CORRESPONDENCE
Blinding of Clinical Investigators
To the Editor: It is a basic principle of clinical trial methodology
that investigators are blinded to the findings of an ongoing, prospective,
randomized trial. This is to reduce the risk of bias on the part of
investigators, which can manifest itself in unpredictable ways. For
example, investigators may favor a treatment regimen that they
interpret as more efficacious. In addition, one wishes to avoid multiple
analyses of the data, which increases the likelihood of a false-positive
finding at some point during the study.
In order to minimize the exposure of patents to an inferior treatment
arm in a randomized study, the activity and toxicity of study arms are
reviewed at specific preset points by an independent data-monitoring
committee. The committee may discontinue a study or one of its arms
as appropriate. Their statistical criteria for doing so will be stricter than
that required for the final evaluation of the study. For example, a P
value of .01 rather than .05 may be used to determine a statistically
significant difference in an interim analysis.
A report of a clinically relevant, three-arm study of patients with
metastatic lung cancer that was published in the Journal of Clinical
Oncology1 is in breach of these principles. The report describes the
findings of an interim analysis in each of the three arms, which resulted
in one of the three arms being discontinued because of inferior survival.
It is appropriate to report the findings in the discontinued arm but not
the findings in the other two arms which are to be continued in the
study. The findings in the latter two arms should rather be reported as
a single group for the purpose of comparison with the discontinued
arm. This will enhance the objectivity and scientific value of this and
other important trials.
R.P. Abratt
Groote Schuur Hospital
Cape, South Africa
REFERENCE
1. Comella P, Frasci G, Panza N, et al: Randomized trial comparing
cisplatin, gemcitabine, and vinorelbine with either cisplatin and gem-
citabine or cisplatin and vinorelbine in advanced non–small-cell lung
cancer: interim analysis of a phase III trial of the Southern Italy
Cooperative Oncology Group. J Clin Oncol 18:1451-1457, 2000
Ascertainment of the Incidence of Beckwith-
Wiedemann Syndrome in the National Wilms
Tumor Study Group
To the Editor: In the study by Porteus et al published in the May
2000 issue of the Journal of Clinical Oncology,1 the authors assume a
correct diagnosis of Beckwith-Wiedemann syndrome (BWS) from
National Wilms Tumor Study Group (NWSTG) data sheets completed
by registering physicians at the time of diagnosis. Apparently, there
was no systematic attempt to confirm the diagnosis of BWS—a crucial
point because several other rare but important “overgrowth” syn-
dromes, notably Perlman syndrome2 and Simpson-Golabi-Behmel
syndrome, are associated with Wilms’ tumor and clinical distinction
can be difficult. To emphasize the point, careful clinical examination of
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an unselected group of children with Wilms’ tumor presenting to one of
our institutions revealed a higher-than-expected level of congenital and
developmental abnormalities, including isolated hemihypertrophy.3
If our supposition about the data collection is correct, it is likely that
the NWTSG survey has underestimated the number of patients with
overgrowth syndromes and/or incorrectly ascribed all such cases to
BWS. The data provided by Porteus et al are, therefore, potentially
valuable, but some “fine tuning” is needed before they can be regarded
as accurate.
Richard Grundy
Institute of Child Health
University of Birmingham
Birmingham, United Kingdom
Jon Pritchard
Institute of Child Health
London, United Kingdom
REFERENCES
1. Porteus MW, Narkool P, Neuberg D, et al: Characteristics and
outcome of children with Beckwith-Wiedemann syndrome and Wilms’
tumor: A report from the National Wilms Tumor Study Group. J Clin
Oncol 18:2026-2031, 2000
2. Grundy RG, Pritchard J, Baraister M, et al: Perlman and Wiede-
mann-Beckwith syndromes: Two distinct conditions associated with
Wilms tumour. Eur J Pediatr 151:895-898, 1992
3. Grundy RG, Blacklay A, Cole T, et al: A review of 60 consec-
utive cases of Wilms tumour with documentation of the dysmorphic
syndromes and associated clinical features. Med Pediatr Oncol 35:126-
130, 2000
In Reply: We agree with Drs Grundy and Pritchard that one must
analyze the data presented in our report1 in light of the methodology
used. They are correct that central review of the cases, in terms of the
presence or absence of overgrowth syndromes, was not performed.
Patients were classified as having Beckwith-Wiedemann syndrome
(BWS) if they were reported as such by their primary treating
oncologist. This could have resulted in misclassification and an
overestimate or underestimate of the number of BWS patients in the
data set. Clinical examination of the patients suspected of having BWS
was beyond the scope of our study. One must interpret the data
regarding Wilms’ tumor and BWS keeping these limitations in mind.
A possible strength of this method is that patients were classified as
having BWS if their clinical oncologist thought they had BWS.
This may be an imprecise but clinically relevant way of looking at
the problem.
Lisa Diller
Dana-Farber Cancer Institute
Boston, MA
REFERENCE
1. Porteus MH, Narkool P, Neuberg D, et al: Characteristics and
outcome of children with Beckwith-Wiedemann syndrome and Wilms’
593
594
tumor: A report from the National Wilms Tumor Study Group. J Clin
Oncol 18:2026-2031, 2000
Hazards of Quality-of-Life Data for Clinical
Decision Making
To the Editor: Jatoi et al’s article, “On Appetite and Its Loss,”1
published in the August 2000 issue of the Journal of Clinical Oncology,
illustrates the challenges of evidence-based clinical oncology as ap-
plied to the management of weight loss in cancer. Jatoi et al begin their
article with an exchange between two physicians, an oncology fellow
and an attending oncologist, who discuss the evidence support for the
use of megestrol acetate to treat appetite loss in a woman, Ms Jones,
with an unspecified cancer. The major focus of this exchange is the lack
of an empirically demonstrated effect of megestrol acetate on quality of
life (QOL).
I found myself both gratified and alarmed by this exchange. As
someone with an abiding interest in psychosocial oncology, I was
gratified that the clinicians in the exchange were considering QOL data
in arriving at a patient management decision. I was alarmed, however,
that these clinicians were taking seriously QOL data from studies that
relied solely on measures of global QOL. As I argue below, exclusive
reliance on global QOL measures to study cancer QOL is misguided
and likely to yield inconsistent and, for the clinician, generally
confusing results.
Jatoi et al themselves highlight concerns over the use of global QOL
data as the basis for prescribing megestrol acetate. They cite method-
ologic criticisms of global QOL studies in an effort to explain the lack
of evidence for a QOL effect of megestrol acetate. Here I would like to
argue against the use of global QOL measures from a broader
conceptual perspective in hopes of more convincingly pointing up the
futility of using these measures to study the effectiveness of most
clinical oncology interventions. In this connection, I will argue for the
use of more disease- or condition-specific measures of QOL to
supplement more generic measures. This is not a new argument by any
stretch,2 but it is one that has been slower to catch on than many of us
in the psychosocial oncology arena would have liked.
The conceptual case for including disease- or condition-specific
QOL measures in cancer research draws from Brenner et al’s proximal-
distal continuum of health outcome measures.3 In clinical research, the
outcomes considered range from the more proximal (signs and symp-
toms) to the more distal (role functioning, general well-being). Accord-
ing to Brenner et al, proximal outcomes are those clinical indicators of
disease that are influenced most directly and powerfully by an effective
intervention. Distal outcomes are more removed from the illness per se
and are usually the product of a multitude of nonillness or “external”
factors; as such, distal outcomes tend to be influenced less directly and
less powerfully by even very effective health inverventions.3 Global
QOL is among the most distal of the indicators in the continuum of
outcomes usually considered in cancer clinical trials and therefore
requires the greatest number of external factors for its explanation.
In contrast to Jatoi et al’s statement that “we cannot totally discount
the possibility that megestrol acetate does improve global quality of life
but that our measurement tools are not detecting it,” the tenets of the
proximal-distal continuum would suggest that megestrol acetate does
not improve global QOL because global QOL is too far removed from
the immediate effects of megestrol acetate for an effect to be detected
reliably. Jatoi et al actually seem to be saying this when they argue that
“global quality of life subsumes appetite [and] is far more intricate and
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CORRESPONDENCE
intangible,” but they also imply that a better measure of global QOL
might be the solution to the lack of an empirical effect.
In fact, the effects of megestrol acetate on QOL are much more likely
to be detected through the use of a symptom-specific QOL measure4
that is responsive to the QOL correlates of appetite and weight gain,
which megestrol acetate has been shown to increase.5,6 Cella et al4 have
developed a brief visual analog measure of the subjective QOL benefits
of appetite and weight gain in the treatment of anorexia/cachexia. This
measure has demonstrated validity among people with acquired im-
mune deficiency syndrome7 and is being tested in an ongoing study of
cancer-related anorexia/cachexia.
Of note, QOL researchers are concerned that disease- and
symptom-specific QOL measures will supplant—rather than supple-
ment—more generic QOL measures. This can result in an incom-
plete picture of the impact of cancer and its treatment. As Moinpour
et al8 have pointed out, if the Southwest Oncology Group trial
comparing orchiectomy plus placebo with orchiectomy plus flut-
amide in the treatment of prostate cancer had included just a
symptom measure, the negative impact on emotional functioning in
the latter arm would have been missed. This underscores the
often-cited need for a modular approach to QOL assessment that
combines disease- or symptom-specific measures with more generic
measures. In terms of the proximal-distal continuum described
above,3 an important analytic strategy to explore would evaluate
indirect causal relations between the treatment and the more distal
outcome of generic QOL. Thus, the effect of megestrol acetate on
generic QOL may operate through the more proximal measure of
subjective QOL benefits of appetite and weight gain.
In conclusion, the literature on megestrol acetate and global QOL
supports the suggestion that having some QOL data is not necessarily
better than having no QOL data, particularly if QOL data of limited
validity are used to make patient management decisions. It is hearten-
ing that the oncology fellow in Jatoi et al’s scenario decided to
prescribe megestrol acetate even after considering the overwhelmingly
negative and null QOL studies. Given the quality of the QOL data they
were considering, it is more appropriate in this instance, as Jatoi et al
argue passionately, to rely on humanity as a guide to patient manage-
ment and to discount the placebo-controlled, randomized data.
Mark Somerfield
American Society of Clinical Oncology
Alexandria, VA
NOTE. The opinions expressed herein are those of the author and do
not necessarily reflect those of the American Society of Clinical
Oncology.
REFERENCES
1. Jatoi A, Kumar S, Sloan JA, et al: On appetite and its loss. J Clin
Oncol 18:2930-2932, 2000
2. Cella DF, Bonomi AE: Measuring quality of life: 1995 update.
Oncology 9:47-60, 1995 (suppl)
3. Brenner MH, Curbow B, Legro MW: The proximal-distal con-
tinuum of multiple health outcome measures: The case of cataract
surgery. Med Care 33:AS236-AS244, 1995 (suppl)
4. Cella DF, Von Roenn J, Lloyd S, et al: The Bristol-Myers
Anorexia/Cachexia Recovery Instrument (BACRI): A brief assessment
of patients’ subjective response to treatment for anorexia/cachexia.
Qual Life Res 4:221-231, 1995
CORRESPONDENCE
5. Loprinzi CL, Lugler JW, Sloan JA, et al: Randomized compari-
son of megestrol acetate verus dexamethasone verus fluoxymesterone
for the treatment of cancer anorexia/cachexia. J Clin Oncol 17:3299-
3306, 1999
6. Bruera E, Macmillan K, Hanson J, et al: A controlled trial of
megestrol acetate on appetite, caloric intake, nutritional status, and
other symptoms in patients with advanced cancer. Cancer 66:1279-
1282, 1990
7. Von Roenn JH, Armstrong D, Kotler DP, et al: Megestrol acetate
in patients with AIDS-related cachexia. Ann Intern Med 121:393-399,
1994
8. Moinpour C, Ganz P, Rowland J, et al: The value of quality of life
data in judging patient benefit: Experts respond to ODAC. Cancer
Letter 25:1-5, 1999
In Reply: We thank Dr Somerfield for his comments. He makes a
critical point with eloquence: global measures of quality of life should
sometimes be supplemented with symptom-specific ones. He draws on
the article by Brenner et al on cataract surgery to discuss proximal and
distal measures of quality of life.1 Somerfield suggests a range of
quality-of-life tools that might be used in cancer symptom control
research, as shown in Fig 1.
We believe our review of 15 placebo-controlled trials of meges-
trol acetate in cancer patients illustrates Somerfield’s point well.2
Improvement in appetite, a proximal measure, occurred in 13 of 15
of these studies, whereas improvement in global quality of life, a
distal measure, occurred in only one (see Table 1 in Jatoi et al2).
Had these 13 studies not measured this proximal symptom, justifi-
cation for prescribing megestrol acetate for cancer-associated an-
orexia would be sparse.
Although we agree with Somerfield’s comments on methods of
measurement, we ourselves continue to struggle with the meaning
behind these measurements. As alluded to in the article by Brenner et
al,1 cataract surgery allows individuals to drive, read, and look people
in the eye. The meaning of such proximal quality-of-life measurements
is obvious. In contrast, appetite stimulation in patients with advanced
cancer carries limited consequences. Patients may eat more, but they do
not live longer, tolerate chemotherapy better, or become more func-
tional. As discussed in our article,2 it is from Meares’ article,3 as well
as from Holden’s,4 that we begin to find meaning behind these
proximal measurements: “Food, from time immemorial, is part of the
nurturing process ... .”
Somerfield’s comments remind us of the challenge of measuring
quality of life in cancer clinical trials and of the challenge of including
both proximal and distal measures in cancer symptom control research.
Fig 1. Quality-of-life (QOL) tools for use in cancer symptom control
research.
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595
Yet, there is another part to that challenge: finding meaning behind
these measurements. Therein lies the art of oncology.
Aminah Jatoi
Mayo Clinic
Rochester, MN
Phuong L. Nguyen
The University of Minnesota Medical School
Minneapolis, MN
Shaji Kumar
Mayo Clinic
Jeff Sloan
Mayo Clinic
Charles L. Loprinzi
Mayo Clinic
REFERENCES
1. Brenner MH, Curbow B, Legro MW: The proximal-distal con-
tinuum of multiple health outcome measures: The case of cataract
surgery. Med Care 33:AS236-AS244, 1995
2. Jatoi A, Kumar S, Sloan JA, et al: On appetite and its loss. J Clin
Oncol 18:2930-2932, 2000
3. Meares CJ: Primary caregiver perceptions of intake cessation in
patients who are terminally ill. Oncol Nurs Forum 24:1751-1757, 1997
4. Holden CM: Anorexia in the terminally ill cancer patient: The
emotional impact in the patient and the family. Hosp J 7:73-84, 1991
When the Tumor Is Not the Target,
Tell the Children
To The Editor: Hilden et al1 make an important contribution by
contrasting the courses of two terminally ill children. They reiterate our
observations made in 1977 and thereafter that the loneliness and fear of
children who are not informed about their impending death can be
abrogated by open discussions with them. We advocated, therefore, that
children older than 5 years be informed about their impending death by
the physician and/or parents when it becomes evident that they would
be unresponsive to further therapy.2-4 However, statements about
incorporating palliative principles into the care of dying children, such
as guiding parents gently to see their children’s perception of their
outcome and discussing the art of aiding terminally ill children, remain
too vague.1,5 Specific guidelines are necessary. Recently, we suggested
that the terminally ill child faces the most profound loss one can
imagine and must respond to this state of severe grief.4 To overcome
the grief, certain milestones need to be reached: acceptance of the loss,
acceptance of a new reality, and the search for and attainment of new
goals. If the latter steps are accomplished, the devastating effect of grief
will be ameliorated. The goals of the children may differ: to be treated
further with experimental drugs, to go home, to see their friends, or to
grow spiritually.2-4 These observations are consistent with Frankl’s
postulate that a person searches for meaning in life and with Byock’s
conclusion that the dying person has the potential for substantial
personal growth.6,7 If this premise is accepted, the team, in addition to
engineering the optimal health care for a dying child, should try to
convey this perception of life to the family and to assist them in finding
new goals. This work by the team should be guided by the awareness
that seeking to protect children from the knowledge of their impending
596
death may deprive them of living to their full potential. Therefore, the
inclusion in the team of professionals in psychology and those skilled
in spiritual guidance is critical. Our more recently formulated model,
grief reaction of a dying person, serves as a framework for our team in
the specific palliative support of the child. We found that the majority
of 73 children who participated in the program of open communication
died with greater calm and composure.4
Our model provides essential insight into the behavior and potential
growth of a dying child. It requires that the caretakers agree that a
person has a deeply rooted need to search for meaning in his life. The
art of taking care of a dying child, therefore, is to convey this
perception convincingly to the child and his family and to assist the
family as guideposts for the child’s journey.
Ruprecht Nitschke
William H. Meyer
Heather C. Huszti
University of Oklahoma Health Sciences Center
Oklahoma City, OK
REFERENCES
1. Hilden J, Watterson J, Chrastek J: Tell the children. J Clin Oncol
18:3193-3195, 2000
2. Nitschke R, Wunder S, Sexauer CL, et al: The final-stage
conference: The patient’s decision on research drugs in pediatric
oncology. J Pediatr Psychol 2:58-64, 1977
3. Nitschke R, Humphrey GB, Sexauer CL, et al: Therapeutic
choices made by patients with end-stage cancer. J Pediatr 101:471-476,
1982
4. Nitschke R, Meyer WH, Sexauer CL, et al: Care of terminally ill
children with cancer. Med Pediatr Oncol 34:268-270, 2000
5. Anderson PM. Editorial commentary: J Clin Oncol 18:3195, 2000
6. Frankl V: Man’s Search for Meaning. New York, NY, Washing-
ton Square Press, 1984
7. Byock I: Dying Well. New York, NY, Riverhead Books, 1997
Conflicting Phase II Efficacy Data for Doxil
To the Editor: A recent article by Gordon et al1 described the phase
II experience in the United States using Doxil (doxorubicin HCl liposome
injection; Alza Corporation, Mountain View, CA) in platinum- and
paclitaxel-refractory epithelial ovarian cancer. This trial demonstrated an
18% (15 of 82 patients) response rate in this patient population.
The Food and Drug Administration (FDA) reviewed this study as
part of a new drug application (NDA) submitted in December 1998.
Both Alza’s and the FDA’s findings were presented publicly at the
meeting of the Oncology Drug Advisory Committee (ODAC) in June
1999 (for further information, contact the FDA’s Website at http:
www.fda.gov/cder/foi). Independent review of the primary tumor
measurements by the FDA confirmed a similar response rate of 17%
(14 of 82 patients) in the trial described by Gordon et al.1 A second
study submitted with the NDA, similar in design to the one presented
by Gordon et al, failed to show any responses in the 36 patients with
platinum- and paclitaxel-refractory epithelial ovarian cancer (NDA
50-718, SE 006, Study 30-47E).
Both trials were multicenter, single-arm, efficacy evaluations of
single-agent Doxil in patients with platinum- and taxane-refractory
ovarian cancer. The second study was conducted exclusively in Europe
and was performed in a similar fashion to that reported by Gordon et al.
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CORRESPONDENCE
Minor differences in baseline patient characteristics were noted when
the two studies were compared. An explanation for the striking difference
in efficacy between the two studies was sought by both the FDA and Alza,
and although these conflicting data were the subject of much discussion by
the ODAC, no compelling explanation was offered.
Based on the tumor measurement data comprising the NDA, which
showed a response rate of 14% in 145 patients, the ODAC voted to
recommend that the FDA grant accelerated approval for Doxil for use
in platinum- and taxane-refractory ovarian cancer. Accelerated ap-
proval is a regulatory provision2 whereby the FDA may approve a drug
based on a surrogate end point for clinical settings where there is no
available therapy. Under this regulation, the company is required to
perform a phase IV trial after NDA approval to demonstrate that
treatment with the approved drug is associated with clinical benefit. On
the basis of response rate as a surrogate end point in the setting of
platinum- and paclitaxel-refractory epithelial ovarian cancer, the FDA
subsequently granted accelerated approval for marketing Doxil for this
supplemental indication.
A fuller description of the clinical evidence supporting Doxil’s
currently approved uses, including data on the second trial, is found in
the package insert for Doxil. Prescribing physicians and patients should
be aware of these data when therapy in platinum- and taxane-refractory
ovarian cancer is being considered.
Gregory Frykman
Grant Williams
Richard Pazdur
Center for Drug Evaluation and Research
United States Food and Drug Administration
Rockville, MD
NOTE. The views expressed herein do not necessarily represent the
views or findings of the United States Food and Drug Administration or
the United States Government.
REFERENCES
1. Gordon AD, Granai CO, Rose PG, et al: Phase II study of
liposomal doxorubicin in platinum- and paclitaxel-refractory epithelial
ovarian cancer. J Clin Oncol 18:3093-3100, 2000
2. 21 Code of Federal Regulations §314.500.
In Reply: As Drs Frykman, Williams, and Pazdur point out, a
description of the evidence supporting the activity of Doxil (doxoru-
bicin HCl liposome injection; Alza Corporation, Mountain View, CA)
in platinum- and taxane-refractory ovarian cancer is present in the
package insert and the public record from the presentation to the
Oncology Drug Advisory Committee in June 1999. This includes the
unpublished results from the European study that they have cited. Two
other studies were presented: the data from Muggia et al,1 which
showed an overall response rate of 26% and a response rate of 21.4%
in platinum- and taxane-refractory patients, and our study,2 which
reported an 18.2% response rate. When all three studies are combined,
the result is the 14% response rate quoted by Frykman, Williams,
and Pazdur.
We also recently reported the results of a randomized phase III trial
of pegylated liposomal doxorubicin compared with topotecan in recur-
rent ovarian cancer at the 36th Annual Meeting of the American
Society of Clinical Oncology in May 2000.3 The response rate in the
platinum- and taxane-refractory subset was 12.1% for pegylated
CORRESPONDENCE
liposomal doxorubicin compared with 6.8% for topotecan. This differ-
ence was not statistically significant.
Although the reasons for the difference in the European study are not
clear, we believe that the other phase II studies, which demonstrated
activity along with the comparable results in the phase III trial, clearly
support a role for liposomal doxorubicin in platinum- and taxane-
refractory ovarian cancer.
Alan N. Gordon
Texas Oncology
Dallas, TX
REFERENCES
1. Muggia FM, Hainsworth JD, Jeffers S, et al: A phase II study of
liposomal doxorubicin in refractory ovarian cancer: Antitumor activity
and toxicity modification by liposomal encapsulation. J Clin Oncol
15:987-993, 1997
2. Gordon AN, Granai CO, Rose PG et al: Phase II study of
liposomal doxorubicin in platinum and paclitaxel refractory epithelial
ovarian cancer. J Clin Oncol 18:3093-3100, 2000
3. Gordon AN, Fleagle JT, Guthrie D, et al: Interim analysis of a
phase III randomized trial of Doxil/caelyx versus topotecan in the
treatment of patients with relapsed ovarian cancer. Proc Am Soc Clin
Oncol 19:380a, 2000 (abstr 1504)
Bleomycin-Induced Lung Toxicity and
Pentoxifylline
To the Editor: A 45-year-old man was treated with three cycles of
bleomycin, etoposide, and cisplatin (BEP) chemotherapy for a stage
IIIc seminoma. The pretreatment carbon monoxide diffusing capacity
of the lungs (DLCO; corrected for hemoglobin) was 100% predicted,
with a forced expiratory volume in 1 second (FEV1) of 117% predicted
and a forced vital capacity (FVC) of 134% predicted.
Four weeks after treatment, a chest x-ray was performed for dyspnea
and cough. Bilateral basilar infiltrates were seen, a 7-day course of
Levaquin failed to help, and prednisone 50 mg/d was begun. The
consolidation diminished, but prominent new bilateral ground-glass
opacities became apparent on chest x-ray and computed tomography
scan, despite continued prednisone use. Symptoms worsened, and the
patient was found to desaturate to 79% on room air. Therefore, 10
weeks after completion of BEP, the patient was admitted and started on
high-dose co-trimoxazole and intravenous methylprednisolone 40 mg
every 6 hours. A thoracoscopic lung biopsy was performed, and the
pathology report supported bleomycin-induced toxicity, with no evi-
dence of fungal, mycobacterial, or PCP involvement. Additionally, the
immunofluorescence study using antisera to antibody and complement
was negative, confirming nonimmunologic alveolar damage. The
patient did not improve after 1 week, and room air transcutaneous
oxygen saturations remained near 86% at rest, with desaturation below
80% on exertion. After 1 week, pentoxifylline was added at a dose of
400 mg orally bid and then increased to 400 mg tid. Four days later,
room air oxygen saturation was steady at 94%. At discharge, DLCO was
28%, FEV1 was 67%, and FVC was 57% of predicted.
The pentoxifylline was discontinued 41/2 months after discharge,
and prednisone was tapered from 50 mg orally bid at intervals of 2 to
4 weeks, first to 75 mg orally daily, then to 50 mg, 40 mg, 30 mg, and
finally 20 mg orally daily. At the most recent follow-up, 5 months after
discharge, the patient was well and walked 1 hour daily without
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597
dyspnea. At almost 4 months after discharge, DLCO was 65%, FEV1
was 106%, and FVC was 115% of predicted. A chest x-ray at 5 months
after discharge showed only a shrinking 4 ⫻ 2-cm right-sided
filled cavity.
Bleomycin-induced lung toxicity has been reported to occur in 2% to
40% of patients, depending on criteria used and the presence of risk
factors, and death occurs in about 2% of treated patients.1 Patients
typically present with cough and dyspnea and have variable radio-
graphic findings, most frequently a bilateral basilar interstitial pattern.
Bleomycin probably induces lung toxicity through the induction of
oxygen radicals, with recruitment of leukocytes and fibroblasts aug-
menting the early inflammatory and later fibrotic reactions.2 In animal
models, Entzian et al3 have found that pentoxifylline decreases neu-
trophil alveolitis and weight loss associated with bleomycin lung
toxicity. Kremer et al,4 by contrast, found no benefit in a mouse lung
injury model. In other studies, pentoxifylline has been shown to inhibit
inflammatory cytokines and exerts in vitro inhibition of fibroblast
proliferation and extracellular matrix production.5 Recently, Delanian
et al6 demonstrated clinical benefit in a cohort of 43 patients with
radiation-induced cutaneous fibrosis using a combination of pentoxi-
fylline and vitamin E.
Our patient suffered clinical and radiographic progression of bleo-
mycin-induced lung injury on prednisone and failed to improve after 1
week of high dose, intravenous methylprednisolone. Clinical symptoms
and oxygen saturation improved 4 days after the addition of oral
pentoxifylline to the patient’s regimen, and the patient experienced a
progressive improvement in his symptoms, radiographic abnormalities,
and, most notably, pulmonary function studies. White and Stover7
reported their experience with 10 patients who developed severe
bleomycin-induced pneumonitis. Seven patients were treated with
corticosteroids, and significant clinical and radiographic improvement
was noted; however, results of pulmonary function tests remained
abnormal. Prolonged therapy was required over several months to
maintain improvement, and tapering of the corticosteroid dosage led to
recurrence both clinically and radiographically in five of the seven
patients. Mortality was 60% among the 10 patients, with three early
deaths in untreated patients and three late deaths occurring 12 to 15
months after diagnosis. Van Barneveld et al8 reported their experience
with eight patients with bleomycin-induced pneumonitis who were not
treated with corticosteroids. In contrast to the series of White and
Stover, the seven surviving patients had complete reversibility of
clinical, radiographic, and pulmonary function abnormalities. The
apparent discrepancy between these two small series may be related to
the relative severity of the pneumonitis, as evidenced by the strikingly
high mortality rate reported by White and Stover, and by the broad
definition of bleomycin-induced pneumonitis and the lack of symptoms
in two out of the eight patients in the Van Barneveld series.
Our patient clearly had severe, symptomatic, bleomycin-induced
pneumonitis. He progressed while receiving corticosteroids, and im-
proved on high-dose corticosteroids only after more than 1 week of
treatment and the addition of pentoxifylline. Unlike the experience
reported by White and Stover, our patient had significant improvements
in his pulmonary function studies as well as his symptoms and
radiographic abnormalities. He tolerated tapering of his corticosteroid
dose well and remains asymptomatic. There are laboratory data to
support a role for pentoxifylline in the treatment of inflammatory and
fibrotic processes as well as clinical data in the setting of radiation-
induced soft tissue fibrosis. The possibility that pentoxifylline contrib-
uted to the recovery of our patient cannot be completely excluded.
It is unlikely that a prospective study of pentoxifylline in this setting
can be undertaken. We present this case with the hope that other
598
clinicians faced with cases of severe bleomycin-induced pneumonitis
with progression on corticosteroids might consider a trial of pentoxi-
fylline and report their experience. As cases accumulate, the merits of
pentoxifylline may be better assessed.
John Goffin
Harvey Kreisman
Victor Sandor
McGill University
Montreal, Canada
REFERENCES
1. Simpson AB, Paul J, Graham J, et al: Fatal bleomycin pulmonary
toxicity in the west of Scotland 1991-95: A review of patients with
germ cell tumours. Br J Cancer 78:1061-1066, 1998
2. Chandler DB: Possible mechanisms of bleomycin-induced fibro-
sis. Clin Chest Med 11:21-30, 1990
3. Entzian P, Zahringer U, Schlaak M, et al: Comparative study on
effects of pentoxifylline, prednisolone and colchicine in experimental
alveolitis. Int J Immunopharmacol 20:723-735, 1998
4. Kremer S, Breuer R, Lossos IS, et al: Effect of immunomodula-
tors on bleomycin-induced lung injury. Respiration 66:455-462, 1999
5. Berman B, Duncan MR: Pentoxifylline inhibits the proliferation
of human fibroblasts derived from keloid, scleroderma and morphoea
skin and their production of collagen, glycosaminoglycans and fi-
bronectin. Br J Dermatol 123:339-346, 1990
6. Delanian S, Balla-Mekias S, Lefaix JL: Striking regression of
chronic radiotherapy damage in a clinical trial of combined pentoxi-
fylline and tocopherol. J Clin Oncol 17:3283-3290, 1999
7. White DA, Stover DE: Severe bleomycin-induced pneumonitis:
Clinical features and response to corticosteroids. Chest 86:723-728,
1984
8. Van Barneveld PW, Sleijfer DT, van der Mark TW, et al: Natural
course of bleomycin-induced pneumonitis: A follow-up study. Am Rev
Respir Dis 135:48-51, 1987
Complemenary Therapies in Cancer Patients
To the Editor: The articles by Richardson et al1 and Boon et al2 and
the accompanying editorial by Burstein3 in the July 2000 issue of the
Journal of Clinical Oncology provide useful and interesting informa-
tion regarding the use of complementary therapies in cancer patients.
Burstein argues that the widespread use of complementary medicine by
cancer patients is a reflection of many needs and concerns that are
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CORRESPONDENCE
not being met by conventional medical practice. This certainly
seems like a plausible interpretation. One might ask, however,
where is the control group, ie, what is the frequency of complemen-
tary medicine use among patients with other diseases or, perhaps
more importantly, in the healthy population? Without citing specific
chapter and verse, I think we all agree that it’s quite high. Again, the
question of why is certainly relevant.
My concern is not with the spiritual practices/psychotherapy/mind/
body activities so much as it is with the ingestion of all kinds of
alternative medicines. It is a mystery to me why society chooses to so
carefully regulate the introduction and use of new pharmaceuticals in
the traditional medicine sphere but tolerates the sale of most anything
from your friendly health food store, not to mention mainstream
supermarket. I think we have got the cart before the horse. Whatever
happened to the notion that one had to prove safety and efficacy before
putting a medicine into your body? We now have the reverse situation,
where we as a medical profession are asked to prove lack of efficacy
and/or safety in order to get people to stop taking these things.
In this regard, most of our leading medical schools, including mine,
rather than standing up for science, have succumbed to this advancing
tide of alternative therapies. It’s a really difficult, unpleasant battle, but
I don’t think we should give up. We should listen to our patients’
concerns, encourage those activities that lessen anxiety, and provide
emotional support but discourage the use of expensive medications of
no proven value and uncertain toxicity. Otherwise, there is no end to it.
Anyone with an incurable disease, malignant or otherwise, becomes
susceptible and all too often a participant in the latest panacea. It’s a
very costly enterprise at a time when we are greatly concerned about
traditional health care costs. The money would far better be channeled
into medical research.
Leonard R. Prosnitz
Duke University Medical Center
Durham, NC
REFERENCES
1. Richardson MA, Sanders T, Palmer JL, et al: Complementary/
alternative medicine use in a comprehensive cancer center and the
implications for oncology. J Clin Oncol 18:2505-2514, 2000
2. Boon H, Stewart M, Kennard MA, et al: Use of complementary/
alternative medicine by breast cancer survivors in Ontario: Prevalence
and perceptions. J Clin Oncol 18:2515-2521, 2000
3. Burstein HJ: Discussing complementary therapies with cancer
patients: What should we talking about. J Clin Oncol 18:2501-2504,
2000