactive Lymphocytosis. Infectious mononucleosis and other viral
illnesses that occur in children and young adults can transiently elevate the
lymphocyte count. The lymphocyte morphology' is fairly easily distin-
guished from cells of CLL. Most of the lymphocytes are T cells, and the B
lymphocytes do not have monoclonal antibodies on their surfaces.
Lymphosarcoma Cell Leukemia. Nodular and diffuse poorly dif-
ferentiated lymphocytic lymphomas can have peripheral blood involve-
ment. 100 These patients usually have prominent lymphadenopathy. The
cells are large and the nucleus typically is notched. These cells usually
have monoclonal antibodies on their cell surfaces, but, in contrast to CLL,
the immunoglobulin staining is intense, frequently with spontaneous cap-
ping. 101
Sezary Syndrome. Patients with the Sezary syndrome usually have dif-
fuse pruritic erythroderma, lymphadenopathy, splenomegaly, and lympho-
cytosis. 102-104 The Sezary cells are large, 15 to 25 /xm in diameter, with promi-
nent nuclear folds. On electron microscopy, the nucleus appears cerebriform.
The cells stain strongly for acid phosphatase and beta-glucuronidase. 104
Immunologic studies show lymphocytes. 102
that these cells are T
Hairy Cell Leukemia. Hairy cell leukemia (leukemic reticuloendothe-
liosis) usually presents as splenomegaly and pancytopenia with atypical
"
lymphocytoid cells in the peripheral blood and other organs. 105 108 The
TABLE 22-4. Clinical Staging of Chronic Lymphocytic Leukemia 114
Stage Absolute lymphocytosis of > 10 X lC/L (10,0007mm 3 ) + 40 percent or more

lymphocytes in bone marrow
Stage I Absolute lymphocytosis plus enlarged lymph nodes
Stage 11° Absolute lymphocytosis plus enlarged liver or spleen, or both
Stage III f Absolute lymphocytosis plus anemia (Hb <11 gm/dL)
Stage IVft Absolute lymphocytosis plus thrombocytopenia (platelet count

<100x KF/dL)
"Stage II patients may or may not have adenopathy.

t Stages III and IV patients may or may not have adenopathy or organomegaly, or both.
| Stage IV patients may or may not have anemia.

22 Chronic Leukemia
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"hairy" cells frequently have wispy edges, moderately abundant cytoplasm,

and homogeneous chromatin. These cells stain strongly for the tartrate-
resistant isoenzyme 5 of acid phosphatase.
109, ,1()
The cells have B lympho-
cyte cell markers, and studies have shown that they can produce immuno-
U1,
globulin. 108 -
112
Acute Lymphocytic Leukemia. Although acute myelogenous leuke-

mia is the most frequent acute leukemia in older adults, acute lymphocytic
leukemia (ALL) is occasionally seen in the elderly. The blast cells have
large, immature nuclei with three or fewer nucleoli. The cytoplasm is
scanty and the cells show a coarse granular staining with periodic acid-
Schiff (PAS). 113 Most patients with ALL have neither B cell nor T cell markers.
Stage and Prognosis
Recently, a simple staging system for CLL has been proposed (Table 22-
4). Using this classification, the prognosis by stage is shown in Table 22-5.
Stages III and IV could be combined, since no real difference in survival is
observed between patients in these two stages. A recent analysis of 129

patients in Paris confirms the value of this method of staging. 116 Although
series differ, increasing age 95, U5 117 and increased bone marrow infiltration
'
96, 118
by lymphocytes are probably correlated with a shorter survival. Once
the patient with CLL
develops a hemoglobin concentration of less than 11
gm/dL or a platelet count of less than 100 x 10 9/dL, his or her survival is
about 20 to 25 months.
A recent study suggests that the size of the patient's lymphocytes does
not affect survival, 119 although earlier reports do not agree with this state-
ment. 120, 121 The CLL variant, prolymphocyte leukemia, may be refractory
to conventional chemotherapy. These patients are reported to have a poor
prognosis with a median survival of four months. 98
TREATMENT
Although reports are conflicting, there is no objective evidence that treat-
ment of CLL in its early stages significantly affects survival. Treat- 95 ' 122, 123
ment has been effective, however, in controlling troublesome symptoms.

The usual indications for therapy are (1) systemic symptoms (weight loss,
excessive perspiration, anorexia), (2) collection of lymphoid tissue, produc-
ing obstruction, discomfort, or disfigurement, (3) the presence of acquired
autoimmune hemolytic anemia or thrombocytopenia, and (4) evidence of
progressive bone marrow failure with granulocytopenia, thrombocytopenia,
or anemia.
The three standard forms of therapy are chemotherapy (usually an al-
kylating agent), adrenocorticosteroids, and radiation therapy. Splenectomy
and leukapheresis are other less frequently used modes of therapy. Because
of wide variability in survival, with a range between 1 and 20 years or
longer, it is difficult to assess the effects of the different forms of therapy.
22 i Chronic Leukemia 847
Chemotherapy with an alkylating agent, with or without an adrenocorticos-

teroid, constitutes the usual therapy for CLL patients. The patient should
be started on allopurinol (300 mg orally daily) and should be well hydrated
prior to therapy.
Chemotherapy
Alkylating Agents. Chlorambucil is the alkylating agent most fre-

quently used in CLL. The recommended daily dose is 0.1 to 0.2 mg/kg.
About 70 per cent of patients receiving this dose will have a decrease in
124 128 "
their elevated lymphocyte counts. The rate of decrease is related to
the amount of drug given. 124 The neutrophil, platelet, and red blood cell
counts are monitored closely to assure that dangerous cytopenia does not
result from the therapy. Many physicians gradually reduce the dose of
chlorambucil as the lymphocyte count falls, and frequently the drug is
stopped when the white blood cell count reaches 20 X 10 W /L.
Chlorambucil induction can also be given in an intermittent fashion, either
by administering higher amounts in a pulse fashion 127125 or by giving the
'
drug on consecutive days with intervening days of rest. 123 Although no sur-
vival advantage has been shown with the different dose schedules, we
favor pulse therapy for ease in monitoring the white blood cell count and
convenience to the patient. Once the desired white blood cell count is
reached, institution of a low daily maintenance dose of chlorambucil does
not appear to be better than discontinuation of therapy until early symp-
toms appear.
Even though the white blood cell count is decreased, lymphocytosis in
the blood and bone marrow, hypogammopathy, mild lymphadenopathy, and
splenomegaly often persist. 95 124 Unlike chronic myelogenous leukemia,
'
pretreatment anemia and thrombocytopenia often are not significantly im-

proved with CLL therapy. 95, 124
Few clinical trials have been performed comparing the efficacy of dif-
ferent alkylating agents in CLL. Chlorambucil has been shown to be better
than busulfan. 33 Cyclophosphamide is probably as effective as chlorambu-
130
cil.
ADRENOCORTICOSTEROIDS. Steroid therapy is effective for short periods

in the treatment of CLL. When a daily dose of 0.5 to 1 mg/kg of prednisone
is given, there is an improvement in constitutional symptoms, a decrease in
the size of the spleen and lymph nodes, and frequently, a lessening of ane-
mia and thrombocytopenia. 124, A sharp rise in the lymphocyte count
129, 131
occurs during the first four to six weeks of steroid administration, but with
continued treatment it usually falls. 124,131 Because steroids have no myelo-
suppressive effects, they are especially useful when the patient has severe
thrombocytopenia or granulocytopenia. The effectiveness of steroids, how-
ever, is counterbalanced by their well-known side effects (see Chapter 5).
A major cause of morbidity and mortality in CLL patients is infection. If
these patients receive steroids for a long period, they tend to have more
frequent and severe infections. 124, 131 In order to lessen the infectious compli-
cations the drug should be given in intermittent schedules when possible.
Coombs' test-positive hemolytic anemia or immune thrombocytopenia

constitutes a clear indication for glucocorticosteroid therapy. These patients
often respond favorably to this treatment but generally require continued
therapy. Chemotherapy frequently is begun with the corticosteroids. Those
patients who require high doses of steroids or do not respond to the drug
should be considered splenectomy.
for
Other Drugs. A
combination chemotherapy protocol that was devel-
oped for multiple myeloma (M-2 protocol) is also effective in CLL. 115,132
The drugs used are vincristine, BCNU, cyclophosphamide, melphalan, and
prednisone. About 70 per cent of patients (many of whom received prior
therapy) have responded to this therapy. It is too early to determine
whether or not survival is increased with the combination. When used as a
single agent, vincristine does not appear to be effective in CLL, 133 and no
data are available on the value of nitrosoureas in CLL.
The combination of cyclophosphamide, vincristine, and prednisone ad-
ministered at three- to four-week intervals may be effective in patients who
are refractory to daily alkylating agents. 134 Mitoclomine, a mechlorethamine
molecule bound to a vitamin K derivative, given orally appears to be effec-
tive in CLL but also produces dangerous neutropenias. 135 Chlorambucil
combined in one molecule with prednisone (Leo 1031) has been given to
CLL patients. 123, 136 It probably has no advantage over chlorambucil and
prednisone when given in combination. Many drugs are known to be effec-
tive in lymphocytic lymphoma, such as bleomycin, the nitrosoureas, dox-
orubicin, and cisplatin.
Radiation
Total Body Irradiation (TBI). Total body irradiation ("spray" irra-

diation) has been used in the treatment of CLL for the last five dec-
ades. 117137
"
140
Therapy with TBI generally consists of daily fractions of 5 to
10 rad three to five times weekly with a total dose usually between 100 and
400 rad. The course of therapy should be interrupted by a rest period of a
few weeks to several months to avoid serious cytopenias. Toxicity is mod-
est, with anemia and thrombocytopenia developing in about 15 per cent of
patients.
In the last decade, Johnson 140, documented the efficacy of TBI. One
141
third of his patients had complete resolution of symptoms and palpable dis-
ease, correction of anemia, near normalization of the bone marrow, and
some had restitution of immunologic competence. The median survival of
the group was 57 months from diagnosis to death —
almost twice that of a
much smaller control group of patients treated with daily chlorambucil or
cyclophosphamide and local irradiation. The assignment of Johnson's pa-
tients to either treatment modality was not random, and the extent to which
corticosteroids were employed in the not clear, which makes
TBI group is
analysis of the data difficult. Nevertheless, this form of therapy appears to

be effective. When the patients become refractory' to repeated courses of
TBI, they are usually also resistant to alkylating agents.
Total body irradiation can be accomplished with intravenous radioactive

142
phosphorus. 117, Depending on the white blood cell count, an initial dose
of 1.5 to 2.5 are repeated when symp-
millicuries of 32 P is injected. Courses
toms develop.
Extracorporeal irradiation of the blood of CLL patients is capable of mark-
edly reducing the circulating lymphocyte count. The effect, however, is
143
usually transient, with the return of high lymphocyte counts within three
to seven months after therapy.
Local Irradiation. Local radiotherapy should be considered when
splenic or lymph node enlargement causes pain, symptoms of obstruction,
or intolerable cosmetic disfigurement.
Splenic irradiation usually relieves painful splenomegaly within seven
days and frequently has the added effect of transiently lowering the periph-
eral blood lymphocyte count and increasing the platelet and red blood cell
counts. 144 The enlarged lymph nodes or spleen is usually treated with 100 to
250 rad, and diminution of tumor size lasts from several weeks to months.
Recently, there have been several reports of systemic treatment of CLL
with mediastinal irradiation. 145,146 Response rates differed between each
146
series, and one group noted severe hematologic and infectious toxicity.
At this time mediastinal irradiation cannot be recommended.
Splenectomy
Splenectomy may be of some value for patients with CLL if the spleen is
massively enlarged. 68, 147, 148 Although peripheral blood lymphocyte counts
do not change, the hemoglobin and platelet counts often increase after the
spleen is removed. The operative mortality rate may, however, approach
10 per cent if the procedure is done late in the course of the disease. 147,149
Splenectomy does not appear to affect the natural history of the disease.
Those CLL patients with autoimmune hemolytic anemia who are refractory
to steroids or require high doses of the drug may respond to splenectomy.
Leukapheresis
Continuous flow blood cell separators provide a method of reducing the

totallymphocyte mass because the circulating lymphocytes are in commu-
nication with all the other lymphocyte compartments. 150 When CLL be-
comes resistant to conventional therapy, repeated leukapheresis may allow
some clearing of lymphocytes from the bone marrow and improve the
platelet and red blood cell counts. This form of therapy offers only tempo-
rary' improvement.
For CLL patients with stage 0, stage I, or stage II disease, no treatment

is usually necessary. The patient is instructed regarding possible adverse
symptoms and followed every three or four months. For regional sympto-
is
matic problems, local radiotherapy is the treatment of choice. For wide-

spread, symptomatic disease (stage III or stage IV), intermittent or daily
chlorambucil with or without a short course of prednisone is usually em-
ployed. Once the desired effect is achieved, therapy is discontinued, or
occasionally a low dose of maintenance chlorambucil is given. Whole body
irradiation therapy may be as effective as chlorambucil, although it is not
clear that the therapist has as much control over the development of ad-
verse side effects using radiation. Infections and autoimmune complications
should be dealt with promptly and vigorously. Above all, the physician
should be guided by the tact that CLL is a disease of relatively long dura-
tion in an older age group, and the therapeutic morbidity and mortal ity
must be carefully balanced against therapeutic benefit.

It is clear that the present management of CLL, although it decreases mor-
bidity,does not have a profound impact on overall survival. Complete re-
missions are rare, and cure of the disease almost never occurs. Combination
chemotherapy with agents that are useful in the treatment of diffuse lym-
phomas should be considered for testing. Likewise, more experience with
whole body irradiation is required.
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CHAPTER 23
B LYMPHOCYTE
NEOPLASMS
CAPABLE OF
IMMUNOGLOBULIN
SYNTHESIS
David W Golde H Phillip Koeffler
The neoplastic disorders of lymphocytes that are capable of immunoglobu-

lin synthesis are characterized by pathologic, clinical, and biologic diversity.
For example, multiple myeloma is generally associated with extensive bony
involvement and is a relatively aggressive disease, whereas Waldenstrom's
macroglobulinemia usually runs a chronic course and is often complicated by
blood hyperviscosity, but it seldom leads to skeletal disease. Similarly, the
light and heavy chain disorders often present as renal disease and lymphoma,
respectively.
Table 23-1 gives a classification of the neoplastic plasma cell disorders.
Effective therapy for these disorders requires a clinician to have a broad
knowledge of the underlying disease process as well as the myriad and
complex effects on other organ systems. Because these neoplasms usually
secrete a monoclonal immunoglobulin, they were the first human malignan-
cies to be rigorously studied by means of a tumor product. These studies have
provided important information regarding tumor cell kinetics in humans.
MULTIPLE MYELOMA
Introduction
Multiple myeloma is a neoplasm of plasma cells characterized most often

by
a proliferation of malignant cells within the bone marrow, the presence of
853
TABLE 23-1. Classification of Neoplastic Plasma Cell Disorders
I. MULTIPLE MYELOMA (PLASMA CELL MYELOM V

1. IgG or IgA myeloma
2. Nonsecretory myeloma
3. Solitary plasmacytoma of bone
4. Extraskeletal plasma cell tumor
5. IgD myeloma
6. IgE myeloma
II. WALDENSTROM'S MACROGLOBULINEMI A (IgM i
III. HEAVY CHAIN DISEASE

1. Y heavy chain disease
2. a heavy chain disease
3. fM heavy chain disease
IV. LIGHT CHAIN DISEASE
lytic bone lesions, and the secretion of monoclonal IgG or IgA. The annual
incidence is about 2 to 3 per 100,000 population, with a clearly higher occur-
rence in blacks. 1,2 The disease is more frequently found in people of advanc-
ing age, and the mean age at diagnosis is 62 years.
Natural History
DIAGNOSIS. Because of the varied clinical manifestations of myeloma,

diagnosis may be difficult at times. Patients can present with early disease or
with complications of advanced disease. The Southwest Oncology Group has
established criteria for the diagnosis of myeloma (Table 23-2) 3 that are
relevant only to symptomatic patients. Other nonspecific features that support
the diagnosis include anemia, hypercalcemia, uremia, bony demineralization,
and hypoalbuminemia. The amount of circulating monoclonal immunoglobu-
TABLE 23-2 Diagnostic Criteria for Multiple Myeloma 3

(Southwest Oncology Group)
MAJOR CRITERIA
I. Plasmacytomas on tissue biopsy
II. Bone marrow plasmacytosis, >30% plasma cells
III. Monoclonal immunoglobulin
1. >3.5 g/dL for IgG
2. >2.0 g/dL for IgA

3. k or A. chain excretion, 1 gm/day without other significant proteinuria
MINOR CRITERIA
a. Bone marrow plasmacytosis 10% to 30%
b. Monoclonal globulin spike present, but less than levels defined above
c. Lytic bone lesions
d. Normal IgM less than 50 mg/dL and IgA less than 100 mg/dL, or IgG
less than 600 mg/dL
DIAGNOSIS CONFIRMED IN SYMPTOMATIC PATIENTS WITH:

1. I + b, I + c, I + d
2. II + b, II + c, II + d
3. Ill
4. a + b + c, a + b + d
23 / B Lymphocyte Neoplasms Capable of Immunoglobulin Synthesis 855
lin is an indirect measure of tumor cell mass and provides a useful tool for the
clinician in assessing the extent of disease and response to therapy. 3,4
Myeloma must be distinguished from "benign" monoclonal gammopathy,
which may occur in up to 0.5 per cent of individuals over 30 years of age.
Those individuals generally are asymptomatic, have a serum immunoglobulin
"peak" of less than 3 gm/dL, have no lytic bone lesions, have no Bence Jones
protein, and their levels of normal immunoglobulins are not depressed. Pa-
tients with this disorder should not be treated.
STAGING. Durie 5 and Salmon, 6 who pioneered in this area, have devel-
oped a staging system for multiple myeloma (Table 23-3). Basically, their
system classifies patients as having high, low, or intermediate myeloma cell
masses. Additionally, these patients may be subclassified on the basis of renal
function. Thus, sub stage a includes patients with a creatinine determination
of less than 2 mg/dL, and substage b includes those with a creatinine determi-
nation greater than 2 mg/dL.
PROGNOSIS. At present, the median survival time in patients with multiple
myeloma is two to three years. A median survival time of 53 months has been
reported for "good risk" patients who respond to chemotherapy. 7 In a large
cohort of patients seen between 1960 and 1971, the median survival time was
20 months. 8 The Southwest group data indicate median survival times of 17,
27, and 39 months for patients with high, intermediate, and low pretreatment
tumor masses, respectively. 9 Survival may vary greatly from patient to patient.
A curious phenomenon is the observation that patients who respond rapidly to
therapy have a poorer survival time than those with a slow response. 10- n
Infection and renal failure are the major causes of death.
TABLE 23-3. Myeloma Staging System
Myeloma Cell Mass

Stage Clinical Staging System Criteria (Cells x 10 12 /m 2 )
I. All of the following:

1. Hemoglobin >10 gm/dL
2. Serum calcium value normal (^12 mg/dL)
3. On x-ray, normal bone structure or solitary bone
plasmacytoma only <0.6 x 10 12
4. Low M-component production rates (Low)
a. IgG value <5 g/dL
b. IgA value <3 g/dL
Urine light chain M-component on electrophoresis
c.
Rn 4 h
II
II. HM >K
Fitting neither f rrS
.
stage I nor stage TT,
III
0.6-1.2 X 10"
., ,. ^
III. One or more of the following:

1. Hemoglobin <8.5 gm/dL
2. Serum calcium >12 mg/dL
3. Advanced lytic bone lesions
4. High M-component production rates 1-2x 10 12
a. IgG value >7 gm/dL (High)
b. IgA value >5 gm/dL
c. Urine light chain M-component on electrophoresis
>12 gm/24 hours

. A= creatinine « 2 mg/dL
B = creatinine > 2 mg/dL
Treatment
General Approach
generally accepted that patients with established multiple myeloma

It is
should be treated as soon as the diagnosis is confirmed. The disease is always

fatal, and untreated patients have a median survival time of 12 months. The5
fact that patients who begintherapy with a lower tumor cell mass have a
better prognosis is also of importance. 510 Conversely, it is clear that patients
with benign monoclonal gammopathy should not be treated and should
simply be observed periodically for signs of possible developing plasmacytic
malignancy.
The aim of therapy is to reduce the tumor cell burden as rapidly as possible
and to alleviate the secondary effects of the disease, including severe pain that
not only causes the patient discomfort but also leads to immobilization. Radia-
tion therapy should be instituted for painful lytic lesions of the spine and
weight-bearing bones. Patients should be encouraged to be as active as possi-
ble.Back braces and appropriate analgesic therapy are important adjuncts to
prevent immobilization and consequent hypercalcemia and further demin-
eralization. Also, the patient must be encouraged to drink 2 to 3 liters of fluid
daily in order to minimize the risk of developing myeloma of the kidney and
acute renal failure, 12 hypercalcemia, and uric acid nephropathy. Allopurinol
should be administered if the serum uric acid concentration is high.
During therapy, the patient must be followed closely for both subjective
and objective signs of response. In the former category, the relief of pain and
an increase in patient activity are the most important goals. Objective criteria
of response to treatment include a decrease in serum myeloma protein con-
centration 9 and excretion of light chain (Bence Jones) protein, improvement
in anemia, 13 and control of renal insufficiency and hypercalcemia. Since the
serum concentration of myeloma protein reflects the size of the malignant
plasma cell mass, it is usually unnecessary to repeat bone marrow biopsies to
determine if there is a reduction in marrow plasmacytosis. Although there is
frequently an arrest of lytic bone lesions during chemotherapy, recalcifica-
tions and bone healing occur relatively infrequently. In one large series, 14
bone repair was observed in 30 per cent of patients responding to chemother-
apy. Serial assessment of lateral skull films may be of some use in confirming
clinical remission and relapses.
Chemotherapy
Alkylating Agents. Although many alkylating agents have been reported

to produce objective improvements in multiple myeloma, melphalan is the
established and most used chemotherapeutic agent in this disease. 8, 15 Mel-
phalan may be given as continuous daily therapy or in intermittent intensive
courses (pulse therapy). 16 19 A third method of administering melphalan is to
"
give an initial loading dose, which is then followed by smaller maintenance

doses. 20 A
simple means of giving continuous therapy is to administer 2 to 4
mg/day subsequent dosage adjustments made
orally (1 or 2 tablets) with
according to the peripheral blood counts. 21 The intermittent schedule that is
used most frequently for melphalan administration is the administration of 9

mg/m 2/day (0.25 mg/kg) for four days even four to six weeks.
Although there is no clear superiority for any of these modes of melphalan
administration, we prefer the intermittent regimen because it is easier for the
patient to tolerate and we feel that it is less likely to produce continuous
immuno- or myelosuppression. Occasional patients develop recurrent pain
before a scheduled course of chemotherapy, and these individuals may be
better managed by a continuous melphalan regimen. The major side effect of
melphalan therapy is peripheral cytopenia due to bone marrow suppression.
In general, the melphalan dose should be adjusted to keep the leukocyte
count above 2 x 10 9 /L (2000/mm 3 and the platelet count above 100 x 10 9 /L
)
(100,000/mm 3 ).
Cyclophosphamide is approximately as effective as melphalan in inducing

remission and prolonging life in patients with multiple myeloma. In two
independent studies, it was found that the survival rate of patients was no
different whether they were treated with melphalan or cyclophosphamide
orally.8*' n Like melphalan, cyclophosphamide may be administered as daily
continuous therapy or intermittently as "pulse therapy." Bergsagel et al. M
treated melphalan-resistant patients with high-dose cyclophosphamide and
obtained good responses in 11 of 19 patients. In these studies, cyclophospha-
mide was administered as a single intravenous dose of 1 gm/nr1 or an oral dose
of 0.25 gm/nr daily for four days and repeated even three weeks. The drug
may also be given in a dose of 10 mg/kg/day for seven to ten days orally or
intravenously as a loading dose with a daily maintenance of 1 to 3 mg/kg/day.
Confirmation of the utility of cyclophosphamide in myeloma patients who fail
to respond to melphalan or who relapse after its administration has recently
been presented by Sherman and Osserman. 25 They found a good partial
response in 20 of 25 patients studied, with a median survival rate of 18
months.
Other alkylating agents have been used in multiple myeloma, including
mechlorethamine, triethylenemelamine (TEM), chlorambucil 28 and aniline
mustard. 27 Although these alkylating agents do have activity in myeloma, they
are clearly inferior to either melphalan or cyclophosphamide.
Prednisone. The role of adrenocorticosteroids in the treatment of multiple
myeloma is uncertain. 3,28 Although corticosteroids are clearly useful in the
treatment of hypercalcemia, 29 there is only scanty evidence that they have a
direct antitumor effect. 30 Treatment with corticosteroids, however, may cause
a fall in serum protein concentration (including that of the myeloma protein)
and a rise in the hemoglobin concentration of some patients. The effect of
prednisone on serum proteins, however, may not reflect an antineoplastic
action, since this drug causes hypercatabolism of myeloma immuno-
"
33
globulin. 31
BCNU. BCXU
an effective agent in the treatment of multiple myeloma,
is
and in previously untreated patients it produces results almost as beneficial as

those seen with melphalan. 34 BCXU is given even six weeks in a dose of 150
mg/m 2 intravenously.
CCXU. CCXU may be of benefit in the treatment of myeloma and has the
advantage of oral administration.
Doxorubicin. Doxorubicin has not been particularly effective in multiple
myeloma when used as a single agent. 35, 36 In a pilot study, doses of 25 to 45
mg/m 2 were beneficial in three of nine patients who did not respond to pulse
therapy with melphalan and prednisone.'"
Procarbazine. Procarbazine may be active in human myeloma; however, it
has not been widely tested as a single agent. It produces a lowering of the
serum monoclonal protein concentration, 37 but there is no direct evidence that
it decreases bone marrow plasmacytosis.
Vincristine. Vincristine has shown some activity in patients with multiple

myeloma who have achieved a partial remission with melphalan. 38 In six of
eight patients, vincristine induced a statistically significant reduction in total
body myeloma cell number (a greater than 24 per cent reduction), whereas
cytosine arabinoside and hydroxyurea were ineffective. Although both vin-
cristine and procarbazine appear to have activity as single agents, the addition
of either procarbazine or vincristine to combinations of melphalan and pred-
nisone has not consistently resulted in additional benefit.
Combination Chemotherapy. As pointed out previously, the role of corti-
costeroids in the treatment of multiple myeloma is uncertain. Nonetheless, it
may be stated that no available regimen is clearly more effective than inter-
mittent melphalan and prednisone, and this appears to be the most popular
combination. A study by the Southwest Cancer Chemotherapy Study Group
showed this regimen to be superior to continuous melphalan. 39, 40 It has been
argued, however, that the study used a suboptimal dose schedule in the
continuous melphalan arm of the protocol. Using retrospective control sub-
jects who received continuous melphalan, George et al.
41
showed increased
response rates with intermittent melphalan and prednisone, but no difference
in the rate of survival was demonstrated. The combination of prednisone and
melphalan appears to be most effective in "good risk" patients. In "poor risk"
patients, the objective response rate with prednisone and melphalan was
found to be no greater than when melphalan alone was given. 7
A number of other combinations are useful in the treatment of multiple
myeloma. For example, the combination of BCNU and prednisone is said to
produce results that are comparable to intermittent melphalan and predni-
sone in terms of remission induction and initial remission duration. 3,34 Also,
combinations of melphalan, cyclophosphamide, BCNU, and prednisone
given intermittently produced impressive responses in one group of 20 pa-
42
tients. Investigators at the Sloan-Kettering Institute for Cancer Research
have reported a response rate of 90 per cent in a group of 36 patients who were
given melphalan, cyclophosphamide, prednisone, BCNU, and vincristine
(M-2 protocol). 43 Recent reports have indicated that this regimen gives a
significantly longer survival time than a historic control group treated with
melphalan and prednisone alone. 44 In contrast, a recent study by the South-
west group reported no advantage to using melphalan and cyclophosphamide
concomitantly in two different combination chemotherapy protocols. 45 The
same study, however, suggested an advantage for combination regimens con-
taining vincristine. Azam and Delamore 46 reported encouraging preliminary
results using a regimen consisting of BCNU, cyclophosphamide, melphalan,
and prednisone in treating myeloma patients who become refractory to single-
agent therapy.
Although doxorubicin has not been a particularly useful single agent in
multiple myeloma, Alberts et al. 47 hjfve reported on the use of this drug and
BCNU given in a dose of 30 mg/m 2

intravenously every three to four weeks. In
a group of 13 patients who were resistant to alkylating agent therapy, there
was a response rate of 54 per cent and there were two complete clinical
remissions. This combination may therefore be of use in patients who have
failed both melphalan and cyclophosphamide therapy. The Southwest group
study, however, did not provide evidence that combinations containing dox-
orubicin were more effective for primary treatment than combinations of
melphalan and prednisone. 45 Recently, the combination of hexamethyl-
melamine (280 mg/m 2 /day for three weeks) and prednisone gave a good
response in 24 per cent of a group of 17 patients who had foiled previous
treatment with alkylating agents and corticosteroids. 48
The question of remission maintenance in multiple myeloma is unsettled.
One study concluded that continuous melphalan-prednisone chemotherapy
was of no major value to responding patients after the first year, 39 and the same
group showed that two other combinations were ineffective in remission
maintenance. 45 These conclusions need further evaluation. A general scheme
of treatment is given in Figure 23-1.
Newer Approaches to Therapy
Although there is evidence for specific immunity to plasma cells in animals

and in humans, there have been no reported trials of immunotherapy in
human multiple myeloma. Presently there is an ongoing protocol by the
Southwest Oncology Group that utilizes BCG, both with and without allogen-
eic myeloma cells, in an experimental therapeutic program for multiple mye-
loma. 3
Although it has been noted by many
observers that the tritiated thymidine
labeling index of myeloma increased after therapy with alkylating
cells is
agents, 49 5<) the clinical use of cell cycle-active agents (cytosine arabinoside
'
and hydroxyurea) has been disappointing. 38 Nonetheless, vincristine appears

to show some promise as a single agent, 38 although its effectiveness has been
variable when used in combination with other drugs. 39,45
MELPHALAN + PREDNISONE
response i— I
r !•
Continue
N°
response
HIGH-DOSE CYCLOPHOSPHAMIDE
response I
Continue
N°
FIGURE 23-1. General treatment plan in multiple response
myeloma.
BCNU & ADRIAMYCIN
response I
r J
Continue
N°
response
EXPERIMENTAL THERAPY
Vincristine
Procarbazine
Hexamethylmelamine
Other combinations
The use of anti-idiotypic antibody has proved efficacious in a plasmacytoma

in BALB-C mice, but there have been no clinical trials in humans. Total
body irradiation may be of some utility in patients with multiple myeloma; 8
however, the results are clearly inferior to alkylating agent therapy. The
exploitation of mouse models of myeloma 15 and the application of recently
derived kinetic data in human myeloma may allow for new and more effective
approaches to therapy.
Management of Special Problems
Hypercalcemia. Since hypercalcemia may occur in one third of all pa-

tients with multiple myeloma, the treating physician should be acutely aware
of the symptoms associated with this complication, such as nausea, vomiting,
polyuria, constipation, weakness, confusion, renal failure, and ultimately
coma. Mild degrees of hypercalcemia may be treated simply by rehydration.
Hydration and diuresis should be initiated with saline solutions because
sodium promotes the renal excretion of calcium. In more serious situations, a
combination of sodium chloride solutions and furosemide may be used.
Prednisone, a highly effective drug for the treatment of hypercalcemia in
patients with multiple myeloma, is frequently given in a dose of 80 to 100
mg/day. As soon as the hypercalcemia is brought under control, the predni-
sone is rapidly tapered. Inorganic phosphates administered intravenously are
also effective, but we do not recommend their use, since they are not without
hazard. 51 We prefer mithramycin in serious situations, which probably has its
major effect on the osteoclast, and a reduction in the serum calcium level can
usually be seen within 24 hours. This drug is given in a dose of 25 Atg/kg, but
frequently the effect of a single intravenous injection of 1 mg is ascertained
before giving larger doses. Mithramycin may also be of use in treating bone
pain and osteolysis in myeloma. 52 Thrombocytopenia can be a serious compli-
cation of mithramycin therapy.
INFECTIONS. Infections with bacterial organisms are frequently seen in
patients with multiple myeloma, and fever should be promptly investigated.
These patients have a special predilection for pneumococcal pneumonia and
pneumococcal meningitis. Recently, the patterns of infection in multiple
myeloma have changed somewhat, and there is now a greater incidence of
gram-negative bacterial infections. 53 It is important to give an antibiotic with
pneumococcal coverage until the infecting organism can be isolated. Treat-
ment with gamma globulin has not proved effective. 54 Aminoglycoside antibi-
otics must be used with caution in patients with impaired renal function, and
no patient with multiple myeloma should be given live vaccines such as vac-
cinia.
Bone LESIONS. As mentioned previously, bony lesions in multiple myelo-
ma usually do not heal well even with successful chemotherapy. Early reports
of the use of fluoride therapy indicated that the induction of fluorosis was not
useful and might in fact be detrimental to the clinical course of patients with
multiple myeloma. 55 Recent studies, using sodium fluoride (100 mg/day) and
calcium carbonate (4 gm/day), 56 suggest that the latter regimen may be a
useful adjunct in the treatment of multiple myeloma. These studies indicated
that the bony and trabecular thickness was significantly increased in

cortical
patients receiving these drugs as compared with a placebo control group.
Renal Failure. Renal insufficiency is one of the major causes of death in
multiple myeloma; it is therefore important to take steps to prevent this
complication. Hydration is most important, as is prevention of hyperuricemia.
Some patients with severe renal insufficiency may be treated with hemodialy-
sis, after which there is a subsequent return of adequate renal function.
The acquired Fanconi's syndrome is seen regularly in patients with light

chain disease. 37 Renal tubular dysfunction is manifested by osteomalacia,
bone pain, renal tubular acidosis, aminoaciduria, hypokalemia, and hypo-
phosphatemia. Most of these cases have had kappa-type light chain in the
urine, although lambda light chain disease has also been reported. It may be
difficult to demonstrate that these patients in fact have a form of myeloma.
The tubular defect and bone disease, however, can effectively be ameliorated
by the administration of vitamin D, potassium, phosphate, and occasionally
bicarbonate. Treatment with calcium carbonate may also be required. Effec-
tive therapy usually results in bone healing and a decrease in bone pain.
ANEMIA. Anemia is seen in most patients at some time in the course of
multiple myeloma. 13 Frequently, successful treatment will stabilize the he-
moglobin level. Androgen therapy may be useful, but women often do not
tolerate this form of treatment. The physician must weigh the risks of an-
drogen side effects versus the potential benefit in the individual patient.
Hyperviscosity Syndrome. Hyperviscosity, hypervolemia, and cryoglo-
bulinemia may be treated most effectively by plasmapheresis. The aim of
treatment is to return the plasma volume toward normal and reduce the
relative serum viscosity to less than 4. The procedure usually relieves the
immediate symptoms of hyperviscosity, but antineoplastic therapy should be
rapidly instituted to inhibit the synthesis of monoclonal protein.
The hyperviscosity syndrome is relatively rare in patients with multiple
myeloma as compared with macroglobulinemia patients.
WALDENSTROM'S
MACROGLOBULINEMIA
Introduction
Macroglobulinemia is a neoplastic disorder of B lymphocytes characterized

by the proliferation of cells that are intermediate in maturity between lym-
phocytes and plasma cells. These cells synthesize and secrete monoclonal
IgM. In macroglobulinemia, enlarged lymph nodes and hepatosplenomegaly
are common, whereas osteolytic bone lesions, hypercalcemia, and renal fail-
ure are unusual. Anemia, bleeding diatheses, and hyperviscosity may be
prominent clinical findings.
Diagnosis
The diagnosis of macroglobulinemia in asymptomatic patient may be made

by the findings of monoclonal IgM in the serum and evidence of bone marrow
and lymphoid organ infiltration with lymphocytes, plasma cells, and "lym-
phoid plasma cells." It may be quite difficult to distinguish the early phase of
macroglobulinemia from benign monoclonal gammopathy, and these asymp-
tomatic patients should not be treated with antineoplastic therapy. Indica-
tions for therapy include extensive bone marrow infiltration, anemia, marked
splenomegaly and lymphadenopathy, hyperviscosity, and bleeding manifes-
tations.
Treatment
Because Waldenstrom's macroglobulinemia is a relatively rare disease,

there have been few comparative therapeutic trials. Also, the average age at
diagnosis is 60 years, and chemotherapy studies in patients with indolent
disease in the older age group are difficult. Although some patients can be
managed by repeated intensive plasmapheresis, 58 most of those who require
therapy for long-term control are more reliably and conveniently treated with
alkylating agents.
A number of alkylating agents are effective in this disease (chlorambucil,
cyclophosphamide, and melphalan), but chlorambucil has been the most
extensively used agent. In a series of 31 patients with macroglobulinemia, 6 of
9 patients from selected studies who were treated with this drug showed a 50
59
per cent or greater decrease in the level of circulating macroglobulin. In a
more recent series of 40 patients treated with alkylating agents, 40 per cent
showed a decrease in serum IgM concentration. 60 In that series, the average
survival rate for the responding group was almost 50 months. There is only
limited experience with multiple-agent chemotherapy in the treatment of ma-
croglobulinemia. 42
Our overall approach to the management of macroglobulinemia rests heavi-
ly on the premise of treating only symptomatic patients with clear indications
for treatment. The acute effects of the hyperviscosity syndrome are managed
by intensive plasmapheresis; however, we favor chlorambucil therapy for
long-term control.
HEAVY CHAIN DISEASE

Heavy chain diseases are neoplastic disorders of B lymphocytes and plasma
cells characterized by the proliferation of cells that secrete a heavy chain or
part of a heavy chain of immunoglobulin. These disorders are rare, and of the
five possible types of heavy chain disease, only three have been recognized
(gamma, alpha, and mu). The diagnosis of these conditions may be quite
difficult and always requires detailed immunologic studies.
Gamma heavy chain disease was the first type to be described. 61 A recent
review of 30 cases with the disorder gives extensive clinical and immunologic
data. 62 The patients usually present with a lymphoma syndrome. Fever, weak-
ness, and general malaise are common symptoms, and there is usually lym-
phadenopathy and hepatosplenomegaly. Uvula edema and erythema are com-
mon clinical findings that are due to the involvement of the lymphatic tissue
of Waldeyer's ring. Examination of the bone marrow usually shows an in-

crease in plasma cells and lymphocytes. There is no accepted form of therapy
for this disease, nor is there evidence from very limited data that alkylating
agents or corticosteroids are useful. Local irradiation can be helpful in con-
trolling tissue infiltration.
Alpha heavy chain disease is probably the most common form of the heavy
chain disorders and has a distinctive clinical presentation. 62 64 The disease is
"
usually seen in young adults, and there is a very high incidence in Mediter-
ranean countries and in certain Asian countries as well as in South America.
In the enteric form of the disease, patients present with manifestations of
malabsorption and severe abdominal pain. Pathologic examination usually
reveals the infiltration of lymphoid plasma cells in the bowel mucosa and
mesenteric nodes. A diagnosis requires the demonstration of a protein in the
serum composed of alpha heavy chain but without There is little
light chain.
information regarding the treatment of this disease; however, complete remis-
sions have been reported in some patients treated with chemotherapy as well
as an occasional remission occurring in patients treated with antibiotics
alone. 63
Mu heavy chain disease is the rarest of these disorders, and most patients
present with chronic lymphocytic leukemia. 85 88 These patients should be
*
managed as in the usual form of CLL (see Chapter 22).
HAIRY CELL LEUKEMIA

Introduction
Hairy cell leukemia is and pathologic entity charac-

a well-defined clinical
terized by splenomegaly and associated with pancytopenia and neoplastic
mononuclear cells in the blood and bone marrow. 67,68 This disease is now
being recognized with increased frequency, and Sebahoun ct al. 98 have
recently reported on a series of 131 cases. The disease is usually seen in
patients more than 30 years of age, and there is a clear male predominance.
Since the description of this disease as leukemic reticuloendotheliosis by
Bouroncle ct al,70 there has been considerable controversy regarding the cell
line of origin of neoplastic hairy cells. 71 Despite some remaining conflicting
viewpoints, we believe that the weight of evidence indicates that hairy cell
leukemia is primarily a disease of B lymphocytes. 68, 72 The most telling point
regarding this conclusion is the demonstration of immunoglobulin synthesis
by neoplastic cells. 73 75 Recently, T lymphocyte variants of this disorder have
"
been reported. 76 Hairy cell leukemia, therefore, appears to be a chronic

lymphoproliferative disorder, similar to chronic lymphocytic leukemia and
lymphocytic lymphoma.
Natural History
Diagnosis. The diagnosis of hairy cell leukemia can be made on the basis
of the usual clinical findings and the observation of morphologically typical
"hairy cells" in the peripheral blood containing the tartrate-resistant isoen-

zyme 5 of acid phosphatase. 77 The bone marrow is often difficult to aspirate,
but biopsy and touch preparations reveal the classic histology and cytology.
Lymphadenopathy is not prominent, but the splenic pathology is typical, and
there is usually diffuse infiltration with the neoplastic mononuclear cells.
Patients may present with symptoms due to splenomegaly, thrombocyto-
penia, or anemia, but in many cases the disease is suspected because of
incidental findings (physical examination or routine blood count) in asymp-
tomatic patients. Many patients with hairy cell leukemia who are diagnosed
incidentally, may have quite indolent disease requiring no therapy. The major
cause of death is infection, and it has been shown that severe granulocytopen-
ia is the most important predisposing cause.
68,69 78
*
Therefore, we treat pa-
tients with hairy cell leukemia only when it is required because of massive
splenomegaly, cytopenias (particularly granulocytopenia), or obviously pro-
gressive infiltrative disease.
PROGNOSIS. The prognosis in hairy cell leukemia is quite variable. In 40
cases reported by Catovsky, 68 the median survival was between two and four
years. In a combined series of 71 patients, we found an actuarial survival of 51
per cent at four years; 79 however, there was no change in actuarial survival at
eight years. A French group 69reported an overall median survival of 42
months. They reported that patients who received chemotherapy had a me-
dian survival of 20 months as compared with 84 patients who received only
supportive therapy showing a median survival of 50 months.
Treatment
There are no controlled trials of therapy in hairy cell leukemia; however, it

77
is clear that splenectomy is the treatment of choice. Removal of the spleen
usually leads to prompt hematologic improvement and increased survival.
The main mechanism whereby splenectomy increases survival may be its
effect on increasing the peripheral granulocyte count, thereby decreasing the
incidence of infection. Catovsky 68 has found a partial or complete response to
splenectomy in over 90 per cent of patients treated. We studied 20 consecu-
tive patients with hairy cell leukemia at UCLA and found that the incidence
of serious infection was 40 per cent. 78 This incidence correlated closely with
the level of the peripheral granulocyte count, and most infections occurred in
patients prior to splenectomy. There were two episodes of serious infection
occurring in our splenectomized patients; both were seen in the immediate
postoperative period. A clear benefit of splenectomy was also seen in the
French series 69 and in a multi-center study of 71 patients. 79
Although corticosteroids have been used in many patients with hairy cell
leukemia, we have found no evidence that this treatment is effective, and we
have observed an increased incidence of infections in patients treated with
steroids. 78 In our series, there was a clear relationship between fungal disease
and corticosteroid therapy, and we observed a single case of Pneumocystis
carinii infection in a steroid-treated patient. Others, however, believe that
68
corticosteroid therapy may improve certain hematologic parameters.
The role of cytotoxic therapy is uncertain. Several observers have indicated
that alkylating agent therapy is without benefit, but we have found that
chlorambucil therapy may be useful, particularly in the postsplenectomy pa-
tient.
Our general approach is to simply observe asymptomatic patients and per-
form splenectomy when indicated because of pancytopenia or massive splen-
omegaly. We have found chlorambucil therapy to be effective in selected
postsplenectomy patients who have high peripheral hairy cell counts.
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Engl J Med 286:1283, 1972. 1958.
56. Kyle RA, et al.: N Engl J Med 293:1334, 71. LoBuglio AF: N Engl J Med 295:219,
1975. 1976.
57. Maldonado JE: Am J Med 58:354, 72. Golde DW, et al.: N Engl J Med 296:92,
1975. 1977.
58. Solomon A and Fahev JL: Ann Intern 73. Fu SM, et al.: Stand J Immunol 3:847,
Med 58:789, 1963. 1974.
59. McCallister BD, et al.: Am J Med 74. Golde DW, et al.: Br J Haematol
43:394, 1967. 35:359, 1977.
60. MacKenzie MR and Fudenberg HH: 75. Debusscher L, et al.: Blood 46:495,
Blood 39:874, 1972. 1975.
61. Franklin EC, et al: Am J Med 37:332, 76. Saxon A, et al.: Ann Intern Med 88:323,
1964. 1978.
*62. Frangione B and Franklin EC: Heavy 77. Yam LT, et al.: Arch Intern Med
chain diseases: clinical features and 130:248, 1972.
molecular significance of the disor- 78. Bouza E, et al.: Blood 51 :851, 1978.
dered immunoglobulin structure. *79. Golomb HM, et al: Hairy-cell leuke-
Semin Hematol 10:53, 1973. mia: a clinical review based on 71 pa-
63. Seligmann M: Arch Intern Med 135:78, tients. Ann Intern Med 89:677, 1978.
1975.
64. Tabbane S, et al.: Cancer 38:1989,
1976.
CHAPTER 24
HODGKINS
DISEASE
Charles M Haskell Robert Parker
INTRODUCTION
More than 150 years have passed since Thomas Hodgkin performed the first
of several autopsies revealing the disease that now bears his name. There has 1
been intense debate about the essential nature of this disease for more than
100 years, and convincing answers to some of the questions about Hodgkin's
24 / Hodgkin's Disease 867
100 1 1 1
TREATED WITH
1009 CASES. ALL STAGES.
6MEV LINEAR ACCELERATOR
X RAY AND/OR CHEMOTHERAPY
(KAPLAN. 1976)
62%
285 CASES.ALL STAGES. TREATED BY

HIGH DOSE 200 KV X RAY THERAPY
(PETERS. 1960)
—A
- 754 CASES.ALL 23%
STAGES. WITH NO
SPECIFIC THERAPY :\
(COMPOSITE OF 6
REPORTS) 8%
I J_ —05%—
6 10
YEARS
FIGURE 24-1. Survival of patients with Hodgkin's disease (all stages) in

three therapeutic eras. (From Kaplan MS: Cancer Res .36:3863, 1976.)
disease (HD) are still not available. However, the last two decades have seen
a dramatic improvement in the prognoses of patients with HD, and it is now
possible to speak of cure for those with limited disease. This is most apparent
in the work of Kaplan, 2
as reflected in the survival curves for 1009 consecu-
tive, previously untreated patients with HD
who were treated at Stanford
University with megavoltage radiation therapy or chemotherapy, or both, as
compared with earlier reports elsewhere of patients who were either untreat-
ed or treated with orthovoltage radiation (Fig. 24-1).
Although this chapter emphasizes therapy, HD
cannot be treated effective-
ly without an understanding of its natural history and biology. Thus, certain of
these features will be discussed including selected epidemiologic findings,
classification, clinical features, and Books about HD are available for
staging.
the reader who is interested in a more complete discussion of these
topics. 3 ' 4
Many of the clinical and histologic features of HD resemble those seen in

some However, a specific etiologic agent has not been
infectious diseases.
defined. The Epstein-Barr virus has been fairly well excluded, 5 but there is
continued interest in RNA viruses as a possible infectious cause for HD.
followed the demonstration of RNA related
Initial interest in this possibility
to the Rauscher murine leukemia virus in HD tissue. 6 This interest was
heightened by subsequent studies showing the simultaneous presence of
high molecular weight RNA and reverse transcriptase (both of which are
characteristic of type-C animal tumor viruses) in HD tissue. 7 This work must
be extended and confirmed; nevertheless, it raises the possibility that HD
may be a virus-induced neoplasm.
Whatare the implications of a possible viral etiology for HD? Certainly, it
suggests the possibility of immunologic prevention, although this is not an
immediate prospect. Of greater immediate concern is whether or not HD is
contagious and if patients with HD pose a hazard to others. It would appear
that HD is not contagious. Gutensohn and Cole 8 have reviewed a variety of
epidemiologic data relevant to this possibility. They point to certain striking
similarities between the epidemiology of HDand that of paralytic poliomyeli-
tis. The peak age of incidence for both diseases is delayed as living conditions
improve. Risk is increased for both diseases with a higher social class and
small family size. These authors suggest that HD, like paralytic poliomyelitis,
may be a rare manifestation of a common infection, with the probability of
developing disease increasing as patient age at time of infection increases.
Observations against a contagious basis for HD
include the following: (1)
HD is no more frequent in physicians than it is in people in the general
population of similar age and socioeconomic status; 9 (2) although HD may

occur as familial aggregates, its occurrence in marital partners is extremely
rare; 9 and (3) in the area around Oxford, England, young patients with HD
could not be linked to each other more frequently than a matched control
group of individuals without the disease. 10
Although the weight of scientific evidence suggests that HD
is not conta-
gious, data that are consistent with an alternative view should be mentioned.
In a study of 59 sibling pairs with HD, it was apparent that siblings of the
same sex as an affected person had a risk of HDthat was double that of
siblings of the opposite sex. 11 Vianna and coworkers 12 13 have reported a
'
cluster of HD cases in Albany that they considered to be consistent with

horizontal transmission of an infectious agent. Finally, Schimpff et al. u have
described a group of patients with leukemia or lymphoma who appeared to be
interlinked by prior close associations. It should be noted that both these
latter studies are open to criticism, and the former study is equally compatible
with a common-source exposure to a carcinogen. Consequently, most physi-
cians do not believe that patients with HD pose any public health risk. 9 15 '
Indeed, the model proposed by Gutensohn and Cole 8 suggests that even if a
patient with HD were to shed a causative virus, it would be one that is
normally encountered in the environment. 8 However, they also point out that
the model predicts an increase in the incidence of HD
in the United States
during the next decade because of the high level of living conditions and the
16
decrease in family size. In a subsequent review, Vianna and Polan have
provided further epidemiologic support for this .model.
Several other epidemiologic features of HD are of interest, although their
practical importance to the individual patient with the disease is uncertain.
HD is an uncommon disease, making up about 1 per cent of all cancer in
humans. It has an unusual bimodal age-specific incidence curve, with one

mode between the ages of 15 and 34 years and another after the age of 50
years. 17 About 60 to 65 per cent of patients are male; 85 per cent of children at
age 10 years or younger are male, but between the ages of 15 and 35, the sex
incidence is about the same. HD
is distributed throughout the world, but the
incidence peaks differ somewhat. An example is Japan, where the age-

incidence curve is not bimodal. It has been postulated that HD
in young
people may be a different disease than in people over age 50 years; however,
most clinicians do not ascribe to this interpretation of the data.
NATURAL HISTORY
A histopathologic diagnosis of Hodgkin's disease demands the presence of

highly characteristic giant cells in an appropriate pleomorphic stromal back-
ground. These giant cells are characterized in fixed-tissue sections by two or
more large, vesicular nuclei with prominent nucleoli; they are usually called
"Reed-Sternberg'' cells, although it is clear that they were described by Tuck-
well and others as long as 30 years before the description of Sternberg (1898)
and Reed (1902). 18 Although Reed-Sternberg cells must be present for a
diagnosis of HD, it is important to emphasize that they are diagnostic only
when present in the proper pleomorphic setting.They have also been noted
in rare cases of carcinoma (breast, lung),melanoma, malignant fibroxanthoma,
mycosis fungoides, and myeloma, as well as in some nonmalignant diseases
(thymoma, myositis, infectious mononucleosis, and rubeola). 1*
Despite its large size and ominous appearance, the Reed-Sternberg cell
does not appear to be capable of replication. It does, however, appear to be
derived from the putative HD neoplastic cell, which Kaplan and Gartner20
have identified as a malignant macrophage or mononuclear phagocyte. This
designation is based on the morphology, phagocytic activity, adherent behav-
ior in vitro, lysozyme secretion, surface marker characteristics, aneuploidy,
and heterotransplantability of giant cells derived from the involved spleens of
25 patients with HD and grown in long-term tissue culture. Kadin et al. 20a
have also studied this question and independently concluded that the Reed-
Sternberg cell is derived from a macrophage precursor. The identification of
the cell of origin for HD
may help to elucidate the pathophysiology of its
various manifestations and suggest new approaches to therapy.

Hodgkin's disease may be subclassified into four categories: lymphocyte-
predominant HD (LP), mixed-cellularity HD (MC), lymphocyte-depleted HD
(LD), and nodular-sclerosing (NS) HD. 3,21 The distinctive histologic features
and relative frequency of these types of HD are given in Table 24-1. These
subtypes have prognostic and clinical importance, as discussed later in this
chapter. Except for nodular sclerosis, HD may evolve from one subtype to
another. Specifically, a patient with lymphocyte-predominant HD may later
be shown to have mixed-cellularity HD or even lymphocyte-depleted HD. It
is unknown why nodular sclerosis does not show such evolutionary
changes.
It should be emphasized that a tissue diagnosis of HD is not always easy to
make and that it may be even more difficult to establish the subcategory of the
TABLE 24-1. Histopathologic Classification of HD 3
Relative
Rye Classification, 1965 Distinctive Features Frequem ^
Lymphocyte predominance Stroma: Abundant mature lymphocytes or 10-15';

histiocytes, or both; no necrosis
'R-S cells: Usually sparse
Nodular sclerosis Stroma: Prominent nodules of lymphoid 20-50%

tissue separated by bands of
collagen
R-S cells: Atypical ("lacunar cells" 21 )
Mixed cellularity Stroma: Pleomorphic mixture of plasma 20-40%

cells, eosinophils, lymphocytes,
fibroblasts; necrosis common
R-S cells: Usually numerous
Lymphocyte depletion Stroma: Paucity of lymphocytes; diffuse 5-15%

fibrosis and necrosis
R-S cells: Usually numerous
°Reed-Sternberg cells. In about 10 to 15 per cent of cases a subclassification cannot be precisel) defined
HD).
('•unclassified"
disease. 22 For difficult or problematic cases, it is essential that a pathologist

who is experienced in the differential diagnosis of lymphomas be consult-
ed.
Clinical Features
Patterns of Spread. Hodgkin's disease may

present as a focal, micro-
scopic area within an enlarged, hyperplastic lymph node, or it may not be
diagnosed until multiple lymph node areas are massively involved. 23 Indeed,
a patient with HD
may undergo several lymph node biopsies before the
diagnosis is established. In about 90 per cent of cases, presents as a HD
superficial lymph node disease; 60 to 80 per cent of these patients have
cervical node enlargement. 24 Approximately 0.25 per cent will present with
primary extranodal disease without evident spread elsewhere. 25 The spread to
localized extranodal sites by direct extension is a common occurrence, as is
disseminated extranodal involvement from hematogenous spread.
There is general agreement that HD
patients with localized disease can be
cured with radiation therapy, whereas those with obvious disseminated dis-
ease are not curable by radiation therapy alone. In 1966, Kaplan 3 pointed out
that in the vast majority of his cases there was a predictable, nonrandom
3
pattern of spread from one group of lymph nodes to the contiguous nodes.
The ability to predict which lymph node areas were at greatest risk added
credence to extended-field radiation therapy, and it spawned the concept that
HD is usually a unifocal disease that spreads by tumor cell transport along
contiguous lymphatic channels. By this schema the spleen usually represents
the final lymph node area to be involved before hematogenous spread
occurs.
This model of spread has been useful in developing improved radiation

therapy, although it suffers from its dependence upon nonphysiologic trans-
26
port of tumor cells against the normal direction of lymphatic flow, a condi-
27
tion that has not been reproducible in experimental animals. Moreover,
several other observations suggest that hematogenous spread may be an early
event in the natural history of the disease for some patients. Specifically,
Reed-Sternberg cells have been found in thoracic duct lymph 28 and in the
blood of some patients, 29 and the invasion of lymph node or splenic blood
vessels by HD
has been associated with a high frequency of disseminated dis-
30
ease.
Although the importance of the finding of vascular invasion in lymph nodes
31 33 "
is controversial, it appears that vascular invasion in the spleen is associat-
ed with a very high risk of extranodal involvement. 30,32 The gross appearance
of splenic involvement by HD is also of interest; it is usually focal, with an
appearance not unlike that seen in experimental animals after intravenous
injection of lymphomatous cells. Thus, it cannot be assumed that a patient
with apparently localized disease is curable with local treatment alone unless
a careful search is made to exclude disseminated extranodal disease. Further-
more, additional work must be done to clarify the meaning of splenic involve-
ment in this disease. Should the spleen continue to be thought of as a lymph
node, or is it more appropriate to think of it as an extranodal site with
involvement by HD being tantamount to dissemination? Although a defini-
tive answer to this question is not available, the approach we use is to
consider splenic involvement with HD to be equivalent to nodal disease,
unless there is unequivocal evidence of splenic vascular invasion. In the
latter case, we feel that disseminated extranodal disease is very likely.
Constitutional Symptoms. Fatigue, weakness, anorexia, cachexia,
diaphoresis (continuous or nocturnal), fever (continuous or cyclic in the ab-
sence of infection), weight loss, pain in areas of HD
immediately following
the ingestion of alcohol, pruritus, and a wide variety of nonspecific skin
conditions may occur with HD. 24 Because some of these symptoms have been
associated with a 20 to 30 per cent reduction in survival, it is essential to
clearly document their presence or absence in the
assessment of the
initial
patient. Based on discussions of this problem at the Ann Arbor Symposium on
Staging HD held in 1971, the most important constitutional symptoms (B
symptoms) are as follows: (1) unexplained weight loss of more than 10 per
cent of body weight in the six months previous to diagnosis, (2) unexplained
fever with temperatures above 38° C, and (3) night sweats. 34 A short, un-
explained febrile illness does not qualify as a B symptom, nor does pruri-
tus.
The basis for these constitutional symptoms is largely unknown, and treat-
ment is that of the underlying disease. In patients with refractory HD, fever
and night sweats may prove to be very debilitating. Aspirin or acetaminophen
(Tylenol) may be useful, although some patients tolerate aspirin poorly. In-
domethacin in substantial doses (50 to 100 mg every four hours) may be more
successful and better tolerated, 35, 36 and the antihelminthic drug levamisole
has been effective experimentally. 37 The fact that indomethacin is effective is
oT interest, since it is a potent inhibitor of prostaglandin synthesis, and a
prostaglandin-producing suppressor cell appears to be responsible for at least
one aspect immunologic hyporesponsiveness in HD. 38 It is also of interest

of
that circulating immune complexes may be associated with the fever and
night sweats seen in HD 39 and that some patients respond well to the immun-
osuppressant glucocorticosteroids.
Immunologic Dysfunction. HD may be associated with an impaired
immune system. One can summarize the major immunologic problems as
follows: (1) impaired ability to express delayed hypersensitivity to new or
previously encountered allergens, or both, abnormally prolonged allograft
(2)
rejection reactions, (3) poor primary humoral antibody responses, and (4)
intact secondary humoral antibody responses. 40 Generally, the degree of im-
munologic impairment may be related to the stage of disease, histopathologic
type, and peripheral lymphocyte count. Early, localized HD
may be associat-
ed with normal immunologic tests or only depressed delayed hypersensitivity
responses, whereas widespread disease with lymphocyte depletion histology
and peripheral lymphocytopenia would be associated with the more profound
immunologic disturbances. As described in the previous section, one possible
cause of immunologic suppression appears to be prostaglandins elaborated by
suppressor lymphocytes. 38 The Stanford group has also shown suppression of
lymphocyte function by serum from patients with HD, although the serum
factor has not been characterized. 41
The clinical importance of immunologic dysfunction in HD is incompletely
defined. It may be a very important contributor to certain infectious complica-
tions, and the immunosuppressive effects of treatment may further contribute
to this problem. 42 43 However, it is highly controversial whether or not the
'
immunologic dysfunction plays a role in the etiology of HD, 40 and it does not
appear to modify prognosis. 44
Organ-Related Problems. The natural history of treated HD may in-
clude the dysfunction of any organ system, and the clinician is frequently
challenged to separate abnormalities related to the underlying neoplastic
disease from other causes. Because of the critical importance of differential
diagnosis, both in establishing an initial therapeutic plan as well as in later
phases of care, we shall briefly comment on some additional clinical consider-
ations as they relate to the various organ systems.
Lymph Nodes and the Lymphangiogram. For reasons that are unclear,
certain lymph node groups are only very rarely involved in HD, although they
are commonly involved in other malignant lymphomas. In a series of 340
untreated patients at Stanford University who underwent staging laparotomy,
less than 1 per cent had involvement of the mesenteric, popliteal, or epi-
trochlear nodes. 3 The retroperitoneal nodes are frequently involved, and
these may be evaluated with fair accuracy by lymphangiography (LAG).
However, LAG is not definitive, giving about a 9.5 per cent false-positive rate
and a false-negative rate as high as 35 per cent. 45 This procedure also carries a
mortality rate of about 0.11 per cent, and it is contraindicated in patients with
severe respiratory insufficiency, iodine allergy, a right-to-left-intracardiac
shunt, or previous radiotherapy to the lungs. 45,46 Because of its diagnostic-
limitations and morbidity, especially in comparison with exploratory laparoto-
my, the use of LAG as a routine procedure in HD is undergoing re-
evaluation. 47 However, the following facts have contributed to its widespread

acceptance in the early evaluation of this disease: 46,48 (1) It may be useful in
2 1 / Hodgkin's Disease 873
establishing the target volume for radiation therapy; (2) itmay help the
surgeon identify nodes for biopsy at laparotomy; and (3) it may be a useful
guide to the success of therapy. In some cases, LAG should be repeated after
completing therapy in order to assess the response to treatment.
Abdominal ultrasound, 49 inferior cavography, computer assisted tomogra-
phy, 50 and the 67 Ga scan 51 have been proposed as other noninvasive tech-
niques for evaluating retroperitoneal or mesenteric nodes, or both, in
HD. All these studies may yield false-positive or false-negative results, but
they may be very useful in some patients. Combinations of tests may be better
than relying on any single noninvasive study. In one review, 51 the estimated
probability of abdominal node involvement by HD
was 95 per cent if two or
more of the following tests were abnormal: LAG, 67 Ga scan, and ultrasound.
If this is confirmed by further study, it may eliminate the need for surgical
staging in some of these patients.
Spleen and Splenectomy. The spleen is involved initially in about 30 per
cent of HD
patients, and late in the course of the disease it is involved in 80
per cent or more of cases. 24 Since 1969, when Glatstein et «/. 52 reported their
initial experience with laparotomy and splenectomy in staging HD, there has
been widespread acceptance of the limitations of noninvasive techniques in
evaluating this organ. 35,53 Indeed, one quarter to one third of "clinically
negative" spleens contain focal or general infiltration with HD, and three
quarters of the enlarged spleens are involved.
Given the importance of splenic vascular invasion,'50 ,!2
as described earlier
in this chapter, we share the view of many clinicans that splenectomy should
be done as part of the initial staging evaluation for new patients with HD,
except if there is a major contraindication, if the patient has a histopathologic
type of HD
that rarely involves the spleen (see later discussion), or if the
patient has already been shown to have advanced disease in need of systemic
chemotherapy. 4 It should be remembered, however, that the procedure
:{ -
carries an operative mortality risk of about 0.5 per cent and a serious immedi-
ate morbidity risk of about 1.4 per cent. 54 It also is associated with herpes
zoster in up to 24 per cent of cases and several bacterial infections (mainly
pneumococcus, Hemophilus, and meningococcus) in patients who have re-
lapsed. 55 Because the risk of pneumococcal infections appears to be especially
high for young children, some clinicians use prophylactic penicillin for splen-
ectomized patients in the pediatric age group. 56
Tonsils and Waldeyer's Ring. Fewer than 1 per cent of cases have involve-
ment of the tonsils. 3, 57 At one time tonsillectomy was thought to predispose
people to HD, but subsequent studies failed to confirm this concern. 58 When
tonsils are involved, however, there is almost always involvement of the
cervical nodes.
Thymus. The thymus may occasionally be the sole site of HD, 59 * 60
a fact
that has only recentlybeen widely accepted by pathologists. It most common-
ly occurs as a variant of nodular sclerosis in younger patients, and its main
significance relates to surgical therapy. It should not be approached with
radical surgery of curative intent; a simple biopsy and radiation therapy are
clearly superior treatment.
Liver. The liver is involved in about 5 to 8 per cent of newly diagnosed
cases of HD, and it is involved in about two thirds of cases studied by
autopsy. 24 Based on findings at laparotomy, it has become clear that the liver is
almost never involved in patients with normal spleens.' If the spleen is
palpable, the risk of liver involvement is about 50 per cent.

There are two patterns of liver metastasis in HD —
diffuse and focal. In
addition, noncaseating epithelioid granulomas may be present that are not
neoplastic 61 but rather appear to be associated with a better prognosis." 1,62
Unfortunately, noninvasive tests are incapable of distinguishing between
benign and neoplastic liver changes in HD. A focal defect on liver scan is
63
suggestive of neoplastic involvement, butit is not diagnostic. Thus, accurate
differential diagnosis requires a tissuespecimen. In some cases, a closed
needle biopsy is adequate, 64 although for newly diagnosed patients more
extensive tissue sampling during peritoneoscopy 65,66 or laparotomy is usually
required. 5, -
53 ' 66-68
Lung and Pleura. The involvement of the lung or pleura with HD almost
3, 24
never occurs without hilar or mediastinal node involvement. Consequent-
ly, a totally normal posteroanterior and lateral chest x-ray makes involvement
of these structures unlikely. However, about two thirds of patients with HD

have intrathoracic node involvement, and in this group the risk of pulmonary
HD has been reported to be at least 17 per cent. 69 We recommend, therefore,
full lung tomograms in patients who are candidates for local therapy but who
demonstrate hilar or mediastinal adenopathy on chest x-ray.
The spread of HD to the lungs is mainly through the lymphatics, although
hematogenous spread may occur occasionally. 3, 24 When the lung is involved
by contiguous spread from hilar nodes, it is usually possible to manage with
radiation therapy. 3 Likewise, most pleural effusions are due to central ob-
struction of lymphatics rather than from pleural metastases, so a pleural
effusion in the absence of a tissue diagnosis of pleural HD is not a contraindi-
cation to radiation therapy. 3 It is unwise to accept a diagnosis of pleural or
intrapulmonary HD without a tissue diagnosis. Tragic mistakes have been
made in which HD was confused with an infectious process, leading to
inappropriate therapy. 3 Pulmonary complications of radiation or drug therapy
may also intervene to confuse this issue in previously treated patients. 70,71
Bone Marrow and Hematologic Abnormalities. Although bone marrow
aspirates are usually nondiagnostic, bone marrow biopsy with a Jamshidi or
similar needle reveals HD in 6 to 14 per cent of previously untreated
cases. 66, 72 Patients with limited disease or lymphocyte-predominant histology
rarely show marrow involvement, whereas symptomatic patients, particularly
those with anemia, leukopenia, or thrombocytopenia, not infrequently have
this finding. 3,
72
In the latter case, multiple biopsies are indicated, since HD
tends to involve the marrow in a focal fashion. Choosing a bone marrow
biopsy site in such patients may be facilitated by ni In bone marrow scin-
tigraphy. 73
Bone marrow dysfunction following radiation therapy or chemotherapy, or
both, is a common
occurrence. Previous splenectomy does not appear to
prevent marrow suppression, 74 and in some cases the bone marrow damage
from radiation therapy may persist for several years. 75 However, delayed bone
marrow dysfunction following earlier recovery of hematopoiesis generally
signifies a relapse of HD.
76,77
Indeed, HD
may mimic or be complicated by
a variety of syndromes involving bone marrow function, including myelofi-
24 / Hodg kin's Disease 875
K0
brosis, 78 thrombocytopenic purpura, 79 -
and Coombs'-positive hemolytic ane-
81
mia. Finally, the value of following serially the erythrocyte sedimentation
rate(ESR) should be emphasized. 82 An ESR greater than 30 mm/hr was found
in 90 per cent of patients in relapse in one series, and a normal value is
commonly found during remission. An unexplained elevation of the ESR in a
patient in remission should prompt a thorough investigation for relapsing dis-
ease.
Musculoskeletal System. Bone involvement by HD
is unusual in asymp-
tomatic patients, and its frequency in different clinics varies between 1 per
cent and 35 per cent. 3, 24 It may be osteolytic, osteoblastic, or a mixture of the
two patterns. Technetium-99m bone scanning is the most sensitive test for
bone involvement; in one series of patients, the results of conventional radio-
grams of the involved bone, which was found by scan, were normal in 35 per
cent of patients. 83 Bone involvement that is contiguous to an area of involved
lymph nodes does not preclude local radiation therapy, whereas multiple,
disseminated areas are an indication for systemic therapy.
Hypertrophic pulmonary osteoarthropathy may rarely complicate HD. 84,85
Another rare complication is osteonecrosis of the femoral head in patients
who have received chemotherapy regimens containing corticosteroids. 8(i
Breast, Skin, and Soft Tissues. Primary, isolated involvement of the skin
87
is rare, but when it occurs, the prognosis appears to be good. Otherwise,
involvement of these tissues is not uncommon and is nearly always associated
with advanced disease and a poor prognosis. 3-24
Pericardium and the Cardiovascular System. Small pericardial effusions
are commonly found through echocardiography. 88 Symptomatic pericardial
effusions are much less common, and in the vast majority of cases they are
associated with a combined myocardial-pericardial injury due to previous
radiation therapy. When mediastinal radiation therapy is given, primarily
through an anterior port, the risk is higher (17 per cent) 89 than with equally
weighted anterior and posterior ports (5 per cent). 3 Most of these cases occur
about six months after radiation therapy and resolve with conservative man-
agement. Rarely they progress and may require a surgical pericardiectomy. 90
In some patients the radiation-induced cardiac or pericardial disease is latent
but can be reactivated by withdrawal from chemotherapy regimens contain-
ing a corticosteroid. 91 Because of this, the Stanford group omits the use of
prednisone when using adjuvant combination chemotherapy ("MOP") in
patients who were previously treated with mediastinal radiation therapy. 92
HD may cause the superior vena cava syndrome. 3 24 Because of the extreme
'
importance of this medical emergency, it is discussed in detail in Chapter 28.

Other, less common complications of the cardiovascular system are radiation-
"
induced coronary artery disease and panaortitis. 93 95
Central Nervous System. Neurologic dysfunction in patients with HD
may result from direct extension of the tumor, from metastases, 3 as a complica-
tion of treatment (see Chapters 3 and 4), or as a nonmetastatic neuromuscular
process (see Chapter 29). 24 The involvement of the nervous system by HD
is
rarely seen in a newly diagnosed patient, but it may occur as a medical

emergency at any time. Spinal cord compression is the most common treat-
able form of involvement; 96 because of its importance, it is discussed in
Chapter 18. Cerebral and meningeal metastases may also occur, but they must
be distinguished from infectious processes, such as eryptococcal meningitis or

herpes infections. 24,97 Rarely, granulomatous angiitis may occur and respond
HK
to treatment directed toward metastatic tumor.
Gastrointestinal Tract. HD rarely involves the gastrointestinal tract.
Even at autopsy, the gut is involved in only about 8 per cent of cases.' As a 1
practical matter, this obviates the need for a systematic search for gut involve-
ment as part of the initial staging process, unless there is evidence of frank
bleeding or obvious gastrointestinal symptoms.
Genitourinary Tract. Newly diagnosed HD
rarely involves the urinary
3
tract; therefore, most clinicians do not obtain an intravenous pyelogram as
part of the pretreatment staging process. However, because of the wide
variety of potential genitourinary problems that may rarely complicate HD, an
IVP should be done if there is any suspicion of renal involvement.
Genitourinary tract problems may include renal dysfunction due to renal
100
infiltration by tumor," ureteral obstruction by tumor (5.5 per cent of cases),
uric acid nephropathy, renal amyloidosis, 101 and very rarely, the nephrotic
syndrome. The nephrotic syndrome may be due to inferior vena cava obstruc-
tion 102 or "lipoid nephrosis." The etiology of lipoid nephrosis is uncertain,
although damage by immune complexes 103 or direct damage of the kidney by
thymus-dependent lymphocytes 104 are two postulated mechanisms. A final
rare renal problem in HD is hypouricemia, which appears to result from a
HD-induced renal secretory defect. 105

Endocrine System. The thyroid gland may rarely be the site of primary or
metastatic HD, and it may be damaged by radiation therapy, leading to
delayed hypothyroidism. 3, 106 Neoplastic involvement of the other endocrine
glands is extremely rare. However, gonadal dysfunction may result from
chemotherapy or radiation therapy, and patients should be informed of this
possibility. 107, 108 In women, this can sometimes be avoided by oophoropexy
performed at the time of staging laparotomy. 109
Miscellaneous Laboratory Abnormalities. A wide variety of biochemical
abnormalities have been found in the blood of patients with HD. Examples
include high serum levels of copper, 110, U1 ferritin, 112 a hydroxyproline-
containing protein, 113 and hemolytic complement, 114 as well as elevated levels
of leukocyte alkaline phosphatase. 115 Although none of these tests are specific
for HD, the serum copper level in particular may complement the erythrocyte
sedimentation rate and serve as a guide to the presence or absence of active
HD.
Delayed Second Neoplasms. Other neoplasms may precede or fol-
low the diagnosis of HD, 116 118 and in some families HD may be only one of
"
many neoplasms apparently linked to a common HLA type. 119 Moreover,

combination chemotherapy and radiation therapy are potentially carcinogen-
120 122
"
ic, and their joint aggressive use may be especially carcinogenic. It is
against this background that one must assess the clinical importance of the
delayed development of acute nonlymphocytic leukemia (ANLL) and a vari-
ety of nonleukemic neoplasms in these patients.
The risk of developing ANLL after any modern treatment for HD appears to
be at least 1 to 2 per cent. 121, 122 The clinical features of this complication are
distinctive. Nearly all patients have pancytopenia, a megaloblastic bone mar-
row, nucleated red blood cells in the peripheral blood, refractoriness to
antileukemia treatment (response rate 6.5 per cent), and a very short survival
time (median one month). 121 Hypodiploid chromosome numbers are also seen
frequently. 123 ANLL occurs most commonly in patients with poorly controlled
HD that was treated aggressively, and the latent period is much shorter in
these patients (mean 3.4 years) than in those who received less aggressive
treatment (mean 7.6 years). 121
The risk of developing nonleukemic neoplasms varies with the kind of
117, 120, 124
treatment and the duration of survival after primary treatment. At ten
years, the cumulative probability of developing multiple primary cancers was
2.54 per cent for a group of patients initially treated at the Memorial Sloan-
Kettering Cancer Center with limited approaches (1950 to 1954) but was 6.52
117
per cent for a more aggressively treated group (1960 to 1964). At the Nation-
al Cancer Institute, the ratio of expected second tumors for
observed to
various treatment approaches was 3.8:1 for intensive radiation therapy alone,
3.2: 1 for intensive chemotherapy alone, but 29: 1 for patients treated with both
intensive chemotherapy and radiation therapy. 1**
We conclude that treated patients with HD have an increased risk of
developing an additional neoplasm and that the relative risk increases as the
treatment becomes more aggressive. This should not be allowed to obscure
the tremendous gains achieved with modern, aggressive therapy, as described
in the sections that follow. Nevertheless, it is critical that optimal treatment
for patients with HD be defined in order to minimize the impact of this
emerging problem.
Staging
It is widely accepted that the anatomic staging system for HD, developed at
34
the Ann Arbor Conference in 1971, is making therapeutic deci-
useful in
sions. This classification, as updated in 1977 by the American Joint Commit-
tee for Cancer Staging, is given in Table 24-2. 125 It should be noted that the
AJC recommends that the stage be further defined as "clinical-diagnostic
(CS), surgical-evaluative, postsurgical treatment-pathologic, or retreatment"
staging. Most clinicians simplify these distinctions by combining "surgical-
evaluative" and "postsurgical treatment-pathologic" staging into one category
commonly referred to as "pathologic staging (PS)." The major criterion sepa-
rating a clinical stage from a pathologic stage is biopsy proof of the presence or
absence of HD in a tissue. As a practical matter, this most commonly relates to
whether or not a staging laparotomy was performed.
Ann Arbor (AJC) stages II and III may include patients with limited extra-
nodal extension from involved nodes (II E III E ). Diffuse or generalized
,
extranodal disease is stage IV. This distinction is drawn because of data

suggesting that limited extranodal involvement that is contiguous with lymph
nodes containing HD does not compromise the chance for control with radia-
tion therapy. 126, 127 However, Levi and Wiernik 128 found a very high relapse
rate in patients with stage II E and stage III E disease that was treated solely
with radiation therapy, whereas relapse was infrequent when chemotherapy
was added to radiation therapy. Failure was almost entirely ascribable to
patients with extranodal pulmonary involvement, and, after reviewing this
TABLE 24-2. Hodgkin's Disease: AJC Modification of Ann Arbor Staging

Classification 125
Stage I Involvement of a single lymph node region (I) or of a single extralymphatic organ or
site (I E ).
Stage II Involvement of two or more lymph node regions (number to he stated) on the same
side of the diaphragm (II), or localized involvement of an extralymphatic organ or
site and of one or more lymph node regions on the same side of the diaphragm 1. 1
Stage III Involvement of lymph node regions on both sides of the diaphragm till), which may
also be accompanied by localized involvement of extralymphatic organ or site (III K )
or by involvement of the spleen (Ills) or both (III ES ).
Stage IV Diffuse or disseminated involvement of one or more extralymphatic organs or tissues

with or without associated lymph node enlargement The reason for classifying the
patient as stage IV is identified further by specifying sites according to the following
notation:
Pulmonary -PUL
Osseus -OSS
Hepatic- -HEP
Brain -BRA
Lymph nodes -LYM
Bone marrow- -MAR
Pleura -PLE
Skin -SKI
Eye -EYE
Other -OTH
Systemic Symptoms:
A Asymptomatic
B Unexplained weight loss of more than 10 per cent of body weight in the six months
before admission — and/or
Unexplained fever with temperature above 38° C — and/or night sweats
report, it would appear that at least some patients with stage IV disease were
called stage II E or stage III E Thus, one should be extremely cautious about
.
employing the "E"' designation for patients with limited pulmonary involve-
ment. Unfortunately, very difficult to distinguish between limited and
it is
diffuse extension of HD
from nodes into contiguous lung tissue.
Clinicians at the University of Chicago have proposed an interesting and
potentially important subclassification of pathologic stage III (Fig. 24- HD
2) si, 129
j n a ser j es of 52 patients with pathologic stage III HD they found that
those with intra-abdominal HD
limited to the spleen or splenic, celiac, or
portal nodes, or all of these, ("anatomic substage HI") had a more favorable
prognosis than did patients with involvement of the para-aortic, iliac, or
mesenteric nodes ("anatomic substage III 2 "). They also found that adding
combination chemotherapy to total nodal irradiation was associated with
improved survival of patients with stage IIL disease but not of those with
stage III, disease. Similar results have been reported by two other
groups, 130, 131
making it likely that this distinction w receive wide attention.
ill
These findings also suggest that laparotomy may not be required in those
cases in which stage IIL disease can be firmly established on clinical
grounds.
In some determining the clinical stage by performing the required

cases,
studies listed in Table 24-3 is adequate in planning therapy. 48 This is espe-
cially true if an unequivocal diagnosis of stage III B or stage IV HD can be
made, in which case chemotherapy alone is recommended. In many clinics
(ours included), patients with limited disease receive radiation therapy alone,
and combined chemotherapy and radiation therapy are not usually recom-
mended. For this reason, we usually recommend that the patient with limited
disease have "pathologic staging" completed before a therapeutic decision is
made. Patients with clinical stage I A or II A disease of the lymphocyte-
predominant or nodular-sclerosing type are exceptions to this recommenda-
tion, as discussed later. Since these patients do not undergo laparotomy, an
especially extensive noninvasive evaluation of the abdomen is indicated,
including LAG, ultrasound, and 67 Ga scanning."11 When pathologic stag-
ing is indicated, this generally includes a laparotomy with splenectomy for
the reasons discussed earlier under the section on Natural History.
Laparotomy — Technical Considerations. It is vital that all the re-
quired studies listed in Table 24-3 be completed prior to surgery. Patients
with an indication for bone marrow biopsy should have this done in both
posterior iliac crests, with the results known prior to laparotomy. 132 Patients
with hilar or mediastinal adenopathy should have whole lung tomograms
done before surgery, 133 since biopsy confirmation of unsuspected pulmonary
involvement with HD
may be more important than laparotomy, and in some
cases a thoracoabdominal approach may then be recommended. Laparotomy
and splenectomy should be performed only if the information obtained will
potentially change therapy for the patient, and not just the stage of the dis-
ease.
When done, it should include the following: a
a staging laparotomy is
splenectomy, with silver clips attached to the splenic pedicle; both a wedge
and a deep needle biopsy of both lobes of the liver; multiple lymph node
"N
r
>m,
tsl
z <
FIGURE 24-2. University of Chicago subdivision of pathologic stage III

HD. A,The location of lymph node sites biopsied at staging laparotomy.
Abbreviations: S, spleen: SN, splenic hilar nodes: CN, celiac nodes; PN, portal
nodes: AN, aortic nodes; MX, mesenteric nodes; IX, iliac nodes; L, liver. B,
The anatomic subdivisions of stage III. (From Desser RK, etai: Blood 49:883,
1977.)
TABLE 24-3. Staging Procedures for Hodgkin's Disease
UCLA Ann Arbor

Staging Procedures for Hodgkin's Disease 1979 1971
Adequate surgical biopsy (reviewed by bematopathologist) R R

History (constitutional symptoms) R R
Complete physical examination including head and neck area R R
Laboratory studies: R R
CBC, platelet count, ESR, serum alkaline phosphatase, renal,
and liver function studies ("SMA-12")
Radiologic studies:
PA and lateral chest x-ray (CXR) R R
Intravenous pyelogram (IVP) O R
Bilateral lower extremity lymphangiogram (LAG) R R
Skeletal bone survey O R
Whole chest tomograms (if CXR abnormal) R° R
Inferior cavagram (if LAG or IVP equivocal) R° R
Isotope scans:
Bone scan (correlated with x-ray) R O
Liver-spleen scan R O
Gallium scan R° E
Bone marrow biopsy (bilateral posterior iliac crest Jamshidi or

open surgical) it:
Elevated serum alkaline phosphatase level
Blood count depression
X-ray or scan evidence of bone disease
Generalized disease of stage III or greater
(At UCLA: presence of B symptoms)
Exploratory laparotomy and splenectomy, if: H'

Management decisions depend on the identification of abdominal
disease (peritoneoscopy may be an alternative)
Miscellaneous:
Serum copper level O E
Estimate of delayed cutaneous hypersensitivity O O
Ultrasound
Key to abbreviations: R, required; R°, required under certain conditions; O, optional ancillary procedure
not definitive for diagnosis; E, promising but experimental.
biopsies, including any abnormal nodes seen on the LAG plus portal, hepatic,
and mesenteric nodes; an appendectomy; and in
periaortic, iliac, celiac,
women of childbearing years, an oophoropexy. 134 136 A surgical bone marrow
"
biopsy should be performed for patients with B symptoms or stage II or stage

III disease. Metal clips should be used to mark the sites of all lymph node
biopsies and the margins of tumor masses.
Individualization of the Staging Work-up. Most patients with pre-
viously untreated HD should complete the staging evaluation already de-
scribed before starting treatment. However, this is not always appropriate.
Patients presenting with locally advanced, life-threatening mediastinal dis-
ease may require local radiation therapy before the staging evaluation is
completed. 137 138 In these patients, a staging laparotomy should at least be
'
postponed. In other patients, the presence of comorbid diseases may increase

the predicted operative mortality rate for laparotomy from the usual 0.5 per
cent to per cent. In these cases, the added risk of death from the procedure
1
outweighs the risk of choosing suboptimal treatment based solely on clinical

staging and the histopathologic subtype of HD.
139
Based on a computer analy-
sis of this question, one group now recommends that symptomatic patients
with a 3 per cent estimated mortality rate from laparotomy and a positive LAG
be treated solely with combination chemotherapy unless they are female
patients with mediastinal involvement and either nodular sclerosis or
lymphocyte-predominant histology. 139
This is just one example of how a multifactorial analysis of risk and benefit
for an individual patient may be used to individualize the staging evaluation
and subsequent treatment. It also underlines the importance of communica-
tion between all the physicians potentially involved in the care of these
patients and the necessity of careful joint review of all the critical data before
making a therapeutic decision.
Prognosis
Modern treatment has dramatically improved the prognosis for patients

with HD, as shown in Figure 24- 1. 2 Nevertheless, some patients with HD
140
still do poorly, and many factors may influence the prognosis in the individ-
ual patient. Some of these factors include the histopathologic subtype of HD,
the anatomic stage, and the presence of B symptoms. As a guide to the relative
contributions of these factors to prognosis, Figures 24-3, 24-4, and 24-5 give
(b2) 173)
i ——
i
(5)
70%-
,82
'
H-h-j 52%
(25)
SURVIVAL
FIGURE 24-3. Actuarial survival and freedom L

of 1009 patients with HD
J I I I I
from relapse in a series

treated at Stanford University as a function of his-
topathologic ti/]>e. (From Kaplan HS: Cancer Res
t ————
i i i
36:3863, 1976.) IV T 78% (35) 76%
40
54% I
48%
(55)
NSHD • —• 16)—
MCHD o — o
(21) T 26%
1 (6)
LPHD —D
LDHD
FREEDOM FROM RELAPSE
I I I
I I I 1 L 1
8 9 10
YEARS
100
(1201(478)
Tî*-_l i
~i
90% (72)'
90%I72)-
1
r t —
yo
HO -
Lf\,
109)>A
8 7%
X
? ^KX
70 *\ 0-^1(250)
(118)
1(250 I
60 i 71%T s 69%
(50)-
'I
i\ \
< 50
45%
37%
H-,4
54%
40 ,Ni
))^X_A (20)
30 (7)
•— • STAGE I (A + B)
20 - O— O STAGE II (A + B)
SURVIVAL
D — D STAGE III (A + B)
10 A— A STAGE IV (A + B)
FIGURE Actuarial survival and freedom
24-4.
I I I I I I
J I L from of 1009 consecutive patients
rcla})se in a series
100
i ———— i i i
with HD
as a function of Ann Arbor clinical stage.
(From Kaplan HS: Cancer Res 36:3863, 1976.)
(8)
80 74% (59)
72%—
70
60 :\Th-iffl±3
50
T TÂ_X41% 51?
40 h I "(9) nil
(12)
30
20
10
FREEDOM FROM RELAPSE
J I I \ I I I I I L
4 5 6 7 8 9 10
(YEARS)
the ten-year actuarial survival and freedom from relapse data for these factors
as seen at Stanford University in 1009 consecutive cases of treated by HD
modern therapy, as reported by Kaplan. 2
HD patients who
survive ten years or more without evidence of tumor
141, 142
appear to be cured. That is, these patients have the same death rate as
normal people of the same age and sex. Rarely, however, relapse may occur
after 10 to 20 years, and, in at least one series, microscopic evidence of HD
was usually found in long survivors dying of causes other than HD. 143 This
suggests that in at least some patients with HD, clinical cure may represent a
state of equilibrium between the host and the tumor.
TREATMENT
Surgery
The surgeon plays an important role in the initial diagnosis and staging of
HD, and an operation may be needed for the treatment of some of the
complications of HD. 144 Examples include the occasional usefulness of ther-
3,
apeutic splenectomy in HD
patients with hypersplenism and surgical pericar-
diectomy for patients with radiation-induced constrictive pericarditis. As a
24 Hodgkin s Disease 883
8 9 10 1 9 10
YEARS
FIGURE 24-5. Actuarial survival and freedom from relapse in a series of

patients with
100!-) HD as a function of the presence or absence of B symp-
toms in stages 11 and III. (From Kaplan HS: Cancer Res 36:3863, 1976.)
general rule, however, surgical excision alone rarely is useful in treating HD

involving lymph nodes or organs. Possible exceptions to this rule are the very
rare cases of isolated extranodal HD
involving stomach, small bowel, or
thyroid, and rare symptomatic cases of recurrent tumor after tumoricidal doses
of radiation therapy. 3
Radiation Therapy
Although Senn 145 prematurely claimed a "curative effect" of irradiation for

patients with Hodgkin's disease in 1903, and for decades radiotherapists had
patients survive without evidence of tumor after treatment, widespread in-
terest in the curative potential of radiation therapy was not aroused until a
report by Peters in 1950. 146 Despite many reports of patient survival five and
ten years following irradiation, 147 151 Easson and Russell's paper, 152 "The Cure
"
of Hodgkin's Disease," was received skeptically by many at the time of its

publication in 1963. Unfortunately, such therapeutic nihilism resulted in less
than the best available treatment for many patients with Hodgkin's disease.
Modern concepts of radiation therapy of HD date to the work of Gilbert, 1*8

first reported in 1925. His fundamental principle was the destruction of all
tumor during the initial course of treatment by extending the irradiated
volume from known sites of tumor to suspected sites of involvement within
the limits of the patient's tolerance. In Toronto, as reported by Peters, 154
similar concepts date to about the same time. However, the necessary deliv-
ery of large radiation doses to large tissue volumes was not possible with the
equipment that was then available. Nevertheless, with estimated tumor doses
that probably did not exceed 1000 rad, in 1939 Gilbert 155 reported a five-year
survival rate of 34.2 per cent for those selected patients treated systematic-
ally.
The
introduction of megavoltage equipment in the 1950s resulted in the
development of therapeutic techniques that made it possible to deliver "ade-
quate" radiation doses to large tissue volumes without intolerable resulting
complications. Encouraging results in the treatment of patients with tumor of
limited extent prompted a systematic attempt to extend curative radiation
therapy to patients with tumor above and below the diaphragm (stage III).
This often necessitated the irradiation of nearly all lymphoid structures in the
body. 156 - 157
In contrast to systemic therapy, the capacity to deliver high doses of ioniz-

ing radiations precisely to specific tissue volumes requires diagnostic sophis-
tication to define the targets of treatment.Such diagnostic accuracy has greatly
increased in the past decade with the introduction of the lymphangiogram,
radioisotope liver, spleen, and bone scans, computerized axial tomography,
diagnostic laparotomy, and improved histologic appraisal. Such improvement
is likely to continue, thus compromising or even invalidating the comparison
of today's treatment with historic controls.

The basic concept of radiation therapy for HD
is eradication of tumor, either
in a selected tissue volume or in all sites in a patient, during the initial course
of treatment. This requires substantial radiation doses to large tissue volumes.
Other usage, such as the restriction of radiation dosage to tumor-containing
tissue volumes to allow treatment in the future, almost always becomes a
self-fulfilling prophecy.
The therapeutic objective for most patients with newly diagnosed Hodg-
kin's disease today is "cure." Palliation as the only goal of treatment for these
patients is rarely justifiable.
Based on current evidence, intensive radiation therapy to eradicate tumor is
appropriate for all patients with stages I A I B II A Hb, and III 1A disease. The
, , ,
role of intensive radiation therapy for patients with stages III 2 a, HIb, and
"
51, 129 131
contiguous forms of stage IV Hodgkin's disease is controversial. 3, At
UCLA, the latter groups of patients are generally treated with chemothera-
py.
Despite agreement in concept that all tumor be eradicated during the initial
course of treatment, there is no unanimity of opinion regarding the tissue
volume requiring treatment or the dose necessary for sites at which tumor is
suspected rather than documented. To date, studies have not documented
that irradiation limited to "involved fields" results in fewer long-term clini-
cally tumor-free survivors than does irradiation of "extended fields" or "total
lymphoid" irradiation (Fig. 24-6, A and B) even though the former more often
requires additional treatment after the initial course. 158
Inasmuch body segments inclusive of lymphoid tissue may ulti-
as large
mately require irradiation, techniques have been developed that reduce the
number of junctions between irradiated tissue volumes, for such sites are
prone to either undertreatment, with the increased potential for tumor persis-
tence, or overtreatment, with the risk of serious damage to normal structures.
Consequently, tumor above the diaphragm usually is included in so-called
Local or Involved Field Extended Field

A (IF) irradiation B EF) irradiation
>- "Mantle" Field irradiati D "Inverted-Y" Field irradiati
FIGURE 24-6. Radiation therapy fields employed in treating Hodgkin's

disease.
mantle which include lymphoid structures in the neck, supraclavicular-

fields,
subclavicular regions, axillae, and mediastinum (Fig. 24-6C). Hodgkin's dis-
ease below the diaphragm can be included in so-called inverted-Y fields,
which include the abdominal para-aortic, pelvic, femoral, and splenic pedicle
nodes, plus the spleen, if not removed surgically (Fig. 24-6D). The single
junction of the "mantle" and "inverted-Y" fields is at the level of the dia-
phragm (eleventh or twelfth dorsal vertebrae), at which point the risk of
neoplasm may be less because of the paucity of para-aortic lymphatics.'
Other specific structures may be irradiated when they are actually involved
or at high risk to be involved by tumor, such as Waldeyer's ring when there is
high cervical adenopathy, pulmonary parenchyma when there is hilar in-
volvement, the spleen when it has not been removed, and the liver when
tumor can be identified.
Although HD may be remarkably responsive to and controlled by relatively
small doses of radiation, as documented by Gilbert 155 and other early workers,
consistent tumor eradication requires relatively high doses. As with other
cancers, the therapeutic objective is the use of the highest dose consistent
with an acceptable complication rate secondary to normal tissue injury. Based
on a compilation of the world literature, Kaplan 159160 has documented that
eradication of tumor is directly proportional to total dose, with the risk of tu-
mor persistence in the irradiated volume dropping from 60 to 80 per cent with
less than 1000 rad to 4.4 per cent with 3500 to 4000 rad and 1.3 per cent with
4400 rad delivered in 4 to 4.5 weeks. In addition, Kaplan 159 estimated that in-
asmuch as lack of tumor control in any single site could lead to the death
of the patient, the probability of eradication of Hodgkin's disease becomes
the product of the probability of control for each site (Pj) (P 2 (P„)-
)
Although the relationship of total radiation dose to the pattern of applica-

tion, including the number and size of increments and overall time, may be
less critical for HD than it is for epithelial cancers, most of the available
data 159, 161 163 involves a total treatment time between 10 and 40 days. Scott
'
and Brizel 161 and Seydel et «/. 162 suggested that nearly 100 per cent local con-
trol results from 2500 rad in 10 days, 3000 rad in 30 days, or 4000 rad in 40
days. Friedman 163 and Kaplan 159 reported higher total doses (10 to 30 per cent)
for the same probability of tumor control.
Seydel et a/. 162 attempted to establish separate regression lines for local
control related to tumor size. This concept — that smaller radiation doses are
required to control smaller tumors — has radiobiologic support, has been
documented in the treatment of subclinical disease in the neck, 164 and con-
forms with the practice of the Toronto group reported by Peters in 1950. 146
The importance of eradicating HD within the irradiated volume with the
165
initial course of treatment is supported by data supplied by Vaeth and
166
Seydel et a/. Those patients with "relapse" within a previously irradiated
site had markedly reduced local tumor control (33 to 60 per cent) and survival
(24 per cent at eight years), compared with similar groups receiving adequate
initial treatment despite reirradiation to "adequate" doses, which sometimes
were in excess of the original doses.
Therapeutic aggressiveness is governed by the acceptability of sequelae to
the patient and physician. Regardless of technical excellence, whenever large
volumes of normal tissues are irradiated to doses in the range of 4000 rad in 4
to 4.5 weeks, complications are inevitable in some patients. Related symp-
toms and signs that occur during or shortly after radiation therapy (acute
reactions) almost always are transient and self-limiting. This acute morbidity
usually is clinically manifested in the gastrointestinal and hematopoietic sys-
tems.
Anorexia, which is not inevitable, usually does not result in much weight
loss, even if it is prolonged through the course of treatment, unless there is

superimposed nausea, vomiting, or diarrhea, or all of these. These reflections
of gastrointestinal irritation can almost always be controlled by a reduction in
the daily dose increment or medication and rarely should interrupt treatment.
Irradiation of "mantle" fields may produce alterations in the saliva (less
volume and increased viscosity), transitory sore throat, and temporary esopha-
gitis. Some patients note an unusual fatigue, temporarily related to the daily
irradiation of large tissue volumes.
Radiation therapy to both "mantle" and "inverted-Y" fields include most of
the functioning bone marrow of an adult. Therefore, whenever possible,
treatment should be started to the body segment that includes the largest
tumor burden and a two- to four-week rest interval should separate irradiation
of the remaining segments.
Radiation therapy of "mantle" fields to 4000 rad in 4 to 4.5 weeks usually
will depress circulating peripheral blood elements to about 50 per cent of
their normal pretreatment levels. 3 After a two- to four-week rest, further
irradiation to the para-aortic nodes and spleen, if not removed, will result in a
further slight reduction in leukocytes and platelets. However, sequential
irradiation of the pelvis without a rest interval is likely to result in a further
sharp depression to 25 per cent or less of the pretreatment levels. 3 Interrup-
tions because of hematopoietic depression during consecutive irradiation of
"mantle" and "inverted-Y" segments or total lymphoid irradiation may pro-
long the overall treatment time beyond that required for a program that
includes a planned two- to four-week rest between the treatment of large body
segments.
Fewer interruptions of radiation therapy secondary to sharp drops in the
circulating leukocytes and platelets were noted in patients having splenec-
tomies prior to treatment. 167 However, splenectomy does not change the
frequency of infection related to treatment-induced leukopenia.
Peripheral levels of circulating erythrocytes (and hemoglobin) reach their
lowest values late in treatment or shortly thereafter and spontaneously recov-
er within a few months without causing a clinical problem unless there are
other reasons for blood loss, such as hemolysis. 168 Hematopoietic depression
that is incident to either radiation therapy or chemotherapy is compounded by
concurrent or consecutive use of these two treatment modalities. 169-171 Al-
though consequent clinical problems and their prevention or treatment con-
tinue to change with the introduction of new treatment regimens, it is well
established that both modalities can be combined in therapeutically ef-
fective dose ranges. 3
Most of the serious sequelae of radiation therapy for HD occur months or
even years after treatment. Only a small proportion are major complications
on rare occasion, death. The problem of second

that cause severe disability or,
neoplasms, including acute nonlymphoeytic leukemia, was discussed pre-
viously.
The frequency and severity of clinically detected radiation pneumonitis are
related to the volume of lung irradiated. When mediastinal adenopathy is
minimal, allowing the shielding of most of the pulmonary parenchyma, the
risk is small. When there is massive mediastinal adenopathy, less lung can be
shielded, and the risk is higher. In the latter situation, the interruption of
treatment after the delivery of 1500 to 2000 rad is often followed by regression
of the mass allowing consequent irradiation of a smaller volume inclusive of
less lung.
The most frequent symptom of radiation pneumonitis —
a nonproductive
cough —is accompanied by dyspnea and evidence of diffuse parenchymal
infiltration only if a large lung volume is affected. A mild reaction should clear
within a few weeks, leaving minimal roentgenologically detectable evidence
of paramediastinal fibrosis with infrequent elevation of the hila. In the critical-
ly important differentiation from mediastinal tumor regrowth, fibrotic changes
often decrease in volume with the progression of time, whereas tumor usually
increases.
If themajor portion of the cardiac silhouette is irradiated to a dose greater
than 3500 rad in 3.5 to 4 weeks, clinically detectable heart damage may result.
In a Stanford study, 3 radiation-induced cardiac changes were detected in 32 of
592 patients (5.4 per cent) receiving a single course of 4000 to 4400 rad in about
four weeks through opposed anterior and posterior fields. Half of these patients
were asymptomatic, and the changes were spontaneously reversible in all of
them. In seven patients (1.1 percent) the symptoms were judged to be severe,
whereas in only four (0.6 per cent) was surgery required for chronic constrictive
pericarditis. Cardiac damage, primarily pericarditis, is more frequent if all
irradiation was through an anterior field
89, 172
or if the patient received more
3
than a single course of treatment.
The CNS complication of consequence is spinal cord damage. The delivery
of about 4000 rad in 4 to 4.5 weeks using meticulous technique should not
result in radiation-induced transverse myelopathy. This disastrous, infrequent-
ly reported complication is usually attributed to high-dose overlap at the
junction of irradiated volumes. A post-treatment syndrome (Lhermitte's sign)
of numbness, tingling, and "electric shock" in the extremities, which is not
associated with neurologic disability and is aggravated by flexion of the neck,
may be detected in approximately 10 per cent of patients 3 and is self-limiting
within several months. Peripheral neuropathy, consequent to the impression
of peripheral nerves by fibrosis, is rare and usually follows reirradiation to high
accumulative doses. 3
The recovery of bone marrow function may continue for several years after
irradiation to4000 to 5000 rad in four to six weeks. 75 Even after extended-field
irradiation of Hodgkin's disease, the granulocyte reserves return to normal
within a few months in all but a few patients.
173
In a Stanford study of 592
3
patients, aplastic anemia or pancytopenia were not recorded, although pan-
cytopenia has been documented in patients who were treated either by
174
irradiation alone or with cytotoxic agents.
The limit of renal tolerance to irradiation appears to be total doses less than
2500 rad in 2.5 to 3 weeks to the whole adult kidney. 175 Ordinarily, moderate
para-aortic adenopathy can be treated with inclusion of only the medial
margins of the kidneys. If massive adenopathy overlies the kidneys, the
interruption of irradiation after a dose of 1500 to 2000 rad to allow for reduction
of the tumor usually permits limiting the dose delivered to the full renal
parenchyma to tolerable levels. Splenectomy reduces the necessary irradiated
volume to that which is inclusive of the splenic pedicle, with consequent
inclusion of less of the left kidney as well as the lung base.
Irradiation of the male pelvis to about 4000 rad in four to five weeks is
followed by transient aspermia in most patients because of unavoidable scat-
176
tered radiations that may reach levels of a few hundred rad.
Since HD often occurs in females between 15 and 40 years of age, problems
related to fertility and pregnancy are common. This disease has no adverse
effect on fertility, the course of pregnancy, the fetus, or labor, and, conversely,
pregnancy seems to have no effect on HD. 177 However, irradiation has a direct
influence on fertility and the products of conception. Deleterious effects from
irradiation are inversely related to fetal maturity. Doses used in the radiation
therapy of HD will abort a pregnancy or at least extensively damage or kill the
fetus. Small doses may reach the fetus even from irradiation that is limited to
structures above the diaphragm. When doses in excess of 10 rad reach the
pelvis during the first trimester, the pregnancy should be interrupted. 178, 179
Later in pregnancy, irradiation below the diaphragm can often be deferred
until after delivery.
Hormonal function and even fertility have been preserved by external
180
shielding or temporary relocation of the ovaries above and lateral to the
181
pelvic brim prior to pelvic irradiation. However, even if fertility is preserved,
genetic damage and an increased mutation rate are inevitable.
The use of megavoltage equipment avoids problems related to skin reac-
tions. Subcutaneous fibrosis is rare following a single course of treatment.
Transitory occipital epilation follows irradiation of "mantle" fields.
Megavoltage radiations are not preferentially absorbed in bone as are pho-
tons of less than 400 kVP. Fractures that are attributable to irradiation of bone
are rare. Suppression of bone growth has not proved to be a clinical problem,
which is perhaps related in part to the "symmetric" irradiation of growth
centers in the vertebrae.
However, special problems arise in the treatment of children because the
late effects of irradiation are more pronounced in the young. The major
differences compared with the adult are suppression of bone growth with
consequent anatomic deformity and a longer period of susceptibility to on-
cogenesis. 178 Thus, the potential advantages of radiation therapy to limited
tissue volumes become even more important in children and make accurate
pretreatment appraisal of the extent of tumor very important. Nevertheless,
radiation therapy is a mainstay of treatment for children with HD, and the
prognosis, stage by stage, is at least as favorable as for adults. 182, 183
The only endocrine disturbance of clinical consequence is suppression of
thyroid function. This was documented in 13 per cent of the patients in a
Stanford study. 3 Another group of patients may have sustained elevations of
pituitary thyroid stimulating hormone. 184
The risk of radiation-induced sequelae, although acceptable in the perspec-
TABLE 24-4. Summary of Single Agents Active Against Hodgkin's Disease

1 "5 m
No. of Response Rate (%)
Selected
Drug Patients Overall Complete
Mechlorethamine 796 64 13
Cyclophosphamide 469 54 12
Chlorambucil 305 60 16
Thiotepa 64 41
Vinblastine 682 68 30
Vincristine 115 58 36
Procarbazine 366 69 38
Prednisone 105° 61
BCNU 213° 44
CCNU 84° 48
MeCCNU 74° 26
Bleomycin 143° 40 8
Doxorubicin 64 36
DTIC 28° 68 11
Streptozotocinf 16° 44 6
Hexamethvlmelatninef 9° 89 22
"Most patients had received extensive prior chemotherapy.

t Experimental drug.
tive of frequent lifetime tumor eradication, requires close post-treatment

evaluation for many years.
Chemotherapy
Single-Agent Chemotherapy. At least 16 drugs are active in treating

185 "
HD, and 194
11 of these are not cross-resistant. Table 24-4 summarizes the
complete and overall response rates reported for these 16 drugs. Two of the
drugs listed are experimental (streptozotocin 192 and hexamethylmela-
mine 193, 194 ), whereas the rest are commercially available. Many of the drugs in
the lower half of the table have not been studied in previously untreated
patients (those marked with *). Thus, they are not necessarily inferior to drugs
listed in the upper half of the table, reportedly showing the higher percentages
of response.
Despite overall response rates of 36 to 89 percent, these drugs are rarely used
as single agents. Most responses are partial and last only a few months, making
single-agent treatment a modality with very little impact on overall survival.
However, elderly or debilitated patients or those with very poor bone marrow
reserve due to previous radiation therapy or combination chemotherapy may
benefit from the conservative, careful use of sequential single-agent therapy.
When this treatment plan is chosen, vinblastine is frequently the initial drug
employed. Guidelines to the use of these agents, including vinblastine, are
given in Chapter 5.
Primary Combination Chemotherapy. In 1965, Lacher and Durant 195
reported the combined use of vinblastine and chlorambucil in treating 34
patients with disseminated disease. Subsequently, a series of studies from the
National Cancer Institute firmly established combination chemotherapy as the
196 200
preferred approach to treatment for advanced HD. The most successful
"
197
combination is that of DeVita et «/., in which mechlorethamine, vincristine,
procarbazine, and prednisone (MOPP) are combined in the schedule and
dosage given in Table 24-5. The schedule and drug dosages for two closely
197 201
related, alternative regimens are also shown for comparison purposes.
'
The usefulness of MOPP was rapidly and widely confirmed,and the 200, 202 - 204
National Cancer Institute has made available ten-year follow-up data on a

substantial number of patients with advanced HD treated per primam with
MOPP. 199 In this series of 194 patients, the complete response (CR) rate was 81
per cent. All 22 patients with advanced, but asymptomatic, achieved a HD
complete remission, compared with 77 per cent of patients with B symptoms.
The actuarial median duration of complete remission has not been reached,
since 66 per cent of the patients with CR remain in remission at five and ten
years. The vast majority of the patients were not maintained on chemotherapy
after a CR had been vigorously and carefully documented, and there were no
relapses after 42 months without treatment. All the asymptomatic patients have
remained in remission, whereas 60 per cent of the symptomatic patients were
in CR at five years. Median survival has also not been reached, with 65 per cent
of patients alive at five years and 58 per cent alive at ten years. It appears that
some patients with advanced HD may in fact be cured by combination chemo-
200
therapy.
MOPP is given in repeated cycles every 28 days. 197
At least six such cycles are
given, provided that the patient has achieved complete remission status prior to
receiving the last two cycles. Patients who respond more slowly may require
many more cycles of treatment, but in either case it is critically important that
complete remission status be carefully documented prior to discontinuing
chemotherapy. This involves repeating all the tests that were abnormal prior to
MOPP administration, with the usual exception of staging laparotomy.
TABLE 24-5. Combination Chemotherapy Regimens for the

Primary Treatment of Hodgkin's Disease
Acronym Drug Regimen Reference
MOPP" Mechlorethamine 6 mg/m* IV days 1 and 8 197

mg/m 2 IV days 1 and 8
Vincristine 1.4
Procarbazine 100 mg/m 2 PO days 1 to 14
Prednisone 40 mg/m 2 PO days 1 to 14
COPP" Cyclophosphamide 600 mg/m 2 IV days 1 and 8 197

Vincristine 1.4 mg/m 2 IV days 1 and 8
MVPP \ Mechlorethamine 6 mg/m 2 IV days 1 and 8 201

Vinblastine 6 mg/m 2 IV days 1 and 8
"Drug administration during a 28-day cycle. Six cycles are usually given as a minimum. Dosage modified
given in Table 24-6. The maximum total single dose of vincristine is 2.0 mg.
for toxicity as
\ Prednisone is given during courses 1 and 4 only.
JDrug administration during a 42-day cycle with 4 weeks of rest.

TABLE 24-6. Guidelines for Modifying Dosage of MOPP Chemotherapy

in Patientswith Bone Marrow Suppression 197
\I O P P
WBC Platelets % Full Dosaci
>4000 > 100,000 100 100 100 100

3000-3999 50 100 50 100
2000-2999 50,000-100,000 25 100 25 100
1000-1999 25 50 25 100
<!()()() < 50 ,000
MOPP' 97 : Sfechlorethamine (nitrogen mustard); Oncovin (Vincristine); Procarbazine; Prednisone.
The importance of documenting complete remission status is reflected in the

controversy over the value of maintenance MOPP in patients who have
achieved a complete remission. At the National Cancer Institute, patients with
meticulously confirmed CR status did not benefit from maintenance chemo-
therapy in a randomized study. 198 199 However, other randomized studies
'
suggested that maintenance MOPP was useful. 203, 204 In retrospect, the major
difference between these studies appears to be the extent to which CR status
was subjected to meticulous restaging. For this reason, we recommend careful
restaging after achieving a CR with MOPP, and we do not recommend mainte-
nance chemotherapy.
The major dose-limiting toxicity of MOPP is bone marrow suppression. 197
This can be managed by delaying cycles of MOPP, although delays should not
be longer than one week. It is far preferable to give each cycle on schedule,
with dosage reductions as needed for toxicity. Table 24-6 provides guidelines
for modifying the dosages of MOPP. Severe nausea and vomiting may also
occur, but this generally can be managed by an antiemetic given prior to the
mechlorethamine injection.
A wide variety of less common toxic reactions may also occur, as detailed in
Chapters 4 and 5 for the individual drugs used in the MOPP combination. Rare
reactions that may be unique to this particular combination also warrant
comment. The Stanford group has treated a large number of patients with
combined radiation therapy and MOPP. 91 92 Patients who had received previ-
'
ous mediastinal radiation therapy appeared to be at increased risk of radiation

pneumonitis, apparently precipitated by prednisone. With the deleti on of
^~ prednisone (MOP) this problem abated, so-prednisone is routinely onTJtt ecT
/L fc^f\ when MOPP is given after radiation therapvv ^Q ther rare and possible unique
9
^ complications include aseptic necrosis of the hip joirit^Jand gynecomastia in

^^prepubertal boys. 205
'""^Because of the toxicity inherent in the MOPP program, as well as the hope
that alternative drug combinations might-prove"supeôr, many modifications of
the MOPP regimen have been tested? 201 204> 206 214 Table 24-7 summarizes the
-
'
clinical results seen with such alternative regrrnens, as well as with selected
studies employing MOPP. There is general agreement that MOPP remains the
best available program of primary combination chemotherapy for advanced
HD. Indeed, preliminary data from Uganda suggest that it may even be an
^^fcccepta45le alternative to radiation therapy for patients with less advanced
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Chemotherapy of Hodgkin's Disease Resistant to MOPP Patients .
who fail to achieve a remission with MOPP or who relapse within one year after
achieving CR may be considered resistant to MOPP. However, those who
relapse after an initial CR lasting longer than 12 months have an excellent
chance of again achieving CR status with MOPP, so MOPP resistance should
not be assumed. 218
Patients with well-documented MOPP resistance are usually treated with
combination chemotherapy regimens lacking the agents used in MOPP. Many
such regimens have been tested, as summarized in Table 24-8. 206 207 219 2:!2 One
"
'
'
of the most widely used is the ABVD (doxorubicin [Adriamycin], bleomycin,

vinblastine, and dacarbazine) regimen, initially developed by Bonadonna and
his colleagues. 206 207 It has clearly shown to be noncross-resistant to MOPP, and
'
its toxicity is tolerable. However, the high response rates reported initially
have not been achieved by others. 221 224 We currently prefer the regimen
"
developed at Stanford known as B-CAVe (bleomycin, CCNU, doxorubicin, and

vinblastine). 219 Guidelines to its use appear in Tables 24-9 and 24-10.
Other regimens, listed in our order of preference, are also given in Tables
24-8 and 24-9. In some cases, a combination ranked below B-CAVe may be
preferable for a given patient based on factors such as previous drug therapy,
bone marrow tolerance, cardiorespiratory functional status, and so forth. For
example, a patient who had failed MOPP and single-agent vinblastine would
be more likely to benefit from B-DOPA, 220 AC, 225 ABCD, 227 or ABDIC 229 than
from B-CAVe. 219 Likewise, a patient with coronary artery disease and conges-
tive heart failure should not receive a doxorubicin-containing regimen but
could be treated with CVB 226 or with single-agent chemotherapy excluding
doxorubicin. 233
Although we rarely employ sequential single-agent chemotherapy in pa-
tients who have failed MOPP, it is important to point out that a randomized
comparative study of single agents used in sequence and combination chemo-

therapy has not been done. Such a study would clearly be of interest.
Immunotherapy
Immunotherapy is an experimental approach to the treatment of HD. Most

studies have employed BCG given after a complete remission has been
induced with radiation therapy or chemotherapy, and at least three randomized
studies can be evaluated 234236 (Table 24-11). Benefit from BCG is suggested in
the study of Sokal et a/., 234 although the number of patients in the study was
235
small, and prognostic factors were not balanced. The studies of Hoerni et al.
and of Bakemeieret a/. 236 show no benefit from the use of BCG. Since BCG may
be toxic, particularly in anergic patients, we do not currently use it in the
treatment of our patients with HD.
Treatment of Primary Hodgkin's Disease. Because of the success of

extended-field radiation therapy and combination chemotherapy in prolonging
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TABLE 24-9. Combination Chemotherapy Regimens for Patients Failing MOPP

B-CAVe 219
Bleomycin 5.0 units/m1 IV days 1,28,35
CCNU 100 mg/m* PO dav 1
Doxorubicin 60 mg/m 2 IV day 1
Vinblastine 5 mg/m 2 IV day 1
Cycles repeated every 6 weeks (if blood counts permit) to a total of 9 cycles.
B-DOPA220
Bleomycin 4 mg/m 2 IV days 2 and 5
Dacarbazine 150 mg/m 2 IV days 1 to 5
Vincristine 1.5 mg/m 2 IV days 1 and 5
Cycles repeated at three- to four-week intervals as tolerated.
ABVD 206 - 207
Doxorubicin 25 mg/m 2 IV every two weeks

Bleomycin 10 units/m 2 IV eveiy two weeks
Vinblastine 6 mg/m 2 IV every two weeks
Dacarbazine 375 mg/m 2 IV every two weeks
Maximum total cumulative dose of doxorubicin 450 mg/m 2 and 450 units bleomycin. Dosage
of drugs reduced for bone marrow suppression.
AC(DL) 225
Adriamycin 60 mg/m 2 IV day 1
(doxorubicin) 45 mg/m 2 IV day 22
CCNU 100 mg/m 2 PO day 1
(Lomustine)
Cycles repeated every six weeks as tolerated.
CVB 226
CCNU 100 mg/m 2 PO day 1
Vinblastine 6 mg/m 2 IV days 1 and 8
Bleomycin 15 units IM days 1 and 8
Cycles repeated as tolerated every 28 days; six cycles or more are generally given.
ABCD 227
Doxorubicin 25 to 30 mg/m IV day
2
1
Bleomycin 15 units IV days5 1 to
CCNU 60 to 70 mg/m 2 PO day 1

Dacarbazine 90 to 100 mg/m 2 IV days 1 to 5
Cycles repeated every four weeks as tolerated.
TABLE 24-10. Guidelines for Modifying Dosage of B-CAVe in Patients

with Bone Marrow Suppression 219
B c A Ve
WBC Platelets % Full Dosage
> 4,000 > 150,000 100 100 100 100

3,500-4,000 120,000-150,000 100 50 100 100
3,000-3,500 90,000-120,000 100 75 75
2,500-3,000 60,000-90,000 100 50
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the lives of patients with limited and advanced Hodgkin's disease, respec-
tively, many centers have explored the use of these two modalities in combina-
tion. The group Stanford provided early leadership for this concept in a
at
randomized study started in August of 1968. By February 1977 they had
randomized 241 patients to receive radiation therapy alone or radiation therapy
plus adjuvant MOP(P). 237 Patients with pathologic stages I A II A and III A
, ,
disease had a significant improvement in the percentage of patients free of

relapse at eight years with MOP(P). However, the freedom from relapse rate for
patients with pathologic stages I B and II B disease was the same, a nd none of the
subgroups had a survival advantage with adjuvant MOP(P).
We are aware of at least ten other studies in which chemotherapy and
radiation therapy were combined for patients with HD restricted to nodal
128, 196>238 " 247
regions, 127, plus an additional four studies that included patients
with advanced HD. 207, 248251 Of these 14 studies, 6 are randomized comparisons
~
of single modality versus combined modality therapy. 127, 128, 242 248 Only one of
these studies has shown a st atistically significant survival ad vantage for com-
m
bined modality therapy, a TInth isstudy the subgroup that appeared to derive
the greatest benefit was a smal l group with pathologic stage II E or III E dis-
ease ^ 7, 128, 246, 247 __T he majority of E-stage patients had pulmonary involve-
ment that was treated with the shrinking-field technique, thus raising the pos-
sibility of inadequate radiation therapy as the explanation for failure in the
group treated solely with radiation therapy. 252 This conclusion is supported
by at least one other study that shows a poor prognosis for patients with very
b ulky mediastinal disease treated solely~~w ith radiation th erapy.* ^
Because of the small number of patients involved in the one randomized
study that showed a survival advantage for combined modality treatment and
our concern that the radiation therapy may have been inadequate in that study,
added to the high probability of delayed second neoplasms in patients receiv-
ing both modalities as well as the high likelihood that delayed "salvage"
treatment will be successful, 254 we conclude that combined modality therapy is
not currently indicated as primary treatment for patients with Hodgkin's
disease —except as part of an experimental study. This is reflected in our
current approach to the management of previously untreated HD, as shown in
Figure 24-7.
Treatment of Hodgkin's Disease in Relapse. Despite the advances in
radiation therapy and chemotherapy already described, some patients will
relapse after primary treatment. Subsequent treatment for these patients must
take into account the presumed mechanism of relapse, the precise sites of
relapse, the duration of time since primary treatment, and the details of
previous treatment. Given the complexity of these factors, it should not be
surprising that this is a controversial problem. 3, 138 255-257
>
In general, these patients should be carefully restaged prior to retreatment.

Local recurrence in a previously irradiated area should be distinguished from a
marginal recurrence in an area that may have received inadequate radiation
therapy. Extranodal relapse should be distinguished from a purely nodal
pattern of relapse. It is important to consider whether the patient has an early
relapse or not (less than one year after chemotherapy or two years after
radiation therapy), since this generally implies tumor cell resistance to the
initial treatment modality or drug combination. In sum, it is critical to distin-
CLINICAL STAGING
r IA, IIA III A, 1MB , iv

IA, IIA
(Supradiaphragmatic (MC, LD or infradiaphragmatic

LP or NS) LP, NS)
or
IB, MB, lll,A
I
Extended field RT PATHOLOGIC STAGING MOPP

(excluding pelvis) 1
I
IA, IIA IB I llo A

MB 1MB, IV
lll
1
A
Extended field RT Total r odal RT MOPP
FIGURE 24-7. An approach to the treatment of newly diagnosed Hodgkin's

disease. Local extension (E) or splenic involvement without vascular invasion
(S) does not usually alter therapy. Abbreviations are explained in the text and
in Appendix C.
guish failure due to incomplete treatment from failure due to tumor cell resis-
tance.
Patients who because of incomplete primary treatment may still benefit
fail
from the initial treatment modality. For example, a marginal recurrence after
radiation therapy may still respond to local radiation therapy, provided that the
patient has no indication for systemic chemotherapy. Conversely, a patient
who received inadequate doses of MOPP because of physician error or patient
noncompliance may still benefit from MOPP or a related polychemotherapy
regimen. If, however, the patient has relapsed because of tumor cell resistance
to primary treatment, one should change to another treatment modality or use a
noncross-resistant drug combination, depending upon the precise combination
of circumstances. These patients require individualized therapy, which occa-
sionally includes the combined use of local radiation therapy and chemothera-
py. It is also important to tailor the doses of retreatment according to the
patient's previous therapy, since some of these patients have persistent organ
dysfunction as an added legacy of their primary therapy.
Special Problems
Hodgkin's Disease During Pregnancy. There is no evidence that HD

adversely affects pregnancy or that pregnancy adversely affects HD. However,
pregnancy may greatly complicate an adequate early diagnosis, staging, and
therapy of HD. This subject has been nicely reviewed by Kaplan 3 and by
Thomas and Peckham. 258 Two general principles are of particular importance:
One should individualize the treatment for each patient and avoid the dangers
of inadequate therapy. These principles are particularly important when HD
presents for the first time during pregnancy, as opposed to pregnancy in
patients in relapse from previously treated HD. These patients usually have
nodular sclerosis, and they may not require pathologic staging. 258 Isotope scans
are contraindicated, but lymphangiography with a single abdominal film taken
24 hours after injection of the dye should be performed.
900 II / Treatment of Specific Neoplasm-,
The decision on how

proceed in these potentially curable patients de-
to
pends upon the and subtype of Hodgkin's disease as well as the
clinical stage
stage of the pregnancy. If the pregnancy is in the first trimester, abortion is
usually recommended. During the second trimester of pregnancy, the fetus is
anatomically spared major exposure to radiation deliverd to the upper body and
is more resistant to the mutagenic effects of radiation therapy and chemothera-
py. Thus, potentially curative treatment may be started during the second
trimester. A stable patient in the third trimester should have treatment post-
poned pending delivery of the infant.
In any case, rapidly advancing Hodgkin's disease should be treated prompt-
ly, and the tragic consequences of inadequate treatment must be avoided. If
very aggressive treatment appears to be necessary, one should probably recom-

mend termination of the pregnancy. Normal infants have been delivered after
polychemotherapy, 258 259 but the chances of a normal infant appear to be even
'
better if pregnancy occurs later during remission. 260

Hodgkin's Disease During Childhood. Numerous reports suggest that
the treatment of HD
in childhood should be substantially the same as in
adulthood. 261 266 This view is moderated, however, by controversy about the
"
role of staging laparotomy in childhood and the widespread concern about

delayed complications of treatment in this group of young patients. 263 We
concur with others that laparotomy should be avoided if at all possible in
children who are less than ten years of age, and when splenectomy is done,
these patients should be placed on prophylactic penicillin. Otherwise, we have
treated these patients as described for adults with HD.

The US Najtt6»al Cancer Institute lists 29 major ongoing clinical trials
~ */ involving HDÎ^Most of these studies relate to new drug combinations or
various combinations of chemotherapy and radiation therapy. Although this
group is made up of too many studies to be discussed separately, we anticipate
progress toward individualizing the staging process so that fewer patients will
undergo exploratory laparotomy. Optimal treatment with minimal delayed
toxicity should also emerge from these studies, as should new approaches to
treatment for the unfortunate patient who relapses. In sum, we can expect at the
very least further refinements in treatment for these patients. Hopefully,
advances in defining the etiology and pathogenesis of may also permit HD
preventive treatment in the future.
1. Hodgkin T: Med Chir Treat (London) Clowes Memorial Lecture. Cancer

18:68, 1832. Res 36:3863, 1976.
*2. Kaplan HS: Hodgkin's disease and *3. Kaplan HS: Hodgkin's Disease. Cam-
other human malignant lymphomas: bridge, Mass, Harvard University
Advances and prospects-G.H.A. Press, 1972.
24 Hodgkin's Disease 901
*4. Lacher MJ (ed): Hodgkin's Disease. 32. Kirschner RH, et al: Cancer 34:1159,
New York. John Wiley & Sons, Inc, 1974.
1976. 33. Naeim F, et al: Cancer 34.655, 1974.
5. Hirshaut V. et al.: Cancer 34:1080, 34. Carbone PP. et al: Cancer Res
1974. 31:1860, 1971.
6. Hehlmann R, et al.: Proc Natl Acad 35. Silberman HR. et al: JAMA 194:597,
Sci USA 69:1727. 1972. 1965.
7. Chezzi C, et al.: Proc Satl Acad Sci 36. Kielv JM: Mayo Clin Proc 44:272.
USA 73:4649, 1976. 1969.
*8. Gutensohn N and Cole P: Epidemiolo- 37. Phillips RH, et al: Br Med J i:1447,
gy of Hodgkin's disease in the young. 1977.
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CHAPTER 25
NON-HODGKIN'S
LYMPHOMAS
Gregory P Sarna A Robert Kagan
INTRODUCTION
The "non-Hodgkin's lymphomas" compose heterogeneous group of a
lymphoid malignancies that are defined as much by what is excluded as by
what is included. They may be defined as the lymphoid malignancies other
than Hodgkin's disease, the acute and chronic lymphoid leukemias, and the
immunoglobulin-synthesizing lymphoproliferative disorders (including

multiple myeloma, Waldenstrom's macroglobulinemia, heavy chain disease,
and hairy cell leukemia). The boundaries between the non-Hodgkin's lym-
phomas and the other lymphomatous malignancies may sometimes be in-
distinct (e.g., chronic lymphocytic leukemia versus diffuse well-
"
differentiated lymphocytic as may the boundaries between
lymphoma), 1 3
malignant and "benign" aberrant lymphoproliferation (e.g., lymphoma ver-

sus "pseudolymphoma" or angioimmunoblastic lymphadenopathy). The
group of diseases categorized under the rubric "non-Hodgkin's lymphoma"
is diverse as to modes of presentation, natural history, and response to ther-
apy. It is a broad category that includes different diseases such as mycosis

fungoides, Burkitt's lymphoma, diffuse histiocytic lymphoma, and diffuse
well-differentiated lymphocytic lymphoma.
Attempts to subdivide the non-Hodgkin's lymphomas into homogeneous
categories on the basis of histology, natural history, and immunology are
ongoing, but no universally accepted classification scheme has yet evolved.
The past and present diversity of approaches as to classification, staging,
and treatment of these diseases makes interpretation and integration of
clinical studies difficult. Certain premises and conclusions, however, can
be drawn and certain principles developed, as will be discussed in this
chapter.
Etiology
A number been related to the etiology of non-Hodgkin's

of factors have
lymphomas. It ishowever, that the occurrence of lymphoma (and
clear,
other malignancies) must be multifactorially determined and that lympho-
mas arise in relationship to the interaction of a number of risk factors rather
than as an inevitable effect of a single cause. The factors that are discussed
in the following paragraphs may contribute etiologically to non-Hodgkin's
lymphoma.
Viruses. RNA viruses have been shown to cause lymphoproliferative
disorders in genetically susceptible animal species (primarily murine). 4 At-
tempts to show similar relationships in humans have not been successful to
date. DNA viruses have been shown to cause lymphoproliferative disorders
in some primates, and one DNA virus —
the Epstein-Barr (EB) virus has —
been implicated strongly in the causality of Burkitt's lymphoma in
humans. 5 The manifestation of EB viral infection as Burkitt's lymphoma
appears to be related to genetic factors and immunosuppression. It also
may be related to age at EB virus infection 6 and to infection with malaria
(perhaps acting via immunosuppression or immunostimulation). 7 There has
also been speculation that viruses may play a role in the etiology of
8
Sjogren's disease and in lymphomas associated with Sjogren's disease.
Genetic Factors. A variety of genetically linked diseases, which are
characterized in part by immunodeficiency, are associated with a high in-
cidence of lymphomas. 9 These diseases will be discussed more fully further
on, but it should be noted that immunodeficiency is not necessarily the
etiologic modus operandi of those genetic defects. Immunodeficiency
might be merely a related phenomenon with an increased incidence of
lymphoma resulting from chronic immunostimulation or genetically deter-

mined factors such as abnormal DNA repair or increased susceptibility to
DNA damage.
Chromosomal abnormalities, particularly of chromosomes 14, 17, 18, 10 and
X, 11- 12 have been linked with both immunodeficiency and lymphoma. The
presence of extra material on chromosome 14 (14 q+) appears to be the
most common abnormality found in lymphoma (in both Burkitt's and non-
Burkitt's types). 13
Immunodeficiency and Immunostimulation. As mentioned pre-
viously, with heritable immunodeficient states (e.g., ataxia-
patients
telangiectasia and the Wiskott-Aldrich syndrome) have an increased inci-
dence of lymphomas, as do patients with iatrogenic immunosuppression
(particularly renal transplantation patients). The relationship of immunode-
ficiency (and immunostimulation) to the pathogenesis of lymphoma has
been reviewed by Louie and Schwartz, 9 who suggest that impaired T cell
regulation may permit unrestricted B presumably leading
cell proliferation,
to a B cell lymphoma. Alternatively, chronic immunostimulation (in relation
to increased infection in immunosuppressed patients or in relation to "au-
toimmune" diseases such as Sjogren's syndrome 8 might predispose to lym-
)
phoma (particularly "immunoblastic sarcoma") by an increased frequency

of mutations in a rapidly dividing cellular population with or without im-
paired T u Decreased immunologic surveillance also has
cell regulation. 9,
been postulated as a mechanism that allows tumors to arise. 15
Purtilo et al. u have described a kindred with an "X linked recessive lym-
phoproliferative syndrome" characterized by a variety of lymphoprolifera-
tive disorders as well as by marrow aproliferative disorders. They postulate
that this kindred has a basic immunodeficiency to EB virus, which can lead
to Burkitt's or other lymphomas, fatal mononucleosis, or an aproliferative
state caused by uncontrolled virus or excessive T cell response. The exis-
tence of Richter's syndrome and the development of "reticulum cell sar-
coma" (primarily diffuse histiocytic lymphoma) 16 on the background of
chronic lymphocytic leukemia should also be mentioned. It is not clear
whether this is related to chemotherapy or immunodeficiency in CLL or
whether it is a "blastic transformation" of CLL cells.
Drugs. Immunosuppressive agents (e.g., azathioprine and cyclophos-
phamide) have been associated with increased frequency of lymphomas, 9 as
have other drugs (e.g., the hydantoins). 17 It is not clear whether these drugs
act directly as carcinogens or whether carcinogenesis is indirectly mediat-
ed.
Radiation. Radiation exposure has not been strongly associated with
lymphoma. A modest relationship, however, has been noted for people
with high-dose exposure (e.g., those who were close to the epicenter at
19
Hiroshima or Nagasaki). 18 *
Incidence and Epidemiology
The estimated incidence of non-Hodgkin's lymphoma cases in the United

States in 1978 is 17,700 (2.5 per cent of all malignancies excluding non-
melanomatous skin cancer and cervical carcinoma in situ), whereas the es-
timated mortality rate is 13,000 (3.3 per cent). 20 This may be compared with
an estimated 7400 cases of Hodgkin's disease. 20
Specific lymphomas occur in high incidence in certain areas of the world.
Burkitt's lymphoma is endemic to the West Nile region of Africa, with an
incidence of 50 to 100 per million per year in northern Uganda. 21 It also
occurs frequently in Papua (New Guinea). 22 "Mediterranean" intestinal
lymphoma is common in the Middle East in Arabs and Jews of Middle
Eastern or North African origin. 23
Splenic "giant follicular" lymphoma has been related to Schistosoma
mansoni infection in Brazil. Nasal lymphoma reported in South American
countries has been related to chronic rhinitis. 22
NATURAL HISTORY
Classification and Histology
Traditional Classification Systems. Prior to the 1960s and 1970s,

the bulk of non-Hodgkin's lymphomas were categorized as lymphosarcoma
(LS), reticulum cell sarcoma (RCS), or giant follicular cell lymphoma (Brill-
Symmers disease, GFCL). This classification scheme has generally been
abandoned because it has not been reproducible (from one institution to
another), comprehensive, or prognostically and therapeutically valuable. 24
The term "lymphosarcoma" has been used both generically and specifical-
ly, and the term "reticulum cell sarcoma" has not been uniformly de-
fined. 24, 25 However, the subset of patients with giant follicular lymphoma,
making up 10 per cent of patients with non-Hodgkin's lymphoma, was rec-
ognized as having a more favorable prognosis than those with lymphosar-
coma or reticulum cell sarcoma. 25, 26
This partially reflects the true favorabil-
ity of nodular lymphomas, whereas it may also be due to the inclusion of
patients with reactive, rather than malignant, changes in this diagnostic cat-
egory. 27 However, only a minority of patients with what we now consider
nodular lymphomas were classified as having giant follicular lymphoma.
The Rappaport Classification System. The Rappaport28 classifica-
tion scheme followed the lead that follicularity (nodularity) may be of prog-
nostic importance. 27 It cross-classified lymphomas that were previously
classed as LS, RCS, or GFCL by nodal architecture —
nodular (N) or dif-
fuse (D) —
and by cellular histology —
well-differentiated lymphocytic
(WDL), poorly differentiated lymphocytic (PDL), histiocytic-lymphocytic or
mixed (M), histiocytic (H), and undifferentiated (U).
The majority of recent clinical studies have been reported in this classifi-
cation scheme. The classification scheme is seen in Table 25-1, and a cor-
relation between that scheme and earlier classification schemes, drawn
from Stanford data, 29 is seen in Table 25-2.
The Rappaport system has the advantages of being relatively reproduc-
30
ible and of having prognostic and therapeutic importance. Byrne has re-
viewed the findings of reference panels of pathologists as to the reprodu-
cibility of lymphoma classification with this scheme. He found a 90 per
25 / Non-Hodgkin's Lymphomas
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cent reliability for nodularity versus diffuseness. The cytologic classification

(i.e., WDL
versus PDL verus M
versus H) is less reliable, with roughly a
50 to 75 per cent reproducibility. Diagnoses of histiocytic and well-
differentiated lymphomas are relatively reproducible, but poorly differentiat-
ed lymphoma and mixed lymphoma are less dependable.
Data from Stanford suggest that, with the exception of the histiocytic
type, lymphomas with areas of both nodularity and diffuseness behave like
nodular disease rather than diffuse disease. 31 Studies of Bitran et al. 32 sug-
gested that the degree of nodularity does not correlate with survival; how-
ever, data from Patchefsky et al. 33 suggest that increasing nodularity corre-
lates with increasing survival. The weight of the evidence suggests that
"diffuse and nodular" lymphomas should be classified as nodular.
When classified by Rappaport criteria, certain histologic subtypes are
found to be "favorable," with higher response rates to therapy and better
survival at any given stage. Favorable histologic types include nodular
well-differentiated lymphocytic (NWDL) lymphoma, nodular poorly dif-
ferentiated lymphocytic (NPDL) lymphoma, nodular mixed (NM) lympho-
ma, and diffuse well-differentiated lymphocytic (DWDL) lymphoma. Un-
favorable histologic types include diffuse, poorly differentiated lymphocytic
(DPDL) lymphoma, mixed (DM) lymphoma, diffuse histiocytic
diffuse
(DH) lymphoma, diffuse undifferentiated (DU) lymphoma, and nodular his-
tiocytic (NH) lymphoma. Lymphocytic subtypes have better prognoses than
histiocytic subtypes, and nodular disease has a better prognosis than diffuse
disease. The prognosis in specific histologic types and data supporting the
delineation between favorable and unfavorable types will be discussed fur-
ther later on.
however, the Rappaport scheme is not totally accurate,
Scientifically,
since the "histiocytic" lymphomas have been shown to consist generally of
malignant transformed lymphocytes rather than true histiocytes. The ap-
proach also does not incorporate immunologic characteristics of the lym-
phomatous cells, and it is not fully comprehensive for all lymphomas.
Newer Classification Systems -Immunologic Aspects of Lym-
phoma. A variety of new histologic-immunologic classification schemes has
arisen. One of these schemes, that proposed by Lukes and Collins, 3437 is
shown in Table 25-3. Other classification systems have been devised by
the Kiel Group, 38 39 Bennett et al., 40 Dorfman, 41 Beard, 42 Mathe et al., 43 and
-
Strauchen et al. 44 This subject has been reviewed by Dorfman. 45

These systems classify diseases by immunologic markers and function, as
well as by morphology. Such an approach has provided information of prog-
nostic and therapeutic importance for some distinct entities (e.g., the lym-
phoblastic and convoluted lymphocytic T cell lymphomas) and has pro-
vided a comprehensive immunologic framework for classifying the heterogen-
eous population of non-Hodgkin's lymphomas. The relative value and cost
efficacy of each system, the validity of immunologically characterizing cells
by morphology when a complete battery of functional tests cannot be done,
and the ease and reproducibility of the classification of each system are yet
to be determined.
Immunologic studies have suggested the following conclusions:
1. Normal lymph nodes include "B cells," "T cells," and "histiocytes." A
TABLE 25-3. Lukes-Collins Classification Scheme 34
U Cell (undefined)
T Cell
Small lymphocyte
Convoluted lymphocyte
— mycosis fungoides
Sezary cell
Immunohlastic sarcoma
Lennert's lymphoma
B Cell
Small lymphocyte
Plasmacytoid lymphocyte
FCC
Follicular or diffuse, with or
without sclerosis
Small cleaved
Large cleaved
Small transformed (noncleaved)
Large transformed (noncleaved)
Immunohlastic sarcoma
Hairy cell leukemia
Histiocytic
schema of normal lymph node architecture, taken from Jaffe, 46 is seen in

Figure 25-1. B cells are antibody-producing lymphocytes that are de-
rived in humans from a postulated "bursa (of Fabricius) equivalent." They
are found in the follicles of lymph nodes, spleen, and tonsils, in the medul-
lary cords of lymph nodes, and in the bone marrow and peripheral blood.
B cells are characterized by the synthesis of immunoglobulin. They tend
to have membrane-bound immunoglobulin and receptors for Fc por-
tions of IgG. Follicular B cells have receptors for C 3 but differentiating B
,
cells (e.g., those in the medullary cords) may have few or none of these
markers. 47 B cells bearing C 3 receptors form rosettes with sheep red blood
cells that are coated with antibodies and complement, but they do not form
rosettes with a low titer of antibody alone.
T cells are lymphocytes processed by the thymus; they are involved in
cell-mediated immunity. They may be heterogeneous regarding function
(e.g., "killer" T cells, "helper" T cells, "suppressor" T cells). They are
found in the thymus, in the periarteriolar-lymphoid sheaths of splenic
white pulp, in the paracortical regions oflymph nodes, and in peripheral
blood and bone marrow. T cells form nonimmune rosettes with sheep red
blood cells alone. They do not synthesize immunoglobulin, and they lack
the B cell receptors.
True histiocytes are not lymphocytes. Rather, they are mononuclear pha-
gocytes of the macrophage-monocyte line. They serve multiple functions,
including the processing of antigen and interaction with lymphocytes.
These cells are characterized by lysosomal enzymes, phagocytosis, and Fc
and C 3 receptors. They will rosette with sheep red blood cells plus an-
tibody (in the presence or absence of complement). They are found in the
subcapsular regions and medullary sinuses of lymph nodes, in the red pulp
of spleen, and in other sites, including liver, lung, and peritoneum.
Most lymphomas are of B cell origin. 34, 35, 37, 47 49 Some are T cell lym-
~
2.
phomas, while others may lack features of B or T cells and may be called "null
cell" lymphomas. 37,48 51
'
3. B cell lymphomas include all nodular lymphomas and most diffuse

lymphomas. Burkitt's lymphoma is a B cell disease. 47 Studies of immuno-
globulin in B cell tumors 47, 5254 generally show single predominant heavy
and light chains, suggesting monoclonality.
4. T cell lymphomas include mycosis fungoides (apparently a neoplasm
of "helper" T cells), 55 convoluted lymphocyte lymphomas (possibly "pre-T
cell" lymphomas 37 ), lymphoblastic lymphomas, and immunoblastic sarcoma
of T cells. T cell lymphoblastic lymphomas may have the biochemical marker
terminal deoxynucleotidyltransferase. 56 A pleomorphic T cell lymphoma
has also been described. 57 Some cases of acute lymphoblastic leukemia and
rare cases of chronic lymphocytic leukemia may be T cell tumors. 47 There
is evidence that "Lennert's lymphoma" is a T cell lymphoma.
58, 59
5. DWDL lymphoma and CLL are generally nonfollicular center B cell

diseases (i.e., lymphomas from the medullary cords). Unlike folli-
B cell
cular center B cell lymphomas, they may have weak or absent C 3 recep-
tors 47 and sparse surface immunoglobulin. 60 These diseases are generally
classified by the Lukes-Collins scheme as small lymphocytic lymphomas,
but some may be classified as plasmacytic lymphomas or perhaps small
cleaved follicular center cell (FCC) lymphomas. 35,61
6. DPDL lymphoma is primarily a B cell disease.
53
The majority of lym-
phomas in this category would be characterized as small cleaved FCC lym-
phomas by the Lukes-Collins scheme. 35, 6I They also might be classified as
small noncleaved or large cleaved FCC lymphomas or as T cell lymphomas
Malignant Histiocytosis Nodular (follicular) Lymphoma

Burkitt's Lymphoma
Chronic Lymphocytic Leukemia Se'zary Syndrome

Well Differentiated Lymphocytic Mycosis Fungoides
Lymphoma Lymphoblastic Lymphoma of Childhood
Waldenstrom's Macroglobulinemia Acute Lymphoblastic Leukemia
Hodgkin's Disease
FIGURE 25-1. Diagrammatic representation of a normal lymph node,

showing the anatomic and functional compartments of the immune system.
The malignant lymphomas are related conceptually and functionally to each
of the above compartments. S = sinuses; F= follicles; PC = paracortex; MC =
medullary cords. (From Jaffe ES: Ann Intern Med 85:356, 1976.)
of lymphoblastic or convoluted lymphocytic type. 62 DM lymphomas would

be classified primarily as large cleaved FCC lymphomas, 1 "'
but may be clas-
sified as DPDL or DH.
Transformed nonmalignant lymphocytes as well as some malignant
7.
lymphocytes may look like "histiocytes." DH lymphomas, when studied

immunologically, are usually lymphocytic rather than true histiocytic (mo-
nonuclear phagocytic) malignancies. Nathwani et a/., 61 in a recent review of
the literature, noted that in 72 patients with DHL who were studied re-
garding immunologic markers, 54 per cent had B cell tumors, 8 per cent
had T cell tumors, 5 per cent had true histiocytic tumors, and 32 per cent
had undefined tumors. Lukes et al. 37 analyzed 425 malignant lymphomas,
and found 12.9 per cent to be undefined and 0.2 per cent to be true histio-
cytic lymphomas. In the Lukes-Collins scheme, DHL would include pri-
marily large noncleaved FCC cell lymphomas. 61 Large cleaved FCC cell
lymphomas, true histiocytic lymphomas, and immunoblastic sarcomas
(usually B cell, possibly T cell) would also be classified as DHL. 35
8. In patients with DHL or DPDL, there is some evidence that T cell or
"null cell" lymphomas may have poorer prognoses than the B cell varie-
49 63
-
ties.
Other Histologic Factors and Classes. Ree and Leone 64 have re-
ported that, in "follicular" lymphomas, the concentration of parafollicular
small lymphocytes correlates positively with improved survival. Sclerosis
has been claimed by Bennett65 to be a favorable histologic finding, but this
observation could not be confirmed by Patchefsky et al. 33 The latter authors
also investigated vascular invasion in the non-Hodgkin's lymphomas. They
found it to be frequent but probably not of prognostic value, except per-
haps as a poor prognostic sign in DHL.
Some investigators believe that "malignant lymphomas with a high con-
tent of epithelioid histiocytes" ("lymphoepithelioid cellular lymphomas" or
"Lennert's lymphoma") constitute a unique clinical-pathologic entity —
usually of advanced stage and unfavorable prognosis —
that can be best
66
managed by combination chemotherapy. Some patients, however, have
had an indolent course, 67 raising the question of whether or not this entity
was "prelymphomatous" rather than lymphomatous. It has been suggested
that Lennert's lymphoma may be a T cell analogue of angioimmunoblastic
lymphadenopathy. 58, 59, 68
"
Angioimmunoblastic lymphadenopathy 69 72 is a lymphoproliferative dis-
order characterized histologically by vascular proliferation, heterogeneous
immunoblastic-plasmacytic infiltration, and amorphous acidophilic intersti-
tial material. Clinically, it is associated with fever, lymphadenopathy, hepa-
tosplenomegaly, skin rash, polyclonal hypergammaglobulinemia, and fre-

quently Coombs'-positive hemolytic anemia. Although it is not histologically
malignant, it is frequently progressive and rapidly fatal, and it may evolve into
frank "immunoblastic" lymphoma. 71 It may also be indolent or remittent, and
the roles of glucocorticoid and cytotoxic chemotherapy are currently not clear.
In some circumstances, this entity appears to be a hypersensitivity reaction. It
is characterized by hyperfunction of B lymphocytes, perhaps with defective
T cell regulation.
69, 70 '
Some
cases previously classified as "pseudolym-
73
phoma" may now be classified under this heading.

This chapter will primarily discuss non-Hodgkin's lymphomas as classi-

fied by the Rappaport system, because that system is the most clinically
useful at present (in view of reproducibility from institution to institution
and the prognostic-therapeutic implications). However, selected subsets of
lymphoma will be discussed as classified by other schemes.
Presentation of Disease. The non-Hodgkin's lymphomas may pre-

sent as "nodal" or "extranodal" disease. In the major review of "lymphosar-
coma" by Rosenberg et oi., 26 64 per cent of patients with non-Hodgkin's
lymphomas presented with peripheral adenopathy, which was painless in
90 per cent of cases. Cervical nodes were the primary site of involvement
in approximately 60 per cent of this group, inguinal nodes were the prima-
ry site in approximately 20 per cent, axillary nodes were the primary site in
approximately 14 per cent, and multiple nodal sites occurred in approxi-
mately 8 per cent. The differential diagnosis of lymphadenopathy would
include infection, collagen vascular disease, allergic reactions, metastatic
malignancy, drug reactions, "sinus histiocytosis with massive lymphade-
nopathy," and immunoblastic lymphadenopathy. This subject and nodal
histologic findings have been reviewed by Dorfman and Warlike. 74
Constitutional symptoms were seen at presentation in 20 per cent of the
patients reviewed by Rosenberg et al.** (malaise in 8 per cent, weight loss
in 9 per cent, fatigue in 10 per cent, fever in 4 per cent, and sweats in 2
per cent). Abdominal pain was found in 8 per cent and anorexia, nausea, or
vomiting was found in 8 per cent. Dysphagia was found in 6 per cent.
Other presenting signs and symptoms (<5 per cent incidence) included
cough, dyspnea, hemoptysis, edema (including "superior vena cava! syn-
drome"), and bone pain.
Extranodal disease was the initial manifestation in 24 per cent of pa-
tients. The most common sites included the head and neck, 8.7 per cent
(naso-oropharynx 7.4 per cent, also thyroid, orbit, and paranasal sinus); the
skin or scalp, 5 per cent; bone, 4 per cent; and gastrointestinal tract, 4.6 per
cent (stomach 2.4 per cent, small intestine 1.5 per cent, and large intestine
0.6 per cent). Rare primary sites of involvement included lung, pleura,
testis, conjunctiva, meninges, bladder, cervix, ovary, and prostate. Others
have observed presentation of lymphoma in extranodal sites such as kid-
ney,75,78 bone marrow, 77 salivary glands, 78 breast, 711 brain, 80-81 and spinal
cord. 81 Extranodal lymphomas tend to be of diffuse histology. 82,83 The sub-
78
ject of extranodal lymphomas has been reviewed by Freeman et a/.
Occasionally, non-Hodgkin's lymphoma presents as autoimmune hemo-
lyticanemia. 84 The non-Hodgkin's lymphomas, particularly the diffuse lym-
phocytic varieties, may be associated with monoclonal gammopathy, partic-
ularly the IgM type. 85
Patient Characteristics Correlated with Histology. Non-
Hodgkin's lymphomas appear to be more frequent in males than in females
in some, but not all, series. There is evidence that the male predominance
82
is primarily for diffuse lymphoma. The median age for occurrence appears
TABLE 25-4. Frequency of Histologic Subtypes of

Non-Hodgkin's Lymphomas
Reference 87 61 33 283
Number of Patients 423 202 293 160
Nodular WDL 1% 0%
PDL 30% 49% 21% 40%
M 13% 3% 18% 8%
H 5% 3% 3% 3%
48% 54% 44% 51%
Diffuse WDL 3% 2% 2% 6%
PDL 13% 15%° 15% 59t
M 4% 0% 10% 4%
H 29% 27% 26% 34%
UN 3% 1% 3% 1%
52% 45% 56% 48%
"Including lymphoblastic lymphoma.
to range from the late 40s to early 50s, but the disease occurs in all age groups.
Diffuse histology is found in almost all cases of childhood lymphomas and
is more common than nodular histology in blacks and in adults who are
24 86 '
<35 years or >60 years of age. A breakdown of histologic frequency (Rap-

paport system) from several major studies is seen in Table 25-4.
Overall, nodular and diffuse lymphomas appear to be equally frequent.
Most nodular lymphomas are NPDL; NWDL
lymphoma is diagnosed very
rarely. The most frequent diffuse lymphoma is DH
lymphoma, but the com-
bined incidence of DPDL plus DM
may be as great. In view of the lack of
reproducibility of the distinction between those two categories and the sim-
ilarity of clinical course, the clinical distinction between them may be
small. It is more than one histologic type of lym-
also of value to note that
phoma may be present in the same patient at one time ("composite lym-
phomas," 11 per cent incidence in the Stanford experience); different his-
tologic types may occur in the same or different nodes. 87,88
Although Table 25-4 is representative of the histologic frequency of non-
Hodgkin's lymphomas in the United States, there may be different histolo-
89
gic profiles in other geographic areas. In a series reported from Italy, for
example, 76 per cent of lymphomas were of diffuse histology. The predomi-
nant nodular form was NWDL
lymphoma (39 per cent versus 9 per cent
NPDL). The predominant diffuse form was DH lymphoma (51 per cent),
and DWDL lymphoma was not rare (19 per cent).
Comparison of Clinical Presentation to that of Hodgkin's Dis-
ease. Compared with Hodgkin's disease, the non-Hodgkin's lymphomas
are clinically diverse. Generalizations regarding that heterogenous group of
diseases are therefore fraught with exceptions. Nevertheless, the non-
Hodgkin's lymphomas tend to be more frequent than Hodgkin's disease
and occur in an older group of patients. Extranodal primary lesions are
more common with the non-Hodgkin's lymphomas. Intrathoracic involve-
ment is less common than in Hodgkin's disease. Although both types of
lymphomas may spread by contiguity, the non-Hodgkin's lymphomas are

more likely to present as stage IV and spread hematogenously or arise mul-
ticentrically.
Staging and Diagnostic Studies
Non-Hodgkin's lymphomas are commonly staged by the same system ap-

plied to Hodgkin's disease (Ann Arbor staging classification, see Chapter
24). This system, however, has been criticized as being of limited value in
evaluating prognosis and determining therapy for both adult 90,91 and child-
hood 92 lymphomas. The value of the staging system is limited because non-
Hodgkin's lymphomas are frequently disseminated at the time of presenta-
tion, surgical staging frequently is not done when clinical studies are suffi-
cient to define treatment, and the system does not incorporate prognostic-
factors such as sites of disease, bulkiness of disease, and histology.
The incidence of dissemination at diagnosis is demonstrated by several
90-93
series. Chabner et «/. found 86 per cent of 170 surgically staged pa-
tients with non-Hodgkin's lymphoma to be stage III (21 per cent) or stage
IV (65 per cent). This compared with 42 per cent stage III and 24 per cent
stage IV prior to lymphangiogram, bone marrow aspiration and biopsy, and
surgical staging. Only 6 per cent of patients with nodular lymphoma and
30 per cent of patients with diffuse histiocytic lymphoma had stage I or
stage II disease. In the subset of patients with DPDL, 79 per cent were
stage IV, but none were stage III after surgical staging. In the Stanford
experience 87 with 423 patients — 225 of whom had staging laparotomy — 80
per cent of patients with nodular lymphomas (40 per cent of patients with
DH) had IV disease.
stage III or stage
61
Nathwaniet al. have reported on 202 patients who were primarily clini-
cally staged. They found stage III and stage IV disease in 75 per cent of
patients with nodular histology (77 per cent NPDL) and in 73 per cent of
patients with diffuse histology (72 per cent DH). These series suggest that
the non-Hodgkin's lymphomas, particularly the nodular types, have usually
disseminated beyond the regional nodes at the time of diagnosis. Autopsy
studies reveal that lymphoma is commonly disseminated to viscera. The
per cent occurrence of site-specific autopsy involvement in Rosenberg's 26
series is presented in Table 25-5.
The frequency of detection of the sites that are involved with non-
Hodgkin's lymphoma at the time of presentation depends upon what diag-
nostic studies are performed. Physical examination may be rewarding for
revealing nodal and extranodal spread of disease. Diagnostic accuracy of
interpreting lymphadenopathy, hepatomegaly, splenomegaly, and skin and
subcutaneous lesions will vary with criteria for interpreting physical find-
ings.
Chest radiographs are of modest yield in non-Hodgkin's lymphomas. Gof-
87
finet's review of the Stanford experience revealed mediastinal (presum-
ably) or hilar involvement, or both, in 23 per cent of patients with nodular
lymphomas and in 28 per cent of patients with diffuse lymphomas. Pulmo-
nary parenchymal lesions were seen in 4 per cent of patients with nodular
TABLE 25-5. Autopsy Findings — Patients with

Non-Hodgkin's Lymphoma 28 °
Site Occurrence (%)
Peripheral lymph node 84

Abdominal lymph node 78
Thoracic lymph node 59
Spleen 54
Liver 51
Gastrointestinal tract 51
Small intestine 32
Stomach 30
Large intestine 25
Esophagus 4
Kidney 47
Lung 40
Female genital tract 37
Pancreas 29
Bone >25
Adrenal 25
Heart 22
Pleura 12
Thyroid 9
Pituitary 3
"No good data exist for bone marrow, meninges, peritoneum, or the CNS. Figures for bone are probably low.
disease and in 8 per cent of those with diffuse disease. Lymphomatous

pleural effusions were found in 1 per cent of patients with nodular disease
and in 3per cent of patients with diffuse disease. Chabner et al. 90 report a
15 per cent incidence of hilar or mediastinal disease, an 8 per cent in-
cidence of pleural effusions, and a 3 per cent incidence of parenchymal
lesions. Full lung tomography has been shown to be of little value in the
non-Hodgkin's lymphomas. 94 The chest radiograph, however, is very impor-
tant in pediatric lymphomas, in which mediastinal disease is common.
As in Hodgkin's disease, the lymphogram is a useful tool for diagnosing
otherwise occult disease. Chabner et al. 90 93 found a positive lymphogram
'
in 90 per cent of patients with nodular lymphomas and in 66 per cent of

patients with diffuse lymphomas. As a result of those positive lympho-
grams, the percentage of patients who were clinically stage III increased
from 42 to 54 per cent; one third of patients who were previously classified
as stage I or stage II were upstaged. The Stanford group has found para-
aortic node involvement in 68 per cent of patients with nodular lymphoma
and in 25 per cent of patients with diffuse lymphoma. They found lymphog-
raphy to have a 13 per cent false-positive error rate and a 12 per cent
false-negative error rate. 87 Veronesi et al. 95 have reported a 4 per cent in-
cidence of both false-positive and false-negative lymphograms. It should be
noted that lymphograms do not visualize mesenteric lymph nodes, which
are areas that are commonly involved in non-Hodgkin's lymphomas. Lym-
phograms may also be technically difficult to perform in children.
The intravenous urogram appears to be a low-yield procedure for defin-
ing occult disease (2 per cent yield of ureteral obstruction). 87 It may be
Non-Hodgkin s Lymphomas 919
usefi.il with bulky retroperitoneal disease as revealed by lym-

for patients
phogram exam or to define the renal contours in patients receiv-
or physical
ing abdominal radiation. The inferior venacavogram has been advocated by
some to evaluate the right retroperitoneal nodes, particularly the superior
nodes that may not be visualized by the lymphogram. 96
Gastrointestinal series, although not generally useful for the asymptoma-
tic patient, may be warranted in the patient with a Waldeyer's ring primary
lesion. The association between the site of involvement and gastrointestinal
involvement has been noted by some authors. 97, 98
Radioisotope scans have also been used to assess the spread of non-
Hodgkin's lymphoma. Clinically suspected bone involvement, verified by
scan, radiograph, or biopsy, has been reported to be rare in non-Hodgkin's
lymphomas at presentation (7 per cent in diffuse histologic types, 1 per
cent in nodular histologic types) but more common in advanced disease. 99
The technetium-99m complex bone scans appear to be reliable and more
sensitise than radiographs. Although positive scans correlate with the pre-
sence of bone pain, elevated alkaline phosphatase levels, bone marrow in-
volvement and otherwise disseminated disease, routine bone scanning re-
99
sults in patients without those risk factors may also be positive.
The role of liver-spleen scans in staging the non-Hodgkin's lymphomas is
not clearly defined but is probably limited. Common abnormalities of liver
scans in patients with non-Hodgkin's lymphoma include hepatomegaly and
diffuse patchy isotope uptake —
findings that are suspicious of lymphoma-
tous involvement but are not diagnostic. 100, 101 This pattern is not surprising
in lymphocytic lymphomas, in which pathologic studies suggest that multi-
ple miliary nodules are the usual finding (regardless of nodularity or dif-
fuseness of nodal disease)."* 2 Histiocytic lymphomas, however, may form
large tumor masses. 10 - and hepatic scans may define advanced disease.
Generally, however, the high incidence of false-positive and false-negative
studies makes hepatic scans unreliable in revealing otherwise occult dis-
ease. 36 -
10°- 102
Splenic imaging may be more useful in evaluating the non-Hodgkin's

lymphomas. In the Stanford experience, more than 90 per cent of palpable
spleens and one third of nonpalpable spleens may be involved with lym-
phoma, suggesting that positive splenic scans might be reliable but that
negative scans would not be able to exclude disease. Moran et a/. 103 found
a 25 per cent false-negative rate with a positive technetium-99 scan or a
gallium scan as criteria for involvement. Zum Winkel et a I. 100 found splenic
scans to have a high yield in the non-Hodgkin's lymphomas but did not have
pathologic confirmation of "positive '
scans.
Total body "gallium scans have received much study in the non-
Hodgkin's lymphomas. Although some authors have found them quite
"
useful, 104 106 others have found significant false-negative and false-positive
studies. 103, 10 ~ Gallium scanning appears to be most useful in the neck and
thorax and for disease that is more than 2 cm in diameter. 106 Some inves-
tigators believe total body indium-bleomycin scans, like gallium scans, to
be a useful staging tool. 108 However, these have generally been considered
to offer no advantage over gallium scans. 104
Other diagnostic techniques are currently under study. Computed tomog-
raphy appears to be a useful technique, particularly for mesenteric lymph

nodes, high retroperitoneal nodes, and for other abdominal sites not fully
studied by lymphogram or liver-spleen scans. 109, n0 Ultrasound studies may
also be useful in those areas." 1
The bone marrow aspirate and biopsy may reveal otherwise occult dis-
ease in a considerable number of patients. Chabner et al. m have reported
lymphomatous involvement of bone marrow in 39 per cent of patients, re-
sulting in an increase of stage IV patients from 24 to 40 per cent (upstaging
of 39 per cent of patients who were previously stage III and rare patients
who were previously stage I or stage II). Marrow involvement in this series
was equally prevalent in nodular and diffuse histologic types and was most
common in DWDL (6 of 6 = 100 per cent) and was least common in NH (1
of 7 = 14 per cent) and DH (6 of 39 = 15 per cent) histologies. In a group
of 109 patients prospectively studied at Stanford, Rosenberg" 2 found mar-
row involvement in 45 patients (41 per cent, 85 per cent of patients with
NPDL). The majority of these 45 patients (78 per cent) had previously been
stage III, whereas 16 per cent had been stage IV. Of 81 patients found to
have bone marrow involvement in this and other Stanford studies, only five
were otherwise stage I or stage II. Dick et al. u3 have reported similar data,
an overall frequency of 40 per cent bone marrow involvement with in-
creased frequency in the NPDL (57 per cent), DU (100 per cent of six pa-
tients), and DWDL (100 per cent of five patients) categories and decreased
frequency in the DPDL (27 per cent) and DH (17 per cent) categories.
Castellani et a/." 4 found 4 of 64 patients (6 per cent) to be upstaged from
stage I or stage II by bone marrow examination and found a 30 per cent
rate of upstaging of stage III patients. Bilateral iliac crest biopsies appear to
have a moderately higher yield than single biopsies." 5
Percutaneous liver biopsy has been found to have an appreciable yield
(20 per cent of biopsies were positive), 87,90 but false-negative results are
common. Chabner et al. 90 reports that of 103 patients with negative percuta-
neous liver biopsies, 35 were shown to have lymphomatous involvement by
peritoneoscopy (29 per cent yield) or laparotomy (21 per cent yield in pa-
tients who showed negative findings by both blind percutaneous biopsy
and biopsy at peritoneoscopy). Peritoneoscopy has also been used by Cas-
tellani et al. u4 to visualize and to biopsy liver and spleen. They found a 22
per cent liver involvement, a 29 per cent splenic involvement, and rare
peritoneal involvement with the procedure. Liver involvement was found
in 19 per cent of patients clinically staged as I or I E in 3 per cent of patients
,
clinically staged as II or II E and in 35 per cent of patients clinically staged as

,
III, III E Ills, or III ES In patients with negative results on peritoneoscopy,

, -
laparotomy diagnosis of occult spleen involvement was made in 10 per cent

and diagnosis of occult hepatic involvement was seen in 6 per cent.
Staging laparotomy has frequently been performed without prior perito-
neoscopy. The Stanford group reports occult involvement of the liver in 16
per cent of patients with nodular disease and in 11 per cent of patients
with diffuse disease; 87 96 per cent of palpable spleens were positive for lym-
phoma, whereas 33 per cent of nonpalpable spleens were positive for lym-
phoma. Bonadonna et al. 116 reports laparotomy findings of occult hepatic
involvement in 12 per cent of patients. The yield was 2 per cent in patients
25 Non-Hodgkix's Lymphomas 921
whose was above the diaphragm only, 16 per cent in pa-

clinical disease
tients whose clinical disease was below the diaphragm only, and 24 per
cent in patients with clinical disease above and below the diaphragm. Oc-
cult splenic involvement was also found in 12 per cent of cases (9 per cent
74 103 117
for stage I and stage II disease). Other laparotomy series show simi- ' '
lar results.
As a result of various surgically and nonsurgically staged series, one can
draw several conclusions:
1. Most patients with non-Hodgkin's lymphoma, particularly those with
nodular histologic types, tend to have disseminated disease (stage III or

stage IV). Diffuse histiocytic lymphoma is the histologic type that is most
likely to be limited at presentation.
2. Para-aortic node involvement is common with nodular disease. When
the para-aortic nodes are involved, other nodal involvement beyond an "in-
verted Y" radiation port (e.g., mesenteric nodes, hepatic portal nodes) is
frequent.
3. If the spleen is palpable, it is usually involved with lymphoma. If it is
large (>900 gm), there is a high likelihood of hepatic involvement. If the

spleen is not palpable, there is still a reasonable chance that it is involved,
particularly if the para-aortic nodes show positive involvement
4. Contiguous nodal spread of non-Hodgkin's lymphoma is common, but
the high incidence of extranodal dissemination suggests hematogenous
spread (or multicentricity) as well. Noncontiguous nodal spread may partic-
ularly be seen with Waldeyer's ring lymphomas. 87 Additionally, "mediastin-
29
al skipping" is not uncommon, particularly with nodular lymphomas.
5. If left supraclavicular nodes are involved, abdominal involvement is
likely. With nodular, but not diffuse, disease, solitary right supraclavicular
involvement also has a high correlation with abdominal involvement.
TABLE 25-6. Recommended Staging Procedures for

Lymphoma
Non-Hodgkin's
All Patients
History, physical examination
Chest radiograph
Screening chemistries, urinalysis. CBC
Bone scan
Liver-spleen scan
Bone marrow aspirate-biopsy
Selected Patients
Lymphogram for all patients with disease that is otherwise stage I or
stage II above the diaphragm as well as for selected other patients.
IVP with bulky retroperitoneal disease or

for patients for those in
whom abdominal radiation therapy is planned.
UGI with small bowel follow-through and barium enema for patients
with appropriate symptoms or a Waldeyer's ring primary lesion.
Computed tomography, ultrasound, gallium scan for selected
patients. (Percutaneous liver biopsy, laparoscopy or laparotomy for
rare patients with otherwise limited disease ).
6. If the negative and disease appears to be limited to

lymphogram is
above the diaphragm, occult disease below the diaphragm is rare with dif-
fuse histologic types but is common with nodular histologic types.
7. Percutaneous liver biopsy, peritoneoscopy, and laparotomy will up-
stage substantial numbers of patients from stage III to stage IV and will
reveal nodal disease in abdominal sites not included in an "inverted Y"
radiation field in others. Roughly 10 to 20 per cent of patients who are
clinically stage I and stage II after studies that include lymphogram and
bone marrow biopsy will be surgically upstaged; this is more common with
nodular histologic types than with diffuse histiocytic lymphoma.
Recommended staging procedures for patients with non-Hodgkin's lym-
phoma are listed in Table 25-6. These recommendations are predicated on
the yield of studies and on relevance of such data to defining therapy.
Therapy as a function of stage and histology is discussed further on.
TREATMENT
Surgical Therapy
The role of surgery in the treatment of non-Hodgkin's lymphomas is not

well defined. Surgical excision of stage IE (extranodal) lymphomas may
under some circumstances be curative — particularly in gastric lympho-
mas. 76, 118> 119
Resection of diffuse histiocytic lymphoma of the bowel has
been advocated by some authors because of the significant failure rate of
chemotherapy, with or without radiation therapy, that is caused by hemor-
rhage and perforation as complications of tumor necrosis.
120
The surgical
treatment of gastrointestinal lymphomas has been reviewed by Naqvi et
al.
119
and by Loehr et al. 12i Limited retrospective data 122 suggest that "re-
ductive" surgery of abdominal Burkitt's lymphoma is of value when more
than 90 per cent of tumor can be removed. Surgery may also be indicated
for acute complications such as gastrointestinal obstruction, intussuscep-
tion, bleeding, and spinal cord compression.
The yield of surgical staging procedures has been discussed previously.
Although splenectomy has been advocated by some authors to improve tol-
erance of chemotherapy, the utility of that operation for that purpose is
doubtful. 123
Radiation Therapy
Radiation therapy is the dependable and potentially curative treatment

for a lymphoma that is confined to either one or two nodal regions limited
by the diaphragm, to a single extralymphatic organ site, or to an extranodal
siteplus nodal involvement within one or more regions limited by the dia-
phragm (Ann Arbor clinical staging system I, I E II, and II E 124 ). The five-
,
year survival rate in patients with stages I, I E II, and II E who are treated
,
with adequate wide field radiations directed to the localized disease ranges
from 20 to 70 per cent. This wide range is easily explained because the
group of diseases categorized into these stages is heterogeneous.
Examples of radiation therapy results include the following: (1) the five-
year survival rate in patients with stage I E lymphomas of the tonsil ap-
proaches 60 to 70 per cent; 125 (2) stage I E lymphoma of the testicle is usual-
126
ly disseminated disease within six months of diagnosis; (3) bilateral lym-
phoma of the orbit and breast (stage I E plus II E or stage IV) can be cured
with localized radiations; 127 132 (4) massive (40 cm x 30 cm x 30 cm) ab-
"
dominal lymphomas (stage I) will eventually disseminate; 133 (5) patients

with stages II and IIE lymphomas that are confined above the clavicles fare
better than those with similar stage lymphomas located below the clavicles;
(6) stage I or stage I E lymphoblastic mediastinal lymphomas usually dissemi-
nate or evolve into a leukemic phase; (7) patients with stage II or stage II E
lymphomas involving the head and neck region and axillary or mediastinal
nodes fare much worse than those with stage II or stage II E lymphomas
that are confined to above the clavicle; (8) lymphocytic lymphomas con-
fined to the stomach 134, l3s may, in some cases, be indistinguishable from a
benign infiltrate (pseudolymphoma), whereas histiocytic lymphoma in that
location always malignant; and (9) patients with stage II E lymphoma of
is
the stomach may have a five-year survival rate of 30 to 50 per cent —

similarly staged patients whose primary lesions arise in the small intestine
have a five-year survival rate of to 15 per cent. 136, 137
One can readily see that results of radiation therapy are dependent upon
anatomic site, histology, and bulk of disease, as well as stage.
Significance of Pathologic Subtype. The implications of histopath-
ologic subtype upon treatment decisions regarding field size, radiation
dose, or the role of chemotherapy for stage I and stage II lymphomas are
by no means clear. The reproducibility of the cytologic classifications and
their apparent increasing complexity (see previous discussion) make firm
138
conclusions premature. Nevertheless, the following statements are appro-
priate:
1. lymphomas are more virulent than lymphocytic
Histiocytic
"
lymphomas, 139 and survival may be reduced from one third to one half
142
allowing for stage and anatomic site.

2. Nodular lymphomas are much more indolent than diffuse lymphoma,
so that survival in stage I diffuse lymphoma and stage II nodular lymphoma

is similar at five years (50 per cent).
3.A higher radiation dose may be needed to sterilize diffuse lymphomas
than to sterilize nodular lymphomas. 141 144 Whether or not the necessity of
"
doses that are biologically more intense than 4000 rad in four to five weeks
can be confined to a specific subtype such as DHL
needs further study. 145
Stanford data 146 indicate that even higher doses may not cure DHL, whereas
Tubiana et a/. 139, 140 and Reilly et a/. 144 show excellent local curability as the
dose approaches 5000 rad. The recurrence rate, as a function of histology and
dose, is depicted in Figure 25-2 (based upon data of Fuks and Kaplan 146 ).
Newall et a/. 147148 showed that the site of the lymphoma (e.g., lymph node,
gastrointestinal tract, bone, connective tissue) was important for radiosensi-
tivity, whereas Peters et a/. 145 stressed the size of the nodes. There may be
difficulty in distinguishing between anaplastic carcinoma and histologic
lymphoma in the sinus region and occasionally in the stomach.
Sites of Relapse. The predominant sites of relapse in patients who
are treated with radiation therapy alone appear to be extralymphatic; nodal
PER CENT
RECURRENCE
80
FIGURE 25-2. The dose-time relation-
NPDLq ship ofNPDL, DPDL, NH, DM, andNM,
60 -
DPDlA as evaluated in terms of per cent recur-
rence against increasing dose, shows de-
nhV creasing failure as the dose approaches
40
DH
dm m\ y\
°^~^/\^C\>
y^
///
^ 4000 to 4500 rad, except for DH. (Modi-
fied from Fuks and Kaplan. Ther Radiol
20 108:675, 1973.) See text for explanation
NMo ~\^Vt of abbreviations.
DOSE IN RAD 1000 2000 3000 4000 5000
relapses are often noncontiguous. 149 151 Relapse at the primary site or at the
"
edge of a wide field radiation port directed at the visible disease is un-
usual. Patients with nodular disease, especially stage I, can relapse in nodes
150
at numerous intervals for ten years or more. Patients with diffuse pat-
terns, however, often relapse within 18 months, frequently in multiple and
extralymphatic sites. 149 150 '
Analyses of the lymphomas with respect to staging, histologic type, and

type of treatment are rarely straightforward. Most series show a five-year
relapse-free survival of 50 per cent in stage I diffuse disease 152 (with the ex-
ception of Hellman's per cent 153 ). They also demonstrate that patients with
stage nodal and extranodal disease have similar survival rates, but in
I
stage II disease prognosis for those with extranodal involvement may be

worse. 152 Notable exceptions exist, however; e.g., Brugere 154 noted that the
survival rate with extranodal disease was similar to that with nodal disease
in stage I or stage II patients. His local failures were in tumors that in-
volved the facial bones. Wang, 155 unlike Brugere, noted excellent results in
stage I of the sinuses; this may have been due to the deliv-
lymphomas
erance of doses greater than 4000 rad. Musshoff et a/. 156,157 and Tubiana
et a/. analyses showed that patients with stages I and I E disease had
139, 14 °
identical survival rates, but that those with stage II E disease did better than
stage II patients. Most series demonstrate that there is a worse survival rate
for stage II in relation to stage I disease and that patients with extranodal
stage II disease fare worse than those with nodal stage II disease. The latter
phenomenon may be due in part to the relative absence of nodular histology
in the extranodal lymphomas.
The efficacy of radiation for early stage lymphomas, therefore, is depend-
ent upon more than the stage of the disease. Technique may vary accord-
ingly. Some therapists insist that doses must be regulated for site: sinus
and bone versus node versus soft tissue versus gastrointestinal tract. Others
emphasize the importance of size (small versus large) or histology (nodular
versus diffuse) as important factors in the modification of dose. One must
consider the distribution of involvement and of specific histologic types in
interpreting the therapeutic results of clinical trials. The stage I diffuse
lymphomas form a rough heterogeneous group that will be less faithful to
generalizations than Hodgkin's disease. A high percentage of nodular dis-
ease or favorable extranodal sites such as eye, tonsil, or stomach will im-
prove survival in any series of stage I patients, whereas diffuse disease and
unfavorable extranodal sites such as sinus, testicle, or small intestine, will
decrease total survival. Other extranodal sites of lymphomas include spinal
165
cord, 158, 159 esophagus,
160
salivary glands, 78, 161 162 ovary, 163 lung, 164 bladder,
-
166
and skin.
Radiation Therapy Technique. The treatment of stage I and stage II
malignant lymphoma should be wide field radiation, e.g., the entire bone,
abdomen, or head and neck. Most errors are made when the irradiated field
is too small. For example, treatment of lymphoma in Waldeyer's ring
should include irradiation of the lower half of the neck. The treatment of bulky
supraclavicular adenopathy must include a portion of the ipsilateral axilla and
the upper anterior mediastinum. The entire abdomen should be included
for lymphomas of the mesenteric nodes or small intestine. The entire ner-
vous system should be included for lymphomas of the brain or spinal cord.
Extended irradiation is not likely to improve survival since, although
contiguous nodal recurrence does take place, it is not often the sole site of
- 149
relapse. 133 - 147 - 151
Total body irradiation in stage III and stage IV lymphomas would ap-
pear to be no more effective than combination chemotherapy, 167 but this
conclusion has been challenged. Although total body irradiation is still in-
vestigational, it would appear to offer remission in patients with nodular
histology and small quantities of disease. This modality may be less effective
in patients with acutely progressive, bulky, or infiltrative disease; in pa-
tients with widespread marrow involvement; or in patients who have failed
previous chemotherapy. Total body radiation can be effective with minimal
toxicity in cases of indolent disease in which the bladder may be com-
promised by cyclophosphamide, diabetes may be adversely affected by
prednisone, or neuromuscular tone may be severely unbalanced by vincris-
tine.
Total nodal irradiation may be associated with prolonged survival in
stage III nodular lymphomas. However, a substantial local failure rate, due
to abdominal disease not included in an "inverted Y" port (e.g., mesenteric
lymph nodes), has led some therapists to the use of total lymphoid irradia-
tion (including whole abdomen irradiation) rather than total nodal irradia-
tion. 168 169 Although these therapies may be effective for pathologic stage
'
III disease, they do not appear to be superior to systemic therapy. Morbidi-

ty of treatment and of staging laparotomy would be factors suggesting that
systemic treatment with total body irradiation or chemotherapy for clinical
stage III nodular disease may be preferable. Radiation therapy for stage III
diffuse disease is unsuccessful, with the disease-free survival rate <20 per
cent at five years. 169

Morbidity of Radiation Therapy. The toxicity of local irradiation of
stage I and stage II disease is minor. Irradiation to the head and neck may
alter salivary function and thus predispose to caries. This effect can be mini-
mized by prophylactic dental care. Myelitis, pericarditis, gastritis, intestinal
perforation, diarrhea, and malabsorption can occur, but the incidence is too
small for practical consideration. Irradiation pneumonitis and nephritis can
possibly be serious complications. Leukemia or aplasia could occur from
the treatment of stage III and stage IV disease with either total nodal or
total body irradiation.
Chemotherapy
Single-Agent Chemotherapy. Published data on the efficacy of che-

motherapeutic agents given singly for the treatment of non-Hodgkin's lym-
phomas are, to a large extent, of limited value. Excluding recent data con-
cerning single-agent alkylator therapy, most of the pertinent literature is
presented for lymphomas classified as "lymphosarcoma" or "reticulum cell
sarcoma." Published results have frequently failed to describe the treated
patients with respect to histology (by Rappaport criteria), extent of disease,
past therapy, schedule and duration of studied treatment, time of assess-
ment of response, and treatment after failure of studied therapy. These fac-
tors contribute to the wide variance of published results and make firm
conclusions difficult. Available data, however, do reflect the approximate
usefulness of chemotherapeutic agents.
It is apparent that the most useful agents include cyclophosphamide, dox-
orubicin, vincristine, and mechlorethamine. Less useful agents are predni-

sone, procarbazine, bleomycin, the nitrosoureas, and DTIC. Prednisone,
procarbazine, and DTIC have been more useful in "lymphosarcoma" than
in "reticulum cell sarcoma." The overall response rate with the more useful
agents is in the 30 to 80 per cent range, with complete response rates gen-
erally less than 10 to 20 per cent and duration of response generally less
than six months. The second line agents generally give a 10 to 40 per
cent response rate. Better quality and duration of response may be seen in
the nodular and lymphocytic varieties than in "reticulum cell" or "histiocy-
tic" lymphomas. Single-agent response data have been reviewed by Bon-
adonna and Monfardini, 170 McElwain, 171 and Ultmann and Nixon. 172
Limited trials of more recent agents have suggested possible roles for
cisplatin, 173 streptozotocin, 174 and ICRF-159 175 in the treatment of non-
Hodgkin's lymphomas. Promising results have also been reported with
high-dose methotrexate administration and leucovorin rescue. 176, 17T Other
chemotherapeutic agents such as methotrexate (standard dose), 178 5-flu-
179
orouracil, cytosine arabinoside, 178 6-mercaptopurine, and dactinomy-
cin 180
have received little study but show evidence of some activity.
However, studies of alkylating agents, analyzed by the Rappaport classifi-
cation system, have shown a useful role for single-agent alkylator therapy
181
in selected advanced lymphomas. In a retrospective analysis, Jones et al.,
reviewing the courses of 110 patients treated with single-agent alkylator
chemotherapy (chlorambucil or cyclophosphamide), noted a 74 per cent re-
sponse rate, with a 48 per cent complete response rate in 19 patients with
NPDL lymphoma. Response rates in other histologic types varied from 60
per cent (DM) to 81 per cent (NM), and complete response rates varied
from 5 per cent (DH) to 31 per cent (NM). The highest complete response
rateswere seen in the nodular histologic types. The median duration of
response was longer in nodular (17+ to 20 months) than in diffuse (5 to 13
months) histologic types. Survival was best in the NPDL lymphoma (me-
dian 39 months), followed by NM lymphoma (median 20 months). Survival

was poor in diffuse lymphomas or NH lymphomas (median 3.5 to 7.5
months). In a later prospective randomized study, 182 the Stanford group
found daily, oral single-agent alkylator therapy (chlorambucil or cyclophos-
phamide) to be as effective as combination chemotherapy (CVP = cyclo-
phosphamide, vincristine, prednisone) with or without total lymphoid ir-
radiation in the treatment of stage IV "favorable histology" non-Hodgkin's
lymphoma (NWDL, NPDL, NM, DWDL). The estimated survival rate in
is >90 per cent from 20 to 50+ months; the median survival
that series
cannot yet be estimated. 182183 In that series, 48 of 63 patients had NPDL
histology (14 of 20 in the single-agent group). The response rate was >95
per cent in each group, with a complete response rate ranging from 65 per
cent in the single-agent group to 83 per cent in the group receiving CVP.
In a similar study, Kennedy et a/. 184 compared CVP with the sequential
use of single-agent therapy (cyclophosphamide until failure, followed by
vincristine until failure, followed by prednisone) in patients with nodular
and diffuse lymphocytic lymphoma (excluding DWDL). Their data suggest-
ed improved total and complete response rates (94 per cent total, with 81
per cent CR versus 77 per cent total, with 46 per cent CR) and improved
long-term survival (63 per cent versus 31 per cent), but not improved me-
dian survival (25 months) with a CVP regimen in disease of nodular his-
tologic type. Surprisingly, in disease of diffuse histologic type no difference
between CVP and sequential therapy was seen; the complete response rate
was 50 per cent and the overall response rate was 91 per cent. The differ-
ences between CVP and single-agent therapy in nodular disease, although
suggestive, were not significant at the p<0.05 level at the published sample
size.
Lister et a/.
185
compared 18 weeks of CVP with 18 weeks of chlorambucil
in patients with NPDL, NM, DWDL, or DPDL lymphomas. They found a
higher complete response rate with CVP (37 per cent) than with chloram-
bucil (13 per cent) but found similar complete response rates plus "good
partial response" rates (83 per cent for CVP and 74 per cent for chlorambu-
cil). The overall median duration of remission was approximately 12
months and did not vary with therapy. Survival data from that series are
premature.
Monfardini et a/. 89 also reported results of sequential single-agent therapy
analyzed by the Rappaport classification scheme. They noted a response
rate of 70 per cent and a median survival of 23 months in nodular disease
and a response rate of 36 per cent and a median survival of 17 months in
diffuse disease.
Tables 25-7 and 25-8 summarize those results. With single agent thera-
py, it appears that the survival and complete response rates are better in
nodular histologic types (excluding NH) than in diffuse histologic types (ex-
cluding DWDL).
Combination Chemotherapy. Combination chemotherapy regimens
have been used extensively in the treatment of the non-Hodgkin's lymphomas.
Cyclophosphamide, vincristine, and prednisone are generally part or all of
most combination regimens. Other drugs that have been useful include dox-
orubicin, bleomycin, CCNU, and procarbazine.
TABLE 25-7. Sequential Single-Agent Therapy in Nodular

Non-Hodgkin's Lymphomas
No. of Median Survival

Histology Patients CR and PR (%) CR (%) (Months) References
NPDL 74 48 39 181
NM 81 31 20
NH 72 28 ~ 5
NPDL 19 of 20 alive 182, 183

NM 95 65 at median
DWDL follow-up
>30
"Lymphocytic" 16 94 81 -29 184
NWDL 8
XPDL 1
70 53 23
NM 2
NH 6
NPDL l
81 ^19 not reached 185
NM 3
"DWDL included in references 13 and 142.
Early studies by Hoogstraten et al., im Luce et al.,

188
1S7
and Lowenbraun et al.
suggested that combination chemotherapy was superior to single-agent thera-
py in the treatment of "lymphosarcoma" or "reticulum cell sarcoma." Improve-

ments with respect to complete response rate, duration of response, and
survival were seen when patients treated with combination chemotherapy
187, 188
were compared with randomized concurrent 186 and historic controls.
TABLE 25-8. Sequential Single-Agent Chemotherapy in Diffuse

Non-Hodgkin's Lymphoma
No. of Median Survival

Histology Patients CR and PR (%) CR (%) (Months) References
DPDL 9 67 22 3.5 181

DM 15 60 13 7.5
DH 19 74 5 7
"Diffuse
Lymphocytic' 12 92 50 184
(no DH)
DWDL
DPDL
DM 36 18 17.4 89
DH (~12 excluding
DU DWDL)
DPDL-DWDL
DM 46 30 20 284
DH
TABLE 25-9. Combination Chemotherapy in NPDL

Lymphoma Stages III and IV
No. OF 2-Year Median

Drugs Patients % CR/% CR + PR Survival Survival References
C, V, P 24 41/95 -90% XR 285

C, V, P 49 67/93 -74% 83 months 189
C, P, BCNU, CH 97 47/81 83% NR 195
C, V, P 17 53/? ? 154 weeks 286
C, V, P± ARA C 20 70/? ? 199 weeks 286
M, O, P, P 14 43/? ? 132 weeks 286
C, V, P, BLEO 15 67/? -78% 184 weeks 286
C, H, O, P 62 77/? -82% NR 286
H, O, P 54 59/? -86% NR 286
C, H, O, P, BLEO 13 62/100 -85% NR 199
C, V±P 20 30/85 ? 4.2 years 197
C= cyclophosphamide, V or O = vincristine, P = prednisone (2nd P= procarbazine), CH =

chlorambucil, ARA C = cytosine arabinoside, BLEO = bleomycin, H = doxorubicin, NR = not
reached.
Results of more modern studies, which were analyzed for NPDL, DPDL, and
DH and 25-11.
histologic types, are presented in Tables 25-9, 25-10,
A variety of combination regimens, used for the treatment of advanced
NPDL lymphoma, has resulted in a complete response rate of approximately 60
per cent and a complete plus partial response rate of approximately 90 per cent.
The survival rate is roughly 85 per cent at two years, with the reported median
survival varying from three to seven years. Late relapses in this disease are
common, 189 19° usually in previously involved areas and primarily in lymph
'
nodes but not infrequently in bone marrow. 179, 191 It appears that in patients
with advanced NPDL lymphoma, disease may be effectively suppressed but is
unlikely to be cured. "Maintenance" therapy after a complete remission may
delay relapse, but since disease that relapses after therapy has been discontin-
ued frequently can be "recaptured," with good survival after relapse, the
overall impact of maintenance on survival is unclear. In patients treated with
TABLE 25-10. Combination Chemotherapy in DPDL

Lymphoma Stages HI and IV
NO. OF 2-Year Median

Drugs Patients % CR/ % CR + PR Survival Survival References
C, V, P 25 32/100 -50% 23 months 189

C, H, O, P 38 68 ? 194
75% at
NR
1 year
H, O, P 38 55/? 194
•*
C, P versus B. P
then 77 25/59 47% 98 weeks 195
BCVP versus CHLOR
BACOP 15 80/93 58% NR 191
C. V±P 19 21/58 - 2.9 years 197, 287
C = cyclophosphamide, V or O = vincristine, P = prednisone, H= A= doxorubicin, B

BCNU, CHLOR = chlorambucil.
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combination chemotherapy, the survival rate of complete responders is superi-

or to that of partial responders or nonresponders. 189 This probably signifies that
the failure to "completely" respond to aggressive therapy is a poor prognostic-
sign rather than signifying that it is necessary to be rendered disease free;
survival may be good in patients who relapse after the discontinuance of
combination chemotherapy as well as in patients who achieve partial responses
with single-agent therapy.
Other favorable histologic types of lymphomas merit separate discussion.
N WDL lymphomas are rare, but they have been reported. Prognosis appears to
be excellent, with prolonged survival even in advanced stages. 29, 2, 19:! For ex-
1! '
ample, a median survival of 51.5 months was found in patients with "pseudo-
nodular" WDL lymphoma, a histologic type that is perhaps better classified as
DWDL. Nodular mixed lymphoma generally behaves similarly to NPDL lym-
phoma in terms of response rate and survival. There is some evidence that
patients with this histologic type of lymphoma who are treated with C-MOPP
may have durable remissions and "cures" rather than the continuous relapse
rate associated with NPDL lymphoma. 189 However, a continuous relapse rate
for at least two to three years reported by McKelvey and Moon 190 in patients
is
with NM lymphoma treated with CHOP and other combination chemotherapy

regimens. Nodular histiocytic lymphoma is rare and has a poor prognosis with
single-agent therapy. 181 Aggressive combination chemotherapy may achieve
complete remissions in a majority of these patients, and best results have been
achieved with CHOP (estimated two-year survival =65 per cent). 194
Many investigators believe that DWDL
lymphoma is on a continuum with
chronic lymphocytic lymphoma. u 3
Survival appears to be good (median surviv-
al five to ten years) regardless of treatment modality and including untreated
189
patients. 1,3,
DPDL lymphoma is clearly more aggressive than NPDL lymphoma when
treated with single-agent 181 or combination 189, 195, 196
chemotherapy. Table
25-10 presents results of combination chemotherapy regimens in this his-
tologic group. The regimens containing doxorubicin (CHOP, HOP, BACOP)
appear to be superior to those using CVP in this histologic type of lymphoma,
at least in complete response rate. Median survival appears to be in the two- to
three-year range with less aggressive regimens and is not yet determined with
the doxorubicin-containing regimens. It is unclear whether or not there is a
long-term plateau in survival past the two- to three-year mark.
Data regarding DM
lymphoma are limited and diverse. Poor results in
patients treated with CVP, C-MOPP, or BACOP were noted by the NCI group
(10 patients, with 10 per cent CR and median survival of four months),
189
and by
the Sidney Farber Center (6 patients with 64 per cent CR and 32 per cent PR
191
but median survival only a little over eight months). Better results were seen
with CHOP and HOP, 194 or merely with cyclophosphamide, vincristine, and
prednisone; 197 with these regimens the CR rate ranged from 50 to 86 per cent
and the median survival figures were three years or have not been reached. All
the series cited are small, and differences in results may be due to site or
bulkiness of tumor or to histologic variability.
Data regarding the treatment of DH lymphoma are summarized in Table
25-11. The CVP-type regimens yield a typical complete response rate of 30 per
cent, with a median survival of roughly between 6 and 14 months. The addition
of other agents, such as doxorubicin, CCNU, bleomycin, procarbazine, metho-
trexate with leucovorin rescue, or cystosine arabinoside, appears to raise the
complete response rate to the 50 to 60 per cent range and the median survival to
the one- to two-year mark. In this disease, the achievement of a complete
response appears to be critical, as the survival of partial responders (as well as
nonresponders) is poor compared with the survival of complete re-
sponders. 189, 198 Furthermore, relapses in unmaintained complete responders
after two years are rare, suggesting the possibility of a significant cure rate in
this disease. 73 ' 189, 194, '"• 200
Long-term disease-free survival may be seen in up to 75 per cent of patients

with DH
lymphoma who enter complete remission. 189 The prognostic signifi-
cance of a "complete remission," however, may depend in part on the certainty
of the absence of detectable disease. Apparent complete response rates and
subsequent relapse rates may be higher in groups of patients who have not
been extensively "restaged" to exclude occult disease and to validate the
presumed clinical complete remission. 201,202 Relapses in diffuse lymphomas
treated with chemotherapy to a complete remission are common in areas not
previously involved. 191 In DH
lymphoma, relapses occur frequently in extra-
nodal sites or in the central nervous system. 203 This pattern suggests that
adjuvant radiation therapy administered to areas of previous disease may not
have a great impact on cure rates for patients treated with chemotherapy to a
complete remission.
Fisher et a/. 196 noted that the complete response rate in DH lymphoma
treated with C-MOPP or BACOP appears to be highest (78 per cent) in patients
with stage III or stage IV skin involvement and lowest (14 per cent) in patients
with bone marrow or gastrointestinal tract involvement. A poor complete
response rate (25 per cent) was also seen in patients with bulky disease (largest
lesion greater than 10 cm in diameter). Hepatic involvement may also be a poor
prognostic factor. 200
Strauchen et a/, 44 using a classification scheme similar to that of Lukes, have
divided DHL into five categories: large cleaved cell, large noncleaved cell,
mixed follicular-center cell, blastic, and pleomorphic pyroninophilic. In re-
viewing the course of 66 patients with DHL subclassified by this approach,
they noted that patients with large cleaved cell disease have the best prognosis
(78 per cent two-year survival), those with large noncleaved and mixed
follicular-center cell disease have an intermediate prognosis (roughly 50 per
cent two-year survival), and those with blastic and pleomorphic pyroninophilic
disease have the worst prognosis (10 to 15 per cent two-year survival). The
complete response rate paralleled survival; histologic prognostic significance
was not dependent upon stage or site of involvement, with the possible
exception of an increased tendency for bone marrow involvement in the groups
with poor prognoses. The patient population that was evaluated is the same
population that was evaluated by Fisher et a/., 196 they had generally been
treated with BACOP or C-MOPP, with radiation therapy as well for early stage
disease.
Patients with diffuse undifferentiated lymphomas (non-Burkitt's) probably
have a poor prognosis. The seven patients reported by McKelvey and Moon 190
had a 43 per cent complete response rate with CVP or C-MOPP and had a
median survival of six months.
Nathwani et al. 62 have identified a group of "lymphoblastic lymphomas,"
which were previously classified primarily with the DPDL or DU categories.
This lymphoma may be convoluted or nonconvoluted in type. Although it is
predominantly a childhood disease, one third of cases may be found in patients
^ 15 years of age. It frequently presents with a mediastinal mass and commonly
has meningeal, bone marrow, and peripheral blood involvement. It is often a T
cell lymphoma, and it may be acid phosphatase-positive. Prognosis appears to
be poor (median survival eight months) with standard lymphoma therapy, and
the disease may be better treated as an acute lymphoblastic leukemia.
Monfardini et al. 204 have reported that patients with non-Hodgkin's lympho-
ma who fail CVP may respond well to doxorubicin, bleomycin, and prednisone.
However, it is not clear which, if any, histologic types of lymphoma will
respond better to second-line combination chemotherapy than to second-line
single-agent chemotherapy administered sequentially. Attempts to improve
treatment results by alternating CVP with doxorubicin, bleomycin, and predni-
sone are ongoing but early. 205
Recent reviews of the role of combination chemotherapy in the non-
Hodgkin's lymphomas would include those of Bonadonna and Monfardini, 170
Bodey and Rodriguez, 203 and Lewis and DeVita. 206 Representative regimens
are cited in Table 25-12.
Morbidity of Chemotherapy. The risks and side effects of individual
drugs have been discussed in Chapters 4 and 5. The risks of the individual
regimens cited would generally include the risks of each drug singly. Promi-
nent among the compendium of risks would be alopecia, nausea, vomiting,
mucositis, diarrhea, bone marrow suppression with possible subsequent hem-
orrhage, infection or anemia, neurotoxicity, infertility, interstitial pneumonitis,
An additional risk, which is probably related to
cardiac toxicity, and phlebitis.
alkylating agentsand perhaps procarbazine and is of increased incidence with
combined modality therapy (chemotherapy plus radiation), would be that of a
second malignancy —particularly acute nonlymphocytic leukemia. This com-
plication is well established for Hodgkin's lymphomas 207-209 and has been
210
reported in non-Hodgkin's lymphoma as well.
Combined Modality Therapy (Radiation

Therapy Plus Chemotherapy)
Although either chemotherapy alone or radiation therapy alone may provide

effective treatment for non-Hodgkin's lymphomas, single modality therapy has
an appreciable failure rate even in limited disease. Because chemotherapy may
be effective in advanced disease, it seems reasonable to use it as adjuvant
therapy for limited disease that is treated to a complete remission by radiother-
apy of curative intent, in an attempt to sterilize residual foci of disease in or out
of the radiation field. Because patients treated with chemotherapy may relapse
in areas of previous tumor involvement, particularly if that tumor was bulky, it
25 | Non-Hodgkin's Lymphomas 935
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seems reasonable to use radiation therapy to areas of previous disease or the

bulky disease after a chemotherapy-induced complete remission.
The efficacy and the risks of combined modality therapy are currently under
investigation. Reports from Stanford 211 show no advantage to the combined
modality approach in stages I and II disease of unfavorable histologic type or in
stage III and stage IV disease of favorable histologic type. In stage III and
stage IV disease of unfavorable histologic type, the combined modality ap-
proach seems superior to chemotherapy alone. Bonadonna et al. 212 found a
higher relapse rate in patients with stage I and stage II non-Hodgkin's lympho-
ma who were treated with radiation therapy alone than in those who were
treated with radiation therapy plus chemotherapy (30 per cent versus 17 per
cent). The sample size in that study was small, however, and that difference
was not significant at the p < .05 level The apparent improvement in that series
.
was seen in diffuse lymphoma but not in nodular lymphoma.

The National Cancer Institute is comparing combination chemotherapy
(CVP or C-MOPP) with combined chemotherapy plus total body irradiation.
Although early results show no advantage to the combined modality ap-
proach, 213, 214 the small number of patients and the heterogeneity of stages and
histologic types makes the analysis of those data premature.
Combined modality therapy has been advocated in Burkitt's lymphoma 215
and in other childhood lymphomas, 216, 217 although a controlled trial in the latter
group has found no utility for the adjuvant radiation therapy. 218
Immunotherapy
Immunodeficiency, as reflected by decreased skin test reactivity to recall

antigens, lymphopenia, and hypogammaglobulinemia, has been found in pa-
tients with non-Hodgkin's lymphomas, particularly those of diffuse histolo-
219
gy. Attempts to improve the results of standard therapy by the addition of
immunotherapy with BCG, although initially promising, 220 have generally
show positive results, 221-223 with the possible exception of marginal
failed to
improvement in a BCG-treated group reported by Jones et al. 224 That study
suggested a higher complete plus partial response rate but no improvement in
complete response rate, survival, or relapse rate in patients treated with CHOP
+ BCG as compared with those treated with CHOP + bleomycin.
Delayed Therapy
Not all patients with disseminated disease need immediate therapy. Portlock
and Rosenberg 183 have reported 35 patients, primarily with disease of "favor-
able" histologic type (13 NPDL, 6 DWDL, 7 NM), who were relatively
asymptomatic and who were observed without therapy being given. Therapy
became necessary in approximately 85 per cent of those patients. One half of
the group required treatment by three years, but one patient required no
therapy for greater than ten years. The overall estimated survival in that
selected group was greater than 70 per cent at five to ten years.
SPECIAL PROBLEMS
Childhood Non-Hodgkin's Lymphomas
The non-Hodgkin's lymphomas of childhood differ from those of adult life
regarding the distribution of histologic types, the patterns of stage and involved
sites,the natural history, and the response to therapy.
The pediatric non-Hodgkin's lymphomas are almost always (98 to 99 per
cent) of diffuse histologic pattern.
225, 226
Dehner225 has reviewed the relative
frequency of histologic subtypes of childhood lymphomas reported in recent
(western) series.The most common histologic type was PDL (47 per cent);
histiocytic lymphoma was also frequent (33 per cent). Undifferentiated (includ-
ing lymphoblastic) lymphomas made up 14 per cent, and Burkitt's lymphoma
made up 3 per cent. Mixed histiocytic lymphocytic lymphomas and unclas-
sified lymphomas each made up 2 per cent. In some of the series reviewed,
however, the "lymphoblastic" forms were classified as poorly differentiated
lymphocytic rather than as a separate category. The incidence of the lympho-
blastic form, therefore, is probably greater than 14 per cent, and the incidence
of nonlymphoblastic PDL lymphomas is probably less than 47 per cent.
Hausner et a/., 227 classifying lymphoblastic lymphomas separately from undif-
ferentiated lymphomas, noted that 9 of 30 patients had lymphoblastic disease.
Pediatric non-Hodgkin's lymphomas occur predominantly in males, with a
227_229
ratio of male to female cases of roughly 3 to l. 225, The poorly differentiated
lymphocytic type is most frequent in patients from three to eight years old. The
involvement of the mediastinum, retroperitoneum, or gastrointestinal tract, or
22
all of these, is common, whereas peripheral adenopathy is not.
"'
The immun-
ologic classification of these lymphomas is heterogeneous. The lymphoblastic
lymphoma has already been discussed briefly. It is probably part of a contin-
uum with acute lymphoblastic leukemia and commonly occurs in adolescence.
It may present with an anterior mediastinal mass, peripheral lymphadenopa-
thy, or bone marrow involvement with or without circulating lymphoblasts, or

all of these. It frequently progresses to invade the meninges. The convoluted
lymphocytic lymphomas compose a histologic subset of the lymphoblastic

lymphoma and are primarily T cell disorders. The nonconvoluted lymphoblas-
tic lymphomas may be heterogeneous regarding immunologic mark-
225, 230, 231
ers. The childhood histiocytic lymphomas tend to occur in children 10
to 15 years of age. They may be limited or extranodal, or both, at presentation,
but they tend to disseminate. 225
The prognosis of the childhood non-Burkitt's lymphomas is not adequately
reflected by the Ann Arbor staging system. 92, 226, 232 The staging system fails
because prognosis appears to be dependent more on the site of disease than on
stage, because noncontiguous dissemination (including marrow and men-
inges) is common, and because stage III disease may be rare. 232 Favorable
prognostic factors include (1) locoregional disease (Ann Arbor stage I or stage
II); (2) extranodal, head and neck, or peripheral nodal primary site; (3) lack of B
or T cell markers; and (4) (rarely) nodular histology. Unfavorable factors

include (1) mediastinal or abdominal nodal primary disease; (2) disseminated
disease (Ann Arbor stage III or stage IV) (particularly with marrow or menin-
geal involvement); and (3) B or T cell markers. When abdominal disease is

present, the prognosis depends upon bulk and resectability; 232 lymphoblastic
or undifferentiated lymphoma may have a poorer prognosis than other his-
tologic types. 227 Murphy 232
has suggested an alternative staging system for
childhood non-Hodgkin's lymphoma. This approach would have childhood
stage I disease equated to Ann Arbor stage I disease of sites other than the
mediastinum or abdomen. Childhood stage II disease would be disease in two
extranodal sites on the same side of the diaphragm or Ann Arbor stage I or stage
II abdominal disease. Childhood stage III disease would be Ann Arbor stage
III disease, any primary intrathoracic tumor (Ann Arbor stages I to III), or
extensive intra-abdominal disease (Ann Arbor stages I to III). Stage IV disease
would be bone marrow or CNS involvement.
The treatment of these childhood non-Hodgkin's lymphomas has been
reviewed by Murphy. 226 For Ann Arbor stage I peripheral nodal disease,
233 234
radiation therapy alone may be curative more than half the time, '
but a
chemotherapy plus radiation therapy approach is superior. Chemotherapy
alone or with radiation therapy seems appropriate for advanced nodal disease.
Abdominal disease may be treated effectively by combined surgical resection,
radiation therapy, and chemotherapy. When resection is "complete,'' the cure
rate may approach 70 to 80 per cent, but if the tumor is unresectable, prognosis
is poor.
226
Mediastinal or lymphoblastic lymphoma is best treated like acute
lymphoblastic leukemia.
Superior results have been reported with the LSA 2 -L 2 regimen of Memorial
Sloan-Kettering Cancer Center. 216, 235 This complex regimen uses induction,
consolidation, and maintenance phases. The induction phase utilizes cyclo-
phosphamide, vincristine, prednisone, and daunomycin as well as intrathecal
methotrexate. Radiation therapy is given to bulky disease. The consolidation
phase utilizes cytosine arabinoside, 6-thioguanine, L-asparaginase, BCNU,
and intrathecal methotrexate. The maintenance phase alternates cycles of
6-thioguanine plus cyclophosphamide, hydroxyurea plus daunomycin, metho-
trexate plus BCNU, cytosine arabinoside plus vincristine, and intrathecal
methotrexate. This regimen, although unwieldy, has had remarkable success,
with the overall survival rate at 70 per cent from two to four years versus
approximately 15 per cent in a series of historic controls.
Patients with nodal and mediastinal primaries did best with the LSA 2 -L 2
regimen (~90 per cent survival at two to five years). Patients with skeletal and
bowel primaries had a poorer prognosis (40 to 60 per cent two- to three-year
survival). In the historic control group, patients with nodal primaries had fared
best (—35 per cent long-term survival), and patients with mediastinal disease
fared worst (no two-year survivors). Patients with mediastinal primaries report-
ed in other series have also fared poorly. Those with mediastinal disease and a
leukemic phase who were treated at Saint Jude's Children's Research Hospital
with an acute lymphoblastic leukemia-type regimen (vincristine, prednisone,
and L-asparaginase induction; mediastinal and CNS radiation; intrathecal
methotrexate; 6-mercaptopurine, methotrexate, and cyclophosphamide main-
tenance) had a high complete response rate (96 per cent) but also had a high
relapse rate and a median survival of 15 months. 226 Mediastinal lymphoblastic
childhood lymphoma appears to have a poorer prognosis than acute lympho-
blastic leukemia.
CNS prophylaxis is included in most childhood lymphoma protocols because

it is effective in decreasing the high incidence (—30 per cent) of meningeal
relapse. 253
It is less effective, however, in prolonging survival; CNS relapse
frequently arises as just one part of systemic failure rather than as local failure
alone. The risk of leukoencephalopathy and the periodic failure of CNS
prophylaxis makes the role of that procedure uncertain. Patients with stage I
nodal or resectable abdominal lymphoma (non-Burkitt's) particularly have a
relatively low risk of CNS involvement. 226
The role of involved field radiation therapy is not defined. Murphy et al. 2ta
randomized 47 patients with childhood lymphomas to combination chemother-
apy plus or minus CNS prophylaxis and involved field radiation therapy. They
found no advantage to the combined modality therapy over chemotherapy
alone in terms of duration of remission or survival. They did note fewer CNS
relapses in the group prophylactic-ally treated with cranial irradiation (2400
rad) and intrathecal methotrexate (12 mg/m 2 x 5).
Burkitt's lymphoma is a disease primarily, but not exclusively, of child-
hood. 236 It is a B cell disorder, possibly derived from germinal center cells. 237
Although it is rare in the United States, 236 it is common in regions of Africa.
Epidemiology and etiology of this disease have already been discussed briefly.
Ziegler et a/. 5 and Klein238 have reviewed the relationship of the EB virus to
Burkitt's lymphoma and other tumors. The characteristic histologic features of
this disease have been described by Berard et al.™
Burkitt's lymphoma is usually disseminated and rapidly progressive at
presentation. If untreated, it is rapidly fatal. African Burkitt's lymphoma tends
236, 24,)
to occur in patients four to nine years of age. Facial bones are the most
commonly involved dominant followed by the abdomen and orbit. Men-
site,
inges are frequently involved, often presenting as paraplegia or cranial neuro-
pathy. 241 The ovaries, kidneys, liver, thyroid, breasts, spleen, and heart are
commonly involved. Bone marrow is often affected when disease is otherwise
disseminated. Other sites of involvement include bone, pleura, testes, and
salivary glands. The lungs, mediastinum*, and peripheral lymph nodes are
usually not involved. 239 240 '
Burkitt's lymphoma is rare in the United States. It typically occurs in

American children at a somewhat later age (mean 12.2 years, median 10 to 12
years) than African Burkitt's lymphoma. Approximately 15 per cent of Ameri-
can cases have occurred in patients >21 years of age. Male predominance (3: 1)
occurs in children but not in adults. Abdominal or pelvic disease is the
dominant presentation for American Burkitt's lymphoma, and facial disease is
rare. Lymphadenopathy and bone marrow involvement may be more common
than in the African variety. 236, 242, 243 American Burkitt's lymphoma, like the
African form, may be associated with EB virus, although American Burkitt's
lymphoma cells are less likely to carry the EB genome. 5
viral
Prognosis is relatively favorable in patients who have extra-abdominal
dis-
ease or surgically resected abdominal disease. Prognosis is poor for those with
unresectable or unresected abdominal disease, meningeal tumor, or otherwise
bulky disease. 236 -
High serum LDH levels (>700 IU/L), 242 age >12
24 °- 242 - 244 - 245
244
years, and early relapse (<12 weeks) 240 may also be poor prognostic signs.
Ziegler 244 has suggested the following staging system for Burkitt's lymphoma:
stage A = single extra-abdominal site; stage B = multiple extra-abdominal
sites; stage intra-abdominal tumor; stage D = intra-abdominal and extra-

C=
abdominal tumor; stage AR = stage C but with >90 percent of tumor surgically
resected. Although American and African patients may differ as to age and site
of involvement, stage for stage, survival is similar in the two groups. 244
Part of the unfavorability of bulky disease may be due to a "Tumor Lysis
Syndrome," a sequela of successful chemotherapy in which rapid tumor
necrosis leads to severe and often fatal hyperkalemia, hypocalcemia, hyper-
phosphatemia, hyperuricemia, and lactic acidosis. 242, 244 This risk may be min-
imized by hydration, treatment with allopurinol, and close attention to el<
trolyte balance. Hemodialysis may be necessary in some patients. Risk may be
decreased by reductive surgery prior to therapy or by decreasing or protracting
initial doses of chemotherapy.
Chemotherapy may complete response
result in a high (60 to 95 per cent)
rate. The relapse rate is roughly 50 per cent, and
higher in the groups with
it is
poor prognoses (see earlier discussion). 240,242,244,245 Relapse usually occurs

within one year after entry into complete remission and is common within
three months. It is rare after one to two years. 240, 244 Although reasonable results
have been obtained with pulse cyclophosphamide as a single agent, 240, 245 there
are some data suggesting that a combination chemotherapeutic approach (e.g.,
cyclophosphamide, vincristine, and methotrexate plus or minus prednisolone)
may be superior, at least in American patients. 244 CNS "prophylaxis," with
intrathecal methotrexate plus or minus cranial irradiation, has commonly been
used. This does not prevent future meningeal involvement from "reseeding,"
but it may diminish the relapse rate. 244 There is no clear role for maintenance
chemotherapy. 245 If surgical "debulking" of abdominal disease is able to
reduce tumor >90 per cent, it appears to be of survival value. 122, 244 Although
attempts to reinduce a remission with standard chemotherapeutic approaches
are generally unsuccessful after relapse (particularly early relapse), intensive
chemotherapy followed by a "rescue" with stored frozen autologous bone
marrow has resulted in long-term disease-free survival for some patients who
have failed standard therapy. 246, 247
The lymphoma is approximately
overall long-term survival rate in Burkitt's
244
55 per cent. roughly 60
It is to 80 per cent for stages A, B, and AR, 40 to 50 per
236, 240, 244, 247
cent for stage C, and 10 to 40 per cent for stage D.
"Mediterranean" Intestinal Lymphomas
An "immunoproliferative small intestinal disease," manifested by diarrhea,

malabsorption, clubbing, and plasma cell infiltration of the small bowel, has
been seen frequently in the Middle East, the Mediterranean region, and Africa.
It is commonly associated with the presence of monoclonal alpha chains in the
serum. Etiology may be related to parasitic or other infections as well as to
racial and genetic factors.
This entity has a high association with small bowel lymphoma (immunoblas-
tic sarcoma, presumably of B cells). In some,
248
but not in all, 249 cases, the
lymphomatous cells have been demonstrated to have the immunologic charac-
teristics of the plasma cells producing alpha chains. Presumably, therefore,
Mediterranean lymphoma generally occurs as a clonal lymphomatous evolu-
25 Xon-Hodgkix's Lymphomas 941
tion of lymphoplasmacytic intestinal infiltration. Not all cases of Mediterran-

ean lymphoma are characterized by alpha chain production, however, and this
phenomenon is absent in the "western" type of intestinal lymphoma 250 and in
the intestinal form of malignant histiocytosis. 2 ' 1
In the Mediterranean lymphomas, the involvement of mesenteric nodes is

common. The involvement of peripheral nodes occurs occasionally, and the
involvement of liver or spleen is rare. 250 252 Survival is frequently less than one
-
year in this disease; 252 optimal therapy has not been defined.
Mycosis Fungoides — Sezary Syndrome

Mycosis fungoides is a lymphoma whose dominant site of involvement and
probable site of origin is the skin. Typically, the diagnosis is made after the skin
lesions have progressed from a nonspecific dermatitis, which has been relative-
ly indolent for three to ten years, to a frank mycotic state. Diagnosis in the
quiescent "premycotie" period is difficult. The disease may also progress extra-
cutaneously.
This lymphoma is a T
malignancy; there is evidence suggesting that it
cell
may be a disease of helper T cells. 55- 25a 254 Major reviews of mycosis fungoides
-
include those of Epstein et a/. 255 and Levi and Wiernik. 2 ™ When the cutaneous
lymphoma of mycosis fungoides has been accompanied by circulating lympho-
ma cells, this disease has been called Sezary syndrome. The history of Sezary
syndrome 257 and the characteristics of the circulating Sezary cells have been
reviewed. 55 - vs - ° On the basis of clinicopathologic and immunologic features,
t5
it is generally accepted that Sezary syndrome is the leukemic phase of mycosis
fungoides rather than a different disease. 261

Mycosis fungoides may present cutaneously as eczematous or "psoriaform"
lesions, as limited or generalized plaques, as exfoliative erythroderma (the
"red man" syndrome when advanced), as nodular or tumorous lesions, as
ulcerating lesions, and as combinations of these. The characteristic histologic
features, which max be absent in the early, indolent premycotie phase of
mycosis fungoides, have been reviewed. 254-25*- 2fi2
Palpable lymphadenopathy is common. Enlarged lymph nodes may be
"dermatopathic" or lymphomatous. Retroperitoneal adenopathy revealed by
lymphogram, 263 laparotomy, 2 *'- 2rt4 or autopsy. 2 * 2 265 is not rare. Visceral involve-
ment is common terminally, with the frequent involvement of the spleen, liver,
lung, bone, bone marrow, kidney, pancreas, oropharynx, thyroid, heart,
thymus, and testis. Other sites of involvement (e.g., parathyroid, breast, adre-
nal, ovary, and meninges) are not rare. 255 262 In a small series of patients staged
-
by laparotomy, Griem et al.'1M reported that 2 of 14 patients had hepatic-

involvement and 4 of 14 patients had splenic involvement.
Prognosis varies with the stage of disease. The "premycotie stage" may last
up to 50 years, but a duration of approximately 6 years is a representative
figure. 255 25fi The overall median survival after biopsy diagnosis is roughly five
-
years. Poor prognostic factors include age greater than 60 years, skin tumors or
ulcers, palpable adenopathy, lymphopenia, and visceral involvement. Patients
with eczematous and limited plaque lesions alone do best (>80 per cent
survival at five to > ten years). Patients with generalized plaque (>25 per cent
body surface area) may have a median survival of approximately five years. The
median survival declines to 1.5 to 3 years for patients with erythrodermatous
lesions, ulcers, tumorous lesions, or lymphadenopathy. 255, 256, 2m 267 Patients
-
with nonmalignant lymphadenopathy fare better than those with malignant

involvement (median survival 34 months versus 18 months). 2 " Patients with
visceral involvement may have a median survival of roughly seven months. 2,,i
Survival beyond three years would be unusual in patients with visceral or
malignant nodal involvement.
However, by itself, the presence of circulating Sezar}Hbells does not appear
261
to be a poor prognostic factor; Schein et a/. noted a median survival of five
years in 12 patients with Sezary syndrome.
The effective treatment of minor cutaneous involvement can be achieved
topically. Mechlorethamine, administered in a 10 to 50 mg/dL solution of tap
water and applied two to three times per week may frequently cause remission
of skin plaques and erythroderma; tumors are less responsive. 255, 256 268 Topical
'
mechlorethamine may act by cytotoxicity or hypersensitivity, or both. Topical

steroids, topical nitrosoureas, and DNCB sensitization have also had some
success for plaque and erythroderma, 256 as has ultraviolet phototherapy after
sensitization with methoxsalen. 269 Such modalities may effectively palliate
skin disease but have not been shown to prolong survival. 255 256'
Electron beam radiation therapy is very effective against cutaneous disease.

When given in high doses, it may result in a significant complete response rate
(high of 86 per cent in limited plaque disease, low of 44 per cent in tumorous
disease) with good ten-year survival for limited plaque disease (76 per cent,
>40 per cent disease free) and generalized plaque disease (44 per cent, >20 per
cent disease free). Patients with tumorous disease had only a 6 per cent ten-year
survival rate. 267
Levi and Wiernik 256 have reviewed the role of single-agent chemotherapy in
advanced disease. Response rates are in the 50 to 75 per cent range for
alkylating agents, methotrexate, bleomycin, doxorubicin, and vinblas-
tine. 256 270 Responses generally last only a few months if not "maintained."
'
Patients who respond have longer survival than nonresponders, 270 but the
overall impact of single-agent chemotherapy on disease is not well defined.
The efficacy of combination chemotherapy has been inadequately studied.
Innovative approaches to the treatment of refractory mycosis fungoides have
included leukapheresis 271 and antithymocyte globulin. 272-274 These ap-
proaches bear further investigation but appear to be of modest value in
selected patients.
Lymphomatous Involvement of the

Nervous System
Primary lymphomas of the brain are rare. 81 They have generally been treated
with surgery and radiation therapy, but the five-year survival rate with that
approach has been <5 per cent. 81 The predominant cell type is lymphocytic,
but "histiocytic" and "lymphoplasmacytic" variants are not uncommon. Since
many patients with "primary" lymphomas had multifocal lesions or sub-
sequently showed lymphoma elsewhere, some cases may have, in fact, been
secondary rather than primary. Other reported cases may not be true lympho-
mas but tumors of brain tissue (i.e., microgliomas). Metastatic brain parenchy-
mal lesions are likely to be diffuse histiocytic lymphomas. Lymphomas of the
spinal cord are very rare but have been reported. 81,275
Non-Hodgkin's lymphoma may present with or be complicated by extradural
lymphoma compressing the spinal cord. This is usually manifested by pain and
lower extremity sensory-motor deficits. Treatment with radiation therapy (and
chemotherapy) may result in good functional recovery and reasonable survival.
Haddad et al. 276 noted a median survival of approximately one year and a
ten-year survival of >15 per cent in patients with extradural non-Hodgkin's
lymphomas. It is not clear in which patients, if any, decompressive laminec-
tomy is appropriate and in which patients radiation therapy alone will provide
adequate local treatment.
Lymphomatous leptomeningitis is not an uncommon complication of non-
Hodgkin's lymphoma; 277-278 incidence may be roughly 10 per cent. Risk factors
would include leukemic conversion of lymphoma, 280 advanced stage, 277, 278
bone marrow involvement, 279 retroperitoneal node involvement, 277 and the
DH, DU, DPDL, Burkitt's, and lymphoblastic histologies. 277-279 NPDL lym-
phoma has also been associated with meningeal disease, 280 but probably in-
frequently. 279
Treatment has generally been cranial or craniospinal radiation, with or
without intrathecal methotrexate or cytosine arabinoside. The response rate
has been roughly 50 per cent. 278, 279 Although some patients have had control of
meningeal lymphoma with such therapy, the overall survival rate has been
poor. High-dose methotrexate and leucovorin rescue has resulted in some
responses as well. 281 The role of CNS "prophylaxis" is not clear. 279
INTEGRATION OF TREATMENT
MODALITIES
Treatment should be defined as a function of a number of variables including
histology, site, and stage. Staging studies of acceptable efficacy, morbidity, and
cost that will influence therapy or that, upon sequential restudy, will be useful
in monitoring therapy should be performed. It is reasonable to study most
patients with history and physical examination, screening chemistries, chest
radiograph, bone scan, liver-spleen scan, bone marrow aspirate-biopsy, and
lymphogram. Lymphography may be deleted in selected patients who other-
wise have apparent Ann Arbor stage III or stage IV disease or who have medical
contraindications to lymphography (e.g., pulmonary insufficiency). Laparosco-
py or laparotomy, although useful procedures for fully defining the extent of
disease (and thus evaluating the efficacy of an investigative protocol for specific
subsets of patients), may not be necessary for defining standard therapy. If one
accepts that there is a significant chance of upstaging clinical stage III disease
and that, regardless, pathologic stage III disease should be considered "dis-
seminated," it is reasonable to treat clinical stage III disease systemically
without submitting patients to the morbidity of a surgical staging procedure.
Clinical stage I or stage II disease, particularly above the diaphragm, is
unlikely to be upstaged. If the histologic type is "unfavorable" (diffuse disease
excluding DWDL lymphoma, as well as NH lymphoma), radiation therapy for

cure followed by adjuvant chemotherapy is a reasonable, although unproven,
option. The chemotherapy would "cover" the patients who would have been
surgically upstaged. It would also be reasonable because of the significant
failure rate of radiation therapy alone in surgical stage I and stage II disease and
because of the documented efficacy and possible "curative" potential of
combination chemotherapy against more advanced disease.
The role of the combined modality approach, however, is not fully defined,
and morbidity (including potentially increased risk of leukemia or other second
malignancy) should be considered. If the histologic type is "favorable" (nodu-
lar disease excluding NH lymphoma, as well as DWDL lymphoma), treatment
with radiation therapy alone is reasonable. The low risk of occult, surgically
detectable disease is tolerable because of the ability to "recapture" disease
with chemotherapy at the time of relapse. Although the surgical upstaging of
clinical stage I or stage II disease would avoid the need for local radiation, that
modality is reasonably well tolerated and might improve therapeutic results by
enhancing local control.
The following scheme, therefore, which based upon clinical staging,
is
seems reasonable. Stage I or stage II disease would be treated with wide field
radiation. If the histologic type is unfavorable (DHL, DU, DM, DPDL, and
NH), radiation would be followed with adjuvant combination chemotherapy
(e.g., six months of CHOP).
Stage III or stage IV disease of favorable histologic type (NVVDL, NPDL,
NM, and DWDL), would be treated with chlorambucil as a single agent.
Patients who are symptomatic or have bulky or threatening disease would be
treated with a combination regimen (e.g., CVP) to induce a more rapid re-
sponse. Spot radiation might be added to areas of bulk disease that are resistant
to chemotherapy. Low-dose fractionated total body irradiation would be an
acceptable alternative for selected patients. Total lymphoid irradiation would
be limited to selected patients with surgical stage III disease and a small tumor
burden.
Stage III or stage IV disease of unfavorable histologic type would be treated
with an aggressive combination chemotherapy regimen (e.g., CHOP) until two
months after a complete remission (restaged in areas of previous involvement)
and for at least six months. Spot radiation therapy would be added to bulky
disease as necessary.
Stage I E or stage II E disease would receive wide field radiation therapy.
Massive disease, disease of unfavorable histologic type, and disease in unfavor-
able sites (testis, intestine, sinus, and so forth) would be treated as well with
six subsequent months of adjuvant chemotherapy (e.g., CVP for disease of
favorable histologic type, CHOP for disease of unfavorable histologic type).
Surgical resection prior to radiation therapy would be considered for resectable
bulky gastrointestinal disease.
Patients failing radiation therapy would be treated with chemotherapy as if
they had stage IV disease (see previous discussion) unless recurrence was
solitary and localized just beyond the border of the radiation field. Those
patients would be treated with radiation therapy. Patients with disease of
favorable histologic type who fail chlorambucil therapy would be managed
25 Xon-Hodgkin's Lymphomas 945
sequentially with CYP, followed at failure by single-agent palliation (e.g.,

doxorubicin —» CCNU
—» bleomycin, and so forth). Patients with disease of
unfavorable histologic type who fail CHOP would be treated with a noncross-
resistant combination chemotherapy regimen (e.g., CCNU, vinblastine, bleo-
mycin). 28 - Patients who have been treated with CHOP
to a stable partial
remission, but who reach a limiting cumulative dosage of doxorubicin, would
be maintained on COPP chemotherapy.
On how to treat Lennert's
the basis of current data, one cannot be certain
lymphoma or angioimmunoblastic lymphadenopathy. A reasonable approach
would be to treat patientswith indolent stage I and stage II Lennert's lympho-
ma in the same manner as patients with disease of favorable histologic type;
patients with advanced disease would be treated in the same manner as
patients with disease of unfavorable histologic type. Patients with angioim-
munoblastic lymphadenopathy would be observed if disease is indolent. For
more aggressive disease, a trial of glucocorticoids would be entertained. If this
failed, the disease would be rebiopsied. Daily chlorambucil or cyclophospha-
mide would be administered for slowly progressing, histologically stable
disease, and CHOP would be administered for rapidly progressing disease or
disease that had evolved into immunoblastic sarcoma.
Stage I or stage II childhood non-Hodgkin's lymphomas (except lymphoblas-
tic or mediastinal) would generally be treated with radiation therapy plus
chemotherapy (e.g., CVP), followed by one to two years of "maintenance"

therapy (e.g., methotrexate, 6-MP, and cyclophosphamide —
as for acute leu-
kemia). Abdominal disease would be resected when possible. CXS prophy-
2
laxis (cranial irradiation, 2400 rad, plus intrathecal methotrexate, 12/mg/m
[< 15 nig] even 3 to 5 days x 5) would be given in addition for stage II disease
or unresectable abdominal disease. Lymphoblastic disease, mediastinal dis-
ease, or stage III or stage IV disease would be treated with the LSA^-Lr *- ** 1
regimen. Burkitt's lymphoma would be treated with cyclophosphamide, vin-

cristine, methotrexate, and prednisone; abdominal Burkitt's lymphoma would
be resected when possible.
Intestinal lymphomas would be resected when feasible; surgery would be
followed by combination chemotherapy (e.g., CHOP). Nonresectable disease
would be treated with chemotherapy alone.
Mycosis fungoides that is limited to the skin would be treated with topical
mechlorethamine when the involved area is small. Extensive cutaneous dis-
ease would be treated with whole body electron beam irradiation. Patients
with lymphadenopathy but no visceral involvement would be treated with
single-agent chemotherapy (e.g., cyclophosphamide), plus topical therapy or
electron beam irradiation as needed. Patients with visceral involvement would
be treated with a combination chemotherapy regimen (e.g., cyclophospha-
mide, vincristine, and methotrexate or bleomycin).
The preceding approach to the staging and treatment of lymphomas is
outlined in part in Tables 2.5-6 and 25-13. It is based upon the data previously
discussed. As clinical data are limited, this approach should be viewed as one of
several that are acceptable; it is not static, but it will evolve as clinical studies
further define optimal therapy.
TABLE 25-13. Recommended Therapy for Patients with

Non-Hodgkin'sLymphoma
Clinical stage I, I f: , II, or II E
Favorable histology (NVVDL, NPDL, NM, DWDL)-wide field radiation.
Unfavorable histology (DPDL, DM, DH, DU, NH) or unfavorable

extranodal site — wide field radiation plus six months of adjuvant chemo-
therapy (e.g., CHOP).
Clinical stage III, IHg, or IV

Favorable histology — most patients would receive single-agent alleviator
therapy chlorambucil). Patients with bulky or aggressive disease
(e.g.,
would be treated with CVP. Spot radiation would be added to chemo-
therapy-resistant bulky disease.
Unfavorable histology— CHOP chemotherapy or similar regimen until a

complete remission, plus two months (^6 months of therapy). Spot
radiation would be added to chemotherapy-resistant bulky disease.

Many questions regarding the optimal use of current therapeutic modalities
remain without definitive answers. Clinical trials over the next several years
may help to further clarify the following:
What is the optimal histologic classification system for the non-Hodgkin's
1.
lymphomas? Which system gives the most prognostic information and is the
best guide toward therapy? What is the reproducibility and cost effectiveness
of that system?
2. Which patients, if any, should be submitted to surgical staging proce-
dures?
Which patients, if any, with limited disease should be treated with
3.
combined modality therapy? What is the optimal regimen of combined modali-
ty treatment?
4. Which undergo a surgical
patients, if any, with extensive disease should
tumor reduction? Which patients, if any, should undergo spot radiation to
involved fields or bulky disease? When should such radiation be given?
5. What are the relative roles of total body irradiation, single-agent chemo-
therapy, combination chemotherapy, and combined modality therapy for ad-

vanced disease of favorable histologic type? Is there a subset of "curable"
patients that can be defined and that should be treated differently from other
patients?
6. What is the role of maintenance therapy in the lymphomas of favorable
histologic type?
7. What is the optimal therapy for Lennert's lymphoma, for angioimmun-
oblastic lymphadenopathy, and for Mediterranean lymphomas? What is the
role ofchemotherapy in mycosis fungoides?
Data from ongoing and future clinical trials may help to elucidate the
answers to these and other questions; data from more basic research may also
lead to clinical advances. The development of new drugs may expand the
therapeutic armamentarium, as may utilization of newer forms of radiation
25 Nox-Hodgkix's Lymphomas 947
therapy (neutrons, protons, pi-mesons, and so forth). Progress in immunothera-

py to define 1\ mphoma-specific antigens and develop techniques to enhance
immunologic cytotoxicity to cells bearing those antigens may be of value.
In addition to the therapeutic advances, progress may be made in prevention
(e.g., vaccines against EB virus in areas endemic to Burkitt's lymphoma or
vaccines resulting from the identification of a putative virus involved in the
etiology of other lymphomas) or diagnosis (e.g., the development of sensitive
techniques to pick up monoclonal proteins or other lymphoma markers).
Progress may also come, on a more basic level, from enhanced cooperation
between medical oncologist, radiation therapist, and surgical oncologist in the
management of these disorders, emphasizing the multidisciplinary approach
in the management of non-Hodgkin's lymphomas.
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CHAPTER 26
THE HISTIOCYTIC
MALIGNANCIES
Martin J Cline
INTRODUCTION
The group of related neoplastic disorders
histiocytic malignancies are a
arising from cells of the mononuclear phagocyte system. These cells are
known as histiocytes or macrophages. The earliest members of the mononu-
clear phagocyte system in humans are the monoblasts and promonocytes of
the bone marrow. After maturating to the level of monocytes, the cells exit
the bone marrow via the blood and enter the tissues, in which they become
macrophages (the mature end cells of the system). These cells are normally
major components of the reticuloendothelial system and are widely distrib-
uted in the body. Included are alveolar and peritoneal macrophages,
Kupffer's cells in the liver, and macrophages lining the sinusoids of the
spleen and the stroma of lymph nodes.
NATURAL HISTORY
Classification
The malignant histiocytoses are aggressive disorders that, when untreat-

ed, are usually fatal within one to two years. They have been observed to
arise spontaneously in both mice and humans and have been induced in
mice by oncogenic viruses. In humans, these malignancies are heterogene-
ous, with variable expression of mononuclear phagocyte differentiation. For
example, some diseases show a predominance of poorly differentiated mon-
oblasts and promonocytes, whereas others manifest mainly well-
differentiated macrophages. Still others are intermediate in the differentia-
tion between these extremes. Table 26-1 lists the principal histiocytic ma-
1
lignancies and their corresponding cell types.

952
26 / The Histiocytic Malignancies 953
TABLE 26-1. The Histiocytic Malignancies
Malignancy Principal Cells
Acute monocytic leukemia Monoblasts, promonocytes
Chronic monocytic leukemia Promonocyte -* mature macrophage
Histiocytic medullar) Promonocyte —» immature macrophage

reticulosis (HMR)
Letterer-Siwe disease (LSD) Monoblast -* immature macrophage
Hand-Schiiller-Christian Immature -» mature macrophage

disease (HSC)
Eosinophilic granuloma Immature -* mature macrophage

of bone (EGB
The histiocytic malignancies exclusive of the leukemic variants are often

These all-inclusive terms are not very
called histiocytosis or histiocytosis X.
useful, since they encompass some highly malignant diseases as well as
relatively benign disorders that are rarely fatal and may even show sponta-
neous resolution. Histiocytic medullary reticulosis (HMR), Letterer-Siwe
disease (LSD), and the variants of these constitute the bulk of the aggres-
sive histiocytic malignancies and will form the basis of subsequent discus-
sion. HMR is primarily a disease of adults, and LSD is primarily one of
children. Logic would suggest including the relatively rare histiocytic lym-
phoma with the histiocytic malignancies, since it arises from the mononu-
clear phagocyte system; however, by convention this disorder is usually
classified with the lymphomas and will be so considered in this text.
Acute monocytic leukemia closely resembles acute myelocytic or myelo-
monocytic leukemia. Similarly, chronic monocytic leukemia is a myelopro-
liferative disorder sharing many features with chronic myelocytic leukemia.
These rare diseases will not be discussed further here, but the general
principles of their management can be found in Chapters 21 and 22.
The clinical manifestations of malignancies of the mononuclear phago-

cyte system are those one would anticipate from actively proliferating, semi-
differentiated cells that are phagocytic and that elaborate a variety of bio-
logically active products. 2 The diagnosis of a histiocytic malignancy is
usually established by finding the characteristic cells in material obtained
from skin, bone marrow, spleen, or lymph node.
Table 26-2 lists the commonly encountered manifestations of these dis-
orders. Debilitating fever and weight loss accompanied by prominent ab-
dominal organomegaly are usual manifestations of these diseases in both
childhood and adult life. Skin rashes resembling eczema or widespread se-
borrheic dermatitis are frequent in LSD. Osteolytic lesions are also com-
mon in LSD, whereas these manifestations are unusual, but not rare, in the
TABLE 26-2. Manifestations of the Malignant Histiocytoses
Manifestation LSD (Childhood) HMR (Adult)

Anemia Often severe Often severe
Leukopenia Variable Variable
Circulating abnormal cells Frequent Rare
Marrow involvement Extensive Spotty
Erythrophagocytosis Not prominent Prominent
Hepatosplenomegaly Frequent Frequent
Marked lymphadenopathy Frequent Rare
Debilitating fever Frequent Frequent
Weight loss Frequent Frequent
Skin involvement Usual Variable
Bone erosion Frequent Variable
Lung involvement Frequent Variable
Lysozymuria Unknown Frequent
Immunodeficiency Occasional Unknown
adult disease. Conversely, phagocytosis of mature blood elements, particu-

larly erythrophagocytosis, is the hallmark of HMR and establishes what
may otherwise be a difficult diagnosis. Phagocytosis by malignant histio-
cytes may produce a profound anemia, leukopenia, or thrombocytopenia.
In all the malignant histiocytoses, defects of phagocytic leukocyte func-
tion may be encountered and may result in enhanced susceptibility to
also
opportunistic pathogens. These manifestations require the frequent use of
supportive red blood cell transfusions as well as appropriate antibiotics in
addition to specific antineoplastic therapy.
TREATMENT
The normal mature macrophage is nonproliferating and relatively insensi-
tive to ionizing irradiation and most of the commonly employed chemother-

apeutic agents. Therefore, in patients treated aggressively for other tumors,
for example, the sole surviving cells in the marrow may be mature ma-
crophages and plasma cells. Conversely, the proliferating normal mononu-
clear phagocyte precursors in the bone marrow are quite sensitive to ir-
radiation and antiproliferative drugs. We assume that the same situation
pertains to the histiocytic malignancies, with the early proliferating precur-
sor cells being most sensitive to attack. No hard data support this assump-
tion.
Because histiocytic malignancies are rare, reports of response to single
therapeutic modalities are mainly anecdotal, and no well-developed scien-
tific literature has been written on this subject. Table 26-3 summarizes our
review of useful and nonuseful agents in a semiquantitative fashion, con-

strained by lack of abundant and secure information.
Surgery
Surgery may be useful in localized eosinophilic granuloma of bone and

occasionally in Hand-Schuller-Christian disease. It has little place in the
management of the disseminated histiocytic malignancies, except in the
rare case in which hypersplenism is a prominent feature of the disease.
TABLE 26-3. Single Agents and Combinations Used in the

Treatment of Histiocytic Malignancy
Approximate
Remission Rate
Agent or Agents Effectiveness (CR + PR) Reference
Irradiation Useful for localized 3,4

collections of malignant
cells experimental in
;
disseminated disease.
Alkylating Agents Sometimes effective ; often 50% 4-6

transient benefit.
Vinblastine Often effective, particularly 50% to 60% 4,5

in early childhood disease.
Vincristine Often effective in childhood 50% 4,5,7

disease.
Corticosteroids Suppresses fever occasional; ? 8

antitumor effect value not ;
established in adult disease.
Vincristine + prednisone Often effective in childhood 60% 8

disease.
Methotrexate + prednisone Often effective in childhood 50% 8

disease.
Doxorubicin, vincristine, Sometimes effective in adult 5 of 7 6

prednisone, cyclophosphamide disease.
Vinblastine + prednisone Often effective in younger 50% to 60% 7

children.
6-MP + prednisone May be effective in younger

children.
Irradiation
Irradiation has generally been reserved for attacking localized collections

of malignant cells. 4 In this setting it may be very effective, although quite
high doses are sometimes necessary before benefit is observed. There is
one interesting report of the use of sequential hemibody irradiation in a
four-month-old infant with histiocytosis, with elimination of apparent dis-
ease in the irradiated field. 3 The infant died, however, and this approach
must still be placed in the "interesting but experimental" category.
Chemotherapy
The primary attack on the histiocytic malignancies is with chemothera-

peutic agents. Because childhood and adult diseases respond so differently
to drugs, it is useful to consider each of these categories separately.
Childhood Histiocytoses. The treatment of childhood histiocytosis
with its rare occurrence and its varied clinical manifestations has not been
adequately investigated in prospective randomized clinical trials. Lahey 7
has reported the treatment of 35 children less than the age of two years
with vinblastine alone, vinblastine plus prednisone, or 6-mercaptopurine
plus prednisone. The three regimens were reported to be equally effective
in younger children, with about one half to two thirds responding. Howev-
er, only 1 of 11 older children responded. The therapeutic strategy for
these programs was based on Lahey's earlier report 9 on the effectiveness of
vinblastine.
Starlingand colleagues 3 described a nonrandom trial in which children
with histiocytic malignancy were treated with either vincristine, vinblastine,
or cyclophosphamide. The response rate of 50 to 60 per cent was the same in
8
all categories. Jones, reporting for Acute Leukemia Group B, described the
treatment of 28 children between the ages of 2 months and 13 years. They

were allotted randomly either to vincristine, 2 mg/m 2 /week, plus prednisone,
or to methotrexate, 30 mg/m 2 twice weekly, plus prednisone. Both groups re-
ceived prednisone, 40 mg/m 2 /day. Responders were randomly allocated to
receive either methotrexate, 30 mg/m 2 twice weekly until disease recurred, or
to receive no maintenance therapy. The complete and partial remission rate
was 50 to 60 per cent for both induction regimens; however, the duration of
the methotrexate-induced remissions was clearly superior, with some patients
free of disease in excess of four years.
The analysis of response by age of less than or greater than two years did
not reveal this to be a prognostic factor in therapeutic response. The extent
of disease was, however, an important prognostic factor, with patients hav-
ing involvement of four or more organ systems doing poorly. 8, Based on
these limited observations, we would recommend that children with less
advanced disease (three or fewer organ systems involved) should be treated
with a combination of methotrexate and prednisone in an attempt to induce
a remission. If achieved, remission should be maintained with methotrexate
for a prolonged period after the disease is clinically undetectable. For chil-
dren failing to achieve remission or having more advanced disease, addi-
tional aggressive therapy including other agents should be considered. Al-

though no firm guidelines exist, the useful agents include vinblastine,
vincristine, and cyclophosphamide.
Adult Histiocytoses. Drug therapy of malignant histiocytosis of the
adult has been described in many reports of a single patient or small
groups of patients. 4 10 In general, alkylating agents, vincristine, and predni-
'
sone have been of minimal benefit, although high-dose prednisone admin-

istration has produced transient responses. Not surprisingly, combinations
of drugs that are effective in non-Hodgkin's lymphoma have been applied
to the histiocytic malignancies, and occasional successes have been report-
ed using vincristine and prednisone or COPP. 10, "
The most extensive report is that of Alexander and Daniels, 4 who re-
viewed the experience with 16 patients seen at Stanford Hospital between
1965 and 1975. The most promising responses were seen in seven patients
treated with cyclophosphamide, doxorubicin, vincristine, and prednisone,
given in weekly courses approximately every three weeks (Table 26—4).
Five of these seven patients showed a response that in some cases persist-
ed for longer than 17 months. The authors caution that the frequent hepatic
involvement with malignant histiocytosis may militate against the use of
full doses of doxorubicin.
In this same study, two of five patients treated with CVP also showed a
beneficial response. Interestingly, patients in both the CVP and CHOP
groups showed a relapse in the central nervous system, although such in-
volvement is unmodified by therapy. In patients un-
rare in disease that is
dergoing treatment, cerebrospinal fluid cytologic studies should be ob-

tained. In this study, it was clear that patients who responded to
combination chemotherapy survived longer than those with unresponsive
disease. Alexander and Daniels 4 also observed two patients with malignant
histiocytosis who failed to respond to CHOP and subsequently responded
to high-dose methotrexate administration with leucovorin rescue.
Based on our review of the available literature, we would recommend
the following program for the management of malignant histiocytosis in the
adult: (1) CHOP therapy combined with irradiation for symptomatic local
lesions; (2) frequent follow-up of cerebrospinal fluid cytologic studies with
a consideration of CNS prophylactic therapy in patients with prolonged re-
mission; (3) consideration of other effective agents in patients resistant to or
TABLE 26-4. CHOP Therapy of Adult Histiocytic Disease'
Agent Dose
Cyclophosphamide 750 mg/m 2 IV day 1
Vincristine 2 mg IV day 1
Prednisone 50 to 100 mg/m 2 PO days 1 to 5
'Repeated every 3 weeks.

relapsing from CHOP, e.g., vinblastine and high-dose methotrexate admin-

istration with leucovorin rescue.

It is clear that we have
go in improving the treatment of the malig-
far to
nant histiocytic disease of both childhood and adult life. Progress has been
hampered by the variability of the diseases and their rarity. Lack of ade-
quate patients at any one medical center has hindered the development of
adequate controlled clinical trials. Nevertheless, progress has been made in
identifying classes of agents and combinations of agents that may be effec-
tive. This progress does allow us to define broad guidelines for the man-
agement of these perplexing diseases.
"1. Cline MJ and Golde DW: A review and 6. Kalderon AE: Cancer 27:659, 1971.
reevaluation of
the histiocytic dis- 7. Lahey ME: Tenth International Cancer
orders. Am J Med 55:49, 1973. Congress (Abstr), Houston, Texas, p.
2. Cline MJ, et al: Ann Intern Med 88:78, 764, 1970.
1978. 8. Jones B, et al: Cancer 34:1011, 1974.
3. Griffin TW: Cancer 39:2435, 1977. 9. Lahey ME: J Pediatr 60:664, 1962.
4. Alexander M and Daniels |R: Chemo- 10. Stein RS, et al: Cancer 38:1083, 1976.
therapy of malignant histiocytosis in 11. Kingdon HS, et al.: Ann Intern Med
adults. Cancer 39:1011, 1977. 72:705, 1970.
5. Starling KA, et al.: Am J Dis Child
123:105, 1972.
Part III
MANAGEMENT
OF SELECTED
COMPLICATIONS
OF CANCER
AND CANCER
TREATMENT
CHAPTER 27
BONE MARROW
FAILURE:
MANAGEMENT
OF ANEMIA,
INFECTIONS,
AND BLEEDING IN
THE CANCER PATIENT
Peter R Graze
INTRODUCTION
Cancer is most often a systemic disease. Multiple organs may be affected
by metastases, and organ failure may develop secondary to direct tumor
replacement, compression or obstruction, or vascular compromise. These
effects may occur in bone marrow, which is the organ of hematopoiesis.
Oncologists today tend to be activists. Their approach to treatment fre-
quently depends on the assumption that the frequency of cure or palliation
justifies the cost of iatrogenic bone marrow failure. As long as the most
effective antineoplastic agents have nonspecific cytotoxicity, damage to pro-
liferating normal tissues will be an important limiting factor. Improved re-
sults in cancer therapy may thus relate to better supportive care for the
patient with bone marrow failure.
In this chapter, the causes and effects of this failure are described, and
preventive measures and supportive management for cancer patients who
are susceptible to this condition are considered.
961
962 III / Management of Selected Complications
ETIOLOGY
The metastatic process may cause bone marrow failure when normal
bone marrow is directly replaced by tumor. A leukoerythroblastic picture
may appear in the peripheral blood in which immature myeloid and
erythroid cells are found. Nucleated red blood cells are characteristic in
this setting,representing an early release phenomenon from bone marrow
induced by the myelophthisic process. The diagnosis of marrow replace-
ment by tumor is established by bone marrow aspiration and biopsy. Pros-
tate and breast carcinomas are examples of solid tumors that are most likely
to cause extensive bone marrow replacement by metastatic disease.
Chronic anemia in cancer patients is more severe when mestastases are
widespread, but it may occur in the absence of bone marrow invasion as
well as in patients with localized disease. For example, occult blood loss
1
from a bleeding gastric or cecal carcinoma may produce an iron deficiency

anemia. Surgery with curative intent may produce iron or B 12 deficiencies
by eliminating the gastric acid or the intrinsic factor secretion that is re-
quired for iron or B 12 absorption in the small intestine. Megaloblastic ane-
2,3
mia is, in fact, a frequent occurrence in cancer patients. This is a diagno-
sis based on morphologic changes in hematopoietic cells, including
neutrophil nuclear hypersegmentation, delayed nuclear maturation, and
nuclear-cytoplasmic maturation disassociation in precursor cells. Causes of
megaloblastic anemia in cancer patients include B 12 deficiency following
gastrectomy, relative folate deficiency secondary to competitive utilization
by tumor cells, 3 and antifolate drug therapy. 4 In severe megaloblastic ane-
mia leukocyte production may also be affected, with resulting leukopenia.
A chronic, hyporegenerative anemia may also accompany malignant dis-
5
ease without nutritional effects or bone marrow replacement. This condi-
tion is characterized by a decreased erythrocyte life span, an impaired bone
marrow response, and an impaired flow of iron from reticuloendothelial
stores to plasma. Cancer patients have an accelerated clearance of iron as
well as of folic acid. 6 The reticuloendothelial uptake of iron is significantly
more rapid in these patients than in normal individuals, even in the ab-
sence of anemia. 7 Thus, the chronic anemia associated with cancer is char-
acterized by decreased iron in the plasma, decreased total plasma iron
binding capacity, decreased transferrin saturation, and normal or increased
iron in the reticuloendothelial tissues, with decreased bone marrow sidero-
blasts. 1
Although this anemia may respond to erythropoietin, the fundamen-
tal defect appears to be in iron transfer from reticuloendothelial cells. 8
Chemotherapy is also a frequent cause of bone marrow depression in
cancer patients. Nonspecific cytotoxic effects of such therapy affect the pro-
duction of myeloid, lymphoid, and erythroid cells and platelets. Anemia is
rarely a consequence of chemotherapy unless accompanied by leukopenia
or thrombocytopenia. Nevertheless, since the turnover of leukocytes and
platelets is much more rapid than that of red blood cells, a treated cancer
patient may have recovered from transient leukopenia and thrombocytopen-
ia induced by prior chemotherapy, even though anemia persists. The bone
marrow toxicity of chemotherapeutic agents has been previously reviewed
(Chapter 4).
27 Bone Marrow Failure 963
should be noted that radiation therapy can also cause depression of all
It
bone marrow elements by damaging stem cells in addition to the rapidly

dividing hematopoietic cell pool. Radiation-induced bone marrow injury
may therefore be prolonged or even permanent, and the clinical significance
depends on the amount of bone marrow within the radiation-treated
field. 8
CONSEQUENCES OF BONE
MARROW FAILURE
The bone marrow replaces per cent of circulating erythrocytes, 10 per
1
cent of platelets, and three to four times the number of circulating blood
granulocytes daily. In addition, the bone marrow produces a large proportion
of the circulating lymphocytes. Bone marrow failure, therefore, manifests
itself clinically as anemia, thrombocytopenia, or leukopenia, or all of these.
Even when peripheral blood counts appear normal or near normal, a limited
reserve function may compromise the hosts ability to adequately meet a
stressful challenge.
Common complaints associated with anemia include fatigability, lassi-
tude, and weakness. Dyspnea and secondary tachycardia, sensed as palpita-
tions, may also occur in severe cases. Most adults, however, can tolerate
chronic anemia with a hematocrit as low as 25 per cent and experience
minimal symptoms. Shortened red blood cell survival, as with blood loss or
hemolysis, may exacerbate an anemia that develops because of inadequate
red blood cell production. Although the anemia of chronic disease that is
manifested in cancer patients is rarely severe enough to justify transfusion
therapy, the diminished erythropoietic reserve may be an important factor
in marrow tolerance of cytotoxic agents. 9
Platelets are crucial for hemostasis. Thrombocytopenia, therefore, is man-
ifested by spontaneous or prolonged bleeding. Petechiae may develop,
especially on dependent extremities (such as the legs) or on mucous mem-
branes (palatal petechiae may be an important early sign of significant
thrombocytopenia). Nevertheless, hemostasis that is adequate for everyday
experiences and is even sufficient for relatively safe surgical procedures
may be maintained with platelet counts that are considerably less than nor-
mal. Gaydos et a/. 10 demonstrated a clear relationship between the degree
of thrombocytopenia and the risk of bleeding for all platelet counts below
100,000/mm 3 Although a distinct threshold was not found, hemostasis was
.
not significantly impaired, provided that the platelet count remained above
this level. The likelihood of gross or severe bleeding, however, increased
dramatically with platelet counts below 20,000/mm 3 10 At that level, the risk
.
of spontaneous intracranial hemorrhage became significant.

The hemostatic efficiency of platelets appears to be age related. Thus, a
population of larger, younger platelets may provide better hemostasis at a
lower platelet count than a similar number of older platelets. 11 The etiology
of thrombocytopenia is therefore an important factor in determining the
bleeding risk. In bone marrow failure states, in which platelet production is
depressed, a lower proportion of circulating platelets will be young; the

risk of spontaneous or severe hemorrhage will therefore be greater for a
given platelet count in patients with prolonged marrow failure than in pa-
tients with recovering thrombopoiesis. 12
Technologic improvements have enabled sophisticated hospital blood
banks to provide platelet as well as red blood cell transfusions on a nearly
routine basis. Complications of anemia and thrombocytopenia, therefore,
can now be managed or prevented with some reliability.
Infection secondary to leukopenia has emerged as the major, and most
challenging, complication of bone marrow failure. It is the single most im-
portant cause of early mortality in bone marrow transplant recipients, re-
flecting the importance of infectious diseases in patients with reduced or
absent bone marrow function. 13
Patients with cancer develop infection more frequently than other pa-
tients for many reasons. Altered barrier defenses (skin and mucosal inte-
grity), obstruction to hollow viscera, tissue breakdown (necrosis), and de-
pressed immune function are all contributing factors. Granulocytopenia,
however, is the single most important factor predisposing cancer patients to
infection. 14,13 A clear-cut relationship between the level of circulating neu-
trophils and the incidence, as well as the severity, of infection was estab-
lished by the classic work of Bodey et a/. 16 Septicemia is much more likely
to occur in granulocytopenic patients than in those with greater than 1000
neutrophils/mm 3 14 More than 75 per cent of septicemias occurring in can-
.
cer patients are associated with a neutrophil count of less than 500/mm 3 ,
whereas there is a major increase in the risk of septicemia with a neu-

trophil count of less than 100/mm 3 A similar relationship between lympho-
.
penia and infection was demonstrated, with the risk of infection increasing
3 16
for lymphocyte counts of less than 1000/mm .
In nearly all series of neutropenic patients with malignant disease the

lung is the most frequent site of infection. 17 20 In the absence of urinary
"
catheters or invasive urologic procedures, urinary tract infections in leu-

kemic patients are generally limited to those with obstructive lesions or a
past history of urinary tract infection. 17 Nevertheless, the urinary tract is the
second most common site of infection leading to sepsis in patients with
solid tumors 19 and is a frequent site of infection in lymphoma patients as
20
well. Other frequent sites of infection occurring in cancer patients include
wounds of the skin, the perianaland rectal area, and the pharynx. Pulmona-
ry and intra-abdominal infections have been associated with a particularly
high mortality rate. 17 19
'
Although fungal and viral infections are becoming more prominent in

cancer patients who are treated with cytotoxic drugs, the most common in-
fections in these patients are bacterial. 15,21 Many surveys have demonstrat-
ed that gram-negative bacilli are the most important causes of serious bac-
terial infections in cancer patients; this is especially true in patients who
are also granulocytopenic. 13 15,21,22 The most common gram-negative bacte-
"
rial pathogens in bone marrow transplant recipients are Pseudomonas aeru-

13
ginosa, Klebsiella pneumoniae, and Escherichia coli. These are also the
three most common bacterial pathogens in granulocytopenic cancer pa-
tients. 22 It is widely believed that many gram-negative bacillary infections
27 / Bone Marrow Failure 965
occurring in the compromised host are caused by endogenous, "opportunis-

tic" organisms, but colonization and subsequent infection by hospital-
acquired organisms may also be important. 15 Hospital-acquired organisms,
rather than endogenous flora, apparently cause most infections in granulo-
cytopenic patients with leukemia. 23
Pseudomonas species may be frequent causes of infection because of
their dissemination and persistence in the hospital environment. These or-
ganisms are particularly adapted for survival in moist environments, such as
nebulizing equipment, drains, faucets, and sinks. Klebsiella infections are
becoming more common in hospitalized cancer patients, in part because of
the growing number of antibiotic-resistant strains. 14 Serratia marcescens
may be a prominent pathogen in some hospitals; not only is this organism
frequently resistant to commonly used antibiotics, but it also has the capac-
24
ity- for contaminating nebulizers and solutions. The most frequently recov-
ered pathogenic organisms from cancer patients with septicemia are pre-
sented in Table 27-1. Curiously, anaerobic bacteria appear to be distinctly
"'
uncommon as significant pathogens in granulocytopenic patients. 2

Although gram-negative bacilli remain the most frequent cause of septi-
cemia in granulocytopenic cancer patients, the incidence of fungal septi-
cemia is increasing. Nearly one third of all granulocytopenic cancer pa-
tients with fever have fungal infection, whereas one half of
granulocytopenic patients who die with bacteremia also have fungal infec-
26
tion. It is not yet clear whether most fungal or protozoan infections in
granulocytopenic patients are endogenous or exogenous. Recent series indi-
cate that fungal sepsis may be a more frequent cause of death than gram-
negative bacillary sepsis. 13,27 Established fungal infections may be particu-
larly difficult to treat. Fungal infections in cancer patients fall into two cate-
gories: (1) those fungi that are rarely pathogenic except in the compromised
host, and (2) those fungi that may infect the general population but are
more likely to cause disseminated disease in cancer patients. 14 Candida,
Aspergillus, Phycomycetes, and Torulopsis compose most of the first group.
Cryptococcus neoformans, Histoplasma capsulatum, and Coccidioides im-
mitis are important examples of the second group.
Candidiasis is the most frequent fungal infection in cancer patients, espe-
cially in those with hematologic malignancy. 14, 15,26, 28 Disseminated candi-
TABLE 27-1. Recovery of Pathogenic Organisms Associated

with Positive Blood Culture Results
Patients with Patients with

Organism Hematologic Malignancy Solid Tumor
Escherichia coli 24% 24%

Pseudomonas aeruginosa 15% 4%
Klebsiella 11% 10%
Staphylococcus aureus 9% 11%
Candida 5% 9%
Bacteroides 11%
Polymicrobic sepsis 17% 10%
'Adapted from Singer C, et al. Am J Med 62:731-742, 1977.

diasis has been found

postmortem examination in 2 per cent of patients
at
with solid tumors or lymphoma and in 20 per cent of patients with acute
leukemia. 14 The association between granulocytopenia and disseminated or
invasive infection is particularly close for Aspergillus infections in cancer
29
patients. Neutropenia is present in more than 75 per cent of patients with
disseminated aspergillosis. 30 Phycomycosis and Torulopsis infections also
tend to occur in neutropenic patients. 14,31 Cryptococcal infections are par-
ticularly associated with steroid therapy; nevertheless, one good review of
cryptococcal infection in cancer patients found that leukopenia and lym-
phopenia were present in each case in which infection occurred. 32
Some infections that are common in patients with depressed cell-
mediated immunity are uncommon in immunologically competent patients
with granulocytopenia. Viral infections are prominent in this category. Her-
pesviruses are the most common viral pathogens in cancer patients. The
ability to control or contain herpesvirus infections is related to specific im-
mune responsiveness rather than to leukocyte numbers. 33 In most cases, the
manifestations of herpesvirus infections in adult cancer patients represent a
reactivation of latent virus infection. 34 Varicella zoster virus infections are
particularly prominent in patients with lymphoma. Although herpes zoster
isgenerally thought to represent the activation of the endogenous virus, it
may also be an exogenously acquired infection in cancer patients. 35 Che-
motherapy-induced granulocytopenia does not appear to cause the progres-
sion of localized zoster to disseminated infection, although drug-induced
immunosuppression may be important. Reactivation of latent cytomegalo-
virus (CMV) infection does seem to follow cytotoxic drug therapy. 36 Al-
though cytomegalovirus infection has been found in nearly 50 per cent of
interstitial pneumonia cases developing in bone marrow transplant recipi-
ents, granulocytopenia alone does not appear to be an important factor in
this disorder. 13 In general, patients with bone marrow failure do not have
an increased incidence of viral disease but do have an impaired ability to
contain the virus once infection or reactivation has occurred. This, in turn,
is probably related to specific immune functions rather than to leukopenia.
In addition to viruses, other pathogens may occur with increased fre-

quency in cancer patients who are immunosuppressed, without correlation
to bone marrow failure or leukopenia. Histoplasmosis and coccidioidomyco-
sis are seen in cancer patients, predominantly as a reactivation of latent
14
infection following steroid or cytotoxic drug therapy. Tuberculosis appears
to occur more frequently in immunosuppressed patients, with no associa-
tion to leukopenia. 37 Similarly, toxoplasmosis infections are more common
in cancer patients receiving chemotherapy, without correlation to leukopen-
ia or overt marrow failure. 38Although immunosuppression and bone mar-
row depression may therefore represent separate phenomena in cancer pa-
tients, it should be recognized that immunosuppressive agents are largely
cytotoxic as well, leading to concurrent granulocytopenia.
Iatrogenic factors are also important in determining the incidence and
etiology of infections in patients with bone marrow failure. The additional
roles played by broad-spectrum antibiotics (leading to superinfection with
resistant organisms), multiple blood transfusions, and surgical manipula-
tions are difficult to distinguish from host factors in this patient population.
Nevertheless, to provide optimum support for granulocytopenic patients, an

aggressive approach to diagnosis and therapy is indicated. Such therapeutic
intervention would logically include measures that decrease exposure to
infectious agents, provide more effective antimicrobial therapy, augment re-
sidual host defenses, or reconstitute host reserves. These will be discussed
in more detail further on.
TREATMENT: PROTECTION
Several important principles in the management of neutropenic patients
warrant special emphasis. Measures of infection prophylaxis include reduc-
ing pathogen acquisition from exogenous sources, avoiding nonessential in-
vasive procedures, reducing endogenous colonization by potential patho-
gens, and improving host defenses. There must be careful monitoring for
the earliest signs of infection, prompt initiation of antimicrobial therapy,
and use of combinations of antimicrobial agents that act synergistically
against likely pathogens.
Antibacterial vaccines, which have long been a theoretic concept, have
recently been shown to be of practical value. Pneumococcal immunization
can provide protection if the patient can mount an antibody response to the
antigenic challenge. 39 Pseudomonas vaccination may also offer some protec-

tion against fatal infection in patients with relatively normal granulocyte
levels. Patients with severe granulocytopenia, however, probably would not
15
profit from this even if antibody titers could be maintained. Since the
cytotoxic therapy that is the common etiology of bone marrow failure in
cancer patients also impairs immune responsiveness, it may be difficult to
successfully vaccinate patients receiving chemotherapy. Certainly, by the
time a patient has been hospitalized with bone marrow failure, it is too late
to consider vaccination.
Ongoing surveillance cultures of nasopharynx, axilla, gingiva, urine,
and stool or rectum can provide information that may be invaluable in
anticipating developing infections or probable pathogens in granulocyto-
penic patients with fever. These cultures are obtained periodically (a week-
ly schedule may be convenient and useful), and are not intended to sup-
plant cultures that are required for evaluating a patient with suspected
active infection. The surveillance cultures provide a means for detecting
the colonization of potential pathogens in the patient, whereas the retro-
spective analysis of culture and sensitivity results can provide guidance in
selecting otherwise empiric antimicrobial therapy. Frequently, developing
systemic fungal infection may be inferred from the findings of several si-
multaneous surveillance cultures that are positive for a fungal pathogen.
For example, positive results from stool and urine cultures for Candida pro-
vide strong presumptive evidence of candidiasis in a patient who remains
febrile despite broad-spectrum antibacterial therapy. 13
Some pathogens develop rapidly invasive infection without detection by
routine culture techniques. Pneumonias that are caused by fungal or pro-
tozoan pathogens are particulary difficult to diagnose without a tissue exam-
ination. An unexplained pulmonary infiltrate in a granulocytopenic patient
should prompt an aggressive diagnostic evaluation. Thus, the following se-

quence is frequently indicated: transtracheal aspiration, followed by bron-
choscopy with brush biopsy, and then open lung biopsy if a diagnosis has
not been established. 14
In addition to a diagnostic review, measures that may reduce the mi-
crobial exposure of the granulocytopenic patient can be helpful. Daily
baths can reduce skin Hexachlorophene-containing soaps kill staphy-
flora.
lococci and may have played a role in the overall reduced incidence of
staphylococcal infections in hospitalized patients. Gram-negative bacteria
and fungi are not killed by hexachlorophene, however. Since colonization
by hospital-acquired or superinfecting microorganisms can be a problem in
granulocytopenic patients, iodine-containing compounds (povidone-iodine)
may provide more effective protection. 15
Most epidemiologic data suggest that a majority of infections occurring in
the compromised host arise from the native fecal flora or develop after colo-
nization of the gastrointestinal tract by hospital-acquired organisms. Pro-
phylactic oral antimicrobial agents can reduce gastrointestinal flora and the
40,41
incidence of infection in granulocytopenic patients. The infection rate
may be reduced with this therapy, even in patients receiving otherwise
standard ward care. 41 Nevertheless, not every study has found oral antibiot-
ic prophylaxis alone to be effective.
42, 43
Malabsorption and weight loss may
occur more frequently in tumor-bearing patients who are receiving oral an-
tibiotic prophylaxis than in cancer patients who are managed without oral
antibiotics. 44 A substantial suppression of gastrointestinal flora probably can
be achieved in granulocytopenic patients who are treated with oral antibiot-
ics, but this depends heavily on good patient compliance. Difficulties
with patient compliance may explain some of the negative reports; it is also
likely that oral antimicrobial prophylaxis is in fact more useful when com-
bined with other protective maneuvers, such as isolation procedures and

41
granulocyte transfusions.
Oral "gut-sterilizing" antibiotics, gentamicin, vancomycin,
including
colistin, polymyxin B, nystatin, neomycin, and amphotericin B, have been
given to granulocytopenic patients in a variety of combinations. One regimen
used extensively at UCLA in the past is given in Table 27-2. This regimen
is very unpalatable, it causes nausea in some patients, and it is very expensive.
However, it isnot absorbed, so drug-resistant systemic infection rarely occurs.

An alternative to the regimen in Table 27-2 is prophylactic therapy with a
combination of trimethoprim and sulfamethoxazole. 40 The usual daily oral
dose is 320 mg of trimethoprim and 1600 mg of sulfamethoxazole, which can
be given easily as 2 tablets of Bactrim twice daily. Several studies suggest
that this combination may reduce bacterial infections in granulocytopenic
patients, 40, 45 and it has the added advantage of reducing the risk of infection
with Pneumocystis carinii. 13 14 Since Bactrim has antifolate properties, it
'
may inhibit the recovery of bone marrow function in some patients. Never-
theless, it appears to be a simple, effective, relatively nontoxic, and inexpen-
sive alternative to the regimen given in Table 27-2.
With the increasing use of prophylactic antibiotics the problem of fever
with negative culture results is becoming more common in granulocytopenic

patients. A clear majority of febrile episodes in these patients will neverthe-
less be due Since infection in the patient with bone marrow
to infection. 15
failure may be rapidly fatal, early and empiric use of broad-spectrum antibi-
otics is justified in these patients. Early, aggressive use of antimicrobial
combinations including an aminoglycoside has resulted in a marked improve-
ment in survival from gram-negative bacteremia. 46 Gentamicin has been the
standard aminoglycoside antibiotic currently in use, but several others,
including tobramycin and amikacin, may prove to be superior to gentamicin.
Amikacin, for example, has the advantage of being active against most Entero-
bacteriaceae, including Serratia, as well as Pseudomonas. 41 Since it is effec-
tive when given only twice daily it may be more convenient than other
antibiotics as well, with nephrotoxicity no greater than that found with
gentamicin. At present, amikacin is indicated for gentamicin-resistant
strains.
Pseudomonas is the most common pathogen associated with life-
threatening infection in granulocytopenic patients. Since half of cancer pa-

tients with Pseudomonas aeruginosa septicemia will otherwise die within
72 hours of the initial positive blood culture, empiric therapy directed
against this pathogen is indicated when septicemia is suspected. 23 Carbeni-
cillin is particularly useful against Pseudomonas infections occurring in
neutropenic patients, and it appears to be effective even in the absence of
granulocytes. 14, l5 Therefore, it is an important addition to an empiric antibi-
otic regimen. Carbenicillin and aminoglycoside antibiotics offer synergy
against Pseudomonas and Klebsiella. 4 * Although the addition of a cephalo-
sporin to this combination may offer more complete coverage against gram-
positive organisms, nephrotoxicity is significantly increased. 49, 50 Carbenicil-
lin, along with either gentamicin or amikacin, remains the best combination
antibiotic regimen for empiric treatment of febrile granulocytopenic pa-

tients. Ticarcillin, a new carbenicillin-like antibiotic, has been promoted as
having greater anti-Pseudomonas activity than the parent compound. Experi-
ence is still too limited with ticarcillin, however, to adequately judge its
usefulness at present. 4S
Once broad-spectrum have been empirically initiated in a fe-
antibiotics
brile granulocytopenic patient, the determination of the length ofsuch ther-
apy becomes a challenging problem for the clinician. If there is evidence of
response to the antibiotic therapy, it is important to maintain antibacterial
TABLE 27-2. Oral Nonabsorbable Antibiotic Prophylaxis

for Granulocytopenic Patients
Nystatin ,000,000 IU q6 hours (at least
Vancomycin 100 mg q8 hours
Colistin 100 mg q8 hours

therapy for a prolonged period after apparent resolution of a severe infection

if granulocytopenia persists. Recurrent bacteremia in patients with pre-
1 "'
viously documented sepsis followed termination of antibiotic therapy in

less than 2 per cent of patients without persisting granulocytopenia. How-
ever, the termination of antibiotics in patients with previously documented
bacteremia and persisting granulocytopenia was followed by recurrent bac-
teremia in nearly 50 per cent of cases. 27
Infection in granulocytopenic patients is rarely cured unless marrow re-
covery occurs. 51 Prolonged antibiotic therapy for granulocytopenic patients
with documented infection and subsequent response to therapy appears to
be justified. For granulocytopenic febrile patients who show negative culture
results but appear to have benefited from empiric antibiotic therapy, a pro-
longed course of antibiotics may also be justified, since an infectious etiolo-
gy is likely. Nevertheless, superinfection with organisms that are resistant
to the initial antibiotic regimen can be at least as dangerous as the initial
problem, and the risk of superinfection must be weighed against the ben-
efits of continuing a course of empiric broad-spectrum antibiotics. Since
superinfections in neutropenic cancer patients become significant only
when broad-spectrum antibiotics are continued for more than seven days,
there is time for at least a reasonable therapeutic In one series
trial.
ls
of bone marrow transplant recipients with persistent fever, no serious bac-

developed within 48 hours
terial infections after antibiotics were discontin-
ued following empiric therapy. 26 Therefore, it appears to be reasonably safe
to discontinue antibiotic therapy, at least briefly, to obtain a new set of
cultures in persistently febrile neutropenic patients.
Reasonable guidelines derived from the foregoing discussion may be for-
mulated. When a granulocytopenic patient becomes febrile, appropriate
cultures and diagnostic review should be performed. If there is no obvious
noninfectious etiology identified, empiric broad-spectrum antibiotic thera-
py, using an aminoglycoside and carbenicillin, should be initiated. A ce-
phalosporin may be substituted for carbenicillin in penicillin-sensitive pa-
tients, although the modified regimen may be less effective against
Pseudomonas. The antibiotic therapy frequently will control, but not elimi-
nate, infection if granulocytopenia persists. Antibiotic therapy should be
withheld if infection is not suspected to avoid selection of fungi or resistant
bacteria. A brief interruption of antibiotic therapy, even in febrile granulo-
cytopenic patients, may be worthwhile to obtain new cultures as part of a
review of management strategy.
Nearly all life-threatening superinfections reported in recent series were
caused by either Candida or Aspergillus. 19 26,46 A pulmonary infiltrate de-
-
veloping despite broad-spectrum antibacterial therapy or the lack of re-

sponse to it must be suspected to be of fungal etiology. Despite multiple
organ involvement at necropsy, the number of antemortem blood cultures
that are positive for Aspergillus has been negligible in reported series of
disseminated aspergillosis. Lung biopsy may be the only reliable way to
make the diagnosis of invasive aspergillosis. 30 Nevertheless, monitoring the
results of surveillance cultures can be an important way of anticipating this
problem. The presence of fungi either in urine or stool correlated strongly
with the subsequent documentation of disseminated fungal disease in bone

marrow transplant recipients. 1 '
Early, empirical use of amphotericin B in the granulocytopenic patient

who remains broad-spectrum antibiotic therapy and granulo-
febrile despite
cyte transfusions may reduce the incidence of fatal fungal superinfec-
tions.
14,
Fever, chills, phlebitis, headache, nausea, and vomiting are com-
2fi
mon side effects of amphotericin B therapy that can be reduced by a

program of gradually increasing the daily dosage. Treatment may then be
given on alternate days rather than daily to maintain maximum effect, while
making therapy more tolerable for the patient. 15 Amphotericin-induced hy-
pokalemia may be more manageable with such an approach.
Clearly, the management of the infected neutropenic patient is a complex
affair. The patient may be critically ill from the primary disease proc-
ess and may face an ever-increasing risk of serious drug toxicity or the haz-
ards of invasive diagnostic and therapeutic procedures. Therefore, increas-
ingly sophisticated means of providing barrier isolation have recently been
devised.
A "Life Island" germ-free isolator unit was first introduced into cancer
treatment in 1966. >2 It was designed to protect the neutropenic patient from
exogenously acquired pathogens. The initial reports using this unit were
generally favorable, with indications that patients with leukemia who were
treated with cytotoxic therapy in the "Life Island" had fewer infections and
tolerated more intensive chemotherapy than their counterparts who were
"
treated conventionally. 29- 42- These reports were derived from nonrandom-
>!
ized or inadequately controlled trials, however. The independent contribu-

tion of simultaneous gut sterilization programs cannot be dissected from
these reports, although it appeared likely that by combining barrier protec-
tion from exogenous pathogens with therapy to reduce endogenous flora,
the incidence of serious infections could be reduced. 43
Improvements in barrier protection technology led to the development of
the laminar air flow (LAF) room. In this system, an entire room is rendered
relatively germ free, providing greater versatility for patient care proce-
dures. In addition to an ultraclean interior, laminar air flow keeps particles
airborne, swept to a high-efficiency particulate air (HEPA) filtration system
with appropriate cooling, heating, and humidification. The unit is designed
as a closed system and will reduce airborne bacterial exposure to less than
43
1 per cent of that found in conventional hospital rooms.
Although to date there has been no definitive, randomized clinical trial

comparing strict patient isolation and prophylactic oral antimicrobial thera-
py with patient management in a LAF room, three studies have indicated
that the incidence of infection in leukemic patients treated in LAF rooms
may be reduced; the mortality rate secondary to infection was also reduced
in these patients compared with their counterparts who were given ward
care. 41 43 The comparison of LAF room management to reverse isolation
"
with oral antibiotic therapy was less direct in these studies, but overall,
LAF room management did appear to provide improved protection from
infection for patients at risk. The combined use of the LAF room and pro-
phylactic oral nonabsorbable antibiotics may provide better protection from
infection than either ward care or reverse isolation procedures combined

with oral antibiotic therapy. 41The incidence of pneumonias and fatal fun-
45
gal infections
41
is reduced with LAF room management, further
particularly
suggesting that these may be primarily exogenously acquired infections.
Relatively little data are currently available that would allow an adequate
comparison of "Life Island protective environments" or the LAF rooms and
the standard protective isolation procedures that are feasible in convention-
ally equipped hospital rooms. LAF rooms and other "protective environ-
ments" are exceedingly expensive, however. Important components of con-
ventional protective isolation procedures are as follows:
1. Hospitalize the patient in a private room, preferably with a positive air
pressure ventilation system.

2. Assure that medical personnel and visitors wear sterile caps, masks,
and gowns and approach the patient only after careful handwashing.
3. Arrange daily showers or baths with a hexachlorophene or povidone
iodine-containing soap.
4. Limit food choices and preparation to provide a low bacterial diet.
5. Administer oral nonabsorbable prophylactic antibiotics, and co-
trimethoxazole therapy for patients at risk for Pneumocystis carinii infec-
tion.
Itshould be emphasized that clean hospital rooms, attentive nursing
care, and the use of oral antibiotics may provide equivalent protection from
infection. 41 Results from more expensive environmental manipulation, in
terms of patient survival and reduced infection rates, must be measured
against results from this standard approach before concluding that the addi-
tional cost would be justified for a given institution.
The prolonged physical isolation imposed on the patient by strict protec-
tive isolation, or the LAF room environment in the extreme case, might be
expected to produce psychologic stress that would limit the usefulness of
such barrier containment strategies. The loss of the ability to touch or to be
touched by others is the most frequent problem described by patients and
observers. 54 Although feelings of frustration and anxiety undoubtedly are
increased in some patients, the most commonly expressed emotion is a
feeling of loneliness. In contrast, intensive nursing care in a special unit
can contribute to a feeling of security in these critically ill patients. Routine
nursing and paramedical supportive measures, as well as doctor-patient in-
teractions, must be modified in protective environmental care. These will
no doubt be improved with greater experience in the future.
TREATMENT: BLOOD
COMPONENT THERAPY
Erythrocytes
The patient with bone marrow should not be transfused with eryth-
failure
rocytes unless there is a symptomatic problem with oxygen delivery and
transfer. When this occurs, it is generally desirable to use packed red blood
cell (RBC) preparations rather than whole blood. In addition to provid-
ing a small volume load to the patient, the exposure to antigens to which
sensitization may occur or has already occurred may be reduced. Packed
RBCs may be washed as an additional, yet safe, procedure that will fur-
ther limit unwanted antigen exposure. An advantage of frozen RBCs — in
addition to unlimited shelf life, preserved function, and reduced risk of
hepatitis —is the elimination of leukocytes, plasma, and platelets by the
washing procedures that are required during deglycerolization. 55

Careful cross-matching procedures are essential. Based primarily on the
Coombs' test technique, these procedures should assure ABO and Rh com-
56
patibility between transfused blood cells and the recipient. The risk of
major hemolytic reactions from RBC transfusions should be reduced to vir-
tually nothing. Erythrocyte ABO antigens are inherited as simple mendel-
ian characters. Anti-ABO antibodies arise in response to exposure to cross-
reacting polysaccharides occurring in a wide variety of microorganisms,
food, and other exogenous sources and frequently persist despite exten-
sive immunosuppression. A complete discussion of immunohematology
and transfusion reactions are beyond the scope of this chapter, and the
reader is referred to standard hematology references. 5 "
Nonhemolytic transfusion reactions cause fever, chills, headache, nausea,
and vomiting. These may develop immediately following exposure or may
be delayed until up to 24 hours later. The symptom complex, especially
fever, must be distinguished from a septic etiology. Frequently, this can be
determined only with retrospective analysis. The most common cause of
nonhemolytic febrile reactions in transfused patients is sensitization to
other blood antigens, primarily those associated with leukocytes or plate-
57
lets. Antihistaminic and antipyretic agents can be useful in controlling
symptoms of nonhemolytic transfusion reactions and are most effective
when given before the blood transfusion.
No specific minimum packed cell volume (hematocrit) or hemoglobin
level can be chosen as an absolute indication for RBC transfusion. With
chronic bone marrow hypofunction, a steady state is reached at which
erythrocyte production equals senescence and destruction. RBC transfu-
sions in this situation provide only transient improvement. For transient
bone marrow failure, however, such as that associated with intermittent cy-
totoxic chemotherapy, RBC transfusions may be useful. They would be in-
dicated for a symptomatic patient or one who might be expected to require
a rapidly available reserve (e.g., preoperatively). Most adults will tolerate a
hemoglobin as low as 8 gm/dL (hematocrit of 25 per cent); children may
tolerate even lower levels. Since patients who are hospitalized with bone
marrow failure or those who are undergoing antineoplastic chemotherapy,
or both, are under additional stress, it is reasonable to plan the RBC trans-
fusion program to maintain a hematocrit of 25 per cent.
Platelets
An improved understanding of platelet physiology and technical advances

in procurement and storage procedures have dramatically improved the avail-
ability of platelet transfusions. They are now an integral part of supportive
management for patients with bone marrow failure.
Platelet preparations for transfusions are invariably contaminated with

RBCs. Provided that the RBC contamination of platelet concentrates is small,
ABO and Rh compatibility are not practically important for effective platelet
transfusion therapy. ABO-incompatible platelets may be transfused to throm-
bocytopenic recipients, provided that the RBCs have been carefully washed
away to prevent transfusion reaction. In practice, ABO-type specific platelets
are preferred for transfusion to reduce this risk. 58
Although ABO and Rh antigens are probably present on platelet mem-
branes, they seem to play only a minor role in alloimmunization. 59,60 In
contrast, histocompatibility (HLA) antigens, which are not present on the
RBC surface, are clinically the most important antigen system on platelets. '"
Antibodies that are produced by the recipient who is sensitized to HLA
antigens of transfused platelets will dramatically reduce platelet survival and
function. 62 Patients receiving platelet transfusions develop antibodies to non-
HLA identical platelets, which are detectable by 20 days following sensitiza-
tion. Reduced platelet survival, however, will occur even more rapidly in
presensitized recipients. 63 Even immunosuppressed patients will develop
antiplatelet antibodies once sensitized. 63
Although the normal half-life of platelets is ten days, the survival of trans-
fused platelets, even in the absence of detectable antiplatelet antibodies, may
be as little as two days. 56 Since shortened platelet survival and sensitization
phenomena may accompany repeated transfusions of HLA matched platelets,
other antigen systems and factors are of obvious importance in determining
the functional utility of platelet transfusions. Platelet survival is reduced if the
patient is febrile or septic. 64, 65 Hepatosplenomegaly (enhanced reticuloen-
dothelial system function), active bleeding, and intravascular coagulation will
also result in an increased utilization or destruction of platelets, thereby
diminishing post-transfusion recovery even without alloimmunization to the
recipient. 65
A "unit" of platelets may be
defined as the platelets recoverable from one
unit of whole blood. In general, this will represent approximately 7 x 10 10
platelets. 65 The average increment in the recipient can be highly variable. In
unsensitized recipients, the circulating platelet count may increase by 10,000
platelets/mm 3 blood/m 2 body surface area. Therefore, one unit of platelets will
raise the platelet count by 5000 to 10,000/mm 3 in unsensitized adults. Because
the actual increment will be modified by many factors, it is common practice
to measure platelets in the recipient's blood before transfusion and one hour
following transfusion to determine the yield from a given platelet transfusion.
For most thrombocytopenic patients receiving platelet transfusions, several
units must be administered at one time, and transfusion therapy may be
required frequently to provide adequate hemostasis for even relatively brief
periods of risk.
Platelet concentrates obtained from fractionated single units of donated
whole blood are the primary source of platelets in most blood banks. In this
setting, platelet transfusion recipients will be given a large platelet antigen
load from a wide variety of random donors even with minimal therapy.
Although this may not be important when a previously unsensitized individu-
al receives one or two platelet transfusions, repeated exposure to random
platelets rapidly leads to decreased platelet survival, increased risk of transfu-
sion reaction, and refractoriness to subsequent random donor platelet transfu-

sions. Therefore, single-donor platelet transfusions are desirable. These limit
both antigen sensitization and risk of hepatitis. Continuous or discontinuous
flow centrifugation plateletpheresis techniques are now available that permit
the safe recovery of multiunit, single-donor platelet concentrates. Members of
the thrombocytopenic patient's immediate family will have a likelihood of at
least partial histocompatibility with the patient and are the best choices for
platelet donors. HLA typing of the recipient and potential donors will of
course identify the best immunologic match.
Prophylactic platelet transfusions can reduce the incidence of serious spon-
taneous hemorrhage in patients with leukemia and thrombocytopenia. 66 Plate-
let transfusions are generally indicated in thrombocytopenic patients for
overt, clinically significant bleeding (including epistaxis, hematuria, and gin-
gival bleeding) and fresh intracutaneous bleeding (ecchymoses). Lesser
bleeding manifestations, such as fresh petechiae, may also be sufficient indi-
cations for platelet transfusions in the cancer patient with thrombocytopenia.
Prophylactic platelet transfusions for patients without bleeding manifesta-
tions may be worthwhile if, in addition to severe thrombocytopenia, the
platelet count has been falling.
67
A reasonable management plan provides
platelet transfusions for all patients with bleeding manifestations and a plate-
let count of less than 20,000/mm and for all patients with a falling platelet
3
count of less than 10,000/mm 3 even without bleeding manifestations.

,
The most common complication of platelet transfusion is a febrile reaction,

which usually secondary to contaminating leukocytes in the ABO-matched
is
recipient and may be related to leukocyte-specific antigens. 68 Although less

common with single-donor therapy and careful technique, infectious hepatitis
and bacterial contamination may also complicate platelet transfusion thera-
py-
Granulocytes
There is between circulating

a clear-cut, quantitative, inverse relationship
leukocytes and the risk of severe infection. This may be seen with lympho-
16
cytes and, even more strikingly, with granulocytes. The risk of infection is
greater when the granulocyte or lymphocyte count falls below 1000/mm 3 and
increases dramatically when either of these counts falls below 500/mm 3 .
Because of this relationship, many centers give leukocyte transfusions to

leukopenic patients with infection. Immunologic factors play a crucial role in
determining the efficacy of leukocyte transfusions in humans. Leukocytes
carry not only the ABO antigen system but also the HLA and leukocyte-
specific antigens. 61, 69_74 ABO matching between donor and recipient is there-
fore not sufficient for optimal survival of transfused leukocytes. Transfused
neutrophils that are poorly matched for HLA antigens with the recipient are
removed from the circulation almost immediately. 73
The recovery of transfused leukocytes is directly related to the degree of
histocompatibility between donor and recipient. Granulocyte- and
lymphocyte-specific antigens, as well as HLA antigens, may result in alloim-
munization of the recipient and decreased in vivo survival of transfused
leukocytes. 74 Leukocyte alloantibodies may be found in patients without

history of prior transfusions and may be active even against HLA-matched
leukocytes. 7 "'
Although granulocyte antigens are determined independently of
the HLA antigen system, screening of potential leukocyte donors is common-
ly limited to HLA typing, for which standard sera are now readily available.
Granulocyte antigen typing systems are as yet poorly defined and experimen-
The leukoagglutination assay for non-HLA granulocyte antigens remains
tal.
inconvenient.
The complexity of the immune response to allotypic transfused leukocytes
has produced some curious post-transfusion phenomena in addition to the
commonly observed minor febrile transfusion reactions. Patients with pre-
formed leukocyte antibodies have enhanced splenic sequestration of infused
white blood cells, 76 and transient pulmonary infiltrates may appear occasion-
77
ally, associated with a feeling of chest or throat constriction. HLA-identical
but ABO-mismatched leukocyte transfusion results in a markedly diminished
post-transfusion recovery. 7 Several principles of leukocyte transfusion may
'
be derived from these immunologic considerations: Donor and recipient

should be ABO-type compatible with a negative cross-match. HLA compati-
bility is desirable. Family members are especially good donor candidates,
since in addition to partial HLA compatibility minor non-HLA antigens are
also more likely to be identical. Preferably, the recipient should be free of
leukoagglutinins directed against the donor.
Leukocyte transfusion strategy for the neutropenic patient aims to supply
sufficient granulocytes to provide a nonspecific, active antimicrobial effect. A
continuing problem in granulocyte transfusion therapy, however, is the diffi-
culty in providing sufficient numbers of adequately matched cells in a practi-
cal time limit and at a reasonable cost. The neutrophil production in normal
adults approaches 10" cells daily, and the circulating neutrophil half-life may
normally be only six hours. 78 To provide enough granulocytes to raise the
recipient's circulating pool by 1000 cells/mm 3 40 units of blood would have to
,
be processed from a normal donor. Single-unit leukapheresis (buffy coat

extraction from whole blood) is thus not practical. Granulocyte collection
techniques have therefore developed from two procurement approaches.
Leukocytes may be obtained by the filtration of heparinized blood passed
through nylon-wool filters. This results in adherence of granulocytes and, to a
lesser extent, monocytes and B lymphocytes by a divalent cation-dependent
mechanism. 74 It is possible to maintain a closed system that permits the
passage of liter quantities of donor blood through filtration packs arranged in
parallel fashion. Granulocytes are efficiently collected by this technique with-
out significant loss of RBCs or plasma from the donor, and the extracorporeal
blood volume is relatively small. When the nylon-wool filters are fully loaded
with adherent leukocytes, the procurement procedure is terminated, and the
filtration circuit is disconnected from the patient. The adherent cells are then
released by elution with an isotonic solution of chelating agents (acid citrate-
dextrose is commonly used), often with mechanical maneuvers to dislodge the
cells.
Leukocytes may also be separated by density centrifugation. A continuous
flow closed system, in which blood components are separated on the basis of
differential density in a centrifugation apparatus, has been designed. This
equipment can be cumbersome, however, and requires a relatively large

extracorporeal blood circulation to continuously fill the centrifuge bowl. It has
largely been found more convenient, therefore, to use a discontinuous flow
modification in which the centrifuge bowl is filled with donor blood. Its
contents are separated by centrifugation and various components are either
collected in a reservoir or (as in the case of RBCs) returned to the donor. The
centrifuge bowl is then refilled using a closed sterile system. Discontinuous
flow centrifugation has the advantage of highly efficient leukocyte collection
and disposability of software to simplify sterility maintenance. The efficiency
of collection, however, is reduced after the processing of 3 to 4 liters of blood
from the donor. 79
The density centrifugation systems provide a higher proportion of low-
density mononuclear leukocytes than does the filtration system. Neutrophil
7
recovery is enhanced by collection into the erythrocyte layer of the cen-

trifugation system. Thus, leukocyte concentrates obtained by centrifugation
have a greater RBC contamination. In fact, a buffy coat hematocrit of 10 per
cent is considered optimal with this technique. 74
Additional maneuvers have been developed to increase the yield of leu-
kapheresis. Donor premedication with dexamethasone, for example, can in-
crease recovery' filtration to 2 to 5 x 10 10 cells/collection. 80 Hydroxyethyl
starch has been used to induce rouleaux formation in the centrifugation
systems, thereby providing more efficient leukocyte separation and recov-
ery 7i. si. 82 Hydroxyethyl starch is added to blood entering the afferent tube of
the cell separator and is therefore infused into the donor via the efferent
limbs. Dexamethasone and hydroxyethyl do not appear to affect gran-
starch
ulocyte function in the recipient. Although these agents have been well
tolerated by normal donors, the true safety of their use is still being evaluated.
Whetiier or not these agents are used, however, the leukocyte recov-
ery/leukapheresis is routinely two to three times greater for filtration than
74 80
for centrifugation. '
Although a larger number of granulocytes will be available for transfusion

when collected by filtration rather than centrifugation, their in vivo useful-
ness may be limited by increased splenic sequestration and diminished re-
covery in the recipient's circulation. 15, 81,83> M Granulocytes that are collected
by filtration have a variety of in vitro abnormalities that are generally not
present in centrifugation-collected granulocytes, including abnormal microbi-
cidal and phagocytic activity. 84 Such functional abnormalities may contribute
to the splenic sequestration and may also account for the higher incidence of
transfusion reactions observed following the infusion of filtration granulo-
cytes. Febrile reactions occur in a majority' of patients receiving granulocytes
that are obtained by filtration, even with complete ABO and HLA matching,
whereas compatible centrifugation granulocyte transfusions are associated
with fever and chills in less than 10 per cent of cases. 80, 85, 86 Such reactions to
filtration granulocytes can occur even when leukocyte-specific leukoagglutin-
ins are excluded in addition to alloantibodies, 73 and these reactions are pre-
sumably related to cell damage caused by the collection technique rather than
an additional antigen system. The severity and frequency of febrile reactions
to granulocyte transfusions can be lessened by reducing the infusion rate to
10 10 cells/hour. 87 Since the half-life of granulocytes is short, however, some
attention to prompt administration after collection is also important to maxi-

mize clinical benefit.
A graft-versus-host reaction has been reported
occur in immunosup-
to
SH
pressed patients receiving granulocyte transfusions. All blood products that
might contain immunocompetent leukocytes, and certainly leukocyte concen-
trates, should be irradiated to prevent this complication in these patients.
Such irradiation will prevent proliferation of immunocompetent cells without
affecting antimicrobial function. With appropriate equipment, this procedure
can be performed following leukapheresis with minimum delay before trans-
fusion. 88
Since the absolute granulocyte count in profoundly neutropenic patients is
generally below the limits of accurate counting techniques, the measurement
of the increment or the recovery of granulocytes following transfusion may not
be a reliable indicator of the effectiveness of the transfusion. For example,
although HLA differences between donor and recipient are associated with
impaired granulocyte recovery following transfusion, the clinical response to
granulocyte transfusion does not appear to be related to the degree of histo-
compatibility. 51, 86, 89, 90 Although the transfusion of an equivalent number of
filtration-collected neutrophils results in only one tenth of the recovery of
centrifugation-collected neutrophils, 81 the former appear to be as effective as
the latter in supporting septicemic, granulocytopenic patients. 86
The evaluation of the role of granulocyte transfusions is complicated by
multiple variables and necessarily crude clinical observations. In general, the
overall patient survival, the duration of fever, and the duration of culture-
positive infection have been used as criteria for response. It is clear, however,
that the effectiveness of available antibiotics, the concurrent changes in the
patient's bone marrow function and underlying disease, and other aspects of
supportive care are also important in determining clinical response. More-
over, the technique used for obtaining granulocytes for transfusion, the cell
dose, and the frequency of transfusion may all be additionally important fac-
91
tors.
The randomized, controlled, prospective trials of granulo-
results of several
cyte transfusion therapy for patients with neutropenia and fever demonstrate
a significant improvement in survival among those patients with documented
infection who were treated with granulocytes and antibiotics, compared with
those who were treated with antibiotics alone. 51,73,81 86 The evidence sug-
'
gests that granulocyte transfusion therapy is most effective when transfusions

are begun relatively soon after signs of infection are noted and when they are
continued daily for a period. For neutropenic febrile patients in whom no
infection is documented, granulocyte transfusions offer no advantage. Never-
theless, since infection may become life threatening before culture results are
available, the prophylactic use of granulocyte transfusions in neutropenic
patients is now being evaluated in several medical centers.
The current indication for granulocyte transfusions is persistent infection,
despite appropriate broad-spectrum antibiotic therapy, associated with severe
leukopenia (less than 500 cells/mm 3 ). First priority for granulocyte transfu-
sions should be given to patients with reversible leukopenia and the likeli-
hood of at least short-term control of malignant disease. Whether or not
prophylactic granulocyte transfusions can reduce infectious complications in
patients with bone marrow failure as dramatically as routine platelet transfu-

sions have reduced hemorrhagic complications remains to be seen. In those
medical centers in which granulocytes can be obtained for transfusion thera-
py, an integrated plan of approach to the febrile neutropenic patient can be
formulated as follows:
1. Obtain appropriate cultures, perform diagnostic studies, and review sur-
veillance culture results.

2. prompt, empiric antibiotic therapy, using an aminoglycoside-
Initiate
carbenicillin combination. Cefazolin may be substituted for penicillin-
sensitive patients.
3. Adjust antibiotic therapy on the basis of culture results (specific organ-
ism and its sensitivity to antibiotics), renal function, and antibiotic blood lev-
els.
4. granulocyte transfusion therapy on a daily basis for patients who
Add
remain febrile after 72 hours of antibiotic therapy. Although HLA-matched
granulocytes are preferable, ABO-identical granulocytes from random donors
can be effective.
5. Re-evaluate the patient who remains febrile after seven days of antibiot-
ic therapy despite granulocyte transfusions. For patients who are stable,

antibiotics may be temporarily discontinued to obtain a new set of cultures.
For patients with deteriorating status or with surveillance culture results that
are positive for fungus, add amphotericin B therapy.
6. Continue antibiotic therapy in the responding patient with documented
systemic infection for a prolonged course; discontinuation of effective antibi-

otic therapy is safest after the recovery of bone marrow function.
AUTOLOGOUS BONE MARROW

CRYOPRESERVATION AND
TRANSPLANTATION
Blood component transfusion is an invaluable form of therapy that has
enabled patients to survive prolonged periods of pancytopenia. Such therapy
cannot provide sufficient protection indefinitely, however; ultimately, we
must depend on the recovery of the patient's endogenous bone marrow. Even
with the availability of sophisticated supportive measures, cytotoxic therapy
must ordinarily be limited, so that marrow recovery will occur. A new ap-
proach to patients with bone marrow failure following cytotoxic therapy is the
complete replacement of bone marrow function.
The transplantation of pluripotent hematopoietic stem cells is capable of
restoring normal hematopoiesis in humans following supralethal doses of
radiation or chemotherapy. 92 When allogeneic bone marrow that is obtained
from a histocompatible sibling is used, graft rejection and graft-versus-host
disease are formidable problems, which are not seen when autologous bone
marrow is the source of stem cells, and immunosuppression is not a require-
ment of the pretransplant conditioning regimen. Autotransplantation, in
which bone marrow is obtained from the patient prior to cytotoxic therapy and
is maintained in a tissue bank for later reinfusion into the patient following a
course of intensive treatment, may therefore provide an approach to the

treatment of selected patients with advanced malignancy. Thus, a reliable
cryopreservation technology is an essential part of the autologous bone mar-
row transplantation program.
Even though an optimal protocol for allotransplantation has not yet been
defined, most cryopreservation procedures meet several basic requirements.
Cells are suspended in a nutrient medium containing plasma or serum. A
cryopreservative is added to prevent intracellular ice crystal formation and to
93
stabilize the cell membrane against osmotic stress. Glycerol and dimethyl-
sulfoxide (DMSO) have each been used, although the latter is now generally
acknowledged to be superior. 94 96 The bone marrow cell suspension is then
"
frozen at a programmed rate that is designed to absorb the heat released with
phase change. 97 A smooth, gradual temperature reduction is thus achieved.
Bone marrow cells are cryopreserved in liquid nitrogen freezing tanks. The
cells are maintained at - 156° C to - 196° C, and may remain in the frozen state
forprolonged periods.
Cell function can be maintained for a year or more under appropriate
conditions. The loss of viable cells is dependent primarily on the freezing and
thawing manipulations rather than on the cold storage. 98 Cell clumping fol-
lowing thaw has been a major technical problem. 99 This may be in part related
to platelet activation, although lysis of differentiated cells, such as mature
neutrophils, with release of nucleic acids that stick to cell membranes and
promote clumping, is probably a more important factor. Clumping may be
reduced or delayed by adjustments in pH or divalent cation concentration. 99
Another approach has been to separate bone marrow cells by density gradient
centrifugation prior to cryopreservation, so that the marrow cell concentrate is
enriched for stem cells and depleted of erythrocytes and mature myeloid
cells.
100
The primarily mononuclear marrow is retained
cell fraction that
contains stem cells that are capable of myeloid colony formation in vitro and
hematopoietic differentiation in vivo.
Bone marrow is obtained for cryopreservation and transplantation from the
iliac crests, using a multiple aspiration procedure that requires anesthe-
sia. Nevertheless, this procedure is well tolerated by cancer patients as
92, I01
well as by normal donors. Hematologic function is not altered by the removal

of the necessary quantity of bone marrow, although the hematocrit falls as a
result of the 800-ml blood loss that accompanies the marrow aspirations. The
aspirated bone marrow sample generally contains up to 90 per cent bone
marrow cells with only 10 per cent peripheral blood cells. 92 For allogeneic
bone marrow transplantation, 1 nucleated bone marrow cells/kg are
to 3 x 10
8
required to provide sufficient numbers of pluripotent stem cells for engraft-

merit. 92,
1()1
Fewer autologous marrow cells are necessary, although the mini-
mum has not been established. 102, I03
number
Several considerations are critical in the selection of potential cancer pa-
tients for marrow cryopreservation and autotransplantation. The natural histo-
ry of the patient's tumor should suggest a low likelihood of bone marrow
involvement, at least at the time the patient is evaluated. There should be a
reasonable likelihood that the malignancy will be sensitive to intensive che-
motherapy or radiotherapy. Younger patients are more likely to withstand the
nonhematologic toxicity of such intensified therapy. Since marrow is obtained
from the ilia, previous pelvic irradiation will compromise marrow stem cell
procurement. These criteria suggest a number of malignant diseases that

could appropriately he considered for intensive cytotoxic therapy and bone
marrow autotransplantation. In our program, the following tumors are under
study: carcinomas of ovary, breast and testis, Hodgkin's and non-Hodgkin's
lymphomas, and soft-tissue sarcomas.
Experience with cryopreserved, autologous bone marrow transplantation
has been limited but encouraging. Early trials provided evidence that bone
marrow autotransplantation is technically feasible and safe. Since therapy was
rarely sufficient to eradicate residual marrow, the clinical importance of the
maneuver was difficult to evaluate. 104 108 Subsequently, unequivocal evidence
"
for autograft function in a patient who was treated with intensive chemothera-
109
py and total body irradiation has been reported. Other investigators have
presented data to suggest that with less intensive chemotherapy, bone mar-
row function may return more rapidly who receive marrow auto-
in patients
transplant than in those who chemotherapy alone. 110, ni In
are treated with
some recent trials, intensive therapy appears to have been successful in
eradicating disseminated lymphoma, and bone marrow allografting or auto-
grafting provided hematologic reconstitution. 112 114
"
Autologous bone marrow obtained from patients in remission from acute

leukemia has also been used to provide reconstitution of hematopoiesis fol-
lowing intensive treatment for subsequent leukemic relapse. 115, 116 Although it
is quite possible that residual acute leukemic cells are present even in bone
marrow from patients in remission, the autotransplant procedure provides an

opportunity for in vitro treatment to remove the residual tumor cells. A
number of physical and serologic approaches to this problem are being evalu-
"
117 119
ated, although none appear to be practical at present. Blast crisis of
chronic myelocytic leukemia may also be controlled, if not cured, by intensive
therapy and the transplantation of autologous bone marrow obtained during
the chronic phase. 120 Although the engraftment of CML bone marrow stem
cells appears to be less predictable than engraftment of normal marrow stem
cells, autografts have permitted intensified antileukemic therapy in this dis-
ease as well.
It appears, from the evidence to date, that pluripotent hematopoietic stem
cells may be cryopreserved, thawed, and reinfused safely into patients with
malignant disease. Patients may thereby be protected from otherwise intoler-
able bone marrow toxicity caused by intensified cytotoxic treatment programs.
The successful management of cancer patients treated in this manner still
depends on the supportive strategies described earlier in this chapter. Never-
theless, bone marrow autotransplantation may permit experimental cancer
treatment programs to provide an objective antitumor effect that could not be
anticipated from conventional therapy.
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CHAPTER 28
COMPLICATIONS
CAUSED BY ORGAN
COMPRESSION
Section 1
Management of Malignant
Pleural Effusions
John H Wittig E Carmack Holmes
INTRODUCTION
The control of malignant pleural effusions is a palliative measure, be-
cause such effusions are regional manifestations of systemic fatal diseases.
As with all palliative measures, the morbidity of the procedure should be
weighed carefully against the severity of the symptoms. However, when
malignant effusions give rise to discomfort — such as dyspnea — aggressive
intervention is indicated.
Although many different therapeutic techniques have been described,
the object of all is relatively simple. The goal is to obliterate the free
pleural space as quickly and as efficiently as the clinical circumstances will
allow. Procedures that have been advocated range from repeated simple
thoracentesis thoracotomy with pleurectomy. Since many malignant
to
pleural effusions can be controlled by simple tube thoracostomy, all other
therapeutic interventions need to be compared with this approach.
This section reviews the pathogenesis and diagnosis of malignant pleural
effusion and attempts to critically evaluate the various modalities currently
used for treatment and compare the efficacy of each with that of simple
tube thoracostomy.
984
28 / Complications Caused by Organ Compression 985
NATURAL HISTORY
Normally, the pleural space contains only a few milliliters of fluid.
Pleural fluid is formed and absorbed constantly, and the net balance of
these processes determines the presence or absence of an effusion. The
parietal pleural vasculature is derived from the intercostal arteries, and
there is a net positive pressure of 9 cm H 2 tending to drive fluid into the
pleural space. The visceral pleural vasculature is supplied by the low-
pressure pulmonary system, which, under normal circumstances, has a net
pressure of -10 cm H 2 and therefore promotes absorption of fluid from
the pleural space. Lymphatic vessels located in the subepithelial layer of
both pleural surfaces also participate in the absorption of fluid and protein
from the pleural cavity. These lymphatics, in turn, drain into the hilar and
mediastinal nodes.
Malignant effusions can be secondary to direct implantation of tumor.
This results in an increase in capillary permeability with an increased pro-
duction of pleural fluid. These effusions usually contain neoplastic cells,
but 40 per cent of patients with pleural metastases may not have clinically
detectable effusion. 1
Other mechanisms, such as pleuritis and pneumonitis secondary to malig-

nant occlusion of a bronchus, may account for increased capillary secretion.
In these cases, elevated protein levels in the pleural fluid are seen without
tumor cells because the pleural space is not directly infiltrated. Malignant
obstruction of the pulmonary lymphatic or vascular circulation results in a
decreased reabsorption of fluid and an increased net hydrostatic pressure
against reabsorption of fluid from the pleural space.
Other causes of pleural effusion are pericardial effusion and superior
vena caval syndrome, which also increase parietal pleural pressure. Non-
neoplastic causes of pleural effusion include congestive heart failure, which
results in an increased pulmonary' vascular pressure with increased tran-
sudation, and hypoproteinemia, which decreases osmotic pressure.
Diagnosis
Symptoms of pleural effusion include pleuritic chest pain, dyspnea, fa-

tigue, cough, and fever. However, in the early stages, patients are often
asymptomatic. A history of breast cancer is significant, since malignant
pleural effusion is the initial sign of recurrence in 6.5 per cent of all preop-
erative patients with recurrent carcinoma of the breast. The effusion is uni-
lateral in the majority of cases, but 5 to 20 per cent of these patients have
"
4
bilateral involvement. 2
Pleural effusions are characterized as exudates or transudates. Exudates
have a protein concentration of greater than 3 gm/dL. Most malignant
pleural effusions are exudates and contain levels of lactic acid dehydrogen-
ase higher than the corresponding serum values. Conversely, the glucose
content is lower than the corresponding serum level. When the pleural
fluid is a transudate, the differential diagnosis includes congestive heart fail-
ure, renal failure, liver cirrhosis, pancreatitis, hypoproteinemia, and, more

rarely, other nonmalignant conditions. A definitive diagnosis of a malignant
effusion can be made by either positive fluid cytologic findings or positive
pleural biopsy findings in 90 per cent of cases. In problem cases it has
been reported that the diagnosis may be supported by the measurement of
pleural fluid CEA 5
or by cytogenetic studies 6 of pleural fluid cells; howev-
er, we have no personal experience with these latter measures.
PRINCIPLES OF TREATMENT
Although a number of methods have been used to treat malignant pleural
effusion, the reportson the efficacy of the various treatments are difficult to
evaluate objectively. A number of investigators assessed the interval of
reaccumulation of significant amounts of pleural fluid, but opinions varied
as to the amount considered significant. Some measured the time that had
elapsed between treatments, and others documented the length of time the
patient had remained asymptomatic. Since the primary objective is pallia-
tion, the duration of the symptom-free interval probably is the best criteri-
on for evaluating the effectiveness of treatment.
Modalities that are available for the control of these effusions are (1) sys-
temic chemotherapy, (2) multiple simple thoracentesis, (3) tube thoracos-
tomy, (4) injection of sclerosing agents, (5) thoracotomy with pleurectomy,
and, rarely, (6) radiation therapy.
Systemic Chemotherapy
Systemic chemotherapy or hormonal therapy can control effusions sec-

ondary to malignancy, especially in carcinoma of the breast. However, if
the effusion does not respond to systemic chemotherapy and significant
symptoms are present, local measures are indicated.
Thoracentesis
Simple thoracentesis, with the removal of two or more liters of fluid, alle-
viates symptoms quickly and can be performed on an outpatient basis. Un-
fortunately, the effects of this technique are short-lived. A 90 to 100 per
cent possibility of recurrence is the rule for malignant effusions treated
with simple thoracentesis only. Our experience indicates that 90 per cent of
patients who undergo simple thoracentesis have recurrence of both symp-
toms and significant effusion. The average time for recurrence varies, but it
is usually between four and six days.
7
Seventy-two per cent of our patients
had recurrence of symptoms and fluid within seven days. Simple thoracen-
tesis, therefore, should be reserved to evaluate the initial effusion and to
determine its etiology and propensity to reaccumulate. It is, of course, ef-
fective in relieving acute symptoms and can be useful in terminal patients
whose life expectancy is only a few days.
Thoracentesis accompanied by the instillation of sclerosing agents has

been evaluated, but overall results have not been very satisfactory. Even with
the use of mechlorethamine, quinacrine hydrochloride, tetracycline, or thio-
tepa, the effusions tend to recur rather quickly and require repetition of
treatment. 8 This recurrence is without doubt due to the inability of thora-
centesis to maintain contact between the visceral and parietal pleural sur-
faces during the action of the sclerosing agent. Our experience with thora-
centesis and the insertion of sclerosing agents has been disappointing, and
no one agent has proved to be superior to another.
Thoracostomy
It has been our experience that the majority of patients with malignant
pleural effusions respond to tube thoracostomy. Tube thoracostomy and
suction should be used first in order to totally evacuate the pleural space
and to keep the visceral and parietal surfaces coapted to allow pleural syn-
thesis to take place. treatment is not effective, sclerosing agents
If this
should be used. Tube thoracostomy alone will generally control more than
50 per cent of malignant pleural effusions without the addition of scleros-
'
ing agents. 8 10
Intrapleural Sclerosing Agents
The use of chemothcrapeutic agents in conjunction with tube thoracos-

tomy malignant pleural effusion is a relatively new con-
for the control of
cept. Whether is tumoricidal seemingly is unimportant.
or not the agent
The therapeutic effect of mechlorethamine, for instance, is most likely re-
lated to its vesicant action rather than to its antineoplastic properties. 11
Postmortem studies have shown almost complete obliteration of the pleural
space secondary to fibrinous serositis despite the presence of abundant
tumor implants. 10 All investigators agree that complete removal of the
pleural fluid before and after instillation is important. The lung must be
expanded and the fluid almost completely removed before the agent is in-
troduced, and coaptation of the parietal and visceral pleural surfaces must
occur during the period of induced pleural inflammation.
Mechlorethamine was one of the first sclerosing agents employed.When
instilled into the pleural cavity at a dose of 0.4 mg/kg, with a maximum
dq.se of 20 mg, a satisfactory response can be anticipated in 50 to 80 per
cent of patients. Patients should be premedicated with an antiemetic to
counteract the nausea and vomiting commonly noted within six hours of
instillation. Most patients develop a fever that begins several hours after
administration and that may reach 103° F; it usually subsides in 48 hours.
Local pleuritic chest pain frequently occurs, sometimes necessitating anal-
gesics. Leukopenia may occur in about 10 per cent of patients. 12 The usual
recommendation is to reduce the dose by at least 50 per cent in patients
with pre-existing bone marrow suppression or in patients who have had or
are having significant functional bone marrow irradiation. Patients who fail
to respond may have their treatment repeated in two weeks if blood counts
permit. With retreatment, subsequent side effects may not be as prevalent
because of decreased systemic absorption resulting from the fibrosis from
the initial treatment. The advantages of meehlorethamine are its relative
ease of administration, its rapid relief of symptoms, and its relatively mild
toxicity.
For malignant pleural effusion that is associated with carcinoma of the
breast, treatment by tube thoracostomy and instillation of meehlorethamine
or thiotepa gives satisfactory responses in 50 to 75 per cent of patients. 2, 8! -
The dose of thiotepa is 30 mg. Approximately 50 per cent of patients expe-

rience nausea and vomiting; less than 4 per cent develop bone marrow de-
pression.
Quinacrine hydrochloride administration is successful in 64 to 84 per
cent of patients. 13, H In vitro cytotoxic and antineoplastic activity with quin-
acrine hydrochloride has been described. Its primary therapeutic effect,
however, is inflammatory and pleural fibrosis, and adhesions with oblitera-
tion of the pleural space follow intrapleural instillation. Quinacrine hydro-
chloride is dissolved in 10 ml of saline and injected into the pleural space
following tube thoracostomy. Initially, 50 to 100 mg is given to determine
individual sensitivity and idiosyncrasy. If there is no significant pain, fever,
hypotension, or hallucination, 100 to 200 mg are given on days two to five
until local pleuritis is produced. Local pleuritic pain usually begins some
hours after treatment and can be severe. Fever occurs in 100 per cent of
patients, beginning 48 hours after treatment and lasting up to 10 days. As a
rule, the frequency and severity of toxic reactions are dose dependent.
When single large doses of 800 mg have been given, hallucinations and
hypotension have been noted. 13 Quinacrine hydrochloride should, there-
fore, be given in divided doses over several days. However, we rarely use
this agent because of its severe toxicity.
Intrapleural tetracycline has been used
malignant pleural effusions.
for
Five hundred milligrams of tetracycline are diluted in 30 ml of saline and
injected into the pleural space through a thoracostomy tube. Satisfactory
results were obtained in 10 of 12 patients in one study, and we have ob-
served similar rates of pleural coaptation. 15 The advantages claimed for this
agent over other intrapleural chemotherapeutic agents include the absence
of interference with systemic chemotherapy and the minimal amount of
pleuritic pain and fever. However, we have found greater pleuritic pain
with the use of tetracycline than with any other intrapleural agent. This
result is not surprising when one considers that this highly acidic agent
(pH 2.4) is able to induce mesothelial destruction. Thoreau 16 found that
tetracycline was more effective than talc, meehlorethamine, or thiotepa in
producing pleural synthesis in an animal model. In our series, 53 patients
were treated with tetracycline; the average duration of control of symptoms
and effusion was 203 days. The only contraindication is hypersensitivity to
the drug and the severe pain already noted.
Talc also can produce sclerosis, pleurodesis, and pleural space oblitera-
tion, with success rates of 90 per cent reported. This mode of treatment
requires a thoracotomy, and therefore is suitable only for those patients
who can withstand major surgical procedures, who have a relatively long
life expectancy or who require thoracotomy for diagnosis. Modification of
this poudrage method, which involves insufflation of talc over the pleural
spaces with tube thoracostomy, has been done experimentally, apparently
with similar results.' 7
Bleomycin instillation in 12 patients with malignant pleural effusions has
been reported, with complete or partial response in 40 per cent. 18 The tox-
icity was minimal. Because of the low general toxicity, the absence of mar-
row toxicity, and the virtual absence of discomfort, many authors feel that
bleomycin may have a place in the management of pleural effusion, espe-
cially in leukopenic patients.
Pleurectomy
Pleurectomy, with or without decortication, has been used to treat malig-

nant pleural effusions, with a high rate of success in properly selected pa-
tients. Jensik et a/. 19 reported 50 patients, on whom 52 pleurectomies were
performed with a 6 per cent mortality rate. Eighteen of the patients had
carcinoma of the breast as a primary lesion. Fifteen had associated decorti-
cation to permit full expansion of the lung and facilitate pleural synthesis.
Only two patients developed recurrent effusions. Martini et al. 20 performed
pleurectomies in 106 patients, 90 per cent of whom had experienced recur-
rence after other attempts to control the effusion. No patient had recurrence
of his effusion, and the median survival was 16 months.
CONCLUSIONS
Recurrent pleural effusions are often the cause of marked symptomatic
debilitation and are a major limitation to the quality of life in patients with
incurable carcinoma. The therapeutic goal is simple: rapid palliation with
minimal toxicity. Initially, simple thoracentesis may provide adequate
symptomatic relief and diagnosis. For recurrence, simple tube thoracostomy
drainage for 48 hours with total expansion of the lung is frequently suffi-
cient. In patients who are refractory to this treatment, a sclerosing agent
should be added. We currently rank the relative value of these agents as
follows: Mechlorethamine and tetracycline appear to be equivalent, bleo-
mycin is of potential value, but not fully tested, and quinacrine hydrochlo-
ride is too toxic for routine use.
Most patients can be treated successfully with tube thoracostomy and the
instillation of sclerosing agents. Radiotherapymay help control recurrent
effusions secondary to lymphatic obstruction and may be useful in addition
to sclerosing therapy. Surgical pleurectomy should be considered in pa-
tientswho are in good general condition and who are refractory to scleros-
ing agents. Repeated simple thoracentesis is to be discouraged, since it is
rarely effective.
Section 2
Superior Vena Caval
Syndrome
INTRODUCTION
The superior vena caval syndrome (SVCS) was first described by William
Hunter in 1757 in a patient who had a luetic aortic aneurysm. Until recent-
ly, benign conditions were the most common cause of the syndrome.
21
Cur-
rently, however, malignant tumors account for almost all causes of SVCS. 22
Following the diagnosis of the syndrome, prompt evaluation and treatment
are necessary to provide rapid decompression, prolonged survival, and pos-
sible cure of the malignant tumor causing the syndrome.
NATURAL HISTORY
Pathophysiology and Classification
As noted by Roswit et al., 23 the superior vena cava is particularly vulnera-

ble to obstruction by primary bronchial tumors or metastatic mediastinal
nodes because it is a thin-walled vessel with a low venous pressure and is
situated to the right of the midline anterior to the trachea and right main-
stem bronchus and posterior to the sternum. It is surrounded by lymph
nodes that drain the structures in the right and the lower part of the left
thoracic cavity. 24
The vena cava makes it apparent why the most
location of the superior
common tumor associated with the SVCS is bronchogenic carcinoma (75
per cent of all cases) 23 and why the syndrome is more common with right-
25
sided lesions (4:1). Lymphomas account for 15 per cent of cases, with
22
metastatic malignancies making up approximately 7 per cent. Benign
causes of the syndrome include substernal goiter, now the most common
benign etiology, 26 mediastinal granulomatous diseases (histoplasmosis, tu-
28
berculosis), 27 pericarditis, and idiopathic fibrosing mediastinitis.
The superior vena caval syndrome is characterized by edema and suffu-

sion of the neck, face, upper extremities, and, on occasion, the upper torso,
as well as the dilation of collateral veins on the chest and abdomen, and
progressive dyspnea, cough, and orthopnea. As the cerebral venous pres-

sure rises, headaches, vertigo, drowsiness, stupor, and unconsciousness can
become manifest. 23
The speed with which the syndrome develops depends on the growth
rate of the obstructing tumor. Fast-growing tumors do not allow sufficient
time for collateral circulation to develop. Lesions above the azygos vein are
generally better tolerated because this important link between the upper
torso and the superior vena cava allows compensatory collateral circula-
tion. 23
After the clinical diagnosis of the superior vena caval syndrome is es-
tablished, the clinician must then, if possible, determine the histopathologic
diagnosis to aid in therapeutic management decisions. A complete history
and physical examination may reveal abnormal tissue that issuperficial and
easily biopsied, e.g., a peripheral lymph node. Sputum cytologic studies
and bone marrow examination should be considered. A patient with early
clinical manifestations and a stable syndrome, in whom other tissue is not
available, may have mediastinal exploration performed through a para-
sternal approach to establish the histology. A cervical approach is contrain-
dicated because of the extensive venous collaterals in the mediastinum.
If the syndrome is progressive with significant venous engorgement, vig-
orous attempts at diagnosis are quite hazardous and must be postponed in
favor of immediate treatment to prevent irreversible nervous system injury
or to avoid pulmonary complications.- 2 The diagnosis regarding the most
likely primary type of tumor is then based on all available clinical informa-
tion. For example, a young woman with a mediastinal mass alone would
suggest a diagnosis of lymphoma, whereas an elderly man with a long
smoking history and a right upper lobe mass would more likely suggest
bronchogenic carcinoma.
Prognosis
The prognosis of a patient with SVCS relates mainly to the histologic

type of the primary tumor. The median survival for lung primary tumors
that present with the syndrome, indicating extensive mediastinal disease, is
three to five months with treatment. In a series of eight patients with SVCS
secondary to lung cancer who were not treated, survival did not exceed ten
weeks. 29 Other nonthoracic primary tumors that metastasize to the medias-
tinum have similar prognoses. However, the prognoses of malignant lym-
phomas that produce this syndrome relate to the stage of the disease as
well as to the histologic type, with a good prognosis and possibility of cure
for limited disease or early stages.
TREATMENT
Surgery
Surgical approaches to SVCS have included bypass grafts and radical ex-
31
cision with vein grafting. 30, However, the surgical mortality and morbidity
rates are high because of the often profound venous engorgement and re-
sultant risk of excessive bleeding.The use of these procedures, therefore,
is avoided except in selected cases that are resistant to radiation and che-
motherapy. 22 In general, bypass grafts have not been successful as long-

term treatment.'12
Radiation Therapy
Radiation therapy is the mainstay of treatment of the superior vena caval

syndrome —both in the palliative situation for bronchogenic carcinoma and
in the curative situation for lymphomas.
Controversy has existed concerning the initial fraction sizes, balancing
the need for local control, and the risk of "radiation edema." Rubin et al. 33
demonstrated that faster and longer relief of symptoms is obtained by using
large initial fractions of radiation rather than beginning with small fractions
and slowly increasing the daily dose. He noted that morbidity did not in-
crease in patients receiving this high-dose therapy.
The total dose depends on the primary tumor and stage of the disease.
For epithelial tumors that are limited to local or regional extent, doses in
the range of 5000 to 6000 rad in five to six weeks are needed in a curative
attempt, whereas if there is distant disease, lower doses in shorter periods
in a palliative attempt are warranted. The lymphomas are more sensitive,
requiring 3500 to 4500 rad for local control.
The fields required also depend on the primary tumor and the extent of
disease. For lung primary tumors, the field is limited to the mediastinal
mass and supraclavicular nodes. A superior venacavagram is very helpful to
ensure inclusion of all areas of obstruction, 34 35 since the subclavian veins
'
can be involved in a significant number of patients 22 but may be excluded

in standard supraclavicular ports. For other tumors that are metastatic to the
mediastinum, palliative radiation using doses of 4500 to 5000 rad in five
weeks is indicated.
The response 75 to 95 per cent, 36, 37 with relief usually
rate to radiation is
noted within 1 week and lasting 20 to 23 weeks. 25 In a recent series by

36
Davenport et al., 36 18 of 19 patients with nonlymphomatous malignant

SVCS responded to high initial fraction (400 rad x 3) and high total dose
(3000 to 5000 rad) radiation. None of the responders has recurred, with a
follow-up of 1 to 39 months (median = six months).
Chemotherapy
Mechlorethamine has been used alone for SVCS and can produce an ac-
ceptable remission rate; however, the duration is much shorter than when
radiation is used. 23 Also, the side effects of chemotherapy, such as vomiting
and hematopoietic depression, may lead to intracerebral hemorrhage. Levitt
et al. 25 compared radiation therapy and mechlorethamine with radiation
therapy alone in a prospective randomized trial and found no difference in
remission induction or duration. However, more severe complications oc-
curred in the combined-treatment group. They concluded that most pa-

tients should receive initial high daily dose radiation, with mechloretha-
mine reserved for those who cannot receive radiation either because of
poor clinical condition precluding transportation to the therapy department
or because of prior radiation to tolerance doses.
Steroids have been advocated in cases in which respiratory compromise
may be associated withSVCS. 23 However, these drugs may decrease surviv-
al in patients with SVCS secondary to bronchogenic carcinoma 38 and there-
fore should not be used routinely.
Diuretics can be quite effective in providing immediate decompression,
but the response is very short-lived unless specific antitumor therapy is
39
given. 33, Fibrinolytic therapy has been used with radiation therapy to pre-
vent thrombosis, 40 although its value has not been established.
Superior vena caval syndrome that is secondary to lymphoma may be as
22
effectively treated with chemotherapy as with radiation; however, the
clinical situation often demands immediate treatment prior to the complete
evaluation of the patient, and systemic treatment may obscure accurate
clinicopathologic staging.

Improvements in the already high response rates for superior vena cava
syndrome by treatment with radiotherapy must await either new chemo-
therapeutic agents or radiation sensitizers that will increase the therapeutic
ratio of radiation.
The incidence of this syndrome can hopefully be reduced by early diag-
nosis and more effective local treatment of primary lung tumors, which ac-
count for three quarters of cases. More effective adjuvant treatment of other
primary tumors may prevent metastases to the mediastinum and subse-
quent development of the syndrome.
References {Asterisk indicates key reference)
1. Mayer E, et al: In Pulmonary Carci- Anderson CB, et al.: The treatment of

noma: Pathogenesis, Diagnosis, and malignant pleural effusions. Cancer
Treatment. Mayer E (ed), New York, 33:916, 1974.
New York University Press, p. 150, *9 Leff A, et al.: Pleural effusion from
1956. malignancy. Ann Intern Med 88:532,
2. Fracchia AA, et al: Cancer 26:626, 1978.
1970. 10. Leininger BJ, et al.: J Thorac Cardio-
3. Donegan VVL: In Cancer of the Breast. vasc Surg 58:758, 1969.
Spratt JS, Jr and Donegan WL (eds), 11. O'Bryan RM, et al.: Henry Ford Hosp
Philadelphia, WB Saunders Co.. Med J16:3, 1968.
p. 201, 1979. 12. Mark JBD, et al: JAMA 187:858,
4. Light RVV, et al.: Ann Intern Med 1964.
77:507, 1972. 13. Gellhorn A, et al: Chest 39:165, 1961.
5. Rittgers RA, et al.: Ann Intern Med 14. Ultmann JE, et al: Cancer i6:283,
88:631, 1978. 1963.
6. DeWald G, et al: N Engl J Med 15. Rubinson RM and Bolooki H: South
295:1494, 1976. Med J 65:847, 1972.
7. Lambert CJ, et al.: Ann Thorac Surg 16. Thoreau GK: Acta Chir Scand (Suppl)
3:1, 1967. 355:1, 1965.
17. Adler RH and Rappole B\V: Surgery 28. Hache L, et al.: Chest 41 :9, 1962.
62:1000, 1967. 29. Rosenbloom SE: Ann Intern Med
18. Cunningham TJ, et al.: Cancer 31:470, 1949.
29:1413, 1972. 30. Avasthi RB and Moghissi K: J Thorac
19. Jensik R, et al.: J Thorac Cardiovasc Cardiovasc Surg 74:244, 1977.
Surg 46:322, 1963. 31. Effeney DJ, et al.: Aust \Z ; Surg
20. Martini N, et al: Cancer 35:734, 1975. 42:231, 1973.
21. Schechter MM: Am
J Med Sci 227:46, 32. Spittell JA: Cardiovasc Clin 5:261,
1954. 1973.
*22. Lokich JJ and Goodman R: Superior "33 Rubin P, et al.: Superior vena cava
vena cava syndrome: Clinical man- syndrome. Slow low dose versus
agement. JAMA 231:58, 1975. rapid high dose schedules. Radiolo-
*23. Roswit B, et al.: The superior vena gy 81 :388, 1963.
cava obstruction in bronchogenic 34. Howard N: Radiology 81:380, 1963.
carcinoma. Radiology 61 :722, 1953. 35. Webb WR, et al: Am J Roentgenol
24. Rouviere H: Anatomy of the Human 129:146, 1977.
Lymphatic System, translated by 36. Davenport D, et al.: Cancer 38:1577,
Tobias MJ. Ann Arbor, Michigan, 1976.
Edwards Bros Inc, 1938. 37. Howard N: Clin Radiol 12:295, 1961.
25. Levitt SH, et al.: Cancer 24:447, 1969. 38. Wolf J: Am J Med 29:1008, 1960.
26. Silverstein GE: Dis Chest 56:519, 39. Holmes KS: Radiology 81 :402, 1963.
1969. 40. Salsali M and Cliffton EE: Surg Gyne-
27. Fairbank JT, et al.: Am J Roentgenol col Obstet 121:783, 1965.
115:488, 1972.
CHAPTER 29
PARANEOPLASTIC
SYNDROMES
Barry B Lowitz
INTRODUCTION
There increasing evidence that the production of ectopic substances
is
may be Although these substances are

a universal feature of neoplasia.
1
found in many normal tissues, they are present in increased amounts in

tumor tissue and often in the peripheral blood. Many are inactive but are
precursors of active substances.
Those ectopic substances that produce distinct clinical syndromes are
discussed in this chapter. 2, The clinical importance of these syndromes is
twofold. First, many of them can be successfully treated, thus providing
important palliation. Second, they can cause diagnostic confusion with be-
nign diseases, for which definitive therapy is quite different than for malig-
nant diseases. 4
29 / Paraneoplastic Syndromes 995
HYPERCALCEMIA
Background
Hypercalcemia is a common feature of many malignancies (Table 29-1). 5

" 9
A number of substances have been associated with its development, includ-

ing parathormone, prostaglandins, and peptides, all of which affect bone
6, 1(M5
turnover. -
appears that bone metastases per se are neither necessary nor sufficient
It
to cause the development of hypercalcemia. For example, in patients who

are hypercalcemic from squamous cell lung cancer, only one in six have
bone metastases. In small cell lung cancer, 20 to 50 per cent of patients
have extensive bone marrow disease with local bone invasion, yet hyper-
calcemia is not a feature. Conversely, the hypercalcemia of multiple mye-
1
loma appears to occur only when bone involvement is present. These data
suggest the local production of hypercalcemic substances by tumors meta-
static to bone. The bone reaction to the various substances that are pro-
duced appears to be that of turnover, i.e., both increased synthesis and deg-
radation. The exception is multiple myeloma, in which bone destruction is
accompanied by minimal bone synthesis, as shown by a normal serum al-
kaline phosphatase determination and bone scan.
Diagnosis
The development
of symptoms is related both to the blood calcium level
and with which the level increases. With rapid onset, there
to the rapidity
are often marked central nervous system effects, ranging from personality
change to coma. With a slower onset, there may be a history of anorexia,
TABLE 29-1. Malignant Causes of Hypercalcemia
Mechanism Tumor Types
Bone metastases with unidentified substances Main neoplasms

causing hypercalcemia
Prostaglandins Lung cancer
Ectopic parathormone Squamous cell lung cancer

Renal adenocarcinoma
Oral cavity cancer
Bladder cancer
Penile cancer
Parotid carcinoma
Histiocytic lymphoma
Esophagus cancer
POsteoclast activating factor and other unchar- Multiple myeloma

acterized substances Acute and chronic granulocytic leukemia
Additive endocrine therapy Breast cancer

TABLE 29-2. Non-Neoplastic Causes of Hypercalcemia
Hyperparathyroidism Milk-alkali syndrome

Hyperthyroidism Myxedema
Thiazide diuretics Renal insufficiency and transplantation
Sarcoidosis Diuretic phase of acute renal insufficiency
Acute adrenal insufficiency Hypervitaminosis A
Benign monoclonal gammopathy Paget's disease of bone
Acromegaly
Vitamin D intoxication
nausea, vomiting, constipation, polyuria and polydipsia, loss of memory,

and shortened QT interval on EKG. In chronic hypercalcemia, one may see
patients with blood calcium levels as high as 15 mg/dL, with only mild
symptoms. With an acute onset, one can see patients comatose at a level of
only 12 to 13 mg/dL.
In patients with known cancer, any of these symptoms should suggest the
diagnosis of hypercalcemia. Many of these patients may be dehydrated and
have complicating electrolyte abnormalities, particularly hypokalemia. 15
Consequently, the evaluation of serum electrolytes should accompany the
measurement of blood calcium, phosphorus, albumin, and serum alkaline
phosphatase.
There is a variety of benign conditions that can result in hypercalcemia

"
in cancer patients (Table 29-2). 16 22
The most important syndromes are hy-
perparathyroidism and Paget's disease of bone, since both are not uncom-
mon in the general population.
Occasionally, an elevated serum calcium level is found with tumors, such
as small cell lung cancer, that are not known to cause hypercalcemia. In
18
this setting, nonmalignant diseases must be considered. Benign and ec-
topic hyperparathyroidism produce hypercalcemia and increased blood par-
athormone levels (PTH) associated with hyperchloremic acidosis and an in-
crease in the ratio of urinary cyclic AMP (cAMP) to creatinine (greater than
4.2 millimoles of cAMP/gm of creatinine). 23-26 In tumors such as lymphomas,
breast cancer, and multiple myeloma, which do not produce PTH-like sub-
stances, these findings suggest parathyroid adenoma. 27, 28
There are several clinical features suggesting a benign cause of hypercal-
cemia. These include a long history of hypercalcemic symptoms, particular-
ly renal stones. Chronic changes on bone films, such as subperiosteal re-
sorption and cysts or a "ground glass" appearance of the skull, suggest
possible hyperparathyroidism.
Paget's disease ofbone may resemble metastatic cancer radiologically
and on bone scan, and the differential diagnosis rests on biopsy. 29 Other
diseases that produce positive bone scans are listed in Table 29-3.
In patients whose cancer is not imminently life threatening, the diagnosis
and treatment of a benign cause may provide better palliation than chronic
management of the hypercalcemia.
Treatment
The treatment of a patient with hypercalcemia depends upon both the

clinical status of the patient and the calcium level in the blood. For mild
elevations of serum calcium to 12.5 mg/dL in patients with minimal symp-
toms, the situation can often be controlled with a voluntary increase in oral
fluids, e.g., 2 to 4 liters per day above normal intake. If the calcium is not
well controlled with this measure, sodium phosphate (Fleet's Phospho-soda),
15 ml three to four times daily by mouth, may be added. If this management is
complicated by varying degrees of diarrhea, other measures may have to be
undertaken.
Moderate to severe hypercalcemia in patients with obvious symptoms re-
quires more aggressive management. 30 Saline diuresis is often effective;
this entails the intravenous administration of 4 to 6 liters of normal saline
per 24 hours with furosemide, 40 to 80 mg intravenously, every four to
eight hours. One must replace potassium and magnesium and observe the
patient closely for signs of fluid overload and congestive heart failure.
Mithramycin is useful for patients whose hypercalcemia does not respond
to saline diuresis and for those with cardiovascular disease or renal disease
who are at high risk of congestive failure with fluid loading. This drug is
given in a dose of 25 /xg/kg every four to five days. 31 With appropriate atten-
tion to liver function studies, blood counts, and coagulation parameters, this
can be carried on indefinitely.
It may take a day or two to lower the serum calcium level with either
mithramycin or saline diuresis. Patients who present with disorientation or

obtundation often require several days of normal blood calcium levels be-
fore their mental status improves.
Other therapeutic measures for the management of the more chronic hy-
percalcemias include the use of glucocorticoids, which are occasionally ef-
fective in the hypercalcemia of breast cancer. Indomethacin is reported to
alleviate the hypercalcemia associated with hypernephroma, 32 but we have
not confirmed this in any of our patients. Hypercalcemia may also improve
with the successful control of the underlying cancer.
Many patients with chronic hypercalcemia tolerate calcium levels as high
as 15 mg/dL with few symptoms. However, because of the danger of renal
damage, the levels should be normalized if at all possible.
TABLE 29-3. Benign Causes of Positive Bone Scan Results
Postfracture repair
Osteomyelitis
Paget's disease of bone
Hyperostosis frontalis interna
Osteoarthritis
Rheumatoid arthritis and other arthritides
Ankylosing spondylitis
Aseptic bone necrosis
Regional osteoporosis
HYPOCALCEMIA
Background
Hypocalcemia is an uncommon accompaniment to cancer. However,

there are several situations in which this condition is found. The first is in
hypocalcemia that results from magnesium deficiency. Patients become hy-
pomagnesemic from prolonged intestinal drainage procedures, from paren-
teral hyperalimentation without magnesium supplementation, and from se-
vere liver disease. 33 38 The magnesium deficiency appears to impair the
"
effect of parathormone on its target organs, resulting in hypocalcemia.

The second situation occurs in patients with breast cancer and wide-
spread lytic bone metastases, who respond to endocrine therapy with rapid
bone healing. 39,40 This is much like hypocalcemia produced by the "hungry
bone" syndrome following removal of parathyroid adenoma.
The third situation is the calcifying chondrosarcoma, 41 an extremely rare
situation in which tumor uptake of calcium appears to exceed the capacity
to mobilize body stores.
The fourth type of hypocalcemia is oncogenic osteomalacia in which a
tumor product appears to impair the production of 1,25-cholecalciferol (1,25
D). 42, 43 Hypocalcemia is unusual in this syndrome but has occurred, and it
responds to replacement of the 1,25 D.
Diagnosis
The principal clinical manifestation of hypocalcemia is tetany. Patients

may experience paresthesias, muscle cramps, laryngospasm, and even sei-
zures. Mental changes may occur and include irritability, lethargy, and loss
of recent memory. Papilledema may accompany long-standing hypocalce-
mia and suggests central nervous system metastases.
Hypocalcemia is found on routine blood studies, and the presence of
hypomagnesemia should be determined.
Tetany may be associated with severe alkalosis of any cause, e.g., hyper-
ventilation and prolonged vomiting. Muscle cramps, such as "charley
horses," are occasionally associated with procarbazine therapy. In these si-
tuations, the serum calcium level is normal.
Treatment
In severe hypocalcemia, a 10 per cent solution of calcium gluconate or

calcium chloride should be given intravenously. If hypomagnesemia com-
plicates the hypocalcemia, magnesium sulphate, 1 gm IV or IM, may be
administered every 8 to 12 hours until the combined defect is corrected.
For patients with healing bone lesions of metastatic breast cancer, the
use of oral calcium supplements can be added in a dose of 2 gm calcium
lactate four times a day orally. The serum calcium level should be moni-
tored every two to three days and the supplement stopped as normal levels
are reached.
URIC ACID NEPHROPATHY

Background
Several neoplastic states are associated with hyperuricemia. 44, 45 The high
"
concentration of uric acid may result in two types of renal damage. 46 48 The
first mechanism is that associated with neoplastic overproduction of uric
acid precursors. This situation is found in polycythemia vera, myeloid met-
aplasia, mast cell disease, and chronic granulocytic leukemia. As a conse-

quence of chronic moderately elevated levels of blood uric acid, either uric
acid renal stones or interstitial deposits of sodium urate may form. These
may result in renal colic, obstructive uropathy, or chronic renal failure.
The second mechanism of hyperuricemia is that which results from rapid
dissolution of neoplastic tissues following chemotherapy or radiation thera-
py. Examples of this situation include the initial treatment of acute leuke-
mias with chemotherapy and the radiation therapy of lymphomas. With
massive release of precursors, uric acid levels rise precipitously. As a re-
sult, uric acid crystals form in the highly concentrated and acidified urine
of the distal tubules. Intrarenal obstruction follows, and acute renal failure
ensues.
Diagnosis
If an underlying neoplastic disease has been diagnosed, hyperuricemia

should be sought and treated before renal damage develops. In patients
presenting with urate stones and hyperuricemia, examination of the periph-
eral blood may provide evidence of an underlying myeloproliferative dis-
order.
Acute oliguria following chemotherapy or radiation therapy suggests the
diagnosis of hyperuricemia, and elevation of uric acid in the blood will
often be far in excess of that associated with acute renal failure.
There are a number of benign diseases that are associated with hyperuri-
cemia and that may coexist with neoplasia. 44 These include hereditary gout,
hyperparathyroidism, psoriasis, sarcoidosis, and renal failure of any cause.
From a therapeutic standpoint, however, the finding of hyperuricemia obvi-
ates the importance of the proximate cause; the therapy is the same.
Treatment
When possible, uric acid nephropathy should be prevented. All patients

with known neoplastic disorders, especially those with myeloproliferative
diseases, should have a baseline serum uric acid determination. If uric acid
elevation of more than 9 mg/dL is found, allopurinol, fluids, and alkaliniza-
tion should be initiated.
All patients receiving chemotherapy for chronic granulocytic
leukemia,
acute leukemia, or highly radiosensitive lymphomas should have baseline
uric acid determinations and should be given allopurinol, as discussed in
Chapter 5. If possible, this regimen should be started a day or two prior to
the initiation of chemotherapy or radiation treatment. Patients with gouty
arthritis histories should also receive colchicine, 0.6 mg orally twice a day,
to avoid the acute attacks that can be associated with allopurinol adminis-
tration. Patients should be kept well hydrated. Alkalinization of the urine
with oral sodium bicarbonate may help prevent nephropathy.
In patients with acute distal tubule uric acid obstruction, management
includes the administration of allopurinol, together with the fluid and elec-
trolyte management used in other forms of acute renal failure.
SYNDROME OF INAPPROPRIATE
ANTIDIURETIC HORMONE (SIADH)
Background
hormone is normally produced by the hypothalamus in re-

Antidiuretic
sponse tohypovolemia or hyperosmolal states. There is a variety of volume
receptors, particularly intrathoracic, which appears to trigger ADH re-
lease. 49 The hormone acts on the distal collecting tubule to decrease free
water clearance. The net result is to reduce the concentration of sodium in
the blood.
A variety of neoplasms may be associated with high blood levels of
ADH. 50 53 The most common is small cell lung cancer. Radioimmunoassay
"
has demonstrated that the hormone is present in these tumors and is also
present in increased concentration in the blood. 54 K Since normal homeo-
'
static mechanisms fail to affect the increased ADH

levels, hyponatremia
develops in the presence of urine that is not maximally dilute. If sodium-
containing solutions are administered, the expansion of the intravascular
space results in prompt natriuresis; the sodium is thereby lost, and the syn-
drome remains uncorrected.
Diagnosis
Cancer patients, particularly those with small cell lung cancer, may de-
velop lethargy, weakness, confusion, convulsions, or coma. Blood electro-
lyte and blood urea nitrogen determinations are always indicated in this
setting. The finding of a low serum sodium concentration with a urine that
is not maximally dilute, i.e., specific gravity greater than 1.003 with a nor-
mal BUN, suggests the diagnosis.

Plasma and urine osmolality determinations are helpful. The urine osmo-
lality need not exceed that of the plasma to establish the diagnosis. A
normal adult should be able to dilute the urine to an osmolality of 50
mOsm/L. If the plasma osmolality is less than 260 to 270 mOsm/L, and one
finds a urine osmolality of 200 mOsm/L, the latter is inappropriately con-
centrated. Because of the already expanded extracellular space, the admin-
istration of saline is followed by prompt natriuresis and little change in
serum sodium levels.
If other fluid-retaining or salt-losing states are present, or if elevated
BUN or peripheral edema exists, the diagnosis cannot be made with cer-
tainty.
A variety of nononcologic clinical situations may result in hyponatremia.

There are three major groups: "benign" inappropriate ADH syndromes,
water-retaining states, and sodium-losing states (Table 29-4). 56 59 Of these,
'
perhaps the most common are heart failure, administration of diuretics with
unrestricted fluid intake, and inappropriate intravenous fluid management.
Although adrenal metastases are common in many forms of cancer, they
rarely cause adrenal insufficiency. However, if Addison's disease is present,
diagnostic confusion may result in patients who maintain their fluid and
salt intake. These patients also have an impaired ability to excrete a free
water load. However, unlike patients with inappropriate ADH syndrome,
fluid restriction in patients with Addison's disease will result in elevation
TABLE 29-4. Hyponatremia
Inappropriate ADH
Malignancies
Chemotherapy — cyclophosphamide; vincristine
Morphine; anesthetics
Pulmonary infections
Respirators
Acute intermittent porphyria
Central nervous system lesions
Other Types
Increased total body sodium (edematous states)
Liver disease
Congestive heart failure
Nephrotic syndrome
Decreased total body sodium

Addison's disease
Drugs — diuretics, chlorpropamide, carbamazepine, clofibrate, acetaminophen
Hypothalamic osmoregulatory defect
Renal salt wasting
of the BUN and hypovolemia occurs with little improvement in sodi-

level,
um When doubt exists, baseline and stimulated plasma Cor-
concentrations.
tisol determinations may be necessary for diagnosis.
Treatment
The mainstay of therapy for the syndrome of inappropriate ADH is fluid

restriction toone liter a day. In the past, lithium carbonate has been used
to ameliorate the syndrome. More recently, demeclocycline has been em-
ployed in doses of 800 mg to 1 gm per day orally. 60 6I Lower doses appear '
to be Many patients have been able to safely liberalize their

ineffective.
fluid intake while taking this agent. Demeclocycline has also been used for
the hyponatremia of chronic liver disease. These patients frequently devel-
op azotemia, which is reversible when the drug is discontinued. 62 Azotemia
has not yet been described as a complication of the use of demeclocycline
in cancer patients, but renal function should be carefully monitored.
Patients who are comatose or who present with serum sodium concentra-
tions of less than 110 mEq/L require aggressive treatment. Saline (3 per
cent) with potassium chloride should be administered at the rate of one
liter every six to eight hours. Furosemide (Lasix) should be used to prevent
fluid overload; the initial dose is 40 to 80 mg IV, with additional doses
administered as needed. 63 Patients must be monitored frequently for the
development of congestive heart failure and hypokalemia. Once the clinical
condition stabilizes, fluid restriction and demeclocycline may be instituted.
ECTOPIC ADRENOCORTICOTROPIC
HORMONE SYNDROME
Background
ACTHappears to be a product of many malignancies (Table 29-5), ,64 67

"
in which this biologically active substance is secreted together with large

amounts of prohormone and preprohormone. These substances have anti-
TABLE 29-5. Ectopic ACTH Syndrome
Frequent
Small cell lung cancer
Thymoma
Pancreatic cancer (especially islet cell)
Bronchial carcinoids
Uncommon
Ovarian cancer
Thyroid cancer
Pheochromocytoma
Prostate cancer
Renal adenocarcinoma
"A large variety of other malignancies have a rare association with ectopic ACTH production.
29 / Paraneoplastic Syndromes J 003
genie activity but little or no function. The precursor peptides may repre-
sent tumor markers, and, to date, benign conditions have not been shown
to produce elevated blood precursor levels.
In the ectopic syndromes, there is a complete loss of feedback control by
adrenal corticoids. There have been no clinical studies to date correlating
radioimmunoassayable ACTH (RIA-ACTH) with plasma Cortisol in a nor-
mal population. The assayable ACTH in patients with tumors does not nec-
essarily reflect physiologically active hormone. Measurable RIA-ACTH in
the face of normal or elevated Cortisol levels strongly suggests, but does not
prove, that the clinical symptoms are due to functional ACTH excess.
Diagnosis
In Cushing's disease or in syndromes from benign pituitary or adrenal

tumors or hyperplasia, the symptoms and signs usually evolve over months
to years. In malignancy, the cause is fulminant because of the aggressive
nature of the underlying cancers.
Typically, the patient will have a small cell lung cancer and complain of
generalized weakness. Cachexia is usually present, but the stigmata of
Cushing's disease — truncal obesity, "moon facies," and "buffalo hump'' —
are absent. Electrolytes show Plasma Cortisol lev-
a hypokalemic alkalosis.
els are elevated in the presence of measurable RIA-ACTH, and these levels
are not suppressed by 8 mg of dexamethasone given the night before. In
some patients the skin may show increased pigmentation, and in those with
slower growing malignancies, more of the clinical features of typical Cush-
ing's syndrome may appear.
The causes of weakness in cancer patients are numerous and include

psychogenic, metabolic, metastatic, and other paraneoplastic syndromes,
which are discussed in other parts of this chapter.
Hypokalemic alkalosis may result from vomiting, prolonged nasogastric
suction, enteric fistulae, and diuretics. Patients with acute deterioration of
chronic lung disease may become alkalotic following respiratory therapy,
particularly if they have received potassium-wasting diuretics. Hypokale-
mia is associated with hypophosphatemia and other electrolyte deficits in
patients undergoing intravenous hyperalimentation. Diarrhea, prolonged
acidotic states, and acute alkalosis of any cause may be associated with
hypokalemia. There is some association with hypercalcemia as well. 15
Treatment
Unless the underlying tumor can be controlled, the symptoms of ectopic

ACTH are difficult to manage. Potassium replacement is difficult to achieve
and requires 80 to 120 mEq or more per day. Attempts to prevent oral
potassium loss by spironolactone administration have not been rewarding,

and very high doses are required. Various combinations of o,p'-DDD, me-
tyrapone, or aminoglutethimide to suppress the adrenal gland usually cause
more toxicity than benefit but can be attempted in patients with very se-
vere symptoms. 68 70
"
NEUROMUSCULAR SYNDROMES
Background
The causes of paraneoplastic neuromuscular syndromes are not well de-

fined. Some occur in the setting of impaired host immunity and may reflect
viral diseases. Other syndromes may occur as a result of autoimmune phe-
nomena. Another postulated mechanism is tumor production of biomole-
cules that interfere with neurotransmitter metabolism or that block neurore-
ceptor sites. To date, only progressive multifocal leukoencephalopathy has
been associated with a causative agent, a papovavirus. However, effector
molecules are not yet identified for any of these syndromes, and all these
mechanisms remain conjectural.
Diagnosis
Table 29-6 gives a list of syndromes that have been associated with can-
71 " 75
cer. Of those affecting the brain, dementia is the most common; cerebel-
lar ataxia is not rare.
Fortunately, paraneoplastic spinal cord syndromes are uncommon, but
they are often dramatic. A large variety of syndromes have been described,
including transverse myelitis, rapidly evolving forms of amyotrophic lateral
sclerosis, and a necrotizing ascending myelonecrosis in which the spinal
cord almost literally turns to jelly. Many of these syndromes are rapidly
lethal. Some cause chronic neurologic disability. None clearly respond to
treatment, although the course is sometimes temporarily stayed with the
control of the underlying tumor.
Peripheral neuropathies of sensory, motor, or combined types are not in-
frequent. A peculiar acquired variant of the Shy-Drager syndrome occasion-
ally accompanies malignancy, particularly small cell lung cancer. This syn-
drome includes deterioration of the autonomic nervous system function
with severe orthostatic hypotension and no accompanying orthostatic in-
crease in pulse rate.
A myasthenic syndrome, known as the Lambert-Eaton syndrome, is also
found most frequently in association with small cell lung cancer. Patients
with this disease develop generalized muscle weakness, which is most
prominent in proximal muscle groups. The electromyogram shows increas-
ing recruitment of muscle units with repetitive stimulation.
Polymyositis may be associated with, or even precede, the diagnosis of
cancer. Only a small percentage of patients developing this condition are
TABLE 29-6. Effects of Cancer on the Nervous System
Direct Effects Type of Tumor
Spinal Cord. Lung, breast, stomach, mye-

Early pain (usually radicular), followed by weakness loma, lymphomas, others.
sensory changes, and incontinence.
Compressive neuropathies of peripheral nerves. Many solid tumors. Amyloi-

dosis secondary to myeloma.
Indirect Effects Type of Tumor
Sensory neuropathy. Ovary, lung, others.
Encephalomyelitis. Oat cell carcinoma of the lung.

Loss of recent memory, hallucinations, seizures, con-
fabulation. Spinal fluid may be normal (40 per cent)
or have increased protein and round cells.
Dementia. Lung, ovary.

Diffusely slow electroencephalogram. Loss of recent
memory.
Subacute cerebellar degeneration. Lung, ovary, Hodgkin's dis-

Dysarthria, ataxia, hypotonia, dementia. No nystagmus, ease, breast.
No focal signs.
Peripheral neuropathy. Lung, myeloma, Hodgkin's

Distal weakness; decreased deep tendon reflexes; ma\ disease.
respond to steroids.
Motor system syndrome. Lung.

Focal amyotrophy or upper limb weakness and fasciculation
with increased lower limb reflexes and Babinski signs.
Subacute necrotic myelopathy. Lung, breast, possible
Rapidly destructive hemorrhagic disease; death in weeks. lymphoproliferative states.
Cerebrovascular accidents. Pancreas, prostate, lung,

Caused by hypercoagulable states, thrombocytopenia, myeloma.
hyperviscosity syndrome.
Infections. Lymphomas, leukemia.

Slow virus syndromes. Lymphomas, leukemia.
Progressive multifocal
leukoencephalopathy.
found have malignancy. Muscle pain and weakness are the important
to
and are associated with the elevation of blood aldolase and
clinical findings
creatine phosphokinase levels.
Carcinomatous myopathy is associated with a number of cancers and
presents with weakness but no enzyme changes or pain.
The most crucial clinical aspect of most of the neurologic syndromes is to

rule out treatable causes.
Organic dementia may result from metastases, both to the brain sub-
stance and to the meninges. The diagnosis may be established by the radio-
isotope brain scan or coaxial transverse tomography (EMI scan). Lumbar
puncture with cytologic studies may demonstrate metastases. Personality
changes may be metabolic in origin, reflecting abnormalities in calcium,
sodium, or even glucose homeostasis. Blood electrolytes, calcium, BU\, and
creatinine determinations should be performed, as should liver function
studies. Organic brain syndromes and psychoses may result from procar-
bazine or high-dose corticosteroid therapy. Patients who have received pre-
vious brain irradiation may later develop encephalopathy, especially with
methotrexate administration.
Cerebellar ataxia resulting from a paraneoplastic syndrome is usually as-
sociated with dementia. The absence of an accompanying dementia leads
one to suspect cerebellar metastases. An EMI scan is usually necessary to
detect these lesions. 5-Fluorouracil can produce a rather disabling cerebel-
lar ataxia that is usually reversible when the drug is discontinued.
Spinal cord syndromes are assumed to result from compression by the
tumor until it is proved otherwise. Patients who develop weakness in their
legs and problems with bowel or bladder control —
with or without back
pain — must have an emergency myelogram done under the supervision of
a neurosurgeon. A lumbar puncture should not be performed prior to the
myelogram, since it makes this procedure difficult to perform or uninter-
pretable. Special fluid for diagnostic studies may be taken at the time of
myelography. Myelography is essential to exclude a compressing lesion or
an obstruction as high as the foramen magnum. Lesions at this level can
initially present with lower extremity symptoms. The paraplegia and very
high cerebrospinal fluid protein levels of ascending hemorrhagic myelone-
crosis suggest cord metastases with obstruction. Meningeal carcinomatosis
may give similar findings and CSF cytology may help in establishing the
diagnosis.
Transverse myelitis is occasionally seen in association with the peripher-
al administration of methotrexate, particularly in previously radiated areas
of the spinal cord. The episodes may cause temporary or permanent signs
of cord transection.
The peripheral nervous system may be affected by neuropathy —
e.g.,
from diabetes, collagen vascular diseases, pernicious anemia, or toxic or nu-
tritional causes. The neurotoxic effects of the vinca alkaloids must be con-
sidered in the differential diagnosis. These drugs can cause irreversible
paraplegia.
Muscle weakness may be caused by iatrogenic or endogenous glucocorti-
coid excess, hyperthyroidism, associated collagen vascular disease, and
even late-onset dystrophies. Potassium deficiency from diarrhea, vomiting,
diuretics, or the ectopic ACTH syndrome may be responsible for weakness.
Determination of the blood levels of calcium and electrolytes may be help-
ful. Thymomas, including invasive types, may be associated with myasthe-
nia gravis. This disease bears no resemblance to the myasthenic syndrome
of Lambert-Eaton, although the two are often contrasted. True myasthenia
gravis involves the facial musculature, shows decreased electromyographic
response to repeated muscle stimulation, and responds to edrophonium
chloride (Tensilon).
Treatment
Few of the paraneoplastic neuromuscular syndromes are responsive to

therapy. The progression of paraneoplastic dementia may be temporarily
stayed by the control of the underlying cancer, but improvement is rarely
seen. The same appears to be true for the other spinal cord syndromes and
neuropathies.
Patients with malignant polymyositis may respond to control of the un-
derlying cancer. Glucocorticoids are of questionable benefit but should
probably be administered in severe cases. Attempts to manage patients
with the malignant Shy-Drager syndrome have included salt loading, fludro-
cortisone (Florinef), and "G-suits," all with questionable benefit and consis-
tently unfavorable outcomes. Patients with the Lambert-Eaton syndrome
may respond well to guanidine hydrochloride in a dose of 125 to 400 mg
three to four times per day in adults. Strength often improves substantially
within a few days.
Experience in the management of ascending hemorrhagic myelonecrosis
is obviously limited. Although most patients rapidly progress to a fatal out-
come, we have tried a combination of cyclophosphamide, in low daily

doses (50 to 100 mg orally), and prednisone (80 mg/m 2 ), with temporary
arrest of the ascending symptoms of cord destruction in two patients. How-
ever, it may well be that these patients represented only part of the spectrum
of the natural historv of this syndrome.

Manx of the distant effects of malignancy are the result of mechanisms
and tumor products that are as yet undiscovered. The paraneoplastic sub-
stances that have been identified to date are normal gene products that are
produced or secreted in excess. There is no reason to suspect that those
products that have not yet been identified are cancer specific. The identifi-
cation of these chemicals and the definition of the mechanisms controlling
their synthesis may nonetheless be of value in cancer treatment. Such sub-
stances may be useful markers of neoplastic cell growth and may therefore
be useful in guiding treatment. A better understanding of their physiologic-
roles may also allow a better definition of the mechanisms of neoplastic cell
growth and differentiation.
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33. BalintIA and Hirschowitz BI: N Engl 22:693, 1962.
J Med 265:631, 1961. 68. Fishman L, et al: J Clin Endocrinol
34. Fletcher RF, et al: Lancet 1:522, 27:481, 1967.
1960. 69. Child DF, et al.: Acta Endocrinol
35. Flink EB, et al: J Clin Med 43:169, 82:330, 1976.
1954. 70. Hutter AM
and Kahoe DE: Am J Med
36. Randall RE, et al: Ann Intern Med 41:581, 1966.
50:251, 1959. *71. Horenstein S: Distant effects of neo-
37. Gitelman HJ and Welt LG: Annu Rev plasms on the nervous system. Post-
Med 20:233, 1969. grad Med 50:85, 1971.
38. Madalle R and Waterhouse C: Ann In- 72. Wilkinson M, et al.: Proc R Soc Med
tern Med 79:76, 1973. 60:683, 1967.
39. Hall TC, et al: N Engl J Med 73. Croft PB, et al: Brain 88:501, 1965.
275:1474, 1966. 74. Brain L, et al: Brain 88:479, 1965.
40. Randall RE and Lirenman DS: J Clin 75. Bames BE: Ann Intern Med 84:68,
Endocrinol Metab 24:1331, 1964. 1976.
CHAPTER 30
PAIN SYNDROMES
IN MALIGNANT
DISEASE
Ulrich Batzdorf
Pain in cancer patients may result either directly from the malignancy or
indirectly from the various modalities of treatment. Paindue to malignancy is
generally severe and persistent, and the type of treatment depends primarily
on its severity an^ location rather than on its mechanism. The group of
syndromes resulting indirectly presents a different problem, since pain may
occur in the absence of known active tumor proliferation. The management of
these conditions, therefore, is akin to that of chronic pain states of benign
origin. Only the direct type of cancer pain is discussed in this chapter.
The most common types of pain syndromes related to cancer are listed in
Table 30-1.
EVALUATION OF PAIN CAUSED BY

MALIGNANCY
Three areas of consideration enter into the evaluation of pain that is due to
the malignant process — namely, pharmacologic, anatomic, and psychologic.
With respect to pharmacologic aspects, it is important to establish the follow-
ing: (1) the availability of a regimen of medication that will suffice to keep the
patient free of pain, (2) the specific drug or combination of drugs and the
TABLE 30-1. Pain Syndromes Related to Malignant Disease
Pain Syndromes Directly Caused by Malignancy

Involvement of viscera and their parietes
Involvement of bone and periosteum
Involvement of nerves, nerve roots, and nerve plexuses
Fain Syndromes Indirectly Related to the Malignant Process

Postirradiation peripheral neuropath
Peripheral neuropathy secondary to chemotherapy
Chronic incisional pain
Phantom limb pain following amputation
Postherpetic neuralgia in the immunosuppressed host
1009
1010 III / Management of Selected Complication >
dosages to accomplish such pain relief, and (3) whether or not the side effects.
if any, of analgesic drugs are acceptable to the patient, the family, and the
physician. If a regimen of analgesics can leave a patient comfortable without

producing undue anorexia, confusion, or somnolence (provided that the pa-
tient is otherwise well enough to be alert and active), such therapy should be
employed in preference to neuroablative operations. Only ready alternatives,
such as radiation therapy (Table 30-2), should be given serious consider-
ation, since it is best to keep the patient free of pain without the administra-
tion of analgesic medication for as long as possible.
Anatomic evaluation of the pain state should include (1) site analysis and (2)
route analysis of the painful condition. Site analysis should provide clear
answers to the following questions: (1) Is the pain focal or diffuse? (2) Is there
just one area of pain or are there multiple foci? (3) Is the pain unilateral or
bilateral? (4) Does the pain involve midline structures or extremities, or both?
The importance of these factors in relation to the choice of a pain-relieving
procedure is discussed in this chapter.
Route analysis aims to establish the neural pathways by which the patient's
pain may be interrupted. This is most readily accomplished by critically
placed nerve blocks that block peripheral nerves, nerve plexuses, nerve roots,
or the spinal cord itself. 2 Sympathetic blockade may also be useful in evalu-
1 '
ating some pain syndromes that are seen in association with malignancy. It is
important that the information obtained by such nerve blocks can be reliably
interpreted, and for this reason radiographic control of needle placement is
recommended whenever necessary.
Successful nerve blocks have the additional advantage of demonstrating to
the patient that the pain can be relieved and is not necessarily inevitable.
They may also serve to provide a means of reassurance, even though therapy
may be declined or postponed.
Although the psychologic aspects of cancer are discussed in Chapter 32, it is
appropriate to mention here that the relationship between pain and the
emotional state of the cancer patient must be clearly recognized. Pain may
provide a means for the cancer patient to express anguish. 3 Persistent, severe
pain undoubtedly also contributes to depression, insomnia, anorexia, and a
sense of isolation. In some centers, a multidisciplinary pain clinic functions
well in the evaluation of pain patients, including those with pain due to can-
cer.
MODES OF PAIN THERAPY

Pain therapy may be classified as local, systemic, or regional, as shown in
Table 30-2.
Local Pain Therapy
The consideration in assessing cancer pain should always be the possi-

first
bility of local therapy. Currently, the most widely used form of pain palliation
in cancer patients is local radiation therapy, which is discussed at length in
Chapter 3.
30 / Pain Syndromes in Malignant Disease 1011
TABLE 30-2. Classification of Modes of Pain Therapy
Local Pain Therapy

Excision and decompression
palliative resection
decompressive laminectomy
Immobilization
nonsurgical
surgical
Radiation therapy
Systemic Pain Therapy

Analgesic drugs
Antineoplastic drugs
Endocrine therapy: supplemental or deprivational
Psychotherapy and hypnosis
Regional Pain Therapy

Denervation procedures
chemical
surgical
peripheral nerve
nerve plexus
nerve root
spinal cord and brain stem
thalamus
frontal lobe
autonomic path\va> s
Acupuncture
Neuroaugmentative procedures
Palliative surgical resection that is carried out primarily for the relief of pain
has been found to be effective number of areas, primarily in tumors
in a
involving the extremities. Excision or decompression of a tumor mass will
often reduce pressure on contiguous nerves and relieve stretching of the
parietes, both of which may be sources of pain. En bloc resection that in-
cludes portions of the brachial plexus has been advocated for pain palliation
in superior sulcus (Pancoast's) tumors of the lung. 4 Local excision of a perineal
sinus has been found to be effective in controlling pain in this area. Decom-
pressive laminectomy of an area of spinal epidural metastasis or mechanical
cord compression will often produce useful relief of local spinal pain.
Simultaneous nerve root decompression may be effective in controlling asso-
ciated root pain. Recently, radiation therapy with steroid coverage has been
advocated in place of laminectomy for patients with carcinoma of the breast
who have spinal metastases. 5,6 It is most important that all patients who
undergo nonsurgical therapy for spinal metastases be followed carefully by a
neurologist or neurosurgeon if disastrous neurologic complications are to be
avoided.
Bone destruction may produce pathologic movement or fractures a sec- —
ond important source of pain. Even temporary immobilization of such lesions
may be very helpful, and it can reduce pain while other, longer range adjunc-
tive measures —such as radiation therapy or chemotherapy —
are under way.
In the extremities, pain may be relieved by limb immobilization, either
externally by plaster splinting that can be removed for radiation therapy or, in
suitable cases, by intramedullary bone stabilization with a metal rod. 7,8
Similar considerations apply to the metastatic involvement of the spine. In

the cervical region, a firm cervical brace may provide sufficient immobiliza-
tion for pain palliation, although when vertebral subluxation threatens spinal
cord function, more rigid immobilization by means of a halo device may be
necessary. Firm bracing with a chair back-type leather and steel brace will
often provide pain relief for patients with thoracic or lumbar vertebral in-
volvement. This technique also affords pain relief and spinal stability to many
patients with multiple myeloma involving the spine while they are undergo-
ing radiation therapy. Patients who require rigid internal stabilization of the
spine may obtain relief by employing either methylmethacrylate or another
method of surgical stabilization. 9 10 '
Systemic Pain Therapy
Analgesic Drugs. When drugs are administered for the relief of pain,
the administration of simple medications should precede the administration
of complex compounds. Likewise, the effectiveness of non-narcotic drugs
should be determined before a narcotic regimen is begun.
Moertel et al. lu 12 have shown by means of randomized studies that acetyl-
salicylic acid or acetaminophen (650 mg), alone or in combination with co-
deine (65 mg), is the most effective analgesic regimen and is superior to many
more complex drug regimens. Among oral narcotics, 13 they found meperidine
(200 mg), anileridine (50 mg), codeine (120 mg), or methadone (15 mg)
highly effective when used in ambulatory patient analgesia.
Concern about the addictive qualities of analgesic drugs is out of place in
most instances of cancer pain management. Fordyce 14 has pointed out the
advantages of employing time-contingent, rather than pain-contingent, proto-
cols of analgesic administration. This shift away from "prn" pain medication
reduces the tendency to pain reinforcement by medication perse. Brompton's
analgesic mixture 15 is effective for patients whose disease is clearly terminal.
The reader is referred to standard treatises in pharmacology for a general
discussion of analgesic drugs. 16
Chemotherapy. Pain relief by chemotherapeutic agents is dependent
upon a reduction of tumor size as well as tumor destruction wherever tumor
invades nerves. The effectiveness of appropriate chemotherapy is discussed
in the specific chapters dealing with various tumor types.
Hormonal Control. Endocrine approaches to the problem of cancer
pain control have been employed chiefly with respect to endocrine-
dependent breast and prostatic tumors and are discussed in the chapters
dealing with these specific tumors. Endocrine ablation by oophorectomy,
adrenalectomy, or hypophysectomy 17 may result in very dramatic relief of
pain, particularly pain due to bony metastases.
The recent demonstration of pituitary destruction or ablation affording
substantial pain relief in patients with tumors that are not endocrine depend-
ent is of considerable theoretic and practical interest. The destruction of the
pituitary by intrasellar instillation of alcohol for pain relief was introduced by
Moricca 18 and is now being employed experimentally with some success in
30 , Pain Syndromes in Malignant Disease 1013
several clinics in this country and abroad. One third to one half of patients
20
with diverse tumors are reported to have obtained pain relief. 19 Diabetes
-
insipidus and pituitary insufficiency develop in most patients; cerebrospinal

fluid leaks and ocular palsies may be encountered complications. Tindall et
al.
n have reported pain relief by transnasal hypophysectomy in a small group
of patients with genitourinary, pancreatic, and adrenal tumors. The numbers
of patients treated in follow-up are not sufficient to permit more than a
tentative opinion at this time; it is hoped that these procedures will be found
useful in the management of cancer pain in years to come.
PSYCHOTHERAPY. A detailed discussion of psychotherapy and hypnother-
apy in the management of pain in the cancer patient is beyond the scope of
this chapter. The reader is referred to various texts on this subject.-- 2:?
Some
patients achieve a degree of pain control through hypnotherapy, thereby
allowing a reduction in the amount of required analgesic medication. When a
patient is amenable to hypnosis and the physician feels it would be beneficial,
this form of therapy should be attempted before large doses of narcotics are
administered or surgery is undertaken for pain relief. 23 The benefits of psy-
chologic support for the distraught cancer patient are beyond question.
Regional Pain Therapy
Local and systemic pain therapy are usually employed before a patient is
considered for regional therapy. Often, these are patients who cannot receive
additional radiation or chemotherapy for palliation.
Interference with the conduction of pain can be carried out at several
different levels of the nervous system —
from the periphery to the cerebral
cortex —
as indicated in Table 30-2. A number of techniques are available for
nerve destruction. Chemical techniques —
using neurolytic agents such as
phenol and alcohol or hypertonic saline —
radiofrequency thermal lesions,
and ablative or destructive surgical techniques are discussed in this sec-
tion.
Careful site and route analyses of the patient's pain must be undertaken
before consideration of a neurodestructive procedure. It is clear that the
potential for the relief of pain, particularly by a more peripheral procedure,
must be established on the basis of appropriate reversible nerve blocks before
a permanent or semipermanent procedure undertaken. 2 Because the inter-
is
1
pretation of a single nerve block procedure may be open to question, it is

probably wise to perform several such blocks, including a placebo or sham
block, before a destructive procedure is performed.
It must be clearly understood by the patient and his family that there is
some type of permanent deficit, usually sensory in nature, associated with

neurodestructive procedures. Often, the temporary block will acquaint the
patient with the type of sensory deficit he can anticipate postoperatively. If
this deficit proves to be unacceptable to the patient, a different approach to
pain relief may have to be considered. Occasional long-term pain relief fol-
lowing a single nerve block has been noted by many observers and further
justifies performing blocks before a destructive procedure is undertaken.
Facial and Head Pain

Peripheral Nerve. The indications for peripheral neurectomy in the treat-
ment of facial pain resulting from cancer are rather limited. Transection or
avulsion of branches of the trigeminal nerve has occasionally been employed
but has largely been replaced by radiofrequency coagulation of the retrogas-
serian nerve roots or thalamotomy. Alcohol blocks may afford relief for several
weeks. 24
Sensory Nerve Root. Rhizotomy of trigeminal rootlets is useful in the
management of facial pain caused by cancer. 25 For many years, retrogasserian
section of the trigeminal rootlets, maxillary and mandibular nerve resection,
and ganglionectomy were all carried out by a subtemporal craniectomy ap-
proach to the middle cranial fossa and Meckel's cavity. In recent years, this
direct surgical approach has, in many instances, been replaced by a percuta-
neous radiofrequency needle electrode procedure, 26 which is carried out
under local anesthesia with ultrashort-acting barbiturate anesthesia (metho-
hexital). The morbidity with this operation is lower than that with subtem-
poral craniectomy because of the surgical approach and the anesthetic used.
The percutaneous procedure should not be considered when tumor has in-
volved the cheek through which the needle must pass or has invaded the bone
at the base of the skull in the area of the foramen ovale. Similarly, when there
is evidence of tumor involvement in the area of the gasserian ganglion, it is
preferable to perform a trigeminal root section under direct vision in the

posterior fossa or to consider the patient for thalamotomy.
Trigeminal rhizotomy by either craniectomy or the percutaneous approach
is best suited for patients whose pain appears to be superficial in the jaw,
cheek, forehead, or eye. Using the craniectomy approach, White and Sweet27
reported pain relief in approximately half of their 36 patients, whereas Leav-
ens and Barrash 25 found worthwhile results following trigeminal rhizotomy in
17 of 19 operations. Using the percutaneous approach, Sweet 28 noted total
pain relief in only 4 of 11 patients. Recurrence of pain on the same or opposite
side, deep facial pain, and pain outside the trigeminal nerve territory are the
major causes of failure with any of these approaches.
Pain in the ears, the pharynx, the palate, and the tongue requires more
extensive nerve root section or other procedures. Multiple cranial nerve
section, including the nervus intermedius and the glossopharyngeal and
vagus nerves, may be necessary and can be carried out in conjunction with
posterior fossa trigeminal rhizotomy. White and Sweet 27 reported complete
and lasting pain relief in 7 of 19 patients surviving this operation, whereas 8 of
the remaining patients experienced transient pain relief. Failures were due to
pain developing in the areas that were not denervated. Approximately two
thirds of 18 patients reportedby Leavens and Barrash had satisfactory relief
2,5
of pain following this procedure. High cervical sensory rhizotomy may be

necessary in addition to achieve pain relief. Dysphagia, dyspnea, and hoarse-
ness are among the complications of this procedure.
The considerable morbidity and mortality associated with posterior fossa
multiple cranial nerve section, as well as the substantial failure rate due to
recurrent pain associated with spreading tumor or scarring, or both, has given
29
impetus to a consideration of thalamotomy for these patients.
Medullary and Mesencephalic Tractotomy. Section of the trigeminal sen-

son tract at the medullary level may be considered for the relief of facial
-
pain.- 7 At present, percutaneous trigeminal rhizotomy is performed more

extensively for such symptoms. Medullary trigeminal tractotomy is con-
sidered primarily in patients who have tumor or necrotic lesions in the
pathway of the other operative approaches. The percutaneous approach has
also been modified for placing radiofrequency lesions within the trigeminal
tract at the brain stem level, but experience with these procedures has been
limited. 30 31 Mesencephalic tractotomy has been largely abandoned because
-
of the resulting high morbidity and mortality rates.

Thalamus. Thalamotomy has been employed for over two decades for the
relief of pain caused by cancer. It is indicated in patients in whom other
pain-relieving procedures have failed or cannot be carried out. Many are
patients with facial pain from malignant tumors, in whom ulcerations, necro-
>is. and fistulas preclude more local procedures. Thalamotomy is carried out
under local anesthesia. Focal destructive lesions of thalamic nuclei have been
produced by radiofrequency thermal lesions," by means of freezing probes, 33
and by targeted radiation. 34 The presence of intracranial metastases is a con-
traindication to this procedure because normal anatomic landmarks would be
distorted. The patient should therefore undergo cerebral computer scanning
before this procedure is considered.
In the early years of stereotactic thalamotomy for the relief of pain, destruc-
tive lesions were placed in the main sensory nuclei of the thalamus — the
posterov entral nuclei. Such lesions produced sensory deficit, but pain relief
was less than satisfactory. Far better pain relief has been achieved with
lesions that are placed in the more medial intralaminar nuclei, the nucleus
centromedian, and the parafascicularis. Lesions that are placed in the anterior
or dorsomedial nucleus have the effect of a frontal leukotomy. Occasionally,
electrodes are left in place at surgery, allowing a lesion in the thalamus to be
built up incrementally in the alert patient outside the operating room over a
period of several days or weeks
In one series of terminal cancer patients, 32 19 of 38 individuals obtained
excellent or good relief of pain. Eight of 20 patients who were treated with the
gamma radiosurgery system had good or moderate relief of pain. 34
The techniques of thalamotomy require special expertise and equipment,
which is not widely available, so that this procedure has been carried out
primarily at selected centers throughout the world. It must be considered a
major operation and should not be undertaken unless clearly indicated.
Frontal Lobe. Frontal leukotomy and the related procedures of frontal
corticectomy and cingulotomv are rarely performed for the relief of pain in
this country.*7, * These procedures deserve consideration in the very anxious,
agitated patient whose pain cannot be controlled by other means. Patients
with disfiguring head and neck tumors are among the most distressed. Since
these procedures do not abolish pain, the results are not as readily evaluated.
A major disadvantage of these procedures is the resulting personality dis-
order, seen particularly after extensive leukotomy. Personality changes are
less severe with unilateral leukotomy and have been further reduced by the
use of gradually enlarged radiofrequency thermal lesions using implanted
electrodes. With the latter technique, White and Sweet 27 achieved gratifying
pain relief in 19 of 22 patients. Equally successful pain relief has been

reported with cingulotomy. 35
Trunk and Extremity Pain — Visceral Pain

Peripheral Nerve. Occasionally, pelvic tumors or tumors metastatic to the
pubic bone may produce severe pain in the distribution of the obturator
nerve. A reversible block of this nerve, using lidocaine or bupivacaine, may
be accomplished under radiographic control. Occasionally, pain relief fol-
1
lowing such blocks may continue well into a course of radiation therapy.
Nerve Plexus. Excision of the lower trunk of the brachial plexus as part of
an en bloc resection has been recommended as a means of pain relief for
4
patients with superior sulcus (Pancoast's) tumors of the lung. Severe motor
and sensory deficit involving the hand results, but similar loss of function is
not uncommon from tumor invasion per se. Substantial loss of function of this
type would be more acceptable when there is a possibility of a curative
resection, assuming that equally effective pain palliation cannot be achieved
by other less disabling procedures. It is a formidable procedure that should be
considered when disease has extended beyond the limits of resectability.
Sensory Nerve Root. Rhizotomy is rarely used for relief of truncal or
extremity pain in cancer patients, because other procedures — notably cordo-
tomy —offer equally effective pain relief without producing total sensory
denervation of the limb and are more easily accomplished. Rhizotomy has,
however, been found useful as an adjunct to high cervical cordotomy in the
treatment of pain caused by superior sulcus (Pancoast's) tumors because relief
of low cervical or shoulder pain does not always follow high cervical cordo-
tomy. 36 Section of the higher cervical nerve roots (C3 and C4) alleviates
shoulder pain without producing disabling neurologic deficit. Section of one
or at the most two posterior roots of the brachial or lumbar plexus may be
acceptable in terms of limb function. White and Sweet27 noted a 58 per cent
early success rate and a 36 per cent early failure rate in 33 patients who
underwent posterior rhizotomy for the relief of pain from cancer in the cervi-
cal and thoracic area. Loeser37 reported 43 per cent long-term pain relief
among 13 patients who underwent rhizotomy.
been advocated as a simple means of relief for patients
Sacral rhizotomy has
with perineal pain who have had a colostomy and are already dependent on
38
catheter drainage of the bladder. Using this technique, Felsoory and Crue
reported satisfactory pain relief in 20 of 28 patients. The least satisfactory
results were seen in patients with carcinoma of the cervix caused by early
lumbosacral plexus invasion. This author is impressed by the difficulty of
controlling perineal pain in spite of anatomically adequate sacral nerve root
section. A less extensive differential sacral rhizotomy can be considered in
patients whose micturition function is preserved. 39
Another alternative technique is the use of intrathecal neurolytic agents
such as phenol or alcohol. 2, 24, 27 These procedures are extremely useful in the
management of pain resulting from cancer and have the advantage of being
applicable to patients who are not well enough to withstand a more extensive
surgical procedure. They must be performed by experienced personnel, since
there are definite risks of motor root destruction and sphincter denervation.
Neurolytic rhizolysis is therefore particularly useful in patients who no longer

have normal sphincter function as a result of either their disease or surgery.
White and Sweet 27 reported 44 per cent successful pain control in 41 patients
employing 7.5 per cent phenol in iophendylate (Pantopaque) and 60 per cent
successful control in 22 patients using 5 per cent phenol in glycerin.
Brechner2 reported good results in 11 of 15 patients receiving intrathecal
phenol in glycerin, preferring a 7.5 per cent solution. Absolute ethanol pro-
vided substantial pain relief in 58 per cent of 322 patients with advanced
cancer, 40 but the duration of effect may be shorter. Chemical neurolytic rhizot-
omy is also useful as an adjunct to pain management in patients with bilateral
pain who cannot undergo bilateral high cervical cordotomy (see later discus-
41
sion). Intrathecal iced saline has also been found useful. Savitz and Malis
reported complete pain relief until death in one third of a group of patients,
whereas another ten patients had almost total relief until pain recurred ap-
proximately eight weeks later.
Spinal Cord and Brain Stern. Spinothalamic tract section has, to date,
been the single most useful procedure for the relief of pain in cancer patients.
For many years, the operation was carried out by direct surgical approach,
requiring a laminectomy — often under general anesthesia. Since 1965, the
open procedure has been largely, but not completely, replaced by a high
cervical percutaneous approach — carried out under local anesthesia w ith a
needle electrode. 42 43 When connected to a radiofrequency generator, a grad-
ed thermal radiofrequency (RF) coagulative lesion is produced. The use of
fluoroscopic image intensification, tissue-impedance measurement tech-
niques, and stimulation testing have all helped greatly to increase the accura-
cy of the percutaneous approach. As a result, many patients who previously
could not be considered candidates for cordotomy may now undergo this
procedure. Morbidity is generally low, the required time of hospitalization is
short, and wound healing problems are eliminated.
Cordotomy is the procedure of choice for unilateral extremity or trunk pain,
but a unilateral procedure is not helpful for midline pain. The operation may
also be performed bilaterally for bilateral pain problems, but this requires
certain modifications. Percutaneous cordotomy carried out at the CI to C2
level produces contralateral pain relief, but often results in denervation of the
diaphragm (phrenic nerve innervation from C2, C3, and C4) ipsilateral to the
cordotomy lesion. 44 Bilateral high cervical cordotomies are thus carried out
more safely at different levels, in order to avoid bilateral phrenic denervation.
An alternative approach is to combine percutaneous cordotomy on one side
with a neurolytic rhizolysis on the opposite side. 2
Similar considerations preclude the use of high cervical cordotomy for
patients who have undergone pneumonectomy or who have a nonfunctioning
lung and pleuritic chest or shoulder pain on the side of their pulmonary
impairment. For the same reasons, chronic lung disease presents a relative
contraindication, depending on the severity of the respiratory insufficiency.
However, when pain is situated in the lower part of the body, such patients
may still be considered for cordotomy at the thoracic level — performed by
the classic open technique under direct vision. Percutaneous cordotomy
using the radiofrequency technique is not always successful. The procedure
can be repeated after an interval of two or three days; if the second attempt
should fail, open cordotomy by the laminectomy approach should be consid-
ered.
The immediate results of cordotomy indicate that at least two thirds to three
43,43" 47
fourths of patients obtain excellent pain relief, 27 '
although somewhat
lower figures have been reported in some clinical studies. Motor weakness
ipsilateral to the cordotomy may occur in 10 to 20 per cent of patients, but it is
most often transient. 27 45, 48, 49 Disturbances in bowel and bladder function and
'
hypotension are encountered particularly after bilateral cordotomies. Morbid-

ity and mortality rates are generally lower for the percutaneous approach.
Tractotomy at the level of the brain stem was advocated particularly for
patients with high shoulder or neck pain, since even a high cervical (CI to C2)
cordotomy may not adequately relieve such pain. 27 High morbidity of the
mesencephalic approach and improvements in technique of percutaneous
cordotomy have made this technique largely obsolete. Spinothalamic tracto-
tomy at the medullary level has been performed for similar indications and
has a better record with respect to morbidity and mortality. 27 These proce-
dures require expertise that is not universally available. Percutaneous ap-
proaches to medullary tractotomy have been developed. 50
Based on anatomic considerations, division of the anterior white commis-
sure at the midline of the spinal cord divides sensory fibers serving pain and
temperature before they enter the spinothalamic tract. The procedure of
median myelotomy has recently gained new favor for the control of bilateral
pain, particularly in the lower half of the body. 51 52
'
Another type of tractotomy, sectioning Lissauer's tract (tractus dorsola-

53
teralis) has been proposed and is of considerable theoretic interest. This
procedure has been used only rarely — partly because of the relative ease of
performing a percutaneous spinothalamic tractotomy.
Thalamus. Thalamotomy should be considered when other pain-
relieving procedures have failed. Although this procedure is more frequently
performed for patients with facial pain, in expert hands it has yielded suc-
cessful relief for cancer pain in other areas. 32 54 The reader is referred to the
'
previous section on thalamotomy for details.

Autonomic Pathways. Because of their proximity to major extremity blood
vessels, some tumors, such as those near the brachial plexus, are associated
with painful vasomotor changes. If sympathetic blockade with local anesthet-
ic agents proves beneficial, long-term sympathectomy, either by means of
phenol injection or by surgical extirpation, should be considered.
Intractable abdominal or back pain caused by carcinoma of the pancreas
responds favorably to bilateral thoracic sympathectomy and splanchnicec-
tomy. In one study of 56 patients, 70 per cent achieved complete or good
pain relief. 55 Recurrence of some pain was seen in about one fourth of the
patients who initially had adequate relief. Splanchnic plexus injection with
phenol or alcohol may be used as an alternative to surgical neurectomy in
suitable cases, if expertise in the injection technique is available. 24 Such
procedures may afford pain relief for several weeks to months, which is often
sufficient to initiate other measures such as chemotherapy or radiation thera-
py and is sometimes adequate for the patient's remaining lifetime.
ACUPUNCTURE. Acupuncture has been used for the treatment of all pain-
ful conditions, including cancer. Critical data are not available at this time to
permit quantitative assessment of the success rate with this technique. It
appears to be a harmless technique, provided that the needles are adequately
sterilized to prevent transmission of hepatitis virus. Patients occasionally
request a trial course of acupuncture before they will consider more serious
interventive therapy. Although a physician might not wish to actively encour-
age acupuncture, a trial course of therapy is acceptable.
Neuroaugmentative Procedures. Transdermal stimulation may be
used as an adjunct to other forms of pain therapy in cancer patients, 56 and in
some individuals it may help to reduce pain to tolerable levels. It is unlikely
to be useful as a sole means of control for severe pain.
Various manufacturers have designed signal generators, which are connect-
ed to simple rubber pads taped to the skin over the painful areas. Except for
local skin irritation caused by the conducting jelly that is experienced by
some patients, there are no known complications. Stimulators may be used for
distal extremity pain in patients with cardiac pacemakers, but should not be
used across the chest or abdomen or in the vicinity of the pacemaker lead. 57
Surgical implantation of an electric stimulator overlying the dorsal columns
of the spinal cord is no longer used for pain control because of serious
associated complications and doubtful effectiveness. 58 Stimulation techniques
using electrodes implanted into the thalamus and into the periaqueductal
gray matter are currently in use at several medical centers."' 9 The electrodes
are activated by a small transmitter that is taped over a subcutaneously
situated receiver.The patient is able to control the intensity of stimulation
with manually operated dials. The relationship of periaqueductal stimulation
to the endorphin system promises to be the key to important future develop-
ments in pain therapy. Periaqueductal stimulation must currently be consid-
ered experimental, but it appears to be promising for the control of cancer
pain. 60

There is no expectation that the cancer pain problem can be solved in the
near future. However, as the investigations in the area of endorphins are
extended, one can anticipate important advances in pain pharmacology.
There is now evidence linking pain relief obtained by periaqueductal brain-
stem stimulation to the endorphin system. It has been suggested that the
enigmatic analgesic effects of acupuncture are related physiologically to this
system; 61 a similar relationship may also exist with pain relief by pituitary
adenolysis. Although implantation of stimulating brain electrodes will be
feasible for only a small number of cancer patients, one may hope that new
and more be developed
effective drugs will as a result of the current inves-
tigations into pain mechanisms.
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Philadelphia, Lea ik Febiger, 1953. 40:143, 1974.
2. Breehner VL: In Neurological Surgery, *27. White JC and Sweet WH: Pain and the
Vol 3. Youmans JR (ed), Philadelphia, Neurosurgeon. Springfield, 111, Char-
WB Saunders Co, 1979. les C Thomas, 1969.
3. Chapman LF: Trauma 7:49, 1965. 28. Sweet WH: Clin Neurosurg 23:96,
4. Paulson DL: J Thorac Cardiovasc Surg 1976.
70:1095, 1975. 29. King RB: In Neurological Surgery, Vol
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6. Cobb CA, et al.: J Neurosurg 47:653, Saunders Co, 1979.
1977. 30. Crue BL, et al.: Bull Los Angeles
7. Parrish FF and Murray JA:/ Bone Joint Neurol Soc 32:86, 1967.
Surg 52A :665, 1970. 31. Hosobuchi Y and Rutkin B: Arch
8. Harrington KD, et al.: J Bone Joint Surg Neurol 25:115, 1971.
58A: 1047, 1976. 32. Mark VH and Ervin FR: In Pain and the
9. Seoville WB, et al.: J Neurosurg 27:274, Neurosurgeon. White JC and Sweet
1967. WH (eds), Springfield, 111, Charles C
10. Hoppenstein R: Bull Hosp Joint Dis Thomas, 1969.
33:66, 1972. 33. Rand RW: Int Surg 49:212, 1968.
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813, 1972. ciples, Pharmacology, Therapy. Lon-
12. Moertel CG, et al.: JAMA 229:55, 1974. don, Churchill Livingstone, p. 194,
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1. 1976. 35. Foltz EL and White LE: J Neurosurg
14. Fordyce WE: In Advances in Neurolo- 19:89, 1962.
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Press, 1974. 23:639, 1965.
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31 / Physical Rehabilitation 1021
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Symposium on the Neurosurgical 61. Marx JL: Science 195:471, 1977.
CHAPTER 3
PHYSICAL
REHABILITATION
Lawrence S Miller Richard M Davis
John Beumer III Joseph W Cullen
INTRODUCTION
Rehabilitation may be
defined as a coordinated multidisciplinary program
of techniques to restore an ill or disabled individual to his or her capabilities
in physical, mental, social, vocational, and economic usefulness. Some forms
of cancer treatment induce major physical defects; comprehensive care for
patients with such defects must include physical rehabilitation. The full
implementation of a rehabilitation program for cancer patients involves all the
standard factors, in addition to specific goal-oriented variations. Examples
include (1) physical therapy for postmastectomy lymphedema, (2) physical
therapy for an amputee, (3) speech therapy following laryngectomy, and (4)
enterostomal therapy for a colostomy. Optimally, these approaches should be
carried out in specialized rehabilitation centers, where the staff is skilled in
dealing with patients with a variety of impairments and disabilities.
In some cases, rehabilitation starts after the completion of therapy, although
it appears that even greater success can be achieved by starting efforts of
rehabilitation during the pretreatment phase of a patient's care. The benefits

of this early attention to rehabilitation may include more than just the pallia-
tion of morbidity and restoration of body function. It may prevent treatment-
induced sequelae that can be as serious as the underlying cancer.
GENERAL CONSIDERATIONS
Medical centers that have instituted physical rehabilitation programs for
cancer patients have been impressed with the reduction in the disease and
treatment-induced somatic dysfunctions. They acknowledge that appropriate
1
therapy for such impairments can markedly improve the function and overall
well-being of the individual. They acknowledge that special consideration
should also be given to the feelings of the personnel who are working with the
cancer patient, the cost-effectiveness of services to the cancer patient, and the
quality of life that can be obtained within the survival period.
Formally constituted cancer rehabilitation centers generally establish ex-
plicit criteria for admission. The first criterion is usually that the patient is
more or less medically stable. Second, there must be a reasonable chance to
achieve desired goals to improve the quality of life. If the patient is to return
home, the patient and family are instructed in the adequate care necessary to
maintain the highest quality of living, even if for only a few months. If
estimated survival time is six months to a year, goals may be to gain improve-
ment in functional performance —concentrating on self-care activities and
ambulation. If long-term survival is a possibility, the goals are directed
toward achieving a stable living environment.
Once goals are established, an appropriate rehabilitation program needs to
be outlined. The program may include many or all of the various services,
depending on the patient's needs. Although many physicians may be in-
volved in the care of the cancer patient, including the family physician,
surgeon, chemotherapist, radiation therapist, and other specialists, as needed,
these physicians do not direct rehabilitation programs because of time con-
straints and lack of training in this specialized area. Consequently, they
typically turn to other health professionals to effectively coordinate the treat-
ments aimed at the total rehabilitation of the patient. Ideally, these other
professionals formally, or at least operationally, compose a team that can
include any or all of the following: a medical director, nurse, enterostomal
therapist, physical therapist, occupational therapist, speech pathologist, psy-
chosocial counselor, and social worker.
A physiatrist, when available, is probably best suited as the medical direc-
tor because of his special training and working knowledge of internal medi-
cine, neurology, and musculoskeletal dysfunction. However, other specialists
have been able to assume the role. The most important attribute of a rehabili-
tation director, besides expertise and commitment to the rehabilitation proc-
ess, is probably his or her ability to effectively lead and organize both physi-
cian and allied health team professional in a consolidated approach to the
cancer patient.
Physical therapists might work on extremity strengthening activities and be
involved in teaching transfers, wheelchair use, and ambulation. They might
also use various modalities such as heat, exercise, and so on in an attempt to
increase strength and range of motion of the extremities as well as reduce
pain. Special pain treatment programs may be indicated, as discussed in
Chapter 30. Occupational therapists might be involved in increasing the
patient's endurance by various task-oriented activities. They might also in-
struct the patient in self-care and other activities of daily living. They could be
involved in instructing the patient and family in proper homemaking activi-
ties and the use of assistive devices. Occupational therapists may also be
involved in prevocational assessment and training, if this is considered realis-
tic.
Rehabilitation nurses could assist the patient in obtaining the most comfort-
able existence possible. They might attempt to motivate him or her to be as
independent as possible and to socialize more. When necessary, they could
work with the family members, instructing them in optimum care of the
patient. They might also be involved in a bowel and bladder training program,
as necessary. Specialized enterostomal therapists might also be available as
needed for these specific areas of training. The social worker and psychologist
give input to the patient and family in addition to providing suggestions and
comments at the team conferences.
It is essential that the treating staff become informed in their approach to
cancer patients. The team psychologist often spends as much time helping the
staff deal with their feelings as he does helping the patients themselves.
These psychologic considerations are discussed further in Chapter 32.
The following discussions of rehabilitation in the enterostomal patient and
in the patient with head and neck malignancies typify the considerations to be
made and the technology that is available for meaningful rehabilitation. Simi-
lar analyses and restorative services also pertain to other cancer sites.
REHABILITATION OF
ENTEROSTOMAL PATIENTS
easy to understand and focus rehabilitative measures on those defects
It is
that are clearly visible, as in the head and neck or with the loss of extremities.
These immediately create problems of appearance, eating, or locomotion. The
problems of urinary or gastrointestinal defects that divert urine and feces
through the abdominal wall to the exterior are equally distressing to the
patient, perhaps even more so because of the psychosocial aspect of interac-
tion with family and society in general. 2
In our culture, the problems of body waste disposal have become quite
personal and private. The concept of bodily cleanliness is culturally impor-
tant. It not only implies the use of soap and water but the application of many
different kinds of lotions and potions to every part of the body to enhance the
male and female image and social attractiveness, not the least of which is
sexual orientation.
Although the concept of colostomy and ileostomy was discussed and even
attempted during the eighteenth and nineteenth centuries, it was not until
1913 that an acceptable ileostomy procedure was devised. 3 By this time the
colostomy had become an accepted surgical procedure. Urinary diversion via
an enterostomy was not developed until 1951 by Bricker and Modlin. 4 Ostomy
methods were further enhanced by many others, but current surgical proce-
dures are principally due to the work of Brooke 5 in England and Crile and
Turnbull 6 7 in the United States.
-
ENTEROSTOMAL THERAPY TEAM
Therapist
Nursing Physician
Generalist
Volunteer Patient's
Family
Social Psychosocial
Worker Support Personnel
FIGURE 31-1. Schematic representation of the dynamic interactions of the

enterostomal therapy health team.
The difficult problems of ileal dysfunction, prolapse, and herniation are

now understood sufficiently to permit corrective measures at the time of
surgery that prevent these complications from taking place. 7 Many different
kinds of colostomies for the treatment of colon dysfunction have been created.
Both temporary and permanent stomas can now be constructed and cared for
in quite a satisfactory manner. In many medical centers, it has also been
most fortunate that surgeons and allied health personnel interested in stomal
management have utilized a team approach. In fact, in the past decade the
clinical literature has been enhanced by many articles written by surgeons,
nurses, psychologists, and others, outlining the multiple methodologies in
enterostomal therapy. Without a question, the nurse-enterostomal therapist
has been a major contributing factor in the excellent stomal care available
today. 8 Figure 31-1 schematically depicts the interactions of the team care
approach, highlighting the patient as the focal point.
Although the colostomy, ileostomy, and urinary diversionary procedures
are performed for medical conditions other than cancer, the physical prob-
lems created are quite similar. The psychologic problems faced by the
cancer patient, however, are different. The situation is usually acute and the
cancer patient has not experienced the prolonged pain and suffering that a
chronic illness, such as ulcerative colitis, creates. The psychologic response
of the patient with the chronic condition who must face an enterostomy
is tempered by the fact that the alternative to the procedure is worse than
the problems created. 9 Conversely, the cancer patient may have to face
the fact of cancer rather suddenly with all the implications for discomfort
and even death. Such an individual must decide accept the medical
to
treatment (including, in this case, a diversionary stoma) for the continua-
tion of life.
Preoperative Preparation
From the surgical standpoint, the most important goal is to carry out the
operation as indicated without compromise. It is important to plan the proce-
dure in advance, however. When the creation of a stoma is involved, the site
should be selected and marked preoperatively, so that the patient can satisfac-
10
torily render optimal care of the effluent. 7, This is true whether the stoma is
temporary or permanent and whether it is an ileostomy, colostomy, urinary
diversion stoma, or mucus fistula. Techniques for these have been described
in many publications, but the most comprehensive discussion is that by
Turnbull and Weakley. 7 It is the responsibility of the surgeon to explain the
surgical procedure to the patient and explain that a stoma will be created in
the selected site. Either the surgeon or the professional enterostomal thera-
pist can then explain the immediate postoperative care and plan that will be
instituted for self-care and management.
Although this need not be done in great detail preoperatively, the general
idea and plan should be discussed. In addition to the patient, the spouse or
closest family member should be advised of this situation and reassured that
stomal care is not difficult and can be effectively managed by the patient
himself. It should also be stressed that social acceptance and activity can be
achieved and maintained in a very short time, often coinciding with recovery
from the surgical procedure.
Successful rehabilitation will depend on the preoperative preparation of
the patient and family, with a clear explanation of the reasons for the surgical
procedure, the defect that will be created, and the manageable outcome. 11
Postoperative Preparation
confidence can be instilled in the patient early in the manage-

If a feeling of
ment of the stoma, his or her concepts of subsequent self-care are en-
hanced. 12, 13 As the patient gradually adjusts to the situation, the enterostomal
therapist and nursing personnel are key facilitators in creating an atmosphere
of confidence and a positive self-image by discussing their care methods in
relation to those that the patient will carry out as soon as possible. It is most
important, therefore, that the nursing postoperative procedures be carried out
meticulously to prevent any unusual soiling or skin irritation from the stoma
effluent. The care of the stoma is then taken over by the patient before he
leaves the hospital under the direct supervision of the expert nursing person-
nel. This includes discussions of various appliances, skin care, and other
problems encountered by people who live with a stoma. 14 If a colostomy
FIGURE 31-2. Postoperative stomal irrigation.
is involved, irrigation procedures should be learned in the hospital before

dismissal (Fig. 31-2). Similarly, diet, management of diarrhea episodes, odors,
accidents, appliance bulge under the clothing and even such topics as sports,
travel, and stomal care away from home should be discussed.
Sexuality problems can be further complicated when the surgical proce-
dures have caused either neurogenic or actual anatomic defects in the geni-
talia. This requires conferences with the spouse and patient to explain the
defect, including the possibility of either permanent impotence or a delay in
return of function. Impotence in the male following rectal carcinoma surgical
procedures can be either temporary or permanent. It may take six months or
longer for final determination, and counseling about such risks is essential.
Cystectomy with urinary diversion creates permanent impotence and should
be so stated. 9 Vaginal defects in the female can be of great concern physically
as well as psychologically with problems affecting the patient's perceived
femininity.
Rehabilitation in sexual compatibilitymay be important to the patient and
may require special counseling in current concepts of sexual interactions
and techniques. 9 It is important that these problems be discussed before the
patient has been dismissed from surgical care. The timing of such discussions
is critical and will depend on the patient's background and experience. This
fact is another reason for a team approach in the patient's treatment plan. A
more detailed discussion of the psychosocial aspects of rehabilitation is treat-
ed in Chapter 32 of this text.
Outpatient Considerations
Follow-up conferences and outpatient care are necessary. Problems en-

countered, even if fully discussed before hospital dismissal, are disturbing
when experienced for the first time by the patient who becomes solely re-
sponsible for his care.
Largely because of medical disinterest in the past, the definitive care of

stomal patients was undertaken by groups of former patients with stomas who
allied themselves into organizations for the mutual benefit of discussion
related to stomal care (ostomy clubs). Although the medical community is now
more accepting of its responsibilities in this regard and is providing enteros-
tomal therapy guidance through outpatient clinics and professional specialty
nursing personnel (enterostomal therapists), there is still a need for these lay
groups to function in supportive roles. It is of great psychologic and material
benefit to patients with the same or similar physical defects to exchange ideas
and problems with one another. 8
PROSTHETIC REHABILITATION OF
HEAD AND NECK DEFECTS
Surgical removal of benign and malignant tumors of the head and neck
region can result in functional disability and cosmetic disfigurement. Prosthe-
ticrestorations may enable these patients to function at near normal levels
and provide an acceptable appearance. The prosthodontist is confronted with
three basic surgical defects: those involving the maxilla and adjacent struc-
tures, those involving the mandible and associated structures, and those
afflicting facial features — such as the nose, eye, ear, or cranium. The degree
of functional restoration and appearance is dependent upon the extent of
surgery and the adaptability of the patient.
Optimal results are obtained when all members of the therapy-
rehabilitation team have the opportunity to see and discuss the patient's
problem prior This affords the prosthodontist the opportunity to
to treatment.
obtain photographs and facial and intraoral impressions that will be useful
during construction of the postsurgical prostheses. This specialist can explain
to the patient the degree to which his defect may be restored by this method.
Successful adjustment to the postsurgical defect is often dependent upon a
realistic understanding by the patient of the degree of potential improvement
afforded by the future prosthetic restorations. 15
Maxillary Defects
Maxillary surgical defects secondary to removal of neoplasms vary from

small perforations of the hard or soft palate to complete eradication of these
structures. These defects, regardless produce major functional
of size,
disability and, occasionally, cosmetic disfigurement. Speech will be hyperna-
sal, mastication will be compromised, and deglutition will be difficult, since
food and fluids are often forced into the nasal passages during function. Some
patients present with substantial facial disfigurement resulting from facial
nerve weakness, loss of the zygomatic arch or the orbital contents, or both.
Prosthetic restorations re-establish the physical separation between oral and
nasal cavities and, in soft palatal defects, enable normal velopharyngeal func-
tion. Most patients can be rehabilitated successfully, with the restoration of
FIGURE 31-3. Following radical maxillectomy, an immediate surgical ob-

turator supports the surgical packing, obturates the defect, and restores
palatal contours, permitting normal speech and swallowing immediately
postoperatively.
speech and swallowing to normal levels, accompanied by substantial im-

provement in appearance.
Surgical Orturation. Restoration of maxillary defects with an immedi-
ate surgical obturator at surgery offers a number of advantages (Fig. 31-3).
The obturator provides a platform upon which surgical packing can be placed;
it reduces oral contamination of the wound and gives the patient the ability to
speak in the immediate postoperative period. It restores swallowing earlier,
often eliminating the need for a nasogastric tube. This restoration renders the
patient's postoperative course more bearable and often lessens the psycholo-
gic and emotional impact of surgery.
The size of the obturator is determined by the surgical boundaries of the
resection. These prostheses are processed in methyl methacrylate. Alteration,
if necessary, can be effected at surgery by the use of a temporary denture
reliner. The prosthesis is anchored to the remaining teeth, alveolar ridge, or

other available structures (zygomatic arch, anterior nasal spine, and so
forth).
When surgical packings are removed (seven
days postoperatively),
to ten
the prosthesis is relined with a temporary denture reliner. As healing pro-
gresses, the obturator is extended further into the defect with subsequent
additions improving seal and retention. Two to three months following sur-
gery, and after initial wound contracture is complete, construction of the
definitive prosthesis is begun.
Definitive Orturation. In both edentulous and dentulous patients, the
shape of the obturator is important for optimal support and retention (Fig.
31^4). The prosthesis is extended posteriorly onto the soft palate to effect an
adequate seal. The superior lateral extension important for cheek support; it
is
also improves retention and provides a seal. The bulb portion of the obturator
should be hollow to reduce weight. Partial maxilleetomy defects can be
effectively restored with this prosthesis. Remaining teeth are valuable in
retaining the restoration in position and enhancing its stability.
Soft Palate Defects
The unlike those in the hard palate, are functional,

soft palate defects,
constantly changing in size and shape during speech and swallowing. The
functional deficits are similar to those of the hard palate, such as hypernasality
FIGURE 31-4. A, Patient with radical maxillectomy and orbital exentera-

tion. B, Same patient.Sote that the lateral wall of the intraoral defect is
lined with a split-thickness skin graft. C, Same patient. The obturator re-
establishes the separation between the oral and nasal passages and provides
support for the teeth. D, Same patient. She is also wearing an orbital prosthe-
sis.
FIGURE 31-5. Following removal of an epidermoid carcinoma of the

of the moutli, the tongue was sutured to the lip to effect closure
(interior floor
of the wound.
of speech and leakage of food and fluids into the nasal passages during deglu-
tition.
The attached to either a partial or complete denture
soft palate obturator is
and remains in a fixed position. During function, the adjacent structures of the
remaining soft palate and the posterior and lateral pharyngeal walls close
around it, thereby achieving velopharyngeal closure. Care must be taken to
prevent positioning the restoration too low in the nasopharynx or it may
interfere with the tongue during deglutition. Speech and swallowing are
restored to normal with this prosthesis.
Mandibular Defects
Unfortunately, most oral cancers arising in the tongue and floor of the
mouth region require a composite resection, unless the lesion is detected
quite early. Such a resection often includes portions of the tongue, floor of the
mouth, alveolar mucosa, and mandible in continuity with a radical neck dis-
section.
Resections of the mandible and associated structures, prompted by an
intraoral malignancy, result in substantial functional disability as well as
cosmetic deformity. The functional disabilities include impairment of speech
articulation, difficulty in swallowing, inability to control salivary secretions,
and deviation of the mandible toward the side of the defect compromising
mastication. Unfortunately, in most patients, neither reconstructive surgery
nor prosthodontics can offer worthwhile restoration of function.
Speech. After most composite resections, control and movement of the
tongue are compromised primarily because this is such a useful tool in effect-
ing surgical closure of the intraoral wound (Fig. 31-5). Even though it may be
surgically released at a later date, the function of the tongue will never
approach presurgical efficiency. Prosthetic restorations have offered little
speech improvement to this group of patients.

Control of Saliva. Inability to control salivary secretions is a bitter

complaint of many patients. It results from impaired tongue function, loss of
lingual and help channel and pool saliva posteriorly, and
labial vestibules that
the impaired sensory function and posture of the lower lip on the side of the
resection. Releasing the tongue and surgically re-establishing the lingual
sulcus is distinctly beneficial.
Mastication. After loss of mandibular continuity, deviation toward the
side of the surgical defect of the remaining fragment occurs. The degree of
deviation varies and depends upon the nature of the surgical closure and
whether pre- or postoperative radiation therapy was employed. This deviation
prevents intercuspation of teeth, thereby making normal mastication impossi-
ble. Impaired tongue control and mobility also compromise chewing efficien-
cy.
After a composite resection, the edentulous patient has little hope of chew-
ing effectively with dentures. Therefore, remaining teeth, particularly in the
mandible, assume added importance; all efforts should be made to save those
that are present. Full dentures that are made for edentulous patients serve
primarily aesthetic functions. They provide support for the lips and cheek and
may improve articulation of selected speech sounds. A mandibular guidance
prosthesis may eliminate mandibular deviation and improve mastication.
Often, the only hope for improvement is to surgically restore the continuity
of the mandible. This may provide improvement as well as
useful functional
cosmetic benefits. When small segments of the mandible have been lost
mandibular bone grafting is useful. However, following many composite
resections, in which one third to one half of the mandible is missing, surgical
reconstruction generally unsuccessful. After these large resections, recon-
is
struction is because of the lack of sufficient soft tissue for graft

difficult
coverage and the difficulty in achieving proper fixation of the graft during the
postsurgical healing period. Preoperative or postoperative radiation therapy
furher compromises the viability of the tissue bed by reducing its vascula-
ture.
A variety of methods have been employed mandi-
in surgically restoring the
ble. Graft sources include the iliac crest, rib, and clavicle. Rib grafts have not
proved to be successful in these patients, and clavicular grafts have been used
only sparingly. Most defects are restored with either particulate autogenous
marrow housed in a metal tray, or with a block of bone, both of which are
normally obtained from the iliac crest.
Facial Defects
Surgical reconstruction of small facial defects possible in most cases and

is
is usually the preferred treatment. Manx patientswould rather mask a defect

with their own tissue than with a prosthetic restoration. However, in large
defects, reconstruction is difficult, and the final cosmetic and functional re-
sults are often limited and unpredictable.
A variety of reasons exist as to why prosthetic rehabilitation of large facial
defects is preferred. First, when a large resection is necessary, and recurrence
of tumor is likely, it is advantageous for the surgeon to be able to closely
FIGURE 31-6. A, This patient required a total rhinectomij for a rhabdo-

myosarcoma. B, Same patient. A nasal prosthesis of polyurethane was added
three months following resection.
monitor the surgical site. A prosthesis allows for this observation, whereas
primary surgical reconstruction may preclude this opportunity and may sub-
stantially delay discovery of recurrent disease. Second, restoration of large
defects is technically difficult and generally requires multiple procedures and
hospitalizations. The usual geriatric age group confronted with this kind of
defect is generally unable to tolerate the multiple procedures required for
such reconstruction. Third, increasing numbers of these tumors are being
treated with radiation therapy. Decreased vascularity and increased fibrosis of
the tissue bed increases the risk of complications and the difficulty associated
with reconstruction. Even when surgical reconstruction is deemed possible,
substantial delay may be necessary for the assurance of tumor control.
Nasal Prosthesis. With total rhinectomy defects, highly acceptable
prostheses can be constructed (Fig. 31-6). The nostrils may be tucked into the
nasolabial folds, and eyeglass frames may be useful in disguising the lateral
and superior margins. Retention is effected with adhesives.
Ear Prosthesis. Presurgical models and photographs are invaluable in
achieving best results. In those patients in whom presurgical consultations
are not obtained, attempts are made to find a suitable "donor ear." An impres-
sion of the patient's normal ear is obtained and a suitable subject whose ears
are similar in form to those of the patient is selected. The donor ear is
reproduced in wax and adapted to the patient. Minor adjustments are usually
necessary to ensure an acceptable result. Ear prostheses are held in position
with skin adhesives. In addition to the obvious cosmetic benefit, the ear
prosthesis helps hold eyeglasses in position and facilitates hearing.
Orbital Prosthesis. Construction of an eye prosthesis is the most de-
manding and difficult of all facial restorations. The color of the iris, position of
the eye, and the contour of the lids are all critical factors. The slightest
discrepancies associated with any of these structures bring attention to the

prosthesis. Margins may be effectively concealed with eyeglass frames (Fig.
31-4D). Retention is accomplished by eyeglass frames or medical grade skin
adhesives.
Large Midfacial Defects
Although advanced tumors of the midfacial region are slowly and locally
invasive, they occasionally require extensive surgical ablation to eradicate the
disease. The resulting surgical defect may involve the loss of both extraoral
and upper lip, cheek, and
intraoral structures, including portions of the nose,
orbital contents, as well as segments of the maxilla, mandible, associated soft
tissue, and teeth (Fig. 31-7). The functional impairment incurred by such
extirpative procedures may be severe. Loss of integrity of the oral cavity
results in difficulty in mastication, swallowing, control of saliva, and speech.
These functional disabilities, in combination with the accompanying cosmet-
ic disfigurement, usually have a substantial psychologic impact on the patient
and his family. However, many patients with such surgical defects have been
rehabilitated successfully with prosthetic restorations (Fig. 31-7). Speech and
swallowing may be restored to near normal levels, and the control of saliva
and mastication may be improved.
The structures that are most important to the restoration of chewing func-
tions are the maxilla and maxillary teeth. If substantial portions of the maxilla
remain, the appliance can render acceptable stability. Residual teeth are
especially helpful in retention, and all efforts should be made to retain as
FIGURE 31-7. A, Patient with a large midfacial defect. B, Same patient.

Midfacial defeet restored with a polyurethane prosthesis.
many as possible, regardless of their condition. If little or no maxilla remains,

mastication cannot be effectively restored.
When surgical reconstruction of the defect isnot contemplated, slight modi-
fications of the operative technique that is used to excise the tumor, if they do
not compromise eradication of the disease, may be beneficial to the prostho-
dontist and the patient. These include retention of the teeth, which sub-
sequently can be used to support and retain the prosthesis, and preparation of
soft-tissue areas that will be opposed by the restorations, such as the creation
of undercut areas for the retention and placement of skin grafts to minimize
tissue contracture. The prosthodontist may aid the surgeon in these proce-
dures by fabricating surgical stents for support of skin grafts and surgical
obturators when portions of the maxilla are to be removed.
Construction of the permanent appliance is begun when healing is com-
plete. For large defects, a two-piece appliance may be advantageous. One
section restores the integrity of the oral cavity, while the other restores facial
structures and contours. The intraoral section is constructed of methyl metha-
crylate; it contains teeth and restores palatal contours, providing the tongue
and associated oral structures with a reasonably complete oral mechanism
with which to formulate speech sounds and facilitate deglutition. When the
intraoral portion is independent of the facial portion, transference of chewing
forces to the facial portion of the prosthesis can be avoided somewhat.
Cranial Defects
Removal of intracranial tumors, trauma, and infection occasionally result in

deficitsapproaching one third to one half of the cranial vault. By utilizing true
projection radiographs, impressions, and other measurements, it is possible to
accurately determine the nature of the deficits and consequently construct
prosthetic restorations for them. Alterations by the prosthodontist at surgical
insertion ensure good adaptation and stability of these preformed cranioplasty
prostheses. They are most often constructed of methyl methacrylate and are
secured in position with stainless steel wire.
REHABILITATION SETTINGS
Whether or not an effective cancer rehabilitation program can be carried out
in a hospital that sets aside ten beds for rehabilitation is questionable. Al-
though this approach may be better than nothing to effectively implement the
procedures outlined in this chapter, a cancer rehabilitation program should
ideally be included within a larger rehabilitation environment in which other
disabilities are treated. A rehabilitation staff is well prepared to deal with
patients with disabilities and impairments. Proper equipment and facili-
ties are needed for the full management program. This concentrated approach
is reflected in current federal regulations for health care facilities. Patients
requiring rehabilitation will not be covered by Medicare and Medicaid unless

they are in centers approved by the federal or state government (or both) for
these services. Already, Medicare and PSRO committees are requiring the
discharge of patients from the hospital once they are considered medically
stable. Convalescent homes and extended care facilities are not prepared to
deal with the problems of the cancer patient with disabilities. However, they
may be the only choice for placement, especially in the case of terminally ill
patients. These patients could be easily transferred to rehabilitation centers
for continued necessary management and treatment. Obviously, each local
hospital cannot have a highly trained staff and equipped facility to give
rehabilitation care. Regional rehabilitation centers must be used more to
provide the specialized care needed to promote effectively the goals and
objectives of cancer rehabilitation. Just as even hospital cannot provide
radiation therapy services, each cannot provide full rehabilitation services.
However, more limited therapy programs can and should be initiated in every
hospital that treats cancer patients.
1. Dietz JH, Jr: Med Clin North Am *9. Morrow L: Psychological problems fol-
53:607, 1969. lowing ileostomy and colostomy, lit
2. McCawlev A, et al.: Conn Med 39:151. Sinai J Med
43:368, 1976.
1975. 10. Rowbotham, JL: Cancer 36:702, 1975.
3. Barker WF: Curr Probl Surg 12:24, '11. Watson PG: Applying rehabilitation
1975. concepts in the care of persons with
4. Bricker EM and Modlin J: Surgery ostomies. ARS J 1:12, 1976.
30:76, 1951. 12 Cross L: Ala J Med Sci 14:50. 1977.
5. Brooke BN: Lancet 2:102, 1952. 13. Rush AM: Nun Clin North Am 11:405,
6. Crile G, Jr and Tumbull RB, Jr.: Ann 1976.
Surg 140:459, 1954. 14 Jackson BS: Nurs Clin North Am
7. Tumbull RB Jr and Weakley FL: Atlas 11:417. 1976.
of Intestinal Stomas. St Louis, The 15 Beumer J et al. (eds): Maxillofacial
CV Mosby Co, 1967. Rehabilitation, Prosthodontics and
S Benfield JR, et al.: Arch Surg 107:62. Surgical Considerations. St. Louis,
1973. The C\' Mosbv Co. 1979.
CHAPTER 32
PSYCHOSOCIAL
PROBLEMS OF
CANCER
David K Wellisch
INTRODUCTION
Cancer causes a profound psychosocial with multiple manifestations
crisis
affecting not only the individual who has the physical illness but also
all those
that compose that patient's social matrix. Therefore, it is essential to inves-
tigate the interpersonal as well as the intrapsychic dimensions of cancer, with
emphasis on the major psychosocial issues of three entities: (1) the individual
who has cancer, (2) the family of the cancer patient, and (3) the providers of
medical services for cancer patients.
Unfortunately, the conceptualization of many behavioral scientists who are
involved in cancer treatment is that mental health professionals can and
should contribute to the care of the cancer patient and his or her family only at
the time of death or when the terminal period becomes a reality. However, it
has been found that if the mental health professional is used properly and the
correct psychologic perspective is assumed at an early stage of the illness by
the involved triad (patient, family, health service providers), the services of
mental health personnel may often not be needed at the time of death. The
principal portion of this chapter, therefore, addresses the involved triad, with
a minimal focus on the psychosocial problems of death and a maximal focus on
the psychosocial problems involved in the entire course of cancer preceding
death. The problematic conflicts that often result when dying becomes a
reality that must be faced can be avoided if the psychosocial problems of
cancer are properly addressed during the course of the illness. Death can then
occur without undo distress for any of the individuals involved and will not
leave pathologic psychosocial sequelae in its wake.
Perhaps another of the primary shortcomings of the mental health consul-
tant in the cancer area can be the tendency to present abstract, theoretic,
1036
32 / Psychosocial Problems of Cancer 1037
nonpragmatic commentaries on the situation of the patient or family that

cannot be translated into actions that create a change in perspective, feeling,
or behavior. An alternate approach is a pragmatic one, in which the concepts
are applicable to the treatment process rather than philosophic abstractions
about the situation of the cancer patient. Thus, the life problems of the entire
psychosocial matrix of the cancer patient require approaches that can be
translated into active interventions, and this becomes the overall mandate of
this chapter.
PSYCHOSOCIAL PROBLEMS OF
THE INDIVIDUAL
The characteristic personality style of the individual will potentially predict
psychologic adaptation or maladaptation to living with cancer. A psychosocial
history may be taken from the patient, addressing two points: (1) the major
stresses, disappointments, or disasters the patient has experienced in his or
her life, and (2) how, exactly, the patient responded to those events. The
treatment team can anticipate what to expect through past characteristic,
enduring responses to stress. The following two examples serve to clarify the
importance of this information.
Case 1. A 58-year-old white female was admitted with recently diag-

nosed acute myelogenous leukemia. She was started on IV medication
and became very anxious. Her response was to pull a screwdriver out of
her purse, remove the cover of the air-conditioning unit in her room, pull
out the filter, and become enraged that the filter was dirty. The house staff
and nurses responded in a state of panic by calling the psychologic
consultant with the concern that this woman was undergoing a psychotic
break with reality. The consultant saw the woman and found her to be not
psychotic but severely neurotic, expressing such neurosis with obsessive-
compulsive behavior. Her usual style was grossly accentuated in the
service of binding her anxiety about having cancer. She had experienced
a total loss of control in the face of her diagnosis, which for this usually
very controlled and controlling woman was the ultimate disorder. The
air-conditioner filter became a small area of her life —even in the hospital
context — that she could control.
Case 2. A 48-year-old white man was admitted for chemotherapy con-
solidation treatment of his malignant melanoma. During the second after-
noon of his hospitalization he became acutely depressed and was ob-
served standing by his fourth floor window. He was approached by the
staff and admitted that he was considering jumping out the window. The
staff became very anxious and indecisive and began to argue among
themselves about how to proceed. The psychologic consultant was
called, and the patient was interviewed and started on a major tranquiliz-
er, after which the anxiety of all involved abated. It emerged that this man
was reacting in an exaggerated form of his usual response (depressive
withdrawal and agitation) to a long series of crises in his marriage.
Both these cases serve to illustrate the notion that one's response to stress-
ful events while also "bearing cancer," as Hinton describes it, will likely be
1
an exaggerated version of usual "trait" personality patterns. Patient, family,

and staff alike will feel more comfortable if they have the knowledge to plan
for emotional crises before they emerge.
Certainly, one of the major questions asked by both the patient's family and
the staff is "How do we and talk with the patient now?" The physician
act
treating the cancer patient must form an effective "interactional plan" in
working with the individual that will enable others to model the doctor-
patient relationship and significantly decrease anxiety. This plan, which will
lead to instructions to the patient's family and staff, must be in accordance
with the personality of the patient.
The interactional plan must start with the proper presentation of the diagno-
sis. Lipowski 2 points out that patients have multiple reactions to a cancer
diagnosis. Some will be inclined to view it as a challenge to be met, whereas

others will view it as an overwhelmingly defeating oppressor. Some patients
will want protection from information, whereas others will want total knowl-
edge and will even take independent steps to gain more information. Notions
of how much to tell patients about a cancer diagnosis have greatly changed
over the past 30 years. The trend is toward greater openness, with several
studies indicating that actual suicide by cancer patients following diagnosis or
during the course of the illness is very low. 3- "
This author encourages the treating physician to include the family and key
staff members in the presentation of the diagnosis to the patient as a way of
role-modeling a beneficial interactional plan. The others can then follow the
physician's lead and work toward establishing an open and cooperative com-
munication that the patient can handle in the face of having cancer. Without
the physician's effective lead, it is this writer's experience that the other
elements of the system often result in fragmented, anxiety-inspiring, and
maladaptive communication with the patient. Needless to say, the patient's
burden then becomes heavier.
If the physician feels at the time of diagnosis that a patient has limited
emotional resources, he should immediately plan for professional emotional
support. Unhappily, such support often is not sought until the weight of the
emotional load of cancer causes the tenuous defenses of the patient to col-
lapse. At that point, psychologic help is sometimes more difficult and less
beneficial because (1) it becomes longer and more expensive, (2) the patient
often lacks the resources and emotional energy to participate actively, and (3)
family tolerance is waning or has run out.
Holland, 3 in discussing indications for psychiatric consultation, points out
several groups of patients who will present extraordinary risk of psychiatric
decompensation in the face of diagnosis or an extended course of cancer.
These include patients with (1) histories of schizophrenia, psychotic depres-
sion, or manic-depressive illness, or (2) histories of neurotic reaction patterns
that have rendered them "psychologic invalids." Among these would be
conversion hysterics, severely obsessive-compulsive individuals, or patients
with limiting and well-defined phobias. Patients with these neuroses are
likely to tolerate treatment such as chemotherapy very poorly and will need
early, focused, and consistent psychologic intervention.
Patients with severe personality or character disorders, especially those
who are substance abusers (opiate users, polydrug abusers, or alcoholics),
also pose serious problems. This group has exceptionally poor internal
resources with which to bind anxiety and will fail to cope when faced with
unremitting or exacerbating stresses. As such, they are a high priority group
for early psychologic intervention.
The primary always involve preconceived

fears of the patient will almost
severe pain, degradation, and dependency. The physician must therefore
explore the patient's imagery about cancer, since it is the boundless fantasy
rather than the circumscribed reality, no matter how depriving or painful, that
generates the most psychologic trauma. If fantasy can be met with fact, the
patient then begins to amass some predictive power, which enhances the
ability to cope. The mapping of a clinical course, as much as a patient wants
and can handle, will often reduce distress.
Finally, the patient's defenses must never be dismantled or breached by the
physician, staff, or family. Here again, the physician must model this notion in
the face of intrusions by others who are involved with the patient. The
internal knowledge of cancer and the conscious ability to handle that knowl-
edge can often be far apart for the patient. Those who interact with the
patient, however well meaning, must not attempt to force these internal and
external experiences together. The patient has psychologic defenses, such as
denial, repression, or sublimation, that put distance between the knowledge
of cancer and the emotional experience of its impact. Very few individuals can
survive psychologically when
they are continually confronting or are being
made As Weisman and Hackett 7
to confront issues of suffering or terminality.
appropriately relate, "The issue of telling the diagnosis, with diametrically
opposite positions of 'always' and 'never' has largely been supplemented by
'how,' 'when' and 'what' should be told the patient." This author would add
that the same is absolutely true for discussions and interactions with cancer
patients beyond diagnosis and through the course of the illness. The diagnos-
tic period simply serves as a psychosocial blueprint for the course to fol-
low.
THE FAMILY
The family interactional system will make the critical emotional difference,
either negatively or positively, for the patient as he or she progresses through
the emotional and physical course of the disease.
Spouses
Although all family members affect the patient's ability to bear the reality of
cancer, no interaction is so vital as that with the patient's spouse. The relation-
ship between the doctor and the cancer patient might best be conceptualized
as triadic rather than dyadic in an emotional sense, including patient, patient's
spouse, and doctor.
It is the patient's spouse who will usually carry the greatest emotional load
of anyone in the patient's psychoemotional matrix and it is also the patient's

spouse who can
offer the critical nurturance that becomes literally the "quali-
during the course of cancer. The treating physician must therefore
ty of life"
create an alliance with the spouse to ultimately maximize the psychosocial
comfort of the patient. He or she must assess (1) the spouse's stress responses
and stress-management style, similar to the assessment performed on the

patient, (2) the spouse's view of the marital and family relationship (not in the
presence of the patient), and (3) the degree of spouse dependency on the
patient. When the spouse is a highly dependent, overprotective, or clinging
individual, difficulties may appear in the face of an ongoing, often highly
dependent and involved relationship between the patient and members of the
treatment team. For example, a patient with leukemia must be repeatedly
separated from his or her spouse, and the hospital staff almost becomes a
substitute family. For some spouses, the intellectual understanding of such a
necessary situation can occur, whereas the emotional acceptance of such a
process is far more difficult. If given the chance, the spouse will often offer
information on many types of problems that will alert the treatment team to
conflicts before they erupt.
Couples in crisis situations are often open to positive change within the
marital relationship — cancer in a spouse is an unfortunate but ideal example
of such a crisis. Jackson, 8 in his classic paper on the functioning of the family
as an emotional unit, delineated the notion of "family homeostasis." He
viewed this as the characteristic interactional cycle within the family and
marital system. Jackson observed that for change to occur in relating, the
family emotional homeostatic cycle had to be thrown greatly off balance, and
only at that point could interventions be made into previously rigidified, often
destructive, cycles of interacting. Thus, a couple who already has a poor,
distant, or frankly destructive relational pattern or history may be very open to
the treating physician's suggestion to seek counseling when they are also
faced with the enormity of coping with cancer. The style of presentation by
the physician is vital in terms of the couple's acceptance or resistance. A
successful approach is usually an explanation that "all couples can benefit
from help with coping and communicating when they must live with cancer,
and you are no different from most couples I have seen in this respect." It is
best for the treating physician to avoid any attempt to convince the couple of
the presence of observed problems in their relationship, since the individuals
usually resist and deny such observations, possibly leading to a sense of
frustration and alienation for all involved parties.
A primary ongoing necessity is for the treating physician to reinforce the
spouse of the cancer patient with regards to caretaking efforts. The patient
often will take such efforts for granted or will be guilt-ridden and will try to
avoid talking about the efforts of the spouse. This can lead to resentment and
feelings of being used on the part of the spouse. If the spouse is either
exhibiting infantilism or expecting too much of the patient, supportive yet —
firm — recognition is necessary on the part of the physician and treatment
team. The nurse, in the hospital situation, will often witness such problems
and must work with the physician in appropriately dealing with the spouse.
The following cases exemplify such spouse problems:
Case 1. The spouse of a 65-year-old man in the terminal phase of
bowel cancer was managing and withholding his pain medications in an
attempt to deny the reality of his severe illness. She gave him the conflict-
inspiring message, You never really could stand pain but if you really
need a pill I'll give one to you.'' If he could then bear the pain, her denial
was reinforced, and she did not have to adjust to the reality of his dying,
Psychosocial Problems of Cancer 1041
which would leave her alone. Thus, the overdemanding of him was a
function of her own conflicts that required confrontation and alteration.
Case 2. The spouse of a 50-year-old woman with metastatic breast
cancer was observed, in the hospital setting, to be enslaved to his wife's
infantile demands and would spend entire days carrying out her wishes on
a minute-to-minute basis. She was hysterical, demanding, dependent on
multiple drugs far beyond the stage of her illness, and had regressed to
the state of behaviorally resembling a small child. The spouse could not or
would not limit her demands or childish behaviors and seemed to be
actively accelerating her regressive-dependent maladaption to the cir-
cumstances surrounding her illness. This spouse, however well meaning,
required modification of his actions to rectify an untenable situation.
It is not unusual, after a time, for the spouse of a cancer patient to feel like
abandoning the patient or even to experience the wish that the patient "get
it over with and die." For some, these feelings become conscious; for others,
they are kept rigidly repressed or suppressed. For all, the feelings are very
disturbing. It can be enormously helpful for the physician to tell the spouse
in the absence of the patient) that he or she might have such feelings and that
these are normal and, in fact, predictable. This simple conversation can some-
times relieve guilt and internal conflict beyond what any medication or
mental health professional can do for the spouse.
The sexual relationship between spouses when one partner has cancer is a
relatively unexplored area of concern. However. Leiber et a/. 9 studied the
relationships of a group of cancer patients undergoing chemotherapy and their
spouses and found for both partners a decreased desire for intercourse and an
increased desire for physical closeness (such as holding). Spouses who are
unfaithful to a partner during the course of cancer are generally following a
behavioral pattern established prior to the onset of the illness. This has been
clinically evident and was the pattern in a study of men with wives who had
undergone mastectomy. 10 Nevertheless, severe anxieties can occur for the
ill spouse in regard to the sexual fidelity of the well spouse. The main anti-
dotes for such fears are honesty between the partners so as to dispel
(1)
anxiety-laden fantasies, (2) individual support for each partner in coping with
their different, but real, frustrations, and (3) attempts to work with the part-
ners to maximize the emotional intimacy of the relationship, which is the
greatest security against sexual infidelity.
Although the spouse is a vital linchpin in the family matrix of the cancer
patient, the realities presented by cancer to all the other family members
must be carefully considered. To understand the psychosocial workings of
the entire family system, the emotional functioning of each individual must
be appreciated.
Children
When considering the children of a cancer patient, the developmental

phase of the child is the most critical variable in terms of the assessment of
potential difficulties. It might be expected that the younger the child, the
more disturbances will be reflected when faced with cancer in a family
member. This has not proved true in clinical practice, however, with preado-
lescents and postadolescents demonstrating fewer coping difficulties than
those children in adolescence. A variety of factors are responsible for the

problems faced by adolescents including (1) stressed parental viewing of
adolescents as totally adult rather than realizing they are still partially chil-
dren, (2) family forces that push the adolescent to assume family responsibili-
ties beyond his or her capacities, including shifts in household tasks such as
childcare or housekeeping duties, and perhaps most troubling, (3) the less
overt more psychologic such as becoming a parent or a pseudospouse to
shifts,
the parent with an absent or dying spouse.
The adolescent is at a stage of development at which separation from the
family is the primary need, and cancer in a family member (especially a
parent) can radically and dramatically reverse this course. The adolescent can
find himself or herself forced back into an unwelcomed, reintensified contact
with parents that is directly contradictory to what would otherwise be chosen.
Thus, the treating physician should be ultra-attentive to the situation of the
adolescent in a family in which cancer is present and should set ground rules
for the family in dealing with that adolescent, which might include (1) not
forcing the adolescent to visit the ill parent in the hospital, and substituting
phone calls, if necessary, (2) enabling the adolescent to keep attachments
secure with peers outside of the family, and (3) keeping the parents sensitized
to role shifts, so that the adolescent will not feel overwhelmed by being
utilized as a pseudoparent or pseudospouse.
Conversely, the preadolescent is not faced with the issues of the adolescent
because he or she (1) is always viewed as a child, (2) is not dealing with
intense separation issues, and (3) can hardly be expected to evidence the
emotional maturity to be a pseudoparent or substitute spouse. However, the
preadolescent child is certainly not immune from the stresses of cancer in a
parent or family member. Greenberg 11 relates that young children in this
situation often show evidence of somatic complaints, withdrawal, depression,
anxieties, and death fantasies. Other dynamic emotional reactions may in-
clude abandonment fears, guilt, and anger relating to the ill parent. The young
child often cannot maintain the distinction between having angry thoughts
about a sick parent and the feeling that such thoughts have actually made the
parent sick. Severe guilt can emanate from such feelings in a child. It is
important for the parents and medical team to explore such ideas in a child
with the reassurance that no matter how angry he or she has been about the ill
family member, these deeds or thoughts did not create the cancer.
The physician and medical team must watch for certain behavior in the
child when cancer is present in a family member, because the distinct pres-
ence of such behavior indicates the need for mental health consultation. Such
behavior may include (1) ongoing night terrors that are unremitting, coupled
with the inability of the child to verbalize his or her fears during the daytime
hours, (2) withdrawal from peers and isolation during playtime, (3) severe
weight loss or weight gain, (4) ongoing loss of toilet training, (5) rage reactions
with siblings or peers that are either unprovoked or not modulated appropri-
ately to situational context, and (6) a sharp decline in academic performance,
as evidenced by the sudden loss of academic abilities that had previously
been mastered. The following two clinical examples serve to illustrate some
of these symptoms.
Case 1. The seven-year-old son of a woman who was recently diag-

nosed as having acute myelogenous leukemia was reported by his teacher
to have suddenly "lost his ability to read" in the school setting. Upon
family interview in the mother's hospital room, it became apparent that
the separation of mother and son was profoundly traumatic for both. An
intervention was made whereby the son would be "tutored" by the mother
in her hospital room. The reading skill rapidly returned. It was apparent
that the boy could not consciously articulate his need for his mother, and
the reading problem served as an unconscious attempt at reconnection
with her.
Case 2. An eight-year-old son of a woman who was recently diag-
nosed as having acute myelogenous leukemia was observed by his grand-
parents to be isolated from his peers and depressed. When assessed by
the mental health consultant, the boy was found to be totally unable to
play, fearful of getting dirty in an obsessive-compulsive fashion, and
behaviorally resembled an old man rather than a young child. When the
mother was interviewed, it was learned that this behavior was present
before her illness, but that now it was severely aggravated, resulting in the
boy's emotional tension. Intensive psychotherapy was initiated with the
child, both to prepare him for the potential loss of his mother and to deal
with these emergent character problems.
The young adult or postadolescent is most able to cope with cancer in the
family since he or she (1) usually can deal with tasks on an adult level, (2) has
already dealt with separation issues, and (3) can often muster the maturity to
"be a parent's parent" for a time and can usually set limits appropriately if
this becomes too enormous a burden.
Family Therapy
The physician and health team are usually adequate sources to guide and
enable the family unit in the process of coping emotionally with cancer. The
recommendation of family counseling becomes important, if not mandatory,
in the cases of families who (1) have long histories of maladaptive coping in
the face of crises, (2) present obvious factions that conflict with one another
emotionally, or (3) who cannot make decisions either because of severe
ambivalences or hostilities. Cancer causes the kind of unremitting stress that
can only aggravate and intensify such problems if they are present at the onset
of the patient's illness.
It should be noted by the physician and family alike that family therapy is
not to be confused with psychoanalysis. The family therapy process is intend-

ed to be short-term, problem focused, and an enhancement of both communi-
cation and behavior change. It should be clearly distinguished from psycho-
analysis, which is a vastly longer, more in-depth, and psychologically
uncovering process.
THE MEDICAL AND NURSING
STAFF
One of the paradoxes of behavioral science efforts in cancer is that little
attention has been focused on the emotional experience of the physician or
nurse in cancer medicine. The extensive focus on the experience of the

patient and family appears to embody the assumption that the health care
deliverers are untouched by the emotional turmoils generated by cancer.
Perhaps it is assumed by the behavioral scientist and by health care deliverers
alike that personnel in cancer treatment through the processes of clinical work
and experience become "objective" and somehow distanced from these con-
flicts. Such assumptions are fallacious in nature, with the high turnover rates
of oncology nurses in inpatient settings being a testimonial to the existence of

such stresses.
The daily involvement in the care of the severely ill, and the frequent
experience of loss are understood facts of life in cancer medicine and may
cease to be acutely disturbing as such for health care personnel. The physi-
cian or nurse dealing with cancer must learn to strike an emotional balance
between aloofness and overinvolvement; to be too aloof is to avoid vital
contact with the patient; to be too involved is to ensure an ultimate emotional
devastation, making it impossible to help any patient. This is not to say,
however, that the experiences of physicians and nurses do not register at an
unconscious level and begin to take their toll in ways that are covert, and yet
negative. These experiences may become manifest through depression, disin-
terest in his or her work, irritability, withdrawal, or emotional unavailability
to colleagues and family members alike. The physician and nurse must learn
to be able to identify within themselves the signs of escalating depression,
which might include (1) sleep disorders, especially those in which the indi-
vidual wakes in the early hours of the morning with severe anxieties, (2)
irritability, such that feedback from others begins to be reduced in the sense
that colleagues, staff, and family members start distancing themselves, (3)
highly disturbing, symbolic dreams that are the latent expression of patient-
related feelings, and (4) confusion or the inability to process information in a
logical coherent fashion. Such a confused state might lead to forgetfulness that
would ordinarily not be the pattern of functioning.
Mental health professionals who deal with severely disturbed or disturbing
individuals — such as those who are chronically suicidal —
know that the
shortest route to professional incompetence and personal despair is to (1) feel
solely responsible for all aspects of the patient's treatment, and (2) keep one's
feelings about the situation completely internalized. Thus, the need to widen
the base of communication and responsibility is vital for one's emotional
survival. The oncologist who
chooses to practice in isolation is certainly
enhancing the experience of personal pressure to the ultimate, but even in
this situation communication with one's staff about patients, families, and the
feelings they generate can make the difference between professional and
emotional survival and nonsurvival.
The knowledge and emotional acceptance of the need to utilize mental
health professionals in patient management is another critical factor in the
emotional maintenance of the cancer physician or nurse. When certain indi-
viduals will overtax the resources of the staff, it should be realized that referral
of those individuals is not a sign of a failure on the part of the health care pro-
viders.
The maintenance of mental health for the physician and nurse in oncology
demands more than communication about patients and open interaction with
colleagues. It is potentially vital for the physician and nurse to organize a life
style that allows complete emotional disconnection from cancer and cancer
patients when not in the clinical setting. If the professional allows cancer to
dominate his or her life to the point of allowing no time for other unrelated
activities, with the expectation that all emotional gratifications and rewards
will come from this area, problems will certainly follow. A life style in which
nonprofessional vacations and nonmedical activities are understood to be as
important as good clinical medicine is essential.
It is only when the physician or nurse dealing with cancer considers his or
her emotional maintenance to be as important as that of the patient that

quality care will be assured.
1. Hinton J: Br J Med Psychol 46:105, *7. Weisman AD and Hackett TP: Predilec-
1973. tion to death. Death and dying as a
2. Lipowski Z: Int J Psychoanal 1:91, psychiatric problem. Psychosom Med
1970. 23:232, 1961.
*3. Holland J:Psychologic Aspects of Can- 8. Jackson DD: Psychiatr Q 31:79, 1957.
cer. In Cancer Medicine. Holland J and 9. Leiber L. et al.: Psychosom Med 38:
Frei E, III (eds), Philadelphia, Lea & 379. 1976.
Febiger, p. 991, 1973. 10. Wellisch DK, et al: Am J Psychiatry
4. Farberow NL, et al.: Med Bull Vet 135:543, 1978.
Admin, No. 9, 1963. 11. Greenberg LI: Soc Casework 56:396,
5. Oken D: JAMA 1 75: 1120, 1961. 1975.
6. Campbell P: Conn Health Bull 80:207,
1966.
Appendix A
NOMOGRAPH FOR
CALCULATING THE
BODY SURFACE AREA
OF ADULTS*
"From Boothby WM, and Sandiford RB: Nomographic charts for the calculation of the metabolic
rateby the gasometer method. Boston Med Surg J JS5(12):337, September 22, 1921.
Based on the formula of DuBois and DuBois:
BSA in m 2 = [71.84] [kg 042S [cm 0725 ] [10~ 4 ]
]
1046
Appendix A / Nomograph for Calculating Adult Body Surface Area 1047
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SUB FACE AREA (DuBOlS)
t JS
Appendix B
PER CENT OF NORMAL

BONE MARROW
IRRADIATED USING
STANDARD RADIATION
PORTS*
Marrow Volume
At Risk
Skull (not including mandible) 12%
Upper limb girdle (unilateral) 4%
(humeral head, scapulae, clavicle)
Sternum 2%
Ribs (all) 8%
Ribs (hemithorax) 4%
Cervical vertebrae (all) 3%
Thoracic vertebrae (all) 14%
Lumbar vertebrae (all) 11%
Sacrum 14%
Pelvis (including both innominates and both femoral 26%
heads and necks)
Mantle (approximate) 25%
Upper para aortic nodes (approximate) 11%
Inverted Y (approximate) 45%
"Based on Ellis RE: Phys Med Biol 5:255, 1961.

1048
Appendix C
SELECTED
ABBREVIATIONS
Selected Organizations, Societies, and Proceedings
AACR American Association for Cancer ECOG, Eastern Cooperative Oncology

Research Group
AJC American Joint Committee for EORTC European Organization for Re-
Cancer Staging and End Results search on Treatment of Cancer
Reporting
ALB, Cancer and Leukemia Cooper-

ALGB, ative Group B GOG Gynecologic Oncology Group
CALB, GTSG Tumor Study
Gastrointestinal
CALGB Group
ASCO American Society of
Proc ASCO, Clinical Oncology
Proc AACR, Proceedings of the
ProcAACR-ASCO ASCO and AACR
ASTR American Society for MDA MD Anderson Hospital and
Therapeutic Radiol- Tumor Institute
ogy MRC Medical Research Council of
Great Britain
BCRC Baltimore Cancer Research

NBCCGA National Bladder Cancer
Center
Collaborative Group A
BCTF Breast Cancer Task Force
NCI National Cancer Institute —
BTSG Brain Tumor Study Group
USA
NPCP National Prostatic Cancer
Project
NSABP National Surgical Adjuvant
CCSG Children's Cancer Studv Group Breast Project
CCG NWTS National Wilms' Tumor
COG Central Oncology Group Study Group
1049
1050 Appendix C / Selected Abbreviations
RPMI Roswell Park Memorial Institute UICC International Union Against

RTOG Radiation Therapy Oncology Cancer
Group
VALG Veterans Administration Lung

Cancer Study Group
SAKK Swiss Group for Clinical Cancer VASAG Veterans Administration
Research Surgical Adjuvant Cancer
SEG Southeastern Cancer Study Chemotherapy Study Group
Group
SKMC Sloan-Kettering Institute
(Memorial Center) WCSG Western Cancer Study Group
SWOG Southwestern Oncology Group WCG
Selected Drug Abbreviations
ADR doxorubicin (Adriamycin), L-ASP L-asparaginase (Elspar)

hydroxydaunomycin L-PAM melphalan, (Alkeran)
araC cytarabine (Cytosar) MeCCNU semustine
RCNU carmustine M or HN2 mechlorethamine hydro-
RLEO bleomycin sulfate chloride (Mustargen)
(Rlenoxane) MEG megestrol acetate (Megace)
CCNU lomustine MMC mitomycin-C (Mutamycin)
CHL chlorambucil (Leukeran) 6-MP 6-mercaptopurine
CYC cyclophosphamide (Cytoxan) MTX methotrexate
D daunomycin OH-urea hydroxyurea (Hydrea)
DACT dactinomycin (Cosmegen) o.p'-DDD mitotane (Lysodren)
DDP cis-dichlorodiammineplati- PRED prednisone
num (II),cisplatin (Platinol) PROC procarbazine (Matulane)
DES diethylstilbestrol STZ streptozotocin
DTIC dimethyltriazenoimidazole TAM tamoxifen (Nolvadex)
carboxamide (dacarbazine) 6-TG 6-thioguanine (Thioguanine
(DTIC Dome) Tabloid brand)
5-FU 5-fluorouracil VBL vinblastine (Velban)
HMM hexamethylmelamine VCR vincristine (Oncovin)
Appendix C / Selected Abbreviations 1051
Selected Drug Combinations (Acronyms)
Acronym Chapter Drugs

ABVD 24 ADR, BLEO, VBL, DTIC
BACON 12 BLEO, ADR, CCNU, VCR, M
BACOP 25 BLEO, ADR, CYC, VCR, PRED
B-CAVe 24 BLEO, CCNU, ADR, VBL
B-DOPA 24 BLEO, DTIC, VCR, PRED, ADR
CAF 7 CYC, ADR, 5-FU
CAMP 8 CYC, ADR, MTX, PROC
CHOP 24-26 CYC, ADR, VCR, PRED
CHOP-Bleo 25 BLEO. ADR, CYC, VCR, PRED
CMF 7 CYC, MTX, 5-FU
CMF VP 7 CYC, MTX, 5-FU, VCR, PRED
COAP 21 CYC, VCR, araC, PRED
COB-MAM 12 CYC, VCR, BLEO, MTX, ADR, MeCCNU
COMB 12 CYC, VCR, MeCCNU, BLEO
COP 25 CYC, VCR, PRED
COPP or C-MOPP 24 CYC, VCR, PROC, PRED
CVP 25 CYC, VCR, PRED
CyVADIC 15 CYC, VCR, ADR, DTIC
MACC 8 MTX, ADR, CYC, CCNU
MOCA 8 MTX, VCR, CYC, ADR
MOPP 24 M, VCR, PROC, PRED
POMP 21 PRED, VCR, MTX, 6MP
TAD 21 6TG, araC, D
VAC 15, 19 VCR, DACT, CYC
VAMP 21 VCR, MTX, 6MP, PRED
Miscellaneous Abbreviations
ACTH Adrenocorticotropic hormone EGB Eosinophilic granuloma of

aFP Alpha-fetoprotein bone
APUD Cells of the amine precursor ER Estrogen receptor
uptake and decarboxylation
system
FCC Follicular center cell
BCG Bacillus Calmette-Guerin
GFCL Giant follicular cell lymphoma

CEA Carcinoembryonic antigen
CLL Chronic lymphocytic leukemia
CML Chronic myelogenous HCG Human chorionic gonado-
leukemia trophin
CR Complete response or HD Hodgkin's disease
remission 5HIAA 5-hydroxyindoleacetic acid
CRF Composite risk factor HMR Histiocytic medullary reticu-
CS Clinical stage losis
DU Diffuse undifferentiated 5HT 5-hydroxytryptamine (sero-
lymphoma tonin)
DWDL Diffuse well differentiated HSC Hand-Schuller-Christian
lymphocytic lymphoma disease
2052 Appendix C / Selected Abbreviations
kVp Peak kilovoltage on the x-ray PgH Progesterone receptor

tube PR Partial response (> 50 per cent
reduction in sum of the
LAF Laminarair flow room products of greater and lesser
LAG Lymphangiogram diameter of tumor and without
LD Lymphocyte depleted HD new lesions)
LET Linear energy transter PS Pathologic stage
LMM Lentigo maligna melanoma PTH Parathyroid hormone
LP Lymphocyte predominant HD
LS Lymphosarcoma
LSD Letterer-Siwe disease RCS Reticulum cell sarcoma
RF Risk factor
MC Mixed cellularity HD SIADH Syndrome of inappropriate

MEN Multiple endocrine neoplasia
ADH secretion
MeV Million electron volts potential
SSM Superficial spreading mela-
on x-ray tube
noma
MTD Maximally tolerated dose of
SVCS Superior vena caval syndrome
an agent
NED No evidence of disease TDT Tumor doubling time

NGF Nerve growth factor TdT Terminal deoxynucleotidyl
transferase
NH, DH Nodular or diffuse histiocytic
lymphoma TSH Thyroid stimulating hormone
NM Nodular melanoma
NM, DM Nodular or diffuse mixed histi-
ocytic-lymphocytic lymphoma
NPDL, Nodular or diffuse poorly dif- VIP Vasoactive intestinal polypep-
DPDL ferentiated lymphocytic lym- tide
phoma
NSD Nominal single dose (of
radiation)
NWDL Nodular well differentiated WDHA Syndrome of watery diarrhea
lymphocytic lymphoma with hypokalemic alkalosis
INDEX
Page numbers in italics indicate illustrations. Page
numbers followed by t indicate tables.
Acute lymphoblastic leukemia (ALL),

Abbe cancer, 526
flap, for lip 805-820
Abbreviation(s), drug, 1050-1051 adult, L-10 protocol for, 817
miscellaneous, 1051-1052 remission rates and survival times in, 816
organizations, 1049-1050 treatment for, 816-817
Abdomen, disease in, in childhood age as prognostic factor in, 810
non-Burkitt's lymphoma, 938 L-asparaginase for, 115
metastases to, in gallbladder carcinoma, bacillus Calmette-Cuerin for, 134, 818
335 central nervous system prophvlaxis in,
palpation of, in pheochromocytoma, effects 813-814
of,623 chemoimmunotherapy for, 150
Abdominoperineal resection, preoperative chemotherapy for, cessation of, 814-815
radiation and, for rectal cancer, 297 continuation of, 814
Ablation, pituitary, 648 intensification of, 813
Ablation therapy, postoperative radioiodine, principles of, 811-815
for thyroid cancer, 602 classification and pathology of. 806-807, 806t
Abnormality(ies), hematologic, in Hodgkin's clinical features of, 807-809
disease, 874-875 complications of therapy in, 818-819
Abortion, for choriocarcinoma, 437 cranial or craniospinal irradiation for,
ABVD, for Hodgkin's disease resistant to complications from, 819
MOPP, 894 description of, 805-806
Achalasia, link with esophageal carcinoma, diagnosis of, 809-810
233 aids in, 810
Acid(s), vanillylmandelic, determination of, drug regimens for, 812
in pheochromocytoma, 624 high-risk, treatment for, 815
elevation neuroblastoma, 761
of, in homogeneous versus heterogeneous, 806
Acromegaly, in pituitary tumors, 642, 642 immunotherapy and combination
radiation therapy for, 646 chemotherapy for, 817
Actinomycin(s), Streptomyces parvulus as immunotherapy for, 817-818, 817t
source of, 70 infections in, 808-809
Actinomycin D. See Dactinomycin. laboratory features of, morphologic types
Acupuncture, for cancer pain, 1019 of, 809
Acute granulocytic leukemia. See Acute myelosuppression and immunosuppression
Myelogenous leukemia (AML). in, 818
Acute leukemia, 802-832 natural history of, 806-811
allopurinol for, 94 neurologic manifestations of, genitourinary
autologous bone marrow from patients in manifestations of, 808
remission, 981 null cell, 806-807
biology of, epidemiology of, viruses as prognosis in, T cell versus null cell, cell
etiologic factor in, 804 reduction in, 811
etiology of, 803-804 prognostic factors in, 810-811
genetic factors in, radiation as cause of, prospects for future in, 819
803 recurrence of, in bone marrow, 815
incidence of, 802 treatment of, 815-816
1053
1054 Index
Acute lymphoblastic leukemia (Continued) Adenocarcinoma(s) (Continued)

remission induction in, failure of, 813 of pancreas, description of, 308
through chemotherapy, 811-814, 812t single-agent chemotherapy for, 316, 316t
symptoms of, laboratory features in, 807 of stomach, combination chemotherapy for,
testicular relapse in, 816 2.58, 259t, 260
treatment of, 811-819 of vagina, description of, 469
Acute myelogenous leukemia (AML), determining extent of, 474
820-829 thyroid, methods of diagnosis of, 597
Auer bodies in, 823 papillary, prognosis in, 595, 596t
bacillus Calmette-Guerin and radioiodine as adjunctive therapy for, 599
Curynebacterium parvum for, 827 well-differentiated, surgery for, 597-598
bone marrow transplantation in, 828 uterine, caused by estrogen therapy, 96
chemoimmunotherapy for, 151 Adenoma(s), chromophobic, effects of,
chemotherapeutic remission induction in, 635-636
824-825 comparison with parathyroid carcinoma,
chemotherapy for, 824-827, 824t, 825t 589
classification of, description of, 820 monomorphic, of salivary glands,
clinical features of, 820-821 description and treatment of, 543
consolidation and maintenance treatment of, 542
chemotherapy in, 825-826 cause of Cushing's syndrome,
pituitary, as
cytosine arabinoside for, 824 646-647
diagnosis of, 821-823 growth hormone in, 646
immunotherapy for, 827-828, 827t implantation for, 648
interstitial
induction therapy in, prognostic factors in, radiation therapy for, 644-648
823 advantages of, controversy over, 645
intensive chemotherapy for, increase in disadvantages of, 647
central nervous system leukemia and, pleomorphic, salivary gland, description
826 of, 541
intensive induction regimens for, surgery for, advantages of, 648
experimental drugs for, 825 Adenopathy(ies), peripheral, as presenting
laboratory features in, 822t, 823 symptom in malignant lymphoma, 915
natural history of, 820-824 retroperitoneal, in mycosis fungoides, 941
physical findings in, 821, 823 Adenosis, vaginal, in women exposed to
prognostic factors in, 823-824 diethylstilbestrol in utero, 470
prospects for future in, 829 Adenosquamous tumor(s), in endometrial
quality of life and cost in, 826-827 carcinoma, 450
symptoms of, leukemic infiltration of bone Adjuvant therapy, 6. See also integration of
marrow in, 821 treatment modalities section for each tumor.
treatment of, 824-828 Adolescent children, of cancer patients,
cost for, 827 problems of, 1042
Acute nonlymphocytic leukemia, in Adrenal cortex, necrosis and atrophy of, from
Hodgkin's disease, 876 mitotane, 108
Adenine nucleoside analogue(s), antiviral neoplasms 627-632
of,
properties of, 88 classification of,628
Adenoacanthoma(s), in endometrial clinical features and diagnosis of,
carcinoma, 450 628-629
Adenocarcinoma(s), cervical, 477-478 hormone production in, 628, 629t
survival in, 484 incidence of, 627
clear cell, incidence of, 479 metastases in, 628, 628t
vaginal, surgery and radiation natural history of, 628-631
therapy for, 474 prognosis in, 630t, 631
comparison with squamous cell carcinoma, staging of, 629, 630t
of vagina, 470, 470t surgery 631
for,
exposure to diethylstilbestrol in utero and, symptoms 629
of,
475 treatment for, 631-632
in bileduct carcinoma, 337 Adrenal medulla, cells of, description of, 621
in endometrial carcinoma, 450 Adrenalectomy, as secondary endocrine
in esophagogastric junction, 235 manipulation, 181
in gallbladder carcinoma, 335 for prostate cancer, 366
in laryngeal cancer, 549 hydrocortisone and fluorohydrocortisone
in lung cancer, 198 following, 182
incidence of, in stomach cancer, 248 Adrenocortical carcinoma, use of mitotane in,
of Bartholin's gland, 467 109
of colon and rectum, radiotherapeutic Adrenocorticosteroid(s), for chronic
approaches to, 296 lymphocytic leukemia, 847-848
Index 1055
Adrenocorticotropic hormone (ACTH), Alveolus(i), cancer of, description of and

postoperative replacement of, in pituitary treatment 527
for,
tumors, 644 Aminoglutethimide, 109-110
Adrenocorticotropic hormone secretion, 634 as secondary endocrine therapy, 181
Adriamycin. See Doxorubicin. clinical features of, 110
Adult(s), bodv surface area of, nomograph for, origin of, 109
1046-1047 Amniography, in hydatidiform mole, 435, 436
Anatoxin, implication of, in liver cancer, 319 Amphotericin B, following antibiotics, for
Age, as prognostic factor, in endometrial febrile patients with granulocytopenia, 971
carcinoma, 451 Ampulla of Vater, carcinoma of, clinical
effect of, on development of colon cancer, features, diagnosis, and treatment of,
268 343
on survival following surgery, for colon pathology and classification of, 342
cancer, 294-295 Amputation(s), for osteosarcoma, 658-659
prognostic significance of, in acute for soft-tissue sarcomas, 672
lymphoblastic leukemia, 810 for subungual melanoma, 687
in neuroblastoma, 764 transmedullary, in osteosarcoma, 659
Agent(s), alkylating, for chronic lymphocytic Amygdalin, presence in laetrile, 115
leukemia, 847 Analysis(es), route, to establish neural
for multiple myeloma, 856-857 pathways for interrupting pain, 1010
for non-Hodgkin's lymphomas, 926 Androgen(s), 102-103
for Waldenstrom's macroglobulinemia, as secondary endocrine manipulation, 182
862 uses for, 102
maturation-inducing, for neuroblastoma, Androgen synthesis, inhibitors of, in prostate
766-767 cancer treatment, 366-367
neurolytic, for sensory root pain. 1016 Androgen therapy, estrogen receptors in
prophylactic antimicrobial, to reduce breast cancer cells and, 102
gastrointestinal flora, 968 side effects of, 103
sclerosing, thoracentesis and, 987 Anemia, consequence of bone marrow
as
Alcohol, laryngeal cancer and, 547 symptoms of, 963
failure,
Alkeran. See Melphalan. chronic, metastases and, 962
Alkyl sulfonate(s), chemical structure of, 63 hemolytic, in chronic lymphocytic
Alkylating agent(s), 53-67 leukemia, 842
chemical classes of, 53, 54 in acute lymphoblastic leukemia, 807-808
choice of, clinical considerations in, 56 in acute myelogenous leukemia, 820-821
cisplatin as, 112 in multiple myeloma, management of, 861
combined with estrogen therapy, 99 pernicious, association with stomach
commercially available, 57t cancer, 247
effects of, 53 Anesthesia, considerations in, for surgery of
for breast cancer, 183, 183t carcinoid tumors, 616, 617t
for chronic lymphocytic leukemia, 847 in cryohypophysectomy of pituitary tumors,
for multiple myeloma, 856-857 642
for non-Hodgkin's lymphomas, 926 in cryosurgery for cutaneous basal and
for Waldenstrom's macroglobulinemia, 862 squamous cell carcinomas, 714
mitomycin-C and, 74 in pheochromocytoma, 626
sterility' and, 37 Angiography, as diagnostic aid, for liver
Alloimmunization, in patients receiving metastases, 327
granulocyte transfusions, 975-976 endoscopy and, in diagnosis of pancreatic
Allopurinol, 94-95 cancer, 310
characteristics of, drug schedules for, 94 for carotid body tumors, 800, 800
combined with cyclophosphamide, 32 for diagnosis of pancreatic cancer, 312
in combination with 6-mercaptopurine, 33 Anorexia, from radiation, in Hodgkin's
Alopecia, in chemotherapy, 36 disease, 887
Alpha blocker(s), in surgical treatment of Anthracycline(s), cardiac damage and, 69-70
pheochromocytomas, 626 characteristics of, 69
Alpha fetal globulin, in diagnosis of Anthracycline therapy, cardiomyopathy and,
hepatomas, 127 70
Alpha heavy chain disease, description of, Antiandrogen(s), in treatment of prostate
863 cancer, 366-367
Alpha-fetoprotein, in staging testicular Antibiotic(s), broad-spectrum, for febrile
carcinoma, 414 patients with granulocytopenia,
levels of, as indication of adult hepatoma, amphotericin B following, 971
320 length of treatment in, 970
ovarian endodermal sinus tumors and, 509 characteristics of, 68t
70.56 Index
Antibiotics! s) (Continual) Anus, cancer of, 304-308

for granulocytopenia, 968, 969t chemotherapy for, integration of
from Streptomyces, use in chemotherapy, treatment modalities in, 307
67 clinical features of, 305
in chemotherapy, 67-75 etiology of, squamous cell carcinoma in,
Antibody(ies), anti-idiotypic, for multiple 304
myeloma, 860 implant for, with surgery, 306
interstitial
humoral, in cancer patients, studies of, 128 without surgery, 307
production of, in cancer patients, 130 pathology of, presenting features of,
to HLA antigen, platelet survival and, 974 304^305
Antibody titer, correlation with complement radiation therapy for, 306-307
fixation, in melanoma and sarcoma, 132 avoidance of perineum in, 306
Anticholinesterase drug(s), in surgical various tissues originating from, 304, 305
management of anterior mediastinal Aplasia, bone marrow, drug-induced, in
thymomas, 783 chronic myelogenous leukemia, 836
Anticonvulsant(s), for brain tumors, 738 Appendix, carcinoid tumors of, surgery for,
Antidiuretic hormone (ADH), normal 615
production 1000 of, APUD cell(s), characteristics of, 622
Antiestrogen(s), 100-101 description of, 621
definition of, 100 Ara-C. See Cytarabine.
uses for, 101 Ara-CTP, cytarabine cytotoxicity and, 89
Antigen(s), carcinoembryonic, 127-128 Arsenic, exposure to, skin cancer and, 697
as tumor marker, 46 Arteriography, pelvic, for detecting invasive
elevated levels of, stage of disease and, bladder cancer, 378
128 Arteriovenous (AV) fistula, creation of, in
302
in colorectal cancer, patients on long-term chemotherapy, 15
in detectingbladder cancer, 378 Artery infusion, continuous hepatic,
in diagnosing recurrent colorectal cancer, complications of, 333-334, 333t
291-293 versus systemic chemotherapy, in
fetal, nonimmunogenic class of, uses for, colorectal cancer metastases, 331, 334
126-127 continuous intrahepatic, of 5-fluorouracil,
individually specific, in neoplasms, 129 for liver metastases, in colorectal cancer,
neoplastic transformation and, 126 329, 330t, 331
tumor-associated, evidence for presence hepatic, following systemic 5-fluorouracil,
of, in human neoplasms, 126-128 in progressive colorectal metastases, 332,
HLA, antibodies to, platelet survival and, 333t
974 Arylsulfatase stain(s), nuclear, for diagnosis of
non-HLA granulocyte, leukoagglutination acute lymphoblastic leukemia, 810
assay for, 976 Asbestos, relationship to mesotheliomas, 200
oncofetal, 126, 127, 129 L-Asparaginase, 114-115
specific, common groups of, 129 clinical features of, 114
tumor-associated, immune response to, methotrexate and, schedule dependency of,
correlations with clinical course of 44
human cancer and, 132-133 uses for, 115
in human neoplasms, 128-129 Aspergillosis, invasive, lung biopsy in
specificity for histologic type, in ovarian diagnosis of, 970
cancer, 504 Aspergillus, infection by, in cancer, 966
Anti-idiotypic antibody, for multiple life-threatening superinfections by, 970
myeloma, 860 Aspermia, transient, from radiation, in
Antimetabolite(s), 79-94 Hodgkin's disease, 889
mechanism of action and characteristics of, Aspiration, bone marrow, in neuroblastoma,
79, 80t 762
Antimicrobial agent(s), prophylactic, to in non-Hodgkin's lymphomas, 920
reduce gastrointestinal flora, 968 in diagnosing breast cancer, 166
Antineoplastic drug(s), therapeutic index for, needle, in renal cell carcinoma, 395
definition of, 30 percutaneous needle, in diagnosing
Antitumor activity, of hexamethylmelamine, prostate cancer, 359
112 in renal cell carcinoma, 396
Antitumor reactivity, specific, in lymphocytes preventing, following operation for
of cancer patients, use of transfer factor in supraglottic cancer, 556
inducing, 138 Assay(s), leukoagglutination, for non-HLA
Antitumor response(s), after bacillus granulocyte antigens, 976
Calmette-Guerin therapy, 136 serum, in diagnosing prostate cancer,
Antitumor therapy, with bacillus 359-360
Calmette-Guerin, factors critical to success Astrocytoma(s), cystic, of cerebellar
of, 136 hemispheres, surgery for, 739
Index 1057
Astrocytoma! s) (Continued) Bacillus(i), gram-negative, infection by,

grade 1 and grade 2 brain, radiation 964-965
therapy for, 742 septicemia from, in granulocytopenia,
Ataxia, cerebellar, dementia and, EMI scan 965
for diagnosing, 1006 BACON, for head and neck cancer, 562
Ataxia-telangiectasia, spontaneous neoplasms Bacon operation, for renal cancer, 284, 285,
in, 129-130 286
transfer factor for, 138 Barium enema, for diagnosis of colorectal
Atrophv, of adrenal cortex, from mitotane, cancer, 272
108 Barium swallow, for diagnosing esophageal
Atvpia, epithelial, in carcinoma in situ, cancer, 235
382 for diagnosing stomach cancer, 249
Auer body(ies), in acute myelogenous Bartholin's gland, adenocarcinoma of, 467
leukemia, 823 Basal cell carcinoma, chemosurgery for,
Autonomic pathway(s), role in blocking disadvantages of, 720
cancer pain, 1018 cutaneous, chemosurgerv for, healing in,
Autotransplant(s), successful, low incidence 717-718
of, in patients with advanced neoplasms, cryosurgery for, 712, 714, 715t, 716
126 description of, 714
Autotransplantation, cryopreservation and, cure rates in, 705, 705t
considerations for patient selection in, description of, noduloulcerative, 698
980-981 fixed-tissue chemosurgery for, 717
procedures for, 980 metastases 700, 701
in,
5-Azacytidine, 90-91 morphea type, curettage and
chemical structure of, 88 desiccation and, 709
origin and mechanism of action of, route of radiation therapy for, 710, 712, 713t
administration of,90 in young patients, 711
toxicities and drug dosages for, 91 recurrent, cure rates for, 719, 719t
sclerosing, description of, 699-700
staging and prognosis in, 700-701
superficial, description of, 699
topical 5-fluorouracil for, 721
B topical chemotherapy for, 720-721
B description of, 912
cell(s), treatment of, 704-722
B lymphocyte neoplasm(s), capable of methods of, 704-705
immunoglobulin synthesis, 853-866 types of, 699-700
Babcock operation, for renal cancer, 284, 284, of vulva, 466
285 B-CAVe, for Hodgkin's disease resistant to
Bacillus Calmette-Guerin (BCG). antitumor MOPP, 894, 896t
therapv with, factors critical to success BCNU. See Carmustine.
of, 136 Beta human chorionic gonadotropin, in
as nonspecific immunotherapy, 135 staging testicular carcinoma, 414
combined with DTIC, reduction in Bile duct(s), divisions of, 339
recurrence rate in high-risk melanoma extrahepatic, carcinoma of, 336-342
patients with, 146 chemotherapy 341, 341t
for,
following pulmonary resection, 223 clinical features and diagnosis of,
following surgical resection. 143 metastases in, 338
for acute myelogenous leukemia, 827 correlation with gallstones, 337
for bladder cancer, 391 etiology of, 336-337
for lung cancer, 223 incidence of, 336
for melanoma, 691 natural history of, 337-338
for multiple myeloma, 859 radiation therapy for, 340t, 341
for ovarian cancer, 506 surgery for, 339
for preoperative immunotherapv, studies treatment of, 339-341
of, 142 malignant neoplasms of, types of,
for renal cell carcinoma, 405-406 diseases associated with, 337
for stomach cancer, 261 Biologic effect(s), long-term, of ionizing
for vaginal cancer, 141 radiations, 21
intralesional injections of, for skin lesions Biology, tumor cell, cvtokinetic concepts in,
of breast cancer, Glaxo strain of, 140 39-40
local tumor destruction and, 141-142 Biopsy(ies), blind needle, in diagnosing liver
role in, prolonging survival, in malignant metastases, 327
melanoma, 145 bone marrow, in Hodgkin's disease, 879
therapy with, tumor regression after, 136 in non-Hodgkin's lymphomas, 920
tumor regression in malignant melanoma cervical, prior to treatment, in invasive
and, 139 carcinoma, 480
1058 Index
Biopsy(ies) (Continued) Bladder cancer (Continued)

diagnostic, 9-10 etiology and epidemiology of, 374-376
endometrial, 447 hematuria in, 376
for melanoma, 681, 683 incidence of, 384
for osteosarcoma, 658 high-stage, high-grade, radiation therapy
importance of proper technique in, 10 for, 385
in bladder cancer, 377 treatment for, 384-388
laryngography prior to, in laryngeal or in urban versus rural populations, 374
hypopharyngeal cancer, 550-551 invasive, inadequacy of transurethral
liver, in neuroblastoma metastases, 765 resection in, 384
lymph node, importance of primary tumor lymphadenectomy in, 387
site identification and, 10 natural history of,376-380

multiple, with endoscopy, for patients with pedal lymphangiography in staging of, 378
previous partial gastrectomy, 251 preoperative radiation therapy in, 386
multiple random, before segmental prospects for the future in, 391-392
resection, in bladder cancer, 385 prostatocystectomy for, 381
needle, advantages of,10 method 387
of,
in diagnosing prostate cancer, 359 radical cystectomy 385

for,
in stage A prostate cancer, 368 complications of,387-388
of pancreas, 311-312 performed in two stages, 388
to diagnose thyroid cancer, 594 Schistosoma haematobium as cause of,
of lymph nodes, in epithelial ovarian 375-376
tumors, 501 segmental resection in, 384-385
of scalene lymph nodes, for staging criteria for, 385
testicular carcinoma, 413 specific chemical-industrial carcinogens as
percutaneous liver, for non-Hodgkin's cause of, 374
lymphomas, 920, 922 stage A, transurethral surgery for, 380
preceding surgery, for cutaneous squamous staging criteria and prognosis in, 379-380
or basal cell carcinomas, 706 staging of, 377-378
prior to curettage and desiccation, for staging systems in, 379-380, 380
squamous and basal cell carcinomas, 708 superficial low-grade lesions in, treatment
types of, importance of eventual treatment of, 380-382
in choice of, 9 treatment of, 380-391
x-rays and, in diagnosing oral cavity cancer, tumor recurrence in, 380-381
525 types of drugs used in, 381
Biopsy tissue(s), microscopic examination of, types of occupations implicated in, 374
in laryngeal and pharyngeal cancer, 551 urine cytology in, 378-379
Biotransformation, of chemotherapeutic Bladder carcinogen(s), increasing
drugs, 31-32 identification of, 374
of dacarbazine, 65 occupational, 374-375
of doxorubicin and daunomycin, 67 Blast cell(s), presence of terminal
Bladder cancer, 374-392 deoxynucleotidyltransferase in, in chronic
adjuvant therapy in, 392 myelogenous leukemia, 838
advanced, instillation of formalin in, 391 myelogenous
Blast crisis, in chronic
intra-arterial infusion of leukemia, chemotherapy for, 836-838,
chemotherapeutic drugs in, 390 837t
radiation therapy for, 389 description of, 834
surgery for, 388-389 increasing survival in, frequency of
symptomatic therapy in, 390-391 meningeal leukemia because of, 838
treatment for, 388-391 Bleeding, in acute myelogenous leukemia,
biopsy in, 377 821
carcinogens in, types of, 375 risk of, thrombocytopenia and, 963-964
carcinoma in situ in, 377 uterine, abnormal, in endometrial
presenting symptoms of, 382 carcinoma, 447
treatment of, 382-384 Blenoxane. See Bleomycin.
change in tumor cell population in, caused Bleomycin, 71-73
by radiation therapy, 386 forhead and neck cancer, 560
chemotherapy for, 389-390 for pleural effusion,989
classification of, 376 mechanisms of action of, characteristics of,
clinical features and diagnosis of, 376-379 tumor resistance for, 72
detection of distant metastases in, 379 mutagenicity and teratogenicity of,
detection of invasion in, methods of, 378 pulmonary toxicity and, 73
diagnosing, intravenous pyelography for, radiation therapy and, for head and neck
377 cancer, 564
effect of tumor invasion on survival in, 384 Streptomyces verticillus as source for, 71
Index 1059
Bleomycin toxicity, appearance of lung in, Bone marrow depression. See also Bone
72-73 marrow suppression and Bone marrow
Blocker(s), alpha, in surgical treatment of failure.
pheochromocytomas, 626 from chemotherapy, 962
Blood, extracorporeal irradiation of, for from chemotherapy and radiation, in
chronic myelogenous leukemia, 839 Wilms' tumor, 775
presence of carcinoembryonic antigen in, from radiation therapy, 963
127 Bone marrow failure. See also Bone marrow
Blood calcium level(s), development of suppression and Bone marrow
symptoms in hypercalcemia and, 995 depression.
Blood cell count, busulfan administration anemia from, thrombocytopenia from,
and, 64 leukopenia from, 963
Blood component therapy, for bone marrow consequences of, 963-967
failure, 972-979 diagnostic evaluation in, 968
Blood-brain barrier, dactinomycin and, 71 erythrocyte transfusions in, 972-973
inability of chemotherapeutic drugs to etiology of, 962-963
cross, factors contributing to, 31 from cancer treatment, 961
methotrexate and, 84-85 granulocyte transfusions for, 975-979
mitomycin-C and, 74 infection in, iatrogenic factors and, 966-967
nirrosureas and, 66 management of, 961-983
procarbazine and, 106 platelet transfusions for, 973-975
Bloodstream, ability of breast cancer to protection against, 967-972
spread di reedy to, 163 treatment of, 967-981
Body(ies), ciliary, choroid and, malignant Bone marrow function, recovery of, in
melanoma of, treatment for, 582^583 Hodgkin's disease, following radiation, 888
iris and, malignant melanoma of, Bone marrow reserve, mechlorethamine
treatment of, 581^582 administration and, 58
malignant melanoma of, prognosis in, 581 Bone marrow suppression. See also Bone
Body surface area, of adult, nomograph for marrow failure and Bone marrow
calculating, 1046-1047 depression.
Bone(s), facial, involvement of, in Burkitt's from doxorubicin and daunomycin, 69
lymphoma, 939 from 5-fluorouracil, 87
fractures resulting from destruction of, from hydroxyurea, 108
immobilization for, 1011 from MOPP, in Hodgkin's disease, 892
long, Ewing's sarcoma in, 663 from vinblastine, 77
tumors metastatic to, production of Bone marrow toxicity, in chemotherapy,
hypercalcemic substances by, 995 34-35, 34, 35
Bone lesion(s), management of, in multiple Bone marrow transplantation, autologous, for
myeloma, 860-861 chronic myelogenous leukemia, 841
Bone marrow, appearance of, in chronic in acute myelogenous leukemia, 828
myelogenous leukemia, 833 Bone metastasis(es), lytic, breast cancer and,
autologous, from patients in remission from hypercalcemia from, 998
acute leukemia, 981 Bone scan(s), in staging lung cancer, 205
biopsy of, in Hodgkin's disease, 879 positive, benign causes of, 996, 997t
cryopreservation and transplantation of, Bowel, large, cancer of, determination of
autologous, 979-981 metastases in, 290
cryopreserved, maintenance of cell incidence of, 265
function in, obtained from iliac crests, obstruction and perforation in,
980 mortality rate in, 289
involvement of, in Hodgkin's disease, surgery for, 287-290
874-875 small, cancer of, 262-265
leukemic infiltration of, in acute clinical course and diagnosis of,
myelogenous leukemia, 821 263-264
normal, per cent irradiated, using standard incidence and etiology of, 262
radiation ports, 1048 natural history of, 262-264
recurrence of acute lymphoblastic leukemia pathology of, 262-263
in, 815 prognosis in, chemotherapy for,
replacement of by tumor, 962 surgery and radiation therapy for,
Bone marrow aplasia, drug-induced, in 264
chronic myelogenous leukemia, 836 treatment for, 264-265
Bone marrow aspirate, biopsy and, in carcinoid tumors of, surgery for, 615
non-Hodgkin's lymphomas, 920 Bowel complication(s), following pelvic
in neuroblastoma, 762 exenteration, 491
1060 Index
Bowel microflora, alteration in, colon cancer Breast cancer {Continued!

and, 266-267 chemotherapy for, 183-186
Bowel transit time, importance of, in colon combination, 184
cancer, 266 choice of treatment for, factors influencing,
Brace, cervical, for metastatic spine 179
involvement, 1012 classification of, 164-166
Brain, lymphomas 942
of, clinical features and diagnosis of, 166-167
neoplasms of, 726-747 CMF in, 184-185
Brain metastasis(es), in gestational disseminated, chemoimmunotherapy for,
trophoblastic disease, 440 149-150
radiation therapy for, 743-744 distribution of hormone receptors and
Brain stem and midbrain tumor(s), radiation response to endocrine therapy in, 178,
therapy for, 743 179t
Brain stem pain, tractotomy for, 1018 effect ofpregnancy on, 190
Brain tumor(s), anticonvulsants for, 738 endocrine manipulation and chemotherapy
biology of, 728-730 in, 186-187
change in immune system from, 729-730 endocrine manipulation in, 180-183, 189
chemotherapy for, 744-747 for post- and perimenopausal women,
combination, 746 182
734
clinical features of, 731, secondary, 181-182
dexamethasone for, 737 epidemiology and etiology of, 160-164
diagnosis of, 734-736 estrogen and progesterone receptors in, 164
methods of, 734 estrogen receptors in, 96
drug treatment of, important properties in, familial risk of, hormonal regulation in
744 development of, 160
etiology of, 727-728 hormone-receptor status in, 189
frequency of, 727t, 728t importance in choosing proper treatment
immunotherapy for, 747 for, 178
incidence of, 727 immunotherapy and, 140-141
local destruction of tissue by, mechanisms importance of axillary lymph node
of death from, 734 involvement in, 171
metastatic, 730, 730t incidence of, progress in reducing, 159
prognosis in, 737 types of, 164, 165t
infiltrating, histologic
natural history of, 731-737 inoperable, radiation therapy for, 175-177
nitrosureas plus radiation therapy for, 745 dose dependence in, 175
primary, prognosis in, 736-737 integration of treatment modalities in,
factors influencing, 736 188-189
radiation as cause of, 728 local excision and radiation therapy for,
radiation therapy for, 741-744 172-174

postoperative, 740-741 local treatment of, 170-178
range of tolerance to radiation of, 741 lyticbone metastases and, hypocalcemia
staging of, 736 from, 998
surgery for, 738-741 male, 190-191
aims of, 738 clinical features of, 191
contraindications to, 740 malignant pleural effusion associated with,
types of, 738-739 mechlorethamine and triethylene
symptoms of, 731 phosphoramide for, 988
treatment 737-747
of, metastatic, androgens for, 102
steroids for,737-738 combination chemotherapy in,
Breast, involvement of, in Hodgkin's disease, doxorubicin as cornerstone for,
875 185-186, 185t
Breast cancer, 159-196 cyclophosphamide and doxorubicin for,
ability to spread directly to bloodstream of, 186
163 treatment for, 188, 189
adjuvant chemotherapy for, 187 systemic, 178-187
advanced, comparative clinical trials in, immunotherapy for, 188
186,186 systemic treatment for, 187-188
simple mastectomy and radiation therapy natural history of, 164-170
for, 1976 nonhormonal chemotherapy in, response
aminoglutethimide administration in, 110 to, 183, 183t
as systemic disease, 163-164 premenopausal patients with, bilateral
bilateral, 190 oophorectomy for, 181
biology of, 162-164 prognosis in, 167, 169t
Index 1061
Breast cancer (Continued)

program of treatment for, 188, 189 Calcification, in anterior mediastinal
prophylactic therapy for, 190 teratomas, 785-786
prospects for the future in, 191 Calcium chloride, for severe hypocalcemia,
psychologic factors and rehabilitation in, 998
189-190 Cancer. See also Carcinomas, Neoplasms,
radiation doses for metastases in, 178 Tumor, and specific lesions,
radiation therapy and surgery for, 171-177, accelerated clearance of iron and folic acid
188 in, 962
relative risk of, by age, 160, 161t, 162 alveolus and hard palate, description of,
removal of axillary and internal mammary treatment for, 527
nodes in, 170 anal, 304^308
skin lesions of, intralesional injections of chemotherapy for, interstitial implant for,
bacillus Calmette-Cuerin and 307
mechlorethamine for, 140 clinical features of, 305
staging in, 167, 168t, 169t etiology of, squamous cell carcinoma in,
'
symptoms of, methods of diagnosis in, 304

166 interstitial implant for, with surgery, 306
thermograms and ultrasound in, 167 pathology of, presenting features of,
treatment for, 146 304^305
general principles in, 180 avoidance of perineum in, 306
tumor doubling time in, 162-163, 162t treatment of, 306-307
early versus late, 163 various tissues originating from, 304, 305
Breast reconstruction, 190 anatomic site of origin and extent of,
Broder's classification, use in stomach cancer, importance of in choosing radiation
248 therapy versus surgery, 24
Bronchial carcinoma, passive immunotherapy bladder, 374^392
in, 144 adjuvant therapy in, 392
Bronchogenic carcinoma, correlation of advanced, instillation of formalin in, 391
survival rate with histologic type and intra-arterial infusion of
stage of disease in, 213 chemotherapeutic drugs in, 390
preoperative mediastinal exploration in, radiation therapy for, 389
212 surgery for, 388^389
screening for, 200 symptomatic therapy in, 390-391
systemic effects of, 202t treatment for, 388-391
Bronchoscopy, fiberoptic, in diagnosing lung biopsy in, 377
cancer, 203 carcinogens in, types of, 375
fordetermining tracheobronchial tree carcinoma in situ in, 377
involvement, in esophageal cancer, 236 presenting symptoms of, 382
Bronchus(i), malignant occlusion of, pleuritis treatment of, 382-384
secondary to, pleural effusion and, 985 change in tumor cell population in,
Buccal mucosa, cancer of, 526-527 caused by radiation therapy, 386
metastases in, 527 chemotherapy for, 389-390
presenting symptoms of, 526 classification of, hematuria in, 376
Burkitt's lymphoma, chemotherapy for, clinical features and diagnosis of,
prognosis 940
in, 376-^379
cyclophosphamide administration in, 61 detection of distant metastases in, 379
description of, 939 detection of invasion in, methods of, 378
Burn(s), carcinomas arising from, 698 diagnosing, intravenous pyelography for.
Burn scar(s), squamous cell carcinoma from, 377
metastases in, 702 effect of tumor invasion on survival in,
Busulfan, 63-64 384
blood cell counts and, toxicities of, chronic etiology and epidemiology' of, 374-376
myelocytic leukemia, 64 high-stage high-grade tumors in,
excretion of, 63 incidence of, 384
in chronic phase of chronic myelogenous radiation therapy for, 385
leukemia, 834-836 treatment for, 384-388
peripheral blood remissions with, 834 in urban versus rural populations,
treatment regimens of, in chronic chemical industrial carcinogens as
myelogenous leukemia, chronic phase, cause of, occupations implicated in,
complications from, 835 374
Bypass, palliative, for cancer of esophagus, influence of host immune response on,
240-241 391
1062 Index
Cancer (Continued) Cancer (Continued)

bladder, invasive, inadequacy of trans- breast, inoperable, dose dependence in
urethral resection in, 384 radiation therapy for, 175

lymphadenectomy in, 387 radiation therapy for, 17.5-177
natural history of,376-380 integration of treatment modalities in,
pedal lymphangiography in staging of, 188-189
378 local excision and radiation therapy in,
prospects for the future in, 391-392 172-174
prostatocystectomy for, 381 lyticbone metastases and, hypocalcemia
method of, 387 from, 998
radiation therapy for, preoperative, 386 male, 190-191
radical cystectomy for, 385 clinical features of, 191
complications of,387-388 malignant pleural effusion associated
performed in two stages, 388 with, mechlorethamine and
Schistosoma haematobium as cause of, triethylenephosphoramide for, 988
375-376 metastatic, doxorubicin and
segmental resection in, 384-385 cyclophosphamide for, 186
criteria for, 385 systemic treatment for, 178-187
stage A, transurethral surgery for, 380 treatment for, 189
staging criteria and prognosis in, 379-380 use of androgens for, 102
staging of, 377^378 micrometastatic, adjuvant chemotherapy
systems for, 379-380, 380 for, 187
treatment of, 380-391 immunotherapy for, 188

treatment of superficial, low-grade systemic treatment for, 187-188
lesions in, 380-382 natural history of, 164-170
tumor recurrence in, 380-381 nonhormonal chemotherapy in, response
types of drugs used in, 381 to, 183, 183t
urine cytology in, 378-379 prognosis in, 167, 169t
breast, 159-196 program of treatment for, 188, i89
advanced, simple mastectomy and prophylactic therapy for, 190
radiation therapy for, 176 prospects for the future in, 191
aminoglutethimide administration in, psychologic factors and rehabilitation in,
110 189-190
axillary and internal mammary nodes in, radiation therapy for, 188
removal of, 170 relative risk of, by age, 160, 161t, 162
axillary lymph node involvement in, skin lesions in, intralesional injections of
importance of, 171 bacillus Calmette-Guerin, and
bilateral, 190 mechlorethamine for, 140
biology of, 162-164 staging of, 167, 168t, 169t
choice of treatment for, factors stimulation of host resistance in, 151
influencing, 179 surgery and radiation therapy for,
classification of, 164-166 171-177
clinical features and diagnosis of, symptoms of, methods of diagnosis in,
166-167 166
CMF, in, 184-185 thermograms and ultrasounds in, 167
combination chemotherapy for, 184 treatments 146
for,
disseminated, chemoimmunotherapy for, tumor doubling times in, 162-163, 162t
149-150 early versus late, 163
distribution of hormone receptors and buccal mucosa, 526-527
response to endocrine therapy in, 178, metastases in, 527
179t presenting symptoms of, 526
effect ofpregnancy on, 190 choice of therapy in, 5-6
endocrine manipulation for, 180-183, 189 colon, alteration in bowel microflora and,
chemotherapy and, 186-187 266-267
in post- and perimenopausal women, association with high levels of sugar
182 consumption and fat intake, 266
epidemiology and etiology of, 160-164 association with low fiber in diet,
estrogen receptors in, 96 265-266
estrogen therapy and, 96, 99 development of, effect of age on, 268
familial risk in, hormonal regulation in diseases associated with, distribution and
development of, 160 gross pathologic features of, 269
hormone-receptor status of tumor in, 189 extended surgery for, 290
immunotherapy and, 140-141 high-risk, postoperative radiation for, 297
incidence of, progress in reducing, 159 histologic features related to prognosis
infiltrating, histologic types of, 164, 165t in, 270
Index 1063

colon, importance of bowel transit time in, colorectal, recurrence of, increased use of
266 immunologic markers to detect,
induction or repression of bacterial 292-293
enzymes as possible cause of, 267 maneuvers to reduce, 291
influence of extent of disease on survival second look operation and
in, 280t carcinoembryonic antigen in
staged resection versus primary resection diagnosing, 291-293
in, 289 screening programs for, 271, 272t
surgery for, survival following, effect of staging systems for, 274t, 275, 275t, 276
age on, 294-295 surgery and adjuvant immunotherapy for,
surgical approach to, 293 147
type of surgery for, factors influencing, surgery for, 276-296
289-290 goals of, extent of spread and, 276
colorectal, 265-304 operative principles in, 276-279
carcinoembryonic antigen in, 302 results of, 279
chemotherapy for, 297-301 suture line recurrence following,
combination, 299-301, 300t, 304 290-291
single-agent, 297, 298t, 299 surgical management of, areas of special
classification, 269-270 importance in,287-296
clinical features and diagnosis of, tests for fecal blood in, 271
270-273 tests of immune response and, 301-302
clinical features of, relationship to tumor treatment for, 276-304
size and 270
location, determination of cure in, 6
diagnosis barium enema and
of, effects of, on nervous system, 1004,
colonoscopy for, 272 1005t
proctosigmoidoscopy for, 271 endocrine pancreas, 603-609
distribution of, five-year survival and, chemotherapy for, 607-608
273t immunotherapy for, 609
Dukes classification of, compared with incidence of, 603
other systems, 273, 275, 273 natural history of, 603-607
electrocoagulation and local excision for, radiation therapy for, 607
295-296 treatment of, 607-609
epidemiology of, 267-269, 267t eradication of, as objective of radiation
etiology of, 265-267 oncology, 19
5-fluorouracil as drug of choice for, esophageal, 233-246
297-298, 298t, 303, 303t anatomic location of, 234, 235
hemoccult test for, 271, 271 barium swallow in diagnosing, 235
high-risk groups for, 268-269 bronchoscopy in, 236
immune suppression in, correlation with cervical, surgery for, 240
poor prognosis of, 301 chemotherapy and immunotherapy for,
immunology and immunotherapy in, 245, 245t
301-302 clinical features and diagnosis of,
integration of treatment modalities in, 235-236
302-004 dysphagia as symptom of, 235
intestinal obstruction in, symptoms of, epidemiology of, 233
288 etiology of, 233-234, 234t
liver metastases in, continuous high thoracic involvement in, colon
intrahepatic artery infusion for, of interposition for, description of, 240
5-fluorouracil, 329, 330t, 331 in esophagogastric junction and lower
continuous hepatic artery infusion thoracic areas, surgery for, 238
versus systemic chemotherapy for, link with achalasia of, 233
331, 334 lower and midthoracic, surgery for,
diagnosis of, 325 238-239
liver resection for, 293 mass screening for, 246
surgery for, 293-294 natural history of, 234-237
thoracotomy for, laparatomy prior to, palliative bypass for, 240-241
294 pathology of, 234-235
trials in, 328 radiation therapy, improvement of
local excision in, 296 dysphagia from, 243
morphology and immune response in, preoperative results of, 243-245, 244t
301 techniques and complications of, 242
natural history 269-276of, role of chronic irritation in development
palliative surgery for,294 of, 233-234
radiation therapy for, 296-297 staging of, 236-237, 236t
1064 Index
Cancer (Continued) Cancer {Continued)

esophageal, surgery for, 237-242 hypopharyngeal and supraglottic, pain in,
goals of, 237 550
preparation prior to, 237-238 immunologv and immunotherapy in,
surgical results in, 241-242, 24 It 124-153
treatment of, 237-246 incidence of, deaths from, 4
upper, surgery for, 239-240, 239 kang, of China, 698
upper thoracic, esophagogastrectomy large bowel, incidence of, 265
for, 238, 239 metastases in, determination of, 290
etiology and pathogenesis of, immunologic obstruction and perforation in, mortality
theories of, 36 289
rate in,
evidence for tumor-specific immune surgery 287-290
for,
response in, 128-129 laryngeal, cigarette smoking and alcohol
fallopian tube, 511-512 and, 547
diagnosis and treatment of, 512 hoarseness in, 549
family therapy to help in dealing with, staging of, 552, 552t
1043 laryngeal and hypopharyngeal, 547-558
floor of mouth and anterior tongue, 527-529 anatomic classification of, 548, .548
diagnosis and treatment of, 528 chemotherapy for, 553
prognosis in, 529 incidence and etiology of, 547
symptoms of, 527-528 laryngography prior to biopsy in, 550-551
glottic, 553-555 natural history of, 548-552
description of, 553 physical examination in, 550-552
dyspnea and stridor in, 549-550 radiation therapy and surgery for,
hemilaryngectomy for, 554, 554 552-553
laryngectomy for, 555 treatment of, 552-558
treatment for, 554 laryngeal and pharyngeal, microscopic
head and neck, BACON and COBMAM for, examination of biopsy tissue in, 551
562 pathology of, 549
bleomycin for, 560 symptoms of, 549-550
chemotherapy for, 558-565 lip, metastases in, radiation therapy or
adjuvant, 563-565 surgery for, 526
combination, 561-562, 561t sun as etiologic factor in, 523
intravenous hyperalimentation prior to, 319-324
liver,
559 chemotherapy for, 321-324
regional, 562-563 regional, 322, 322t, 324
types of drugs used in, 563 etiology and epidemiology of, 319
single-agent, 559-561, 561t immunotherapy for, 324
chemoimmunotherapy for, 150 natural history of, 320
chemotherapy and surgery for, 564-565 pathology of, clinical course of, diagnosis
cisplatin for, 561 320
of,
disseminated, 559 surgery and radiation therapy for, 321
levamisole for, 148 systemic chemotherapy for, 321-322, 322t
methotrexate and leucovorin for, 564 treatment of, 321-324
methotrexate for, 559-560, 560t lung, adjuvant immunotherapy in, 143-145
methotrexate or bleomycin and radiation advanced, tumor cell vaccine as adjuvant
therapy for, 564 therapy in, 144
mucositis from administration of bacillus Calmette-Guerin and
methotrexate in, 565 Corynebacterium parvum for, 223
unresectable tumors in, drug regimen for, chemotherapy, in, 219-222
562 adjuvant single-agent, 222
host immunity against, clinical evidence clinical features and diagnosis of,
for, 125-133 200-203
human, correlations between clinical disseminated, chemoimmunotherapy for,
course of and immune response to 149
tumor-associated antigens, 132-133 etiology and incidence of, 197
importance of cellular and humoral histologic types of, classification of, 197,
immune responses in controlling 198t
growth of, 132 immunosuppression in, 222
hypercalcemia and, 996 immunotherapy for, 222-223
hypopharyngeal, 557-558 importance of preventive measures in,
cervical metastases in, 557 226
dysphagia in, 550 integration of treatment modalities in,
staging of, 552, 553t 224-225
Index 1065

lung, levamisole for, 223 nasopharyngeal, clinical features and
metastatic, development of in kidney diagnosis of, natural history of, 536-537
transplant patients, 130 prognosis in, 538
as adjuvant treatment to operation, 144 race predilection in, 535
mediastinoscopy 212-213
in, sequelae of, 538
natural history of, 197-200 symptoms cervical metastases in, 537
of,
occurrence of second primary tumors in, treatment 537-538
of,
pneumonectomy versus lobectomy for, natural history of, 3-5
213 oral cavity, biopsv and x-ravs in diagnosing,
operable, symptomatic status in, 208 525
palliative treatment for, 218-219 clinical features and treatment of,
perioperative mortality rates in, 525-529
relationship of tumor size to prognosis leukoplakia and, 522
in, 207 vitamin and mineral deficiencies and,
preoperative assessment of, lymph node 523
metastases in, 211 oral cavity and oropharynx, 522-530
prospects for the future in, 225-226 classification of, 523
radiation therapy for, 214-219 clinical features and treatment of,
courses of, dose-time relationships in, 525-530
216 diagnosis of, 523, 525
for palliation, chemotherapy and, 218 incidence and etiology of, 522^523
postoperative for, 217 natural history of, 523-525
preoperative, 216-217 staging of, 524t, 525
versus surgery, 214-215 oropharyngeal, clinical features and
screening for, 200 treatment of, 529-530
small cell, 201 lymphomas in, 523
Lambert-Eaton syndrome and, 1004 metastases in, 529
symptoms of syndrome of otalgia in, radiation therapy and surgery
inappropriate antidiuretic hormone for, 530
secretion in, 1000 ovarian, 492-515
stage-grouping in, 207t advanced, chemotherapy as adjunct to
staging of, 203-206 surgery and radiation therapy, 503
surgical, 211-212 bacillus Calmette-Guerin for, 506
techniques of, 205, 206t biology of, 492-493
supportive care in, 223-224 biopsy of abnormal nodes in, 497
surgery and adjuvant chemotherapy or chemoimmunotherapy for, 150
immunotherapy in, 225 chemotherapy for, 503-504, 514
surgery for, 210-214 combination, 504
surgical resection for, 212-214 classification and pathology of, 493, 496
selecting candidates for, 210 clinical features and diagnosis of,
survival rates in, 207-208 496-497
symptoms of, 200-201, 201t complete resection of tumor in,
treatment of, 210-225 correlation with prognosis, 499-500
types of carcinoma comprising, 198-200 control of, 512
types of tumors in, preoperative passive immunization as method of,
irradiation used for, 217 506
unresectable, factors correlating with elevation of urinary estrogens or
poor prognosis in, 208 pregnanediol in, 510
mouth, snuff as etiologic factor in, 522 grading of, 499, 500t
nasal cavity, and paranasal sinus(es), immunotherapy for, 504-505
531-535 epidemiology and etiology of, 492
classification and pathology of, 531-532 exploratory operation for, radiation
clinical features of, 532-533 therapy and chemotherapy for, 507
diagnosis of, CAT scan for, 533 extension of disease in, 493
epidermoid carcinomas in, treatment for, factors influencing difficult diagnosis of,
534 513
incidence of, 531 histologic classification of, 493, 495t-496t
olfactory neuroepithelial tumors in, 532 increased risk of developing leukemia in,
prosthesis for, prognosis in, 535 514
treatment of, 533-535 initial staging of, mistakes in, 499
nasopharyngeal, 535-538 integration of research and control in,
age and sex incidence in, 536 514-515
classification and pathology of, 536, integration of treatment modalities in,
536t 506-507
1066 Index

ovarian, laparotomy 498 in, prostate, chemotherapy for, 367-368
lymphangiography in, 497 plus hormone therapy in,367
methods of active immunotherapy in, clinical features and diagnosis of,
506, 507t 359-360
natural history of, 493-500 correlation of histologic grade and
presence of human chorionic prognosis in, 360
gonadotropin in, 514 diagnosis of, needle biopsy for, 359
presence of Regan isoenzyme in, radioimmunoassay for, 360
513-514 serum assays for, 359-360
prognosis in, 498-500 distant metastases in, hormonal therapy
radiation therapy for, radioactive gold for, 365
and phosphorus for, 502 endocrine manipulation for, 363-367
separation of benign and malignant advantages and disadvantages of, 365
epithelial neoplasia in, 496 estrogen therapy for, 96, 99
specificity of tumor-associated antigens hormone therapy for, effect on survival,
for histologic type in, 504 364
staging of, 497-198, 498t incidence and etiology of, 358
subdivisions in, 499 lymphangiography in, 362
symptoms of, 497 natural history of, 359-363
treatment of, 500-515 orchiectomy or oral estrogen for, 364, 365
tumor markers in diagnosis of, 513 prednimustine for, 368
types of drugs used in, 503-504 stage A, description of, 361-362
pancreatic, 308-319 importance of determining tumor
chemotherapy for, 316-318 involvement and differentiation in,
clinical features of, 309-310 needle biopsy for, 368
curative operations for, 313-315, 314 treatment of, 368-369
diagnosis of, 310-312 stage A 2 pelvic lymph node dissection
,
endoscopy and angiography for, in, 369

310-311 stage B, hormone therapy for, 370-371
tests for, overview of, 312 radiation therapy for, 370
ultrasound, and CT scan in, 311 radical prostatectomy for, 369, 370t
distribution of, 308, 309t treatment of,369-371
etiology and epidemiology of, 308 for aged patient, 369
histology of, metastases in, 309 stage B 2 lymphadenectomy
, in,
immunology and integration of treatment complications of, 370
modalities in, 318 stage C, hormone therapy for, 371, 373
laparotomy for, results of, 315 improving staging of, 371-372
natural history of, 308-309 lymph node metastases in, radical
palliative operations for, external beam prostatectomy for, 371
radiation and interstitial implants for, pelvic lymph node dissection in, 372
315 radiation therapy for, 372
physical findings in, diabetes mellitus treatment of, 371-373
and, 310 stage B, description 362
of,
radiation therapy for, 315-316 stage C, description 362
of,
radical excision of, total pancreatectomy stage D, description of, 362-363
for, performance status in, 313 stages D, and D 2 treatment for, 373
,
staging of, 312-313 staging and prognosis of, 360-363

surgery for, 313-315 staging systems for, 360-363, 361t
treatmentof, 313-318 surgery and radiation therapy for, 363
Whipple procedure for, 313, 314 treatment of, 363-374
patterns of spread in, 4-5 by stage, 368-373
peripheral neuropathies caused by, types types of drugs used for, 367
of, 1004 psychosocial management of, involved triad
physical rehabilitation and, 1021-1035 in, 1036
poliomyelitis and, 1004-1005 psychosocial problems of, 1036-1045
postoperative course of, correlation with in individual, 1037-1039
patient sensitivity to DNCB, 131 pyriform sinus, prognosis in 557
pragmatic approach, to, by mental health rectal, abdominoperineal resection and
consultant, 1036-1037 preoperative radiation for, 297
prostate,358-373 anterior resection or abdominal perineal
adrenalectomy and hypophysectomy in, resection for, 279-282, 281
366 anteroposterior versus low anterior
antiandrogens and inhibitors of Resection in, comparison of five-year
androgen synthesis in treatment of, survival rates of, 281-282, 282t
366-367 Babcock operation for, 284, 284, 285
Index 1067

rectal, Bacon operation for, 284, 285, 286 stomach, geographic incidence of, 246
direction of lymphatic spread in, 281 high risk of, in patients with benign
electrocoagulation, in, 295 ulcer disease, 250
five-year survival rates in, after surgical immunology in, immunotherapy for,
resection, 274t splenectomy for, 260-261
Kraske operation for, 282, 283 incidence of adenocarcinoma in, 248
preoperative radiation for, 296-297 integration of treatment modalities in,
sphincter-saving operations for, 282-287 261
trans-sacral technique of surgery for, 287, lymph nodes in immunologic
287, 288 investigations of, 260
Tumbull-Cutait operation for, 286, 287 natural history of, 248-254
residual, in irradiated larynx and pharynx, partial gastrectomy for, 254, 254
551^552 prognosis in, by stage, 253-254, 253
role of nutrition in surgical management of, radiation therapy for, 255-257
16 staging of, 251-253, 251,252, 252t, 253t
skin, 695-725 surgery for, results of, correlation with
classification of, 698-700, 699t stage of disease at presentation, 255
delayed hypersensitivity reactionin, 722 treatment for, 254-261
development of, following x-radiation for tumor infiltration in, 126
benign conditions, 697 unresectable, photon radiation therapy
diagnosis of, 700 for, 255, 257
epidemiology of, 695-696 use of immunologic reactivity of
etiology of, 696-698 leukocytes in diagnosing, 260
immunotherapy and, 141 subglottic, description of, 556
incidence of, 695 treatment of, 556-557
multiple, syndromes that predispose to, Mipraglottic, 555-556
698 description of, 555
natural history of, 698-702 preventing aspiration following operation
ratio of basal cell to squamous cell for, 556
carcinomas in, 696-697 thyroid gland, 591-603
staging and prognosis in, 700-702 administration of thyroid-stimulating
types of, especially suited for hormone in, 599-600, 602
immunotherapy, 721 chemotherapy for, 602-603
x-ray-induced tumors in, 696 classification of, 593, 593t
small bowel, 262-265 clinical features of, 593
chemotherapy for, clinical course and diagnosis of, 594
diagnosis of, 263-264 doxorubicin for, 603
incidence and etiology in, 262 epidemiology of, 592
natural history in, 262-264 etiology of, 591-592
pathology in, 262-263 extent of operation in, 597
surgery and radiation therapy for, indications for surgery in, 596
prognosis in, 264 natural history of, 593-596
treatment of, 264-265 postoperative radioiodine ablation
stomach, 246-262 therapy for, 602
advanced, radiation therapy in radiation of, leukemia in, 601
conjunction with chemotherapy for, radioiodine for, 599-603
256t, 257 studies on, 601
anatomic location and spread of, 248 therapeutic dosages of, 600
association with pernicious anemia, 247 staging and prognosis in, 595-596
bacillus Calmette-Guerin for, 261 staging of, 595, 595t
biology of, 247-248 surgery for, 596-599
Broder's classification for, 248 thyroxine for, dosage of, 602-603
chemotherapy for, 257-260 treatment of, 596-603
combination, 258-260 tongue, areas affected, 527
single-agent, 257-258, 257t metastases to lymph nodes in, 528
classification of, 248-249 total body irradiation as systemic treatment
classification for, 249
systems for, 21
clinical features of,249 treatment of, manipulation of endocrine
contiguous organ involvement in, surgery system in, 95
and, 255 types of, mechlorethamine used in, 59
diagnosis of, 249-251 melphalan used in, 62-63
x-ray studies for, 249-250 vaginal,468-476
epidemiology and etiology of, 246-247 exposure to diethylstilbestrol and, 473
factors associated with, 247, 247t lymphatic drainage of, 471
1068 Index
Cancer (Continued) Cancer surgery (Continued)

vaginal, prognosis in, 4.72 importance of wide surgical margin in, 11,
staging of,471^72, 471t lit
topical immunotherapy in, 141 integration of into treatment plan, 16-18
treatment for, 472—475 patient factors in, 17
vulvar, 457-468 principles of, 8-18
squamous cell carcinoma in, 457-462 radiation therapy combined with. 14
clinical features and diagnosis of, techniques of, 10-11
457-1.58 treatment goals in, 18
correlation between histologic and treatment of primary tumor in, 10-12
clinical stages of, 458 Cancer treatment, bone marrow failure
incidence and etiology of, 457 caused by, 961
natural history of, 457—160 multimodality treatment in, related
prognosis in, 458^459 morbidity of, intent in, 6
staging of, 458-460, 459t potential of recombinant D\'A techniques
Cancer cell(s), characteristics of, 29 in, 7
drug-resistant, combination chemotherapy proposed use of hydrazine sulfate and
and, 42 vitamin C in, 116
multimodality treatment and. 4 unproved methods of, 115-116
inherent genetic instability of, 3^4 Candida, life-threatening superinfections by,
specificity of immunotherapy for, 133 in granulocytopenic patients, 970
Cancer immunology and immunotherapy, Candidiasis, chronic subcutaneous, use of
124-153 transfer factor in, 138
Cancer immunotherapy, studies on use of in cancer patients, 965-966
xenogeneic immune RNA, 138-139 Carbenicillin, for Pseudomonas infection, in
Cancer pain, acupuncture for, granulocytopenic patients, 969
neuroaugmentative procedures in, 1019 Carcinoembryonie antigen (CEA), 127-128
Cancer patient(s), adolescent children of, as tumor marker, 46
problems in, 1042 discovery of, presence in blood of, 127
care of, importance of wide base of elevated levels of, stage of disease and,
communication among medical staff in, tumor recurrence and, 128
1044 for colorectal carcinomas, 302
indications for mental health consultation in detecting bladder cancer, 378
in, 1042 serum levels of, carcinomas of colon and,
psychosocial problems in, 1041-1045 127-128
dealing with death in, 1036 use in diagnosing recurrent colorectal
emotional disconnection from, of medical cancer, 291-293
staff not in clinical setting, 1045 Carcinogen(s), bladder, increasing
interaction with family, plan for, identification of, 374
professional emotional support for, 1038 occupational, 374-375
personality of, dealing with cancer and, environmental, studies of, 7
1037 mediastinal vascular tumors and, 792
primary fears of family of, 1039 procarbazine as, 107
psychologic problems associated with specific chemical-industrial, as cause of
enterostomal therapy in, 1024-1025 bladder cancer, 374
psychosocial problems of family of, 1039 types of, in bladder cancer, 375
sexual relationship with spouse, 1041 Carcinogenicity, of streptozotocin, 111
spouse of, psychosocial problems of, of sun exposure, 696
1039-1041 Carcinoid spectrum, mediators of, 612, 614t
treatment team as substitute family for, Carcinoid syndrome(s), by anatomic site, 612,
1040 613t
Cancer rehabilitation, role of nurses in, Carcinoid tumor(s), 609-620
1023 chemotherapy for, 618-619, 618t
role of physical therapist in, 1022-1023 by hepatic artery infusion, 619
Cancer rehabilitation center(s), criteria for single-agent versus combination, 618
admission medical teams in, 1022
into, classification of, 611, 61 It
Cancer research, ovarian, 513-514 clinical features of, elevated levels of
integration with ovarian cancer control, 5HIAA in, 612
514-515 diagnosis of, 612, 614
Cancer surgery, anatomic location of tumor as etiology of, 609-610
consideration for, 16 experimental approaches to, 620
as form of immunotherapy, 132, 133 general care of, integration of treatment
definitive, timing of, 15-16 modalities in, 619
importance of common patterns of spread incidence of, 609
in neoplasms and, 10 metabolism of tryptophan in, 610, 610
Index 1069
Carcinoid tumor(s) (Continued) Carcinoma (Continued)

metastatic behavior of, syndrome bronehagenic, screening for, 200
production by, 612, 613t systemic effects of, 202t
natural history of, 611-615 cervical, 476-492
of appendix and small bowel, surgery for, advantages of operation over radiation
615 therapy for, 486
prognosis in, 614-615, 615t biology of, 477-479
radiation therapy for, 617 bipedal lymphangiography in, 482
rectal, livermetastases in, cardiac disease classification and incidence of, biologic
in, surgery for, 616 behavior of invasive, 479
sites of occurrence of, 612, 613t clinical features and diagnosis
of, 480
staging of, 614, 614t decreased 476
mortality' rate from,
surgery for, 615-617 pre- and postoperative support in, 491
anesthesia considerations in, 616, 617t disseminated, chemotherapy for
treatment of, 615-620 palliation of, 489-490
Carcinoma, anaplastic thyroid, description of, endometrial extension in, 484
596 epidemiology and etiology of,
surgery for, 599 implication of herpes virus, type II in,
adenoid cystic, of salivary glands, 477
description of, 544 metastases to lymph nodes in, 482
adrenocortical, use of mitotane in, 109 tumor volume as prognosticator of, 483
basal cell, cutaneous, chemosurgery for, natural history of, 479-484
716-720, 718t, 720t occult metastases to pelvic lymph nodes
disadvantages of, 720 in, 485
fixed-tissue, 717 pelvic and periaortic lvmphadenectomy
healing in, 717-718 in, 483
metastases in, 700 pelvic exenteration for, 490-491
sites of, 701 description of, 490
morphea type, curettage and prognosis in, 484
desiccation and, 709 radiation therapv for, complication of,
noduloulcerative, description of, 698 487^88
recurrent, cure rates for, 719, 719t description of, 486-487
sclerosing, description of, 699-700 factors influencing type of used, 487
staging and prognosis in, 700-701 radical hysterectomy and bilateral
superficial, description of, 699 pelvic lvmphadenectomy for, 486
topical 5-fluorouracil for, 721 recurrence in, 490
types of, 698-700 stage la, treatment for, 485
in skin cancer, 695 stage lb radiation therapy for,
vulvar, 466 vesicovaginal fistula resulting from,
chemotherapy and immunotherapy for, 488
705 treatment of, 485-488
cryosurgery' for, 712, 714, 715t, 716 stage II, radiation therapy for, 488-489
description of, 714 radical hysterectomy with pelvic
cure rates for, 705, 705t lymphadenectomv for, 488
curettage and desiccation for, 707-710, treatment 488-489, 489
of,
711t stage III, radiation therapy for, 488-489
cosmetic results in, 709 radical hysterectomy with pelvic
cure rates in, 709, 710t lymphadenectomy for, 488
immunotherapy for, 721-722 treatment of, 488-489, 489
radiation therapy for, 710, 712, 713t stage IV, pelvic exenteration for, 489
in young patients, 711 treatment of, 489-490
indications for 2 712 staging of, 481^82, 48 It
recurrent, 707 treatment of, 484-491, 487, 489
surgery for, 706-707, 707t, 708t embryonal, seminomas as origin of, 408
advantages of, 706 endometrial, 442-456
topicalchemotherapy for, 720-721 age as prognostic factor in, 451
treatment of, 704-722 biology of, 444-446
methods of, 704-705 cervical and vaginal metastases in, 445
bronchial, passive immunotherapy in, chemotherapy for, 454^55
144 classification of, 446, 447t
bronchogenic, correlation of survival rate clinical features and diagnosis of,
with histologic type and stage of 447^48
disease of, 213 dissemination of, 444, 445
preoperative mediastinal exploration in, endocervical curettage in, 448
212 estrogens as cause of, 443
1070 Index
Carcinoma (Continued) Carcinoma (Continued)

endometrial, etiology and epidemiology of, gallbladder, treatment of, 335-336
443-444 hepatocellular, alpha-fetoprotein in, 414
follow-up 455
of, intraepithelial, of vagina, methods of
histologic grade and prognosis in, treatment for, 473
lymphangiography for, tumor topical chemotherapy for, 475
differentiation in, 450 predisposition to, 472
hyperestrinism and, conditions associated squamous, description of, 469
with, 443, 444t treatment of, 472-473
incidence and detection of, 442 wide local excision for, 460
involvement of myometrium in, 444, 445 invasive, cervical, metastases in, 479
involvement of uterine isthmus in, 446 presenting symptoms in, biopsy prior
lymph node metastases in, 444^445 to treatment for, 480
pelvic, 449-450 pretreatment evaluation of, 482
lymphadenectomy as staging procedure vaginal, 474-475
in,452^*53 evaluation of pelvic and periaortic
medical evaluation 448^449
of, tests for, lymph nodes in, 476
as prognostic indicator, 450 implantation radiation for, prospects for
natural history of, 446-451 the future in, 475
operation in, as staging procedure for, radiation therapy for, 474
449 stage I, vaginectomy for, 474
prognosis 449-451, 449t
in, medullary thyroid, 598-599
radiation therapy for, myometrial coexistent pheochromocytoma and,
penetration as guide to, operation prior removal 599
of,
to, 453 description 596
of,
screening for, 447^148 inheritance of, 592
stage I, hysterectomy and bilateral thyroidectomy for, 598
salpingo-oophorectomy for, 431 microinvasive, cervical, 481
radical hysterectomy with pelvic miscellaneous primary, in salivary glands,
lymphadenectomy 452 for, 545
stage II, treatment for, 453-454 nonsmall cell, of lung, chemotherapy for,
stage III, treatment of, 454 combination, 222, 222t, 225
stage IV, treatment of, 455 single-agent, results of, 219, 219t
staging of, 448-449, 448t preoperative radiation therapy for,
surgery with radiation therapy for, integration of treatment modalities
451^54, 452 in, 225
symptoms of, obesity in, 447 types of drugs used for, 220
treatment of, 451^56 of ampulla of Vater, 342-343
difficulties in, 455 clinical features and diagnosis of,
uterine size as prognostic factor in, treatment of, 343
450-451 pathology and classification of, 342
variation in reports of studies on, 455 parathyroid, 588-591
epidermoid, of head and neck, adjuvant clinical features and diagnosis of,
chemotherapy for, 558 588^89
of nasal cavity and paranasal sinuses, clinical features of, histologic criteria of,
treatment for, 534 588, 589t
extrahepatic bile duct, 336-342 compared with adenomas, recurrent, 589
chemotherapy for, 341, 34 It histopathology of, 589t, 590
clinical features and diagnosis of, incidence of, 588
metastases in, 338 local recurrence after surgery in, 591
diseases associated with, 337 natural history of, 588-590
etiology of, 336-337 operative findings in, 589-590
incidence of, 336 prognosis in, 590
natural history of, 337-338 treatment of, 590-591
radiation therapy for, 340t, 341 posterior mediastinal, 792
surgery for, 339 ratio of basal cell to squamous cell, in skin
treatment of, 339-341 cancer, 696-697
follicular thyroid, description of, 596 renal cell, 392-406
frank, development of, following carcinoma adjunctive nephrectomy for, 402^04
383
in situ, asymptomatic primary and disseminated
gallbladder, 334^336 metastases in, chemotherapy and
correlation of cholelithiasis and immunotherapy for, 404
gallstones with, 334 chemotherapy and hormone therapy for,
surgery and adjuvant radiation therapy 405
in, 336 classification of, etiology of, 393
Index 1071
Carcinoma (Continued) Carcinoma (Continued)

renal cell, clinical features of, diagnosis of, squamous cell, disseminated, systemic
394 chemotherapy for, 475
diagnosis of, 394-396 in anal cancer, 304
systematic approach to, 395, 395 in body of esophagus, 235
excision of solitary foci of tumor in, for in cancer of vulva, 457-462
palliation, 403-404 chemotherapy for, 462
immunotherapy for, 405-406 clinical features and diagnosis of,
incidence of, 392 457^58
involvement of regional lymph nodes in, correlation between histologic and
400 clinical stages of, 458
metastases in, at time of diagnosis versus incidence and etiology of, 457
laterdevelopment of, effect on involvement of pelvic lymph nodes in,
survival, 398, 399 459, 460t
cellular and circulating immune local recurrence in, surgery and
response in, 405 radiation for, 461—462
cumulative survival in, 398, 398 natural history of, 457—460
frequency of regression in, after prognosis in, 458—459
palliative nephrectomy, 403 prospects for future in, 467—468
radiation therapy for, 404-405 radiation therapy and
natural history of, 393-399 lymphadenectomy for, 461
needle aspiration in, 395 radical vulvectomy 459, 460, 468
for,
nephrectomy for, percutaneous staging in, 458-460, 459t
transaortic occlusion prior to, 400-401 surgery for, 460-461
palliative nephrectomy for, impact on treatment of, 460-462
survival, 403, 403 in nasal cavity and paranasal sinus
primary, surgery for, 399-401 cancer, 531
prognosis in, 397-399 in oral cavityand oropharynx, 523
clear cell versus granular cell tumors in skin cancer,695
and, 393 invasive, complete removal of vulva and
radiation therapy for, 404-405 lymph nodes for, 460
spontaneous regression in, 397, 402 of head and neck, chemoimmunotherapy
staging in, 396-397 150
for,
systems for, 396, 397, 397t scrotal,exposure to soot and, 697
surgery for, 399-404 vaginal, determining extent of, 474
factors affecting outcome of, 401 recurrence of, 475
treatment 399-406
of, versus transitional cell, in
transfer factor for, 406 schistosomiasis, 376
variability in growth rate of primary testicular, 406-426
tumor, and metastatic tumor doubling advanced, treatment plan for, 423, 423t
time in, 398 anaplastic primary tumors metastasizing
small cell, integration of treatment to adult teratomas in, association with
modalities in, 224-225 chemotherapy, 408
of lung, versus nonsmall cell, brain classification and pathology of, 407—409
metastases in, 217-218 clinical features and diagnosis of, 411
chemotherapy for, results of, 219 incidence and etiology of, 406-407
combination, radiation therapy and, incidence of, variation among races and
220, 22 It geographic regions, cryptorchidism as
MOCA, 224, 224t causative factor in, 407
plus radiation therapy, 225 metastases in, 409-411
prophylactic whole brain irradiation for involvement of lymph nodes and,
brain metastases in, 220 409
radiation therapy for, 215 spread of, 410
squamous 477
cell, cervical, natural history of, 407—415
comparison with adenocarcinoma, of nonseminomatous, importance of lymph
vagina, 470, 470t node dissection to proper treatment in,
cutaneous, chemosurgery for, 716-720, 426
718t, 720t retroperitoneal lymph node dissection in,
description of, 700 410,410
disadvantages of, 720 seminoma in, 406
fixed-tissue, 717 types of, 408-409
grading of, 701 staging of, 412—414
healing in, 717-718 angiograms for, 413—414
metastases in, 701-702, 702t bilateral pedal lymphangiography for,
staging and prognosis in, 701-702 412-413
7072 Index
Carcinoma (Continued) Catheter(s), intrahepatic, for infusion

testicular, staging of, chest x-ray and full chemotherapy in patients with distant
lung tomography for, intravenous metastases, 14
pyelogram for, 412 Cauda equina, ependymomas of,
scalene lymph node biopsy for, postoperative radiation for, 752
computerized tomography and Cauterization, in rectal cancer, 296
abdominal ultrasound for, Cavity(ies), nasal, cancer of, 531—535
radionuclide scans for, 413 incidence of, 531
system for, 412, 412t paranasal sinuses and, cancer of,
tumor markers in, 414 classification and pathology of,
treatment of, 415-426 531-532
types of, in laryngeal and pharyngeal natural history of, 531-533
cancer, 549 oral, cancer of, 522-530
uterine, response rate of progestins in, 101 biopsy and x-rays for, 525
vaginal, clinical features and diagnosis of, classification of, 523
470-471 clinical features and treatment of,
detection and etiology of, 469 525-529
incidence of, 468 diagnosis of, 523, 525
natural history of, 470-472 incidence and etiology of, 522-523
Carcinoma in situ, cervical, treatment of, 485 leukoplakia and, 522
development of frank carcinoma following, natural history of, 523-525
excision of lymph nodes in, surgery for, staging of, 524t, 525
383 vitamin and mineral deficiencies and,
in bladder cancer, 377 523
presenting symptoms of, 382 oral and
nasal, re-establishment of physica'
treatment of, 382-384 separation between, by prosthetic
progression to, of cervical dysplasia, 478 restoration, 1027
radiation therapy in, 384 peritoneal, lymphatic drainage of, role of
Carcinosarcoma(s), in lung cancer, 200 omentum 493
in,
Cardiac damage, administration of CCNU. See Lomustine.
anthracyclines and, 69-70 Cecum, tumors of, right colectomy for, 276
Cardiac disease, in carcinoid tumors, surgery Cell(s), acute myelogenous leukemic,
for, 616 description of, 823
Cardiac toxicity, in chemotherapy, 37 APUD, characteristics of, 622
Cardiomyopathy, anthracycline therapy and, of adrenal medulla, description of, 621
70 B and T, description of, 912
Cardiovascular system, effects of breast cancer, estrogen receptors in,
corticosteroid therapy on, 104 androgen therapy and, 102
involvement of, in Hodgkin's disease, 875 cancer, characteristics of, 29
Carmustine (BCNU), dosages for, 66 derived from neural crest, 762
for multiple myeloma, 857 drug-resistant, combination chemotherapy
mechanisms of action of, 65 and, 42
pharmacologic characteristics of, 54t-55t, multimodality treatment and, 4
66 inherent genetic instability of, 3-4
treatment of gliomas with, 744 specificity of immunotherapy for, 133
Carotid body tumor(s), 799-801 murine leukemia, tumor transplantation
angiography in, 800, 800 resistance in, role of neuraminidase in
description of, 800 inducing, 138
etiology of, 799 normal and malignant, quantitative
treatment for, 801 differences between, 29
Castration, prophylactic, mastectomy and, number and type killed by repeated
181 specific radiation dose, 22
CAT scan, as diagnostic technique, in brain packed red blood, for erythrocyte
tumors, 734 transfusions, 972
for presence of cerebral metastases, 740 proliferating malignant, life cycle of
in adrenal cortical neoplasms, 629 specific phases of, differential drug
in cancer of nasal cavity and paranasal efficacy during, 38
sinuses, 533 radiation damage to, 22
in invasive anterior mediastinal red blood, contamination of platelet
thymoma, 781 preparations with, 974
in pituitary tumors, 637 Reed-Sternberg, in diagnosis of Hodgkin's
Catharanthus roseus, as origin of vinblastine disease, 869
and vincristine, 75 Sezary, in mycosis fungoides, 942
V
Index 1073
Cell(s) {Continued) Cervix (Continued)

tumor, biology of, cytokinetic concepts in, carcinoma of, endometrial extension in,
39-40 484
deposition of, in hepatic parenchyma, in epidemiology and etiology of,
disease metastatic to liver, 325 implication of herpes virus, type II in,
surface of, alterations of, as method for 477
increasing immunogenicity, 138 invasive, biologic behavior of, metastases
types of, causing salivary gland tumors, 539 in, 479
Ceil cycle, 38-40, 38 presenting symptoms in, 480
G, and S phases in, 39 pretreatment evaluation of, 482
Cell function, maintenance of, in metastases to lymph nodes in, 482^483
cryopreserved bone marrow, 980 natural history of, 479-484
Cell kinetics, maturation of, chemotherapy pelvic and periaortic lymphadenectomy
and, 49 in, 483
Cell-mediated response, impaired, correlation pelvic exenteration for, 490-491
with clinical course of malignancy, 131 description of, 490
Cellular immunity, suppression of, by pre- and postoperative support in, 491
chemotherapeutic drugs, 35 prognosis in, 482^484, 482t
Central nervous system (CNS), effects of radiation therapv for, complications of,
corticosteroid therapy on, 104 487-488
effects of mitotane on, 109 description of, 486-487
involvement of, in Hodgkin's disease, factors influencing type used, 487
875-876 recurrence in, 490
primary tumors of, classification of, 731, stage la, treatment for, 485
732t-733t stage lb, radiation therapy for,
Central nervous system leukemia, 815-816 vesicovaginal fistula resulting from,
increase in, in acute myelogeneous 488
leukemia, 826 radical hysterectomy and bilateral
methotrexate for, 816 pelvic lymphadenectomy for, 486
treatment of, complications of, 814 treatment of, 485-488
Central nervous system prophylaxis, for stage IV, pelvic exenteration for, 489
childhood non-Hodgkin's lymphomas, 939 treatment of, 489-490
Central nervous system toxicity(ies), in stages IIand III, radiation therapy for,
chemotherapy, 37 488^189
Central nervous system tumor(s), contiguous radical hysterectomy with pelvic
extension in, 729 lymphadenectomy for, 488
Cerebellum, hemangioblastomas of, surgery treatment of, 488-489, 489
for, 739 staging of, 481^182, 481t
Cerebrospinal fluid (CSF), seeding of, by treatment of, 484-491, 487, 489
primary central nervous system tumors, 729 regimens for, 486, 486t
Cerebrovascular leukostasis, in chronic Chemical(s), as etiologic factor in acute
myelogenous leukemia, 838 leukemia, 803-804
Cerebrum, metastases in, CAT scan in Chemodectoma, posterior mediastinal, 791
evaluation for presence of, 740 Chemoimmunotherapy, for breast cancer, 146
Cervical intraepithelial neoplasia (CIN), for disseminated lung cancer and malignant
definition and description of, 478 melanoma, 149
Papanicolaou smear for detecting, 480 for disseminated malignant disease,
Cervix, adenocarcinoma of, 477^78 148-151
survival in, 484 for disseminated solid tumors, effectiveness
biopsy of, prior to treatment, for invasive of, 152
carcinoma, 480 for ovarian carcinoma and head and neck
carcinoma in situ of, treatment of, 485 cancers, 150
carcinoma of, 476-492 for solid tumors, 149-150
advantages of operation over radiation surgery and, for soft-tissue sarcomas, 148
therapy for, 486 Chemosurgery, description of, 716-717
biology of, 477-479 fixed-tissue versus fresh-tissue techniques
bipedal lymphangiography in, 482 of,716
classification of, 479 for cutaneous basal and squamous cell
clinical features and diagnosis of, 480 carcinomas, 716-720, 718t, 720t
decreased mortality rate from, 476 disadvantages of, 720
disseminated, chemotherapy for healing in, 717-718
palliation of, 489-490 fresh-tissue, advantages of, 717
1074 Index
Chemosurgery (Continued) Chemotherapy (Continued)

in conjunction with radiation therapy, tor combination, plus immunotherapy, for acute
advanced stomach cancer, 256t, 257 lymphoblastic leukemia, 817
in vitro growth patterns of leukemic cells principles of, drug-resistant cancer cells
and, 823-824 and, for advanced nonhematologic
Chemotherapy, adjuvant, for epidermoid tumors, 42
carcinomas, of head and neck, 558 surgery and, followed by cyclic
for head and neck cancer, 563-565 chemotherapy, for advanced
for inadequate surgical procedure, 11 nonseminoma, 420
for melanoma, 690 vincristine in, 78
for micrometastatic breast cancer, 187 complementary inhibition in, sequential
for retroperitoneal metastatic disease, in blockade in, 43
testicular carcinoma, 418 complications in, examples of, 38
for stage C seminoma, 416, 416t, 417t consolidation and maintenance, in acute
radiation therapy and, for head and neck myelogenous leukemia, 825-826
cancer, 563-564 continued therapy with, for acute
single-agent, for lung cancer, 222 lymphoblastic leukemia, 814
surgery and, for breast cancer, 146 Corynebacterium parvum and, in clinical
for lung cancer, 225 trials, 137
alopecia in, skin reactions in, 36 cyclic, following combination
association with anaplastic primary tumors chemotherapy and surgery, for advanced
metastasizing as adult teratomas. 408 nonseminoma, 420
biologic factors in, 38-41 cytoreductive surgery prior to, for advanced
bone marrow depression from, 962 nonseminoma, 425
bone marrow toxicity in, 34-35, 34, 35 cytosine analogues in, 88
by hepatic artery infusion, in carcinoid cytotoxic, quality of life in patients
tumors, 619 receiving, versus endocrine therapy, 180
cessation of, in acute lymphoblastic drug interactions in, 32-33
leukemia, 814-815 drug resistance in, mechanisms of, 33
choice of specific dosages in, 45-46 drug toxicity in, 33-38
combination, biochemical approaches to, drugs used in, 53-124
43,43 endocrine manipulation and, in breast
criteria for. intermittent versus continuous, cancer, 186-187
44 fibroblast suppression resulting from, 14
doxorubicin as cornerstone for, in following radiation failure, for stage IV
metastatic breast cancer, 185-186, 185t non-Hodgkin's lymphomas, 944-945
drug schedules and, 41^5 for acute myelogenous leukemia, 824-827,
5-fluorouracil in, 88 824t, 825t
for adenocarcinoma of pancreas, 317t, for adrenal cortical neoplasms, 632
318 for advanced bladder cancer, 389-390
for brain tumors, 746 for anal cancer, 307
for breast cancer, 184 for anterior mediastinal thymomas, 784
for colorectal cancer, 299-301, 300t, 304 for blast crisis, in chronic myelogenous
for head and neck cancer, 561-562, 561t leukemia, 836-838, 837t
for Hodgkin's disease, 890-893 for brain metastases, 747
for lymphosarcoma and reticulum cell for brain tumors, 744-747
sarcoma, 928 for breast cancer, 183-186
for multiple myeloma, 878-879 for Burkitt's lymphoma, prognosis in, 940
for non-Hodgkin's lymphomas, 927-934, for carcinoid tumors, 618-619, 618t
929t, 93 It, 935t for choriocarcinoma in nonseminoma, 419
stage III or stage IV, 944 for chronic lymphocytic leukemia, 847-
for nonsmall cell carcinoma of lung, 222, 848
222t, 225 for chronicphase of chronic myelogenous
for NPDL lymphomas, 929 leukemia, 834-836
for ovarian cancer, 504 for colorectal cancer, 297-301
for ovarian dysgerminomas, 509 for DPDL lymphoma, 932
for small cell carcinoma of lung, 220, 22 It for endocrine pancreas tumors, 607-608
for stomach adenocarcinomas. 258. 259t, for endometrial carcinoma, 454^55
260 for esophageal cancer, 245, 245t
for stomach cancer, 258-260 for Ewing's sarcoma, 665-666
methotrexate in, role of schedule for extrahepatic bile duct carcinoma, 341,
dependency in, 84 341t
Index 1075
Chemotherapy (Continued) Chemotherapy (Continued)

for gestational trophoblastic disease, intensification of, in acute lymphoblastic
438-440, 438t, 439t leukemia, 813
high-risk metastatic, 439-440, 439t intensive, in acute myelogenous
preservation of reproductive function leukemia, 826
and, 438-439 intensive intermittent, effects on host
for glucagonoma of pancreas, 607 defense mechanisms, 35-36, 36
for head and neck cancer, 558-565 intermittent cycles of, for Ewing's sarcoma,
for histiocytic malignancy, 956-958 666, 666
for histiocytoses, adult, 957-958 intravenous hyperalimentation prior to, in
childhood, 956-957 head and neck cancers, 559
for Hodgkin's disease, 890-894, 890t-893t, intravesical, for transitional bladder tumors,
896t 381
resistant to MOPP,
894 ionizing radiation and, insensitivity of
for hydatidiform mole, 438 mature macrophages to, 954
for Kaposi's sarcoma, 799 long-term, creation of AV fistula in patients
for laryngeal and pharyngeal cancer, 553 undergoing, 15
for liver cancer, 321-324 maturation of cell kinetics and, 49
for liver metastases, 329-334 mechanisms and sites of action of selected
for lung cancer, 219-222 drugs used in, 28, 29
for mediastinal hemangiopericytomas, 796 mediastinal radiation and, 59
for medulloblastomas, 746 MOCA, in small cell carcinoma of lung,
for melanoma, 689-691, 690t 224, 224t
advanced, 689-690 monitoring toxicity in, importance of, 45
for multiple myeloma, 856-859 morbidity of, in non-Hodgkin's lymphomas,
for neuroblastoma, 766 934
for non-Hodgkin's lymphomas. 926-934 nonaggressive, for older patients with acute
for osteosarcoma, 147, 659-660, 66 It myelogenous leukemia, 826
for ovarian cancer, 503-504, 507, 514 nonhormonal, in breast cancer, response to,
for Paget's disease, of vulva, 466 183, 183t
for pain, 1012 ovarian choriocarcinoma and, 509
for palliation of disseminated cervical pharmacologic factors in, 30-38
carcinoma, 489—490 plus hormone therapy, in prostate cancer,
for pancreatic cancer, 316-318 367
for prostate cancer, 367-368 plus radiation therapy, for non-Hodgkin's
for renal cell carcinoma, 405 lymphomas, 934, 936
for retinoblastoma, 575 for primary Hodgkin's disease, 898
f
for retroperitoneal disease in small cell carcinoma of lung, 225
nonseminoma, 421, 421t, 422t preoperative, importance of, in allowing
bowel cancer, 264
for small surgical resection of nonseminoma with
for soft-tissue sarcomas, 674-675, 674t retroperitoneal disease, 422
for spinal cord tumors, 755 principles of, 27-52
for stomach cancer, 257-260 in acute lymphoblastic leukemia,
for superior vena caval syndrome, 992-993 811-815
for thyroid cancer, 602-603 prior to irradiation, for seminoma, 416,
for vulvar malignant melanoma, 464 416t, 417t
for vulvar squamous cell carcinoma, 462 prior to lymphadenectomy, for
for Wilms' tumor, 774-775, 755t nonseminoma, 418
future goals in, 49-50 prophylactic, in nonseminoma with nodal
gastrointestinal toxicity' in, examples of, 34 involvement, 418-419
guidelines for use of, 45-49 pulmonary toxicity' in, 37
hepatic toxicity in, 36-37 radiation and, bone marrow depression
histologic diagnosis prior to, importance of, from, in Wilms' tumor, 775
45 rapid dissolution of neoplastic tissues
history of, 27, 28t following, hyperuricemia from, 999
host immune response and, in regional, for disease metastatic to liver, 329
choriocarcinoma, 441 for head and neck cancer, 562-563
immunosuppression in, 35-36 types of drugs used in, 563
immunotherapy and, for asymptomatic for liver cancer, 322, 323t, 324
primary and disseminated metastases, regional perfusion of, in melanoma,
404
in renal cell carcinoma, 690-691
for cutaneous squamous and basal cell in melanoma, efficacy of, 691
carcinomas, 705 remission induction by, in acute
infusion, intrahepatic catheters for, in lymphoblastic leukemia, 811-814, 812t
patients with distant metastases, 14 schedule dependency in, 44
1076 Index
Chemotherapy (Continued) Choledochopancreatography (Continued)

second malignancies and, 37-38 correlation with gallbladder carcinoma,
second-line, for non-Hodgkin's lymphomas, 334, 335
934 Chondrosarcoma, calcifying hypercalcemia
selective toxicity in, 28-30 from, 998
factors contributing to, 30, 30 CHOP, for adult histiocytoses, 957, 957t
single-agent, for adenocarcinoma of for NM
lymphomas, 932
pancreas, 316, 316t Chordoma, posterior mediastinal, 792
for colorectal cancer, 297, 298t, 299 Choriocarcinoma, anterior mediastinal,
for head and neck cancer, 559-561, 56 It 786-787
for Hodgkin's disease, 890 chemotherapy and host immune response
for mycosis fungoides, 942 in, 441
for non-Hodgkin's lymphomas, 926-927 description of, 434
for stomach cancer, 257-258, 257t examination of products of conception at
versus combination, in carcinoid tumors, abortion for presence of, 437
618 in nonseminoma, chemotherapy for, 419
sterility and congenital malformations in, ovarian, chemotherapy and, 509
types of toxicities in, 37 Choroid, ciliary' body and, malignant
surgery and, 14-15 melanoma of, treatment for, 582-583
for head and neck cancer, 564-565 prognosis in, 581
for testicular tumors, 419, 420, 420t Chromosome, Philadelphia, in chronic
systemic, for disseminated squamous cell myelogenous leukemia, 832
carcinoma, 475 Chromosome analysis, of leukemic
for liver cancer, 321-322, 322t lymphoblasts, 810
for pleural effusion, 986 Chromosome D group, deletion of,
versus continuous hepatic artery retinoblastoma and, 570
infusion, in colorectal cancer Chronic leukemia, 832-852
metastases, 331, 334 Chronic lymphocytic leukemia (CLL),
three-drug regimen of, for acute 841-850
lymphoblastic leukemia, 812 adrencorticosteroids for, chemotherapy for,
topical, for cutaneous basal and squamous 847-848
cell carcinomas, 720-721 alkylating agents for, 847
for intraepithelial carcinoma, 473 chlorambucil for, 62
for vaginal intraepithelial carcinoma, 475 classification of, 842, 844
use of antibiotics in, 67-75 description of, 841
from Streptomyces, 67 differential diagnosis of, 843t, 844, 846
use of hormones in, 95-105 drugs for^48
with radiation therapy, in lung cancer, 218 etiology 0^841-842
Chest, involvement of, in esophageal cancer, hemolytic anemia in, 842
surgery for, 238 integration of treatment modalities in,
Chest radiograph(s), in diagnosing childhood 849-850
lymphomas, 918 leukapheresis splenectomy for, local
for,
in hydatidiform mole, 436 849
irradiation for,
Childhood, Hodgkin's disease during, 900 natural history of, 842-846
Childhood solid tumor(s), 759-777 staging and prognosis in, 844t, 845t, 846
Children, of cancer patient, developmental treatment of, 846-850
phase of, 1041 indications for, 846
psychosocial problems of, 1041-1043 Chronic myelocytic leukemia, busulfan for,
China, kang cancers of, 698 64
Chlorambucil, dosages for, 61-62 Chronic myelogenous leukemia (CML),
for chronic lymphocytic leukemia, side 832-841
effects of, 62 blast cells in, presence of terminal
for seminoma, 416 deoxynucleotidyl transferase in,
for stage I or II non-Hodgkin's lymphomas, cerebrovascular leukostasis in, 838
944 blast crisis in, chemotherapy for, 836-838,
Cholangiocarcinoma(s), 320 837t
Cholangiography, percutaneous transhepatic, description of, 834
in diagnosing extrahepatic bile duct chronic phase of, busulfan for, 834-835
carcinoma, 338 peripheral blood remissions from, 834
Cholecystitis, as symptom of gallbladder treatment regimens of, complications
carcinoma, 335 from, 835
Cholecystojejunostomy, as palliative chemotherapy for, 834-836
operation, for pancreatic cancer, 315 drugs for, 836
Choledochopancreatography, endoscopic classification of, 833, 833t
retrograde, in diagnosing extrahepatic drug-induced bone marrow aplasia in, 836
bile duct carcinoma, 338 hypersplenism in, splenectomy for, 840
Index 2077
Chronic myelogenous leukemia (Continued) Colon cancer. See also Colorectal cancer and
incidence of, 832 Rectum, cancer of.
leukapheresis for, immunotherapy for, alteration in bowel microflora and, 266-267
survival in, 840 association with high levels of sugar
natural history of, 833-834 consumption and fat intake, importance
presenting symptoms in, diagnostic aids in of bowel transit time in, 266
juvenile, 833 association with low fiber in diet, 265-266
prospects for future in, 841 development of, effect of age on,
radiation therapy for, splenomegaly in, hyperplastic versus adenomatous polyps
splenectomy for, 839 in, 268
splenectomy for, 839t, 840 familial risk of, distribution and gross
treatment of, 834-840 pathologic features of, diseases
Cigarette smoking, cancer of larynx and, 547 associated with, 269
renal cell carcinoma and, 393 histologic features related to prognosis in,
Ciliary body, choroid and, malignant 270
melanoma of, treatment for, 582-583 induction or repression of bacterial
iris and, malignant melanoma of, treatment enzymes as possible cause of, 267
of, 581^582 influence of extent of disease on survival
malignant melanoma of, prognosis in, 581 in, 280t
Cirrhosis, clinical deterioration in, as isolated metastatic, pulmonary resection
indication of liver cancer, 320 for, 293-294
Cisplatin, chemical structure of, 106, 112 metastatic to liver, incidence of death in,
clinical features of, 113 325
for head and neck cancer, 561 staged resection versus primarv resection
proposed mechanisms of action of, 112-113 for, 289
toxicity associated with, in advanced surgery for, extended, 290
nonseminoma, 424 survival following, effect of age on,
uses for, 114 294-295
Citrovorum factor. See Leucovorin. type of, factors influencing, 289-290
Clark's levels of invasion, 683-684, 684, 686t surgical approach to, 293
lvmph node metastases and, in melanoma, Colon interposition, high thoracic
for
688 esophageal cancer, 239-240, 239
Clinical trial(s), criteria for, 47^19 Colonoscopy, for diagnosis of colorectal
types of, 49t cancer, 272
Clomiphene, characteristics of, dosages for, Colorectal cancer, 265-304
100 chemotherapy for, 297-301
toxicities of, 100-101 combination, 299-301, 300t, 304
CMF, for breast cancer, 184-185 single-agent, 297, 298t, 299
Coagulation, bipolar, in spinal cord tumors, classification of,269-270
752 clinical features and diagnosis of, 270-273
Cobalt-60, for retinoblastoma, 574 Dukes classification of, compared with
Cobalt-60 teletherapy unit(s), radiation other systems, 273, 273, 275
therapy and, 21 electrocoagulation and local excision in,
COBMAM, for head and neck cancer, 562 295-296
Coccidioidomycosis, in cancer patients, 966 epidemiology of, 267-269, 267t
Coffee, as cause of bladder cancer, 375 etiology of, 265-267
Colectomv, left, for tumors of sigmoid colon, 5-fluorouracil as drug of choice for, 297,
278, 279 298, 298t, 303, 303t
partial or total excision and, 290 hemoccult test for, 271, 271
right, for tumors of cecum and ascending high-risk groups for, 268-269
colon, 276 immune suppression in, correlation with
suture line recurrence following, 290-291 poor prognosis, 301
Coley's toxins, 135 immunology and immunotherapy in, test of
Colitis, ulcerative and granulomatous, colon immune response and, 301-302
cancer and, 269 immunotherapy in, carcinoembryonic
Colon, adenocarcinomas of, radiotherapeutic antigen for, 302
approaches to, 296 integration of treatment modalities in,
ascending, tumors of, right colectomy for, 302^04
276 intestinal obstruction in, symptoms of, 288
carcinomas of, serum levels of liver metastases in, continuous hepatic
carcinoembryonic antigen and, 127-128 artery infusion versus systemic
right, adenocarcinoma of, resection method chemotherapy for, 331, 334
for, 276, 277 continuous intrahepatic artery infusion,
tumors of, resection methods for, 277, 278, of 5-fluorouracil, 329, 330t, 331
279 diagnosis of, 325
sigmoid, left colectomy for, 278, 279 trials in, 328
7078 Index
Colorectal cancer (Continued) Corpus uteri, cancer of, staging of, 448, 448t
liver resection for, 293 Cortex, adrenal, neoplasms of, 627-632
local excision for, 296 classification of, 628
metastatic, surgery for, 293-294 clinical features and diagnosis of,
thoracotomy laparotomy prior to, 294

for, 628-629
morphology and immune response in, 301 hormone production and, 628, 629t
natural history 269-276
of, incidence of, 627
radiation therapy for, 296-297 metastases in, 628, 628t
recurrent, increased use of immunologic natural history of, 628-631
markers to detect, 292-293 prognosis in, 630t, 631
maneuvers to reduce, 291 staging of, 629, 630t
second look operation and surgery for, 631
carcinoembryonic antigen for, symptoms 629
of,
diagnosing, 291-293 treatment 631-632

for,
screening programs for, 271, 272t Corticosteroid(s), 103-105

second look operation for, trials of, 292 for hairy cell leukemia, 864
staging and prognosis of, 273-276 therapy with, anti-inflammatory and

staging systems for, 274t, 275, 275t, 276 immunosuppressive effects of, 103
surgery and adjuvant immunotherapy for, lymphocytopenia and, 103-104
147 peptic ulcers and, 105
surgery for, 276-296 side effects of, 104
areas of special importance in, 287-296 uses for and administration of, 105
goals of, 276 Cortisol. See Hydrocortisone.
operative principles in, 276-279 Corynebacterium parvum, 136-137
palliative 294 as nonspecific immunotherapy, 135
results of, 279 for acute myelogenous leukemia, 827
suture line recurrence following, 290- for bladder cancer, 391
291 for lung cancer, 223

immunostimulatory properties of, 136
treatment for, 276-304
in cancer immunotherapy, clinical features
Colorectal metastasis(es), progressive, hepatic
of, 137
artery infusion following systemic
5-fluorouracil therapy in, 332, 333t
Cosmegen. See Dactinomycin.
Counseling, for couples in crisis situations,
Colostomy, history of, 1023
irrigation procedures in, 1025-1026, 1026
1040
Cranial nerve section, multiple, for pain,
Communication, wide base of, importance in
health care of cancer patient, 1044
1014
Complement fixation, correlation with Craniopharyngioma(s), incidence of, 635
radiation therapy for, 648-649
antibody titer, in melanoma and sarcoma,
surgery for, difficulties in, 649
132
Complementary inhibition, in chemotherapy, Cranium defects of, prosthetic reconstruction
for, 1034
43
Compression, organ, complications caused Crest(s), iliac, bone marrow obtained from,
by, 984-994 for cryopreservation, 980
spinal cord, 751 neural, cells derived from 762
Computerized tomography (CT), for staging Crisis situation(s), couples in, counseling for,
testicular carcinoma, 413 1040
in diagnosis of pancreatic cancer, 311 Cryohypophysectomy, for pituitary tumors,
Concentration threshold, toxicity and, in 641-643
methotrexate and leucovorin rescue advantages of, 643
therapy, 83 history of, 641
Conjunctivae, eyelid and, malignant problems in, 642-643
melanoma of, treatment of, 581 Cryopreservation, autologous bone marrow,
malignant melanoma of histology of, 579
,
979-981
Contrast study(ies), of inferior vena cava, in autotransplantation and, considerations for
Wilms' tumor, 770 patient selection in, 980-981
Cooper regimen, 184-185, 184t procedures for, 980
COPP, for adult histiocytoses, 958 Cryosurgery, around eyes, protective
Cord, spinal, compression of, by extradural measures for, 716
non-Hodgkin's lymphomas, 943 703
for actinic keratoses,
damage to, from radiation, in Hodgkin's cutaneous squamous and basal cell
for
disease, 888 carcinoma, 712, 714, 715t, 716

pain in, therapy for, 1017-1018 description of, 714
Cordotomy, for sensory root pain, 1016 halo thaw time in, 716
for spinal cord pain, 1017-1018 Cryotherapy, for retinoblastoma, 576
Index 1079
Cryptorchidism, as causative factor in Cytarabine (Continued)

testicular carcinoma, 407 cytotoxicity and pharmokinetics of, 89
Culture(s), surveillance, as protection against drug scheduling of, 42
neutropenia, 967 mutagenicity and teratogenicity of, 90
Cure, determination of, in cancer, 6 therapy with, immunosuppression in, 90
Curettage, endocervical, in endometrial toxicities of, 89-90
carcinoma, 448 Cytidine, pharmacokinetics of cytarabine and,
for actinic keratoses, 703 89
Curettage and desiccation, description of, Cytoreductive surgery, prior to
biopsy prior to, 708 chemotherapy, in advanced nonseminoma,
for cutaneous squamous and basal cell 425
carcinoma, 707-710, 71 It Cytosine analogue(s), in chemotherapy, 88
cosmetic results in, 709 Cytosine arabinoside, for acute myelogenous
cure rates in, 709, 710t leukemia, 824
Curve(s), bimodal age-specific, in Hodgkin's Cytoxan. See Cyclophosphamide
disease, 868-869 Cytotoxic drug(s), bacterial infection from,
Cushing's syndrome, mitotane for, 109 964-965
pituitary adenoma as cause of, 646-647 Cytotoxicity, of cytarabine, ara-CTP and, 89
Cutaneous hypersensitivity, delayed, role in CyVADIC, for soft-tissue sarcomas, 674
assessment of cell-mediated immune
reaction, 130
CVP, for adult histiocytoses, 958
fornon-Hodgkin's lymphomas, 927
Cyanide poisoning, from laetrile, 115
Cycle, cell, 38-40, 38
G,S and phases in, 39 Dacarbazine, 63, 64-65
Cyclophosphamide, 59-61 biotransformation of, dosages for, toxicities
administration and distribution of, side of, 65
effects of, 60 characteristics of, 64
allopurinol and, 32 combined with bacille Calmette-Guerin,
biotransformation of, 31-32 reduction in recurrence rate in high-risk
in liver, 59-60, 59 melanoma with, 146
doxorubicin and, for metastatic breast Dactinomycin, absorption of, dosages for,
cancer, 186 blood-brain barrier and, toxicities of, 71
drug scheduling of, 42 DNA and RNA synthesis and, 70
for acute lymphoblastic leukemia, for advanced nonseminoma, 425
complications from, 818-819 for gestational trophoblastic disease, 439
for advanced bladder cancer, 389 for nonseminoma, 418, 419
for childhood histiocytoses, 957 tumor resistance to, 70-71
for multiple myeloma, 857 use with radiation therapy, 26
for non-Hodgkin's lymphomas, 926 Daunomycin, 67-70
for retinoblastoma, 575 chemical structure of, 68
for seminoma, 416 disruption of RNA synthesis by, 67
hemorrhagic cystitis and, 37, 60, 61 dosages of, 69
immunosuppression caused by, renal experimental status of, 70
excretion of, for Burkitt's lymphoma, 61 for acute myelogenous leukemia, 824-825
Cyst(s), ovarian, observation of, 497 pharmacology of, 54t-55t
reduplication, bronchogenic and toxicities of, 69
enterogenic, posterior mediastinal, 791 Death, dealing with, in the cancer patient,
renal,nephrotomography for diagnosing, 1036
395 mechanisms of, from brain tumors, 734
Cystadenocarcinoma(s), of pancreas, 318-319 Decadron. See Dexamethasone
Cystathionine, elevated urinary levels of, in Decompression, spinal cord, surgical, 753
neuroblastoma, 762 indications for, 754
Cystectomy, radical, complications of, in Defect(s), cranial, prosthetic reconstruction
bladder cancer, 387-388 for, 1034
for carcinoma 383
in situ, facial, prosthetic rehabilitation of,
with urinary diversion, impotence and, 1031-1033
1026 surgical reconstruction for, 1031
Cystitis, hemorrhagic, cyclophosphamide head and neck, prosthetic rehabilitation of,
and, 37, 60, 61 1027-1034
Cytadrerr. See Aminoglutethimide surgical, major, 1027
Cytarabine, 89-90 mandibular, functional disabilities in, 1030
chemical structure of, 88 prosthetic rehabilitation of, 1030-1031
1080 Index
Defect(s) (Continued) Disease(s). See also specific names,

maxillary, definitive obturation for, associated with bile duct carcinoma, 337
1028-1029, 1029 disseminated, in non-Hodgkin's
prosthetic rehabilitation of, 1027-1029 lymphomas, 921
surgical obturation for, 1028, 1028 role of immunotherapy in, 148
midfacial, large, prosthestic rehabilitation extranodal, in non Hodgkin's lymphomas,
for, 1033-1034, 1033 915
soft palate, prosthetic rehabilitation for, gestational trophoblastic, 434—442
1029-1030 chemotherapy for, 438-440, 438t, 439t
Defense mechanism(s), antimicrobial, classification and pathology of, 434—435
impairment of, in acute lymphoblastic clinical features and diagnosis of,
leukemia, 809 435-438
Delalutin. See Medroxyprogesterone components of, 434
caproate. cure rate in, prospects for future in,
Delayed cutaneous hypersensitivity, role in 441^442
assessment of cell-mediated immune high-risk, metastatic, chemotherapy for,
reactions of, 130 439-440, 439t
Delta-1-testolactone, 102-103 human chorionic gonadotropin as tumor
Dementia, organic, EMI scan to diagnose, marker in, 441
1006 immunotherapy for, 440-441
etiology of, 1005-1006 metastatic versus nonmetastatic, 435
Density centrifugation system, for obtaining methotrexate or dactinomycin for, 439
leukocytes, 976-977 natural history of, 434—438
Deoxyribonucleic acid. See DNA. preservation of reproductive function in.
Depression, bone marrow. See also Bone chemotherapy and, 438—439
marrow failure. radiation therapy for, brain metastases in,
from chemotherapy, 962 440
from chemotherapy and radiation, in treatment of, 438-442
Wilms' tumor, 775 heavy chain, 862-863
from radiation therapy, 963 alpha and mu, description of, 863
Dexamethasone, duration of action of, 104 gamma, description of, 862
for brain tumors, 737 Hodgkin's, 866-905
Diabetes, somatostatinomas and. 607 aggressive treatment of, correlation with
Diagnosis, histologic, importance of, prior to development of second neoplasms in,
chemotherapy, 45 877
histopathologic, techniques for, 9 bimodal age-specific curve in, 868-869
proper presentation of, to cancer patient, bone marrow biopsy in, 879
1038 chemotherapy for, 890-894, 890t-893t,
Diabetes mellitus, in pancreatic cancer 896t
310
patients, single-agent, 890
Dibromomannitol, for chronic phase of classificationand pathology of, 869, 869t
chronic myelogenous leukemia, 836 clinical features of,870-877
Dietary sweetener(s), as cause of bladder clinical presentation of, comparison with
cancer, 375 that of non-Hodgkin's lymphomas,
Diethylstilbestrol (DES), description of, 99 916-917
dosages for, 98t, 99 combination chemotherapy for, 890-893
exposure to, in utero, adenocarcinoma and, complete remission in, restaging after
475 achieving, bone marrow suppression
vaginal adenosis and, 470 from, 892
vaginal adenocarcinoma and, 469 constitutional symptoms in, 871-872
vaginal cancer and, 473 contagiousness of, 868
for endocrine manipulation in cure in, 882
postmenopausal breast cancer patients, delayed second neoplasms in, 876-877
182 during childhood, 900
for prostate cancer, 365 during pregnancy, 899-900
therapy with, gynecomastia resulting from, etiology and epidemiology of, 867-869
100 immunologic dysfunction in, 872
toxicities of, 99-100 immunotherapy for, 894, 897t
Differentiation, of tumor, in endometrial in relapse, due to incomplete therapy
carcinoma, effect on prognosis, 450 versus tumor cell resistance, 899
pathways of, in testes tumors, 407, 408, factors influencing, restaging for, 898
Disability(ies), functional, in mandibular integration of treatment modalities in,
defects, 1030 894, 898-899
Index 1081
Di^ ontinu, Disease< s 1
[Confirm,
Hodgkin's. in troduction of megavoltage metastatic, in colorectal cancer, surgerv for.
radiation and. v 293-294
laparotomv tor. technical considerations Paget's. of vulva, chemotherapy and
in.879-880 radiation therapy for. 466
liver involvement in. S73—874 natural history of. 465
"
lymph node involvement in. v treatment of. 465-466
major symptoms in and treatment for. premalignant. in endometrium. 451
hematogenous spread ot, 871 retroperitoneal metastatic, in testicular
meehlorethamine for. 59 carcinoma, adjuvant chemotherapy for. 418
MOPP as treatment of choice for. 891 spectrum of. associated with anterior
natural history of. 869-^ mediastinal thymomas, 781

newly diagnosed, treatment for. 898. -temic. breast cancer as. 163-164
ulcer, benign, high risk for stomach cancer
organ-related problems in. 872-876 in patients with, 250
organs involved in. 874-876 Dissection, neck, anterior. 598
- ~--~-
pathol _ - _
~ lymph node, importance to proper
patterns of spread in, 870-871 treatment ot nonseminomatous
primary, radiation therapy plus testicular carcinoma, 426
chemotherapv for. 898 in determination of spread of disease. 13
treatment 3 ^8 pelvic, in prostate cancer, stage Ac 369
prognosis i si, 883 stage C. 372
proportionality ot eradication ot tumor to retroperitoneal, for stages A and B
total dose of radiation in, 886 nonseminoma. 418
radiation pneumonitis in. heart and for testicular carcinoma. 410. 410
spinal cord damage in. S88 Diuresis, saline, tor moderate to severe
radiation therapy for, 883-8S9, 885 hypercalcemia. 997
effects ot splenectomv on, 887 Diuretict sK tor immediate decompression, in
superior vena caval syndrome, 993
history of. ,883-884 osmotic, for intracranial pressure. ~ -
in children, in pregnant women. DNA. on tumor cells. 113
transient aspermia from. 889 recombinant, potential for use in cancer
inverted-Y fields in.886 prevention and treatment. 7
mande fields in. SS5-886 DNA replication, effects of alky lating agents
prior ti stag _ w ork-upin. 880 on. 53
renal tolerance to.888-889 DNA synthesis, dactinomycin and. 70
resistant to MOPP. chemotherapv for. DNCB, regression of cutaneous metastases of
melanoma and. 140
RNA viruses as possible etiologic agent cancer patient sensitivity to. correlation
in. S67-868 with postoperative course. 131
special problems in. 899-900 reactivity, difference in, in solid
splenectomy in. 882 neoplasms, 131
splenic involvement in. splenectomv for. use in vaginal cancer, 141
n L-Dopa, use as predictive test of hormonal
stage III. subclassification of. 878. 879 responsiveness, 180
staging in. S77-881 ,8781 S80t Doppler flow meter, evaluation of
staging work-up in. individualization of. mediastinal hemangioperievtomas bv,
-881 794. 795
surgery for. SS2-SS3 Dos ag ecific. in chemotherapy.
survival in. - choice of. 45-46
tissue volume irradiated in, 884-885 Dosage modification, of doxorubicin and
treatment of. 8S2-900 vincristine. 1
types of. S69 Dosage schedule! s>. for 5-fluorouracil. 87
vascular invasion of spleen in. S71 Dose fractionation, protracted application
inflammatory or malignant, leukemoid by, in radiation therapy, 21
reaction from, 834 Dose-response relationship^, in radiation
Letterer-Siwe, 9.53 therapy. 172
malignant, allogeneic tumor cell vaccines Doxorubicin. 67-70
adjuvant immunotherapy for. clinical as cornerstone for combination
tests of. 137 chemotherapy in metastatic breast
disseminated, chemoimmunotherapv for. cancer. 18.5-186, 185t
14S-151 chemical structure of. 68
immunotherapy for, studies on. 134 cyclophosphamide and, for metastatic
pain syndromes in. 1009-1021. 1009t breast cancer, 186
1082 Index
Doxorubicin (Continued) Drug dosage(s), for allopurinol, 94

disruption of RNA synthesis by, 67 for aminoglutethimide, 110
dosage modification of, in liver for L-asparaginase, 1 14
dysfunction, 32 for 5-azacytidine, 91
dosages of, 69 for bleomycin, 72
for advanced bladder cancer, 389-390 for cisplatin, 113
for multiple myeloma, 857-858 for cytarabine, 89
for non-Hodgkin's lymphomas, 926 99
for diethylstilbestrol, 98t,
for osteosarcoma, 660 for hexamethylmelamine, 112
for stomach cancer, 258 for hydroxyprogesterone caproate and
for thyroid cancer, 603 megestrol acetate, 101
for Wilms' tumor, 775 for hydroxyurea, 108
pharmacology of, 54t-55t for mithramycin, 73-74
radiation therapy and, toxicity of, plasma for mitomycin-C, 74-75
clearance time in, 69 for mitotane, 109
tocopherol and, 70 for procarbazine, 106
Drug(s), abbreviations for, 1050-1051 for tamoxifen, nafoxidine,
analgesic, for pain, 1012 clomiphene, 100
anticholinesterase, in surgical management for testosterone propionate, 102
of anterior mediastinal thymomas, 783 for vinblastine, 77
antineoplastic, mutagenicity and for vincristine, 78
teratogenicity of, 37 Drug efficacy, differential, during specific
therapeutic index for, definition of, 30 phases of life cycle of proliferating
as etiologic factor, in acute leukemia, malignant cells, 38
803-804 Drug interaction(s), in chemotherapy, 32-33
non-Hodgkin's lymphomas, 907
in mechanisms of, 32
chemotherapeutic, 53-124 Drug resistance, in chemotherapy,
biotransformation of, 31-32 mechanisms of, 33
damage to kidney by, 37 Drug schedule(s), combination chemotherapy
distribution and absorption of, 31 and, 41^5
excretion of, 32 Drug toxicity(ies), in chemotherapy, 33-38
experimental use of, 47^19 Drug treatment, of brain tumors, important
intra-arterial infusion of, in advanced properties in, 744
bladder cancer, 390 DTIC-Dome. See Dacarbazine.
phase-specific and phase-nonspecific, Duct(s), extiahepatic bile, carcinoma of,
definition of, 39 336-342
selected, pharmacologic characteristics chemotherapy for, 341, 34 It
of, 55t-56t clinical features and diagnosis in,
choice of, for large versus small tumors, 40 metastases in, 338
cytotoxic, bacterial infection from, 964-965 correlation with gallstones, 337
differential efficacy of, during specific etiology of, 336-337
phases of life cycle of proliferating incidence of, 336
malignant cells, 38 natural history of, 337-338
experimental, for acute myelogenous radiation therapy for, 340t, 341
leukemia, 825 surgery for, 339
for bladder cancer, 381 treatment of, 339-341
for chronic lymphocytic leukemia, 848 divisions of, 339
for histiocytic malignancies, 955, 955t Dukes classification, of colorectal cancer,
for multiple myeloma, 857 compared with other systems, 273, 273, 275
for nonsmall cell carcinoma of lung, 220 Dysfunction, immunologic, in Hodgkin's
for ovarian cancer, 503-504 disease, 872
for prostate cancer, 367 Dysgenesis, testicular, in testicular
for regional chemotherapy of head and carcinoma, 407
neck cancer, 563 Dysgerminoma(s), ovarian, combination
for tumor regression, in neuroblastoma, 766 chemotherapy for, unilateral
radiation-enhancing, in treatment of salpingo-oophorectomy for, 509
Ewing's sarcoma, 665 description of, 508
regimen of, for unresectable tumors in radiation therapy for, 508-509
head and neck cancer, 562 Dysphagia, as symptom of esophageal cancer,
Drug action, pharmacologic characteristics of, 235
49 improvement of, from irradiation, in
Drug combination(s), for Ewing's sarcoma, esophageal cancer, 243
666 in hypopharyngeal cancer, 550
Index 1083
Dysplasia, cervical, progression to carcinoma Endocrine manipulation (Continued)

in situ of, 478 for post- and perimenopausal women with
vaginal, diagnosis of, 471 breast cancer, 182
Dyspnea, in glottic cancer, 549-550 in breast cancer, 180-183, 189
in older women versus vounger women,
179, 180
in prostate cancer, 363-367
advantages and disadvantages of, 365
Ear, prostheses for, 1032 primary, in premenopausal patients,
Ecchymosis(es), in neuroblastoma, 760, 761 180-181
Ectopic adrenocorticotropic hormone secondary, in breast cancer patients,
syndrome, 1002-1004, 1002t 181-182
diagnosis and differential diagnosis of, tamoxifen and diethylstilbestrol in, in
1003 postmenopausal breast cancer patients,
treatment of, 1003-1004 182
Edema, cerebral, in brain tumors, 731 tamoxifen for, 181
Effusion(s), pleural,bleomycin for, Endocrine pancreas, cancer of, 603-609
pleurectomy for, 989 chemotherapy for, 607-608
control of, 984 immunotherapy for, 609
diagnosis of, 985-986 incidence of, 603
intrapleural sclerosing agents for, natural history- of, 603-607
987-989 radiation therapy for, 607
malignant, associated with breast cancer, treatment of, 607-609
mechlorethamine and glucagonomas of, description of, 603-604
triethylenephosphoramide for, 988 diagnosis of, necrolytic migratory
definitive diagnosis of, 986 erythema, 604
mechlorethamine for, 987-988 incidence of, 603
side effects of, 987 insulinomas of, 604-605
natural history of, 985-986 incidence of, presenting symptoms of,
quinacrine hydrochloride for, tetracycline diagnosis of, 604
for, 988 laboratory tests for, 605, 605t
symptoms of, secondary to direct Endocrine study(ies), of pituitary tumors, 637
implantation of tumor, 985 Endocrine system, effects of corticosteroid
systemic chemotherapy for, 986 therapy on, 104
talc and thoracotomy for, 988-989 involvement of, in Hodgkin's disease, 876
therapeutic goals of, 989 manipulation of, in treating cancer, 95
thoracocentesis for, 986-987 Endocrine therapy, quality of life in patients
recurrence in, 986 receiving, versus cytotoxic
thoracostomy for, 987 chemotherapy, 180
treatment of, principles of, 986-989 response to, in breast cancer, 178, 179t
Electrocoagulation, in colorectal cancer, Endocrine tumor(s), 586-654
295-296 Endodermal sinus tumor(s), of anterior
in rectal cancer, 295 mediastinum, choriocarcinoma and,
Electroencephalogram, for diagnosing brain 786-787
tumors, 734 diagnosis of, 787
Elipten. See Aminoglutethimide Endolarynx, examination of, 550
Elliot's B solution, use in methotrexate Endometrium, carcinoma of, 442^56
toxicity, 85 age as prognostic factor in, 451
Elspar. See ^-Asparaginase. biology of, 444-446
Embolization, vascular, prior to resection, in cervical and vaginal metastases in, 445
mediastinal hemangiopericytomas, 795, 796 chemotherapy for, 454-455
EMI scan, to diagnose organic dementia, classification of, 446, 447t
1006 clinical features and diagnosis of,
Emotional support, of cancer patient's 447-448
spouse, 1039 difficulties intreatment of, 455
professional, for cancer patient, 1038 dissemination of, 444, 445
Encephalography, air, for diagnosing brain endocervical curettage in, 448
tumors, 734 estrogens as cause of, 443
Endocrine manipulation, chemotherapy and, follow-up of, 455
in breast cancer, 186-187 histologic grade and prognosis in, 450
clinical response correlation with
to, hyperestrinism and, conditions associated
quantitative level of estrogen receptors, with, 443, 444t
179 incidence and detection of, 442
1084 Index
Endometrium (Continual) Enucleation (Continued)

carcinoma involvement ot myometrium
of, role and timing of, in ocular malignant
in, 444, 445 melanoma, 583
involvement of uterine isthmus in, Enzyme(s), bacterial, induction or repression
ovarian metastases in, 446 of, as possible cause of colon cancer, 267
lymph node metastases in, 444—445 Ependymoma(s), brain, radiation therapy for,
lymphadenectomy as staging procedure 742
in, 452^53 of cauda equina, postoperative radiation
lymphangiography in, 450 for, 752
medical evaluation of, tests for, 448—449 postoperative radiation therapy for, 754
metastases to fallopian tubes from, 511 Epipodophyllotoxin(s), 76
myometrial penetration in, as guide to Epithelial atypia, in carcinoma in situ, 382
radiation therapy, 453 Epithelium, of female genital tract,
as prognostic indicator, 450 progestational changes of progestins in, 101
natural history of, 446-451 Erythema, from 5-fluorouracil, in actinic
obesity in, 447 keratoses, 704
operation in, as staging procedure, 449 necrolytic migratory, in pancreatic
prior to radiation therapy in, 453 glucagonomas, 604
pelvic lymph node metastases in, Eryrhrocyte(s), circulating, peripheral levels
449-450 of, in Hodgkin's disease, 887
premalignant disease in, treatment of, Erythrocyte transfusion(s), cross-matching
451 procedures for, nonhemolytic reactions
prognosis in, 449-451, 449t to, 973
screening for, 447-448 forbone marrow failure, 972-973
stage I, radical hysterectomy with pelvic packed red blood cells for, 972
lymphadenectomy for, 452 Erythrophagocytosis, in histiocytic medullary
stage II, treatment for, 453^54 reticulosis, 954
stage III, treatment of, 454 Esophagogastrectomy, for upper esophageal
stage IV, treatment of, 455 cancer, 238, 239, 239
staging of, 448-449, 448t Esophagogastric junction, adenocarcinoma in,
studies on, 455 235
surgery with radiation therapy for, involvement of, in esophageal cancer,
451-454, 452 surgery for, 238
treatment of, 451-456 Esophagoscopy, 236
tumor differentiation in, effect on Esophagus, body of, squamous cell carcinoma
prognosis, 450 in, 235
uterine size as prognostic factor in, cancer of, 233-246

450-451 anatomic location of, 234, 235
Endorphin(s), investigations into, future chemotherapy and immunotherapy for,
relief from pain and, 1019 245, 245t
Endoscopy, angiography and, in diagnosis of clinical features and diagnosis of,
pancreatic cancer, 310-311 235-236

for diagnosing stomach cancer, 250 epidemiology of, 233
with multiple biopsy, for patients with etiology of, 233-234, 234t
previous partial gastrectomy, 251 high thoracic involvement in, colon
Enema, barium, for diagnosis of colorectal interposition for, description of, 240
cancer, 272 mass screening 246 for,
Energy, increasing, changes in physical natural history' 234-237

of,
characteristics of ionizing radiation in palliative bypass for, 240-241

proportion to, 20 pathology of, 234-235
Enterostomal patient(s), rehabilitation of, preoperative radiation for, results of,
1023-1027 243-245, 244t

Enterostomal therapy, psychologic problems radiation therapy for, 242-245
associated with, in cancer patients, surgery for, 237-242
1024-1025 goals of, 237
team care approach 1024, 1024
to, preparation prior to, 237-238
Enterostomy, outpatient considerations in, results in, 241-242, 24 It
1026-1027 treatment of, 237-246
preoperative preparation for, 1025 cervical, cancer of, surgery for, 240
Enucleation, for choroid and ciliary body lower and midthoracic, cancer of, surgery
melanomas, 582 for, 238-239
for unilateral retinoblastoma, upper, cancer of, surgery for, 239-240, 239
573 Esdander flap, for lip cancer, 526
Index 1085
Estradiol mustard, estrogen therapy and, 99 Exfoliative cytology, for diagnosing stomach
Estramustine. estrogen therapy and, 99 cancer, 250
Estrogen(s), 96-100 Exudate(s), versus transudates, in pleural
as cause of endometrial carcinoma, 443 effusions, 985-986
effects on tumor growth, 99 Eye(s), cryosurgery around, protective
oral, for prostate cancer, 364 measures for, 716
versus orchiectomy, in treatment of effects of corticosteroid therapy on, 104
prostate cancer, 365 neoplasms of, 569-585
urinary, elevation of, in epithelial ovarian Eyeball(s), metastatic melanoma of,
cancer, 510 application of liquid nitrogen prior to
Estrogen receptor(s), activity of, variation in, excision in, 582
in hreast cancer, 178 Eyelid(s), conjunctiva and, malignant
in breast cancer, 96, 164 melanoma of, treatment of, 581
in breast cancer cells, androgen therapy malignant melanoma of, 578
and, 102 histology of, 579
quantitative level of, correlation with
clinical response to endocrine
manipulation, 179
Estrogen therapy, combined with alkylating
agents, 99
uterine adenocarcinoma caused by, 96 Face, pain of, regional therapy for, 1014
Estrone hypothesis, 443 Facial defect(s), prosthetic rehabilitation of,
Ewing's sarcoma, 662-667 1031-1033
chemotherapy for, 665-666 Fallopian tube(s), metastases to, from ovaries
clinical features of, diagnosis of, incidence or endometrium, 511
of, 663 Fallopian tube cancer, diagnosis and
discovery of, 662 treatment of, 512
drug combinations for, 666 symptoms of, 511-512
intermittent cycles of chemotherapy for, Family therapy, to help in dealing with
666, 666 cancer, 1043
natural history of, 663-664 Fat, high intake of, association with colon
radiation therapy for, 665 cancer, 266
staging and prognosis in, surgery for, 664 Fear(s), primary, of cancer patient, 1039
treatment of, 664-667 Female genital tract, epithelium of,
Examination(s), radiographic, of larynx, 551 progestational changes of progestins in, 101
Excision, colectomy and, 290 Fetal antigen(s). See also Carcinoembryonic
for iris melanoma, 581 antigen.
for metastatic melanoma of eyeball, liquid nonimmunogenic class of, uses for, 126-127
nitrogen application prior to, 582 tumor-associated, evidence for presence in
local, for colorectal cancer, 296 human neoplasms, 126-128
for soft-tissue sarcomas, 672 types of, neoplastic transformation and, 126
radiation therapv and, in breast cancer, Fever, neutropenia and, approach for patients
172-174 with, 979
selection of patients for, 173 together with organomegaly and weight
muscle group, for soft-tissue sarcomas, 672 loss, as symptoms of malignant
of lymph nodes, in carcinoma in situ, 383 histiocytosis, 953
of solitary foci of tumor, for palliation, in Fibroblast(s), suppression of, resulting from
renal cell carcinoma, 403^404 chemotherapy, 14
radical pancreatic, of carcinoma, total Fibroepidielioma, description of, 700
pancreatectomy for, 313 Field(s), inverted-Y, in radiation of Hodgkin's
radical wide, for primary melanoma, 686 disease, 886
surgical, for anterior mediastinal mantle, in radiation of Hodgkin's disease,
seminomas, 787 885-886
total,of draining lymphatics, importance of, Filtration, for obtaining granulocytes, in vivo
to success of surgery for colorectal usefulness of, 977
cancer, 279 AV, creation of in patients on
Fistula(e),
wide local, for intraepithelial carcinomas, long-term chemotherapy, 15
460 vesicovaginal, as complication of radiation
Excretion, renal, of cyclophosphamide, 61 therapv, for stage lb cervical carcinoma,
Exenteration, pelvic, for cervical carcinoma, 488
490-491 Flap, Abbe or Estiander, for lip cancer, 526
description of, 490 Flora, gastrointestinal, antimicrobial agents to
pre- and postoperative support in, 491 reduce, 968
stage IV, 489 Floxuridine (FUDR), 86, 86
1086 Index
Fluid(s), oral, increase of, for treatment of Gallbladder carcinoma (Continued)

mild hypercalcemia, 997 pathology of, clinical features and diagnosis
Fluid restriction, for syndrome of of, 335
inappropriate antidiuretic hormone surgery and adjuvant radiation therapy in,
secretion, 1002 336
5-Fluorodeoxyuridylate, inhibition of RNA treatment of, 335-336
synthesis and, 85 Gallium scan(s), total body, in non-Hodgkin's
Fluorohydrocortisone, following lymphomas, 919
adrenalectomy, 182 Gallstones, correlation with bile duct
5-Fluorouracil (5-FU), 85-88 carcinoma, 337
administration of, routes in, 86-87 correlation with gallbladder carcinoma, 334
as adjuvant chemotherapy for head and Gamma heavy chain disease, description of,
neck cancer, 563 862
as drug of choice for colorectal cancer, 297, Ganglioneuroblastoma, posterior mediastinal,
298, 298t, 303, 303t 790
continuous intra-arterial infusion of, for Ganglioneuroma(s), description of, 763
hepatic metastases, UCLA experience posterior mediastinal, 790
with, 331-334, 332t, 333t Gastrectomy, for Zollinger-Ellison syndrome,
continuous intrahepatic artery infusion of, 606
for liver metastases, in colorectal cancer, partial, endoscopy and multiple biopsy for
329, 330t, 331 patients with previous, 251
distribution and clearance of, degradative for gastric cancer, 254, 254
and activating pathways of, 86 gastroduodenostomy or gastrojejunostomy
dosage schedules for, bone marrow for reconstruction in, 255
suppression and, toxicities of, 87 Gastric ulceration, steroids and, 737
dosages of, in UCLA experience with Gastrinoma. See Zollinger-Ellison syndrome.
332
intra-arterial hepatic infusion, Gastroduodenostomy, for reconstruction in
for advanced bladder cancer, 389 partial gastrectomy, 255
for hepatoma, 324 Gastrointestinal flora, antimicrobial agents to
for stomach cancer, 257-258 reduce, 968
history of, 85 Gastrointestinal toxicity, in chemotherapy,
infusion of, for inoperable hepatoma, 14 examples of, 34
methotrexate and, schedule dependency of, Gastrointestinal tract, effects of corticosteroid
44 therapy on, 104
81
sites of action for, 81, effects of mitotane on,109
systemic, prior to hepatic artery infusion, in involvement of, in Hodgkin's disease, 876
progressive colorectal metastases, 332, neoplasms of, 231-357
333t earlier diagnosis and adjuvant therapy in,
topical, for actinic keratoses, 703-704 232
erythema from, 704 incidence and mortality rates in, 231,
cutaneous basal cell
for superficial 232t
carcinoma, 721 surgery for, 131-132
types of tumors benefited by, 88 Gastrojejunostomy, for reconstruction in
with Me-CCNU and vincristine, for partial gastrectomy, 255
colorectal cancer, 299, 300t, 301 Gastroscopy, in previous gastrectomy
Fluoxymesterone, 102-103 patients, 250
Folic acid, accelerated clearance of, in Gastrostomy, tube, in ovarian epithelial
cancer, 962 tumors, 501
as origin for methotrexate, 79 Genital tract, female, epithelium of,
chemical structure of, 80 progestational changes of progestins in,
Formalin, instillation of, in advanced bladder 101
cancer, 391 Genitourinary neoplasm(s), 358-433
Fossa(e), renal, radiation to, in Wilms' tumor, Genitourinary toxicity, in chemotherapy, 37
773 Genitourinary tract, involvement of, in
Rosenmiiller's, as site of origin for Hodgkin's disease, 876
nasopharyngeal cancer, 536 Gentamicin, for infection from gram-negative
Frontal lobe(s), pain of, leukotomy for, bacteria, 969
corticectomy for, cingulotomy for, 1015 Germ cell tumor(s), anterior mediastinal,
Ftorafur, 86, 86 784-788
anterior mediastinal, classification of, 785
treatment of, 507-509
G, phase, in cell cycle, proliferative activity Gestational trophoblastic disease (GTD),
and, 39 434-442
Gallbladder carcinoma, 334-336 brain metastases in, 440
correlation of cholelithiasis and gallstones chemotherapy for, 438-440, 438t, 439t
with, 334 classification and pathology of, 434-435
Index 1087
Gestational trophoblastic disease (Continued) Glottis (Continued)

clinical features and diagnosis of, 435-438 cancer of, laryngectomy for, 555
components of,434 treatment for, 554
cure rate in, 441^442 reconstruction of, 555
high-risk, metastatic, chemotherapy for, Glucagonoma(s), of endocrine pancreas.
439-440, 439t 6034504
human chorionic gonadotropin as tumor description of, 6034504
marker in, 441 incidence of, 603
immunotherapy for, 440-441 pancreatic, necrolytic migratory erythema
metastatic versus nonmetastatic, 435 in, 604
methotrexate or dactinomycin for, 439 chemotherapy for, 607
natural history of, 434^438 diagnosis of, 604
preservation of reproductive function in, surgery for, 607
chemotherapy and, 438^439 Glucocorticoid(s) for chronic hypercalcemia,
prospects for the future in, 441^442 997
radiation therapy for, 440 in treatment of malignant polymyositis,
treatment of, 438-442 1007
Gland, Bartholin's, adenocarcinoma of, 467 Glucose:insulin ratio, in insulinomas of
parotid, tumors of, 540 endocrine pancreas, 605
as metastatic site of primary tumors in Gold, radioactive, use in ovarian carcinoma,
other organs, 540 502
pineal, tumors radiation therapy for, 743
of, Gompertzian growth, cell growth and, 40
pituitary, arterialsupply of, 634 Gompertzian process, human fetal and
description of, 633 childhood growth as, 40, 41
salivary, adenoid cystic carcinoma and Gonad(s), stroma of, tumors of. See Sex cord
acinic cell tumors of, description of, 544 tumors.
benign tumors of, 541-543 Gonadal dysfunction, alkylating agents and,
carcinoma of, staging of, 541, 54 It 37
malignant mixed tumors in, description Gonadotropin secretion, 634
of, 544-545 Grade, histologic, correlation with prognosis,
malignant tumors of, 543-545 in prostate cancer, 360
miscellaneous primary carcinomas in, Graft(s), skin, danger of wound seeding in.
545 12
monomorphic adenomas of, description Graft-versus-host reaction, in
and treatment of, 543 immunosuppressed patients receiving
mucoepidermnid tumors of, description granulocyte transfusions, 978
of, 543 Granulocyte(s), filtration for obtaining, in
prognosis in, 544 vivo usefulness of, 977
pleomorphic adenoma in, 541-542 Granulocyte transfusion(s), alloimmunization
tumors of, 5384546 in patients receiving, 975-976
classification and pathology of, 5394340 for bone marrow failure,975-979
classification by anatomic site of, 539 for leukopenic patients with infection, 975
clinical features of, 5414545 graft-versus-host reactions in
diagnosis of, 5404541 immunosuppressed patients receiving,
operation for, 541 978
incidence of, 5384539 indications for, 978-979
natural history of, 5394541 patient response in, 978
radiation therapy for, 546 Granulocytopenia, antibiotics for, 968, 969t
surgery 545
for, broad-spectrum antibiotics for patients
symptoms 540
of, with, length of treatment in, 970
treatment of, 5454546 diagnostic evaluation in, 968
thyroid, cancer of, 5914503 febrile patients with, amphotericin B
Glioblastoma(s), neural, mitotic index of, 729 following broad-spectrum antibiotics in,
procarbazine for, 745 971
Glioma(s), brain, high-grade, radiation in acute lymphoblastic leukemia, 808
therapy for, 742 infection and, 964
epidemiology of, 727, 727t life-threatening infection from
malignant, brain, radiation therapy for, 741 Pseudomonas in, carbenicillin for, 969
neutron therapy for, 755 pneumonia in patients with, prophylactic
treatment with carmustine and lomustine, therapy for, 968-969
744 septicemia from gram-negative bacilli in,
Globulin, alpha fetal, in diagnosis of 965
hepatomas, 127 vinblastine and, 77
Glottis, cancer of, 5534555 Granulosa cell neoplasm(s), ovarian,
description of, 553 description and treatment of, 510
hemilaryngectomy for, 554, 554 Grawitz' tumor. See Renal cell carcinoma.
1088 Index
Groin, regional lymph nodes in, metastases Hemangioendothelioma(s), mediastinal,

to, in vulvar malignant melanoma, 464 and diagnosis
clinical features of,
Growth, Gompertzian, cell growth and, 40 staging and prognosis in, 797
human, fetal and childhood, as treatment of, 797-798
Gompertzian process, 40, 41 wide local resection followed by
pattern of, in glial tumors, 729 radiation for, 798
Growth hormone, elevated secretion of, Hemangiopericytoma(s), mediastinal, 793-
pituitary tumors and, 635 797
in pituitary adenomas, 646 clinical features and diagnosis of,
Guilt, in spouse of cancer patient, 1041 793-794
Gynecologic neoplasms, 434^521 etiology of, 793
Gynecomastia, resulting from evaluation of, bv Doppler flowmeter.
diethylstilbestrol therapy, 100 794, 795
integration of treatment modalities in,
795, 797
H radiation therapy for, chemotherapy for,
Hard palate, cancer of, description of, 796
treatment for, 527 staging and prognosis of, malignant,
Hairy cell leukemia, 863-865 biologic behavior of, 794
description of, 863 treatment of, 794-797
diagnosis of, natural history of, 863-864 vascular embolization prior to resection
prognosis in, differential diagnosis of, in, 795, 796
splenectomy and corticosteroids for, 864 Hematopoiesis, restoration of, by
treatment of, 864-865 transplantation of pluripotent
Halo thaw time, in cryosurgery for basal and hematopoietic stem cells, 979
squamous cutaneous carcinoma, 716
cell Hematuria, in bladder cancer, 376
Halotestin, 102-103 renal cell carcinoma and, 394
Head, cancer of, levamisole for, 148 Hemilaryngectomy, for glottic cancer, 554,
neck and, cancer of, adjuvant 554
chemotherapy for, 563-565 Hemisphere(s), cerebellar, cystic
BACON and COBMAM for, 562 astrocytomas of, surgery for, 739
bleomycin for, 560 Hemoccult test(s), for colorectal cancer, 271,
chemotherapy and surgery for, 564-565 271
chemotherapy for, 558-565 Hemorrhagic cystitis, cyclophosphamide and,
combination, 561-562, 56 It 37, 60. 61
intravenous hyperalimentation prior Hepatectomy, partial, for gallbladder
to, 559 carcinoma, 335
regional. 562-563 Hepatic artery infusion, chemotherapy by, in
types of drugs used in, 563 carcinoid tumors, 619
single-agent, 559-561, 561t continuous, complications of, 333-334, 333t
cisplatin for, 561 following systemic 5-fluorouracil, in
disseminated, 559 progressive colorectal metastases, 332,
methotrexate and leucovorin for, 333t
methotrexate or bleomycin and Hepatic dysfunction, in renal cell carcinoma,
radiation therapy for, 564 394
methotrexate for, 559-560, 560t from streptozotocin, 111
mucositis from, 565 testosterone and, 102
radiation therapy and adjuvant Hepatic parenchyma, as site of tumor cell
chemotherapy 563-564
for, deposition, in liver metastases, 325
unresectable tumors in, drug regimen Hepatic toxicity(ies), in chemotherapy, 37
for, 562 Hepatoma(s), adult, levels of
epidermoid carcinomas of, adjuvant alpha-fetoprotein as indication of, 320
chemotherapy for, 558 diagnosis of, alpha fetal globulin in, 127
neoplasms of, 522-568 •5-fluorouracil for, 324
pain regional therapy for, 1014
of, inoperable, 5-fluorouracil infusion for, 14
Head and neck defect(s), prosthetic Hepatosplenomegaly, in renal cell carcinoma,
rehabilitation of, 1027-1034 394
surgical, major, 1027 Herpes simplex virus, type II, implication in
Heart, radiation damage to, in Hodgkin's cervical carcinoma, 477
disease, 888 Herpesvirus, in cancer patients, 966
Heavy chain 862-863
disease(s), laryngeal cancer and, 547
alpha and mu, description
of, 863 Hexamethylmelamine, absorption and
gamma, description of, 862 excretion of, 111-112
Hemangioblastoma(s), of cerebellum, surgery dosages for, toxicities of, 112
for, 739 mechanism of action of, 111
Index 1089
5HIAA, elevated levels of, in carcinoid Hodgkin's disease (Continued)

tumors, 612 introduction of megavoltage radiation and,
Histiocyte(s), description of, 912 884
Histiocytic malignancy(ies), 952-958, 953t involvement of liver in, 873-874
for, laparotomy for, technical considerations in,
classification of, 952-953 879-880
clinical features and diagnosis
of, 953-954, lymph node involvement in, 870
954t lymphangiography for detecting, 872-873
defects in phagocytic leukocyte function major symptoms in, vascular invasion of
and, 954 spleen by, 871
description of, symptoms of, 953 mechlorethamine administration in, 59
irradiation for, 956 MOPP as treatment of choice for, 891
natural history of, 952-954 natural history of, 869-882
surgery for, useful drugs in, 955, 955t newly diagnosed, treatment for, 898, 899
treatment of, 954-958 organ-related problems in, 872-876
Histiocytic medullary reticulosis, 953 organs involved in, 873, 874-876
erythrophagocytosis in, 954 pathologic staging of, 877-878
Histiocvtosis(es), adult, chemotherapy for, patterns of spread in, 870-871
957-958 primary, radiation therapy plus
CHOP for, 957, 957t chemotherapy for, 898
childhood, chemotherapy for, prognostic treatment of, 894, 898
factors in,956-957 prognosis in, 881^882, 881-883
drug regimens for, 957 radiation pneumonitis in, heart and spinal
Histologic diagnosis, importance of, prior to cord damage, in 888
chemotherapy, 45 prior to staging work-up, 880
Histologic grade(s), correlation with radiation therapy for, 883-889, 885
prognosis, in prostate cancer, 360 effects of splenectomy on, 887
Histology, of pancreatic cancer, 309 goals of, 884
Histoplasmosis, in cancer patients, 966 high-dose, splenectomy and, 887
HLA antigen(s), antibodies to, platelet history of, 883-884
survival and, 974 in children, transient aspermia from,
Hoarseness, in laryngeal cancer, 549 pregnancy problems from, 889
Hodgkin's disease, 866-905 inverted-Y fields in, 886
aggressive treatment for, development of mantle fields in, 885-886
second neoplasms and, 877 renal tolerance to irradiation in, 888-889
bimodal age-specific curve in, 868-869 resistant to MOPP, chemotherapy for, 894,
bone marrow biopsy in, 879 895t, 896t
chemotherapy for, 890-894, 890t-893t, 896t RNA viruses as possible etiologic agent in,
combination, 890-893 867-868
single-agent, 890 special problems in, 899-900
classification and pathology of, 869, 870t splenectomy for, curein, 882
clinical features of, 870-877 stage III, subclassification of, 878, 879
clinical presentation of,comparison with staging in, 877-881, 878t, 880t
that of non-Hodgkin's lymphomas, individualization of, 880-881
916-917 surgery for, 882-883
clinical stage and subtype of, during survival in, 867, 867
childhood, 900 tissue volume irradiated in, 884-885
complete remission with MOPP, restaging treatment of, 882-900
after achieving, bone marrow types of, Reed-Sternberg cell in diagnosis
suppression from, 892 of, 869
constitutional symptoms in, 871-872 vinblastine therapy in, 77
contagiousness of, 868 Homovanillie acid (HVA), as diagnostic aid in
delayed second neoplasms in, 876-877 retinoblastoma, 572
during pregnancy, 899-900 Hormone(s), antidiuretic, normal production
etiology and epidemiology of, 867-869 of, 1000
hematogenous spread in, 871 antitumor, 98t
immunologic dysfunction in, 872 cell and, interaction of, 95
immunotherapy for, 894, 897t estrogenic and androgenic, increased levels
in relapse, due to incomplete therapy of, in sex cord tumors, 509
versus tumor cell resistance, 899 influence on melanoma, 690
factors influencing, restaging for, 898 mechanisms of action of, 95-96, 95
treatment of, 898-899 pituitary gland, secretion of, 633
integration of treatment modalities in, 894, postoperative replacement of, in pituitary
898^899 tumors, 644
1090 Index
Honnone(s) (Continued) Hydroxyprogesterone caproate, route of

selected, chemical structures 97
of, administration and dosages for, 101
specific, hypersecretion of, syndromes Hydroxyurea, 107-108
caused by, 636 absorption and excretion of, side effects of,
secretion of, cell types related to, 108
634-635 chemical structure of, 106, 108
thyroid, as adjunctive therapy, in thyroid for blast crisis, in chronic myelogenous
cancer, 602 leukemia, 838
thyroid-stimulating, effect on thyroid for chronic phase of chronic myelogenous
tumors, 592-593 leukemia, 836
use in chemotherapy, 95-105 Hyperalimentation, intravenous, prior to
Hormone control, for relief of pain, chemotherapy, in head and neck cancers,
1012-1013 559
Hormone production, in cortical adrenal prior to surgery, in esophageal cancer, 237
neoplasms, 628, 629t Hypercalcemia, 995-997
in lung cancer, 201 cancer and, 996
Hormone receptor(s), distribution of and development of symptoms in, blood
response to endocrine therapy, in breast calcium level and, 995
cancer, 178, 179t diagnosis of, 995-996
Hormone receptor status, importance of, in differential diagnosis of, 996, 996t
choosing proper treatment in breast cancer, in parathyroid carcinoma, 588
178 malignant causes of, 995, 995t
Hormone therapy, for prostate cancer, management of, in multiple myeloma, 860
363^367 mithramycin therapy in, 73
effect on survival of, 364 treatment of, 997
metastatic, 365 Hyperemesis gravidarum, hydatidiform mole
stage B, 370-371 and, 435
stage C, 371, 373 Hyperestrinism, endometrial carcinoma and,
for renal cell carcinoma, 405 conditions associated with, 443, 444t
plus chemotherapy, for prostate cancer, 367 Hypernephroma. See Renal cell carcinoma.
Host immune response, chemotherapy and, Hyperparathyroidism, hypercalcemia and,
in choriocarcinoma, 441 996
influence on bladder tumor, 391 pheochromocytoma and, 622
Host immunity, against cancer, clinical Hyperplasia, endometrial, description of, 443
evidence for, 125-133 Hypersecretion, of specific hormones,
Host resistance, stimulation of, in treatment syndromes caused by, 636
of cancers, 151 Hypersensitivity, delayed cutaneous, role in
Human chorionic gonadotropin (HCG), as assessment of cell-mediated immune
tumor marker, 46 reactions of, 130
in gestational trophoblastic disease, 441 Hypersensitivity reaction, delayed, in skin
assays of, in hydatidiform mole, 436 cancer, 722
elaboration by trophoblastic tumors, 435 Hypersplenism, in chronic myelogenous
immature ovarian teratomas and, 508 leukemia, splenectomy for, 840
presence in ovarian cancer, 514 Hypertension, pheochromocytoma and, 622
Human growth, fetal and childhood, as Hyperuricemia, resulting from rapid
Gompertzian process, 40, 41 dissolution of neoplastic tissues following
Human neoplasm(s), evidence for chemotherapy or radiation therapy, 999
tumor-associated fetal antigens in, 126-128 Hyperviscosity syndrome, management of, in
Humoral antibody production, lack of defect multiple myeloma, 861
cancer patients, 130
in, in Hypocalcemia, diagnosis and differential
Humoral immunity, suppression of, by diagnosis of, etiology of, 998
chemotherapeutic drugs, 35 treatment of, 998-999
Hydatidiform mole, amniography in, 435, 436 Hypogammaglobulinemia, in chronic
chemotherapy for, surgery for, 438 lymphocytic leukemia, 842
chest x-rays and HCG
assays in, 436 Hyponatremia, 1001, lOOlt
clinical features and diagnosis of, 435 Hypopharynx, cancer of, cervical metastases
Hydrazine sulfate, proposed use for cancer in, 557
treatment, 116 chemotherapy for, 553
Hydrea. See Hydroxyurea. laryngography prior to biopsy in, 550-551
Hydrocortisone, after adrenalectomy, 182 microscopic examination of biopsy tissue
aminoglutethimide and, 110 in, 551
duration of action of, 104 natural history of, 548-552
mechanisms of action of, 103 physical examination in, 550—552
synthetic analogues of, pharmacology of, radiation therapy and surgery for,
54t-55t, 104 552-553
Index 1 091
Hypopharynx (Continued) Immune system, anatomic and functional

cancer of, staging of, 552, 552t compartments of, in normal lymph node,
surgery and radiation therapy for, 557 912, 9i3
treatment of, 552-558 change in, from brain tumors, 729-730
larynx and, cancer of, 547-558 effects of corticosteroid therapy on, 104
anatomic classification of, 548, 548 Immunity, cell-mediated, depressed, common
reconstruction of, 558 infections in, 966
supraglottis and, cancer of, pain in, 550 cellular and humoral, suppression of, by
Hypophysectomy, as secondary endocrine chemotherapeutic agents, 35
therapy, 181 host, against cancer, clinical evidence for,
in prostate cancer, 366 125-133
Hypothesis, log cell kill, 40-41 impaired, contribution to death from
Hypoxanthine. as related to allopurinol, 94 infection, in cancer patients, 36
Hysterectomy, bilateral salpingo- tumor-specific, first cases of, 124
oophorectomy and. for cervical studies of, role of laboratory rodents in,
carcinoma in situ, 485 124-125
for epithelial ovarian tumors. 500 Immunization, passive, as method of ovarian
for fallopiantube cancer, 512 cancer control, 506
for ovarian endodermal sinus tumors, 509 Immunocompetence, in tumor regression,
for ovarian teratomas and importance of, 140
dysgerminomas, 508 Immunodeficiency, in non-Hodgkin's
for stage I endometrial carcinoma, 451 lymphomas, 907
radical, bilateral pelvic lymphadenectomy Immunogenicity, alterations of tumor cell
and, for stage lb cervical carcinoma, surface as method for increasing, 138
486 Immunoglobulin synthesis, B lymphocyte
pelvic lymphadenectomy and, for stage I neoplasms capable of, 853-866
endometrial carcinoma, 452 Immunologic dysfunction, in Hodgkin's
for stages II and III cervical disease, 872
carcinoma, 488 Immunology, in cancer, 124-253
in colorectal cancer, 301-302
in neuroblastoma, 767
in pancreatic cancer, 318
in stomach cancer, 260-261
tumor, early frustrations in, 124
I Immunostimulation, in non-Hodgkin's
IgM, in chronic lymphocytic leukemia, 842 lymphomas, 907
Ileostomy, history of, 1023 Immunosuppression, caused by
Iliac crest(s), bone marrow obtained from, for corticosteroids, 103
cryopreservation, 980 caused by cyclophosphamide, 61
Imaging, splenic, in non-Hodgkin's correlation with poor prognosis, in
lymphomas, 919 colorectal cancer, 301
Immobilization, of bone fractures, 1011 drug-induced, in acute lymphoblastic
Immune mechanism, role in preventing leukemia, 818
metastases in cancer patients, 126 granulocyte transfusions in patients with,
Immune reaction(s), of lymphocytes, in vitro graft-versus-host reaction in, 978
tests of, 131 in chemotherapy, 35-36
Immune response, cellular, influence on in cytarabine therapy, 90
prognosis in colon cancer, 270 in lung cancer, 222
cellular and circulating, in metastatic renal malignancy in, 130-131
cell carcinoma, 405 procarbazine and, 106
cellular and humoral, in controlling growth relationship to presence of tumor, 131
of human cancer, 132 skin cancer and, 698
in controlling development of neoplasia, Immunosuppressive therapy, increased
129-130 incidence of malignant neoplasms in
morphology and, in colorectal cancer, 301 patients on, 130
nonspecific stimulation of, 135 Immunotherapy, 133-139
tests of, colorectal cancer and, 301-302 active, in ovarian cancer, methods of, 506,
to tumor-associated antigens, correlation 507t
with clinical course of human cancer, active specific, 137-138
132-133 adjuvant, 143-148
tumor-specific, in cancer patients, evidence for malignant disease, allogeneic tumor
for,128-129 cell vaccines as, clinical tests of, 137
Immune RNA, xenogeneic, studies on use in for soft-tissue sarcomas, for colorectal
cancer immunotherapy, 138-139 cancer, 147
1092 Index
Immunotherapy (Continued) Immunotherapy (Continued)

agents used 135-139
in, strictlycontrolled clinical trials in
chemotherapy and, for asymptomatic establishing role of, 135
primary and disseminated metastases, studies on use of xenogeneic immune RN A
in renal cell carcinoma, 404 in, 138-139
for cutaneous basal and squamous cell success of nonspecific stimulators in, need
carcinomas, 705 for accurate monitors in, 152
combination, for acute lymphoblastic surgery and, in lung cancer, 226
leukemia, 817 topical, in vaginal cancer, 141
Corynebacterium parvum in, clinical Implant(s), interstitial, for anal cancer, with
features of, 137 surgery', 306
for acute lymphoblastic leukemia, 817-818, without surgery, 307
817t for pancreatic cancer, 315
for acute myelogenous leukemia, 827-828, for pituitary adenoma, 648
827t Impotence, in cystectomy with urinary
for brain tumors, 747 diversion, 1026
for breast cancer, 140-141 Index, therapeutic, for antineoplastic drugs,
micrometastatic, 188 definition of, 30
for chronic myelogenous leukemia, 840 from cytotoxic drugs,
Infection(s), bacterial,
for colorectal cancer, 301-302 964-965
for cutaneous squamous and basal cell bone marrow failure and, iatrogenic factors
carcinomas, 721-722 and, 966-967
lor endocrine pancreatic cancer, 609 common, in patients with depressed
for epithelial ovarian cancer, 504-505 cell-mediated immunity, 966
for esophageal cancer, 245 death from, in cancer patients, contribution
for gestational trophoblastic disease, of impaired immunity to, 36
440-441 from gram-negative bacteria, gentamicin
for head and neck cancer, possible future for, 969
role of, 565 in acute lymphoblastic leukemia, 808-809
for Hodgkin's disease, 894 in acute myelogenous leukemia, 821
for liver cancer, 324 in leukopenic patients, granulocyte
for lung cancer, 222-223 transfusions in, 975
for malignant disease, studies on, 134 management of, in multiple myeloma, 860
for melanoma, 691 sites of, secondary to leukopenia,
for multiple epidermal neoplasms, 722 granulocytopenia and, 964
for non-Hodgkin's lymphomas, 936 Infusion(s), hepatic artery, chemotherapy by,
for osteosarcoma, 147, 660 in carcinoid tumors, 619
for renal cell carcinoma, 40.5-406 hepatic arterv, continuous, complications
for skin cancer, types especially suited for, of, 333-334, 333t
721 intra-arterial, continuous, of 5-fluorouracil,
for specific neoplasms, clinical evaluation 332
of, 139 for hepatic metastases, UCLA
for spinal cord tumors, 755 experience with, 331-334, 332t,
for stomach cancer, 260-261 333t
for subclinical microscopic disease, 134 of chemotherapeutic drugs, in advanced
for vulvar malignant melanoma, 464^65 bladder cancer, 390
history of, 124 Inheritance, of retinoblastoma, 570
in cancer, 124-153 of tendency to develop melanoma, 679
in conjunction with chemotherapy, 144-145 Inhibition, complementarv, in chemotherapy,
in conjunction with other forms of cancer 43
therapy, 134 Insulinoma(s), endocrine pancreatic, 604-605
local, description of, 139 chemotherapy for, 608
preoperative, 141-142 laboratory tests 605, 605t
for,
nonspecific, for cervical carcinoma, 491 presenting symptoms of, incidence of,
passive, 135, 138-139 diagnosis of, 604
approaches to, 138 surgery for, 607
in bronchial carcinoma, 144 Interaction(s), between family and cancer
reduction in tumor burden as form of, patient, plan for, 1038
132-133 Intercalation, antibiotics and, 67
role in disseminated disease, 148 Intestinal lymphoma(s). "Mediterranean,"
skin cancer and, 141 940-941
specificity for cancer cells of, 133 Intestinal obstruction, in ovarian cancer, 507
Index 1093
Intravenous pyelogram, abnormal, in cervical J

carcinoma, 490 Jaundice, cholestatic, as manifestation of liver
for diagnosing bladder cancer, 377 dysfunction, in 6-mercaptopurine
for diagnosing neuroblastoma, 761, 762 therapy, 93
for diagnosing Wilms* tumor, 770, 770 obstructive, in carcinoma of extrahepatic
Intravenous urogram, for diagnosing bile ducts, 338
non-Hodgkin's lvmphomas, 918-919
Invasion, Clark's levels of, 683-684, 684, 686t
depth of, measurement of, in melanoma,
685 K
early stromal, in cervical carcinoma, 481 Kang cancer, of China, 698
Invasive mole, description of, 437 Kaposi's sarcoma, mediastinal, 798-799
Inverted-Y field(s), in radiation of Hodgkin's clinical features and diagnosis of, staging
disease, 886 and prognosis in, 798
Iodine-125, implantation of, in prostate treatment of, 799
cancer, stage C, 372 Kamofsky performance scale, 47t
Iridocyclectomy, for melanoma of iris and correlation with survival, in unresectable
ciliary body, 582 lung cancer, 208
body and, malignant
Iris, ciliary melanoma Keratosis(es), actinic, curettage for, 703
treatment of, 581-582
of, description of, 696
malignant melanoma of, 578 prophvlactic measures to prevent,
mortality rate in, 580 702-703
Iron, accelerated clearance of, in cancer, 962 topical 5-fluorouracil for, 703-704
Irradiation. See also Radiation therapy. treatment for, 702-704
cranial, for meningeal leukemia, 838 methods of, 703
cranial or craniospinal, in acute Kidnev(s), as site of origin for Wilms' tumor,
lvmphoblastic leukemia, complications 768
from, 819 damage to, by chemotherapeutic drugs, 37
for choroid melanoma, 582 dysfunction of, modification of
for chronic myelogenous leukemia, 839 methotrexate treatment in, 32
for esophageal cancer, improvement of excretion of cisplatin by, 113
dysphagia from, 243 excretion of 5-fluorouracil by. 86, 87-88
for histiocytic malignancies, 956 excretion of procarbazine by. 106
for retinoblastoma, 574—575 excretion of streptozotocin by. Ill
complications of, 575 methotrexate toxicity and, 83
judging effectiveness of, 19 radiation of, tolerance to, in Hodgkin's
local, for chronic lvmphocvtic leukemia, disease, 888-889
849 role in elimination of vinblastine and
preoperative, in lung cancer, goals of, 216 vincristine, 77, 78
types of tumors used for, 217 role in excretion of chemotherapeutic
in nonsmall cell carcinoma of lung, 225 drugs, 32
prophylactic whole brain, in small cell Kidney transplant(s), development of
carcinoma of lung, 220 metastatic cancer in patients receiving, 130
renal tolerance to, in Hodgkin's disease, Kraske operation, for cancer of rectum, 282,
888-889 283
splenic, for chronic myelogenous leukemia,
839
total bodv, as svstemic treatment in cancer,
21
for chronic lvmphocvtic leukemia,
848-849 Laetrile, amygdalin in, cyanide poisoning
whole brain, in gestational trophoblastic from, 115
disease, 440 Lambert-Eaton syndrome, small cell lung
Irrigation procedure(s), in colostomy, cancer and, 1004
1025-1026, 1026 Laminar air flow room, for neutropenic
Isoenzyme(s), Regan, presence in ovarian patients, 971
cancer, 513-514 Laminectomy, radiation and, for epidural
Isolation procedure(s), components of, 972 metastases, 754
Isotope scan(s), for diagnosis of vertebral Laparotomy, in fallopian tube cancer, 512
metastases, 751 in lung cancer, 204
Isthmus, uterine, involvement of, in in ovarian cancer, 498
endometrial carcinoma, 446 in pancreatic cancer, results of, 315
1094 Index
Laparotomy {Continued) Leukemia {Continued)

prior to thoracotomy, for metastatic acute lymphoblastic, 80.5-820
colorectal cancer, 294 adult, L-10 protocol for, 817
staging, in non-Hodgkin's lymphomas, remission rates and survival times in,
920-921 816
Laryngectomy, followed by radiation, for treatment of, 816-817
subglottic cancer, 556-557 age as prognostic factor in, 810
for glottic and supraglottic cancer, 555 L-asparaginase for, 115
Laryngography, prior to biopsy of laryngeal bacillus Calmette-Guerin for, 134, 818
or hypopharyngeal cancer, 550-551 central nervous system prophylaxis in,
Larynx. See also Glottis and Supraglottis. 813-814
cancer of, cervical metastases in, 550 chemoimmunotherapy for, 150
chemotherapy for, 553 chemotherapy for, cessation of, 814-815
cigarette smoking and alcohol and, 547 principles 811-815
of,
hoarseness and. 549 classification and pathology of, 806-807,
laryngography prior to biopsy in, 550-551 806t
natural history of, 548-552 clinical features of, 807-809
pathology of, 549 complications of therapy in, 818-819
physical examination in, 550-552 continuation chemotherapy for, 814
radiation therapy and surgery for, cranial or craniospinal irradiation in,
552-553 complications from, prospects for #
hypopharynx and, cancer of, 547-558 future in, 819
anatomic classification of, 548, 548 description of, 805-806
incidence and etiology of, 547 diagnosis of, 809-810
irradiated, residual cancer in, 551-552 drug regimens for, 812
microscopic examination of biopsy tissue high-risk, treatment of, 815
in, radiographic examination of, 551 homogeneous versus heterogeneous, 806
staging of, 552, 552t immunotherapy and combination
symptoms of, 549-550 chemotherapy for, 817
treatment of, 552-558 immunotherapy for, 817-818, 817t
Leiomyosarcoma(s), mitotic index of, 516 infections in, 808-809
uterine, prognosis in, 517 intensification of chemotherapy in, 813
Lennert's lymphoma(s), prognosis of, 914 laboratory features in, morphologic types
treatment of, 945 of, 809
Lentigo maligna melanoma (LMM), myelosuppression and
description of, 680 immunosuppression in, 818
Leptomeningitis, lymphomatous, in of, 806-811
natural history
non-Hodgkin's lymphomas, 943 neurologic manifestations in,
Lesion(s), bone, management of, in multiple genitourinary manifestations in, 808
myeloma, 860-861 null cell, 806-807
superficial, low-grade, in
bladder cancer, prognosis in, T cell versus null cell, cell
treatment of, 380-382 reduction in, 811
Letterer-Siwe disease, 953 prognostic factors in, 810-811
Leucovorin, methotrexate and, for head and recurrent, treatment of, 815-816
neck cancer, 564 remission induction in, failure of, 813
Leucovorin rescue, 81 through chemotherapy, 811-814, 812t
methotrexate and, 82, 82 symptoms of and laboratory features in, T
nomogram for modifying, 83, 83 cell and B 807
cell,
Leukapheresis, for chronic lymphocytic 816
testicular relapse in,
leukemia, 849 treatment of, 811-819
for chronic myelogenous leukemia, 840 acute myelogenous, 820-829
maneuvers to increase yield of, 977 bacillus Calmette-Guerin and
Leukemia, acute, allopurinol for, 94 Corynebacterium parvum for, 827
autologous bone marrow from patients in bone marrow transplantation in, 828
remission from, 981 chemoimmunotherapy for, 151
biology and epidemiology of, viruses as chemotherapeutic remission induction in,
etiologic factor in, 804 824-825
etiology of, 803-804 chemotherapy for, 824-827, 824t, 825t
genetic factors in, radiation as cause of, consolidation and maintenance,
803 825-826
incidence of, 802 classification of, hematologic features of,
6-mercaptopurine and 6-thioguanine 820
therapy in, 93 clinical features of, 820-821
Index 1095
Leukemia (Continued) Leukemia (Continued)

acufe myelogenous, cvtosine arahinpside chronic myelogenous, chronic phase of,
for, 824 chemotherapy 834-836

in,
of, 821-823
diagnosis drugs for treatment of, 836
immunotherapy for, 827-828, 827t classification of, 833, 833t
increase in CNS leukemia in, future prospects in, 841
hematologic remission in, 826 hvpersplenism in, treatments for, survival
induction therapy in, prognostic factors in, 840
in, Auer bodies in, 823 incidence of, 832
intensive induction regimens for, irradiation for, splenomegaly in, 839
experimental drugs for, 825 natural history of, 833-834
laboratory features in, 822t, 823 presenting symptoms in diagnostic aids
leukemic infiltration of bone marrow in, in, juvenile, 833
821 splenectomy 839-840
for,
natural history of, 820-824 treatment 834-840
of,
physical findings in, 821, 823 hairy cell, 863-865
prognostic factors in, 823-824 description of, 863
prospects for future in, 829 diagnosis of, natural history of, 863-864
quality of life and cost in, 826-827 differential diagnosis of,844
symptoms of, 821 prognosis splenectomy for,
in,
treatment of, 824-828 corticosteroids for, 864
treatment of, cost for, 827 treatment of, 864-865
acute nonlymphocytic, in Hodgkin's immunotherapy for, 150-151
disease, 876 in radiated thyroid cancer, 601
central nervous system, 815-816 increased risk for, in ovarian cancer
increase of, in acute myelogenous patients, 514
leukemia, 826 isolation in laminar air flow room for
methotrexate for, 816 patients with, 971
prophylaxis for, 813 lymphosarcoma cell, differential diagnosis
treatment of, complications of, 814 of, 844
chemicals and drugs as etiologic factors in, histopathologic evaluation of, 813
803-804 meningeal, increase of, cranial irradiation
chronic, 832-852 for, 838
chronic lymphocytic, 841-850 prolvmphocytic and T cell, description of,
adrencorticosteroids for, chemotherapy 842
for, 847-848 prophylactic platelet transfusions for
alkylating agents for, 847 patients with, 975
chlorambucil administration in, 62 therapy-linked, smoldering, 828
classification of, 842, 844 urinary tract as site of infection in, 964
description of, 841 Leukemia cell(s), murine, tumor
differential diagnosis of, 843t, 844, 846 transplantation resistance in, role of
drugs 848
for, neuraminidase in inducing, 138
etiology 841-842
of, Leukeran. See Chlorambucil.
hemolytic anemia in, IgM in, Leukoagglutination assay(s), for non-HLA
hypogammaglobulinemia in, 842 granulocyte antigens, 976
integration of treatment modalities in, Leukocyte(s), immunologic reactivity of, use
849-850 in diagnosing stomach cancer, 260
leukapheresis for, splenectomy for, local methods for obtaining, 976-977
radiation for, 849 Leukocyte count(s), in acute lymphoblastic
natural history of, 842-846 leukemia, 809
radiation for, 848-849 in diagnosis of chronic myelogenous
staging and prognosis in, 844t, 845t, 846 leukemia, 833
treatment 846-850
of, Leukocyte function, phagocytic, defects of, in
indications for, 846 histiocytic malignancies, 954
chronic myelocytic, busulfan for, 64 Leukocyte transfusion(s), post-transfusion
chronic myelogenous, 832-841 phenomena in, 976
blast cells in, presence of terminal Leukopenia, as consequence of bone marrow
deoxynucleotidyltransferase in, 838 failure, 963
blast crisis in, chemotherapy for, infection in patients with, granulocyte
836-838, 837t transfusions for, 975
description of, 834 infection secondary to, granulocytopenia
chronic phase of, busulfan in, 834-835 and, 964
treatment regimens of, complications Leukoplakia, laryngeal cancer and, 547
from 835 oral cavity cancers and, 522
1096 Index
Leukoplakia (Continued) Liver metastasis(es) (Continued}

squamous cell carcinoma and, in cancer of in colorectal cancer, continuous
vulva, 457^58 intrahepatic artery infusion for, of
Leukostasis, cerebrovascular, in chronic 5-fluorouracil, 329, 330t, 331
myelogenous leukemia, 838 diagnosis of, 325
Levamisole, as adjuvant treatment to trials in, 328
operation, in lung cancer, 144 management of, 325—334
for cancer of head and neck, 148 natural history of, 325-327
for lung cancer, 223 radiation therapy for, 328-329, 328t
uses for, 137 surgery for, 327-328
with radiation therapy, in breast cancer, treatment of, 327-334
146 Liver resection, for disease metastatic to
"Life Island" germ-free isolator unit, for liver, 327
neutropenic patients, 971 for metastatic colorectal cancer, 293
Light, ultraviolet, melanoma and, 678-679 Liver scan(s), radioisotope, in picking up
Limb perfusion, isolated, in soft-tissue primary and secondary' liver tumors, 326
sarcoma, 674 Liver-spleen scan(s), in non-Hodgkin's
Limb salvage, in osteosarcoma, 660, 662 lymphomas, 919
Linear accelerators(s), use in radiation Lobectomy, for thyroid adenocarcinoma, 597
therapy, 21 versus pneumonectomv, in lung cancer,
Liver, as site of metastatic involvement in 213
lung cancer, 205 Log cell kill hypothesis, 40-41
biopsy of, in neuroblastoma metastases, Lomustine (CCNU), for gliomas, 744
765 for multiple myeloma, 857
biotransformation in, of cyclophosphamide, mechanisms of action of, 65
59-60, 59 pharmacologic characteristics of, 54t-55t, 66
excretion of hydroxyurea by, 108 LSA2-L2 regimen, for childhood
5-fluorouracil excretion and, 86, 87-88 non-Hodgkin's lymphomas, 938
involvement of, in Hodgkin's disease, L-10 protocol, for adult acute lymphoblastic
873-874 leukemia, 817
irradiation of, in gestational trophoblastic Lukes-Collins classification system, for
disease, 440 non-Hodgkin's lymphomas, 911, 912t
radiation to, in stage IV-S neuroblastoma, Lumbar puncture, diagnostic, in brain
766 tumors, 735
role in excretion of chemotherapeutic Lung(s). See also Pulmonary entries,
drugs, 32 as site of infection, neutropenia and, 964
mitomycin-C clearance 74
role in nonsmall cell carcinoma of, combination
testosterone metabolized by, 102 chemotherapy for, integration of
vinblastine excretion and, 77 treatment modalities in, 225
Liver cancer, 319-324 results of single-agent chemotherapy for,
chemotherapy for, 321-324 219, 219t
regional, 322, 323t, 324 pleura and, involvement of, in Hodgkin's
systemic, 321-322, 322t disease, 874
description of, 320 small cell carcinoma of, chemotherapy for,
etiology and epidemiology of, 319 plus radiation therapy, 225
immunotherapy in, 324 combination, radiation and, 220, 221t
surgery and radiation therapy for, 321 results of, 219
treatment of, 321-324 MOCA chemotherapy in, 224, 224t
Liver dysfunction, dosage modification of prophylactic whole brain irradiation in,
doxorubicin and vincristine in, 32 220
in 6-mercaptopurine therapy, cholestatic Lung cancer, 197-230
jaundice as manifestation of, 93 advanced, tumor cell vaccine as adjuvant
Liver function, importance of monitoring in therapy in, 144
6-thioguanine and 6-mercaptopurine bacillus Calmette-Guerin and
therapy, 93 Corynebacterium parvum for, 223
Liver metastasis(es), angiography as chemotherapy in, 219-222
diagnostic aid in, liver resection for, 327 adjuvant single-agent, 222
chemotherapy for, 329-334 clinical features and diagnosis of, 200-203
regional, 329 disseminated, chemoimmunotherapv for,
clinical features and diagnosis 325-327
of, 149
diagnosis of, laboratory aids in, 326 dose-time relationships of radiation therapy
in carcinoid tumors, surgery for, 616 in, 216
Index 1097
Lung cancer (Continm Lung cancer (Continued)

etiology and incidence of, 197 types of tumors in, preoperative irradiation
fiberoptic bronchoscopy or thoracotomy in used for, 217
diagnosing, 203 unresectable, factors correlating with poor
histologic tvpes of, classification of, 197, prognosis in, 208
198t untreated, survival rate in, 210t
immunosuppression in, _ Lymph node(s), aortic, metastases to, in
immunotherapy for, 222-11 uterine sarcoma, 518
adjuvant, 143-145 axillarv. involvement of, in breast cancer,
importance of preventive measures in, 226 171
integration of treatment modalities in, biopsy of, in epithelial ovarian tumors, 501
224- primary tumor site identification and, 10
levamisole for, 223 cervical, removal of, in metastatic disease,
as adjuvant treatment to operation, 144 598
mediastinoscopy in, 212-213 dissection of, 426
metastatic, effects of. 201. 201t in determination of spread of disease, 13
natural history of. 197-200 in nonseminoma. 417—418
operable, symptomatic status in, 208 retroperitoneal, for stages A and B
palliative treatment in, 218-219 nonseminoma, 418
perioperative mortality rates in. carcinoma, 410. 4 10
in testicular
relationship of tumor size to prognosis in, excision carcinoma in situ, 383
ot. in
207 in immunologic investigations of stomach
pneumonectomy versus lobectomy in, 213 cancer, 260
preoperative assessment of, lymph node in staging lung cancer, 144
metastases in, 211 in staging renal cell carcinoma, 396
prognosis in, 206-210 internal mammary, procedures for
prospects for future in, 225-226 sampling, 13
radiation therapy for. 214-219 involvement of, in Hodgkin's disease, 870
as palliative therapv, chemotherapv and, in melanoma, 687, 688t
218 in metastatic testicular carcinoma, 409
as primary therapy. 214 in prostate cancer, 363
courses of, 216 stage A, 368
postoperative. 217 stage B>, 362
preoperative. 216-217 malignant, parotidectomy to remove, 13
goals of. 216 metastases to, in cervical carcinoma, 482
treatment techniques for. 215-216 tumor volume as prognosticator of, 483
versus surgery. 214-215 in endometrial carcinoma. 444—145
radiographic appearance of, 202 in lung cancer, importance and
screening for, 200 determination of, 211
second primary tumors in, 213 in melanoma. Clark's levels and, 688
small cell, Lambert-Eaton svndrome and, in prostate cancer, stage C, 371
1004 in tongue cancer. 528
symptoms of syndrome of inappropriate occult, in cervical carcinoma, 485
antidiuretic hormone secretion in, 1000 pelvic, in endometrial carcinoma,
staging of, 203-206 449-450
importance of lymph nodes in, 144 normal, anatomic and functional
techniques in, 205, 206t compartments of immune svstem in, 912,
supportive care in. 223-224 913
surgery for, 210-214 pelvic, dissection of, in prostate cancer,
adjuvant chemotherapy or stage A 2 369 ,
immunotherapy and, 225 stage C. 372

surgical resection for, 212-214 involvement of, in vulvar squamous cell
results of, 213-214 carcinoma. 459. 460t
selecting candidates for, 210 pelvic and periaortic, evaluation of. in
surgical staging of, 211-212 invasive carcinoma, of vagina, 476
surgicallv treated, survival rate in, 208, problems in, related to Hodgkin's disease,
209t lvmphangiographv for detecting, 872-
survival rates in. 207-208 873
survivorship in. resectability and. 204 regional, in groin, metastases to, in vulvar
symptoms of, 200-201. 201t malignant melanoma, 464
treatment of. 210-225 involv ement of, in renal cell carcinoma,
types of carcinomas comprising, 198-200 400
1098 Index
Lymph node(s) (Continued) Lymphoblastic leukemia (Continued)

regional, status of, in melanoma, prognosis acute, adult, treatment of, 816-817
and, 686 diagnostic aids in. 810
removal of, complete removal of vulva and, L-asparaginase for. 115
for invasive squamous cell carcinoma, bacillus Calmette-Guerin for. 134. 818
460 cell reduction in, 811
scalene, biopsy of, for staging testicular central nervous system prophylaxis for,
carcinoma, 413 813-814
supraclavicular and internal mammary, chemoimmunotherapy for, 150
metastases of, 174 chemotherapy for, cessation of, 814-815
Lymphadenectomy, as staging procedure, in intensification of,813
endometrial carcinoma, 452^453 principles of, 811-815
chemotherapy prior to, for nonseminoma, classification and pathology of, 806-807,
418 806t
for melanoma, morbidity in, 688 clinical features of, 807-809
for treatment of clinically evident regional complications of therapy in, 818-819
metastases, 13 continuation chemotherapy for, 814
in bladder cancer, 387 cranial or craniospinal irradiation for,
in stage B.,* prostate cancer, complications complications from, 819
of, 370 description of, 805-806
inguinal, in anal cancer, 306 diagnosis of, 809-810
pelvic, bilateral, radical hysterectomy and, drug regimens for, 812
for stage lb cervical carcinoma, 486 high-risk, treatment of, 815
with radical hysterectomy, for stage I homogeneous versus heterogeneous,
endometrial carcinoma, 452 806
and III cervical
for stages II immunotherapy and combination
carcinoma, 488 chemotherapy for, 817
pelvic and periaortic, in cervical carcinoma, immunotherapy for, 817-818, 817t
483 infections in, 808-809
radiation therapy and, for vulvar squamous laboratory features in, morphologic types
cell carcinoma, 461 of, 809
regional, formelanoma, 687-689 myelosuppression and
retroperitoneal, for seminoma, 414, 417 immunosuppression in, 818
thoracotomy following, in nonseminoma, natural history of, 806-811
423 neurologic manifestations in,
Lymphadenopathy(ies), angioimmunoblastic, genitourinary manifestations in, 808
in non-Hodgkin's lymphomas, 914 null cell, 806-807
in mycosis fungoides, 941 prognosis in, T cell versus null cell, 811
Lymphangiography, bilateral pedal, for prognostic factors in, 810-811
staging of testicular carcinoma, 412-413 prospects for future in, 819
in cervical carcinoma. 482 recurrence of, in bone marrow, 815
in endometrial cancer, 450 treatment of, 815-816
in Hodgkin's disease, 872 remission induction in, failure of, 813
in ovarian cancer, 497 through chemotherapy, 811-814, 812t
in prostate cancer, 362 symptoms of, laboratory features and, T
pedal, in staging bladder cancer, 378 cell and B 807
cell,
Lymphangiosarcoma(s), mediastinal, testicular relapse in, 816
description of, 799 treatment of, 811-819
Lymphatic(s), draining, total excision of, Lymphocyte(s), immune reactions of, in vitro
importance to success of colorectal tests of, 131
surgery, 279 of cancer patients, specific antitumor
regional, dissemination of tumor to, 12-13 reactivity in, use of transfer factor in
Lymphatic drainage, in melanoma, 688 inducing, 138
of peritoneal cavity, role of omentum in, Lymphocyte infiltration, of neuroblastoma,
493 correlation with survival, 762
in vaginal cancer, 471 Lymphocytic leukemia, chronic, 841-850
Lymphatic spread, direction of, in cancer of adrenocorticosteroids for, 847-848
rectum, 281 alkylating agents for, 847
Lymphoblast(s), leukemic, chromosome chemotherapy 847-848
for,
810
analysis of, chlorambucil 62for,
Lymphoblastic leukemia, acute, 805-820 classification of, 842, 844
adult, L-10 protocol for, 817 description of, 841
remission rates and survival time in, differential diagnosis of, 843t, 844, 846
816 drugs for, 848
Index 1099
Lymphocytic leukemia (Continued) Lymphoma(s) (Continued)

chronic, etiology of, 841-842 non-Hodgkin's, classification and histology
hemolytic anemia in, IgM in, of, 908-915
hypogammaglobulinemia in, 842 new,
classification systems in,
integration of treatment modalities in, immunologic aspects of, 911-914
849-850 traditional, 908
leukapheresis for, splenectomy for, local using immunologic markers and
radiation for, 849 function, 911
natural history 842-846
of, clinical features and diagnosis of,
radiation therapy for, 848-849 915-917

staging and prognosis in, 844t, 845t, 846 clinical presentation of, comparison with
treatment of, 846-850 that of Hodgkin's disease, 916-917
indications for, 846 constitutional symptoms in, extranodal
Lymphocytopenia, seen with corticosteroid disease and, 915
therapy, 103-104 CVP for, 927
Lymphocytosis(es), reactive, differential definition of, 905
diagnosis of, 844 diagnostic aids in, 917, 919
Lymphoepithelioma. See Thymoma(s), of disseminated disease in, para-aortic node
anterior mediastinum. involvement in, extranodal
Lymphogram(s), for diagnosing occult dissemination in, 921
non-Hodgkin's lymphomas, 918 at diagnosis, 917
Lymphoma(s), B cell origin of, 913 etiology of, genetic factors in, 906-907
Burkitt's, chemotherapy for, prognosis in, extradural, compression of spinal cord
940 by, 943
cyclophosphamide for, 61 favorable histologic types of, 911
sites of involvement in, geographic geographic incidence of, 908
incidence of, prognosis in, 939 histologic factorsand classes in, 914-915
chemotherapy for, 932 immunodeficiency and
childhood, chest radiography in diagnosing, immunostimulation in, drugs and
918 radiation as etiologic factors in, 907
convoluted lymphocytic, description of, immunotherapy for, delayed therapy in, 936
937 incidence and epidemiology of, 907-908
non-Burkitt's, abdominal disease in, integration of treatment modalities in,
radiation therapy for, 938 943-946
diffuse histiocytic, complete remission in, intravenous urogram for diagnosing,
subdivision of, 933 918-919
description of, 914 Lukes-Collins classification system in,
follicular, sclerosis in, Lennert's, prognosis 911, 912t
914
in, natural history of, 908-922
in oropharyngeal cancer, 523 occult, lymphogram for diagnosing, 918
intestinal and Lennert's, treatment of, 945 patient characteristics correlated with
lymphoblastic, description of, 934 histology in, 915-916, 916t
"mediterranean" intestinal, 940-941 percutaneous liver biopsy in, 920, 922
geographic incidence and etiology of, presentation of disease in, 915
940 radiation therapy for, 922-926
mesenteric node involvement in, 941 efficacy of, 924-925
nodular and diffuse, equal frequency of, indications for, 922
916 morbidity of, 92.5-926
non-Hodgkin's, 905-951 plus chemotherapy, 934, 936
angioimmunoblastic lymphadenopathy results of, 923
in, 914 sites of relapse in, 923-925
bone marrow aspirate and biopsy in, 920 technique in, 925
chemotherapy for, 926-934 radiologic dose-time relationship in, 923,
combination, 927-934, 929-93 It, 935t 924
morbidity of, second-line, 934 Rappaport classification system in, 908,
single-agent, 926-927 909t, 910t, 911
sequential, 927, 928t recommended staging procedures for,
useful single agents in, 926 92 It, 922
childhood, 937-940 recommended therapy for, 944-945, 946t
central nervous system prophylaxis in, risk of morbidity from combined
939 treatment modalities in, 944
histology of, sex predilection in, 937 special problems in, 937-943
LSA2-L2 regimen for, 938 staging and diagnostic studies in,
treatment of, 945 917-922
7700 Index
Lymphoma(s) (Continued) Malignancy(ies) (Continued)

non-Hodgkin's, staging laparotomy in, 920- immune suppression in, 130-131
921 second, in chemotherapy, 37-38
staging procedures in, 943 types benefited from chemotherapy, 47, 48t
surgery for, 922 Malignant melanoma, vulvar, 462^165
survival rates in, 924 and diagnosis of,
clinical features
treatment of, 922-936 462-463
viruses as etiologic factors in, 906 depth of invasion in, prognosis and, 463,
visceral dissemination of, autopsy studies 463t
and, 917, 918t etiology and epidemiology of, 462
of brain, 942 metastases to regional groin lymph nodes
of nervous system, 942-943 in, 464
of small bowel, association with natural history of, 462^64
"Mediterranean" intestinal lymphomas, prognosis 463-464
in,
940-941 symptoms of, 463
T cell, diseases composing, 913 treatment of, 464^165
Lymphosarcoma(s), combination Mammogram(s), in diagnosing breast cancer,
chemotherapy for, 928 166
peripheral adenopathy as presenting Mandible, restoration of continuity of, after
symptom in, 915 composite resection, 1031
Lymphosarcoma cell leukemia, differential Mandibular defect(s), functional disabilities
diagnosis of, 844 in, 1030
Lysodren. See Mitotane. prosthetic rehabilitation of, 1030-1031
Mantle field(s), in radiation of Hodgkin's
disease, 885-886
Marker(s), immunologic, increased use of, to
detect recurrence, in colorectal cancer,
M 292-293
Macroglobulinemia, Waldenstrom's, use in classification systems for
description of, 861 non-Hodgkin's lymphomas, 911
diagnosis of, 861-862 of response, 46
treatment of, 862 tumor, for staging testicular carcinoma, 414
Macrophage(s), mature, insensitivity to in diagnosis of ovarian cancer, 513
ionizing radiation and chemotherapy, 954 Marrow, bone, acute lymphoblastic leukemia
of, by Corynebacterium
stimulation in, recurrence of, 815
jmrvum, 137 appearance of, in chronic myelogenous
Macrophage infiltration, in bacillus leukemia, 833
Calmette-Guerin therapy, 136 aspiration and biopsy of, in
Magnesium deficiency, hypocalcemia from, non-Hodgkin's lymphomas, 920
998 autologous, from patients in remission
Male(s), predominance of childhood from acute leukemia, 981
non-Hodgkin's lymphomas in, 937 biopsy of, in Hodgkin's disease, 879
Malformation(s), congenital, in cryopreserved, maintenance of cell
chemotherapy, 37 function in, obtained from iliac crests,
Malignancy(ies), clinical course of, 980
correlation with impaired cell-mediated depression of, from chemotherapy, 962
response, 131 from radiation therapy, 963
colorectal,265-304 drug-induced aplasia of, in chronic
development of, orchiopexy to prevent, 407 myelogenous leukemia, 836
diagnosis of, following abnormal chest failure of, anemia from,
x-ray, 203 thrombocytopenia from, leukopenia
establishing presence of, in stomach ulcers, from, 963
249-250 blood component therapy for, 972-979
histiocytic, 952-958, 953t consequences of, 963-967
for, diagnostic evaluation in, 968
classification of, 952-953 erythrocyte transfusions for, 972-973
clinical features and diagnosis of, etiology of, 962-963
953-954, 954t from cancer treatment, 961
defects in phagocytic leukocyte function granulocyte transfusions for, 975-979
in, 954 infection and, iatrogenic factors in,
description of, symptoms of, 953 966-967
irradiation for,956 management 961-983
of,
natural history of, 952-954 973-975
platelet transfusions in,
untreated, heterogeneity of, 952 protection as treatment for, 967-972
useful drugs in, surgery for, 955, 955t treatment for, 967-981
Index 1101
Marrow {Continued) Mediastinum (Continued)

bone, involvement of, in Hodgkin's anterior, endodermal sinus tumors and
disease, 874-875 choriocarcinoma of, diagnosis of, 787
leukemic infiltration of, in acute incidence of, 786
myelogenous leukemia, 821 germ cell tumors of, 784-788
normal, per cent irradiated, using 785
classification of,
standard radiation ports, 1048 seminomas 787-788
of,
recovery of function of, following teratomas of, 785-786

radiation, in Hodgkin's disease, 888 description of, 787
replacement of, by tumor, 962 prognosis in, 788
suppression of, with MOPP, in symptoms of, treatment for, 786
Hodgkin's disease, 892 thymomas of, 780-784
transplantation of, autologous, for chronic classification of, 780
myelogenous leukemia, 841 clinical presentation of, 780-781
Mass(es). abdominal, in neuroblastoma, radiation therapy for, chemotherapy
760 for, integration of treatment
in Wilms' tumor, 769 modalities in, 784
Mastectomy, after radiation therapy, case spectrum of diseases associated with,
studies of, 176 781
modified radical, 188 staging and prognosis in, 782
current use of, 170-171 surgery for, 783
prophylactic castration at time of, 181 treatment for, 783-784
radical, case studies of, 174 hemangioendothelioma of, 797
history of, 170 treatment for, 797-798
simple, radiation therapy and, 173-174 wide local resection for, followed by
case studies of, 174 radiation, 798
for advanced breast cancer, 176 hemangiopericytomas of, 793-797
Mastication, after composite resection, chemotherapy for, 796
restoration of continuity of mandible for, etiology of, 793
1031 evaluation of, by Doppler flowmeter.
Matulane. See Procarbazine. 794, 795
Maxillary defect(s), definitive obturation for, integration of treatment modalities in,
1028-1029, 1029 795, 797
prosthetic rehabilitation of, 1027-1029 malignant, 294
surgical obturation for, 1028, 1028 radiation therapy for, 796
MeCCNU. See Semustine. treatment for, 794-797
Mechlorethamine, 56-59 vascular embolization prior to resection
bone marrow reserve and, fall in platelet in, 795, 796
and white blood cell counts from, Kaposi's sarcoma of, 798-799
dosages for, 58 treatment of, 799
derivatives of, chemical structures of, carcinoma and chordoma
posterior, of, 792
56,58 ganglioneuroblastoma of, 790
for mycosis fungoides, 942 ganglioneuroma of, 790
for non-Hodgkin's lymphomas, 926 mesenchymal tumors of, 791-792
for pleural effusions, 987-988 miscellaneous tumors of, 791-792
side effects of, 987 neurilemoma of, 789-790
for superior vena caval syndrome, 992 neurocrest tumors and reduplication
intralesional injections of, for skin lesions cysts of, 791
of breast cancer, 140 neurofibroma of, 788-789
method of administration and radiographic appearance of, 789, 789
characteristics of, 56 neurosarcoma of, 790
side effects of, 58-59 tumors of, 788-792
58
titration of, 56, classification of, 788
triethylenethiophosphoramide and, 64 tumors of, 778-792
for malignant pleural effusion associated usual location of, 778, 779t
with breast carcinoma, 988 vascular, 792-801
types of cancer used in, as topical therapy, Medical treatment staff, emotional balance
59 between aloofness and overinvolvement
Mediastinoscopy, cervical, in diagnosis of in, 1044
anterior mediastinal thymomas, 781 emotional disconnection from cancer
in lung cancer, 205, 212-213 patient of, 1045
Mediastinum, anatomic compartments of, importance of wide base of communication
778, 779 in care of cancer patient and, 1044
1102 Index
Medical treatment staff (.Continued} Melanoma(s) [Continued)

in cancer rehabilitation centers, 1022 malignant, clinical features and
psychosocial problems of, 1043-1045 diagnosis of, 462-463
"Mediterranean" intestinal lymphoma(s), depth of invasion in, prognosis and,
940-941 463, 463t
geographic incidence and etiology of, 940 etiology and epidemiology of, 462
mesenteric node involvement in, 941 metastases to regional groin lymph
Medullary reticulosis, histiocytic, nodes in, 464
erythrophagocytosis in, 954 natural history of, 462^164
Medullary thyroid carcinoma, inheritance of, prognosis in, 463^164
592 radiation for, 464
Medulloblastoma(s), brain, radiation therapv surgery 464
for,
742-743
for, symptoms 463
of,
chemotherapy for, 746 treatment of, 464-465
Megace. See Megestrol acetate. operation, bacillus Calmette-Guerin, and
Megavoltage radiation, introduction of, tumor cell vaccine in, studies of, 145
Hodgkin's disease and, 884 preoperative local immunotherapy in,
Megestrol acetate, route of administration 142
and dosages for, 101 management of, 692, 692
Melanoma(s), 678-694 measurement of depth of invasion in,
adjuvant chemotherapy for, 690 685
advanced, chemotherapy for, 689-690 natural history of, 679-686
chemotherapeutic regional perfusion in, nodular malignant (NM), description of,
690-691 680-681
efficacy of, 691 ocular malignant, 577-583
chemotherapy for, 689-691, 690t classification and prognostic factors in,
classification of, 680-681, 680t 579-580
clinical staging of, 683-685, 684t, 686t classification of, 580, 580t
correlation between antibody titer and clinical features and diagnosis of,
complement fixation in, 132 578-579
cutaneous, early detection of, 693 incidence and etiology of, 577-578
cutaneous metastases of, regression of, natural history of, 578-581
DNCB and vaccinia virus administration roleand timing of enucleation in, 583
and, 140 treatment of, 581-583
developmental biology of, 681 of choroid, irradiation of, 582
diagnosis of, 681-683 palliative surgery for, 689
differential clinical features of, 682t primary, surgery for, 686-687
epidemiology and etiology of, 678-679 wide radical excision for, 686
familial, 679 prognosis in, 685-686
immunotherapy for, 691 parameters influencing, 685
increase in, 678 status of regional lymph nodes and, 686
influence of hormones on, 690 pulmonary metastases in, radiation therapy
involvement of regional lymph nodes in, for, 689
687, 688t regional lymphadenectomy for, 687-689
lentigo maligna, description of, 680 subungual, amputation for, 687
lymphatic drainage in, 688 superficial spreading (SSM), description of,
malignant, 139-140, 145-146 680
bacillus Calmette-Guerin 134 for. surgery for, 686-689
choroid and ciliary body, prognosis in, symptoms and signs of, 679
radiation for, methods of, 583 uncommon types of, 681
treatment of, 582-583 wide excision for, split-thickness skin grafts
disseminated, chemoimmunotherapy in, 687
for, 149 work-up prior to therapy in, 683

metastatic, high risk of occult Melphalan, for multiple myeloma, 856-857
micrometastases in, 145 prednisone and, for multiple myeloma, 858
of eyelid and conjunctiva, histology of, toxicity of, 62
579 types of cancer used in, 62-63
treatment of, 581 Meningioma(s), spinal, total removal of tumor
or iris, in, 580
mortality rate in, 752
of and ciliary body, treatment

iris of, Mental health consultant, pragmatic approach
581-582 to cancer by, 1036-1037
of vulva, 462-465 Mental health consultation, indications for, in
chemotherapy for, 464 cancer patient's children, 1042
Index 1103
6-Mercaptopurine(6-MP), 93-94 Metastasis(es) (Continued)

in combination with allopurinol, 33 in ovarian cancer, 493
mechanism of action of, 92 in pheochromocytoma, 626
sites of action for, 91, 92 in renal cell carcinoma, frequency of
uses for, 80t, 93 regression in, after palliative
with prednisone, for childhood nephrectomy, 403
histiocytoses, 957 in soft-tissue sarcomas, 669
Mesothelioma(s), in lung cancer, 200 in squamous cell carcinoma of burn scar
Metabolism, effects of corticosteroid therapy origin, 702
on, 104 in testicularcarcinoma, 409-411
Metaplasia, cervical, neoplastic in uterine sarcomas, 517-518
transformation and, 477 in Wilms' tumor, 768, 769t
Metastasis! es), cerebral, CAT scan in lymph node, determination of, in lung
evaluation for presence of, 740 cancer, 211
cervical, in hypopharyngeal cancer, 557 in breast cancer, postoperative radiation
in laryngeal and pharyngeal cancer, 549 for reducing, 175
in laryngeal cancer, 550 in cervical carcinoma, 482
in nasopharyngeal cancer, 537 tumor volume as prognosticator of, 483
chronic anemia and, 962 in endometrial carcinoma, 444^445
cutaneous, of melanoma, regression of, in melanoma, Clark's levels and, 688
D\CB and vaccinia virus administration in prostate cancer, stage C, 371
and, 140 in tongue cancer, 528
disseminated, asymptomatic primary and, pelvic, occult, in cervical carcinoma, 485
in renal cell carcinoma, chemotherapy endometrial carcinoma. 449-450
in
and immunotherapy for, 404 lytic bone, breast cancer and,
distant, 13-14 hypercalcemia from, 998
detection of, in bladder cancer, 379 ovarian, in endometrial carcinoma, 446
in prostate cancer, hormonal therapv for, presenting at time of diagnosis, effect on
365 survival, in renal cell carcinoma, 398, 399
infusion chemotherapy in patients with, pulmonary, excision of, in renal cell
intrahepatic catheters for, 14 carcinoma, 403
types amenable to complete surgical in melanoma, 689
excision, 13 in nonseminomatous testicular tumor,
frequency of regression of, after palliative 410
nephrectomy, in renal cell carcinoma, in Wilms' tumor, 773
403 treatment of, 774
hepatic, continuous intra-arterial infusion wedge resection of, for stage C
of 5-fluorouracil for, UCLA experience nonseminoma, 423
with, 331^334, 332t, 333t regional, lvmphadenectomy for treatment
in breast cancer, radiation doses for, 178 13
of,
in cancer of buccal mucosa, 527 retroperitoneal, in nonseminoma, radiation
in carcinoid tumors, 612, 613t therapy for, 419
surgery for, 616 in testicular carcinoma, 410
in carcinoma of extrahepatic bile ducts, 338 role of immune mechanism in preventing,
in cervical invasive carcinoma, 479 126
in colorectal cancer, continuous hepatic sites of, in cutaneous basal cell carcinoma,
artery infusion versus systemic 701
chemotherapy for, 331, 334 in influencing choice of therapy, 179
continuous intrahepatic artery infusion in pancreatic cancer, 309
for, of 5-fluorouracil, 329, 330t, 331 spinal, cervical brace for, 1012
diagnosis of, 325 types of, prognosis in, 753
in cutaneous basal cell carcinoma, 700 stage of, as consideration for cancer
in cutaneous squamous cell carcinoma, surgery, 17
701-702, 702t symptomatic, radiation therapy as local
in Ewing's sarcoma, 663 treatment for, 177-178
in glottic cancer, 553 time interval for, 15
in large bowel cancer, determination of, to abdomen, in gallbladder carcinoma, 335
290 to aortic lvmph nodes, in uterine sarcomas,
in lip cancer, 526 518
in lung cancer, 204 to brain, 730, 730t
in neonatal neuroblastoma, 760-761 chemotherapy for, 747
in neuroblastoma, liver biopsy for, 765 440
in gestational trophoblastic disease,
in oropharyngeal cancer, 529 in small cellcarcinoma of lung, 217-118
in osteosarcoma, 657 prognosis in, 737
pulmonary resection for, 659 radiation therapy for, 743-744
1104 Index
Metastasis(es) {Continued) Methotrexate ^Continued)

to cervical lymph nodes, removal of, 598 neurological toxicity of. 85
to cervix, and vagina in endometrial use of Elliot's B solution in, 85
carcinoma, 445 radiation therapy and, for head and neck
to fallopian tubes, from ovaries or cancer, 564
endometrium, 511 renal clearance of, 82
to groin regional lymph nodes, in vulvar side effects of, types of tumors benefited
malignant melanoma, 464 by, 84
to liver, angiography as diagnostic aid in, sites of action for, 81, 81
resection for, 327 toxicity of, kidneys and, 83
chemotherapy for, 329-334 transverse myelitis and, 1006
regional, 329 vincristine and, for osteosarcoma, 660
clinical features and diagnosis of, Metronidazole, use with radiation therapy, 26
325-327 Microadenoma, in pituitary tumors, 639
laboratory aids in, 326 Microflora, in bowel, alteration in, colon
natural history of, 325-327 cancer and, 266-267
radiation therapy for, 328-329, 329t Micrometastasis(es), occult, high risk of, in
surgery for, 327-328 metastatic malignant melanoma, 145
treatment of, 327-334 Microsurgery, for spinal cord tumors, 752
to paratracheal node, in subglottic cancer, Midfacial defects, large, prosthetic
556 rehabilitation for, 1033-1034, 1033
to parotid gland, from primary tumors in Mineral deficiency(ies), oral cavity cancer
other organs, 540 and, 523
varying growth rate and tumor doubling Mithracin. See Mithramycin.
time of, in renal cell carcinoma, 398 Mithramycin, alternate-day administration of,
vertebral, diagnosis of, isotope scans for, 73-74
751 for hypercalcemia and testicular tumors, 73
Methotrexate, 79-85 for moderate to severe hypercalcemia, 997
L-asparaginase and, schedule dependency toxicities of, 74
of, 44 Mitomycin-C, for stomach cancer, 258
blood-brain barrier and, 84-85 mechanisms of action of, drug dosages for,
chemical structure of, 80 Streptomyces caespitosus as origin for,
cytarabine and, 89 74
distribution and clearance of cytotoxicity myelosuppression and, 35
of, reversal by leucovorin, 81 toxicities of, uses for, 75
dosages for, 82 Mitosis(es), in parenchymal cells, in
effects of other drugs on, 33 diagnosis of parathyroid carcinoma, 590
experimental use of, 82-83 Mitotane, 108-109
5-fluorouracil and, schedule dependency Mitotic index, of leiomyosarcomas, 516
of, 44 of neural glioblastomas, 729
folic acid as competitive substrate, 79 MOCA chemotherapy, in small cell
for acute lymphoblastic leukemia, carcinoma, of lung, 224, 224t
complications from, 818 Model(s), tumor, in neuroblastoma, 767
for advanced bladder cancer, 390 Mohs' chemosurgery, definition of, 716
for blast crisis, in chronic myelogenous Molar pregnancy, evacuation of, 436
leukemia, 838 Mole, hydatidiform, amniography in, 435, 436
for central nervous system leukemia, 816 chemotherapy and surgery for, 438
439
for gestational trophoblastic disease, chest x-rays and HCG assays in, 436
for head and neck cancer, 559-560, 560t '
clinical features and diagnosis of, 435
in combination chemotherapy, role of invasive, identification of, spontaneous
schedule dependency in, 84 perforation of uterus in, 437
intrathecal, neurotoxicity and, 85 hydatidiform and, similarities of, 434
leucovorin and, for head and neck cancer, MOPP, as treatment of choice for Hodgkin's
564 disease, 891
leucovorin rescue and, 82, 82 complete remission with, restaging after
time and concentration thresholds and, achieving, in Hodgkin's disease, 892
83 Hodgkin's disease resistant to,
mechanism of action of, 79 chemotherapy for, 894, 895t, 896t
modification of treatment in renal Morbidity, related to cancer treatment, 6
dysfunction, 32 Mortality rate(s), perioperative, in lung
mucositis from, in head and neck cancer, cancer, 207
565 Motor weakness, from spinal cord tumors, 750
Index 1105
Mouth, and anterior tongue, cancer

floor of, Myelogenous leukemia (Cotitinued)
527-529
of. acute, clinical features of, 820-821
cancer of, diagnosis and treatment of, 528 consolidation and maintenance
prognosis in, 529 chemotherapy in, 825-826
snuff as etiologic factor in, 522 cytosine arabinoside for, 824
symptoms of, 527-528 diagnosis of, 821-823
\lu heavy chain disease, description of, 863 hematologic remission of, chemotherapv
Mucoepidermoid tumor(s), of salivary glands, for, 826
description of, 543 immunotherapy for, 827-828, 827t
Mucosa, buccal, cancer of, 526-527 increase in central nervous system
metastases in, 527 leukemia in, 826
presenting symptoms of, 526 intensive remission induction regimens
Mucositis, from methotrexate administration, for, experimental drugs for, 825
in head and neck cancer, 565 laboratory features in, 822t, 823
Multiple endocrine neoplasia, (Ml natural history of, 820-824
586-587 physical findings in, 821, 823
syndromes of, 586-587, 587t prognostic factors in, 823-824
Multiple endocrine neoplasia I, description prospects for future in, 829
of, 586 quality of life and cost in, 826-827
inheritance of, 587 symptoms of, leukemic infiltration of
Multiple endocrine neoplasia II, inheritance bone marrow in, 821
of, 587 treatment 824-828
of,
pheochromocytoma and, 620 cost for, 827
Multiple endocrine neoplasia Ha, description chronic, 832-841
of, 586 blast cells in, presence of terminal
Multiple endocrine neoplasia lib, description deoxynucleotidyltransferase in,
of, 587 cerebrovascular leukostasis in, 838
Multiple myeloma. See Myeloma, multiple. blast crisis in, chemotherapv for,
Murine leukemia cell(s), tumor 836-838, 837t
transplantation resistance in, role of description of, 834
neuraminidase in inducing, 138 chronic phase of, busulfan in, 834-835
Muscle invasion, in bladder cancer, 379 chemotherapy in, 834-836
Musculoskeletal system, effects of drugs for, 836
corticosteroid therapy on, 104 classification of, 833, 833t
involvement of, in Hodgkin's disease, 875 drug-induced bone marrow aplasia in,
neoplasms of, 655-677 836
Mustargen. See Mechlorethamine future prospects in, 841
Mutagenicity, of bleomycin, 73 incidence of, 832
of cytarabine, 90 leukapheresis for, immunotherapy for,
of procarbazine, 106 survival in, 840
of streptozotocin, 111 natural history of, 833-834
Mutamycin. See Mitomycin-C presenting symptoms in, diagnostic aids
Myasthenia gravis, in mediastinal thvmoma, in, juvenile, 833
780-781, 782 splenectomy for, 839-840
Mycosis fungoides, etiology and diagnosis of, splenomegaly in, splenectomy and,
description of, 941 radiation for, 839
prognosis in, 941-942 treatment of, 834-840
treatment of, 945 hypersplenism in, splenectomy for, 840
methods for, 942 Myelography, contrast, for diagnosis of spinal
Myelitis, transverse, methotrexate cord tumors, 751
administration and, 1006 for spinal tumors,752-753
Myelocvtic leukemia, chronic, busulfan for, Myeloma, multiple, 853-861
64 alkylating agents for, 856-857
Myelogenous leukemia, acute, 820-839 anti-idiotypic antibody for, 860
Auer bodies in, induction therapy in, 823 bacillus Calmette-Guerin for. remission
bone marrow transplantation in, 828 maintenance in, 859
chemoimmunotherapy for, 151 bone lesions in, management of, 860-861
chemotherapeutic remission induction in, chemotherapy for, 856-859
824-825 combination, 858
chemotherapy for, 824-827, 824t, 825t diagnosis of, 854-855, 854t
classification of, hematologic features of, drugs for, 857
820 general treatment plan for, 859, 859
1106 Index
Myeloma (Continued) Neck (Continued)

multiple, hypercalcemia and infections in, head and, cancer of, chemotherapy for.
management of, 860 558-565
natural history of, 854-855 adjuvant, 563
prognosis 855
in, combination, 561—562, 561t
renal failure, anemia, and hyperviscosity intravenous hyperalimentation prior
syndrome in, management of, 861 to, 559
special problems in, management of, regional, 562-563
860-861 types of drugs used in, 563
staging of, 855, 855t single-agent, 559-561, 561t
therapyof, new approaches to, 859-860 cisplatin for, 561
treatment of, 856-860 disseminated, 559
general approach to, aims of, 856 methotrexate and leucovorin or
Mvelonecrosis, hemorrhagic, management of, bleomycin and radiation therapy for,
1007 564
Myelosuppression, drug-induced, 34t methotrexate for, 559-560, 569t
in acute lymphoblastic leukemia, 818 mucositis in, from administration of
general guidelines for treatment of, 35 methotrexate, 565
grades of, 35, 35t radiation therapy and adjuvant
mitomycin-C and, 74 chemotherapy for, 563-564
6-thioguanine and, 93 unresectable tumors in, drug regimen
Myleran. See Busulfan. for, 562
Myoma(s), distinguishing from sarcoma, 516 epidermoid carcinomas of, adjuvant
Myometrium, involvement of, in endometrial chemotherapy for, 558
carcinoma, 444, 445 neoplasms of, 522-568
penetration of, in endometrial carcinoma, Neck dissection, anterior, 598
as guide to radiation therapy, 453 Necrosis, of adrenal cortex, from mitotane,
as prognostic indicator, 450 108
methods of determining, 456 Needle aspiration, in renal cell carcinoma,
395
percutaneous, in prostate cancer, 359
in renal cell carcinoma, 396
Needle biopsy, advantages of, 10
Neo-Hombreol. See Testosterone propionate.
N Neoplasia(s), cervical intraepithelial,
Nafoxidine, characteristics of, dosages for, definition and description of, 478
100 development of, importance of immune
toxicities of, 100-101 response in controlling, 129-130
Nasal cavity, cancer of, 531-535 epithelial, separation of benign and
incidence of, 531 malignant, in ovarian cancer, 496
olfactory neuroepithelial tumors in, 532 multiple endocrine, 586-587
Nasal cavity' and paranasal sinus cancer, Neoplasm(s), adrenal cortical, 627-632
classification and pathology of, 531-532 classification of, 628
clinical features of, 532-533 clinical features and diagnosis of,
diagnosis of, 533 628-629
natural history of, 531—533 hormone production in, 628, 629t
treatment of, 533-535 incidence of, 627
Nasopharynx, cancer of, 535-538 metastases in, 628, 628t
age and sex incidence in, 536 natural history of, 628-631
cervical metastases in, 537 prognosis in, 630t, 631
classification and pathology of, 536, 536t staging of, 629, 630t
clinical features and diagnosis of, natural surgery 631
for,
history- of, 536-537 symptoms 629
of,
prognosis in, 538 therapy for, 632
race predilection in, 535 treatment for, 631-632
symptoms of, 537 associated with high blood levels of
treatment of, 537-538 antidiuretic hormone, 1000
sequelae of, 538 B lvmphocvte, capable of immunoglobulin
Neck, cancer of, levamisole for, 148 synthesis, 853-866
head and, cancer of, BACON and carcinoembrvonic antigen in, discovery of,
COBMAM for, 562 127
bleomycin for, 560 common patterns of spread in, importance
chemotherapy- and surgery for, 564—565 in successful cancer surgery 10 ,
Index 1107
Neoplasr Nephrotomography, in diagnosing renal cvsts,

epidermal, multiple, immunotherapy tor, 395
729 Nerve\s), cranial, involvement of, in
selective sensitivity to specific agents of, nasopharyngeal cancer, 537
_
72i- :_ peripheral, pain in, therapy for, 1016
genitourinary. 358-4 Nerve block(s), for cancer pain, 1010
granulosa cell, ovarian, description and Nerve growth factor, in ganglioneuromas.
treatment of. 510 763
gynecologic, 434-58 Nerve plexus, pain in, therapy for, 1016
human, specific, tumor-associated antigens Nervous svstem, effects of cancer on, 1004,
in. 12S. 129 1005t
individually specific antigens in, 129 lymphomatous involvement of, 942-943
malignant increased incidence of. in neoplasms of. 726-759
patients on immunosuppressive incidence of, 726
therapy. 130 Neural crest, cells derived from, 762
of bile ducts, types Neural pathway* s>, to interrupt pain, route
of brain, 726-747 analysis to establish, 1010
of eye, 569- 5 Neuraminidase, role in inducing tumor
of gastrointestinal tract 231- transplantation resistance, in murine
earlier diagnosis and adjuvant therapy in, leukemia cells, 138
_ : Neurectomy, peripheral, indications for, 1014
incidence and mortality rates in, 231. Neurilemoma, posterior mediastinal.
: _ 789-790
surgeiy for, 131-132 spinal, total removal of tumor in, 752
of head and neck. 522^568 Neuroblastoma* si. 759-767
of musculoskeletal system, 655-677 chemotherapy for. radiation to liver in, 766
of nervous sytem. 726-759 clinical staging of, 764. 764t
incidence of, 726 cyclic nucleotides in, immunology for,
of small bowel. 263. 263t tumor models in. 767
overproduction of uric acid precursors in, diagnosis of. 761-762
intravenous pyelogram for. diagnostic
second, delayed, in Hodgkin's disease, signs in, 761
8 hymoses in, 760, 76i
in Hodgkin's disease, correlation with elevated levels of urinary cystathionine in,
^~~
aggressive treatment bone marrow aspiration in, infiltration of
solid, differences in DNCB reactivity of lymphocytes by, 762
different types of, 131 grading of. 763. 76'3t
specific, immunotherapy for, clinical histopathologic variation in, pathology of,
evaluation of. 139 762-763
spontaneous, in ataxia-telangiectasia and immediate surgical removal of, prognostic
Wiskott-Aldrich syndrome. 129-130 significance of age in, 764
olastic transformation, fetal antigens and, in situ discovery of, 763
126 incidence of, 759
Nephrectomy, adjunctive, in renal cell maturation-inducing agents and, 766-767
carcinoma, 402—404 natural history of. 760-764
palliative, factors influencing decision for. neonatal, clinical features of. 760-761
in renal cell carcinoma. 402 paraspinal. description of, 761
frequency of regression of metastases presenting symptoms of, 760
following, in renal cell carcinoma primary, sites of, 760, 760t
impact on survival, in renal cell radiation therapy for. 765-766
carcinoma, 403. 4Q3 indications for, preoperative. 765
percutaneous transaortic occlusion prior to, spontaneous regression in. 125, 760
in renal cell carcinoma, 400-401 surgery for. 764-765
radical, for primary renal cell carcinoma, treatment of. 764-766
399 Neurodestructiv e procedure^), permanent
techniques of, 400 deficits from. 1013
transabdominal, for Wilms turn ~~ Neurofibroma(s), posterior mediastinal,
1 :
Nephroblastoma. See Wilms' tumor. 788-789

Nephromas >. congenital mesoblastic, radiographic appearance of, 789, 789
description of, 76S-769 Neuromuscular syndrome(s), 1004-1007
Nephropathyues), uric acid, 999-1000 diagnosis of. 1004-1005
diagnosis and differential diagnosis of, differential, 1005-1006
etiology of, 1004
treatment of, 1000 treatment of, 1007
1108 Index
Neuropathy(ies), peripheral, types of, caused Node(s) {Continued)

by cancer, 1004 lymph, normal, anatomic and functional
Neurosarcoma(s), posterior mediastinal, 790 compartments of immune system in,
Neurotoxicity(ies), from procarbazine 912, 9J3
administration, 106 pelvic and periaortic, evaluation of, in
intrathecal methotrexate and, 85 invasive carcinoma of vagina, 476
Neutron therapy, for malignant gliomas, 755 pelvic, dissection of, in prostate cancer,
Neutropenia, fever and. approach to patients 369, 372
with, 979 involvement of, in vulvar squamous
patient response to granulocyte cellcarcinoma, 459, 460t
transfusions in, 978 metastatic, in endometrial carcinoma,
leukocyte transfusion strategy for patient 449-450
with, 976 problems in, related to Hodgkin's
lung as site of infection and, 964 disease, lymphangiography for
management of, 971 detecting, 872-873
protective measures against, 967 regional, in groin, metastases to, in
Nitrogen, liquid, for cryosurgery in cutaneous vulvar malignant melanoma, 464
basal and squamous cell carcinomas, involvement of, in renal cell
712 carcinoma, 400
use prior to excision in metastatic
of, status of, in melanoma, prognosis and,
melanoma of eyeball, 582 686
Nitrogen mustard. See also Mechlorethamine removal of. and complete removal of vulva
derivatives of, tumor cell resistance to, for invasive squamous cell carcinoma,
history of, 56 460
Nitrosourea(s), 65-67 retroperitoneal, dissection of, in
availability of, 65 nonseminoma, 418
blood-brain barrier and distribution and in testicular carcinoma, 410, 410
excretion of, 66 supraclavicular and internal mammary,
characteristics of, uses for, 67 metastases of, 174
chemical structures of, 66 mesenteric, involvement of, in
for treatment of brain tumors, 744 "Mediterranean" intestinal lymphomas,
myelosuppression and, 35 941
plus radiation therapy, for brain tumors, para-aortic, involvement of, in
745 non-Hodgkin's lymphomas, 921
toxicities of, 66-67 paratracheal, metastases to, in subglottic
Node(s), abnormal, biopsy of, in ovarian cancer, 556
cancer, 497 Nolvadex. See Tamoxifen.
lymph, aortic, metastases to, in uterine Nominal single dose concept, 25
sarcoma, 518 Nomograph, for calculating body surface area
axillary, involvement of, in breast cancer, of adult, 1046-1047
171 Non-Burkitt's lymphoma, childhood,
internal mammary and, removal of, in abdominal disease in, 938
early breast cancer, 170 prognosis of, 937
biopsy of, importance of primary tumor Non-Hodgkin's lymphoma(s). 905-951
site identification in, 10 angioimmunoblastic lymphadenopathy in,
cervical, removal of, in metastatic 914
disease, 598 bone marrow aspirate and biopsy in, 920
dissection of, in nonseminoma, 417^418 chemotherapy for, 926-934
excision of, in carcinoma in situ, 383 combination, 927-934, 929t-931t, 935t
in immunologic investigations of stomach morbidity of, second-line, 934
cancer, 260 single-agent, 926-927
in staging renal cell carcinoma, 396 sequential, 927, 928t
involvement of, in Hodgkin's disease, useful single agents in, 926
870 childhood, 934-940
in melanoma, 687, 688t description of, male predominance in,
in metastatic testicular carcinoma, 409 937
in prostate cancer, 362, 363, 368 treatment of,945
metastases to, in cervical carcinoma, 482 classification and histology of, 908-915
tumor volume as prognosticator of, classification systems in, new, immunologic
483 aspects of, 911-914
in melanoma, Clark's levels and, 688 traditional, 908
in prostate cancer, 371 using immunologic markers and function,
in tongue cancer, 528 911
Index 1109
Non-Hodukin's lymphoma(s) (Continued) Nonlymphocytic leukemia, acute, in

clinical features and diagnosis of, 915-917 Hodgkin's disease, 876
clinical presentation of, comparison witii Nonseminoma(s), advanced, combination
Hodgkin's disease, 916-917 chemotherapy and surgery followed by
CVP for, 927 cyclic chemotherapy for, 420
definition of, 905 toxicity associated with cisplatin in. 424
diagnostic aids in, 917, 919 treatments for, correlation between
disseminated disease in, para-aortic node recurrence and stage in, 425
involvement in, extranodal dissemination choriocarcinoma in, chemotherapy for, 419
in, 921 dactinomycin for, 418, 419
dissemination at diagnosis in, 917 retroperitoneal disease in, chemotherapy
etiology of, genetic factors in, 906-907 for, 421, 42 It, 422t
extradural, compression of spinal cord by, staging procedures for, 421

943 thoracotomv following lvmphadenectomv
favorable histologic types of, 911 in, 423
geographic incidence of, 908 treatment of, 417-426
histologic factorsand classes in, 914-915 with extensive retroperitoneal metastases,
immunodeficiency and immunostimulation radiation therapy for, 419
in, drugs and radiation as etiologic with nodal involvement, prophylactic
factors in, 907 chemotherapy for, 418-419
immunotherapy for, delayed therapv in, Nose, prosthesis for, 1032
936 Nucleoside analogue(s), 88-91
incidence and epidemiology of, 907-908 Nucleotide(s), cyclic, in neuroblastoma, 767
intravenous urogram for diagnosing, Nurse(s), role in cancer rehabilitation, 1023
918-919 Nursing procedure(s), postoperative, in care
Lukes-Collins classification svstem in, 911, of stoma, 1025
912t Nutrition, in surgical management of cancer
natural history- of, 908-922 patients, 16
occult, lymphograni for diagnosing, 918 NVYTS-1 and 2, research in Wilms' tumor by,
patient characteristics correlated with 776
histology in, 915-916, 916t
percutaneous liver biopsy in, 920, 922
presentation of disease in, 915
radiation plus chemotherapy for, 934, 936 O
radiation therapv for, 922-926 Obesity, in endometrial carcinoma. 447
924-925
efficacy of, Obstruction, by large bowel carcinoma,
indications for, 922 surgery for, 287-290
morbidity of, 925-926 intestinal, in colorectal cancer, svmptoms
results of, significance of pathologic of, 288
subtype in, 923 in ovarian cancer, 507
sites of relapse in, 923-925 ureteral, in seminoma, 411
technique in, 925 Obturation, definitive, for maxillarv defects,
radiologic dose-time relationship in, 923, 1028-1029, 1029
924 surgical, for maxillary defects, 1028, 1028
Rappaport classification system in, 908, Obturator, soft palate, 1030
909t, 910t, 911 Occlusion, percutaneous transaortic, prior to
recommended staging procedures for, nephrectomy, in renal cell carcinoma,
92 It, 922 400-401
recommended therapy for, 944-945, 946t Occupation(s), types of, implicated in bladder
risk ofmorbidity in, from combined cancer, 374
treatment modalities, 944 Oligodendroglioma(s), brain, radiation
special problems in, 937-943 therapy for, 742
staging and diagnostic studies in, Omentum, role of, in lymphatic drainage of
917-922 peritoneal cavity, 493
staging laparotomy in, 920-921 Oncofetal antigen(s), 126, 127, 129
staging procedures in, 943 Oncology, radiation, eradication of cancer as
surgery for, 922 objective of, 19
survival rates in, 924 principles of, 19-27
treatment of, 922-936 radioresistarice in, 22
viruses as etiologic factors in, 906 Oncovin. See Vincristine.
visceral dissemination of, autopsy studies Oophorectomy, adrenalectomy following,
and, 917, 918t versus ovarian radiation, bilateral, 181
1110 Index
Operation(s), as staging procedure, for Oropharynx (Continued)

endometrial carcinoma, 449 cancer of, description of, 529
Babcock, for renal cancer, 284, 284, 285 diagnosis of, 523, 525
Bacon, for renal cancer, 284, 285, 286 incidence and etiology of, 522-523
curative, for pancreatic cancer, 313-315, metastases in, 529
314 natural history of, 523-525
exploratory, for ovarian cancer, 507 otalgia in, radiation therapy and surgery
extent of, in thyroid cancer, 597 for, 530
for cervical carcinoma, advantages of over staging of, 524t, 525
radiation therapy, 486 Ortho-Novum, to prevent uterine bleeding, 102
for diagnosis of salivary gland tumor, 541 Osmolality determination(s), plasma and
for supraglottic cancer, preventing urine, to diagnose syndrome of
aspiration following, 556 inappropriate antidiuretic hormone
Kraske, for cancer of rectum, 282, 283 secretion, 1001
modification of technique in, for prosthetic Osteomalacia, oncogenic, hypocalcemia
reconstruction, 1034 from, 998
palliative, for pancreatic cancer, 315 Osteosarcoma(s), 655-662
prior to radiation therapy, in endometrial chemotherapy for, 659-660, 66 It
carcinoma, 453 classification and pathology of, types of,
second look, for assessing effectiveness of 656-657
adjuvant 5-fluorouracil therapy, in clinical features and diagnosis of, 657-658
colorectal cancer, 292 diagnosis of, biopsy for, staging and
in diagnosing recurrent colorectal cancer, prognosis in, 658
291-293 etiology of, radiatiQn as cause of, 656
in ovarian cancer, 514-515 immunotherapy and chemotherapy for, 147
sphincter-saving, in rectal cancer, 282-287 immunotherapy for, 660
Turnbull-Cutait, for renal cancer, 286, 287 incidence of, 655
Ophthalmoscopy, indirect, to diagnose ocular limb salvage in, 660, 662
malignant melanoma, 578 metastases in, 657
Oral and nasal cavity(ies), re-establishment of pulmonary resection for, 659
physical separation between, by prosthetic natural history of, 656-658
restoration, 1027 radiation therapy for, transmedullary
Oral cavity, cancer 522-530
of, amputation for, 659
and mineral
classification of, vitamin surgeryfor, 658-659
deficiencies and, 523 symptoms of, parosteal and periosteal, 657
clinical features and treatment of, treatment of, 658-662
525-529 Otalgia, in oropharyngeal cancer, 530
diagnosis of, 523 Ovary(ies), cancer of, 492-515
biopsy and x-rays for, 525 active immunotherapy in, 506, 507t
incidence and etiology of, 522-523 advanced, chemotherapy as adjunct to
leukoplakia and, 522 surgery and radiation therapy in, 503
natural history of, 523-525 bacillus Calmette-Guerin in, 506
staging in, 524t, 525 biology of, 492-493
Orbit(s), invasion of, by sinus tumor, 533 biopsy of abnormal nodes in,
prosthesis for, 1032-1033 lymphangiography in, symptoms of,
Orchiectomy, for prostate cancer, 364 497
radical, radiation therapy following, for chemotherapy for, 503-504, 514
seminoma, 415 combination, 504
versus oral estrogen, in treatment of classification and pathology of, 493, 496
prostate cancer, 365 clinical features and diagnosis of,
Orchiopexy, in preventing malignant 496-497
development, 407 complete resection of tumor in,
Organ(s), dysfunction of, related to Hodgkin's correlation with prognosis, 499--500
disease, 872 control of, 512
Organ compression, complications caused by, passive immunization as method of, 506
984-994 diagnosis of, tumor markers in, 513
Organization(s), abbreviations for, 1049- epidemiology and etiology of, 492
1050 exploratory operation for, radiation and
Organomegaly, together with fever and chemotherapy for, 507
weight loss, as symptoms of malignant extension of disease in,493
histiocytosis, 953 histologic classification of, 493, 495t-496t
Oropharynx, cancer of, 522^530 immature teratomas of, treatment of, 508
classification of, 523 increased risk of developing leukemia in,
clinical features and treatment of, presence of human chorionic
529-530 gonadotropin in, 514
Index 1111
Ovary(ies) (Continued) Pain (Continued)

canter of, integration of research and in nerve plexus and peripheral nerve,
control in, 514-515 therapy for, 1016
integration of treatment modalities in, in sensory root, therapy for, 1016-1017
506-507 spinal cord, cordotomy for, 1017-1018
laparotomy in, 498 spinothalamic tract section for, 1017
metastases to fallopian tubes from, state of, anatomic evaluation of, 1010
nonspecific stromal tumors of, 511 trunk and extremity, regional therapv for,
mistakes in initial staging of, 499 1016-1018
natural history of, 493-500 Pain syndrome(s), in malignant disease,
presence of Regan isoenzyme in, 1009-1021, 1009t
513-514 Pain therapy, analgesic drugs for,
prognosis in, 498-500 chemotherapy for, 1012
radiation therapy for, side effects of, hormone control and systemic, 1012-1013
techniques 502
of, local, 1010-1012
separation of benign and malignant modes of, classification of, 1010, 101 It
epithelial neoplasia, 496 psychotherapy in, 1013
specificity of tumor-associated antigens regional, 1013-1019
for histologic type in, 504 Palate, hard, cancer of, description of,
staging of, 497-498, 498t treatment for, 527
subdivisions of stages of, 499 Palliation, at time of surgery, in pancreatic
treatment for, 500-515 cancer, goals of, 315
types of drugs used in, 503-504 radiation therapy for, 1010
dysgerminoma of, combination in breast cancer, 177
chemotherapy for, unilateral surgical resection for, 1011
salpingo-oophorectomy for, 509 Palpation, abdominal, effects of, in
radiation therapy for, 508-509 pheochromocytoma, 623
endodermal sinus tumors of, hysterectomy Pancreas, adenocarcinoma of, chemotherapy
for, alpha-fetoprotein and, 509 for, combination, 317t, 318
epithelial cancer of, elevation of urinary single-agent, 315, 316t
estrogens or pregnanediol in, 510 description of, 308
biopsy of lymph nodes in, 501 cancer of, 308-319
grading of, 499, 500t angiography in diagnosis of, 312
immunotherapy for, 504-505 chemotherapy for, 316-318, 607-608
epithelial tumors of, hysterectomy with clinical features of, 309-310
bilateral salpingo-oophorectomy, CT scan in diagnosis of, 311
500 curative operations for, 313-315, 314
radiation therapy for, 501-503 diabetes mellitus and, physical findings
surgery for, 500-501 in, 310
treatment for, 500-507 diagnosis in, 310-312
estrogen-producing tumors of, clinical endoscopy and angiography in,
manifestations of, 51 It 310-311
granulosa cell neoplasms of, description ultrasound and CT scan in, 311
and treatment of, 510 distribution of, 308, 309t
etiology and epidemiology of, 308
external beam radiation and interstitial
implants for, laparotomy in,315
histology of, metastases in, 309
immunology and integration of treatment
Paget's disease, of bone, hypercalcemia and, modalities in, 318
of vulva, chemotherapy and radiation performance status in,313
therapy for, 466 radiation therapy for, 315-316
natural history of, 465 staging of, 312-313
treatment of, 465-466 surgery for, 313-315
Pain, conduction of, interference with, 1013 treatment for, 313-318
facial and head, regional therapy for, 1014 Whipple procedure for, 313, 314
from cancer, acupuncture for, endorphins stadenocarcinoma of, 318-319
c>
and, 1019 diarrheogenic tumors of, description of, 606
treatments for, 1018 endocrine, cancer of, 603-609
in brain stem, tractotomy for, 1018 chemotherapy for, 607-608
in hypopharyngeal and supraglottic cancer, incidence of, 603
1112 Index
Pancreas (Continued) Pelvic exenteration, bowel complications

endocrine, cancer of, radiation therapy for, following, 491
607 for cervical carcinoma, 490-491
treatmentfor, 607-609 description of, 490
glucagonomas of, 603-604 pre- and postoperative support in, 491
chemotherapy for, 607 Stage IV, 489
description of, 603-604 Peptic ulcer(s), corticosteroid therapy and,
diagnosis of, necrolytic migratory 105
erythema in, 604 Perforation,by large bowel carcinoma,
incidence of, 603 surgery 287-290
for,
insulinomas of, 604-605 Performance status, in pancreatic cancer,
incidence of, presenting symptoms of, 313
diagnosis of, 604 Pericardium, involvement of, in Hodgkin's
laboratory tests for, 605, 605t disease, 875
needle biopsy of, 311-312 Perineum, avoidance of, in radiotherapy of
Pancreatectomy, total, for radical pancreatic anal cancer, 306
excision of carcinoma, 313 Peripheral nerve(s), pain in, therapy for, 1016
Pancreaticoduodenectomy, trials of, 313 Peritoneal cavity, lymphatic drainage of, role
Papanicolaou (Pap) smear, for detecting of omentum in, 493
cervical cancer, 491 Peritoneoscopy, in diagnosing liver
for detecting CIN, 480 metastases, 327
increased use of, 476 Pharynx, cancer of, pathology of, 549
Papillary cystadenoma lymphomatosum, of symptoms of, 549-550
salivary glands, description and treatment larynx and, irradiated, residual cancer in,
of, 542 547-551
Paraganglioma, posterior mediastinal, 791 Phenesterin, estrogen therapy and, 99
relationship to pheochromocytoma, 621 Pheochromocytoma(s), 620-627
Paraganglion, description of, 621 anesthetic management in, 626
Paralysis, facial, in salivary gland tumors, 540 classification of, 621-622
Parameter(s), cytokinetic, correlation with clinical features of, 622-624, 623t
prognosis, in acute myelogenous leukemia, coextant with thyroid medullary carcinoma,
823 removal of, 599
Paraneoplastic syndrome(s), 994-1008 determination of vanillylmandelic acid in,
ectopic substances in, 994 624
Parathyroid carcinoma, 588-591 effects of abdominal palpation in, physical
clinical features and diagnosis of, 588-589 examination in, 623
clinical features of, histologic criteria in, incidence and etiology of, 620, 62 It
588,589t laboratory diagnosis in, 624-625, 624t, 625t
comparison with adenomas, 589 malignant, medical management of, 627
histopathology of, 589t, 590 metastases in, 626
incidence of, 588 multiple endocrine neoplasia II and, 620
local recurrence after surgery in, 591 natural history of, 621-625
natural history of,588-590 posterior mediastinal, 791
operative findings in, 589-590 prognosis and staging in, 625
prognosis in, 590 surgery for, 625-626
recurrent, 589 alpha blockers in, 626
treatment of, 590-591 symptoms of, thyroid tumors and
Parotid gland, as metastatic site of primary hyperparathyroidism and, 622
tumors in other organs, 540 treatment of, 625-627
tumors of, 540 Philadelphia chromosome, in chronic
Parotidectomy, to remove malignant lymph myelogenous leukemia, 832
nodes, 13 Phosphorus, radioactive, for chronic
Pathogen(s), tissue examinations for, 967-968 myelogenous leukemia, 839
Pathway(s), autonomic, in blocking cancer for diagnosing ocular malignant
pain, 1018 melanoma, 579
degradative and activating, of for ovarian carcinoma, 502
5-fluorouracil, clinical relevance of, 86 Photocoagulation, for choroid melanoma, 583
neural, to interrupt pain, route analysis to for retinoblastoma, 576
establish, 1010 Physiatrist(s), as director for cancer re-
Patient(s), cancer, psychologic problems habilitation. 1022
associated with enterostomal therapy in, Physical rehabilitation, cancer and,
1024-1025 1021-1035
enterostomal, rehabilitation of, 1023-1027 specific goal-oriented variations in, 1021
Pedal lymphangiography, in staging bladder Physical therapist(s), role in cancer
cancer, 378 rehabilitation, 1022-1023
Index 1113
Pineal gland tumor(s), radiation therapv for, Platelet transfusion(s) (Continued)

743 improved availability' of, 973
Pituitary ablation, 648 in bone marrow failure, 973-975
Pituitary adenoma(s), as cause of Cushing's prophylactic and single-donor, 975
syndrome, 646-647 Platinum complex(es), 112-114
interstitial implantation for, surgery for, 648 Pleura, lungs and, involvement of, in
radiation therapy for, 644-648 Hodgkin's disease, 874
advantages of, controversy over, 645 Pleural effusion, bleomycin for, pleurectomy
disadvantages of, 647 for, 989
Pituitary gland, arterial supply of, 634 control of, 984
description of, 633 diagnosis of, natural history of, 985-986
Pituitary gland hormone(s), secretion of, 633 intrapleural sclerosing agents for, 987-989
Pituitary thyrotropin secretion, suppression malignant, associated with breast cancer,
of, by thyroid hormone, 602 mechlorethamine and triethylenethio-
Pituitary tumor(s), 633-653 phosphoramide for, 988
acromegaly in, 642, 642 definitive diagnosis of, 986
radiation therapy for, 646 mechlorethamine for, 987-988
biology of, 633-634 side effects of, 987
classification and pathology of, 634-635 qufnacrine hydrochloride for, tetracycline
classification of, techniques
634 of, for, 988
clinical findings and diagnosis of, 635-637 symptoms of, secondary' to direct
cryohypophysectomy for, 641-643 implantation of tumor, 985
advantages of, 643 systemic chemotherapy for, thoracentesis
anesthesia in, 642 for, recurrence in, 986
history of, 641 talcand thoracotomy for, 988-989
problems in, 642-643 thoracentesis for, 986-987
CT scan for, 637 thoracostomy for, 987
elevated secretion of growth hormone and, treatment of, principles of, 986-989
635 Pleural space, free, thoracentesis or
endocrine studies in, 637 thoracotomy with pleurectomy to
epidemiology and etiology of, 633 obliterate, 984
natural history of, 634-637 normal, description of, 985
postoperative hormone management in, 644 Pleurectomy, for pleural effusion, 989
radiologic findings in, 636-637 Pleuritis. secondary to malignant occlusion
surgery for, 638-644 of bronchi, pleural effusion and, 985
symptoms of, 636 Plummer-Vinson syndrome, esophageal
transfrontal transsphenoidal surgerv for, carcinoma and, 233
640-641 Pneumonectomy, versus lobectomy, in lung
description of, 640 cancer, 213
indications for, 641 Pneumonia, aspiration, in esophageal cancer,
traiisnas.il transsphenoidal surgery for, 237
638-640, 638 in granulocytopenic patients, prophylactic
contraindications to, 640 therapy for, 968-969
description of, 639 Pneumonitis, radiation, in Hodgkin's disease,
treatment for, 637-649 888
Plasma clearance time, in doxorubicin Poliomyelitis, cancer and, 1004-1005
therapy, 69 Polymyositis, malignant, glucocorticoids in
Plasma osmolality determination(s), to treatment of, 1007
diagnose syndrome of inappropriate adenomatous,
Polyp(s), hyperplastic versus in
antidiuretic hormone secretion, 1001 development of colon cancer, 268
Platelet(s), for transfusions, source of, Polypectomy, in colon cancer, 268
974-975 Population(s), tumor cell, change in, from
survival of, antibodies of HLA antigens radiation therapy, in bladder cancer, 386
and, 974 urban versus rural, bladder cancer in, 374
unit of, definition of, 974 Potassium replacement, for ectopic
Platelet count(s), fall in, mechlorethamine adrenocorticotropic hormone svndrome,
administration and, 58 1003
in acute lymphoblastic leukemia, 810-811 Precursor(s), uric acid, neoplastic
in diagnosis of chronic myelogenous overproduction of, 999
leukemia, 833 Prednimustine, for prostate cancer, 368
Platelet production, decreased, in acute Prednisone, duration of action of, 104
myelogenous leukemia, 821 for multiple myeloma, 857
Platelet transfusion(s), 964 for remission induction in acute
contamination with red blood cells, 974 lymphoblastic leukemia, 812, 812t
1114 Index
Prednisone (Continued) Prostate cancer (Continued)

melphalan and, for multiple myeloma, 858 incidence and etiology of, 358
vincristine and, for blast crisis, in chronic lymphangiography in, 362
myelogenous leukemia, 836 natural history of, 359-363
Pregnancy, depression of cell-mediated and prednimustine for, 368
humoral immune responsiveness in, 441 stage A, description of, 361-362
effect on breast cancer, 190 importance of determining tumor
effect on chronic myelogenous leukemia, involvement and differentiation in,
835 needle biopsy in, 368
Hodgkin's disease during, 899-900 treatment of, 368-369
clinical stage and subtype of, influence stage A 2 pelvic lymph node dissection
,
on treatment for, 900 in. 369

molar, evacuation of, 436 stage B, hormone therapy for, 370-371
problems in, from radiation, in Hodgkin's radiation therapy for, 370
disease,889 radical prostatectomy for, 369, 370t
test for, comparison of sensitivity of, 436, treatmentof, 369-371
437 inaged patient, 369
Pregnanediol, elevation of, in epithelial stage B 2 lymphadenectomy
, in,
ovarian cancer, 510 complications of, 370
Preleukemia, 828 stage C, hormone therapy for, 371, 373
Pressure, intracranial, osmotic diuretics for, improving staging of, 371-372
738 lymph node metastases in, radical
Procarbazine, 105-107 prostatectomy in, 371
absorption and excretion of, dosages for, radiation therapy in, pelvic node
106 dissection in, implantation of
chemical structure of, 106 iodine-125 in, 372
clinical features of, 107, 107t treatment of, 371-373
for glioblastomas, 745 stage D, description of, 362-363
multiple myeloma, 878
for stages B and C, description of, 362
mechanism of action of, 105 stages D, and D 2, treatment for, 373
Prochlorperazine, mechlorethamine staging and prognosis of, 360-363
administration and, 58 staging systems for, 360-363, 361t
Proctosigmoidoscopy, in diagnosis of surgery and radiation therapy for, 363
colorectal cancer, 271 treatment 363-374
of,
Progestational agent(s), 101-102 by 368^373
stage,
Progesterone(s), in treating renal cell types of drugs used for, chemotherapy plus
carcinoma, 405 hormone therapy in, 367
Progesterone receptor(s), in breast cancer, Prostate tumor(s), inhibition of, methods of,
164 364
Progestin(s), lack of toxic side effects of, 101 occult, treatment approach to, 369
uses for, 102 stage B 2 involvement of lymph nodes in,
,
Prognosis, assessment of, 5 362

Prolactinoma, 635 Prostatectomy, radical, for prostate cancer,
Prophylaxis, central nervous system, in acute 369, 370t, 371
lymphoblastic leukemia, 813-814 Prostatic hypertrophy, benign, stage A
Prostate cancer, 358-373 prostate tumors and, 359
adrenalectomy and hypophysectomy in, Prostatocystectomy, in bladder cancer, 381
366 method 387
of,
antiandrogens and inhibitors of androgen Prosthesis(es), ear and nasal, 1032
synthesis in treatment of, 366-367 for nasal cavity and paranasal sinus
chemotherapy for, 367-368 cancer, 535
clinical features and diagnosis of, 359-360 orbital, 1032-1033
diagnosis of, needle biopsy and polyurethane, for large midfacial defects,
percutaneous needle aspiration for, 359 1033
radioimmunoassay for, 360 Prosthetic restoration(s), re-establishment of
serum assays for, 359-360 physical separation between oral and nasal
endocrine manipulation in, 363-367 cavities by, 1027
advantages and disadvantages of, 365 Pseudomonas, infection by, 964-965
estrogen therapy for, 96, 99 life-threatening, granulocytopenic
histologic grade and prognosis in, patients, carbenicillin for, 969
correlation of, 360 Psychiatric consultation, indications for, 1038
hormone therapy in, effect on survival of, Psychosocial problem(s), of cancer,
364 1036-1045
Index 1115
Psychosocial problem(s) (Continued) Radiation (Continued)

of cancer patient, 1037-1039 to liver, in stage IV-S neuroblastoma, 766
of cancer patient's children, 1041-1045 to renal fossa, in Wilms' tumor, 773
of cancer patient's family, 1039 total dose of, proportionality to eradication
of cancer patient's spouse, 1039-1041 of tumor, in Hodgkin's disease, 886

of medical and nursing staff, 1043-1045 whole body, with radioiodine, in thyroid
Psychotherapy, for pain, 1013 cancer, 600
Pulmonary dysfunction, caused by Radiation dose(s), interval between, 26
bleomycin, 72 repeated specific, number and type of cells
Pulmonary metastasis(es), excision of, in killed by, 22
renal cell carcinoma, 403 Radiation edema, risk of, in treatment of
in nonseminomatous testicular tumors, 410 superior vena caval syndrome, 992
Pulmonary resection, bacillus Radiation oncology, eradication of cancer as
Calmette-Guerin following, 223 objective of, 19
contraindications to, 211 principles of, 19-27
for isolated metastatic colon cancer, radioresistance in, 22
293-294 Radiation pneumonitis, in Hodgkin's disease,
in metastatic osteosarcoma, 659
radiation therapy following, 217 Radiation port(s), standard, per cent of
Pulmonary bleomycin and, 37
toxicity(ies), normal bone marrow irradiated using, 1048
Purine analogue(s), 91-95 Radiation therapy, adjuvant, for inadequate
chemical structure of, 91, 92 surgical procedure, 11
Purine nucleotide(s), synthesis of, inhibition adjuvant chemotherapy and, for head and
by methotrexate, 79 neck cancer, 563-564
Pyelography, intravenous, for diagnosing advantages and disadvantages of, 19-20
bladder cancer, 377 applicability of, location and extent of
for diagnosing neuroblastoma, 761, 762 tumor in determining, 22
for diagnosing Wilms' tumor, 770, 770 as adjunct to radical surgery, 174-175
for staging testicular carcinoma, 412 as adjunct to surgery, in gallbladder
Pyriform sinus(es), cancer of, prognosis in, carcinoma, 336
557 as cause of brain tumors, 728
Pyrimidine(s), fluorinated, chemical as cause of osteosarcoma, 656
structures of, 85, 86 as cause of thyroid cancer, 591-592
as etiologic factor in non-Hodgkin's
lymphomas, 907
as local treatment for symptomatic
metastases, 177-178
as palliative therapy, in lung cancer, 218
Quality of patient life, importance of, 5 as primary therapy, for lung cancer, 214
Quinacrine hydrochloride, for pleural biologic basis for, 21-23
effusion, 988 bone marrow depression from, 963
change in tumor cell population caused by,
in bladder cancer, 386
chemotherapy and, bone marrow
R depression from, in Wilms' tumor, 775
Rad, measurement of, 20 chemotherapy as adjunct to, in advanced
Radiation, damage to cells by, 22 ovarian cancer, 503
electron beam, in mycosis fungoides, 942 clinical basis for, 23-25
external beam, for pancreatic cancer, 315 combined with other modalities, 25-26
implantation, for invasive carcinoma, 475 combined with surgery, 14
integration of different types and doses in courses of, dose-time relationships in, in
same patient, 24 lung cancer, 216
and intracavitary, 21
interstitial damage from, to heart, in Hodgkin's
ionizing, changes in physical characteristics disease, 888
of, in proportion to increasing energy, dose dependence in, for inoperable breast
of, 20
types cancer, 175
chemotherapy and, insensitivity of dose-response relationships in, 172
mature macrophages to, 954 doxorubicin and, 69
long-term biologic effects of, 21 effect of, after limited and radical surgery,
megavoltage, introduction of, Hodgkin's 172, 173t
disease and, 884 effect of dose on survival, in patients
photon, for unresectable stomach cancer, receiving simple mastectomy and, 173
255, 257 followed by surgery, for local control of
range of tolerance to, of brain tumors, 741 tumor, 176
1116 Index
Radiation therapy (Continued) Radiation therapy (Continued)

following chemotherapy, for seminoma, for Hodgkin's disease, MOPP and, 892
416, 416t, 417t prior to staging work-up, 880
following laryngectomy, for subglottic recovery of bone marrow function
cancer, 556-557 following, 888
following pulmonary resection, 217 transient aspermia from, pregnane)
following radical orchiectomy, for problems from, 889
seminoma, 415 for intraepithelial carcinoma, 473
following wide local resection, for for invasive carcinoma, of vagina, 474
mediastinal hemangioendotheliomas, 798 for laryngeal and hypopharyngeal cancer,
for acromegaly, in pituitary tumors, 646 surgery and, 552-553
for adrenal cortical neoplasms, 632 for lip cancer, 526
for anal cancer, 306-307 for liver cancer, 321
avoidance of perineum in, 306 for liver metastases, 328-329, 329t
for anterior mediastinal seminomas, 787 for lung cancer, 207, 214-219
for anterior mediastinal thymomas, 784 small cell versus nonsmall cell carcinoma
for bladder cancer, advanced, 389 in, 217-218
high-grade high-stage, 385 versus surgery, 214-215
short-course, high-dose, 386 for malignant brain gliomas, 741
for brain tumors, 741-744 for mediastinal hemangiopericytomas, 795
for breast cancer, 188 for melanoma, 689
inoperable, 175-177 and paranasal sinus cancer,
for nasal cavity
local control of, 175 533-534
local excision and, 172-174 for nasopharyngeal cancer, methods of,
surgery and, 171-177 537-538
for cancer of buccal mucosa, 526 for neuroblastoma, 765-766
for cancer of small bowel, 264 indications for, 765
for cancer of tongue and floor of mouth, for non-Hodgkin's lymphomas, 922-926
528 indications for, 922
for carcinoid tumors, 617 results of, significance of pathologic
for carcinoma in situ, 384 subtype in, 923
for carcinoma of extrahepatic bile ducts, 923-925
sites of relapse in,
340t, 341 for nonseminoma, advanced, 425
for cervical carcinoma, advantages of with extensive retroperitoneal
operation over, 486 metastases, 419
complication of, 487^188 for oropharyngeal cancer, 530
description of, 486-487 for osteosarcoma, 659
factors influencing type used, 487 for ovarian cancer, 507
surgery and, vesicovaginal fistula advanced, 503
resulting from, 488 side effects of, 502
for childhood non-Burkitt's lymphoma, 938 techniques of, 501
for chronic lymphocytic leukemia, 848-849 for ovarian dysgerminomas, 508-509
for colorectal cancer, 296-297 for ovarian epithelial tumors, 501-503
for craniopharyngiomas, 648-649 for Paget's disease, of vulva, 466
high-dose, 649 for palliation, 1010
for cure, in lung cancer, 215, 215t in breast cancer, 177
for cutaneous basal and squamous cell for pancreatic cancer, 315-316
carcinoma, 710, 712, 713t for pheochromocytoma, 627
indications for, 712 for pituitary adenomas, 644-648
for endocrine pancreas cancer, 607 advantages of, controversy over, 645
for endometrial carcinoma, myometrial disadvantages of, 647
penetration as guide to, operation prior for pituitary tumors, 644-649
to, 453 for prostate cancer, 363, 370, 372
for esophageal cancer, 242-245 for renal cellcarcinoma, 404-405
techniques and complications of, 242 for retinoblastoma, bilateral, 574
for Ewing's sarcoma, 665 unilateral, 573
for gestational trophoblastic disease, 440 for salivary gland tumors, 546
for glottic cancer,554 for soft-tissue sarcomas, 673
forHodgkin's disease, 883-889, 885 for spinal cord tumors, 754-755
goals of, 884 indications for, 754
high-dose, splenectomy and, 887 recurrence in, 755
history of, 883-884 for stomach cancer, 255-257
inverted-Y fields in, 886 for superior vena caval syndrome, 992
Index 1117
Radiation therapy (Continued) Radiation therapy (Continued)

for supraglottic cancer, 556 with levamisole, in breast cancer, 146
for thyroid cancer, 599-602 with nitrosurea therapv, for brain tumors,
for vulval malignant melanoma, 464 745
for vulvar squamous cell carcinoma, with surgery, for breast cancer, 172
surgery and, 461—462 for endometrial carcinoma, 451—454, 452
for Wilms' tumor, 773-774, 774t Radiograph(s), appearance of, in lung cancer,
sequelae of, 774 202
freedom from anatomic restriction in, 19 chest, in diagnosing childhood lvmphomas,
host factors and, versus surgery 24 918
-
importance of accurate diagnosis before of skull, for diagnosing brain tumors, 734
instituting, 23 Radioimmunoassay(s), in diagnosing prostate
intervalbetween doses in, dactinomycin cancer, 360
and metronidazole with, surgery and, 26 Radioiodine, for thyroid cancer, 599-603
laminectomy and, for epidural metastases, ablation therapy with, postoperative, 602
7.54 as adjunctive therapy, 599
hmphadenectomy and, for valvar studies on, 601
squamous carcinoma, 461
cell in scans, to diagnose thyroid cancer, 594
mediastinal, chemotherapy and, 59 therapeutic dosages of, 600
methotrexate or bleomycin and, for head Radioiodine imaging, for recurrent thyroid
and neck cancer, 564 cancer, 601
ovarian, versus oophorectomy, 181 Radioisotope scan(s), for diagnosing
physical basis of, 20-21 non-Hodgkin's lymphomas. 919
postoperative, controversv over value of. liver, fordiagnosing primary and secondary
174 tumors, 326
for brain tumors, 740-741 Radionuclide scan(s), for staging testicular
for ependymomas of cauda equina, 752 carcinoma, 413
for high-risk colon cancers, 297 Radioresistance, in radiation oncology, 22
for reducing chest wall recurrence and Radiosensitivity, modification of, 22-23
metastases of lymph nodes, in breast Rappaport classification system, in
cancer, 175 non-Hodgkin's lvmphomas, 908, 909t, 910t,
in lung cancer, 217 911
versus preoperative, in Wilms' tumor, Reaction(s), delayed hypersensitivity, in skin
773 cancer. 722
preoperative, abdominoperineal resection graft-versus-host, in immunosuppressed
and, for rectal cancer, 297 patients receiving granulocyte transfusions,
for bladder cancer, 386 978
for esophageal cancer, results of, leukemoid, from inflammatory or malignant
243-245. 244t disease, 834
for rectal cancer, 296-297 Receptor(s), estrogen and progesterone, in
for renal cell carcinoma, 404 breast cancer, 164
in neuroblastoma, 765 hormone, distribution of and response to
prior to segmental resection, in bladder endocrine therapv, in breast cancer, 178,
cancer, 385 179t
protracted application of, by dose Receptor transformation, 96
fractination, cobalt-60 teletherapy units Recombinant DNA technique* s). potential in
and linear accelerators and, 21 cancer treatment and prevention, 7
rapid dissolution of neoplastic tissues Reconstruction(s), prosthetic, for cranial
following, hyperuricemia from, 999 defects, modification of operative
side effects of, short-term versus long-term, technique for, 1034
25 surgical, for facial defects, 1031
simple mastectomy and, 173-174 Rectum, adenocarcinomas of,
case studies 174of, radiotherapeutic approaches to, 296
for advanced breast cancer, 176 cancer of, abdominoperineal resection and
wide field, for non-Hodgkin's lvmphomas, preoperative radiation for, 297
944 anterior resection or abdominal perineal
with chemotherapy, for advanced stomach resection for, 279-282, 281
cancer, 256t, 257 anteroposterior versus low anterior
combination, for small cell carcinoma of resection in, comparison of five-year
lung, 220, 22 It survival rates of, 281-282, 282t
for non-Hodgkin's lymphomas, 934, 936 Babcock operation for, 284, 284, 285
for primary Hodgkin's disease, 898 Bacon operation for, 284, 285, 286
in lung cancer, 218 cauterization in, 296
in small cell carcinoma of lung, 225 direction of lymphatic spread in, 281
1118 Index
Rectum (Continued) Renal cell carcinoma (Continued)

cancer of, electrocoagulation in, 295 excision of solitary foci of tumor in, for
Kraske operation for, 282, 283 palliation,403-404
preoperative radiation for, 296-297 immunotherapy for, 405-406
sphincter-saving operations for, 282-287 incidence of, 392
trans-sacral technique of surgery for, 287, involvement of regional lymph nodes in,
287, 288 400
Turnbull-Cutait operation for, 286, 287 metastatic, at time of diagnosis versus later
carcinoid tumors of, surgery for, 616 development, effect on survival of, 398,
mid- and upper, tumors of, choice of 399
operation for, 279 cellularand circulating immune response
Recurrence(s), local, in vulvar squamous cell 405
in,
carcinoma, 461^462 cumulative survival in, 398, 398
Red blood cell(s), contamination of platelet frequency of regression of, following
preparations with, 974 palliative nephrectomy, 403
packed, for erythrocyte transfusions, 972 radiation therapy for, 404^405
Reed Sternberg cells, in diagnosis of natural history of, 393-399
Hodgkin's disease, 869 needle aspiration in, 395
Regan isoenzyme(s), presence of in ovarian nephrectomy percutaneous transaortic
for,
cancer, 513-514 occlusion prior to, 400-401
Regression, after palliative nephrectomy, in palliative nephrectomy for, impact on
metastatic renal cell carcinoma, 403 survival, 403, 403
of neuroblastoma, drugs for, 766 prognosis in, 397-399
spontaneous, in neuroblastoma, 760 clear cell versus granular cell tumors
in renal cell carcinoma, 397, 402 and, 393
of well-established tumors, 125 radiation therapy for, 404-405
Rehabilitation, cancer, role of nurses in, 1023 preoperative, 404
role of physical therapist in, 1022-1023 spontaneous regression in, 397, 1022
of enterostomal patients, 1023-1027 staging in, 396-397
physical, from cancer, 1021-1035 staging systems for, 396, 397, 397t
specific goal-oriented variations in, 1021 surgery for, 399-404
prosthetic, for facial defects, 1031-1033 factors affecting outcome of, 401
for head and neck 1027-1034
defects, treatment for, 399-406
for large midfacial defects, 1033-1034, transfer factor for, 406
1033 variability in growth rate in, of primary
for mandibular defects, 1030-1031 tumor, 398
for soft palate defects, 1029-1030 tumor and doubling time of metastases
of maxillary defects, 1027-1029 in, 398
Rehabilitation center(s), cancer, criteria for Renal clearance, of methotrexate, 82
admission into, medical teams in, 1022 Renal cyst(s), nephrotomography in
Rehabilitation settings, 1034-1035 diagnosing, 395
Remission(s), hematologic, as purpose of Renal dysfunction, from streptozotocin
therapy in acute myelogenous leukemia, administration, 111
826 modification of methotrexate treatment in,
Remission induction, chemotherapeutic, in 132
acute myelogenous leukemia, 824-825 Renal excretion, of cyclophosphamide, 61
failure of, in acute lymphoblastic leukemia, Renal failure, bleomycin and, 72
813 management of, in multiple myeloma, 861
through chemotherapy, in acute Renal fossa, radiation to, in Wilms' tumors,
lymphoblastic leukemia, 811-814, 812t 773
Renal adenocarcinoma. See Renal cell Reproductive function, preservation of, in
carcinoma. gestational trophoblastic disease, 438-439
Renal cell carcinoma, 392^406 Research, ovarian cancer, 513-514
adjunctive nephrectomy in, 402^404 Resection, abdominoperineal, preoperative
asymptomatic metastases in, chemotherapy radiation and, for rectal cancer, 297
and immunotherapy for, 404 anterior or abdominal perineal, for cancer
chemotherapy and hormone therapy for, of rectum, 279-282, 281
405 anteroposterior versus low anterior, in
classification of, etiology of, 393 cancer of rectum, comparison of five-year
clinical features of, diagnostic tests for, 394 survival rates of, 281-282, 282t
diagnosis of, 394-396 composite, control of saliva following,
systematic approach to, 395, 395 mastication after, 1031
Index 1119
Resection (Continued) RNA synthesis, dactinomycin and, 70

composite, impairment of speech following, disruption of, by doxorubicin and
1030, 1030 daunomycin, 67
for bulk of tumor, in neuroblastoma, 765 inhibition of, 5-fluorodeoxyuridylate and,
liver, for metastatic colorectal cancer, 293 85
for metastatic liver cancer, 327 RNA transcription, effects of alkylating agents
palliative surgical, 1011 on, 53
pulmonary, bacillus Calmette-Guerin RNA virus(es), as possible etiologic agent in
following, 223 Hodgkin's disease, 867-868
contraindications for, 211 Rodent(s), laboratory, role in tumor-specific
for isolated metastatic colon cancer, immunity studies, 124-125
293-294 Roentgenogram(s), appearance of anterior
for metastatic osteosarcoma, 659 mediastinal teratomas on, 785
radiation therapy following, 217 for diagnosing Wilms' tumor, 770
segmental, in bladder cancer, 384-385 Root(s), sensorv, pain in, therapy for,
criteria for, 385 1016-1017
staged versus primary, in colon cancer, 289 Rosenmiiller's fossa, as site of origin for
surgical, bacillus Calmette-Guerin nasopharyngeal cancer, 536
following, 143 Route analysis(es), to establish neural
of nonseminoma with retroperitoneal pathways to interrupt pain, 1010
disease, 422
transurethral, in invasive bladder cancer,
inadequacy of, 384
in prostate cancer, 366
vascular embolization prior to, in
mediastinal hemangiopericytomas, 795, S phase, in cell cycle, 39
796 Saliva, control of, after composite resection,
wedge, of pulmonary metastases, for 1031
nonseminoma, 423 Salivary gland(s), adenoid cystic carcinoma
wide local, followed by radiation, for and acinic cell tumors of, description of,
mediastinal hemangioendothelioma, 798 544
Response(s), markers of. 46 benign tumors of, 541-543
Reticulum cell sarcoma. See non-Hodgkin's carcinoma of, staging of, 541, 54 It
lymphoma. malignant tumors of, 543-545
Retinoblastoma, 569-577 description of, 544-545
bilateral, surgery for, 573-574 miscellaneous primary carcinomas in, 545
versus unilateral involvement in, 570 monomorphic adenomas of, description and
chemotherapy for, 575 treatment of, 543
clinical features and diagnosis of, 571-572 mueoepidermoid tumors 543, 544
of,
diagnostic aids in, 572 pleomorphic adenoma 541-542
in,
epidemiology and etiology of, 569-570 Salivary gland tumor(s), 538-546
incidence of, sex and race predilection in, classification and pathology of, 539-540
569 classification of, by anatomic site, types of
inheritance of, 570 cells causing, 539
irradiation of, 574-575 clinical features of, 541-545
modes of therapy for, 576 description of, 523
natural history of, 571-573 diagnosis of, 540-541
pathology and classification of, presenting operation for, 541
symptoms of, 571 incidence of, 538-539
radiation therapy for, 574, 575 natural history of, 539-541
results of treatment in, 576, 576t radiation therapy for, 546
role of immune mechanisms in, 577 surgery for, 545
staging and prognosis of, 572-573 symptoms of, 540
staging of, 572, 572t treatment of, 545-546
unilateral, surgery for, 573 Salpingo-oophorectomy, bilateral, with
Rhabdomyosarcoma(s), rhinectomv for, 1032, hysterectomy, for endometrial
1032 carcinoma, 451
Rhizotomy, sacral, for sensory root pain, 1016 for epithelial ovarian tumors, 500
trigeminal, for sensory nerve root pain, for fallopian tube cancer, 512
1014 unilateral, indications for, in ovarian
RNA, xenogeneic, immune, studies on use in dysgerminomas, 509
cancer immunotherapy, 138-139 Sanctuary effect, definition of, 31
1120 Index
Sarcoma(s), 147-148 Scan(s) (Continued)

cervical, incidence of, 479 isotope, for diagnosis of vertebral
correlation between antibody titer and metastases, 751
complement fixation in, 132 liver-spleen, in non-Hodgkin's lymphomas,
distinguishing from a myoma, 516 919
endometrial stromal, uterine, prognosis in, radioiodine, to diagnose thyroid cancer,
517 594
Ewing's, 662-667 radioisotope, for diagnosing non-Hodgkin's
for, lymphomas, 919
and diagnosis of,
clinical features radionuclide, for staging testicular
incidence of, 663 carcinoma, 413
discovery of, 662 Schedule dependency, in chemotherapy, 44
drug combinations for, 666 of antimetabolites, 79
intermittent cycles of chemotherapy for, role in methotrexate combination
666, 666 chemotherapy, 84
natural history of, 663-664 Schistosoma haematobium, as cause of
radiation therapy for, 665 bladder cancer, 375-376
staging and prognosis in, surgery for, 664 Schistosomiasis, squamous cell versus
treatment of, 664-667 transitional cell carcinoma376in,
head and neck, results of surgery for, Schwannoma(s), malignant, posterior
672-673 mediastinal. See Neurosarcoma,
in laryngeal cancer, 549 posterior mediastinal.
Kaposi's, mediastinal, clinical features and posterior mediastinal. See Neurilemoma,
diagnosis of, 798 posterior mediastinal.
staging and prognosis in, 798 Sclerosing agent(s), intrapleural, for pleural
treatment of, 799 effusion, 987-989
reticulum cell. See non-Hodgkin's thoracentesis and, 987
lymphoma, classification. Sclerosis, in follicular lymphomas, 914
retroperitoneal, surgery for, results of, 672 Scoliosis, reduction of, in Wilms' tumor,
soft-tissue, 667-676 773-774
adjuvant immunotherapy for, 147 Secobarbital sodium, mechlorethamine and,
chemotherapy for, 674-675, 674t 58
classification and histopathology of, 668, Secretion(s), pituitary thrytropin, suppression
668t of, by thyroid hormone, 602
clinical features and diagnosis of, 669 Section, cranial nerve, multiple, for pain,
drug combinations for, 674 1014
etiology of, 667-668 spinothalamic tract, for pain, 1017
incidence of, 667 Seizure(s), from brain tumors, 731, 734
integration of treatment modalities in, Selective toxicity(ies), factors contributing to,
675 30,30
natural history of, 668-671 Sella turcica, enlargement of, diagnosis of
radiation therapy for, surgical principles pituitary tumors and, 635
in, 673 Seminoma(s), adjuvant chemotherapy for,
staging and prognosis in, 669-670, 670t, 416, 416t, 417t
671t anterior mediastinal, 787-788
surgery and chemoimmunotherapy for, as origin of embryonal carcinomas, 408
148 beta human chorionic gonadotropin in, 414
surgery for, 672-673 clinical features of, 411
uterine, 515-518 in testicular carcinoma, 406
classification of, 515, 516t metastatic, staging of, 412, 413t
clinical features and diagnosis of, 517 prognosis in, radical orchiectomy and
incidence and etiology of, 515 radiation therapy for, 415
metastases in, prognosis in, 517-518 recurrent disease in, treatment of, 417, 417t
pathology of, 515-517 retroperitoneal lymphadenectomy for, 417
treatment of, metastastes to aortic lymph spermatocytic, difference from typical
nodes in, 518 seminoma, 409
vulvar,466-467 survival rates in, 415-416, 415t
Scalene lymph node(s), biopsy of, for staging treatment of, 415-417
testicular carcinoma, 413 types of, in testicular carcinoma, 408-409
Scan(s), bone, in staging lung cancer, 205 ureteral obstruction in, 411
positive, benign causes of, 996, 997t Semustine, pharmacologic characteristics of,
EMI, to diagnose organic dementia, 1006 54t-^5t, 66
gallium, total body, in non-Hodgkin's with vincristine and 5-fluorouracil, for
lymphomas, 919 colorectal cancer, 299, 300t, 301
Index 1121
Sensory root(s), pain in, therapy for, Soft palate defect(s), prosthetic rehabilitation
1016-1017 of, 1029-1030
Septicemia, from gram-negative bacilli, in Soft palate obturator, 1030
granulocytopenia, 965 Soft-tissue sarcoma(s), 667-676
Sequential blockade(s), in chemotherapy, 43 adjuvant immunotherapy for, 147
Sertoli-Leydig tumor(s), ovarian, description chemotherapy for, 674-675, 674t
and treatment of, 510-511 classification and histopathology of, 668,
Serum assay(s), in diagnosing prostate cancer, 668t
359-360 clinical features and diagnosis of, 669
Serum glutamic-oxaloacetic transaminase drug combinations for, 674
(SGOT) determination, as diagnostic aid, etiology of, 667-668
for liver metastases, 326 incidence of, 667
Serum glutamic-pyruvic transaminase (SPGT) integration of treatment modalities in, 675
determinations, as diagnostic aid, for liver natural history of, 668-671
metastases, 326 radiation therapy for, surgical principles in,
Sex cord tumor(s), 509-511 673
Sex hormone(s), levels of, brain tumors and, staging and prognosis in, 669-670, 670t,
728 67 It
Sexual relationship(s), of cancer patient and surgery and chemoimmunotherapy for, 148
spouse, 1041 surgery for, 672-673
Sexuality, problems in, from surgery, 1026 treatment of, 672-676
Sezary cell(s), in mycosis fungoides, 942 Solid tumor(s), miscellaneous, 778-802
Sezary syndrome. See also Mycosis Somatostatinoma(s), chemotherapy for, 608
fungoides. description of, 606-607
differential diagnosis of, 844 surgery for, 607
Sialography, in diagnosis of salivary gland Soot, exposure to, scrotal squamous cell
tumors, 540 carcinoma and, 697
Sigmamotor pump, 331, 332 Speech, impairment of, after composite
Sinus(es), maxillary, tumors of, classification resections, 1030, 1030
of, 531, 532t Spinal cord, compression of, 751
description of, 532 by extradural non-Hodgkin's lymphomas,
paranasal, cancer of, 531-535 943
incidence of, 531 damage to, from radiation, in Hodgkin's
nasal cavity and, cancer of, natural disease, 888
history of, 531-533 pain in, cordotomy for, brain stem and,
pyriform, cancer of, prognosis in, 557 1017-1018
Sipple's syndrome, description of, 586 Spinal cord syndrome(s), symptoms of, 1006
Skin cancer, 695-725 Spinal cord tumor(s), 747-756
classification of, 698-700, 699t biology of, 748
delayed hypersensitivity reaction in, 722 chemotherapy and immunotherapy for, 755
diagnosis of, 700 classification of, 748-749, 748t, 749t
epidemiology of, 695-696 clinical features and diagnosis of, 749-751
etiology of, 696-698 diagnostic techniques in, neurologic-
exposure to arsenic and, 697 function and removal of, staging of, 751
from x-rays, 696, 697 etiology and epidemiology of, 747-748
immunotherapy and, 141 incidence of, 747
incidence of, 695 metastatic, classification of, 749, 750t
multiple, syndromes that predispose to, 698 myelography 752-753
for,
natural history of, 698-702 natural history of, 748-752
ratio of basal cell to squamous cell neurologic manifestations of, symptoms of,
carcinomas in, 696-697 749

staging and prognosis in, 700-702 prognosis in, 751-752
types especially suited for immunotherapy, radiation therapy for, indications for, 754
721 recurrence in, 755
Skin graft(s), danger of wound seeding in, 12 surgery for, 752-754
split-thickness, for wide excision in new techniques of, 752
melanoma, 687 treatment for, 752-755
Skin reaction(s), in chemotherapy, 36 Spinal metastasis(es), types of, prognosis in,
Skull, radiographs of, for diagnosing brain 753
tumors, 734 Spine, metastatic involvement of, cervical
Snuff, as etiologic factor in mouth cancer, 522 brace for, 1012
1122 Index
Spine (Continued) Squamous cell carcinoma (Continued)

vertebral, erosive changes in, from tumors, in cancer of vulva, surgery for, 460-461
Spinothalamic tract section, for pain, 1017 in oral cavity and oropharynx, 523
Spironolactone, for prostate cancer, 366-367 invasive, complete removal of vulva and
Splanchnicectomy, sympathectomy and, for lymph nodes for, 460
abdominal or back pain, 1018 of body of esophagus, 235
Spleen, vascular invasion of Hodgkin's of bum scar origin, metastases in, 702
disease in, 871 of cervix, 477
Splenectomy, for chronic lymphocytic of head and neck, chemoimmunotherapv
leukemia, 849 for, 150
for hairy cell leukemia, 864 radiation therapy for, 710, 712, 713t
in chronic mvelogenous leukemia, 839- scrotal, exposure to soot and, 697
840 vaginal, comparison with adenocarcinoma,
forhypersplenism, 840 470, 470t
for splenomegaly, 839 determining extent of, 474
in Hodgkin's disease, 882 recurrence of, 475
for splenic involvement.873 versus transitional cell carcinoma, in
on radiation therapy. 887
effects schistosomiasis, 376
in stomach cancer, 260-261 Staff, medical treatment, emotional balance
Splenomegaly, in chronic myelogenous between aloofness and
leukemia, splenectomy for, 839 overinvolvement in, 1044
Spouse(s), of cancer patient, caretaking efforts psychosocial problems of, 1043-1045
of, physician's reinforcement of, 1040 Stem, brain, pain in, tractotomv for, 1018
feelings of guilt in, 1041 therapy for, 1017-1018
importance of emotional support in, tumors of, radiation therapy for, 743
1039 Stem cell(s), pluripotent hematopoietic,
psychosocial problems of, 1039-1041 transplantation of, for restoration of
Squamous cell carcinoma, chemosurgery for, hematopoiesis, 979
disadvantages of, 720 Sterility, alkylating agents and, 37
cutaneous, chemosurgery for, healing in, Steroid(s), for brain tumors, 737-738
717-718 for superior vena cava! syndrome, 993
cryosurgery for, 712, 714, 715t, 716 ulceration of stomach and, 737
description of, 714 Steroid hormone(s), pattern of interaction of,
cure rates in, 705, 705t 95-96
description of, 700 Stoma(s), care of, postoperative nursing
fixed-tissue chemosurgery for, 717 procedures for, 1025
grading of, 701 creation of, 1025-1026
metastases in, 701-702, 702t Stomach cancer, 246-262
radiation therapv for, in voung patients, advanced, radiation therapy in conjunction
711 with chemotherapy for, 256t, 257
staging and prognosis in, 701-702 anatomic location and spread of,
topicalchemotherapy for, 720-721 adenocarcinoma in, 248
treatment of, 704-722 bacillus Calmette-Guerin for. integration of
methods of, 704-705 treatment modalities in, 261
in anal cancer, 304 biology of, 247-248
in cancer of nasal cavity and paranasal chemotherapy for, 257-260
sinus, 531 combination, 258-260
in cancer of vulva, 457^462 single-agent, 257-258, 257t
chemotherapy 462
for, classification of, 248-249
clinical features and diagnosis of, Broder's, 248
457-458 clinical features of, 249
correlation between histologic and contiguous organ involvement in, surgery
clinical stages of, 458 and, 255
incidence and etiology of, 457 diagnosis of, 249-251
involvement of pelvic lvmph nodes in, barium swallow for, 249
459, 460t endoscopv and exfoliative cvtology for,
local recurrence in, surgery and radiation 250
therapy for, 461—462 x-ray studies for, 249-250
natural history of, 457—460 epidemiology and etiology of, 246-247
prognosis in, 458-459 factors associated with, 247, 247t
prospects for future in, 467^468 geographic incidence of, 246
radiation therapv and lvmphadenectomy immunologic investigations of lymph nodes
461
for, in, 260
radicalvulvectomy for, 459, 460, 468 immunology in, immunotherapy for,
staging in, 458-460, 459t splenectomy for, 260-261
Index 1123
Stomach cancer (Continued) Surgery (Continued)

natural history of, 248-254 chemoimmunotherapy and, for soft-tissue
prognosis in, by stage, 253-254, 253 sarcomas, 148
radiation therapy for, 255-257 chemotherapy and, 14-15
staging of, 251-253, 251, 252, 252t, 253t combination, followed by cyclic
surgery for, results of, correlation with chemotherapy,for advanced
stage of disease at presentation, 255 nonseminoma, 420
treatment 254-261
for, for head and neck cancer, 564-565
tumor 126
infiltration in, for testicular tumors, 419, 420, 420t
unresectable, photon radiation therapy for, cytoreductive, prior to chemotherapy, for
255, 257 advanced nonseminoma, 425
Streptomyces, antibiotics from, use in extended, for colon cancer, 290
chemotherapy, 67 factors affecting outcome of, in renal cell
Streptomyces acromogenes, as origin for carcinoma, 401
streptozotocin, 110 for adrenal cortical neoplasms, 631
Streptomyces caespitosus, as origin for for anal cancer, 306
mitomycin-C, 74 for anterior mediastinal thymomas, 783
Streptomyces parvulus, as source for for bladder cancer, advanced, 388-389
actinomycins, 70 for brain tumors, 738-741
Streptomyces plicatus, as source for aims of, 738
mithramycin, 73 contraindications to, 740
Streptomyces verticillus, as source for types 738-739
of,
bleomycin, 71 for breast cancer, 170-171
Streptozotocin, 110-111 for cancer, advances in, limited
chemical structure of, 106, 110 effectiveness of, 9
clinical features of, 111 anatomic location of tumor as
mechanism of action of, 110 consideration for, 16
Stress(es), response to, dealing with cancer combined with radiation therapy, 14
and, 1037 common patterns of spread in neoplasms
Stridor, as presenting complaint in subglottic and, treatment of primary tumor by, 10
cancer, 556 definitive timing of, 15-16
in glottic cancer, 549--550 early problems in, 8
Stroma, gonadal, tumors of. See Tumors, sex integration into treatment plan, 16-18
cord. of buccal mucosa, 526
Subglottis, cancer of, description of, 556 of small bowel, 264
treatment of, 556-557 patient factors in, stage of metastases
Sugar, high levels of consumption of, colon and, 17
cancer and, 266 principles of, 8-18
Sun, as etiologic factor in lip cancer, 523 techniques of, 10-11
exposure to, carcinogenicity of, 696 treatment goals in, 18
Superior vena caval syndrome, 990-993 tumor factors and, 16-17
chemotherapy for,992-993 wide surgical margin in, lit
clinical features and diagnosis of, natural for carcinoid tumors, 615-617
history of, 990-991 anesthesia considerations in, 616, 617t
diagnostic aids in, prognosis in, 991 of appendix and small bowel, 615
pathophysiology and classification of, 990 for carcinoma in 383
situ,
radiation therapy for, mechlorethamine for, for cardiac disease and rectal and liver
992 metastases, in carcinoid tumors, 616
steroids for, 993 for colon cancer, survival following, effect
surgery for, 991-992 of age on, 294-295
treatment of, 991-993 for colorectal cancer, 276-296
Supraglottis, cancer of, description of, 555 goals of, extent of tumor spread and, 276
operation for, preventing aspiration operative principles in, 276-279
following, 556 results of, 279
treatment of, 555-556 suture line recurrence following, 290-291
Surgery, adjuvant chemotherapy and, in for craniopharyngiomas, difficulties in, 649
advanced ovarian cancer, 503 for cutaneous basal and squamous cell
in breast cancer, 146 carcinomas, 706-707, 707t
immunotherapy and, in lung cancer, 226 advantages of, 706
adjuvant immunotherapy and, in colorectal for epithelial ovarian tumors, 500-501
cancer, 147 for esophageal cancer, 237-242
adjuvant radiation and, in gallbladder goals of, 237
carcinoma, 336 in esophagogastric junction and lower
advantages of, for pituitary adenomas, 648 thoracic areas, 238
1124 Index
Surgery (Continued) Surgery (Continued)

tor esophageal cancer, palliative, for colorectal cancer, 294
lower and midthoracic, 238-239 for melanoma, 689
preparation prior to, 237-238 radiation therapy and, effects of, 172, 173t
results of, 241-242, 24 It for breast cancer, 171-177
for Ewing's sarcoma, 664 for cervical carcinoma, 488
for extrahepatic bile duct carcinoma, 339 for endometrial carcinoma, 451-454. 452
for gallbladder carcinoma, 335 for hypopharyngeal cancer, 557
for glottic cancer, 554 for laryngeal and hypopharyngeal cancer,
for glucagonomas, insulinomas, 552-553
diarrheogenic tumors, and for malignant melanoma, of conjunctiva,
stomatostatinomas, 607 581
for histiocytic malignancy, 955 for same anatomic site versus adjacent
for Hodgkin's disease, 882-883 anatomic sites, 26
for hydatidiform mole, 438 for soft-tissue sarcomas, 673
for kidney tumors, 401 for squamous cell carcinoma, of vulva,
for lip cancer, 526 461-462
for liver cancer, 321 for vaginal clear cell adenocarcinoma,
for liver metastases, 327-328 474
for lung cancer, 210-214 radical, radiation therapy as adjunct to,
for malignant melanoma, of eyelid, 581 174-175
of vulva, 464 sexuality problems from, 1026
for mediastinal hemangiopericytomas, trans-sacral technique of, for rectal cancer,
794-795 287, 287, 288
for melanoma, 686-689 transurethral, for bladder cancer, 380
primary, 686-687 type of, for colon cancer, factors
for metastatic disease, in colorectal cancer, influencing, 289-290
293-294 versus radiation therapy, importance of
for nasal cavity and paranasal sinus cancer, anatomic site of origin and extent of
533-534 cancer in, 24
for neuroblastoma, 764-765 in lung cancer, 214-215
for non-Hodgkin's lymphomas, 922 Surgical excision(s), complete, types of
and perforation by
for obstruction large distant metastases amenable to, 13
bowel carcinoma, 287-290 Surgical resection, bacillus Calmette-Guerin
for oropharyngeal cancer, 530 administration following, 143
for osteosarcoma, 658-659 of nonseminoma with retroperitoneal
for Paget's disease, of vulva,465-466 disease, importance of preoperative
for pancreatic cancer, 313-315 chemothrapy in, 422
for parathyroid carcinoma, 590-591 types of tumor not treatable by, 16
local recurrence following, 591 Suture line recurrence, in surgery for
for pheochromocytoma(s), 625-626 colorectal cancer, 290-291
for pituitary tumors, 638-644 Sweetener(s), dietary, as cause of bladder
transfrontal transsphenoidal, 640-641 cancer, 375
transnasal transsphenoidal, 638-640, 638 Sympathectomy, splanchnicectomy and, for
for prostate cancer, 363 abdominal or back pain, 1018
for renal cell carcinoma, 399-404 Syndrome(s). See also specific syndrome
metastatic, 401 names,
primary, 399-401 carcinoid, by anatomic site, 612, 613t
for retinoblastoma, 573-574 caused by hypersecretion of specific
for salivary gland tumors, 545 hormones, 636
for soft-tissue sarcomas, 672-673 Cushing's, mitotane for, 109
for spinal cord tumors, 752-754 pituitary adenoma as cause of, 646-647
new techniques of, 752 ectopic adrenocorticotropic hormone,
for squamous cell carcinoma, for vulva, 1002-1004, 1002t
460-461 diagnosis and differential diagnosis of,
for stomach cancer, 254-255, 254 1003
contiguous organ involvement and, 255 treatment of, 1003-1004
for superior vena cava! syndrome, 991-992 hyperviscosity, management of, in multiple
for supraglottic cancer, 555-556 myeloma, 861
for thyroid cancer, 596-599 diagnosis of, 1000-1001
indications for, 596 differential diagnosis of, 1001-1002
for tongue and floor of mouth cancer, 528 symptoms of, in small cell lung cancer,
for well-differentiated thyroid 1000
adenocarcinoma, 597-598 treatment of, 1002
for Wilms' tumor, 772-773 vincristine and, 78
for Zollinger-Ellison
tumors, 607 Lambert-Eaton, small cell lung cancer and,
head and neck defects from, 1027 1004
Index 1125
Syndrome(s) (Continued) System(s) (Continued)

neuromuscular, 1004-1007 musculoskeletal, involvement of, in
differential diagnosis of, 1005-1006 Hodgkin's disease, 875
etiology of, 1004 neoplasms of, 655-677
treatment of, 1007 nervous, effects of cancer on, 1004, 1005t
of inappropriate antidiuretic hormone lymphomatous involvement of, 942-943
secretion, 1000-1002 neoplasms of, 726-759
diagnosis of, 1000-1001 incidence of, 726
differential diagnosis of, 1001-1002
symptoms of, in small cell lung cancer,
1000
treatment of, 1002
vincristine and, 78 T cell(s), description of, 912
pain, in malignant disease, 1009-1021, Talc, thoracotomy and, for pleural effusion,
1009t 988-989
paraneoplastic, 994-1008 Tamoxifen, characteristics of, dosages for, 100
ectopic substance in, 994 for endocrine manipulation, 181
renal cell carcinoma and, 394 in postmenopausal breast cancer patients,
Plummer-Vinson, esophageal carcinoma 182
and, 233 toxicities of, 100-101
predisposing to multiple skin cancers, 698 Team care approach, to enterostomal therapy,
predisposing to non-Hodgkin's lymphomas, 1024, 1024
907 Teratocarcinoma(s), of testes, 408
production of, by carcinoid tumors, 612, Teratogenicity, of bleomycin, 73
613t of cytarabine, 90
Sezary, differential diagnosis of, 844 of procarbazine, 106
Sipple's, description of, 586 Teratoma(s), adult, anaplastic primary tumors
spinal cord, symptoms of, 1006 metastasizing to, in testicular carcinoma,
superior vena caval, 990-993 chemotherapy and, 408
for, anterior mediastinal, 785-786
clinical features and diagnosis of, natural incidence of, 785
history of, 990-991 symptoms of, treatment for, 786
diagnostic aids in, prognosis in, 991 benign cystic, immature ovarian, 508
pathophysiology and classification of, 990 Terminal deoxynucleotidyl transferase,
radiation therapy for, mechlorethamine presence in blast cells, in chronic
for, 992 myelogenous leukemia, 838
immediate
steroids for, diuretics for Testae, 102-103
decompression in, 993 Test(s), diagnostic, for pancreatic cancer,
surgery for, 991-992 overview of, 312
treatment of, 991-993 for renal cell carcinoma, 394
Wermer's, description of, 586 hemoccult, for colorectal cancer, 271, 271
Wiskott-Aldrich, spontaneous neoplasms in, pregnancy, comparison of sensitivity of,
129-130 436, 437
transfer factor for, 138 Testis(es), carcinoma of, 406-426
Zollinger-Ellison, description of, 605-606 advanced, treatment plan for, 423, 423t
gastrectomy for, 606 classification and pathology of, 407-409
Synthesis(es), immunoglobulin, B clinical features of, diagnosis of, 411
lymphocyte neoplasms capable of, 853-866 cryptorchidism as causative factor in,
System(s), cardiovascular, effects of incidence of, variation among races
corticosteroid therapy on, 104 and geographic regions, 407
involvement of, in Hodgkin's disease, incidence and etiology of, 406—407
875 metastases in, 409-411
central nervous, effects of corticosteroid natural history 407—415
of,
therapy on, 104 retroperitoneal lvmph node dissection in,
involvement of, in Hodgkin's disease, 410,410
875-876 staging of, 412^14
endocrine, effects of corticosteroid therapy angiograms for. 413-414
on, 104 bilateral pedal lymphangiography for,
involvement of, in Hodgkin's disease, 412-413
876 chest x-ray and full lung tomography
immune, anatomic and functional for, intravenous pyelogram for, 412
compartments of, in normal lymph scalene lymph node biopsy for,
node, 912, 913 computerized tomography and
and musculoskeletal, effects of abdominal ultrasound for,
corticosteroid therapy on, 104 radionuclide scans for, 413
change in, from brain tumors, 729-730 system for, 412, 412t
1126 Index
Testis(es) (Continued) Thymoma(s) (Continued)

carcinoma of, staging of, treatment of, anterior mediastinal, radiation therapy for,
415-426 784
tumor markers for. 414 surgery for, 783
teratocarcinoma of, 408 treatment for, 783-784
tumors of, chemotherapy and surgery for, Thymus, involvement of, in Hodgkin's
419,420, 420t disease, 873
pathways of differentiation and total removal of, in anterior mediastinal
transformation of, 407-408, 408 thymomas, 783
undescended, malignant change in, 411 Thyroid adenocarcinoma, diagnosis of,
Testicular dysgenesis, in testicular methods for, 597
carcinoma, 407 radioiodine as adjunctive therapy for, 599
Testosterone propionate, 98t well-differentated, surgery for, 597^598
absorption and excretion of, dosage for, 102 Thyroid anaplastic carcinoma, surgery for, 599
Tetracycline, for pleural effusion, 988 Thyroid cancer, 591-603
Thalamotomy, for cancer pain, 1015, 1018 chemotherapy for, thyroxine for, 602-603
Therapeutic index, for antineoplastic drugs, classification of, 593, 593t
definition of, 30 clinical features of, 593
Thermogram(s), in breast cancer, 167 diagnosis of, 594
6-Thioguanine (6-TG), cytarabine and, 90 doxorubicin for, 603
dosages and toxicities of, 93 epidemiology of, 592
mechanism of action of, 92 etiology of, 591-592
site of action for, 91, 92 extent of operation in, 597
uses for, 80t, 93 natural history of, 593-596
Thiotepa. See Triethylenethiophos- pheochromocytoma and, 622
phoramide. radiated, leukemia in, 601
Thoracentesis, for pleural effusions, 986- radioiodine for, 599-603
987 postoperative, 602
recurrence in, 986 therapeutic dosages of, 600
to obliterate free pleural space, 984 recurrent, radioiodine imaging for, 601
with sclerosing agents, 987 staging and prognosis in, 595-596
Thoracostomy, for pleural effusion, staging of, 595, 595t
chemotherapeutic agents and, 987 surgery for, 596-599
Thoracotomy, following lymphadenectomy, indications for, 596
in nonseminoma, 423 thyroid-stimulating hormone for, 599-600
for metastatic colorectal cancer, laparotomy as adjunctive therapy, 602
prior- to, 294 treatment of, 596-603
in diagnosing lung cancer, 203 tumor ablation for, procedures of, 600, 600t
right, for upper esophageal cancer, 239 Thyroidectomy, for medullary carcinoma, for
talc and, for pleural effusion, 988-989 thyroid adenocarcinoma, 598
with pleurectomy, to obliterate free pleural Thyroiditis, transient, from radioiodine
space, 984 administration, in thyroid cancer, 600
Thorotrast, renal cell carcinoma and, Thyroid-stimulating hormone (TSH), effect
393 on thyroid tumors, 592-593
Thrombocytopenia, as consequence of bone for thyroid cancer, 599-600
marrow failure, manifestations of, Thyrotropin, influence on growth of thyroid
963 tumors, 593
in acute myelogenous leukemia, Thyroxine, dosage of, in thyroid cancer,
821 602-603
prophylactic platelet transfusions for Time threshold, toxicity and, in methotrexate
patients with, 975 and leucovorin rescue, 83
risk of bleeding and, 963-964 Tissue(s), anal cancer originating from, 304,
vincristine therapy in, 78 305
Thymidine, synthesis of, inhibition by biopsy of, microscopic examination of, in
methotrexate of, 79 laryngeal and pharyngeal cancer, 551
Thymoma(s), anterior mediastinal, 780-784 examination pathogens, 967-968
of, for
chemotherapy for, 784 local destruction of, by brain tumor, 734
classification of, symptoms of, 780 necrosis of, mitomycin-C and, 75
clinical presentation of, 780-781 vincristine and, 78
diagnostic studies in, spectrum of neoplastic, rapid dissolution of, following
diseases associated with, staging and chemotherapy or radiation therapy,
prognosis in, 781 hyperuricemia from, 999
integration of treatment modalities in, 784 soft, involvement of, in Hodgkin's disease,
myasthenia gravis and, 780-781, 782 875
Index 1127
Tissue(s) (Continued) Toxicity(ies) (Continued)

volume of, irradiated, in Hodgkin's disease, of streptozotocin, 111
884-885 of tamoxifen, 100-101
Titration, of mechlorethamine, 56, 58 of 6-thioguanine, 93
Tobacco, as cause of bladder cancer, 375 of vinblastine, 77
Tocopherol, doxorubicin toxicity- and, 70 of vincristine, 78
Tomography, computerized, for staging pulmonary, in chemotherapy, 37
testicular carcinoma, 413 selective, in chemotherapy, factors
for spinal cord tumors, 750 contributing to, 30, 30
full lung, chest x-ray and, for staging Toxin(s), Coley's, 135
testicular carcinoma, 412 Tract(s), gastrointestinal and genitourinary,
Tongue, anterior, cancer of, 527-529 involvement of, in Hodgkin's disease,
areas affected, 527 876
diagnosis and treatment of, metastases to urinary, as site of infection, in leukemia,
lymph nodes in, 528 964
prognosis 529
in, Tractotomy, for brain stem pain, 1018
symptoms of, 527^528 medullarv and mesencephalic, for pain,
Tonsil(s), cancer of, 529 1015
involvement of, in Hodgkin's disease, 873 Transcription, RNA, effects of alkylating
Total body irradiation, as systemic treatment agents on, 53
in cancer, 21 Transfer factor, for inducing specific
Toxicity(ies), associated with cisplatin, in anti-tumor reactivity in lymphocytes of
advanced nonseminoma, 424 cancer patients, 138
bone marrow, in chemotherapy, 34-35, 34, for treatment of renal cell carcinoma, 406
35 Transformation(s), neoplastic, in cervical
concentration threshold and time threshold metaplasia, 477
in, in methotrexate and leucovorin rescue Transfusion(s), erythrocyte, cross-matching
therapy, 83 procedures for, nonhemolytic reactions
gastrointestinal, in chemotherapv, examples to, 973
of, 34 forbone marrow failure, 972-973
hepatic, in chemotherapy, 36-37 packed red blood cells for, 972
importance of monitoring, in granulocyte, alloimmunization in patients
chemotherapy, 45 receiving, 975-976
lack of, from progestins, 101 for bone marrow failure, 975-979
manifestations of, in mechlorethamine for leukopenic patients with infection, 975
administration, 58 indications for, 978-979
of allopurinol. 94-95 patient response in, 978
of aminoglutethimide. 110 leukocyte, post-transfusion phenomena in,
of androgen therapy, 103 976
of L-asparaginase. 114-115 platelet, 964
of 5-azacytidine, 91 improved availability of, 973
of bacillus Calmette-Guerin. 136 single-donor, prophylactic, complications
of bleomycin, 72-73 from, 975
of busulfan, 64 source of, 974-975
of cisplatin, 113 preparations for, contamination of, with
of clomiphene, 100-101 red blood cells, 974
of corticosteroid therapy, 104 Transplant(s), bone marrow, autologous, 979-
of cyclophosphamide, 60 981
of cytarabine, 89-90 myelogenous leukemia, 828
in acute
of dacarbazine, 65 kidney, development of metastatic cancer
of dactinomycin, 71 in patients receiving, 130
of diethylsti'lbestrol, 99-100 Transudate(s), versus exudates, in pleural
of 5-fluorouracil, modifications for, 87 effusions, 985-986
of hexamethylmelamine, 112 Trauma, in development of osteosarcoma, 656
of hydroxyurea, 108 Treatment team(s), as substitute family, for
of melphalan, 62 cancer patient, 1040
of methotrexate, Elliot's B solution for, 85 Triethylene melamine (TEM), for
kidneys and, 83 retinoblastoma, 575
principal sites of occurrence, 83-84 Triethylenethiophosphoramide, 63, 64
of mithramycin, 74 for bladder cancer, 381
of mitomycin-C, 75 mechlorethamine and, for malignant
of mitotane, 109 pleural effusions associated with breast
of nafoxidine, 100-101 carcinoma, 988
of nitrosureas, 66-67 Trunk and extremity pain, regional therapy
of procarbazine, 106 for, 1016-1018
1128 Index
Tryptophan, metabolism of, in carcinoid Tumor(s) {Continued}

tumors, 610, 610 carcinoid, 609-620
metabolites of, as cause of bladder cancer, chemotherapy for, 618-619, 618t
375 hepatic artery infusion in, 619
Tube(s), fallopian, cancer of, diagnosis and single-agent versus combination, 618
treatment of, 512 classification of, 611, 61 It
metastases to, from ovaries or clinical features of, 612
endometrium, 511 diagnosis of, 612, 614
symptoms of, 511-512 etiology of, 609-610
Tumor(s). See also Canceris), Carcinoma(s), experimental approaches to, 620
and Neoplasm(s). general care of, integration of treatment
acinic cell, of salivary glands, description modalities in, 619
544
of, incidence of, 609
advanced nonhematologic, combination liver metastases in, of rectum, cardiac
chemotherapy for, 42 disease in, surgery for, 616
anaplastic primary, metastasizing as adult metabolism of tryptophan in, 610, 610
teratomas, chemotherapy and, in metastatic behavior of and syndrome
testicular carcinoma, 408 production by, 612, 613t
anatomic location of, histologic types of not natural history- of, 611-615
treatable by surgical resection, of appendix and small bowel, surgery for,
determining stage of, 16 615
aortic body, posterior mediastinal, 791 prognosis in, 614-615, 615t
benefited by 5-fluorouracil, 88 radiation therapy for, 617
benefited by methotrexate, 84 sitesof occurrence in, 612, 613t
benign, hypercalcemia and, 996 staging of, 614, 614t
salivary gland, 541-543 surgery for, 615-617
bilateral, in Wilms' tumor, 772 anesthesia considerations in, 616, 617t
brain, anticonvulsants for, 738 treatment of, 615-620
biology of, 728-730 carotid body, 799t301
change in immune system from, 729-730 angiography in, 800, 800
chemotherapy for, 744-747 description of, 800
combination, 746 etiology of, 799
clinical features of, 731, 734 treatment for, 801
dexamethasone for, 737 central nervous system, contiguous
diagnosis of, 734-736 extension in, 729
methods of, 734 childhood solid, 759-777
drug treatment of, important properties clear cell versus granular cell, prognosis in
in, 744 renal cell carcinoma and, 393
etiology of, 727-728 colonic, resection methods for, 277 278,
,
immunotherapy for, incidence of, 747 279

local destruction of tissue by, complete resection of, correlation with
mechanisms of death from, 734 prognosis, in ovarian cancer, 499-500
metastatic, 730, 730t delta-cell, of endocrine pancreas, 605-607
chemotherapy for, 747 diarrheogenic, chemotherapy for, 608
prognosis in, 737 of pancreas, description of, 606
natural history of, 731-737 surgery for, 607
nitrosureas plus radiation therapy for, differentiation of, in endometrial
745 carcinoma, effect on prognosis of, 450
postoperative radiation therapy for, diffuse or poorly differentiated, in prostate
740-741 cancer, 361
primary, biology of, 728-730 direct implantation of, pleural effusion
factors influencing prognosis in, 736 secondary to, 985
prognosis in, 736-737 dissemination of, to regional lymphatics,
radiation as cause of, 728 12-13
radiation therapy for, 741-744 endocrine, 586-654
range of tolerance to, 741 endodermal sinus, anterior mediastinal,
staging of, 736 786-787
surgery for, 738-741 ovarian alpha-fetoprotein and, 509
aims of, 738 epithelial ovarian, biopsy of lymph nodes
contraindications to, 740 in, 501
types of, 738-739 hysterectomy with bilateral
symptoms of, 731 salpingo-oophorectomy for, 500
treatment 737-747
of, radiation therapy for, 501-503
steroids for, 737-738 surgery for, 500-501
Index 1129
Tumor(s) (Continued) Tumor(s) (Continued)

eradication of, proportionality of to total pituitary, 633-653
dose of radiation, in Hodgkin's disease, acromegaly in, 642, 642
886 biology of, 633-634
estrogen-producing ovarian, clinical classification and pathology of, 634-635
manifestations of, 51 It classification of, techniques of, 634
treatment for, 500-507 clinical findings and diagnosis of,
extremity, head and neck, integration of 635-637
treatment modalities in, 675 cryohypophysectomy for, 641-643
germ cell, anterior mediastinal, 784-788 advantages of, 643
785
classification of, anesthesia in, 642
glial,partem of growth of, 729 history of, 641
high-stage high-grade, in bladder cancer, problems in, 642-643
treatment for, 384-388 CT scan for, 637
incidence of, 384 diagnosis of, enlargement of sella turcica
radiation therapy for, 385 in, elevated secretion of growth
histologic identification of, 23 hormone in, 635
hormone-receptor status of, in breast endocrine studies in, 637
cancer, 189 epidemiology and etiology of, 633
incomplete excision of, complications natural history of, 634-637
caused by, 15 postoperative hormone management in,
infiltration by, in stomach cancer, 126 644
invasive characteristics of, importance to radiation therapy for, 644-649
determining type, 10 radiologic findings in, 636-637
involvement and differentiation of, surgery for, 638-644
importance of determining, in prostate symptoms of, 636
cancer, 368 transfrontal transsphenoidal surgery for,
kidney, surgery for, 401 640-641
large versus small, choice of drugs for, 40 transnasal transsphenoidal surgerv for,
local control of, with radiation followed by 638-640, 638
surgery, 176 contraindications to, 640
location and extent of, in determining description of, 639
applicability of radiation therapy for, treatment for, 637-649
22 posterior mediastinal, 788-792
malignant mixed, in salivary glands, classification of, 788
description of, 544-545 presence of, relationship to
maxillary sinus, description of, 532 immunosuppression, 131
mediastinal, 778-792 primary, occurrence of second, in lung
posterior miscellaneous, 791-792 cancer, 213
usual location of, 778, 799t of central nervous system, classification
mesenchymal, posterior mediastinal, of, 731, 732t-733t
791-792 seeding of cerebrospinal fluid by, 729
metastatic to bone, production of reconstruction of site of, 11-12
hypercalcemic substances by, 995 surgical treatment of, 10-12
mid and upper rectal choice of operation variability in growth rate of, in renal cell
for, 279 carcinoma, 398
midbrain, radiation therapy for, 743 production of hormones by, in lung cancer,
mucoepidermoid, of salivary glands,
-
201
description of, 543 prostate, benign prostatic hypertrophy and,
prognosis in, 544 259
multiple, in retinoblastoma, 571 involvement of lymph nodes in, 362
natural history and treatment of, 7 replacement of bone marrow by, 962
neurocrest, posterior mediastinal, 791 resection of bulk of, in neuroblastoma, 765
nonfunctional and functional, in adrenal responsive to bleomycin, 73
cortical neoplasms, 628 responsive to mitomycin-C, 75
nonseminomatous testicular, pulmonary round cell, in Ewing's sarcoma, 663
metastases in, 410 salivary gland, 538-546
survival rates in, 424t classification and pathology of, 539-540
occult, in prostate, treatment approach to, classification by anatomic site of, types of
369 cells causing, 539
olfactory neuroepithelial, in nasal cavity clinical features of, 541-545
cancer, 532 description of, 523
oropharyngeal, description of, 529 diagnosis of, 540-541
ovarian nonspecific stromal, types of, 511 incidence of, 538-539
pineal gland, radiation therapy for, 743 malignant, 534-545
1130 Index
Tumor(s) (Continued) Tumor(s) (Continued)

salivary gland, natural history of, 539-541 transitional cell, anal, 304
operation for diagnosis of, 541 bladder, intravesical chemotherapy for,
radiation therapy for, 546 381
staging of, 541, 54 It trophoblastic, elaboration of human
symptoms 540
of, chorionic gonadotropin by, 435
surgery for, 545 types of, in lung cancer, 200
treatment of, 545-546 preoperative irradiation used for, 217
Sertoli-Leydig, ovarian, description and undifferentiated, versus differentiated,
treatment 510-511
of, radioiodine uptake of, 599
sex cord, 509-511 unresectable, in head and neck cancer,
increased levels of estrogenic and drug regimen for, 562
androgenic hormones in, 509 urothelial, in bladder cancer, 376
sigmoid colon, left colectomy for, 278, 279 variation in estrogen receptor activity in, in
sinus, invasion of orbit by, 533 breast cancer, 178
size and location of, relationship to clinical vascular, mediastinal, 792-801
features of colorectal cancer, 270 incidence of, 792
size of,and prognosis, in lung cancer, 207 Warthin's, of salivary glands, description
solid, chemoimmunotherapy for, 149-150 and treatment of, 542
disseminated, chemoimmunotherapy for, well-established, spontaneous regression
effectiveness of, 152 of, 125
doubling time 42 of, Wilms', 767-776
miscellaneous, 778-802 chemotherapy for, 774-775, 775t
solitary foci of, excision of, for palliation in diagnosis of, intravenous pyelogram for,
renal cell carcinoma, 403-404 770, 770
spinal cord, 747-756 incidence and etiology of, 767-768
biologyof, 748 initial workup in, 770-771
chemotherapy and immunotherapy for, kidney as site of origin for, 768
755 metastases in, 768, 769t
classification of, 748-749, 748t, 749t natural history of, 768-771
clinical features and diagnosis of, pathology of, 768-769
749-751 pulmonary metastases in, treatment of,
diagnosis of, neurologic function and, 774
staging of, 751 radiation therapy for, 773-774, 774t
etiology and epidemiology of, 747-748 postoperative versus preoperative, 773
incidence of, 747 reduction of scoliosis in, 773-774
manifestations of, 750 staging and prognosis in, 771, 771t
metastatic classification of, 749, 750t treatment of, 771-775, 775
myelography 752-753
for, x-ray induced, in skin cancer, 696
natural history of, 748-752 Zollinger-Ellison, chemotherapy for, 608
neurologic manifestations of, 749 surgery for, 607
prognosis in, 751-752 Tumor ablation, in thyroid cancer,
radiation therapy for, 754-755 procedures of, 600, 600t
indications for, 754 Tumor activity(ies), assessment of, 23
recurrence in, 755 Tumor deposition of, in hepatic
cell(s),
surgery for, 752-754 parenchyma, in disease metastatic to
new techniques of, 752 liver, 325
symptoms 749
of, DNA on, 113
treatment for, 752—755 surface of, alterations of as method for
suitable for chemosurgery, 718 increasing immunogenicity, 138
testis, cell type of, correlation with age, 406 Tumor cell biology, cytokinetic concepts in,
chemotherapy and surgery for, 419, 420, 39-40
420t Tumor cell population(s), change in, due to
cisplatin for, 114 radiation therapy, in bladder cancer, 386
mithramycin for, 73 Tumor cell resistance, to dactinomycin, 70-71
pathways of differentiation and to nitrogen mustard derivatives, 56
transformation of, 407^408, 408 Tumor cell vaccine(s), allogeneic, as adjuvant
thyroid, consistency of, thyrotropin and, immunotherapy for malignant disease,
593 clinical tests of,137
effect of thyroid-stimulating hormone on, Tumor doubling time (TDT), early versus
592-593 late, in breast cancer, 163
pheochromocytoma and, 622 in breast cancer, 162-163, 162t
total removal of, in meningiomas and in solid tumors, 42
neurilemomas, 752 Tumor factor(s), cancer surgery and, 16-17
Index 1131
Tumor growth, effects of estrogens on, 99 Uterus (Continued)

Tumor immunology, early frustrations in, 124 size of, as prognostic factor, in endometrial
Tumor invasion, effect on survival, in bladder carcinoma, 450-451
cancer, 384 spontaneous perforation of, in patients with
Tumor marker(s), for staging testicular invasive mole, 437
carcinoma, 414
human chorionic gonadotropin as, in
gestational trophoblastic disease, 441
in diagnosis of ovarian cancer, 513
Tumor recurrence, in bladder cancer, Vaccine(s), antibacterial, 967
380-381 tumor cell, allogeneic, as adjuvant
subclinical, carcinoembryonic antigen immunotherapy for malignant disease,
levels and, 128 clinical tests of, 137
Tumor regression, after therapy with bacillus Vaccinia virus(es), administration of,
Calmette-Guerin, 136 regression of cutaneous metastases of
importance of immunocompetence in, 140 melanoma and, 140
in malignant melanoma, bacillus Vagina, adenocarcinoma of, description of,
Calmette-Guerin therapy and, 139 469
in neuroblastoma, drugs for, 766 clinical features and diagnosis of,
Tumor resistance, to drugs, 33 470-471
Tumor response(s), 46, 46t detection and etiology of, 469
Tumor site(s), 139-142 incidence of, 468
Tumor size, relation to radiation dose, in natural history of, 470-472
Hodgkin's disease, 886 cancer of, 468^176
Tumor spread, visualization of, 10-11 exposure to diethylstilbestrol and, 473
Tumor transplantation resistance, in murine lymphatic drainage of, 471
leukemia cells, role of neuraminidase in prognosis in, 472
inducing, 138 staging of, 471^472, 471t
Tumor volume(s), as prognosticator for lymph symptoms of, 470
node metastases, in cervical carcinoma, 483 topical immunotherapy in, 141
Tumor-specific immunity, first cases of, 124 treatment 472^475
for,
studies of, role of laboratory rodents in, clear cell adenocarcinoma of, surgery and
124-125 radiation therapy for, 474
Tumor-specific transplantation antigens comparison of adenocarcinoma and
(TATA), 125 squamous cell carcinoma of, 470, 470t
Tumbull-Cutait operation, for renal cancer, dysplasia of, diagnosis of, 471
286, 287 intraepithelial carcinoma of, topical
chemotherapy for, squamous cell
carcinoma of, 475
invasive carcinoma of, 474—475
evaluation of pelvic and periaortic lymph
U nodes in, 476
Urogram(s), intravenous, for diagnosing radiation therapy for, 474
non-Hodgkin's lymphomas, 918-919 metastases to, in endometrial carcinoma,
Uterine bleeding, abnormal, in endometrial 445
carcinoma, 447 Vaginectomy, for stage I invasive carcinoma,
Uterine evacuation(s), histologic examination 474
of tissue obtained at, in molar pregnancy, total, for intraepithelial carcinoma, 473
436 Vanillylmandelic acid (VMA), as diagnostic
Uterine isthmus, involvement of, in aid in retinoblastoma, 572
endometrial carcinoma, 446 determination of, in pheochromocytoma,
Uterus, adenocarcinoma of, estrogen therapy 624
as cause, 96 elevation of, in neuroblastoma, 761
carcinoma of, response rate to progestins Varicella zoster infection(s), in cancer
in, 101 patients, 966
sarcomas of, 515-518 Velban. See Vinblastine.
classification of, 515, 516t Vena cava, inferior, contrast studies of, in
clinical featuresand diagnosis of, 517 Wilms' tumor, 770
incidence and etiology of, 515 Vesicovaginal fistula(s), as complication of
metastases in, 517^518 radiation therapy for cervical carcinoma,
to aortic lymph nodes, 518 488
pathology of, 515-517 Vinblastine, Catharanthus roseus as origin
prognosis in, 517-518 of, 75
treatment of, 518 characteristics of, 77
1132 Index
Vinblastine (Continued) Vulva (Continued)

in treating renal cell carcinoma, 405 malignant melanoma of, depth of in-
pharmacology of, 54t-55t, 77 vasion in, prognosis and, 463, 463t
role of kidney and liver in elimination of, etiology and epidemiology of, 462
77,78 immunotherapy 464—465
for,
Vinca alkaloid(s), 75-78 natural history 462—464
of,
characteristics of, 76, 76t prognosis in, 463—464
chemical structure of, 76, 76 surgery for, radiation for, chemotherapy
Vinca rosea Linn, as origin of vinblastine and for, metastases in, 464
vincristine, 75 symptoms of, 463
Vincristine, 77-78 Pager's disease of, chemotherapy and
Catharanthus roseus as origin of, 75 radiation therapy for, 466
characteristics of, 78 natural history of, 465
dosage modification of, in liver treatment of, 465—466
dysfunction, 32 sarcoma of, 466—467
for childhood histiocytoses, 957 squamous cell carcinoma of, chemotherapy
for non-Hodgkin's lymphomas, 926 for, 462
for retinoblastoma, 575 local recurrence in, surgery and radiation
for seminoma, 416 for, 461-462
methotrexate and, for osteosarcoma, 660 surgery for, 460-461
prednisone and, for blast crisis, in chronic treatment of, 460—462
myelogenous leukemia, 836 Vulvectomy, radical, complications of,
role of kidney and liver in elimination of, 460-461
77,78 for squamous cell carcinoma, 459, 460,
with 5-fluorouracil and semustine, for 468
colorectal cancer, 299, 300t, 301 reconstruction of defects left by, 461
Virilization, from androgen therapy, 103
Virus(es), as cause of osteosarcoma, 656
804
as etiologic factor, in acute leukemia,
in non-Hodgkin's lymphomas, 906 W
herpes, laryngeal cancer and, 547 Waldenstrom's macroglobulinemia,
herpes simplex, type II, implication in description of, 861
cervical carcinoma, 477 diagnosis of, 861-862
RNA, as possible etiologic agent in treatment of, 862
Hodgkin's disease, 867-868 Warthin's tumor, of salivary glands,
vaccinia, administration of, regression of description and treatment of, 542
cutaneous metastases of melanoma and, Weakness(es), motor, from spinal cord
140 tumors, 750
Viscera, dissemination of non-Hodgkin's Wedge resection(s), of pulmonary metastases,
lymphomas to, autopsy studies and, 917, for stage C nonseminoma, 423
918t Weight together with organomegaly and
loss,
Vitamin B, 2 , for neuroblastoma, 766—767 fever, as symptoms of malignant
deficiency of, in megaloblastic anemia, 962 histiocytosis, 953
Vitamin C, proposed use in cancer treatment, Wermer's syndrome, description of, 586
116 Whipple procedure, for pancreatic cancer,
Vitamin deficiency(ies), oral cavity cancer 313,314
and, 523 White blood cell (WBC) count, fall in,
Vulva, basal cell carcinoma of, 466 mechlorethamine administration and, 58
cancer of, 457—468 Wilms' tumor, 767-776
squamous cell carcinoma in, 457—462 chemotherapy for, 774-775, 775t
clinical features and diagnosis of, clinical features and diagnosis of, 769-771
457-458 diagnosis of, intravenous pyelogram for,
correlation between histologic and 770, 770
clinical stages of, 458 diagnostic aids in, 769-770
incidence and etiology of, 457 diagnostic signs of, abdominal mass in, 769
natural history of, 457^60 doxorubicin for, 775
prognosis of, 458^459 incidence and etiology of, 767-768
prospects for future in, 467—468 initial work-up in, 770-771
staging of, 458^60, 459t kidney as site of origin for, 768
complete removal of, and lymph nodes, for metastases in, 768, 769t
invasive squamous cell carcinoma, 460 natural history of, 768-771
malignant melanoma of, 462—465 pathologyof, 768-769
clinical features and diagnosis of, pulmonary metastases in, 733

462^63 treatment of, 774
Index 1133
Wilms' tumor (Continued) X-ray(s) (Continued)

radiation therapy for, 773-774, 774t chest, in hydatidiform mole, 436
postoperative versus preoperative, 773 for benign conditions, development of skin
research in, by NWTS-1 and 2, 776 cancer after, 697
reduction of scoliosis in, 773-774 skin cancer caused by, 696
staging and prognosis in, 771, 771t X-ray study(ies), for diagnosing stomach
surgery for, 772-773 cancer, 249-250
transabdominal nephrectomy in, bilateral
tumors in, 772
treatment of, 771-775, 775
Wiskott-Aldrich syndrome, spontaneous
neoplasms in, 129-130
transfer factor for, 138
Wound seeding, local, techniques to prevent, Yolk sac tumor(s). See Endodermal sinus
12 tumors.
Xanthine oxidase, inhibition of, by

allopurinol, 94
role in degradation of 6-mercaptopurine, 92 Zenker's solution, use in pituitary tumor
X-ray(s), biopsy and, in diagnosing oral cavity surgery, 640
cancer, 525 Zinc chloride fixative paste, in chemosurgery,
chest, abnormal, diagnosis of malignancy 716
following, 203 Zollinger-Ellison syndrome, description of,
for diagnosis of anterior mediastinal 605-606
thymomas, 781, 782 chemotherapy for, 608
full lung tomography and, for staging gastrectomy for, 606
testicular carcinoma, 412 surgery for, 607
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UNIVERSITY OF CALIFORNIA

SAN FRANCISCO LIBRARY

CHARLES M. HASKELL, M.D.

With 53 collaborators and a Foreword by

1 St. Anne's Road

Eastbourne, East Sussex BN21 3UN, England

Library of Congress Cataloging in Publication Data

Main entry under title:

1. Cancer. I. Haskell, Charles M. [DNLM: 1. Neoplasms-

Cancer Treatment ISBN 0-7216-4566-6

© 1980 by W. B. Saunders Company. Copyright under the International Copyright Union.

Last digit is the print number:

SAMUEL C. BALLON, M.D. JOSEPH W. CULLEN, Ph.D.

MICHAEL BERMAN, M.D. JEAN B. deKERNION, M.D.

MARTIN J. CLINE, M.D. ERIC W. FONKALSRUD, M.D.

ROBERT P. GALE, M.D. H. PHILLIP KOEFFLER

JEROME M. HERSHMAN, M.D. ROBERT G. PARKER, M.D.

GUY J. F. JUILLARD, M.D. KENNETH P. RAMMING, M.D.

GREGORY P SARNA. M.D. RONALD K. TOMPKINS. M.D.

DONALD G SKINNER, M.D. WATSON WATRING. M.D.

ROBERT B. SMITH. M.D. THOMAS H. WEISENBURGER. M.D.

ALAN S. TESLER. M.D JACOB ZIGHELBOIM. M.D.

including the School of Medicine, the Jonsson Comprehensive Cancer

PART II TREATMENT OF SPECIFIC

Section 1. ESOPHAGUS 233

Section 1. CANCER OF THE PROSTATE 358

Section 1. GESTATIONAL TROPHOBLASTIC

Section 1. CANCER OF THE ORAL CAVITY

Section 2. NASAL CAVITY AND PARANASAL

Section 3. NASOPHARYNX 535

Section 6. CHEMOTHERAPY OF HEAD AND

Section 1. RETINOBLASTOMA 569

Section 1. MULTIPLE ENDOCRINE

Section 1. OSTEOSARCOMA 655

Section 1. BRAIN 726

Section 1. NEUROBLASTOMA 759

Section 1. MEDIASTINAL TUMORS 778

Section 1. ACUTE LYMPHOBLASTIC

Section 1. CHRONIC MYELOGENOUS LEUKEMIA... 832

PART III MANAGEMENT OF SELECTED

Section 1. MANAGEMENT OF MALIGNANT

SELECTED ABBREVIATIONS 1049

ed by a variety of professionals: surgeons, radiation therapists, medical on-

NATURAL HISTORY OF CANCER

1979 ESTIMATED CANCER INCIDENCE BY SITE AND SEXt

1979 ESTIMATED CANCER DEATHS BY SITE AND SEX

ment, as seen in the development of drug-resistant cancer cells. It is possible

tumors nun metastasize to distant organs prior to or coincident with their

For most types of malignant neoplasms the extent or stage of disease is a

critical determinant of prognosis and treatment. Thus, throughout this book

stances we retained well-established and widely employed alternative stag-

A variety of other factors have been proposed as important prognostic

The concern in establishing a treatment plan should be the quality of

Integrated Cancer Treatment

The importance of integrating the cancer treatment modalities is generally

of successful local treatment undertaken prior to metastatic spread. Lines C,

for clinically evident cancer is palliative; it fails because of cancer cell

chemotherapy is used immediately after local treatment in a patient with a

PROSPECTS FOR THE FUTURE

References (Asterisk indicates key reference)

treatment of cancer. Early surgical attempts, however, often resulted in the

toprevent airway obstruction, and nasogastric decompression of the stomach,

py for sarcomas, and immediate touch preparations for lymphomas may be

will result in a compromised operation or in severe wound healing