OCNA Sept 2009 Radiosurgery and Radiotherapy For Benign Skull Base Tumors

Radiosurgery and Radiotherapy for Benign Skull Base Tumors
Contents
Preface xiii
Robert A. Battista
Glossary e1
The History of Stereotactic Radiosurgery and Radiotherapy 593

John M. Lasak and John P. Gorecki
Stereotactic neurosurgery originated from the pioneering work of Horsley and
Clarke, who developed a stereotactic apparatus to study the monkey brain in
1908. Spiegel and Wycis applied this technology to the human brain in 1947,
which ultimately lead to the development of multiple stereotactic neurosurgi-
cal devices during the 1950s. It was Lars Leksell of Sweden, however, who
envisioned stereotactic radiosurgery. Leksell developed the gamma knife
to treat intracranial lesions in a noninvasive fashion. His work stimulated
worldwide interest and created the field of stereotactic radiosurgery.
Basic Principles of Radiobiology Applied to Radiosurgery and Radiotherapy

of Benign Skull Base Tumors 601
Christopher J. Anker and Dennis C. Shrieve
Various types of ionizing radiation may be used therapeutically for benign
skull base tumors. Treatment may involve single-dose radiosurgery, or
may be fractionated into multiple doses. Designing and implementing
a radiotherapy plan that maximizes the therapeutic ratio requires knowl-
edge of the biophysical and radiobiological principles involved in these
treatments. These basic radiobiological tenets are discussed in this chap-
ter, with the focus on radiotherapy of benign skull base tumors. Animal and
clinical data, however, acquired from the radiation of malignant tumors are
necessarily included, as they comprise much of our knowledge of fraction-
ation schedules, central nervous system (CNS) toxicity, and CNS volume
effects.
Radiation Effects on the Auditory and Vestibular Systems 623

Niranjan Bhandare, William M. Mendenhall, and Patrick J. Antonelli
Definitive or postoperative radiation therapy (RT) is commonly used for the
management of intracranial and extracranial head and neck tumors. Be-
cause of the variability of tumor location and dimensions, sparing of non-
target normal tissue and organs may not be possible. Treatment modalities
that deliver the highest doses of radiation to the auditory system include
stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy
(FSRT) for the treatment of vestibular schwannomas (VS), and fractionated
radiotherapy (FRT) or intensity-modulated radiation therapy (IMRT) for the
treatment of head and neck malignancies. Radiation therapy for VS is
viii Contents
unique because of its involvement of the inner ear and preexisting auditory
and vestibular dysfunction. Auditory and vestibular dysfunction following
RT for VS may be limited by limiting the total dose of cranial nerve VIII
irradiation and by fractionation.
Gama Knife Radiosurgery for Vestibular Schwannoma 635

Robert A. Battista
In 1951, Dr. Lars Leksell from Sweden conceived of what is now known as
gamma knife radiosurgery (GKRS). Since Leksell first treated a patient who
had a vestibular schwannoma in 1967, there has been a year-to-year in-
crease in the number of patients treated with the gamma knife for vestib-
ular schwannoma. This article outlines the technique of GKRS and
discusses the current results of its use to treat vestibular schwannomas.
Other topics discussed include tumor control, treatment of recurrent/re-
sidual and cystic vestibular schwannomas, and the results of treatment
of neurofibromatosis type 2.
Stereotactic Radiotherapy for Vestibular Schwannoma 655

Patrick Sweeney, Santosh Yajnik, William Hartsell, George Bovis,
and Jagannath Venkatesan
Vestibular schwannomas are benign tumors of the Schwann cells of the
eighth (VIII) cranial nerve. Precision radiotherapy techniques used to man-
age these tumors include stereotactic radiotherapy (SRT), which can be
delivered with either a conventional or hypofractionated regimen. The ra-
dio–biologic rationale and reported clinical outcomes of patients treated
with SRT are reviewed.
Cyberknife Radiotherapy for Vestibular Schwannoma 665

Gordon T. Sakamoto, Nikolas Blevins, and Iris C. Gibbs
Stereotactic radiosurgery is a well-established treatment modality for ves-
tibular schwannoma. Initial reports using single-stage radiosurgery have
demonstrated excellent tumor control rates. Many patients now elect to
undergo radiosurgery given the potential for tumor control while avoiding
the morbidity associated with microsurgical resection. In attempt to im-
prove hearing preservation rates of single-state radiosurgery, staged
frame-based radiotherapy using a 12-hour interfraction interval was
used at the authors’ institution and has shown a hearing preservation
rate of 77% at 2 years of follow-up. With the arrival of the Cyberknife,
a frameless, image-guided radiotherapy system, staged stereotactic ra-
diotherapy for vestibular schwannoma became more practical. This article
outlines the rationale and treatment protocols developed at Stanford Uni-
versity (California) and reports the authors’ initial experience using the Cy-
berknife to treat vestibular schwannoma.
Contents ix
Stereotactic Radiosurgery and Stereotactic Radiotherapy in the Treatment

of Skull Base Meningiomas 677
John M. McGregor and Atom Sarker
Meningiomas are the most common nonglial brain tumors. They tend to be
slow growing and benign and can reach substantial sizes before becoming
symptomatic. Complete surgical resection of intracranial meningiomas re-
mains the treatment of choice. Location of a meningioma within the cranial
vault may make complete surgical resection unlikely; tumors arising from
the dura of the skull base are particularly challenging. Advances in radia-
tion therapy, including stereotactic techniques, can expand the options
for treatment available in these situations. They may be used as adjuncts
to surgery or as alternative modalities in the treatment of these complex
tumors.
Radiosurgery for Glomus Jugulare Tumors 689

Jonathan P. Miller, Maroun T. Semaan, Robert J. Maciunas,
Douglas B. Einstein, and Cliff A. Megerian
Glomus jugulare tumors arise from adventitial chemoreceptor tissue in the
jugular bulb. Although histologically benign, these tumors can be locally
aggressive because of their proximity to the lower cranial nerves and major
vascular structures. Traditional treatment involves microsurgical removal
with or without endovascular embolization, but morbidity following total re-
section can result in injury to the facial and lower cranial nerves. Radiosur-
gery has recently emerged as a promising alternative to older therapeutic
strategies for treatment of glomus jugulare tumors. This article reviews the
latest benefits of radiosurgery and demonstrates how this modality repre-
sents an effective treatment option for glomus jugulare tumors with excel-
lent tumor control and low risk for morbidity. In addition, this article will
detail the role of minimally invasive sub-total resection of glomas jugulare
tumors as a surgical complement to gamma knife therapy.
Microsurgery After Radiosurgery or Radiotherapy for Vestibular Schwannomas 707

William H. Slattery III
Radiosurgery or radiotherapy for vestibular schwannomas has become
a common practice with a high chance for tumor control. Despite the
high rate of tumor control, there are some tumors that cannot be con-
trolled with radiation therapy. Surgical treatment after radiosurgery or ra-
diotherapy may be necessary for tumors that continue to grow, or for
patients who develop brainstem compressive symptoms, disabling hem-
ifacial spasm, or hydrocephalus. The House Ear Clinic (Los Angeles,
California) experience with microsurgery after irradiation has demon-
strated that the facial nerve is different once it has been radiated. An ir-
radiated facial nerve’s regeneration potential is diminished, and the
recovery from microsurgical trauma is not as robust. It is recommended
that patients who require microsurgical excision following radiosurgery
or radiotherapy have a more conservative approach compared to non-
irradiated cases.
x Contents
Neoplastic Transformation After Radiosurgery or Radiotherapy: Risk and Realities 717

Ajay Niranjan, Douglas Kondziolka, and L. Dade Lunsford
In recent years, the use of radiosurgery or radiotherapy for benign brain tu-
mors has increased significantly. Although long-term follow-up from sev-
eral centers suggests that radiosurgery or radiotherapy is effective and
safe, there are particular concerns regarding development of radiation-in-
duced tumors. This article reviews the use of radiosurgery and fractionated
radiation therapy with particular regard to new tumor induction and malig-
nant transformation. The authors have found that the risk of radiation as-
sociated tumors after radiosurgery or radiotherapy for benign brain
tumors is very low. All patients should be informed about the risks and con-
sequences of radiation and microsurgery. The current practice standards
for radiosurgery should not be modified because of this very low risk.
Index 731
Radiosurgery and Radiotherapy for Benign Skull Base Tumors
Preface
Robert A. Battista, MD
Guest Editor
Benign tumors of the base of the skull, such as vestibular schwannoma, glomus jugu-
lare, and meningiomas commonly cause symptoms referable to the realm of an otolar-
yngologist. Specifically, the symptoms of these types of tumors may include hearing
loss, dizziness, tinnitus, facial numbness, facial paralysis, or difficulty swallowing.
For this reason, otolaryngologists are the physicians most frequently involved in the
care of these patients.
Over the last two decades, radiosurgery and radiotherapy have been used with
increasing frequency to treat benign tumors of the skull base. Stereotactic radiation
is now used for both primary management and secondary management of recurrent
or planned residual disease. While traditional microsurgery remains the main treatment
for skull-base tumors, The North American Skull Base Society predicts that, in the near
future, a greater percentage of vestibular schwannomas will be treated with radiosur-
gery than by traditional microsurgery.
In order to prepare for this paradigm shift in treatment, otolaryngologists must
become familiar with the different types of radiation treatments, as well as the potential
complications associated with radiation treatment for benign skull-base tumors. It is
for this reason that this edition of Otolaryngologic Clinics of North America was
compiled.
The issue begins with the fascinating history of stereotactic radiosurgery and radio-
therapy in an article by Drs. Lasak and Gorecki. The next article, by Drs. Anker and
Shrieve, is a thorough discussion of the biologic effects of radiation. The article by
Dr. Bhandare and colleagues narrows the discussion of radiation effects by focusing
on radiation’s effects on the auditory and vestibular systems. Articles by Drs. Battista,
Sweeney and colleagues, Sakamoto and colleagues, McGregor and Sarkar, Miller and
colleagues, are devoted to various radiation techniques to treat vestibular
schwannoma, glomus tumors, and meningiomas. Because there are stereotactic radi-
ation failures, the article by Dr. Slattery is devoted to the results of microsurgery
following stereotactic radiation. The final article, by Dr. Niranjan, discusses the unfor-
tunate—but rare—chance of malignancy following stereotactic radiation. For each
contributing author, I would like to extend my many thanks for your efforts.
Otolaryngol Clin N Am 42 (2009) xiii–xiv

doi:10.1016/j.otc.2009.05.001 oto.theclinics.com
0030-6665/09/$ – see front matter ª 2009 Elsevier Inc. All rights reserved.
xiv Preface
Finally, a note regarding terminology used throughout the book:

Radiosurgery is radiation delivered with a single dose of radiation, commonly with
rigid immobilization of the head.
Radiotherapy is radiation delivered in more than one fraction.
Isocenter is the precise mathematical location where the radiation dose is aimed.
Conformal is the close approximation of radiation delivery to tumor.
Fractionated therapy is radiation delivered in multiple sessions.
Marginal dose is the dose of radiation delivered to the outer edge of tumor.
Tumor size, unless noted otherwise, is reported as the maximal tumor diameter of
its cerebellopontine angle component.
I hope that you enjoy and learn from this issue of the Otolaryngologic Clinics of
North America.
Robert A. Battista, MD
The Ear Institute of Chicago, LLC
Department of Otolaryngology
Northwestern University Medical School
303 East Chicago Avenue
Chicago, IL 60611-3008, USA
E-mail address:
r-battista2@northwestern.edu
Radiosurgery and Radiotherapy for Benign Skull Base Tumors xi
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Surgical Management of Nasal Obstruction:
Cough: An Interdisciplinary Problem Rhinologic Perspective
Kenneth W. Altman, MD, PhD, and Samuel S. Becker, MD, Guest Editor
Richard S. Irwin, MD, Guest Editors
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Thyroid and Parathyroid Surgery
Palliative Therapy in Otolaryngology^Head
Ralph Tufano, MD, and Sara Pai, MD, and Neck Surgery
Guest Editors
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and Geoffrey P. Dunn, MD, FASC,
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Access your subscription at:
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Glossary
Radiosurgery Radiation delivered with a single dose of
radiation, commonly with rigid
immobilization of the head
Radiotherapy Radiation delivered in more than one
fraction
Isocenter Precise mathematical location where
radiation dose is aimed
Conformal Close approximation of radiation delivery
to tumor
Fractionated therapy Radiation delivered in multiple sessions
Marginal dose Dose of radiation delivered to the outer
edge of tumor
Otolaryngol Clin N Am 42 (2009) e1

The Histor y
of Stere ot actic
Radiosurger y
a nd Radiotherapy
John M. Lasak, MDa,b,c,d,*, John P. Gorecki, MDb,d,e
KEYWORDS
Stereotactic radiosurgery Stereotactic radiotherapy
Gamma knife Linear accelerator (LINAC) Cyberknife
Historical review
Stereotactic radiosurgery evolved from the pioneering work reported in 1908 by

Horsley, a neurophysiologist and neurosurgeon, and his associate Clarke, a mathema-
tician. Horsley and Clarke1 developed a tool that could localize an intracranial struc-
ture in three dimensions, enabling the insertion of a needle electrode for studying
a desired locale within the monkey brain. These early investigators developed a stereo-
tactic atlas of the monkey brain based on a cartesian coordinate system relative to
landmarks (the inferior orbital rim and internal auditory canal) on the monkey’s skull.2,3
Similar to today’s stereotactic head frames, their stereotactic apparatus was fixed to
the monkey’s skull. Using this apparatus, Horsley and Clarke were the first to describe
the stereotactic destruction of an intracranial target using electrode electrocoagula-
tion.2,3 Despite the fact that Clarke patented the use of this device in humans, it
was never applied outside the animal model.4,5
Spiegel, a neurologist and director of experimental neurology at Temple Medical
School in Philadelphia, began developing the first stereotactic device for human
use. Spiegel and colleagues,6 a neurosurgeon who worked in Spiegel’s laboratory
as a medical student, reported on their human stereotactic apparatus in 1947. Their
device was fixed to the patient’s head in much the same way as Horsley and Clarke’s
simian model; however, intraoperative radiographs were used for localizing intracra-
nial structures during the procedure. By 1952, Spiegel and Wycis7 had developed
a
Department of Pediatrics, Kansas University School of Medicine-Wichita, Wichita, KS 67214, USA
b
Department of Surgery, Kansas University School of Medicine-Wichita, Wichita, KS 67214,
USA
c
The Wichita Ear Clinic, 9350 East Central Avenue, Wichita, KS 67206, USA
d
The Jack B. Davis Gamma Knife Center, Wesley Medical Center, Wichita, KS 67214, USA
e
Department of Surgery, The Wichita Surgical Specialists, PA, 818 North Emporia, S-200,
Wichita, KS 67214, USA
* Corresponding author. The Wichita Ear Clinic, 9350 East Central Avenue, Wichita, KS 67206.
E-mail address: Jlasak@wichitaearclinic.com (J.M. Lasak).
Otolaryngol Clin N Am 42 (2009) 593–599

594 Lasak & Gorecki
a stereotactic atlas of the human brain, and they coined their technique stereoence-
phalotomy. Their methods paved the way for functional human stereotactic neurosur-
gery. By this time, it was understood that sectioning the extrapyramidal system could
be used to treat movement disorders such as Parkinson’s disease; however, open
neurosurgical operative mortality was quite high at the time. Russell Meyers,8,9
a neurosurgeon at the University of Iowa and a leader in functional neurosurgery for
movement disorders, reported that his open neurosurgical techniques carried
a 15.7% mortality rate. By 1958, Spiegel and colleagues10 were reporting the opera-
tive mortality for stereotactic surgery for movement disorders to be 2%. Their method-
ology and reduced mortality rate were met with enthusiasm by the worldwide
neurosurgical community. Multiple stereotactic apparatus designs were developed
in the 1950’s, and it was estimated that nearly 25,000 functional stereotactic proce-
dures were done worldwide before the introduction of L-dopa therapy for movement
disorders.11,12
Lars Leksell is known as the father of stereotactic radiosurgery for his pioneering
work applying the stereotaxic technique to radiation delivery. Leksell was born in
Fassberg, Sweden, in 1907, and attended medical school at the Karolinska Institute.
By 1935, he began his neurosurgical training under Herbert Olivecrona, and ultimately
succeeded him as chairman of neurosurgery in 1961. Leksell understood that much of
the morbidity and mortality associated with neurosurgery during this time was a conse-
quence of invasive procedures, and therefore, he dreamed of developing a minimally
invasive approach to treat intracranial lesions. Building on the principles produced by
Horsley and Clarke and applied by Spiegel and Wycis, Leksell13 developed his arc-
centered stereotactic apparatus for intracerebral surgery in 1947. The device enabled
the precise placement of a needle or electrode into a desired location within the
human brain. Leksell first described the concept of stereotactic radiosurgery in
1951.14 The initial device used a collimated x-ray beam (gamma rays) that could
move along the semicircular arch of his stereotactic apparatus to strike an intracranial
target.14 Leksell14 discussed the potential of using stereotactic radiosurgery to
produce a lesion within the human brain, and noted the technology might be well-
suited for functional neurosurgery. As exciting as the concept was, the effect of radi-
ation on the central nervous system was poorly understood. Further research was
needed, and Leksell14 developed a feline stereotactic radiosurgical device to deter-
mine the effects on the cat brain.
During the late 1950s and early 1960s Leksell searched for an ideal form of radiant
energy convenient for clinical stereotactic radiosurgery. Physicists Liden and Larrson
of Uppsala University in Sweden were integral in the development of a system that
used a cyclotron to direct proton beams at a target.15–17 These physicists determined
in the animal model that a sharply delineated stereotactic lesion was produced with
high-energy protons.15 In 1960, Leksell and colleagues16 performed their first human
stereotactic proton beam operation (a bilateral anterior capsulotomy) at the Gustaf
Werner Institute in Uppsala. About the same time, Woodruff and colleagues18 at
University of California at Berkeley introduced a similar cyclotron-based radiosurgery
system and began irradiating pituitary lesions. The cyclotron ultimately was deter-
mined to be too cumbersome and impractical for clinical use. Leksell eventually
settled on gamma rays as a practical compromise for stereotactic radiosurgery. The
first gamma unit was installed in the Sophiahemmet Hospital in Stockholm, Sweden,
in 1968. The device used 179 sources of cobalt-60 distributed with collimators to
create a sharply circumscribed disc-shaped lesion, and the device initially was in-
tended for use during functional neurosurgery.19–21 The second gamma unit was
installed at the Karolinska Hospital in Stockholm, Sweden, in 1974 (Fig. 1). This
Fig.1. Lars Leksell and the 2nd gamma Knife in the world; 1974. Courtesy of Dan Leksell, son
of Lars Leksell; Stockholm, Sweden.
updated version was designed specifically for stereotactic radiosurgery and produced
a more practical spherical radiation field.22 Plain radiographs and air encephalography
typically were used to identify the target during these early procedures.20 In 1972,
Steiner and colleagues23 applied angiography to radiosurgery when treating the first
arteriovenous malformation.
Target localization improved dramatically when CT was used in conjunction with the
stereotactic apparatus, as reported by Bergstom and Grietz24 in 1976. Leksell25
described the application of CT during radiosurgery and noted the technique enabled
rapid and accurate target localization. With the advent of better imaging methods,
solid tumors became radiosurgical targets. Leksell and Jernberg’s26 rationale for
treating vestibular schwannomas with radiosurgery is detailed in his A Note on the
Treatment of Acoustic Tumours. Leksell26 discussed how Harvey Cushing referred
to the cerebellopontine angle as the bloody angle, and that a noninvasive modality
to treat these tumors was needed. Furthermore, he quoted Pool,27 who stated
complete acoustic tumor removal was ‘‘ not only one of the most exacting and labo-
rious, but also one of the most dangerous and unpredictable operations in the entire
neurosurgical repertoire.’’ Leksell further discussed the evolution of vestibular
schwannoma surgery and the operative morbidity and mortality reported by vestibular
schwannoma surgeons of the time (Pool, Olivecrona, House, and Hitselberger).27–30
He discussed that despite improving mortality rates, incomplete tumor removal was
common and often had unsatisfactory long-term results. Leksell believed stereotactic
radiosurgery was a logical approach to decrease the morbidity and mortality associ-
ated with vestibular schwannoma surgery.
From 1968 to 1982, Leksell22 treated 762 patients who had stereotactic radiosurgery
using the Gamma Knife (Elekta, Stockholm, Sweden), and over half of these patients
had arteriovenous malformations or benign tumors, including 94 vestibular schwanno-
mas. By 1985, Leksell and colleagues31 reported the potential application of MRI to ra-
diosurgery, pointing out the many advantages of this detailed imaging modality. Today
CT, MRI, and angiography are used commonly during radiosurgical planning.
After 4.5 years of intensive regulatory review, the first Gamma Knife unit was
installed in the United States at the University of Pittsburgh in 1987 under the
596 Lasak & Gorecki
leadership of Lunsford, a neurosurgeon.32 Lunsford’s effort paved the way for the
installation of Gamma Knife units throughout the United States. The first updated
model C Gamma Knife unit was installed in Krefeld, Germany, in 1999.33 This unit
included sophisticated treatment planning software and an automated positioning
system (APS) that was less cumbersome and time-consuming than the model B
manual trunnion system. The APS offered more conformal dose plans and less radia-
tion exposure to personnel.34,35 The model C Gamma Knife is the most commonly
used unit throughout world today. The latest version of the Gamma Knife, the Leksell
Gamma Knife Perfexion was introduced in 2006 and the first unit became operational
at the Timone University Hospital of Marseille, France. The Perfexion is reported to
have a wider treatment range, enabling the collision-free management of hard-to-
reach targets in a shorter period of time.36
Although Leksell considered employing linear accelerator (LINAC) technology for
stereotactic radiosurgery, technical and accessibility limitations led him to use gamma
rays. The first report using a LINAC- based radiotherapy system was in 1983 by Betti
and Derechinsky.37 Their early device employed several isocentric fixed radiation
fields arrayed on different planes, and the patient’s head then was rotated around
a horizontal lateral axis.37 Shortly thereafter, Colombo and colleagues38 reported their
technique based on multiple converging arc irradiations. Hartman and colleagues re-
ported a similar technique in 1985.39 It was Lutz and Winston, however, who created
the technology to quantify and calculate dosimetry and improve the accuracy of the
LINAC- based system.40,41 Most commercially available LINAC systems today are
an evolution of Lutz and Winston’s original work. Since linear accelerators were
more available and less expensive, the LINAC became a popular radiosurgery system.
Sophisticated and easy-to-use dosimetry planning software has been produced, and
starting in the mid-to-late 1980s, the Brigham and Women’s Hospital in Massachu-
setts and the University of Florida began treating patients with their LINAC stereotactic
radiotherapy systems.42,43 Today, over 150 LINAC radiotherapy systems are in use
worldwide, and many different models are emerging to meet the needs of this increas-
ingly popular form of radiotherapy.
Perhaps the most innovative LINAC based system developed in recent years was
produced by Adler and colleagues, a neurosurgeon at Stanford University (Stanford,
California) (Fig. 2). In 1997, Adler44 introduced the Cyberknife (Accuray Incorporated,
Sunnyvale, California) at the 12th meeting of the World Society of Stereotactic Func-
tional Neurosurgery. Cyberknife is a frameless stereotactic radiotherapy system that
mounts a lightweight (130 lb) 6 mV linear accelerator on a highly mobile robotic
arm. This revolutionary design incorporates a real-time guidance system, which obvi-
ates the need for rigid fixation as used in frame base systems. Cyberknife determines
the location of the skull or spine in the coordinate frame of the radiation delivery
system by comparing digitally reconstructed CT phantoms obtained from the patient’s
treatment planning images with real-time oblique radiographs obtained during the
procedure.45 If needed, fiducials may be implanted within the target and used during
image registration. The dose placement accuracy has been determined to compare
favorably with frame-based systems.46,47 When the patient (target) moves, the system
detects the change, and the robot makes appropriate adjustments to maintain accu-
rate targeting. It is also possible, through sophisticated infrared tracking, to accom-
modate target movement during respiration.48 This innovative system has enabled
stereotactic radiotherapy to be expanded to include the head, spine, chest, abdomen,
and pelvis.
The future role of stereotactic radiosurgery and radiotherapy is certain to expand.
Technological and clinical advancements have occurred in every decade since the
Fig. 2. John Adler and the Cyberknife. Courtesy of Stanford University, Department of
Neurosurgery; Stanford, CA.
1940s. The medical community and patients have a well-founded combination of

anticipation and expectation for noninvasive treatment methods. The potential for
decreased morbidity and improved quality of life with the use of radiosurgery and
radiotherapy is being realized. The growing involvement of medical disciplines outside
of neurosurgery and radiation oncology, such as neurotologists, thoracic surgeons,
general surgeons, and urologists undoubtedly will lead to fundamental shifts in the
use of radiosurgery and radiotherapy. Stereotactic radiosurgery and radiotherapy
will continue to advance treatment options for patients, and the future of this evolving
field should be interesting.
REFERENCES
1. Horsley V, Clarke RH. The structure and functions of the cerebellum examined by
a new method. Brain 1908;31:45–124.
2. Clarke RH, Horsley V. On a method of investigating the deep ganglia and tracts of
the central nervous system (cerebellum). Br Med J 1906;2:1799–800.
3. Horsley V. The function of the so-called motor area of the brain. The Linacre
Lecture. Br Med J 1909;2:125–32.
4. Levy R. A short history of stereotactic neurosurgery. Park Ridge (IL): American
Association of Neurological Surgeons; 1992.
5. Schaltenbrand G. Personal observations on the development of stereotaxy.
Confin Neurol 1975;37:410–6.
6. Spiegel EA, Wycis HT, Marks M, et al. Stereotactic apparatus for operations on
the human brain. Science 1947;106:349–50.
598 Lasak & Gorecki
7. Spiegel EA, Wycis HT. Stereoencephalotomy, part I. New York: Grune & Stratton;
1952.
8. Meyers R. The modification of alternating tremors, rigidity, and festination by
surgery of the basal ganglia. Res Publ Assoc Res Nerv Ment Dis 1942;21:602–65.
9. Meyers R. Historical background and personal experiences in the surgical relief
of hyperkinesias and hypertonus. In: Fields W, editor. Pathogenesis and treatment
of parkinsonism. Springfield (IL): Thomas; 1958. p. 229–70.
10. Spiegel EA, Wycis HT, Baird HW, et al. Long-range effects of electropallido–an-
trostomy in extrapyramidal and convulsive disorders. Neurology 1958;8:734–40.
11. Gildenberg PL. Principles of stereotaxis and instruments. In: DeSalles AAF,
Goetshe SJ, editors. Stereotactic surgery and radiosurgery. Madison (WI):
Medical Physics; 1993. p. 17–28.
12. Spiegel EA. Methodological problems in stereoencephalotomy. Confin Neurol
1965;26:125–32.
13. Leksell L. A stereotaxic apparatus for intracerebral surgery. Acta Chir Scand
1947;99:229–33.
14. Leksell L. The stereotactic method and radiosurgery of the brain. Acta Chir Scand
1951;102:316–9.
15. Larsson B, Leksell L, Rexed B, et al. The high-energy proton beam as a neurosur-
gical tool. Nature 1958;182:1222–3.
16. Leksell L, Larsson B, Andersson B, et al. Lesions in the depth of the brain
produced by a beam of high-energy protons. Acta Radiol 1960;54:251–64.
17. Leksell L, Larsson B, Rexed B. The use of high-energy protons for surgery in
man. Acta Chir Scand 1963;125:1–7.
18. Woodruff KH, Lyamn JT, Lawrence JH, et al. Delayed sequelae of pituitary irradi-
ation. Hum Pathol 1984;15:48–54.
19. Leksell L. Stereotaxis and radiosurgery. An operative system. Springfield (IL):
Charles Thomas; 1971.
20. Larsson B, Liden K, Sarby B. Irradiation of small structures through the skull. Acta
Radiol Ther Phys Biol 1974;13:512–34.
21. Wennerstrand J, Ungerstedt U. Cerebral radiosurgery II. An anatomical study of
gamma radiolesions. Acta Chir Scand 1970;136:133–7.
22. Leksell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychiatr 1983;46:
797–803.
23. Steiner L, Leksell L, Greitz DM, et al. Stereotactic radiosurgery for cerebral arte-
riovenous malformations. Acta Chir Scand 1972;138:459–64.
24. Bergstrom M, Greitz T. Stereotaxic computed tomography. Am J Roentgenol
1976;127:167–70.
25. Leksell L, Jernberg B. Stereotaxis and tomography. A technical note. Acta Neuro-
chir 1980;52(1–2):1–7.
26. Leksell L. A note on the treatment of acoustic tumours. Acta Chir Scand 1971;
137:763–5.
27. Pool JL, Pava AA. The early diagnosis and treatment of acoustic tumors. Spring-
field (IL): Thomas; 1957.
28. Olivecrona H. The surgical treatment of intracranial tumors. In: Handbuch der
Neurochirurgie, vol. 4. Heidelberg (Germany): Springer; 1967.
29. House W. Management of the large acoustic tumor. In: Hamberger CA, Wersaall J,
editors. Nobel symposium 10. Disorders of the skull base region. Stockholm
(Sweden): Almqvist & Wiksell; 1969.
30. Hitselberger W. Management of the large acoustic tumor. In: Hamberger CA,
Wersaall J, editors. Nobel symposium 10. Disorders of the skull base region.
Stockholm (Sweden): Almqvist & Wiksell; 1969.
31. Leksell L, Leksell D, Schwebel J. Stereotaxis and nuclear magnetic resonance.
J Neurol Neurosurg Psychiatr 1985;48:14–8.
32. Lunsford L, Flickinger J, Lindner G, et al. Stereotactic radiosurgery of the brain
using the first United States 201 cobalt-60 gamma knife. Neurosurgery 1989;
24(2):151–9.
33. Horstmann GA, Schopgens H, van Eck AT, et al. First clinical experience with the
automatic positioning system and Leksell gamma knife model C. Technical note.
J Neurosurg 2000;93(3):193–7.
34. Tlachacova D, Schmitt M, Novotny J, et al. A comparison of the gamma knife
model C and the automatic positioning system with Leksell model B. J Neurosurg
2005;102:25–8.
35. Horstmann GA, Van Eck AT. Gamma knife model C with the automatic positioning
system and its impact on treating vestibular schwannomas. J Neurosurg 2002;
97(5):450–5.
36. Regis J, Manabu T, Guillot C, et al. Radiosurgery of the head and neck with the
worlds first fully robotized 192 Cobalt-60 source Leksell gamma knife perfection
in clinical use. Available at: www.elekta.com. Accessed November 15, 2008.
37. Betti O, Derechinsky V. Irradiation stereotaxique multifasceaux. Neurochirurgie
1983;29:295–8.
38. Colombo F, Benedetti A, Pozza F, et al. External stereotactic irradiation by linear
accelerator. Neurosurgery 1985;16:154–60.
39. Hartmann G, Schlegel W, Sturm V, et al. Cerebral radiation surgery using moving
field irradiation at a linear accelerator facility. Int J Radiat Oncol Biol Phys 1985;2:
1185–92.
40. Lutz W, Winston K, Maleki N. A system for stereotactic radiosurgery with a linear
accelerator. Int J Radiat Oncol Biol Phys 1988;14:373–81.
41. Winston K, Lutz W. Linear accelerator as a neurosurgical tool for stereotactic
radiosurgery. Neurosurgery 1988;22:454–64.
42. Kooy H, Nedzi L, Loeffler J, et al. Treatment planning for stereotactic radiosurgery
of intracranial lesions. Int J Radiat Oncol Biol Phys 1991;21:683–93.
43. Friedman W, Bova F. The University of Florida radiosurgical system. Surg Neurol
1989;32:334–42.
44. Adler JR, Chang SD, Murphy MJ, et al. The Cyberknife: a frameless robotic
system for radiosurgery. Stereotact Funct Neurosurg 1997;69:124–8.
45. Chang SD, Adler JR. Robotics and radiosurgery. Stereotact Funct Neurosurg
2001;76:204–8.
46. Murphy MJ, Cox RS. The accuracy of dose localization for an image-guided
frameless radiosurgery system. Med Phys 1996;23:2043–9.
47. Maciunas RJ, Galloway RL, Latimer JW. The application of accuracy of stereo-
tactic frames. Neurosurgery 1994;35:682–95.
48. Schweikard A, Glosser G, Bodduluri M, et al. Robotic motion compensation for
respiratory movement during radiosurgery. Comput Aided Surg 2000;5(4):263–7.
Basic Princ iples of
Radiobiolo gy Applie d
to Radiosurger y a nd
Radiotherapy of Benign
Skull Base Tumor s
Christopher J. Anker, MD*, Dennis C. Shrieve, MD, PhD
KEYWORDS
Radiobiology Radiotherapy Radiosurgery Benign tumors
Normal tissue tolerance
Various benign tumors arise in the base of the skull including epithelial, fibro-
osseous, mesenchymal, neurogenic, and vascular varieties. Despite the slow growth
of benign skull base tumors, significant clinical symptoms, and even death, may
result from compression and dysfunction of adjacent vital structures. The mainstay
of treatment of benign skull base tumors is surgical resection. Radiation may be indi-
cated in nonoperable cases or in the postoperative or recurrent setting. The goal of
radiotherapy is to provide local control without a high risk of treatment-related
toxicity.
Radiotherapy of tumors of the skull base may involve one of several types of
ionizing radiation, given as single fraction (most commonly referred to as stereotactic
radiosurgery or SRS) or fractionated radiotherapy. An understanding of the biophys-
ical and radiobiological principles involved in these treatments is essential to the
design and delivery of safe and efficacious treatment. The purpose of this chapter
is to discuss the basic radiobiological principles applied to radiotherapy of skull
base tumors.
TYPES OF IONIZING RADIATION

Gamma Rays and X-Rays
Gamma rays and X-rays are electromagnetic radiation with energies in the range of
100 to 2 billion electron volts (eV). X-rays are produced when electrons transition
from a higher to lower energy level, usually in the outer shell of heavy atoms and
Department of Radiation Oncology, Huntsman Cancer Hospital, University of Utah, 1950 Circle
of Hope, Room 1570, Salt Lake City, UT 84112-5560, USA
* Corresponding author.
E-mail address: chris.anker@hci.utah.edu (C.J. Anker).

602 Anker & Shrieve
are thus produced outside the nucleus. X-rays may be the products of radioactivity
(electron capture) or may be man made from X-ray tubes or linear accelerators, which
accelerate electrons onto a heavy metal target producing a continuous spectrum of
photon energies up to that of the accelerated electrons. Gamma rays are photons
emitted by radioactive nuclei (eg, Cobalt-60) and have a much narrower range of ener-
gies than X-rays, 10 keV to 10 MeV. Gamma rays and X-rays are otherwise identical
and once produced are indistinguishable.
Protons
The applicability of protons to radiotherapy is based on the physical properties of
these particles and the related characteristics of dose deposition in irradiated tissues.1
Quantitatively, the entrance dose for particle beams is low compared to photons. An
unaltered beam will deposit more than 50% of its energy over a 2- to 3-cm narrow path
at a depth in water that depends on the beam energy. This peak in energy deposition
at depth is referred to as the ‘‘Bragg Peak.’’ The beam may be altered to spread the
Bragg peak to conform to the thickness and depth of the volume to be treated.
However, the entrance dose is significantly increased in this case (Fig. 1).
X-rays, gamma rays, and protons are considered to be low linear energy transfer
(LET) radiation with roughly equivalent biological effectiveness. Protons have only
a slightly higher radiobiological effectiveness (RBE) than Cobalt-60. In practice this
small difference is taken into account when prescribing treatment by calculating
dose for protons in cobalt Gray equivalents (CGE), whether for single or multiple
fractions.
BASIC PRINCIPLES OF RADIOBIOLOGY

Direct Versus Indirect Effects of Radiation
When tissues are irradiated with low-LET radiation, the vast majority of photons
interact with intracellular water molecules by stripping an electron from a hydrogen
atom. This results in a fast electron and an ionized water molecule through Compton
scattering. The fast electrons interact with surrounding water molecules through
further ionizing events. The positively charged water molecules are extremely unstable
and dissociate into an H1 ion and an OH$ free hydroxyl radical. The hydroxyl radical is
highly chemically reactive with sufficient energy to break chemical bonds in nearby
Depth Dose Distribution in Water

120
Spread-out Bragg Peak
100
Relative Dose (%)
80
60
10 MVp X rays
40
20
Unmodulated Proton Beam
0
0 4 8 12 16 20
Depth (cm)
Fig. 1. Depth dose curves for a 160 MeV proton beam. Both unmodulated and spread-out
Bragg Peak curves are shown. A 10 MVp X-ray curve is shown for comparison.
Basic Principles of Radiobiology 603
(within 2 nm) molecules. This indirect effect of radiation acting through the free radical
intermediary is responsible for 70% of the damage in irradiated tissues. The remaining
damage is caused by the direct effect resulting from fast electrons interacting with the
biologically important molecules.2
Mammalian Cell Survival Curves

Survival of cells following single doses of ionizing radiation is a probability function of
absorbed dose measured in the unit Gray (1 Gy 5 1 J/kg absorbed dose). Mammalian
cell survival curves obtained following single-dose irradiation in culture (Fig. 2) have
a characteristic shape including a low-dose shoulder region followed by a steeply
sloped, or more continuously bending, high-dose region. The shoulder region is
a reflection of the accumulation of sublethal cellular damage at low doses with lethality
resulting from the interaction of two or more such sublethal events.3,4 One model
considers that DNA is the target molecule for cell killing by ionizing radiation and
that a double-strand break in the DNA is necessary and sufficient to cause cell death
(defined as loss of ability to divide). Double-strand breaks may result from the passage
of a single particle track or by two separate particle tracks causing two single-strand
breaks occurring closely in space and time (Fig. 3). Cellular mechanisms of single-
strand break repair are efficient, and therefore these represent sublethal damage.
By definition, in this model, double-strand breaks are irreparable and lethal. Such
a model is described by the linear-quadratic formula
2
SF 5 eðaD1bD Þ
where SF is the fraction of cells surviving a dose, D, of radiation expressed in Gy.5 a is

the coefficient related to single-event cell killing, and b the coefficient related to cell
killing through the interaction of sublethal events. a/b is the ratio of the relative contri-
butions of these two components to overall cell kill. The b component, related to the
amount of reparable damage, is the more variable of the two coefficients among tissue
types. Cell types and tissues may vary in the a/b, resulting in slightly differently shaped
1
Surviving Fraction
0.1
D2
0.01
SF = e-(αD+βD2)
0.001
0 5 10 15
Dose (Gy)
Fig. 2. Curve for mammalian cell survival as a function of dose of radiation (solid line) given
as a single fraction. The a/b is 10 Gy, a dose at which the contributions to cell killing by single
events (aD, dashed line) and the interaction of sublethal events (bD2) are equal.
604 Anker & Shrieve
Fig. 3. Double-strand break production by single events (aD) or interaction of events (bD2).
response curves (Fig. 4A). The ratio a/b is the single dose at which overall cell killing is
equally attributed to these two components (see Fig. 2).
aD 5 bD2
or
D 5 a=b
Most mammalian cell survival curves are well fit to the linear-quadratic model.6,7 Cell
survival following a single dose of radiation in vitro reflects the intrinsic radiosensitivity
of a particular cell type to a particular type of radiation. There are few in vitro model
systems for the study of the radiobiology of benign skull base tumors.
Radiobiology of Fractionated Radiotherapy

A spectrum of fractionation schedules are used to treat benign skull base tumors,
ranging from single-fraction radiosurgery to fully fractionated courses of radiotherapy.
For fractionated radiotherapy, each dose (fraction) produces similar biological effects
A B
Low α/β
High α/β
Effect
Effect
High α/β
Low α/β
Dose Dose
Fig. 4. Comparison of single-dose effect curves (A) and fractionated dose-effect curves (B) for
low and high a/b tissues. The small advantage seen in the low dose region sparing low a/b
tissues (A) is amplified through dose fractionation (B).
(eg, cell survival) given sufficient interfraction interval (Fig. 4B). The linear quadratic
formula for fractionated doses thus becomes

2 n
SF 5 e-ad-bd
where d is the dose per fraction and n is the total number of fractions.
A basic principle of radiobiology and radiotherapy is that dose fractionation spares
virtually all cell and tissue types. ‘‘Sparing’’ means that for a given total dose, there will
be a lower level of biological effect associated with multiple fractions compared to
a single dose. As the number of fractions increases, the total dose (n d) required
to achieve a certain level of biological effect also increases (Fig. 5A). The magnitude
of the sparing effect of dose fractionation varies, however, and depends on a/b. The
biologically effective dose is represented by

d
BED Gya=b 5 nd 11
a=b
where BED is expressed in Gya/b to indicate that it should be used only to compare
effects in tissues with the same a/b, n is the number of fractions of dose d and nd
is, therefore, the total dose (D). BED can be expressed as

BED Gya=b 5 D F
where F is a fractionation factor

d
F 5 11 :
a=b
F increases with increasing dose per fraction d, but this effect is dampened by
a/b and may be negligible for very high a/b, where F approaches 1.
The linear-quadratic formulation provides a means of estimating the effects of dose
fractionation. Other factors, such as a rapid doubling time, may be accounted for by
additional terms.8 In the context of benign skull base tumors, which typically grow
slowly, a time factor is not likely to be important and has not, therefore, been included
for the purposes of this discussion.
A Total Dose Required to Acheive BED B Relative BED of Fractionated vs Single-

Equivalent to 20 Gy in a Single Fraction Dose RT
80 1.2
70
Total Dose (Gy)
1
Relative BED
60
50 0.8
40 0.6
30 0.4
20
10 0.2
0 0
0 5 10 15 20 25 0 5 10 15 20 25
Number of Fractions Number of Fractions
Fig. 5. The effect of dose fractionation on the biological effectiveness of radiation for low
a/b (solid lines) versus high a/b (dashed lines) tissues. (A) Isoeffect curves show the increase
in total dose required to maintain biological effectiveness with increasing number of frac-
tions. (B) Decreasing biological effectiveness with increasing fraction number while main-
taining total dose.
606 Anker & Shrieve
A larger a/b indicates little contribution from the interaction of sublethal events. A
lower a/b indicates a greater contribution from this type of damage, the potential for
more interfraction repair, and a greater degree of sparing by fractionation than for
cell types with a larger a/b (see Figs. 4 and 5). This principle is the basis for fraction-
ated radiotherapy.
Malignant tumors and rapidly proliferating normal tissues (eg, skin, mucosa, and
bone marrow) demonstrate a high a/b (range: 8–12) and obtain modest sparing through
dose fractionation. Other normal tissues, including those of the central nervous system
(CNS) have a lower a/b (range: 2–4) and exhibit marked sparing with dose fraction-
ation.4,9 This effect is demonstrated by comparing the total dose required to maintain
a certain BED when various numbers of fractions are used (see Fig. 5). The magnitude
of this effect of dose fractionation is quantitatively very different for low compared to
high a/b tissues. This forms the basis for simultaneously maintaining treatment efficacy
for tissues with high a/b, while decreasing toxicity for tissues with low a/b through dose
fractionation.
Application of the Linear-Quadratic Equation to Benign Brain Tumors

Little information is available regarding the a/b of benign brain tumors. Using clinical
data, it may be possible to estimate a/b based on isoeffective fractionation schedules.
If two fractionation schedules result in an equivalent clinical effect, they may be
assumed to have the same BED and the linear quadratic model may be used to calcu-
late the a/b.10 Since

d
BED Gya=b 5 D 11
a=b
by setting BED1 5 BED2, the unknown a/b is calculated as follows
BED1 5 BED2
or

d1 d2
D1 11 5 D2 11
a=b a=b
or
ðD2 d2 Þ ðD1 d1 Þ
a=b 5
D1 D2
This approach has been used to estimate a/b for benign meningioma, assuming,
based on clinical data, that a single radiosurgery dose of 15 Gy and fractionated treat-
ment to 54 Gy in 30 fractions result in equivalent local control. The resulting a/b is
3.3.10
While meningiomas have been almost exclusively treated with radiosurgery or fully
fractionated radiotherapy, vestibular schwannomas have been treated with a number
of fractionation schedules (Table 1). Historically, radiosurgery doses have decreased
from approximately 18 Gy to 12–13 Gy without compromise of local tumor control and
with significant decrease in morbidity, including hearing loss and trigeminal and facial
neuropathies.11 Equivalent local control and levels of hearing preservation have been
achieved with schedules between 1 and 32 fractions without significant trigeminal or
facial neuropathies.12–17 Using these data, the a/b may be estimated using the recip-
rocal plot method of Douglas and Fowler (Fig. 6A).18 This method involves
Table 1
Fractionation schedules used to treat vestibular schwannomas
Total
Reference Dose Calculated BED Local Hearing
Author # (Gy) Fractions a/ba (Gy3) Control Preservation
11
Flickinger 13 1 – 69 99% 6yr 70% 6yr
et al
15
Poen 21 3 2.75 70 97% 2yr 77% 2yr
et al
17
Williams 25 5 3.67 67 100% 70% 3yr
17
Williams 30 10 4.65 60 100% 100% 3yr
16
Wallner 45 25 2.75 72 94% 15yr –
et al
12
Andrews 50 25 1.86 83 97 3yr 70 3yr
et al
13
Chan 54 30 1.75 86 98% 5yr 88% 3yr
et al
14
Combs 57.6 32 1.46 92 93% 5yr 94% 5yr
et al
a
a/b calculated assuming isoeffectiveness with 13 Gy in one fraction.
rearrangement of the linear-quadratic equation so that inverse total dose (1/D) may be
plotted against dose per fraction (d):

1 a b
5 1 d
D InðSFÞ InðSFÞ
The intercept on the abscissa provides an a/b estimate of 2.3 Gy. What is clear from
this analysis is that a/b for vestibular schwannomas is not near the 10 Gy value assumed
and measured for many malignant tumors (Fig. 6B). None of these fractionation sched-
ules appear to have a clear advantage in terms of therapeutic ratio, since each result in
excellent tumor control and equivalent rates of useful hearing preservation. The
Acoustic Neuroma Local Control

A 0.09
B 70
1/Total Dose, 1/D (1/Gy)
0.08
60
0.07
Total Dose (Gy)
2
0.06 50
3
0.05 40
0.04 30
0.03 10
20
0.02
0.01 10
0 0
-4 -2 0 2 4 6 8 10 12 14 0 5 10 15 20 25 30 35
Dose per fraction, d (Gy) Number of Fractions
Fig. 6. (A) Reciprocal of the total dose as a function of dose per fraction for various reported
treatment regimens used to successfully treat vestibular schwannomas (see Table 1). The
slope is proportional to b. The intercept on the ordinate axis is proportional to a. The inter-
cept on the abscissa gives a value of d equal to -a/b, which equates to 2.3 Gy. (B) Total dose
versus number of fractions for vestibular schwannoma treatment regimens. Symbols repre-
sent data points. Curves represent modeling for a/b of 2, 3 and 10 Gy anchored at 13 Gy in
a single fraction. These data points to fit an a/b between 2 and 3.
608 Anker & Shrieve
decision to fractionate or use single-dose radiosurgery for vestibular schwannomas is

based on tumor size and volume effects on normal tissue risk for brain, brain stem, and
nerve.
Time Interval Required for Maximal Repair Between Fractions

Allowing for sufficient time to pass between fractions thus permitting maximal repair of
sublethal damage in normal tissues is crucial to take full advantage of the sparing
effects of dose fractionation. Information on the kinetics of repair of sublethal radiation
damage in the CNS comes from the work of Ang and colleagues.19 They found biex-
ponential repair kinetics with half times of 0.7 and 3.8 hours for the fast and slow
components, respectively. This work indicates that even a 6- to 8-hour interval will
allow accumulation of unrepaired sublethal damage and lower the tolerance dose of
spinal cord.20 This prediction has been supported by increased rates of myelopathy
in patients treated for head and neck cancers with three fractions per day.21
Model Predicting Tumor Control Probability Based on Cell Survival

Tumor control probability (TCP) is a function of the likelihood of inactivating all tumor
cells in a given tumor following Poisson statistics. In Poisson statistics the probability
of a specific number of events (eg, no surviving tumor cells) occurring is governed by
ðex Þðxn Þ
PðnÞ 5
n!
where x is the average number of events and n is the specific number of events for
which the probability (P) is calculated. Therefore, the probability of a tumor containing
no surviving cells following treatment is
ðeN Þðx0 Þ
Pð0Þ 5 5 eN
0!
where N is the average number of tumor cells remaining per tumor, determined by the
pretreatment number of cells per tumor (N0) and the surviving fraction (SF). Assuming
every tumor cell must be killed to control a tumor, the probability of tumor control is
given by
TCP 5 eSFN0
This model leads to a sigmoid dose response curve for TCP (Fig. 7). Radiosensitivity
is not equivalent to radio responsiveness. Some CNS tumors are very radioresponsive
but inevitably recur (eg, CNS lymphoma), while others may show little or no radio-
graphic evidence of response but are well controlled by modest radiation doses (eg,
meningioma and vestibular schwannoma).
Model Predicting Normal Tissue Complications
The normal tissues of particular interest in the treatment of benign skull base tumors
are the optic apparatus and other cranial nerves, the spinal cord and brainstem, and
brain parenchyma. The effects on the vasculature within normal and tumor tissue are
also of interest.
The probability of normal tissue complication (NTCP) following radiation is, like
tumor control probability (TCP), a function of dose and dose per fraction, the tissue
at risk (radiosensitivity) and the volume irradiated. NTCP has been shown to be well
represented by the model
A 0.91 TCP
B 0.91 TCP
NTCP
0.8 NTCP 0.8
0.7 0.7
TCP/NTCP
TCP/NTCP
0.6 0.6
0.5 0.5
0.4 0.4
Uncomplicated
0.3 Cures 0.3 Uncomplicated
0.2 0.2 Cures
0.1 0.1
0 0
0 5 10 15 20 25 30 0 20 40 60 80 100 120
Dose (Gy) Dose (Gy)
Fig. 7. Curves comparing the probability of tumor control (TCP) with the probability of
a normal tissue complication (NTCP). (A) The curves are positioned close to one another.
Normal tissue complications may be avoided only by minimizing the dose to the critical
normal structure. Such a situation may occur when a normal structure, such as optic nerve,
lies adjacent to a benign tumor being treated with single-dose radiosurgery. (B) Dose frac-
tionation separates the TCP and NTCP curves allowing for a higher probability of tumor
control without significant risk of normal tissue complication. The Uncomplicated Cure
curve is TCPNTCP.
NTCP 5 1 expR
where R is the variable related to dose and volume
k
R 5 d=d0
with d being the administered dose, d0 determining the slope of the NTCP versus dose
curve and k being a constant accounting for volume effects.22,23 This model leads to
a sigmoid-shaped curve similar to that obtained for tumor cure (see Fig. 7). Curves
for a wide variety of normal tissue endpoints have been generated. Although each
has a similar shape, the relative placement of these curves along the dose axis may
be quite different. In clinical radiotherapy, the relative positions of the curves for tumor
cure and normal tissue complication defines what is known as the therapeutic ratio.
The therapeutic ratio may be calculated as
Probability of Tumor Cure

Probability of Complication
An ideal therapeutic ratio would be described by curves that allow 100% tumor cure
without appreciable probability of normal tissue complication. The opposite extreme
would occur when a tumor requiring high-dose radiation for cure was located within
a critical normal structure with a low tolerance to radiation. For the situation where
the a/b for a tumor is higher than that for critical normal tissue, dose fractionation
will always serve to separate the TCP and NTCP curves and increase the therapeutic
ratio (see Fig. 7). Although in general the benefit from fractionation for benign skull
base tumors is less than for malignant tumors that possess a higher a/b ratio, multiple
treatments may still be essential for their sparing properties in various instances, such
as those involving the optic apparatus.
NORMAL TISSUE TOLERANCES
For a particular tissue, the tolerance dose is a function of the chosen toxicity
endpoint, volume irradiated, total dose, dose per fraction, and an acceptable risk
610 Anker & Shrieve
level.24–27 One method to express tolerance doses is by estimation of the D5/5, or the
dose expected to produce complications in 5% of patients within 5 years of treat-
ment.26 This concept may be useful for effects such as necrosis or pituitary dysfunc-
tion, but it is not useful for effects such as optic neuropathy or paralysis, where 5%
could be considered an unacceptably high risk. When planning treatment for benign
tumors, a dose regimen thought to be safe would certainly be preferable. Ideally, the
chosen dose and fractionation scheme would also be effective in tumor control.10,28
Models have been developed to help determine NTCP, and will be described below
along with other time-dose-volume data reported in the literature. Along with these
models, the formula for BED can be used to compare regimens of varying total doses
and dose per fraction in a particular tissue. The equation may also be manipulated to
determine isoeffective total doses (D) associated with different doses per fraction (d)
D1 =D2 5 ða=b1d2 Þ=ða=b1d1 Þ

From the data which follow, Tables 2 and 3 have been constructed with recom-
mended dose limits for use in clinical practice with fractionated and single-dose
radiotherapy.
Table 2
Recommended normal structure dose constraints to avoid complications using standard fractionation
(1.8 Gy/d)
Standard Fractionation
Structure Dose Constraint Reference #
Brain %60 Gy Marks et al24 Sheline et al29
Brainstem surface %64 Gy Debus et al31
Brainstem center %54 Gy
Brainstem parenchyma <1.0 cc R60 Gy
Spinal Cord %45–50 Gy Wara et al39 Rades et al40
Marcus and Million41
Schultheiss et al42
Pituitary Dmin %50 Gy & Dmax %70 Gy Pai et al47
Hypothalamus Dmax %50 Gy Pai et al47
Optic Chiasm/Nerves %54–59 Gy Goldsmith et al28 Parsons
et al51 Urie et al57
Cranial Nerves III, IV, VI %60 Gy recommended, Selch et al58 Uy et al59
but MTD unknown Morita et al60
Cranial Nerve V MTD unknown Andrews et al12 Chan et al13
(Trigeminal) Combs et al14 Williams17
Uy et al59 Morita et al60
Cranial Nerve VII (Facial) MTD unknown Andrews et al12 Chan et al13
Combs et al14 Williams17
Merchant et al73 Million
and Cassisi88
Cochlea 75% Volume <45 Gy Merchant et al73
Cranial Nerves IX-XII MTD unknown Johnston et al83 Zhang et al84
Dose constraint is a maximum unless otherwise specified.

Abbreviations: Dmin, minimum dose received by entire structure; Dmax, maximum dose to any
part of a structure.
Table 3
Recommended normal structure dose constraints to avoid complications using a single fraction
Structure Single Fraction Dose Constraint Reference #

Intraparenchymal brain %24 Gy (MTD unknown) Shaw et al30
lesion %2 cm
Brain lesion >2 cm & %3 cm %18 Gy
Brain lesion >3 cm & %4 cm %15 Gy
Brainstem % 16 Gy if prior WBRT Fuchs et al32 Yen et al33
% 20 Gy if no prior WBRT Hussain et al34 Fuentes
et al35 Huang et al36
Spinal Cord % 10 Gy to 10% cord volume Ryu et al45
(defined as 6 mm above &
below target)
MTD unknown
Pituitary %15 Gy (mean) Jezkova et al48 Vladyka et al49
Optic Chiasm/Nerves %8–10 Gy Tishler et al52 Leber et al53
Stafford et al 54
Cranial Nerves III, IV, VI MTD unknown Leber et al53 Kuo et al61
Cranial Nerve V (Trigeminal) %12.5–13 Gy Flickinger et al11 Flickinger
et al65 Flickinger et al66
Beegle et al67 Hasegawa
et al 68 Lunsford et al69
Meijer et al70
Cranial Nerve VII (Facial) %12.5–15 Gy Beegle et al67 Hasegawa
et al68
Cochlea %3.7 Gy (mean) Rowe et al80
Cranial Nerves IX–XII MTD unknown Martin et al85 Flickinger et al86
Dose constraint is a maximum unless otherwise specified.

Abbreviation: WBRT 5 whole brain radiation therapy.
Brain Parenchyma
Sheline and colleagues reviewed the literature and found 80 cases of cerebral necrosis
occurring 4 months to 7.5 years following cranial irradiation. From this, the authors
were able to derive a model for predicting the risk of brain necrosis as a function of
total dose, number of fractions, and treatment time.29 They defined the neuret, similar
to BED, as
Neuret 5 D N0:44 T0:06

where D is the total dose in cGy, N the number of fractions, and T the overall time in
days. The N exponent reflects the amount of sublethal damage repair that occurs
with fractionation while the T exponent reflects recovery from repopulation of neural
cells. Repair of sublethal damage is the primary recovery mechanism resulting in
a strong dependence on N, a surrogate for fraction size. The relatively weak depen-
dence on T reflects the near negligible effect of repopulation on neural recovery.
Based on an approximate suggested threshold of 1000 neuret, necrosis may be
avoided with a limit of 35 Gy in 10 fractions, 60 Gy in 35 fractions, and 76 Gy in 60 frac-
tions for treatments given 5 d/wk. These data may also be well fit to the linear-
quadratic model using an a/b of 2.0 Gy without a time factor. Marks and colleagues
supported daily dose and total dose as the most significant factors in determining
612 Anker & Shrieve
the risk of radionecrosis. With standard fractionated whole-brain radiotherapy, they

found no incidence of brain necrosis in 51 subjects receiving total doses less than
57.6 Gy. The incidence increased to 3.3% and 17.8% for total doses of 57.6 to 64.8
Gy and 64.81 to 75.6 Gy, respectively. They recommended a threshold dose biolog-
ically equivalent to 54 Gy in 30 fractions, and thus treating benign tumors with this
regimen carries minimal risk of necrosis of brain parenchyma.24
A study undertaken by the Radiation Therapy and Oncology Group (RTOG) exam-
ined the maximum tolerated dose (MTD) of single-fraction radiosurgery as a function
of irradiated volume30 (see Table 3). All tumors were recurrent following previous
radiotherapy. The single fraction MTD was 15 Gy for lesions with a diameter of 4
cm, the maximal size evaluated, but the MTD was not reached for tumors smaller
than 4.2 cc (<2 cm diameter) at 24 Gy. Larger lesions require a dose reduction,
because as tumor volume increases, so does the volume of surrounding normal tissue
that is irradiated leading to increased toxicity.
Brainstem
Debus and colleagues31 in their analysis of 367 subjects treated for base of skull
tumors with a photon/proton combination using standard fractionation, found toxicity-
free survival at 10 years was 96% if less than 1.0 cc of brainstem received greater than
or equal to 60 CGE, but it decreased sharply to 79% above this volume. Additional
dose constraints used by the authors included a maximum dose of 64 CGE to the
brainstem surface and 54 CGE to the center.
In regards to brainstem radiosurgical tolerance, a total of 38 subjects were treated in
two separate reports for brainstem gliomas to an overall mean marginal dose of 12.4
Gy (range, 9–20 Gy), with only one transient complication at 13 Gy.32,33 Subjects
receiving radiosurgery for brainstem metastases may additionally receive a course
of whole-brain radiation confounding the true brainstem single-dose tolerance.
Hussain and colleagues reported one case of hemiparesis following a marginal
dose of 18 Gy preceded by 30 Gy in ten fractions of whole-brain radiotherapy. The
other 22 subjects were without sequelae after receiving a median tumor margin
dose of 16 Gy (range, 14–23 Gy).34 In two other series, both of which included
many subjects who also received whole brain radiation, no permanent sequelae
were seen in 28 subjects treated to a mean dose of 19.6 Gy (range, 11–30 Gy)35 or
in 26 subjects receiving a median dose of 16 Gy (range, 12–20 Gy).36 Metastases in
each of these two series had an average diameter of 17 mm (range, 10–36 mm).
Despite the lack of volume effect in these studies, a report from the University of
California, San Francisco (UCSF) found a higher complication rate with lesions greater
than or equal to 1 cc in size,37 which corresponds to a diameter of 12.5 mm assuming
a spherical shape.
Spinal Cord
The neuret model has been applied to the spinal cord in multiple studies,38,39 also
showing the importance of fractionation for this structure. Wara and colleagues39
described the time-dose relationship for radiation induced spinal cord injury. They
used an effect single dose (ED), where
ED 5 DðcGyÞ N0:377 T0:058

An ED of about 1000 rets was estimated to result in a 1% incidence of myelopathy
for the thoracic cord, although the risk may actually be much lower. Commonly used
regimens including 2000 cGy in five fractions, 3000 cGy in 10 fractions, and 5000 cGy
in 25 fractions were described as safe. Similar regimens retrospectively evaluated by

Rades and colleagues40 for metastatic spinal cord compression revealed no late
toxicity. Data from Marcus and Million suggest that 5000 cGy in conventional fraction-
ation would yield an incidence of myelopathy less than 0.2%, as the only two of 1112
total subjects who experienced complications received between 45 and 50 Gy.41
These data led Schultheiss and colleagues42 to suggest that the commonly accepted
radiation limit to the spinal cord of 45 Gy in 25 fractions is conservative and it may be
relaxed if treating to a higher dose could improve tumor control. They calculated a 5%
NTCP of 57 to 61 Gy in the absence of chemotherapy. In regards to the anatomic level
irradiated, early reports that proposed the thoracic spinal cord is more radiosensitive
than the cervical cord43,44 have not since been substantiated.39,42
In the first report of partial volume spinal cord tolerance to SRS, Ryu and
colleagues45 found that the partial volume tolerance of the human spinal cord is at
least 10 Gy to 10% of the circumferential spinal cord volume defined as 6 mm above
and below the target. For a total of 230 metastatic lesions treated in 177 subjects, only
one case of myelopathy was reported. Although rat and primate models show a defi-
nite volume effect on spinal cord tolerance to radiation,27,46 the partial volume toler-
ance in the human spinal cord is unknown.42
Pituitary
In a retrospective review of 107 patients treated for base of skull tumors, Pai and
colleagues47 found that a minimum pituitary dose (Dmin) greater than or equal to50
CGE was associated with a higher rate of hypoprolactinemia (p50.045), hypothy-
roidism, and hypogonadism. Significantly increased rates of hypogonadism and hypo-
adrenalism were noted for maximum pituitary doses (Dmax) greater than or equal to 70
CGE. Dmax greater than or equal to 50 CGE to the hypothalamus was associated with
higher rates of endocrine dysfunction. Deficits could occur after many years, with the
10-year rates for hyperprolactinema, hypothryroidism, hypogonadism, and hypoa-
drenalism at 84%, 63%, 36%, and 28%.
In two series of subjects treated with single fraction radiotherapy, no T4 or sex
hormone deficiency occurred with a median pituitary dose less than or equal to 15
Gy and no cortisol deficiency developed with a median dose less than or equal to
18 Gy.48,49 In other studies margin doses up to 40 Gy caused no complications.50
Optic Apparatus
Attempts to model isoeffective dose regimens for the risk of optic neuropathy
following fractionated radiotherapy have lead to a model published by Goldsmith
and colleagues.28 They defined the optic ret as
Optic ret 5 D N0:53

but found that the linear-quadratic model did not fit the data well. They identified less
than or equal to 890 optic ret as safe to avoid optic neuropathy, corresponding to
commonly used fractionation schedules of 5400 cGy in 30 fractions, 3750 cGy in 15
fractions and 3000 cGy in 10 fractions. This model emphasizes fraction size, a crucial
factor in determining optic nerve tolerance to radiotherapy.51 Although not based on
single fraction data, the optic ret model predicts that a single fraction of 8.9 Gy would
be safe to the optic apparatus. This coincides very well with single fraction tolerance
doses proposed in the literature, which range from 8 to 10 Gy.52–54 In these reports the
majority of optic neuropathies developed in under 2 years, but in some cases they pre-
sented over 3 years later.54 It has been noted that small volumes of optic nerve or
614 Anker & Shrieve
chiasm may tolerate higher doses of radiation,54–56 but clear dose-volume guidelines
are unavailable.
For fractionated radiation to the optic apparatus, Parsons and colleagues51 found
no injuries following doses less than 59 Gy in 215 optic nerves treated in 131 subjects.
Fraction size was more important than total dose among nerves that received greater
than or equal to 60 Gy, as the 15-year actuarial risk of optic neuropathy was 11% when
administered in fraction sizes less than 1.9 Gy versus 47% when given at 1.9 Gy or
greater. In a series of 20 subjects treated at the University of Michigan, all moderate
or severe optic nerve complications occurred at max doses greater than or equal to
64 Gy, and the severe chiasm complication involved a max dose of 59.5 Gy. However,
two mild complications occurred at 48 and 57 Gy, underscoring the fact that staying
within the perceived dose tolerance does not eliminate the chance of complications.55
Extraocular Nerves (Cranial Nerves III, IV & VI)

Empiric equations such as neuret defining safe fractionation and dose do not seem to
extrapolate to other cranial nerves. The tolerance of cranial nerves III, IV and VI
appears to be substantially higher than for other cranial nerves. Urie and colleagues57
analyzed dose-response data for cranial neuropathies after mixed photon/proton
radiotherapy. They found no neuropathies for doses less than 59.3 CGE among 594
cranial nerves and nuclei examined, and estimated a risk of 5% at 70 CGE. Recent
reports of cavernous sinus doses up to 60 Gy using stereotactic radiotherapy58 and
intensity modulated radiotherapy (IMRT)59 described no cranial neuropathies.
Regarding radiosurgery, data discussing complications involving these cranial
nerves are rare. No clear dose tolerance was apparent in 150 patients treated by
Tishler and colleagues52 and Morita and colleagues60 receiving up to 40 Gy in areas
such as the cavernous sinus. Leber and colleagues53 studied 210 nerves among 50
subjects who received single doses of up to 30 Gy to the cavernous sinus with no
subject developing neuropathy. Although multiple series of benign cavernous sinus
tumors treated with radiosurgery report transient or permanent extraocular nerve
complication rates at approximately 2%,61,62 the majority of series find no harm to
these nerves.63,64
Trigeminal (Cranial Nerve V)

Patients with vestibular schwannoma treated with fractionated radiotherapy have had
trigeminal preservation rates above 93%,12–17 and there are multiple reports of frac-
tionated regimens to cavernous sinus tumors with no discernable trigeminal
complications.58,59
Using CT treatment planning and a marginal vestibular schannoma dose of 17 Gy,
Flickinger and colleagues65 noted a facial numbness complication rate of 33%
following radiosurgery. With the use of MRI planning and a marginal dose prescription
less than or equal to 13 Gy, the trigeminal complication rate has decreased to under
5% in the treatment of various skull base lesions.11,64,66–69 Aside from one retrospec-
tive series showing better preservation of the trigeminal nerve for those receiving
fractionated treatment versus SRS for a vestibular schwannoma (98% vs 92% pres-
ervation, P 5 .048),70 there is no clear evidence that fractionation spares the trigeminal
nerve. Beegle and colleagues67 reviewed subjects treated for schwannoma and
found, on multivariate analysis, that prior tumor growth and treatment volume were
significantly associated with facial numbness. Dose was the most important factor,
with the risk of cranial neuropathy increasing by a factor of six with each 2.5 Gy
increase over 12.50 Gy.
Facial Nerve (Cranial Nerve VII)

Facial nerve injuries are rarer than trigeminal nerve complications, which is partly
attributed to the fact that the trigeminal is a somatosensory nerve. In standard fraction-
ation head and neck cases, the facial nerve routinely receives over 70 Gy without
complication.71 Multiple fraction regimens treating cases of vestibular schwannoma
have resulted in facial nerve preservation rates of 94% to 100%.12,14,17,72
With modern stereotactic radiosurgery planning techniques employing MRI and
a margin dose less than or equal to 13 Gy, the risk of permanent facial weakness
has been reduced to less than 1% in most series.11,67–69 This is a clear improvement
over older series showing complication rates of approximately 30% for patients who
received marginal doses as high as 20 Gy using CT planning.65 As with the trigeminal
nerve, Beegle and colleagues found the facial nerve to have an approximate six-fold
increase in complication risk for every 2.5 Gy above 12.5 Gy prescribed to the tumor
margin. Only marginal dose correlated with facial weakness in a review of 190 subjects
described by Flickinger and colleagues66 involving modern radiation techniques, with
no subject experiencing facial weakness with doses less than 15 Gy.
Cranial Nerve VIII

Hearing loss may follow radiation to benign skull base tumors, and it is of particular
concern in the treatment of vestibular schwannomas. In general, high-frequency range
hearing is the most sensitive to radiation damage.73,74 Despite the effects of radiation,
hearing preservation still appears superior to observation75 and microsurgical tech-
niques.76 For these tumors fractionated radiotherapy has resulted in preservation of
useful hearing from 68% to 94%.12–15 Hearing preservation for patients treated with
radiosurgery ranges from 40% to 75%.11,66,77,78 With the marginal dose prescription
decreases over time from 16–20 Gy79 down to 12 Gy,11,77 hearing loss incidences
have decreased but may still potentially occur in 40% of patients.11,77 As a group,
patients with neurofibromatosis type 2 have less favorable hearing preservation rates
ranging from 33% to 67%.14,80 As there has been no randomized trial comparing frac-
tionated regimens versus SRS, there is no clear evidence of the superiority of one
treatment over another in terms of tumor control and toxicity.
For subjects treated with radiosurgery, Massager and colleagues81 found that radi-
ation dose to the cochlea and hearing outcome were very strongly correlated, with the
average cochlear dose at 3.7 Gy for those with hearing preservation versus 5.29 Gy for
those with hearing loss. Other volumetric and dosimetric parameters found to portend
hearing loss include the intracanicular volume and the integrated dose delivered to the
intracanicular tumor volume.79 A recent study of subjects treated with fractionated
radiation for schwannomas identified cochlear radiation dose as the only prognostic
variable regarding hearing deterioration. They found if greater than or equal to
73.3% of the cochlea volume received greater than or equal to 45 Gy, there was a
median hearing loss of 25 dB compared to only 10 dB below this volume.72 The hypo-
thesis of cochlear sensitivity is supported by other fractionated series, with various
inner ear thresholds for sensorineural hearing loss ranging from 32 to 65 Gy.73,74
Radiation also has an apparent effect on the vestibular portion of cranial nerve VIII,
although it is less often reported. In the irradiation of 125 subjects for vestibular
schwannoma by Andrews and colleagues,12 the most common post-treatment
symptom was a gait ataxia that occurred 4 to 6 months after treatment with either
single or multiple-fractionated radiation. If found objectively on examination, the
presumed cause was vestibular dysfunction or hydrocephalus and for one SRS
subject these symptoms abated after placement of a shunt. Post-treatment
616 Anker & Shrieve
symptoms of vertigo or gait ataxia persisted in less than 5% of subjects regardless of

fractionation scheme.
Cranial Nerves IX to XII

Damage to the ninth, tenth, eleventh and twelfth cranial nerves have been only rarely
reported, usually in the context of radiation for a head and neck carcinoma.82,83 In
a report by Kong and colleagues82 of long-term survivors of nasopharyngeal carci-
noma, they found increasing incidence of posterior cranial nerve palsy over time
with 37.3% subjects exhibiting a deficit at 20-year follow-up. Older treatment tech-
niques, soft tissue fibrosis potentially compressing nerves, and radiation dose were
all found on multivariate analysis to be risk factors.
Lower cranial nerves appear to have a high tolerance to radiosurgery. In multiple
series of jugular foramen tumors involving these nerves, no new complications were
noted following SRS.84,85
SUMMARY
Various types of ionizing radiation may be used in the treatment of base of skull
tumors, which all cause DNA damage by way of direct and indirect pathways. Tumor
control probability and normal tissue complications may be estimated from the linear-
quadratic formula, which is dependent on the alpha and beta values of a tissue related
to single and multiple event killing, respectively. CNS complications may also be pre-
dicted with dose-fractionation models of tolerance, which emphasize the importance
of the number of fractions, or fraction size, over the insignificant effect of overall treat-
ment time. Dose fractionation has an established history of safe and efficacious treat-
ment of benign skull base and brain tumors, helping to maximize the therapeutic ratio.
Single-dose radiosurgery may be preferable for smaller tumor volumes when normal
tissue tolerance is respected. Fractionated radiotherapy should be considered for
larger volumes and when the use of high doses per fraction carries an unacceptable
risk for normal tissue complication.
A summary of accepted dose tolerances using standard 180 cGy/fraction are listed
in Table 2, and single-fraction doses in Table 3. Equivalent biologically effective doses
may be estimated from BED calculations based on the linear quadratic formula. In
determining the dose constraints of a particular structure for a specific patient, it is
important not to take specified dose limits as an absolute guide below which radiation
delivery is completely safe. Other variables deserving consideration include host
factors such as age, diabetes, or hypertension, and prior or concomitant therapy
including surgery, chemotherapy, or radiation. Based on experimental and retrospec-
tive clinical data, compelling evidence exists that long-term repair of radiation damage
occurs in the CNS, in particular the spinal cord and optic apparatus.19,86–88 However,
caution must be exercised when extrapolating from this information.
The best approach to avoiding radiation-induced CNS toxicity is always to minimize
the dose and volume of irradiated tissue. Modern treatment planning techniques,
including the use of CT and MRI and methods to attain accurate and precise patient
immobilization, play important roles to minimize the volume treated and to accurately
measure doses to normal structures. An essential element in the optimization of treat-
ment planning is dose-volume histogram analysis. Conformal treatment delivery tech-
niques have reduced the total dose and dose per fraction received by a normal
structure, as well as the volume irradiated. A regimen that maximizes the probability
of an uncomplicated cure is optimal.
REFERENCES
1. Munzenrider JE, Crowell C. Charged particles. In: Mauch PM, Loeffler JS, editors.
Radiation oncology: biology and technology. Philadelphia: W.B. Saunders
Company; 1994. p. 34–55.
2. Hall E, Giaccia AJ. Radiobiology for the radiologist. 6th edition. Philadelphia: Lip-
pincott Williams & Wilkins; 2005.
3. Elkind MM, Sutton H. X-ray damage and recovery in mammalian cells in culture.
Nature 1959;184:1293–5.
4. Withers H. Biologic basis for altered fractionation schemes. Cancer 1985;55(9):
2086–95.
5. McBride WH, Withers HR. Biological basis of radiation therapy. In: Perez CA,
Brady LW, Halperin EC, et al, editors. Principles and practice of radiation
oncology. 4th edition. Philadelphia: Lippincott, Williams and Wilkins; 2004. p.
96–136.
6. Taghian A, Suit H, Pardo F, et al. In vitro intrinsic radiation sensitivity of glioblas-
toma multiforme. Int J Radiat Oncol Biol Phys 1992;23:55–62.
7. Fertil B, Malaise EP. Intrinsic radiosensitivity of human cell lines correlated with
radioresponsiveness of human tumors. Int J Radiat Oncol Biol Phys 1985;11:
1699–707.
8. Travis EL, Tucker SL. Isoeffect models and fractionated radiation therapy. Int J
Radiat Oncol Biol Phys 1987;13:283–7.
9. Thames HD, Withers HR, Peters LJ, et al. Changes in early and late radiation
responses with altered dose fractionation: Implications for dose-survival relation-
ships. Int J Radiat Oncol Biol Phys 1982;8:219–26.
10. Shrieve DC, Hazard L, Boucher K, et al. Dose fractionation in stereotactic radio-
therapy for parasellar meningiomas: radiobiological considerations of efficacy
and optic nerve tolerance. J Neurosurg 2004;101:390–5.
11. Flickinger JC, Kondziolka D, Niranjan A, et al. Acoustic neuroma radiosurgery
with marginal doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 2004;60:225–30.
12. Andrews DW, Suarez O, Goldman HW, et al. Stereotactic radiosurgery and frac-
tionated stereotactic radiotherapy for the treatment of acoustic schwannomas:
Comparative observations of 125 patients treated at one institution. Int J Radiat
Oncol Biol Phys 2001;50:1265–78.
13. Chan AW, Black PM, Ojemann RG, et al. Stereotactic radiotherapy for vestibular
schwannoma: favorable outcome with minimal toxicity. Neurosurgery 2005;57:
60–70.
14. Combs SE, Volk S, Schulz-Ertner D, et al. Management of acoustic neuromas with
fractionated stereotactic radiotherapy (FSRT): long-term results in 106 patients
treated with a single institution. Int J Radiat Oncol Biol Phys 2005;63:75–81.
15. Poen JC, Golby AJ, Forster KM, et al. Fractionated stereotactic radiosurgery and
preservation of hearing in patients with vestibular schwannoma: a preliminary
report. Neurosurgery 1999;45:1299–305.
16. Wallner KE, Sheline GE, Pitts LH, et al. Efficacy of irradiation for incompletely
excised acoustic neurilemomas. J Neurosurg 1987;67:858–63.
17. Williams JA. Fractionated stereotactic radiotherapy for acoustic neuromas. Int
J Radiat Oncol Biol Phys 2002;54(2):500–4.
18. Douglas BG, Fowler JF. The effect of multiple small doses of x rays on skin reac-
tions in the mouse and a basic interpretation. Radiat Res 1976;66(2):401–26.
19. Ang KK, Price RE, Stephens LC, et al. The tolerance of primate spinal cord to re-
irradiation. Int J Radiat Oncol Biol Phys 1993;25:459–64.
618 Anker & Shrieve
20. Ang KK, Jiang GL, Guttenberger R, et al. Impact of spinal cord repair kinetics on
the practice of altered fractionation schedules. Radiother Oncol 1992;25:287–94.
21. van den Bogaert W, van der Schueren E, Horiot JC, et al. Early results of the
EORTC randomized clinical trial on multiple fractions per day (MFD) and misoni-
dazole in advanced head and neck cancer. Int J Radiat Oncol Biol Phys 1986;
12(4):587–91.
22. Alber N, Nusslin F. A representation of an NTCP function for local complication
mechanisms. Phys Med Biol 2001;46:439–47.
23. Lyman JT, Wolbarst AB. Optimization of radiation therapy. III. A method of assess-
ing complication probabilities from dose-volume histograms. Int J Radiat Oncol
Biol Phys 1987;13:103–9.
24. Marks JE, Baglan RJ, Prassad SC, et al. Cerebral radionecrosis: Incidence and
risk in relation to dose, time, fractionation and volume. Int J Radiat Oncol Biol
Phys 1981;7:243–52.
25. Marks LB, Spencer DP. The influence of volume on the tolerance of the brain to
radiosurgery. J Neurosurg 1991;75:177–80.
26. Emami B, Lyman J, Brown A, et al. Tolerance of normal tissue to therapeutic irra-
diation. Int J Radiat Oncol Biol Phys 1991;21(1):109–22.
27. Ang KK. Radiation injury to the central nervous system: Clinical features and
prevention. In: Meyer JL, editor. Radiation Injury: Advances in Management
and Prevention. Vol 32. Basil: Karger; 1999. p. 145–54.
28. Goldsmith BJ, Rosenthal SA, Wara WM, et al. Optic neuropathy after irradiation of
meningioma. Radiology 1992;185:71–6.
29. Sheline GE, Wara WM, Smith V. Therapeutic irradiation and brain injury. Int J
Radiat Oncol Biol Phys 1980;6(9):1215–28.
30. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recur-
rent previously irradiated primary brain tumors and brain metastases: Final report
of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 2000;47:291–8.
31. Debus J, Hug EB, Liebsch NJ, et al. Brainstem tolerance to conformal radio-
therapy of skull base tumors. Int J Radiat Oncol Biol Phys 1997;39(5):967–75.
32. Fuchs I, Kreil W, Sutter B, et al. Gamma Knife radiosurgery of brainstem gliomas.
Acta Neurochir Suppl 2002;84:85–90.
33. Yen CP, Sheehan J, Steiner M, et al. Gamma knife surgery for focal brainstem
gliomas. J Neurosurg 2007;106(1):8–17.
34. Hussain A, Brown PD, Stafford SL, et al. Stereotactic radiosurgery for brainstem
metastases: Survival, tumor control, and patient outcomes. Int J Radiat Oncol Biol
Phys 2007;67(2):521–4.
35. Fuentes S, Delsanti C, Metellus P, et al. Brainstem metastases: management
using gamma knife radiosurgery. Neurosurgery 2006;58(1):37–42.
36. Huang CF, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for brain-
stem metastases. J Neurosurg 1999;91(4):563–8.
37. Kased N, Huang K, Nakamura JL, et al. Gamma knife radiosurgery for brainstem
metastases: the UCSF experience. J Neurooncol 2008;86(2):195–205.
38. van der Kogel AJ. Central nervous system radiation injury in small animals. In:
Gutin PH, Leibel SA, Sheline GE, editors. Radiation injury in the nervous system.
New York: Raven Press, Ltd.; 1991. p. 91–111.
39. Wara WM, Phillips TL, Sheline GE, et al. Radiation tolerance of the spinal cord.
Cancer 1975;35:1558–62.
40. Rades D, Stalpers LJ, Veninga T, et al. Evaluation of five radiation schedules and
prognostic factors for metastatic spinal cord compression. J Clin Oncol 2005;
23(15):3366–75.
41. Marcus RB Jr, Million RR. The incidence of myelitis after irradiation of the cervical
spinal cord. Int J Radiat Oncol Biol Phys 1990;19(1):3–8.
42. Schultheiss TE, Kun LE, Ang KK, et al. Radiation response of the central nervous
system. Int J Radiat Oncol Biol Phys 1995;31(5):1093–112.
43. Glanzmann C, Aberle HG, Horst W. The risk of chronic progressive radiation
myelopathy. Strahlentherapie 1976;152(4):363–72.
44. Kramer S. Radiation effect and tolerance of the central nervous system. Front
Radiat Ther Oncol 1972;6:332–45.
45. Ryu S, Jin JY, Jin R, et al. Partial volume tolerance of the spinal cord and compli-
cations of single-dose radiosurgery. Cancer 2007;109(3):628–36.
46. Hopewell JW, Morris JH, Dixon-Brown A. The influence of field size on the late
tolerance of the rat spinal cord to single doses of X-rays. Br J Radiol 1987;60:
1099–108.
47. Pai HH, Thornton A, Katznelson L, et al. Hypothalamic/pituitary function following
high-dose conformal radiotherapy to the base of skull: demonstration of a dose-
effect relationship using dose-volume histogram analysis. Int J Radiat Oncol Biol
Phys 2001;49(4):1079–92.
48. Jezkova J, Marek J, Hana V, et al. Gamma knife radiosurgery for acromegaly–
long-term experience. Clin Endocrinol (Oxf) 2006;64(5):588–95.
49. Vladyka V, Liscak R, Novotny J Jr, et al. Radiation tolerance of functioning pitui-
tary tissue in gamma knife surgery for pituitary adenomas. Neurosurgery 2003;
52(2):309–16.
50. Choi JY, Chang JH, Chang JW, et al. Radiological and hormonal responses of
functioning pituitary adenomas after gamma knife radiosurgery. Yonsei Med J
2003;44(4):602–7.
51. Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation optic neuropathy after mega-
voltage external-beam irradiation: Analysis of time-dose factors. Int J Radiat
Oncol Biol Phys 1994;30(4):755–63.
52. Tishler RB, Loeffler JS, Lunsford LD, et al. Tolerance of cranial nerves of the
cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 1993;27(2):215–21.
53. Leber KA, Bergloff J, Pendl G. Dose-response tolerance of the visual pathways
and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neuro-
surg 1998;88:43–50.
54. Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation tolerance of the
optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol
Phys 2003;55(5):1177–81.
55. Martel MK, Sandler HM, Cornblath WT, et al. Dose-volume complication analysis
for visual pathway structures of patients with advanced paranasal sinus tumors.
Int J Radiat Oncol Biol Phys 1997;38:273–84.
56. Ove R, Kelman S, Amin PP, et al. Preservation of visual fields after peri-sellar
gamma-knife radiosurgery. Int J Cancer 2000;90(6):343–50.
57. Urie MM, Fullerton B, Tatsuzaki H, et al. A dose response analysis of injury to
cranial nerves and/or nuclei following proton beam radiation therapy. Int J Radiat
58. Selch MT, Ahn E, Laskari A, et al. Stereotactic radiotherapy for treatment of
cavernous sinus meningiomas. Int J Radiat Oncol Biol Phys 2004;59(1):101–11.
59. Uy NW, Woo SY, Teh BS, et al. Intensity-modulated radiation therapy (IMRT) for
meningioma. Int J Radiat Oncol Biol Phys 2002;53(5):1265–70.
60. Morita A, Coffey RJ, Foote RL, et al. Risk of injury to cranial nerves after gamma
knife radiosurgery for skull base meningiomas: experience in 88 patients. J Neu-
rosurg 1999;90(1):42–9.
620 Anker & Shrieve
61. Kuo JS, Chen JC, Yu C, et al. Gamma knife radiosurgery for benign cavernous
sinus tumors: quantitative analysis of treatment outcomes. Neurosurgery 2004;
54(6):1385–93.
62. Pollock BE, Stafford SL. Results of stereotactic radiosurgery for patients with
imaging defined cavernous sinus meningiomas. Int J Radiat Oncol Biol Phys
2005;62(5):1427–31.
63. Nicolato A, Foroni R, Alessandrini F, et al. Radiosurgical treatment of cavernous
sinus meningiomas: experience with 122 treated patients. Neurosurgery 2002;
51(5):1153–9 [discussion: 1159–61].
64. Lee JY, Niranjan A, McInerney J, et al. Stereotactic radiosurgery providing long-
term tumor control of cavernous sinus meningiomas. J Neurosurg 2002;97(1):
65–72.
65. Flickinger JC, Lunsford LD, Linskey ME, et al. Gamma knife radiosurgery for
acoustic tumors: multivariate analysis of four year results. Radiother Oncol
1993;27(2):91–8.
66. Flickinger JC, Kondziolka D, Niranjan A, et al. Results of acoustic neuroma radio-
surgery: an analysis of 5 years’ experience using current methods. J Neurosurg
2001;94(1):1–6.
67. Beegle RD, Friedman WA, Bova FJ. Effect of treatment plan quality on outcomes
after radiosurgery for vestibular schwannoma. J Neurosurg 2007;107(5):913–6.
68. Hasegawa T, Fujitani S, Katsumata S, et al. Stereotactic radiosurgery for vestib-
ular schwannomas: analysis of 317 patients followed more than 5 years. Neuro-
surgery 2005;57(2):257–65.
69. Lunsford LD, Niranjan A, Flickinger JC, et al. Radiosurgery of vestibular schwan-
nomas: summary of experience in 829 cases. J Neurosurg 2005;102(Suppl):
195–9.
70. Meijer OW, Vandertop WP, Baayen JC, et al. Single-fraction vs. fractionated linac-
based stereotactic radiosurgery for vestibular schwannoma: a single-institution
study. Int J Radiat Oncol Biol Phys 2003;56(5):1390–6.
71. Million RR, Cassisi NJ. Management of head and neck cancer: a multidisciplinary
approach. Philadelphia: JB Lippincott; 1984.
72. Thomas C, Di Maio S, Ma R, et al. Hearing preservation following fractionated
stereotactic radiotherapy for vestibular schwannomas: prognostic implications
of cochlear dose. J Neurosurg 2007;107(5):917–26.
73. Merchant TE, Gould CJ, Xiong X, et al. Early neuro-otologic effects of three-
dimensional irradiation in children with primary brain tumors. Int J Radiat Oncol
Biol Phys 2004;58(4):1194–207.
74. Oh YT, Kim CH, Choi JH, et al. Sensory neural hearing loss after concurrent
cisplatin and radiation therapy for nasopharyngeal carcinoma. Radiother Oncol
2004;72(1):79–82.
75. Charabi S, Thomsen J, Mantoni M, et al. Acoustic neuroma (vestibular schwannoma):
growth and surgical and nonsurgical consequences of the wait-and-see policy.
Otolaryngol Head Neck Surg 1995;113(1):5–14.
76. Regis J, Pellet W, Delsanti C, et al. Functional outcome after gamma knife surgery
or microsurgery for vestibular schwannomas. J Neurosurg 2002;97(5):1091–100.
77. Iwai Y, Yamanaka K, Shiotani M, et al. Radiosurgery for acoustic neuromas:
results of low-dose treatment. Neurosurgery 2003;53(2):282–7 [discussion:
287–8].
78. Combs SE, Thilmann C, Debus J, et al. Long-term outcome of stereotactic radio-
surgery (SRS) in patients with acoustic neuromas. Int J Radiat Oncol Biol Phys
2006;64(5):1341–7.
79. Massager N, Nissim O, Delbrouck C, et al. Role of intracanalicular volumetric

and dosimetric parameters on hearing preservation after vestibular schwannoma
radiosurgery. Int J Radiat Oncol Biol Phys 2006;64(5):1331–40.
80. Rowe JG, Radatz M, Walton L, et al. Stereotactic radiosurgery for type 2 neuro-
fibromatosis acoustic neuromas: patient selection and tumor size. Stereotact
Funct Neurosurg 2002;79(2):107–16.
81. Massager N, Nissim O, Delbrouck C, et al. Irradiation of cochlear structures
during vestibular schwannoma radiosurgery and associated hearing outcome.
J Neurosurg 2007;107(4):733–9.
82. Kong L, Lu JJ, Hu C, et al. Cranial nerve palsy after definitive radiation therapy for
nasopharyngeal carcinoma. Int J Radiat Oncol Biol Phys 2006;66(3):S413.
83. Johnston EF, Hammond AJ, Cairncross JG. Bilateral hypoglossal palsies: a late
complication of curative radiotherapy. Can J Neurol Sci 1989;16(2):198–9.
84. Zhang N, Pan L, Dai JZ, et al. Gamma knife radiosurgery for jugular foramen
schwannomas. J Neurosurg 2002;97(5 Suppl):456–8.
85. Martin JJ, Kondziolka D, Flickinger JC, et al. Cranial nerve preservation and
outcomes after stereotactic radiosurgery for jugular foramen schwannomas.
Neurosurgery 2007;61(1):76–81.
86. Flickinger JC, Deutsch M, Lunsford LD. Repeat megavoltage irradiation of pitui-
tary and suprasellar tumors. Int J Radiat Oncol Biol Phys 1989;17(1):171–5.
87. Nieder C, Grosu AL, Andratschke NH, et al. Update of human spinal cord reirra-
diation tolerance based on additional data from 38 patients. Int J Radiat Oncol
Biol Phys 2006;66(5):1446–9.
88. Million RR, Cassisi NJ. Management of head and neck cancer: a multidisciplinary
approach. 2nd edition. Philadelphia: Lippincott Williams & Wilkins; 1993.
Radiation Effe c ts
on the Auditor y
a nd Vestibular
Systems
Niranjan Bhandare, MSa,William M. Mendenhall, MDa,
Patrick J. Antonelli, MDb,*
KEYWORDS
Radiation Auditory Vestibular Toxicity Complication
Definitive or postoperative radiation therapy (RT) is commonly used for the manage-
ment of intracranial and extracranial head and neck tumors. Because of the variability
of tumor location and dimensions, sparing of nontarget normal tissue and organs may
not be always possible. Parts of the auditory and vestibular systems often receive high
doses of radiation and exhibit radiation-induced morbidity. Treatment modalities that
deliver the highest doses of radiation to the auditory system include stereotactic radio-
surgery (SRS) and fractionated stereotactic radiotherapy (FSRT) for the treatment of
vestibular schwannomas (VS), and fractionated radiotherapy (FRT) or intensity-
modulated radiation therapy (IMRT) for the treatment of head and neck malignancies.
Radiation therapy for VS is unique because of its involvement of the inner ear and pre-
existing auditory and vestibular dysfunction. Direct otologic involvement is rarely
observed in other neoplasms that are routinely treated with RT. The assessment of
postirradiation effects thus differs in these two situations and is more complex in
the treatment of VS.
RADIATION BIOLOGY
A comprehensive discussion of the tissue effects of radiation is beyond the scope of

this article. However, a brief overview of this topic is necessary to fully understand
radiation effects on the auditory and vestibular systems.
Tissue effects of radiation are dependent on a number of factors. Megavoltage
X rays in the therapeutic range interact with tissue primarily by way of the Compton
a
Department of Radiation Oncology, University of Florida College of Medicine, 1600 SW
Archer Road, Gainesville, FL 32610, USA
b
Department of Otolaryngology, University of Florida College of Medicine, 1600 SW Archer
Road, Gainesville, FL 32610, USA
E-mail address: pa@ufl.edu (P.J. Antonelli).

624 Bhandare et al
effect. The Compton mass attenuation coefficient is independent of the atomic

number and depends only on the number of the electrons per gram of the interacting
material. The attenuation of beam is related to density thickness (density of material
multiplied by the thickness) expressed as g/cm2, thus a relative decrease in attenua-
tion leads to increased penetration in air-filled spaces or air cavities, such as the lungs
and temporal bones.
Deposition of radiation energy in tissue results in cell injury and death. Most of radi-
ation’s tissue effect is thought to be a result of the damage to DNA. This occurs both
directly and indirectly. The latter, the predominant mechanism, involves ionization of
surrounding water molecules to form free radicals, which, in turn, result in double-
strand breaks in DNA. This injury may result in cell death during mitosis, induction
of apoptosis (ie, programmed cell death), recovery, and cell cycle arrest or terminal
differentiation through activation of repair pathways that may also play a role in tumor
suppression (eg, activation of p53).
The radio-response of a tissue depends on the inherent sensitivity of the cells, the
kinetics of cell population, total dose, dose per fraction, and time-dose fractionation.
Cells with fast turnover rate or higher mitotic activity exhibit more sensitivity to radia-
tion, subjecting to cell death in attempting subsequent mitosis. This is the basis for
therapeutic RT (ie, relatively greater damage to highly reproductive tumor cells).
Further, RT fractionation offers the potential for greater differential sparing of normal
tissues and killing of tumor cells.1,2
These factors also determine the unwanted manifestations of RT. Skin and mucosa,
which cycle quickly, manifest more significant early, transient, and inflammatory
changes. Organ dysfunction are often manifest by cell lines with slow turnover (eg,
radionecrosis of bone). In some tissues, such as inner-ear hair cells, functional
progenitor cells may be lacking, resulting in greater organ system dysfunction. It is
unclear how RT leads to long-term dysfunction in cells, such as neurons and inner-
ear hair cells, which lose mitotic activity after differentiation. Such cells are dependent
on supporting cells (eg, glia) and small blood vessels. Though a wide range of morpho-
logic changes in neural tissue in response to RT have been observed,3,4 the effect of
RT on neurons cannot be distinguished from the effect on the supporting cells and the
vasculature.
Finally, radiation dose to the target and surrounding tissues is controlled by the
choice of modality (eg, conventional external beam, IMRT, or SRS) and treatment
plan. In SRS, doses are prescribed to the tumor margin. The maximal dose within
the target area may vary tremendously, depending on the specifics of the treatment
plan. For example, single or multiple isocenters may be used.
For further information, please see the Treatment Planning/Radiation Delivery
Section in the Gamma Knife Radiosurgery for Vestibular Schwannoma chapter of
this publication.
RADIATION AND THE EAR
The entire auditory-vestibular system is vulnerable to RT injury. Nearly half of all

patients that have undergone RT for head and neck tumors demonstrate evidence
of auditory or vestibular system pathology.3 RT-induced injury may be manifest as
chronic otitis externa, stenosis of the external auditory canal, chronic otitis media
with effusion, tympanic membrane perforation, osteonecrosis, chronic suppurative
otitis media, middle ear fibrosis, conductive, mixed, or sensorineural hearing loss, lab-
yrinthitis, vestibular paresis, and vertigo. The focus of this discussion will be on the
inner ear and central pathways rather than the middle and external ear.
Radiation Effects 625
Measurement or scoring of ototoxicity after fractionated RT for head and neck

tumors has historically been qualitative and descriptive. Comparing results from
such assessments has been difficult. Newer scoring systems have been developed,
but none have been widely used and validated. The Radiation Therapy Oncology
Group criteria are applicable for retrospective analyses of acute toxicity, but not late
complications. Detailed prospective assessment of delayed RT-induced ototoxicity
has been addressed by the Late Management of Normal Tissue/Somatic Objective
Management Analytic (LENT/SOMA) scoring system (Table 1). This system does
not distinguish between external, middle, and inner ear toxicity and has a narrow cate-
gorization of hearing loss. The National Cancer Institute Common Toxicity Criteria (NCI
CTC) includes auditory side effects, but only gross changes in hearing are addressed
(Table 2). The NCI CTC system has been mainly applied to chemotherapeutic studies.
Note that these classification systems correspond to RT of nonacoustic tumors. These
classification systems have not been used for SRS or FSRT of VS. The evaluations of
post-RT hearing status of patients with VS have consistently been presented accord-
ing to the Gardner-Robertson scale.
The unique nature of the inner ear cell lines leads to unique manifestations of RT
injury. Acute dysfunction after RT is a result of transient alterations in the homeostasis
of endolymph and perilymph,5 whereas delayed sensorineural hearing loss (SNHL)
most commonly exhibits a chronic, progressive, and irreversible evolution.6 Hair cells
and the stria vascularis have been implicated as the two major sites of inner ear radi-
ation toxicity.5
Table 1
Late radiation ear morbidity according to the Late Management of NormalTissue/Somatic Objective
Management Analytic Scoring System Scale
Grade 1 Grade 2 Grade 3 Grade 4

Subjective
1. Pain Occasional and Intermittent and Persistent and Refractory and
minimal tolerable intense excruciating
2. Tinnitus Occasional Intermittent Persistent Refractory
3. Hearing Minor loss, no Frequent Frequent Complete
impairment in difficulties with difficulties with deafness
daily activities faint speech loud speech
Objective
4. Skin Dry Otitis externa Superficial Deep ulceration,
desquamation ulceration necrosis
5. Hearing <10 dB loss in 10–15 dB loss in >15–20 dB loss in >20 dB loss in
one or more one or more one or more one or more
frequencies frequencies frequencies frequencies
Management
6. Pain Occasional Regular Regular narcotic Parenteral
non-narcotic non-narcotic narcotics
7. Skin Occasional Regular eardrops Eardrums Surgical
lubrication/ or antibiotics intervention
ointments
8. Hearing Hearing aid
Score the 8 SOM parameters with 0 to 4 (0 5 no toxicity); total the score and divide by 8 5 LENT
score.
626 Bhandare et al
Table 2
Ear morbidity according to the National Cancer Institute CommonToxicity Criteria
Grade 1 Grade 2 Grade 3 Grade 4

External External otitis External otitis External otitis Necrosis of canal,
auditory with moist or with moist with soft tissue or
canal dry desquamation discharge, bone
desquamation mastoiditis
Inner ear/ Hearing loss on Tinnitus or Tinnitus or Severe unilateral
hearing audiometry hearing loss hearing loss, or bilateral
(including only not requiring correctable hearing
conductive hearing aid or with hearing loss(deafness),
hearing loss) treatment aid or not
treatment correctable
Middle ear/ Serous otitis Serous otitis or Otitis with Necrosis of the
hearing without infection discharge, canal, soft
subjective requiring mastoiditis or tissue or bone
decrease in medical conductive
hearing intervention; hearing loss
subjective
decrease
in hearing;
rupture of
tympanic
membrane
with
discharge
In animal studies, the earliest post-RT changes with lower doses were observed in
the stria vascularis. With increasing dose, shriveling of hair cells and distention of
Reissner’s membrane were observed.7 Experimental fractionated radiation of chin-
chillas led to loss of myelinated nerve fibers in the osseous spiral lamina, inner and
outer hair cells, and supporting cells.8 Hair cell damage and compound action poten-
tial changes have been linked to stria vascularis degeneration,9 but direct damage to
hair cells is feasible at high- radiation doses. Similar findings have been reported for
the vestibular system.7,10,11
Post-mortem observations of human temporal bones after RT have included loss of
inner and outer hair cells and spiral ganglion cells in the basal turn of the cochlea,
atrophy of the stria vascularis, and changes in vessels of the facial nerve.11–13 Further
histologic studies have shown that the greatest damage to inner ear is the result of
injury to the vessels of stria vascularis.14 Vestibular damage has also been observed
in cases manifesting with vestibular complaints. An autopsy study after a high dose of
radiation demonstrated absence of the organ of Corti, macula of the utricle and the
cristae of the semicircular canals.14 Overall, however, the vestibular apparatus is
more resistant to effects of radiation than the cochlea.7
Sensorineural hearing loss following fractionated RT may begin early or may be
delayed. Transient SNHL begins early.15,16 Recovery usually occurs in 6 to 12 months,
but may be delayed.17 This delay has been attributed to an inner ear vasculitis, and has
been associated with auditory recruitment.18 Permanent post-RT SNHL may occur in
up to 54% of patients receiving high doses to the inner ear.15 A review by Jerekczeck-
Fossa and colleagues19 suggested that post-RT SNHL occurs in one third of the
patients treated with definitive RT with the inner ear receiving high radiation doses.
Raaijmakers and Engelen’s review20 reported a pure tone average loss of greater
than 10 dB occurred in 18 ( 2%) of patients and a 4 kHz loss occurred in one of three
patients receiving a dose of 70 Gy at 2 Gy per fraction to the inner ear. The pooled inci-
dence of post-RT SNHL is 44% and 36% for treatment of the nasopharynx and
parotid, respectively.21
Ho and colleagues22 prospectively studied the latency for SNHL after fractionated
RT and found it to be 1.5 to 2.0 years after RT. Kwong and colleagues15 also reported
the progression of SNHL to plateau within 2 years of treatment. Most other studies are
in agreement with these observations.15,16 Onset of hearing deterioration has been
reported to be as early as 3 months after completing RT.23 In one study, the stability
of postlatency SNHL was followed up for a period of 13 years.24 Though cumulative
risk of persistent SNHL (>15 dB) has been reported to stabilize at 2 years, the cumu-
lative risk for severe SNHL (>30 dB) continues to increase through the third and fourth
year after RT.25
Vestibular dysfunction occurs in roughly 25% to 30% of patients treated with RT to
the temporal bone.26 Caloric weakness has been reported in 9% to 36%.27–29 Young
and colleagues30 attributed post-RT vertigo mainly to a peripheral labyrinthine
disorder(69%), followed by central vestibular lesions (31%). The authors proposed
two mechanisms that contribute to the peripheral labyrinthine dysfunction: (1) direct
injury to the inner ear, or (2) RT-induced otitis media with effusion (OME) with
a secondary labyrinthitis. In the study by Young and colleagues,30 the mean interval
from completion of RT to occurrence of vertigo was 10 years. The relationship
between OME and vertigo, however, has not been supported in other studies.16 RT-
induced degenerative changes in the vestibular sensory epithelia has been observed
in experimental animal studies10 and human temporal bones.14
TREATMENT-RELATED PARAMETERS
Dose
Honore and colleagues24 used linear and logistic regression methods to evaluate the
dose-response relationship of RT and inner ear dysfunction. They observed a general
increase in hearing loss with increased dose to the inner ear, but this was not a linear
relationship. A statistically significant relationship between dose and the incidence of
SNHL was only observed at 4 KHz. Probability of SNHL increased above 40 Gy to the
inner ear when delivered at 2.0 Gy per fraction. Others have reported SNHL at total
doses above 45 to 50 Gy.31,32 Delayed toxicity increases as a function of dose per
fraction. The dose per fraction and the total dose must be considered for the develop-
ment of late ear toxicity.
Patient Age
Grau and colleagues31 found that the raw data suggested a correlation between
patient age and post-RT SNHL, but this disappeared when RT dose and age were
taken into account. Other reports have indicated an increase in the incidence of
post-RT SNHL, implicating increasing age as a possible risk factor.15,22,24,33 One
series16 reported a statistically significant increase in the incidence of post-RT
SNHL above the age of 50. Pretreatment hearing loss, which is more common with
advancing age, may be a more important risk factor for post-RT hearing loss.22,24
Adjuvant Chemotherapy
A number of reports12,16 have associated chemoradiation with the development of
SNHL, yet others15,29 have reported no relationship. The ototoxic effect of cisplatin,
one of the most commonly used chemotherapeutic agents, is well known.34,35
628 Bhandare et al
Cisplatin ototoxicity is thought to be greater if given after RT, compared with before
RT.15,36 It is unclear whether cisplatin and RT ototoxicities are truly synergistic.34
Atrophy of the stria vascularis and loss of inner and outer hair cells with reduced spiral
ganglion cells, have been reported in patients receiving cisplatin, RT, or the two
combined.12
RADIATION THERAPY FOR VESTIBULAR SCHWANNOMA
The options for delivery of radiation therapy for VS include SRS, FSRT, intensity-
modulated radiotherapy (IMRT), three-dimensional conformal radiotherapy (3DCRT)
and, rarely, conventional RT. SRS uses multiple, convergent, nonparallel, noncoplaner
radiation beams to deliver a high dose of irradiation to a small target volume while
delivering low doses to the surrounding normal tissues. This can be accomplished
with either a gamma knife (GK-SRS) or a linear accelerator. Depending on the choice
of prescription isodose line covering the target, up to 50% or more variation may be
seen between the peripheral dose and the maximum dose.
FSRT offers the advantages of SRS and conventional RT. Like SRS, FSRT allows the
conformation of the irradiation dose precisely to the target volume. In addition, it
allows the fractionated delivery of the dose, which is thought to result in differential
sparing of cranial nerves relative to the tumor.1,2
VS typically presents with auditory or vestibular dysfunction. This dysfunction is
thought to result from any one, or a combination, of the direct compression of the
eighth cranial nerve, labyrinthine vasculature, or the development of poorly under-
stood changes within the inner ear fluids. Symptoms may include tinnitus, ataxia,
dizziness, unsteadiness, vertigo, a sensation of fullness in the ear and gradual hearing
loss.37 Most patients present with hearing loss (98%), tinnitus (70%), and disequilib-
rium (67%).38 Thus, it can be difficult to distinguish the auditory and vestibular effects
of RT for VS from those caused by the natural progression of VS.
As hearing is the most readily measured parameter of auditory and vestibular func-
tion, hearing preservation serves as the best indicator of RT impact on the auditory
systems, particularly for VS. Hearing preservation rates, according to the Gardner
Robertson criteria, ranging from 50% to 70%,39–42 and local control rates ranging
from 95% to 100% have been reported with GK-SRS39,43,44 and LA-SRS45–47 for
VS. Immediate SNHL post-SRS for VS has been rarely reported.48 SNHL within
3 months of SRS may result from neural edema or demyelination. Most SNHL has
been reported at 3 to 24 months after SRS.49 Foote and colleagues38 reported
a median time to the onset of SNHL after GK-SRS among subjects with sporadic
VS to be 18 months (range, 8.9–30 months). In subjects with neurofibromatosis type
2 (NF-2)-associated VS treated with SRS, Linskey and colleagues50 observed
progressive SNHL with a median time of onset to be 4 months (range, 3–12 months).
Subach and colleagues51 reported a median time of onset of SNHL at 4 months
(range, 3–15 months) with none documented before 3 months after SRS.
Many RT and tumor parameters have been found to affect auditory outcomes in the
treatment of VS. These parameters include involved nerve length, total dose, fraction-
ation, and tumor type.
Irradiated Nerve Length

Niranjan and colleagues49 estimated that, for an intracranial VS, the length of the
eighth nerve irradiated in a GK-SRS varied between 4 to 12 mm, with many tumors
(5 of 15) occupying only part of the internal auditory canal (4–7 mm) and more tumors
(10 of 15 tumors) extending the entire length of the canal (8–12 mm). The authors
concluded that neither the position of the tumor in the canal (lateral versus medial) nor
the length of the nerve irradiated correlated with hearing preservation (P 5 0.1).
Although tumor diameter was significantly related to hearing preservation in the
univariate analysis (P 5 0.025), only margin dose was significant in the multivariate
analysis (P 5 0.0009).
Total Radiation Dose

Paek and colleagues52 reported that subjects who retained useful hearing after SRS
had a mean dose delivered to the cochlea of 6.9 Gy, compared with 11 Gy in subjects
who exhibited significant hearing loss. Niranjan and colleagues49 found that SRS dose
extending beyond the canalicular tumor volume was the most important factor
responsible for cochlear nerve injury. Serviceable hearing was preserved in 100% of
the subjects who received a dose of 14 Gy or less, which dropped to 20% in subjects
who received more than 14 Gy. Massager and colleagues53 suggested that intracana-
licular tumor volume (<100 cm3 versus R100 cm3) and intracanalicular integrated
dose (dose volume) were determinants of hearing loss and postulated that ‘‘wors-
ening of hearing after GK-SRS could be attributed to cochlear injury inside the internal
auditory canal caused by enlargement of the intracanalicular part of the VS during the
inflammatory edema phase after SRS through an increase of intracanalicular pres-
sure.’’ Rowe and colleagues54 reported hearing results after treatment using GK-
SRS for NF-2. These authors reported three groups of subjects: group one treated
with a mean marginal dose of 25 Gy, group two with a mean dose of 17.8 Gy and group
three with a mean dose of 13.4 Gy. The authors concluded that the dose reduction
from group one to group three increased hearing preservation (P 5 0.05). Based on
the available data, the general trend has been to reduce SRS dose from 18 to
20 Gy initially, to 12 to 16 Gy.
Fractionation
Combs and colleagues55 reported outcomes of 106 subjects with VS treated with
FSRT to a total dose of 57.6 Gy delivered by standard fractionation. The 5-year local
control rate was 93% with serviceable hearing preservation in 94%. In a recent
report56 of 26 subjects treated with SRS to a median total dose of 13 Gy (range 11–
20 Gy), local control of 91% and serviceable hearing preservation of 55% was
reported. Onset of SNHL after FSRT has been reported mostly in the first 6 months
and less commonly beyond 12 months after treatment.55,57–59 Andrews and
colleagues60 found that the probability of retaining serviceable hearing was signifi-
cantly higher after FSRT versus GK-SRS (81% versus 33%; P 5 0.0228). Compared
with GK-SRS, FSRT resulted in a significantly lower pure tone average (P 5 0.0120)
and significantly higher mean speech discrimination scores (P 5 0.0466). Their high
rate of early hearing preservation at pretreatment levels after FSRT is in agreement
with an earlier report by Williams.61 A greater chance of hearing preservation may
be associated with FSRT using standard-dose fractionation not exceeding a conven-
tional 2 Gy dose per fraction.61–63 Further prospective studies comparing postirradia-
tion hearing preservation are needed to evaluate the potential advantages of FSRT
compared with GK-SRS.
Compared with standard fractionation, hypofractionation delivers the total dose
over a shorter period of time using a smaller number of higher dose fractions, but
compared with single high-dose fractions as used in SRS, it delivers a lower dose
per fraction. Most hypofractionation schedules deliver total doses ranging from 21
to 30 Gy in 3 to 10 days with a dose per fraction ranging from 3 to 7 Gy. Although
hypofractionation reduces fraction size compared with that delivered in SRS, late
630 Bhandare et al
irradiation effects, such as hearing loss, are strongly dependent on fraction size and
rises as fraction size increases above the standard once-daily fraction size of 1.8 to
2.0 Gy. Experience with hypofractionated RT in regards to hearing preservation
remains very limited. Meijer and colleagues57 treated 12 subjects with SRS to a total
dose of 10 to 12 Gy and 25 with a hypofractionated SRT regimen of either five fractions
of 4 Gy or five fractions of 5 Gy. They found no significant differences in the rate of local
control and hearing loss. It is still not clear if there is an advantage in using hypofrac-
tionation compared with SRS for hearing preservation. For further information
regarding hypofractionation hearing preservation rates, see the Stanford University
Experience Section in the CyberKnife Radiosurgery for Vestibular Schwannoma
Chapter.
Neurofibromatosis Type 2
Unlike sporadic VS that tends to displace the auditory portion of the eighth cranial
nerve, VS associated with NF-2 often form grapelike clusters,64 engulf the facial and
cochlear nerves,65,66 and invade the cochlea and other parts of the temporal
bone.65 Accordingly, there are lower rates of tumor control and hearing preservation
with SRS or FSRT for VS associated with NF-2.60,66,67
VERTIGO
There is little data that addresses the impact of SRS or FSRT on the vestibular system.
Petit and colleagues68 reported 17 subjects with imbalance before GK-SRS for VS.
The imbalance was unchanged in 13 of the 17 subjects after treatment, while four
subjects had improvement of their imbalance. New cases of vertigo were not
observed. Niranjan and colleagues49 found that 3 of 11 subjects continued to have
episodic vertigo who presented with vertigo after treatment with GK-SRS for VS. Ito
and colleagues69 reported the results of caloric function testing after GK-SRS for
VS. Thirteen of 46 subjects had intact caloric function before treatment. Nine of the
13 subjects developed canal paresis after GK-SRS. The median onset of loss of
caloric function was 8 months. The authors did not report the subjects’ symptom of
dizziness in their manuscript.
SUMMARY
RT to the region of the temporal bone and surrounding structures may result in audi-
tory and vestibular dysfunction both peripherally and centrally. Auditory and vestibular
dysfunction following RT for VS may be limited by limiting the total dose of cranial
nerve VIII irradiation and by fractionation.
REFERENCES
1. Buatti JM, Friedman WA, Meeks SL, et al. The radiobiology of radiosurgery and
stereotactic radiotherapy. Med Dosim 1998;23:201–7.
2. Safdari H, Fuentes JM, Dubois JB, et al. Radiation necrosis of the brain: time of
onset and incidence related to total dose and fractionation of radiation. Neurora-
diology 1985;27:44–7. PM:3974866.
3. Masurovsky EB, Bunge MB, Bunge RP. Cytological studies of organotypic
cultures of rat dorsal root ganglia following X-irradiation in vitro. I. Changes in
neurons and satellite cells. J Cell Biol 1967;32:467–96. PM:10976234.
4. Masurovsky EB, Bunge MB, Bunge RP. Cytological studies of organotypic
cultures of rat dorsal root ganglia following X-irradiation in vitro. II. Changes in
Schwann cells, myelin sheaths, and nerve fibers. J Cell Biol 1967;32:497–518.
PM:10976235.
5. Linskey ME, Johnstone PA. Radiation tolerance of normal temporal bone struc-
tures: implications for gamma knife stereotactic radiosurgery. Int J Radiat Oncol
Biol Phys 2003;57:196–200. PM:12909233.
6. Pollock BE, Lunsford LD, Kondziolka D, et al. Outcome analysis of acoustic
neuroma management: a comparison of microsurgery and stereotactic radiosur-
gery. Neurosurgery 1995;36:215–29.
7. Gamble JE, Peterson EA, Chandler JR. Radiation effects on the inner ear. Arch
Otolaryngol 1968;88:156–61. PM:5301997.
8. Bohne BA, Marks JE, Glasgow GP. Delayed effects of ionizing radiation on the
ear. Laryngoscope 1985;95:818–28. PM:4010422.
9. Ocho S, Iwasaki S, Umemura K, et al. A new model for investigating hair cell
degeneration in the guinea pig following damage of the stria vascularis using
a photochemical reaction. Eur Arch Otorhinolaryngol 2000;257:182–7. PM:
10867831.
10. Winther FO. X-ray irradiation of the inner ear of the guinea pig. Early degenerative
changes in the vestibular sensory epithelia. Acta Otolaryngol 1969;68:514–25.
PM:4907323.
11. Nadol JB Jr. Comparative anatomy of the cochlea and auditory nerve in
mammals. Hear Res 1988;34:253–66. PM:3049492.
12. Hoistad DL, Ondrey FG, Mutlu C, et al. Histopathology of human temporal bone
after cis-platinum, radiation, or both. Otolaryngol Head Neck Surg 1998;118:
825–32. PM:9627244.
13. Felix H. Anatomical differences in the peripheral auditory system of mammals
and man. A mini review. Adv Otorhinolaryngol 2002;59:1–10. PM:11885648.
14. Leach W. Irradiation of the ear. J Laryngol Otol 1965;79:870–80. PM:5830715.
15. Kwong DL, Wei WI, Sham JS, et al. Sensorineural hearing loss in patients treated
for nasopharyngeal carcinoma: a prospective study of the effect of radiation and
cisplatin treatment. Int J Radiat Oncol Biol Phys 1996;36:281–9. PM:8892450.
16. Bhandare N, Antonelli PJ, Morris CG, et al. Ototoxicity after radiotherapy for head
and neck tumors. Int J Radiat Oncol Biol Phys 2007;67:469–79. PM:17236969.
report. Neurosurgery 1999;45:1299–307.
18. Borsanyi SJ, Blanchard CL. Ionizing radiation and the ear. JAMA 1962;181:
958–61. PM:13871468.
19. Jereczek-Fossa BA, Zarowski A, Milani F, et al. Radiotherapy-induced ear toxicity.
Cancer Treat Rev 2003;29:417–30. PM:12972360.
20. Raaijmakers E, Engelen AM. Is sensorineural hearing loss a possible side effect
of nasopharyngeal and parotid irradiation? A systematic review of the literature.
Radiother Oncol 2002;65:1–7. PM:12413668.
21. Bhide SA, Harrington KJ, Nutting CM. Otological toxicity after postoperative
radiotherapy for parotid tumours. Clin Oncol (R Coll Radiol) 2007;19:77–82.
PM:17305258.
22. Ho WK, Wei WI, Kwong DL, et al. Long-term sensorineural hearing deficit
following radiotherapy in patients suffering from nasopharyngeal carcinoma:
a prospective study. Head Neck 1999;21:547–53. PM:10449671.
23. Wang LF, Kuo WR, Ho KY, et al. A long-term study on hearing status in patients
with nasopharyngeal carcinoma after radiotherapy. Otol Neurotol 2004;25:
168–73. PM:15021778.
632 Bhandare et al
24. Honore HB, Bentzen SM, Moller K, et al. Sensori-neural hearing loss after radio-
therapy for nasopharyngeal carcinoma: individualized risk estimation. Radiother
Oncol 2002;65:9–16. PM:12413669.
25. Grau C, Overgaard J. Postirradiation sensorineural hearing loss: a common but
ignored late radiation complication. Int J Radiat Oncol Biol Phys 1996;36:
515–7. PM:8892478.
26. Singh IP, Slevin NJ. Late audiovestibular consequences of radical radiotherapy to
the parotid. Clin Oncol (R Coll Radiol) 1991;3:217–9. PM:1657112.
27. Chao WY, Tseng HZ, Tsai ST. Caloric response and postural control in patients
with nasopharyngeal carcinoma after radiotherapy. Clin Otolaryngol Allied Sci
1998;23:439–41. PM:9800080.
28. Gabriele P, Orecchia R, Magnano M, et al. Vestibular apparatus disorders after
external radiation therapy for head and neck cancers. Radiother Oncol 1992;
25:25–30. PM:1410586.
29. Johannesen TB, Rasmussen K, Winther FO, et al. Late radiation effects on
hearing, vestibular function, and taste in brain tumor patients. Int J Radiat Oncol
Biol Phys 2002;53:86–90. PM:12007945.
30. Young YH, Ko JY, Sheen TS. Postirradiation vertigo in nasopharyngeal carcinoma
survivors. Otol Neurotol 2004;25:366–70. PM:15129119.
31. Grau C, Moller K, Overgaard M, et al. Sensori-neural hearing loss in patients
treated with irradiation for nasopharyngeal carcinoma. Int J Radiat Oncol Biol
Phys 1991;21:723–8. PM:1869465.
32. Pan C, Eisbruch A. Ototoxicity after radiotherapy of head-and-neck cancer: the
perils of retrospective dose-response estimations: in regard to Bhandare et al.
(Int J Radiat Oncol Biol Phys 2007;67:469–479). Int J Radiat Oncol Biol Phys
2007;68:1582.
33. Moretti JA. Sensori-neural hearing loss following radiotherapy to the naso-
pharynx. Laryngoscope 1976;86:598–602. PM:1263730.
34. The Department of Veterans Affairs Laryngeal Cancer Study Group. Induction
chemotherapy plus radiation compared with surgery plus radiation in patients
with advanced laryngeal cancer. N Engl J Med 1991;324:1685–90.
35. Skinner R, Pearson AD, Amineddine HA, et al. Ototoxicity of cisplatinum in chil-
dren and adolescents. Br J Cancer 1990;61:927–31. PM:2372498.
36. Walker DA, Pillow J, Waters KD, et al. Enhanced cis-platinum ototoxicity in chil-
dren with brain tumours who have received simultaneous or prior cranial irradia-
tion. Med Pediatr Oncol 1989;17:48–52. PM:2913475.
37. Mendenhall WM, Friedman WA, Amdur RJ, et al. Management of acoustic
schwannoma. Am J Otolaryngol 2004;25:38–47.
38. Foote RL, Coffey RJ, Swanson JW, et al. Stereotactic radiosurgery using the
gamma knife for acoustic neuromas. Int J Radiat Oncol Biol Phys 1995;32:
1153–60.
39. Noren G. Long-term complications following gamma knife radiosurgery of vestib-
ular schwannomas. Stereotact Funct Neurosurg 1998;70(Suppl 1):65–73 PM:
9782237.
40. Leksell L. Stereotactic radiosurgery. J Neurol Neurosurg Psychiatry 1983;46:
797–803. PM:6352865.
41. Thomassin JM, Epron JP, Regis J, et al. Preservation of hearing in acoustic
neuromas treated by gamma knife surgery. Stereotact Funct Neurosurg 1998;
70(Suppl 1):74–9. PM:9782238.
42. Traquina DN, Guttenberg I, Sasaki CT. Delayed diagnosis and treatment of
acoustic neuroma. Laryngoscope 1989;99:814–8. PM:2755290.
43. Kondziolka D, Lunsford LD, McLaughlin MR, et al. Long-term outcomes after
radiosurgery for acoustic neuromas. N Engl J Med 1998;339:1426–33.
44. Ogunrinde OK, Lunsford DL, Kondziolka DS, et al. Cranial nerve preservation
after stereotactic radiosurgery of intracanalicular acoustic tumors. Stereotact
Funct Neurosurg 1995;64(Suppl 1):87–97. PM:8584844.
2001;94:1–6. PM:11147876.
with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 2004;
60:225–30. PM:15337560.
47. Iwai Y, Yamanaka K, Shiotani M, et al. Radiosurgery for acoustic neuromas:
results of low-dose treatment. Neurosurgery 2003;53:282–7 PM:12925242.
48. Pollack AG, Marymont MH, Kalapurakal JA, et al. Acute neurological complica-
tions following gamma knife surgery for vestibular schwannoma. Case report.
J Neurosurg 2005;103:546–51. PM:16235688.
49. Niranjan A, Lunsford LD, Flickinger JC, et al. Dose reduction improves hearing
preservation rates after intracanalicular acoustic tumor radiosurgery. Neurosur-
gery 1999;45:753–62. PM:10515468.
50. Linskey ME, Lunsford LD, Flickinger JC. Tumor control after stereotactic radiosur-
gery in neurofibromatosis patients with bilateral acoustic tumors. Neurosurgery
1992;31:829–38. PM:1436407.
51. Subach BR, Kondziolka D, Lunsford LD, et al. Stereotactic radiosurgery in the
management of acoustic neuromas associated with neurofibromatosis Type 2.
J Neurosurg 1999;90:815–22. PM:10223445.
52. Paek SH, Chung HT, Jeong SS, et al. Hearing preservation after gamma knife
stereotactic radiosurgery of vestibular schwannoma. Cancer 2005;104:580–90.
PM:15952200.
53. Massager N, Nissim O, Delbrouck C, et al. Role of intracanalicular volumetric and
dosimetric parameters on hearing preservation after vestibular schwannoma
radiosurgery. Int J Radiat Oncol Biol Phys 2006;64:1331–40. PM:16458446.
54. Rowe JG, Radatz MW, Walton L, et al. Clinical experience with gamma knife
stereotactic radiosurgery in the management of vestibular schwannomas
secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry 2003;74:
1288–93. PM:12933938.
treated in a single institution. Int J Radiat Oncol Biol Phys 2005;63:75–81. PM:
16111574.
56. Combs SE, Thilmann C, Debus J, et al. Long-term outcome of stereotactic radio-
surgery (SRS) in patients with acoustic neuromas. Int J Radiat Oncol Biol Phys
2006;64:1341–7. PM:16464537.
57. Meijer OW, Vandertop WP, Baayen JC, et al. Single-fraction vs. Is radiotherapy in
vestibular schwannoma: early results from a single centre. Clin Oncol (R Coll
Radiol) 2007;19:517–22. PM:17400433.
58. Horan G, Whitfield GA, Burton KE, et al. Fractionated conformal radiotherapy in
vestibular schwannoma: early results from a single centre. Clin Oncol (R Coll
Radiol) 2007;19(7):517–22.
59. Sakamoto T, Shirato H, Takeichi N, et al. Annual rate of hearing loss falls after frac-
tionated stereotactic irradiation for vestibular schwannoma. Radiother Oncol
2001;60:45–8.
634 Bhandare et al
60. Andrews DW, Suarez O, Goldman HW, et al. Stereotactic radiosurgery and
fractionated stereotactic radiotherapy for the treatment of acoustic schwanno-
mas: comparative observations of 125 patients treated at one institution. Int J Ra-
diat Oncol Biol Phys 2001;50:1265–78.
61. Williams JA. Fractionated stereotactic radiotherapy for acoustic neuromas. Acta
Neurochir (Wien) 2002;144(12):1249–54; discussion 1254.
62. Andrews DW, Silverman CL, Glass J, et al. Preservation of cranial nerve function
after treatment of acoustic neurinomas with fractionated stereotactic radio-
therapy. Preliminary observations in 26 patients. Stereotact Funct Neurosurg
1995;64:165–82. PM:8817804.
63. Hoban PW, Jones LC, Clark BG. Modeling late effects in hypofractionated stereo-
tactic radiotherapy. Int J Radiat Oncol Biol Phys 1999;43:199–210. PM:9989527.
64. Jaaskelainen J, Paetau A, Pyykko I, et al. Interface between the facial nerve and
large acoustic neurinomas. Immunohistochemical study of the cleavage plane in
NF2 and non-NF2 cases. J Neurosurg 1994;80:541–7. PM:8113868.
65. Linthicum FH Jr, Brackmann DE. Bilateral acoustic tumors. A diagnostic and
surgical challenge. Arch Otolaryngol 1980;106:729–33. PM:7436847.
66. Hirsch A, Noren G. Audiological findings after stereotactic radiosurgery in
acoustic neurinomas. Acta Otolaryngol 1988;106:244–51. PM:3051887.
acoustic tumors: multivariate analysis of four year results. Radiother Oncol
1993;27:91–8. PM:8356233.
68. Petit JH, Hudes RS, Chen TT, et al. Reduced-dose radiosurgery for vestibular
schwannomas. Neurosurgery 2001;49:1299–307.
69. Ito K, Kurita H, Sugasawa K, et al. Analyses of neuro-otological complications
after radiosurgery for acoustic neurinomas. Int J Radiat Oncol Biol Phys 1997;
39:983–8. PM:9392535.
Gamma Knife
Radiosurger y
for Vestibular
Schwa nnoma
Robert A. Battista, MDa,b,c,*
KEYWORDS
Gamma knife radiosurgery Vestibular schwannoma
Neurofibromatosis type 2 Cystic vestibular schwannomar
Tumor control
In 1951, Dr. Lars Leksell from Sweden conceived of what is now known as gamma
knife radiosurgery (GKRS). The Leksell Gamma Knife (Elekta, Norcross, Georgia)
uses a focused array of 201 intersecting beams of cobalt-60 gamma radiation to treat
lesions within the brain. The gamma knife is so named because of its accuracy in deliv-
ering an exact field of radiation to the target. The combined intensity of radiation at the
focus (or isocenter) is extremely high whereas the intensity only a short distance from
the isocenter is very low. This enables a high dose of radiation to be delivered to the
lesion while sparing the adjacent healthy brain tissue.
Leksell first used the gamma knife in 1969 to treat a patient who had a vestibular
schwannoma.1 Gamma knife radiosurgery has grown considerably in the United
States since the first gamma knife unit was installed in North America at the University
of Pittsburgh in 1987. Currently, there are more than 50 gamma knife centers in the
United States and 249 centers worldwide. Based on a worldwide survey in December
2006 by the Leksell Gamma Knife Society, 397,672 lesions have been treated with
GKRS since the introduction of the gamma knife (202 of 249 gamma knife centers
reporting). Slightly more than 9% (36,180) of the lesions treated were vestibular
schwannomas.2 A similar survey in December 2004 by the Leksell Gamma Knife
Society reported 28,306 cases of patients who had vestibular schwannoma had
been treated worldwide (181 out of 213 centers reporting).3
a
Department of Otolaryngology, Northwestern University Medical School, Chicago, IL 60611,
USA
b
The Ear Institute of Chicago, LLC, 11 Salt Creek Lane, Suite 101, Hinsdale, IL 60521, USA
c
Illinois Gamma Knife Center, Alexian Neurosciences Institute, Alexian Brothers Medical
Center, Elk Grove Village, IL 60007, USA
* Corresponding author. The Ear Institute of Chicago, 11 Salt Creek Lane, Suite 101, Hinsdale,
IL 60521.
E-mail address: r-battista2@northwestern.edu

636 Battista
Based on these data, it seems that there is a steady, growing demand for GKRS as
treatment of vestibular schwannomas. This may be due, in part, to improved patient
outcomes and an expanding body of knowledge of long-term tumor control. Prior to
1992 high doses (typically 16 Gy or greater to the tumor margin) resulted in significant
rates of facial weakness (21%) and facial numbness (27%) after GKRS.4 Since then,
dose reduction (typically 12–13 Gy to the tumor margin), the introduction of MRI scans,
and more sophisticated dose planning software and equipment have improved
outcomes considerably. This article outlines the technique of GKRS and discusses
the current results of the use of this technique to treat vestibular schwannomas using
marginal doses of 12 to 13 Gy or less.
STEREOTAXY
The aim of the stereotactic technique as it pertains to the gamma knife is to relate the
location of structures or lesions within the boundaries of a head frame to a 3-D Carte-
sian axis system. This is done initially by fixing a rigid titanium head frame to the head
(Fig. 1). The borders of the frame then constitute the Cartesian axes, whereas the
cranium serves as a platform to support the frame. The way in which a point within
the frame is defined in terms of the Cartesian axes is depicted in Fig. 2. By convention,
the X axis runs from side to side, the Y axis runs from behind forwards, and the Z axis
runs from above downwards. The common zero point is above and behind the right
ear. It is the frame and not the head that is used to localize. This is helpful because
there may be times when it is necessary to place the frame eccentrically or to rotate
the frame with respect to the head.
Reference points relative to the titanium head frame must be visible on radiographic
imaging. This is accomplished by means of plastic plates that are attached to each
side of the head frame. Embedded in the walls of the plastic plates are three metal
rods or strips (CT), or three hollow channels filled with a copper-containing liquid
(MRI). These rods or channels are radiopaque, creating fiducial lines. Of the three
Fig. 1. Leksell titanium head frame. (Courtesy of Elekta Inc., Norcross, GA; with permission.)
Gamma Knife Radiosurgery 637
Fig. 2. Cartesian axis system as referenced to the head frame.
rods or channels, two are parallel and vertical. The third rod or channel is oriented at
a 45 angle to the other two. This creates three fiducial lines in the configuration of
a backwards ‘‘N’’. In this way, on each image slice, three sets of dots are identifiable
(Fig. 3). As one moves through an imaging set, only the middle dot moves sequentially.
Determination of the separation of the two fixed dots in relation to the moving middle
dot makes calculation of the Z coordinate for each slice a simple geometric exercise.
Thus, a stereotactic space is created.
THE GAMMA KNIFE MACHINE
There have been several generations of the Leksell Gamma Knife machine. The Leksell
Gamma Knife 4B and 4C models are the machines used most commonly at present.
The basic construction of the model 4 is described here.
The Leksell Gamma Knife 4C unit (Fig. 4) consists of a thick-cast, hemispheric steel
shell containing a dome-shaped core of 201 cylindric cobalt-60 sources, each 1 mm in
diameter and 20 mm in length. These sources are radially aligned toward a common
focal point. The steel shell is equipped with two thick mechanical doors through which
the head of the patient is introduced. Each cobalt-60 source undergoes a primary
collimation within the casting. A second collimation is performed through a helmet
Fig. 3. Schematic of fiducial lines created by the MRI or CT box attachment to the Leksell
head frame. Two separate ‘‘slice’’ examples are shown.
638 Battista
Fig. 4. (A) Leksell Gamma Knife 4C unit, front view. (B) Schematic of Leksell Gamma Knife 4C
unit, side view. (Courtesy of Elekta Inc., Norcross, GA; with permission.)
in which the patient’s head is positioned. The collimator helmet bears 201 collimators
that are designed to align with the corresponding primary collimator. The collimator
helmet is fixed to a movable bed on which the patient lies. With the patient’s head
in the Leksell head frame, the head frame is likewise fixed to the bed. The frame is
placed inside the concavity of the collimator helmet so that the targeted lesion is at
the center of the helmet. When the primary collimator and the collimator helmet are
aligned, it is possible for the gamma rays to converge on the target.
Four collimator helmet sizes are available corresponding to different aperture sizes
(4, 8, 14, and 18 mm). Helmet sizes are chosen based on the prescribed treatment plan
(discussed later). More than one size of helmet may be used throughout the course of
a treatment.
The only movements in the Leksell Gamma Knife system are that of the bed, which
draws patients in and out, and that of the doors at the mouth of the machine, which
open prior to movement of the bed. When the treatment is over, the bed automatically
moves out and the doors close.
INDICATIONS/TREATMENT GOALS
The goals of any form of treatment for vestibular schwannoma should be long-term
tumor control, preservation of cranial nerve function, and maintenance of a high
quality of life. The aim of any form of treatment for vestibular schwannoma is to prevent
the functional consequences due to growth of the untreated tumor rather than
improvement of preoperative symptoms. GKRS attempts to achieve this goal by stop-
ping tumor growth. With this in mind, the indications for GKRS have expanded over the
years as more centers have gained experience with this technique. Common indica-
tions for GKRS for vestibular schwannoma are listed in Table 1. It is recommended
that patients who have tumors larger than 3 cm in diameter not undergo GKRS
because of the high probability of radiation damage that may occur to the surrounding
brainstem. In addition, patients who have signs of intracranial hypertension or brain-
stem compression should not undergo GKRS. These patients need rapid decompres-
sion of their tumor and for this reason require microsurgical removal.
TECHNIQUE
Pre-gamma Knife Evaluation
Prior to undergoing GKRS, patients are evaluated with a thorough neurotologic history
and physical examination, high-resolution MRI with gadolinium, and audiometric eval-
uation to include pure-tone air/bone and word recognition score testing. Hearing is
graded with the American Academy of Otolaryngology–Head and Neck Surgery
1995 guidelines5 or the Gardner-Robertson6 classification system (Table 2). Facial
nerve function is assessed most commonly using the House-Brackmann (H-B)
grading system.7
After the initial evaluation, gamma knife treatment consists of four main steps: (1)
placement of a head frame; (2) an imaging study; (3) treatment/dose planning; and
(4) radiation delivery.
Several specialists are typically involved in the gamma knife treatment process.
These specialties include a radiation oncologist, a physicist, and a neurosurgeon or
neurotologist. Most commonly, the neurosurgeon or neurotologist places the head
frame while three specialists—a radiation oncologist, physicist, and neurosurgeon
or neurotologist—all are involved in the treatment planning.
Placement of Head Frame/Imaging Study

The gamma knife procedure begins with a patient’s head undergoing rigid fixation in
an MRI-compatible Leksell stereotactic head frame. Fixation is performed with various
size pins in a bifrontal and bicoronal fashion after application of a local anesthetic. An
oral sedative often is given prior to placement of the head frame. The frame is placed in
an attempt to locate the tumor as close to the center of the frame as possible. This
ensures proper positioning of the head frame and the targeted lesion in or near the
center of the collimator helmet.
Plastic plates with radiopaque lines for fiducial marking are attached to the head
frame. High-resolution MRI then are obtained after double-dose gadolinium is given.
Double-dose gadolinium is given to maximize contrast between tumor and
surrounding tissue. Volume acquisition studies require 1- to 1.5-mm axial slice thick-
nesses that subsequently are reformatted in coronal and sagittal projections. At the
Table 1
Indications for gamma knife radiosurgery
1. Small- to medium-sized tumor (tumor <3 cm in maximum diameter)

2. Elderly/medically infirm patient
3. Recurrent/residual tumor
4. Patient choice
640 Battista
Table 2
Gardner-Robertson hearing classification
Class Pure Tone Average (dB) Speech Discrimination (%)

1—Good 0–30 70–100
2—Serviceable 31–50 50–69
3—Nonserviceable 50–90 5–49
4—Poor 91 maximum 1–4
5—None Nontestable 0
If the pure-tone average and speech discrimination scores do not qualify for the same class, the
class appropriate for the poorer of the two scores is used.
Data from Gardner G, Robertson JH. Hearing preservation in unilateral acoustic neuroma
surgery. Ann Otol Rhinol Laryngol 1988;97(1):55–66.
author’s treating facility, T1 and T2 constructive interference in steady state magnetic

resonance sequences are obtained. The T1 images define the tumor margins whereas
the constructive interference in steady state sequences help to define cranial nerves.
Treatment Planning/Radiation Delivery

The imaging study is downloaded into the treatment software in order to begin treat-
ment planning. The goal of GKRS treatment planning is to provide the maximum, safe
amount of radiation to a tumor without damaging surrounding structures. Typical
parameters considered by a gamma knife team are the number and position of isocen-
ters, their collimator sizes, their relative weights, and the prescription isodose. The
plan of radiation delivery is designed to closely adhere, or conform, to the shape of
the tumor with a sharp falloff of radiation at the edge of the tumor. A high degree of
conformity of the prescription isodose to the target volume, while ensuring that tumor
is completely encompassed, is one of the prerequisites for complication-free lesion
control with good tumor control.8 These parameters and goals are described more
fully later.
The center of the radiosurgery beam is called the isocenter. Treatment planning
consists of placing these beams, or shots, over the target volume. The isocenter radi-
ation distribution tends to be circular or elliptic in shape. A typical radiosurgical treat-
ment can be conceived of as trying to fill an irregular-shaped volume (the tumor) with
‘‘balls’’ of different sizes. Thus, the Leksell Gamma Knife has 4-, 8-, 14-, and 18-mm
‘‘balls’’ (corresponding to the different-sized collimator helmets) with which dose plans
can be created. The goal is to maximally fill the treatment volume with these shots.
Because most tumors are not truly spherical, the dose from a single beam of radiation
will not match the shape of the tumor. By overlapping multiple isocenters of varying
sizes, the dose distribution can be fashioned to produce a conformal treatment
plan. The ‘‘weight’’ of each isocenter can be adjusted, if necessary, to further conform
to the tumor volume.
The amount of radiation given is called the prescribed isodose. The distribution of the
isodose around the tumor can be demonstrated visually through circumferential lines
that extend outward from the target. These lines are the isodose curves (or isodose
lines) of radiation distribution (Fig. 5). The isodose lines are expressed in percentages.
Assuming the center, or near center, of the target receives 100% radiation, the isodose
lines are constructed with a 10% decrement: 90%, 80%, 70%, and so forth.
The prescription isodose is defined most commonly as the amount of radiation
delivered to the 50% isodose line. Most gamma knife plans prescribe the 50% isodose
to the margin of the tumor. This is because there is a steep falloff in radiation dosage at
Fig. 5. Leksell gamma Plan for a right-sided vestibular schwannoma. 13 Gy is prescribed to

the 50% isodose line (yellow line).
the edge of the 50% isodose line, which ensures radiation sparing of surrounding
structures. Gamma knife prescription isodoses typically are 12 to 13 Gy to the margin
of the tumor. This also may be expressed as 12 to 13 Gy prescribed to the 50%
isodose line.
Factors taken into account when determining a prescription isodose include the size
and location of the tumor, the hearing level, and the tumor status (primary versus
recurrent/residual). In general, 12 Gy is given when the tumor of medium size or the
hearing is serviceable. When the tumor is small, the hearing is nonserviceable, and
the tumor is recurrent/residual, 13 Gy is typically considered.
Finally, the gamma knife planning software is capable of mapping the location of the
maximal dose, or hot spot, in the stereotactic space. A gamma knife team attempts to
keep the hot spot well away from the facial nerve and, if necessary, the cochlear nerve.
Using the Leksell Gamma Knife 4C unit, the actual time of radiation delivery varies
from approximately 45 to 120 minutes. At the conclusion of the procedure, the head
frame is removed and patients receive intravenous steroids (typically 40 mg methyl-
prednisolone). Patients are observed for a short period and are discharged the
same day unless immediate complications (rare) develop, such as vomiting, dizziness
or headache.
FOLLOW-UP
Patients are followed with serial contrast-enhanced MRI studies, which typically are
obtained at 6 months, 12 months, 2 years, 4 years, 8 years, and 16 years. Initial radio-
graphic follow-up often demonstrates loss of central enhancement along with slight
tumor enlargement and capsular thickening. Audiometric testing is performed at the
time of their MRI follow-up for patients who have preserved hearing. Patients typically
return to their pretreatment level of functioning or employment within 3 to 10 days post
treatment.9
RESULTS/COMPLICATIONS
Tumor Control
Currently there is no consensus as to the definition of tumor control after radiosurgery.
One nonstandardized means to describe tumor control is tumor shrinkage or no tumor
642 Battista
growth, also known as radiologic control. A widely accepted definition of tumor growth
is that of Flickinger and colleagues,10 who describe tumor growth as a 1-mm increase
in tumor diameter in any two directions or 2-mm in one direction. Another definition of
growth is a greater than 10% increase in tumor volume11 whereas another is an
increase of 100% of the initial volume at 2 years post treatment.12
Clinical, rather than radiologic, tumor control is another means of defining the
outcome of GKRS. Clinical tumor control means, ‘‘the absence of the need for further
microsurgical or radiosurgical intervention.’’13 Patients who require microsurgical or
radiosurgical treatment after radiosurgery are patients who have documented
progression of tumor growth or worsening symptoms, such as ataxia.
Tumor expansion after vestibular schwannoma radiosurgery does not necessarily
mean a lack of tumor control, however. Transient tumor swelling occurs in as many
as 80% of cases after GKRS.9,14,15 The swelling typically peaks between 6 to 7
months16,17 but may continue for 1 to 3 years after treatment.18–20 In one study, the
mean increase in tumor volume was 120% of the initial tumor volume.16,19,20 Pollock20
and Myrseth and colleagues21 have noted that some schwannomas may enlarge after
GKRS and continue to remain stable in size. In a study by Pollock,20 8 of 28 (29%) of
tumors enlarged after GKRS and remained stable in size for a maximum follow-up
period of 8.2 years (median 56 months).
Transient tumor swelling, or growth that plateaus after radiosurgery, may lead to
unnecessary microsurgery or revision radiosurgery.19,20 In order to differentiate true
tumor growth from tumor expansion, the tumor size must be mapped with serial
MRI scans. Hasegawa and colleagues19 also have suggested that magnetic reso-
nance spectroscopy, single photon emission tomography, or positron emission
tomography may help determine if tumors are actively growing or showing signs of
temporary expansion.
Tumor regression is a favorable prognostic sign of tumor control. Tumors that shrink
rarely show signs of growth.22 In addition, the chance for tumor growth is extremely
low for stable tumors 4 years post GKRS.13,18,23 Continuous monitoring after 4 years
is necessary, however, because there has been at least one report of a patient devel-
oping an expanding cyst at the tumor margin 60 months after GKRS.18
Some factors associated with continued tumor growth for unilateral vestibular
schwannoma after gamma knife treatment have been imaging/targeting error, tumor
biology, and large tumor volume and cystic tumor (the latter two factors are discussed
later). Spatial distortion is known to occur with MRI.24,25 These distortions are most
pronounced at soft tissue-bone interfaces, such as that in the internal auditory canal.
As a means to accommodate this distortion and to prevent imaging/targeting error,
some centers combine CT and MRI.16,26 Another possible cause for MRI error is
that gadolinium may not enhance the lateral most extent of the intracanalicular portion
of a vestibular schwannoma.27
There has been no difference, however, in tumor control rates between patients
receiving current doses of 12 to 13 Gy to the tumor margin and those patients who
have received higher doses.10,13
Table 3 provides a summary of tumor control rates from various, worldwide treat-
ment centers. Inclusion criteria for the table were the following: minimum 100 patients
reported, mean marginal dose of 13.5 Gy or less, and an average of 3 years of follow-
up or longer. In a study by Myrseth and colleagues,21 tumor size was reported as the
maximal tumor diameter, including the intracanalicular portion (17.5% were 0–10 mm;
66% were 11–20 mm; and 16.5% were 21–30 mm).
Based on studies (see Table 3), radiologic control ranged from 89% to 96%,
whereas clinical control (no further radiation treatment or microsurgery) ranged from
Table 3
Control rates from various treatment centers for patients underwent gamma knife radiosurgery for vestibular schwannoma
Underwent
Further
Previous No Microsurgery or
Author, Microsurgery Mean Tumor Mean Marginal Mean Follow-up Growth Regression Growth Radiosurgery
Year N (N) Volume (Range) Dose (Range) (Range) (%) (%) (%) (%)
Prasad, 153 57 2.8 cm3 (0.02–18.3 cm3) 13.3 Gy (9–20 Gy) 38 mo (1–10 yrs) 17 75 8 NR
200028
Litvack, 134 18 NR 12 Gy (0.6 Gy) 36 mo (12–72 mo) 61 46 4 2
200329
Chung, 195 76 4.1 cm3 13 Gy (median) 36 mo (2–109 mo) 35 58 7 3
200530 (11–18 Gy)
Lundsford, 157 NR 2.5 cm3 12–13 Gy 120–180 mo 25 73 NR 2
200513
Myrseth, 102 5 See text 12 Gy (10–20 Gy) 71 mo (12–170 mo) 40 49 11 5
200521
<15 cm3: 277 R15 cm3: 24
Gamma Knife Radiosurgery

Hasegawa, 301 72 13.2 Gy 91 mo median 31 62 7 9
200518
Hempel, 116 NR 1.6 cm3 (0.1–9.9 cm3) 13 Gy (median) 98 mo (63–129 mo) 40 56 4 3
200631 (10–14.5 Gy)
As a reference, a tumor volume of 15 cm3 corresponds approximately to a mean intracranial diameter of 3 cm.
Abbreviation: NR, not reported.
643
644 Battista
91% to 98%. Tumor growth was variously defined as greater than 2 mm in mean
pretreatment tumor diameter,18,29 greater than 110% of the original tumor volume,30
a 1-mm increase in tumor diameter in any two directions or 2-mm in one direction,13
and no growth or tumor regression.21 Two studies did not clearly define tumor
growth.28,31
Two results in the table should be clarified. First, the definition of radiologic tumor
control is strict in the study by Myrseth and colleagues21 (no growth or tumor regres-
sion). Four of 102 patients in this study had a growth plateau. If these four patients
were taken into account, the radiologic control rate would be 93%. Secondly, in the
study by Hasegawa and colleagues18 the clinical control rate of 91% may be skewed.
In this study, six patients (2%) underwent microsurgery after GKRS at a separate insti-
tution. These patients had unchanged tumor volume or slight tumor expansion without
neurologic changes. It is possible that microsurgery may have been unnecessary if
there was a longer period of observation.
Repeat GKRS for continued tumor growth has been reported.18,32 In one report, six
patients underwent repeat GKRS between 24 and 70 months after the first gamma
knife treatment.18 The mean marginal dose was 11 Gy. Three of the six patients
achieved tumor shrinkage without complication and the other three required microsur-
gery for continued growth. In another report, eight patients underwent repeat GKRS.32
Indications for retreatment were documented tumor growth for at least 3 years after
initial GKRS. The median marginal tumor dose at retreatment was 12 Gy (range,
10–12 Gy). Follow-up after repeat GKRS was from 26 to 121 months, with six patients
demonstrating regression and two patients stabilization of tumor growth at last follow-
up. There were no new neurologic deficits.
Acute Side Effects/Complications

The vast majority of acute side effects after GKRS are mild and brief.33,34 These side-
effects may include headache, nausea, vomiting, marked fatigue, and pin-site related
problems.
There have been a few reports of acute facial paralysis occurring between 1 and
7 days after GKRS.35–38 In all cases, the facial paralysis improved to at least a H-B
level 2 within 6 to 24 months after onset. Oral or intravenous steroids were given in
each case, but it is unknown if this treatment improved facial function. A case of
permanent, profound sensorineural hearing loss also has been reported shortly after
GKRS. The hearing loss was the result of acute intracochlear hemorrhage occurring
within 24 hours of GKRS.35
Hearing Results
Preservation of functional hearing (Gardner-Robertson class 1 or 2) has been reported
as ranging from 33% to 79%, with observation periods of 2 to 15 years of follow-up
(Table 4). There also are sporadic reports of permanent hearing improvement after
GKRS.9,12,13,28,29 In those patients whose hearing worsens, hearing loss typically
does not develop until 3 to 12 months after gamma knife treatment. Once hearing
loss develops, the hearing deterioration may continue up to the eighth year post
treatment.28 In general, hearing preservation rates worsen as tumor size increases.29
The cause for hearing deterioration after GKRS is not precisely known. Some theo-
ries of hearing deterioration include direct radiation damage to the auditory system,40
decreased blood flow to the auditory system due to hyalinization of blood vessels, and
tumor enlargement in the internal auditory canal. Paek and colleagues40 measured the
radiation doses delivered to the cochlea, cochlear nerve, and cochlear nucleus for
patients treated with gamma knife for vestibular schwannoma. The investigators
Table 4
Hearing preservation rates after gamma knife radiosurgery
Preoperative Postoperative
Mean Marginal Mean Follow-up With Functional With Functional Preservation
Author,Year Dose (Range) (Range) Hearing Hearing (%)
Prasad, 13.3 Gy 51 mo 36 21 58
200028 (9–20 Gy)
Andrews, 12 Gy 30 mo 69 23 33
200139
Rowe, 14.6 Gy 35 mo 49 37 76
200222 (13–15 Gy)
Regis, (12–14 Gy) 48 mo 48 24 50
20029
Litvack, 12 Gy 26 mo 47 29 62
200329 (0.6 Gy) (12–60 mo)
Chung, 13 Gy 31 mo median 20 12 60
200530 (median) (6–74 mo)
(12–17 Gy)
Lunsford, (12–13 Gy) 36–180 mo 267 210 79
200513
Hasegawa, %13 Gy 91 mo median 74 50 68
200518
Functional hearing defined as Gardner-Robertson class 1 or 2.
concluded that the maximum dose delivered to the cochlear nucleus was the most
significant prognostic factor of hearing deterioration.
Facial Paralysis
New-onset, permanent facial neuropathy (defined as a decline in H-B facial nerve
grade) is rare after GKRS using the current marginal doses of 12 to 13 Gy. Rates of
new-onset, permanent facial neuropathy have been reported as ranging from 0% to
0.5%.9–11,21,22,30,31,41 Transient facial paralysis has been reported with rates of
approximately 1% to 1.5%.9–11,21,22,30,31,41 Transient facial paralysis may last up to
6 months. If facial paralysis develops, it usually develops within the first year after
treatment but has been reported as late as 62 months after GKRS.30
Trigeminal Neuralgia/Neuropathy
New-onset, temporary or permanent trigeminal nerve symptoms, ranging from numb-
ness to trigeminal neuralgia, are uncommon. Rates for trigeminal symptoms range
from 0.2% to 4%.9–11,13,28,30 There also are a few reports of improvement of pretreat-
ment trigeminal symptoms.9,22,29,30 Similar to facial nerve dysfunction, trigeminal
symptoms have been reported to develop between 5 and 48 months post
treatment.10,28
Hemifacial Spasm
Approximately 2% to 4% of patients develop hemifacial spasm after GKRS.9,20,42 In
most cases, the symptoms improve with time or respond to carbamazepine. Hemifa-
cial spasm has been reported to occur as early as 1 month after radiosurgery42
whereas several reports note that spasm typically develops between 1 and 2 years
646 Battista
after radiosurgery.9,20 Pollock20 has postulated that hemifacial spasm is the result of
tumor expansion with irritation of the facial nerve or a delayed vascular insult.
Dizziness
The symptom of dizziness is rarely discussed in the current gamma knife literature.
Two articles that specifically address this condition report new-onset dizziness after
GKRS in 16 of 120 patients (13%)31 and in 27 of 104 patients (26%),9 respectively.
If dizziness develops, it often is transient but may last for several weeks.9,31 The
University of Pittsburgh report on 829 cases states that their group has no data to
support the notion that dizziness before treatment is made worse by GKRS.13
As a means to treat patients who have dizziness before GKRS, the author’s group
has begun to use intratympanic gentamicin prior to and, as necessary, after GKRS.
This treatment is based on the finding of Brantberg and colleagues43 who successfully
treated a patient who had dizziness and a vestibular schwannoma and who refused
microsurgery and radiosurgery.
Hydrocephalus
Hydrocephalus in the absence of progressive tumor growth has been reported as
occurring in 0% to 7% of patients.9,12,13,18,21,28 The median time to development of
hydrocephalus is approximately 1 year. Hydrocephalus is believed the result of tumor
necrosis, with proteinaceous debris blocking cerebrospinal fluid flow. The develop-
ment of hydrocephalus is more common after treatment of larger (>25 mm diameter)
tumors. The hydrocephalus may resolve spontaneously44 but most often requires ven-
ticuloperitoneal shunting.
SPECIAL SITUATIONS
Large Tumors
GKRS is not an ideal treatment for patients who have large vestibular schwannomas
(mean tumor diameter greater than 3 cm). One reason is that there is an increased risk
for complications relative to smaller tumors. Significant tumor edema invariably occurs
after GKRS for tumors larger than 3 cm in diameter.45 The edema has the immediate
effect of potentially causing severe headache, vomiting, and dizziness. Brainstem
compression may develop leading to ataxia and obstructive hydrocephalus. As
a means to avoid these complications, it has been recommended that the dose
prescribed be decreased when treating large tumors.23 Marginal doses lower than
12 Gy, however, have been associated with increased tumor recurrence.46
A second reason that GKRS is not ideal for large tumors is that large tumors demon-
strate reduced rates of tumor control compared to smaller tumors even with marginal
doses of 12 Gy or higher. In one study, the 10-year progression-free survival rates for
vestibular schwannoma GKRS was found statistically better for small- to-medium-
sized tumors (<15 cm3 in total volume) versus larger tumors (>15 cm3) (95% versus
57% progression-free survival, respectively).18 These results indicate that large
tumors (>15 cm3) should not undergo GKRS as initial treatment. A more favorable
option for treatment of large vestibular schwannomas is complete microsurgical exci-
sion and, when necessary, adjuvant GKRS for residual tumor.
Residual/Recurrent Vestibular Schwannoma After Microsurgery

GKRS has been used to treat residual and recurrent vestibular schwannoma after
microsurgery.45,47–49 In general, reported rates of tumor control are similar to those
of primary GKRS for unilateral tumors (Table 5).
Table 5
Summary of reports for gamma knife radiosurgery for residual or recurrent vestibular schwannoma after microsurgery
Median Time After Median Tumor Median Marginal MedianTime of

Author N Residual Recurrent Microsurgery (Range) Volume Dose (Range) Follow-up (Range) Facial Paralysisa Tumor Controlb
3
Pollock et al, 78 52 26 57 mo (12–144 mo) 2.8 cm 15 Gy (12–20 Gy) 37 mo (12–101 mo) 23% 92%
199848
Unger et al, 50 34 16 39 mo (6–324 mo) 3.4 cm3 13 Gy 75 mo (42–114 mo) 0% 96%
200249
Yang et al, 61 — — 5.8 mo (0.3–96 mo) 3.65 cm3 12.5 Gy mean 53.7 mo (24–102 mo) 0% 98%
200745 (9–14 Gy)
a
Facial paralysis: new or worsened paralysis of patients who have pre-GKRS with H-B grade I–III.
b
Gamma Knife Radiosurgery

Tumor control: absence of the need for further microsurgery or radiosurgery.
647
648 Battista
In a study by Pollock and colleagues,48 76 patients (78 tumors) were treated with
GHRS for residual/recurrent vestibular schwannoma after microsurgery. Documented
tumor growth was the indication for treatment in 86% of cases. The indication for
treatment in the remaining 14% of cases was not reported. Of the 47 patients who
had H-B grade I–III facial function prior to GKRS, 11 patients developed new or
increased facial weakness at a median of 7 months (range 3–11 months) after
GKRS. When these results were stratified based on a marginal dose of 12 to14 Gy,
only 3 of 22 (14%) patients developed new or worsened facial paralysis. Twelve
percent of patients developed new, permanent trigeminal symptoms. All three patients
lost hearing and had Gardner-Robertson class 1 or 2 hearing prior to GKRS. One
patient required a ventriculoperitoneal shunt for hydrocephalus. There were six
patients who required revision microsurgery after radiosurgery because of increased
ataxia (two patients) or documented tumor growth (four patients). Failure of GKRS was
documented between 12 and 45 months after treatment.
In a study by Unger and colleagues,49 the indications for GKRS for residual/recur-
rent vestibular schwannoma after microsurgery were not reported. There was tempo-
rary facial paralysis and transient trigeminal dysfunction in five and four cases,
respectively. There was no change in pre-existing hearing status in any patient. One
patient required a ventriculoperitoneal shunt for hydrocephalus. After gamma knife,
two tumors required revision microsurgery at 4 and 18 months post radiosurgery
due to progressive tumor enlargement.
In the report by Yang and colleagues,45 the indications for GKRS also were not
reported. There were no reported changes in hearing or trigeminal function as a result
of GKRS. At last follow-up, four patients had tumor enlargement. One of these four
patients required revision microsurgery whereas the other patients had continued
tumor observation due to lack of symptoms.
Based on the results of these studies, it seems that GKRS is an acceptable thera-
peutic option for small- to medium-sized residual/recurrent vestibular schwannoma
after microsurgery. Adjuvant GKRS for residual vestibular schwannoma should be
reserved for cases of documented, progressive tumor growth, because it is known
that residual tumors may not grow.50,51
Cystic Tumors
Vestibular schwannoma cysts may be classified as peritumoral, when the cyst lies on
the outside of the tumor, and intratumoral when inside. Relative to solid vestibular
schwannoma, vestibular schwannoma with intratumoral cysts is associated more
commonly with sudden expansion,52–54 shorter symptom duration,52,54,55 atypical
initial symptoms (such as dysgeusia, vertigo, facial pain and unsteadiness),55 and
an increased rate of preoperative facial palsy.52,55,56
Treatment results are mixed regarding the use of the gamma knife to treat intratumoral
cystic vestibular schwannomas. In one study, six cases of vestibular schwannoma with
macrocystic components (cyst component of at least one third of the entire tumor
volume) demonstrated significant enlargement after treatment with GKRS.57 The six
cases were from a series of 74 cases of vestibular schwannoma treated with the
gamma knife. Cyst enlargement developed between 1 and 8 months after GKRS.
Cyst enlargement was associated with new or worsened neurologic symptoms in all
cases. Three cases required microsurgery for treatment, whereas two cases
decreased spontaneously and one case remained stable. Neurologic symptoms
resolved in the two cases that decreased spontaneously.
In another study by Hasegawa and colleagues19 there was no correlation found
between the presence of pretreatment intratumoral cysts and the chance for
post-treatment tumor expansion. Cyst formation after GKRS, however, was correlated
significantly with tumor expansion associated with neurologic changes.
Neurofibromatosis Type 2
Approximately 5% of patients who have a vestibular schwannoma have neurofi-
bromatosis type 2 (NF-2). NF-2 vestibular schwannomas are histologically distinct
from sporadic vestibular schwannomas.58 Only a few groups have reported their
results using GKRS for NF-2 vestibular schwannoma. Table 6 summarizes these
results.
Kida and colleagues59 reported the results of 20 patients who had NF-2 who under-
went GKRS to manage 20 vestibular schwannomas. Seventy percent of these patients
had prior microsurgery. The group reported 100% tumor control (50% no growth and
50% regression) after a mean follow-up period of 33.6 months. Transient radiation-
induced facial paresis, hemifacial spasm, and ataxia occurred in two patients each,
but each symptom resolved completely.
Roche and colleagues60 reported the outcome of 27 patients who had NF-2 in
whom GKRS was used to manage 37 vestibular schwannomas. There were two
temporary facial nerve deficits and one permanent. The group reported that 26
(74%) of the tumors were controlled by GKRS (40% no growth and 30% regression)
at last follow-up. Three tumors required microsurgical removal for continued growth.
The treatment required for the remaining eight cases was not reported.
Rowe and colleagues61 reported a large series of NF-2 patients who had vestibular
schwannoma managed using GKRS. They irradiated 122 tumors in 96 patients
between 1986 and 2000. Twenty percent of the cases were treated with one or
more prior microsurgical resections. The majority of patients were treated for docu-
mented tumor growth. For those cases without tumor growth, other indications for
GKRS included a rapid deterioration in hearing, tumor near 3 cm in size, or planned
adjuvant therapy for significant residual tumor after microsurgery. The serviceable
hearing preservation rate was 22%. When hearing results were examined using
current marginal radiation doses (10–16 Gy, mean 13 Gy), 38% of the tumors had
hearing preservation at 3 years after radiosurgery. In this lower-dose group, facial
and trigeminal function worsened in 8% and 2% of the patients, respectively. There
was a statistical reduction in cochlear, facial, and trigeminal dysfunction with reduced
Table 6
Results of gamma knife radiosurgery for patients who had neurofibromatosis type 2
Average
Average Marginal Serviceable Local
Patients/ Follow-up Average Dose Hearing Control
Series Tumors (Range) Tumor Size (Range) Preservationa Rateb
Kida et al, 20 patients/ 34 mo 24.4 mm 13 Gy 33.3% 100%
200059 20 tumors (18–84 mo) (10–15 Gy)
Roche et al, 27 patients/ 62 mo 4.0 cm3 13 Gy 57% 74%
200060 35 tumors (27–123 mo) (10–18 Gy)
Rowe et al, 96 patients/ 50 mo 5.3 cm3 15 Gy 22% 79%
200361 122 tumors (4–154 mo) (10–25 Gy)
Mathieu 60 patients/ 64 mo 5.7 cm3 14 Gy 40% 88%
et al, 200762 72 tumors (4–196 mo) (11–20 Gy)
a
Serviceable hearing defined as Gardner-Robertson class 1 or 2.
b
Local control rate defined as no further microsurgery or radiation after GKRS.
650 Battista
radiation dosage. Tumor volume was found to be the only factor predictive of local
control, with worse control associated with larger tumors.
Mathieu and colleagues62 reported the results of 60 patients and 72 tumors treated
between 1987 and 2005. Twenty-one tumors in 17 patients had at least one microsur-
gical resection before GKRS. The indications for GKRS were progressive tumor
growth, recurrence of tumor after gross total resection, continued growth after frac-
tionated radiation therapy, or hearing deterioration. Overall, the serviceable hearing
preservation rate was 40%. When hearing results were examined using marginal radi-
ation doses less than 14 Gy, the serviceable hearing preservation rate was 53%. At
latest evaluation, 39% of tumors regressed in size, 44% were stable in size, and
17% (12 tumors) increased in size. Nine of these 12 enlarging tumors underwent
microsurgical resection, further GKRS, or both. The treatment required for the remain-
ing three failures was not reported. As with the study by Rowe and colleagues,61 there
was a statistical reduction in control rate with increasing tumor size.
Based on these results, GKRS seems less efficacious in treating vestibular schwan-
noma secondary to NF-2 when compared with sporadic tumors. This finding is most
likely due to the differences in tumor biology of NF-2 tumors and the tendency of these
tumors to invade adjacent cranial nerves.58 Despite the differences in results
compared to sporadic tumors, GKRS does seem to have a role to play in treating
NF-2 vestibular schwannoma. As more data become available using GKRS for
NF-2, the management strategies for these tumors may become more clearly defined.
FURTHER CONSIDERATIONS
The Leksell Gamma Knife 4C system and earlier models are limited to treatment of
cranial lesions. The latest gamma knife machine, first put into practice in 2006, the
Leksell Gamma Knife Perfexion, has the capability to treat lesions of the cervical spine
and other areas of the head and neck. The Perfexion unit is based on a single, inte-
grated permanent collimator system (Fig. 6). The collimators are partitioned into eight
segments around the circumference of the device, each containing an independently
moveable sector. These eight sectors, each containing 24 cobalt-60 sources, are
operated by individual servo drives. Depending on the sector position, the collimator
size of each sector can be individually varied between 4, 8, and 16 mm. In this way, the
need for changing the collimator helmet during treatment is no longer necessary,
which can result in a reduction in treatment time.
In addition to improvements in radiation delivery, MRI and CT technology certainly
will continue to evolve. Improvements in radiologic techniques will translate directly to
improvements in accuracy and predictability of 3-D stereotactic radiation.
Fig. 6. Schematic drawing of side view of Leksell Gamma Knife Perfexion showing one unit
housing 4-, 8- and 16-mm collimators. (Courtesy of Elekta Inc., Norcross, GA; with permission.)
SUMMARY
GKRS is now an established means of treatment of small- to medium-sized vestibular

schwannomas. The procedure has a low morbidity when used appropriately. Tumor
control, however, needs to be better defined. The results of GKRS treatment of
residual/recurrent vestibular schwannoma after microsurgery suggest that GKRS is
a viable treatment option for residual/recurrent vestibular schwannoma. Some centers
are now reporting their results of revision GKRS for vestibular schwannoma; the long-
term results of retreatment are, as yet, unknown. When radiosurgery is offered as
treatment, the prospect of radiosurgical failure, and the results of subsequent treat-
ment for radiosurgical failure, must be discussed with patients.
REFERENCES
1. Leksell L. A note on the treatment of acoustic tumors. Acta Chir Scand 1971;137:
763–5.
2. Society Leksell Gamma Knife. World wide indications treated. Available at:
http://www.elekta.com/healthcare_us_treatment_statistics.php; 2006. Accessed
January 20, 2008.
3. Society Leksell Gamma Knife. World wide indications treated. 2004.
4. Flickinger JC, Kondziolka D, Pollock BE, et al. Evolution in technique for vestibular
schwannoma radiosurgery and effect on outcome. Int J Radiat Oncol Biol Phys
1996;36(2):275–80.
5. American Academy of Otolaryngology–Head and Neck Surgery Foundation, INC.
Committee on Hearing and Equilibrium guidelines for the evaluation of hearing
preservation in acoustic neuroma (vestibular schwannoma). American Academy
of Otolaryngology–Head and Neck Surgery Foundation, INC. Otolaryngol Head
Neck Surg 1995;113(3):179–80.
6. Gardner G, Robertson JH. Hearing preservation in unilateral acoustic neuroma
surgery. Ann Otol Rhinol Laryngol 1988;97(1):55–66.
7. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck
Surg 1985;93(2):146–7.
8. Lomax NJ, Scheib SG. Quantifying the degree of conformity in radiosurgery treat-
ment planning. Int J Radiat Oncol Biol Phys 2003;55(5):1409–19.
9. Regis J, Pellet W, Delsanti C, et al. Functional outcome after gamma knife surgery
or microsurgery for vestibular schwannomas. J Neurosurg 2002;97(5):1091–100.
with marginal tumor doses of 12 to 13 Gy. Int J Radiat Oncol Biol Phys 2004;
60(1):225–30.
11. Wowra B, Muacevic A, Jess-Hempen A, et al. Outpatient gamma knife surgery for
vestibular schwannoma: definition of the therapeutic profile based on a 10-year
experience. J Neurosurg 2005;102(Suppl):114–8.
12. Pellet W, Regis J, Roche PH, et al. Relative indications for radiosurgery and
microsurgery for acoustic schwannoma. Adv Tech Stand Neurosurg 2003;28:
227–82 [discussion: 82–4].
195–9.
14. Nakamura H, Jokura H, Takahashi K, et al. Serial follow-up MR imaging after
gamma knife radiosurgery for vestibular schwannoma. AJNR Am J Neuroradiol
2000;21(8):1540–6.
652 Battista
15. Linksey ME, Lundsford LD, Flickinger JC. Neuroimaging of acoustic nerve sheath
tumors after stereotaxic radiosurgery. AJNR Am J Neuroradiol 1991;12:1165–75.
16. Muacevic A, Jess-Hempen A, Tonn JC, et al. Results of outpatient gamma knife
radiosurgery for primary therapy of acoustic neuromas. Acta Neurochir (Wien)
2004;91:75–8.
17. Yu CP, Cheung JY, Leung S, et al. Sequential volume mapping for confirmation of
negative growth in vestibular schwannomas treated by gamma knife radiosur-
gery. J Neurosurg 2000;93(Suppl 3):82–9.
surgery 2005;57(2):257–65 [discussion: 257–65].
19. Hasegawa T, Kida Y, Yoshimoto M, et al. Evaluation of tumor expansion after
stereotactic radiosurgery in patients harboring vestibular schwannomas. Neuro-
surgery 2006;58(6):1119–28 [discussion: 1119–28].
20. Pollock BE. Management of vestibular schwannomas that enlarge after stereo-
tactic radiosurgery: treatment recommendations based on a 15 year experience.
Neurosurgery 2006;58(2):241–8 [discussion: 241–8].
21. Myrseth E, Moller P, Pedersen PH, et al. Vestibular schwannomas: clinical results
and quality of life after microsurgery or gamma knife radiosurgery. Neurosurgery
2005;56(5):927–35 [discussion: 35].
22. Rowe JG, Radatz M, Walton L, et al. Gamma knife radiosurgery for unilateral
acoustic neuromas. J Neurol Neurosurg Psychiatry 2003;74:1536–42.
23. Inoue HK. Low-dose radiosurgery for large vestibular schwannomas: long-term
results of functional preservation. J Neurosurg 2005;102(Suppl):111–3.
24. Borden JA, Tsai JS, Mahajan A. Effect of subpixel magnetic resonance imaging
shifts on radiosurgical dosimetry for vestibular schwannoma. J Neurosurg
2002;97(Suppl 5):445–9.
25. Yu C, Apuzzo ML, Zee C, et al. A phantom study of the geometric accuracy of
computed tomographic and magnetic resonance imaging stereotactic localiza-
tion with the Leksell Stereotactic System. Neurosurgery 2001;48:1092–8.
26. Poetker DM, Jursinic PA, Runge-Samuelson CL, et al. Distortion of magnetic
resonance images used in gamma knife radiosurgery treatment planning:
implications for acoustic neuroma outcomes. Otol Neurotol 2005;26(6):
1220–8.
27. Selesnick SH, Rebol J, Heier LA, et al. Internal auditory canal involvement of
acoustic neuromas: surgical correlates to magnetic resonance imaging findings.
Otol Neurotol 2001;22(6):912–6.
28. Prasad D, Steiner M, Steiner L. Gamma surgery for vestibular schwannoma.
J Neurosurg 2000;92(5):745–59.
29. Litvack ZN, Noren G, Chougule PB, et al. Preservation of functional hearing after
gamma knife surgery for vestibular schwannoma. Neurosurg Focus 2003;14(5):
1–5.
30. Chung WY, Liu KD, Shiau CY, et al. Gamma knife surgery for vestibular schwan-
noma: 10-year experience of 195 cases. J Neurosurg 2005;102(Suppl):87–96.
31. Hempel JM, Hempel E, Wowra B, et al. Functional outcome after gamma knife
treatment in vestibular schwannoma. Eur Arch Otorhinolaryngol 2006;263(8):
714–8.
32. Yomo S, Arkha Y, Delsanti C, et al. Repeat gamma knife surgery for regrowth of
vestibular schwannomas. Neurosurgery 2009;64(1):48–55.
33. St. George EJ, Kudhail J, Perks J, et al. Acute symptoms after gamma knife radio-
surgery. J Neurosurg 2002;97(Suppl 5):631–4.
34. Werner-Wasik M, Rudoler S, Preston PE, et al. Immediated side effects of stereo-
tactic radiosurgery. Int J Radiat Oncol Biol Phys 1999;43:299–304.
35. Franco-Vidal V, Songu M, Blanchet H, et al. Intracochlear hemorrhage after
gamma knife radiosurgery. Otol Neurotol 2007;28(2):240–4.
36. Ogunrinde OK, Lunsford LD, Flickinger JC, et al. Cranial nerve preservation after
stereotactic radiosurgery for small acoustic tumors. Arch Neurol 1995;52(1):73–9.
37. Pollack AG, Marymont MH, Kalapurakal JA, et al. Acute neurological complica-
tions following gamma knife surgery for vestibular schwannoma. Case report.
J Neurosurg 2005;103(3):546–51.
38. Tago M, Terahara A, Nakagawa K, et al. Immediate neurological deterioration
after gamma knife radiosurgery for acoustic neuroma. Case report. J Neurosurg
2000;93(Suppl 3):78–81.
comparative observations of 125 patients treated at one institution. Int J Radiat
Oncol Biol Phys 2001;50(5):1265–78.
40. Paek SH, Chung HT, Jeong SS, et al. Hearing preservation after gamma knife
stereotactic radiosurgery of vestibular schwannoma. Cancer 2005;104(3):580–90.
41. Hasegawa T, Kida Y, Kobayashi T, et al. Long-term outcomes in patients with
vestibular schwannomas treated using gamma knife surgery: 10-year follow up.
J Neurosurg 2005;102(1):10–6.
ular schwannomas. Stereotact Funct Neurosurg 1998;70(Suppl 1):65–73.
43. Brantberg K, Bergenius J, Tribukait A. Gentamicin treatment in peripheral vestib-
ular disorders other than Meniere’s disease. ORL J Otorhinolaryngol Relat Spec
1996;58(5):277–9.
44. Selch MT, Pedrose A, Lee SP. Stereotactic radiosurgery for the treatment of
acoustic neuromas. J Neurosurg 2004;101(Suppl 3):362–70.
45. Yang SY, Kim DG, Chung HT, et al. Evaluation of tumor response after gamma
knife radiosurgery for residual vestibular schwannomas based on MRI morpho-
logical features. J Neurol Neurosurg Psychiatry 2007;79:431–6.
46. Foote RL, Coffey RJ, Swanson JW, et al. Stereotactic radiosurgery using the
gamma knife for acoustic neuromas. Int J Radiat Oncol Biol Phys 1995;32(4):
1153–60.
47. Park CK, Jung HW, Kim JE, et al. Therapeutic strategy for large vestibular
schwannomas. J Neurooncol 2006;77(2):167–71.
48. Pollock BE, Lunsford LD, Flickinger JC, et al. Vestibular schwannoma manage-
ment. Part I. Failed microsurgery and the role of delayed stereotactic radiosur-
gery. J Neurosurg 1998;89(6):944–8.
49. Unger F, Walch C, Papaefthymiou G, et al. Radiosurgery of residual and recurrent
vestibular schwannomas. Acta Neurochir (Wien) 2002;144(7):671–6 [discussion:
6–7].
50. Lownie SP, Drake CG. Radical intracapsular removal of acoustic neurinomas.
J Neurosurg 1991;74:422–5.
51. Wazen J, Silverstein H, Norrell H. Preoperative and postoperative growth rates in
acoustic neuromas documented with CT scanning. Otolaryngol Head Neck Surg
1985;93:151–5.
52. Charabi S, Tos M, Thomsen J, et al. Cystic vestibular schwannoma—clinical and
experimental studies. Acta Otolaryngol 2000;543:11–3.
53. Lanser MJ, Jackler RK, Pitts LH. Intratumoral hemorrhage and cyst expansion as
a cause of acute neurological deterioration in acoustic neuroma patients. In: Tos M,
654 Battista
Thomsen J, editors. Acoustic Neuroma: Proceedings of the First International Confer-

ence on Acoustic Tumors, Copenhagen, Denmark, August 25–29, 1991. Amsterdam:
Kugler Publications; 1992. p. 229–34.
54. Benech F, Perez R, Fontanella MM, et al. Cystic versus solid vestibular schwan-
nomas: a series of 80 grade III-IV patients. Neurosurg Rev 2005;28(3):209–13.
55. Kameyama S, Tanaka R, Kawaguchi T, et al. Cystic acoustic neurinomas: studies
of 14 cases. Acta Neurochir (Wien) 1996;138(6):695–9.
56. Matthies C, Samii M, Krebs S. Management of vestibular schwannomas (acoustic
neuromas): radiological features in 202 cases–their value for diagnosis and their
predictive importance. Neurosurgery 1997;40(3):469–81 [discussion: 81–2].
57. Pendl G, Ganz JC, Kitz K, et al. Acoustic neurinomas with macrocysts treated
with gamma knife radiosurgery. Stereotact Funct Neurosurg 1996;66(Suppl 1):
103–11.
58. Sobel RA. Vestibular (acoustic) schwannomas: histologic features in neurofibro-
matosis 2 and in unilateral cases. J Neuropathol Exp Neurol 1993;52(2):106–13.
59. Kida Y, Kobayashi T, Tanaka T, et al. Radiosurgery for bilateral neurinomas asso-
ciated with neurofibromatosis type 2. Surg Neurol 2000;53(4):383–9 [discussion:
389–90].
60. Roche PH, Regis J, Pellet W, et al. [Neurofibromatosis type 2. Preliminary results
of gamma knife radiosurgery of vestibular schwannomas]. Neurochirurgie 2000;
46(4):339–53 [French] [discussion: 54].
61. Rowe JG, Radatz MW, Walton L, et al. Clinical experience with gamma knife
stereotactic radiosurgery in the management of vestibular schwannomas
secondary to type 2 neurofibromatosis. J Neurol Neurosurg Psychiatry 2003;
74(9):1288–93.
62. Mathieu D, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for vestib-
ular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor
control, complications, and hearing preservation rates. Neurosurgery 2007;60(3):
460–8 [discussion: 468–70].
Stere ot ac tic
Radiotherapy
for Vestibular
Schwa nnoma
Patrick Sweeney, MDa,*, SantoshYajnik, MDb, William Hartsell, MDc,
George Bovis, MDa, JagannathVenkatesan, MSa
KEYWORDS
Vestibular schwannomas Schwannoma
Stereotactic radiotherapy Radiosurgery
Vestibular schwannomas (acoustic neuromas) are typically benign tumors that arise
from the Schwann’s cells of the eighth (VIII) cranial nerves. Treatment options include
observation, surgical resection, and radiation therapy, which can be delivered in
a conformal or stereotactic manner. The choice of treatment is multifactorial and
includes patient and physician preference, age, tumor size, and symptoms.
Stereotactic techniques for treating vestibular schwannoma include single fraction
stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (SRT).
Evaluation of management trends from 10 years ago predicted an explosive growth
of SRS for vestibular schwannomas in the next century,1 and this growth has been
realized. A similar growth potential also can be surmised for SRT, but there is no
consensus as yet on the optimal technique, dose, or fraction size. This article
describes the basic concepts of stereotactic radiotherapy and the radiobiologic ratio-
nale for this treatment and reports the clinical results.
STEREOTACTIC RADIOSURGERY VERSUS RADIOTHERAPY

Stereotactic Radiosurgery
The definition of SRS is defined variably but generally is considered to be a single high
dose of radiation delivered with rigid immobilization to an intracranial target to achieve
a
Illinois Gamma Knife Center, Alexian Neurosciences Institute, Alexian Brothers Medical
Center, 800 Biesterfield Road, Elk Grove Village, IL 60007, USA
b
Advocate Illinois Masonic Medical Center, Department of Radiation Oncology, 836 West
Wellington Avenue, Chicago, IL 60657, USA
c
Advocate Good Samaritan Hospital, Department of Radiation Oncology, 3815 Highland
Avenue, Downers Grove, IL 60515, USA
E-mail address: psweeney@chicagocancer.org (P. Sweeney).

656 Sweeney et al
a biologic result.2 As a rule, this treatment implies the use of a halo or frame that is af-
fixed rigidly to the patient ’s skull to allow for precise immobilization and to provide the
reference for defining the target in space relative to a Cartesian coordinate system.
The treatment can be delivered with a dedicated radiosurgery machine such as a Lek-
sell Gamma Knife (Elekta, Norcross, Georgia) or a modified linear accelerator, of which
there are various commercially available products. The invasive nature of this fixation,
usually by pins that are screwed into the skull, makes this technique feasible only for
single-fraction treatment. Further, the fact that a high dose is delivered in one fraction
limits this treatment to small targets, usually less than 3 cm. SRS has been very effec-
tive in treating various intracranial targets, including vestibular schwannomas, menin-
giomas, vascular lesions, trigeminal neuralgia, and primary and metastatic brain
tumors.
Stereotactic Radiotherapy
SRT is a technique that attempts to combine the biologic advantages of fractionation
(ie, delivering multiple small doses of radiation) with the physical advantages of the
precision immobilization seen in SRS. This technique is performed on a linear accel-
erator with a relocatable stereotactic frame such as with the Novalis (BrainLab Incor-
porated, Westchester, Illinois) or Radionics (Burlington, Massachusetts) systems or
with frameless systems that use optical tracking such as Cyberknife (Accuray Incorpo-
rated, Sunnyvale, California). Much of published experience with SRT has been with
the Gill-Thomas-Cosman relocatable head ring, an example of which is shown in
Fig. 1. Treatments can be delivered with multiple noncoplanar arcs or with fixed fields.
Multiple noncoplanar arcs imply that a finely collimated linear accelerator delivers the
radiation dose while rotating around the patient, whereas with fixed fields, the beam is
fixed but delivered through multiple points that converge on the target lesion. As a rule,
the precision for SRT is less than that of SRS, with a relocatable accuracy of approx-
imately 2 mm,3 and often safety margins of 2 to 5 mm are added to the planning
volume to account for this uncertainty.
In recent years, the development of intensity-modulated radiation therapy (IMRT)
and image-guided radiation therapy (IGRT) has refined SRT further. IMRT is the ability
to modulate the intensity of the radiation beam through the treatment volume to allow
for maximum sparing of normal tissues with improved dosimetry to the target. IGRT is
the use of daily imaging of the target volume before treatment delivery to account for
patient movement to assure target accuracy. One could argue that these techniques
Fig. 1. The Gill-Thomas-Cosman relocatable head ring. (Courtesy of Integra LifeSciences

Corporation, Plainsboro, NJ; with permission).
have replaced SRT in that they are imaging- and not coordinate (or frame)-based.
However defined, these techniques are used widely in many radiation oncology
departments and have allowed for treatments with SRT-like precision to be performed
on many of the same intracranial targets as SRS. One posited advantage of SRT rela-
tive to SRS is that because of the ability to fractionate the treatment, targets larger
than 3 cm/or those involving or adjacent to critical structures such as the brainstem
or optic apparatus can be treated with SRT without undue risk of complications. These
size and dose constraints are much more limiting in single-fraction SRS. Further, these
developments are being applied to extracranial targets, including tumors in the lungs,
pancreas, liver, prostate, and spine.
RADIOBIOLOGIC RATIONALE FOR STEREOTACTIC RADIOTHERAPY
SRS involves delivery of a single dose of radiation while SRT involves administering
a more protracted and fractionated course of treatment. For both SRS and SRT, the
megavoltage radiation delivered during treatment causes free radical-mediated
damage to the DNA of the target. When treating fast-growing tumors such as squa-
mous cell carcinomas of the head and neck or uterine cervix, both fraction size and
overall treatment time help to determine the tumor control probability.4 Such fast-
growing tumors can experience accelerated repopulation, whereby surviving cancer
cells, during a protracted course of radiotherapy, begin to divide and multiply more
rapidly. The potential for accelerated repopulation necessitates that the treatment of
such fast-growing tumors be completed in a timely manner. If there are unplanned
breaks during a course of radiotherapy, this may lead to a decrease in tumor control.
For slow-growing tumors such as vestibular schwannomas, on the other hand, the
overall treatment time has little influence on tumor control probability. The daily
dose of the radiation therapy that is delivered is considered the principle factor in
determining the late effects of radiation therapy.4 Therefore, a radiobiological concept
favoring SRT over SRS for treating vestibular schwannoma would be that fractionation
would not be expected to adversely impact tumor control probability, while it may
reduce long-term damage to surrounding normal tissues by allowing nearby critical
structures to repair sublethal radiation-induced damage.
Little is known about the precise radiobiological mechanisms that mediate the
effects of ionizing radiation on vestibular schwannoma. An interesting study was
done at the University of Pittsburgh in which athymic mice were transplanted with
human xenografts of vestibular schwannoma tissue.5 This study sought to describe
the mechanism of SRS-induced tumor control. Various SRS regimens ranging from
10 Gy to 40 Gy were delivered in a single fraction, and mice subsequently were sacri-
ficed and the tissue studied at 2 weeks, 1 month, and 2 months after SRS. An average
tumor volume reduction of about 16.4% was noted at 3 months in the 10 Gy arm.
Histologic examination showed a higher incidence of hemosiderin deposits and
vascular mural hyalinization in SRS xenografts versus controls, suggesting both
a cellular and vascular effect from radiosurgery.
As will be shown in the next section, both SRS and SRT lead to high tumor control
probability rates, with good preservation of hearing and limited facial nerve dysfunc-
tion. Understanding of the radiobiological mechanisms governing tumor control and
normal tissue damage from radiation, however, is in its nascency. Although it is not
known what the optimal dose and optimal fractionation regimen are for treating vestib-
ular schwannoma, tumor control probability with SRS and SRT is excellent, and the
risk of long-term morbidity from these treatments remains low.
658 Sweeney et al
CLINICAL RESULTS
In reviewing the data on SRT for vestibular schwannoma, one must compare outcome
measures with the mature results obtained for SRS. These measures include tumor
control, hearing preservation, and the development of cranial neuropathies. Chopra
and colleagues6 recently reported the results from the University of Pittsburgh of
patients treated with Gamma Knife radiosurgery with marginal tumor doses of 12
Gy to 13 Gy. The authors reported a 10-year actuarial resection-free control of
98%, with a cranial nerve complication rate of less than 5%. Although hearing preser-
vation is a more difficult parameter to quantify, they reported that among those
patients who had testable hearing, the hearing preservation rate was 78% to keep
the same Gardner-Robertson level and 97% to preserve any testable level of hearing.
Similarly, Friedman and colleagues,7 in their series of 390 patients treated with single-
fraction linear accelerator radiosurgery with a marginal dose of 12.5 Gy, described
a 5-year actuarial control rate of 90%, with a cranial nerve complication rate of less
than 5%. Thus, when analyzing the results of SRT, it is important that the outcomes
approach those of these and other mature SRS series.
In addition, it is helpful to distinguish between SRT series that use conventional frac-
tionation and those that use hypofractionation. Conventional fractionation SRT is
based on longstanding experience in the treatment of cranial (and extracranial) tumors
with nonstereotactic techniques and generally implies 5 to 6 weeks of daily treatment
with total doses of between 45 Gy and 58 Gy. Conversely, hypofractioned SRT is by
definition the use of larger but fewer doses of radiation delivered over a shorter period.
Hypofractionation is used to gain some of the advantages of fractionation in terms of
sparing normal tissues, with the convenience of a more limited treatment time. Hypo-
fractionation schedules typically range from three to six fractions. Unfortunately, the
optimal dose/fractionation schedule for this approach is unknown in terms of tumor
control and complication potential. Hypofractionation is more akin to single-fraction
SRS than conventional SRT and, therefore, would require more precision than conven-
tional fractionation SRT. Conventional fractionated SRT, on the other hand, is more
analogous to conventional radiation therapy techniques.
A summary of the reported series for conventionally fractionated SRT is shown in
Table 1. In the studies referenced in Table 1 treatment consisted of conventional frac-
tionation schedules between 45 Gy and 57.6 Gy delivered over 5 to 7 weeks. These data
are remarkable for being fairly consistent with local control rates of greater than 86%.
Local control generally is defined as tumor stability or regression. Included in this group
is the series with the longest follow-up of 80 months reported by Maire and colleagues.8
Maire and colleagues described an actuarial 15-year local control rate of 86%, which is
quite good given the large median tumor size of 3.1 cm, but also underscores the possi-
bility of late recurrences and the need for life-long follow-up, especially in younger
patients. It is interesting that this series of patients was treated without stereotactic
immobilization but only with mask fixation. In other words, the target was defined
using mask fiducials on a day-to day basis as opposed to stereotactically defining
the isocenter as with SRT. Thus, although stereotactic treatment has become the
predominant treatment approach for vestibular schwannomas, conventional external
beam treatment remains an effective modality. The remainder of the series with
stereotactic immobilization show local control rates of greater than 90% but at shorter
follow-up intervals.9–17
The reported complications of the studies in Table 1 were low for both facial and
trigeminal neuropathies and were similar to what has been reported for SRS.6,7 Other
reported complications included the development of hydrocephalus requiring shunt
Table 1
Acoustic neuromas: conventional stereotactic radiotherapy
First Author/ Number Local Median Complications

Institution of Dose Fraction Tumor Size Control Follow- Cranial Cranial Hearing
(Reference) Patients (Gy) Size (Gy) Technique (Range) cm3 (%) up (mo) NerveVII Nerve V Other Pres (%)
Maire/Bordeaux, 45 51 1.8 Mask– 3.1* 86% 80 0% 0% 4- hydrocephalous; 77.7%
France8 fixed (1.1–5.5) 1- mpnst
Andrews/ 56 50 2 GTC–arcs 2.78 97% 26.5 2% 7% 81%
T. Jefferson,
Philadelphia9
Sawamura/ 101 48 2 Mask–arcs 1.9* 91% 45 1% 4% 11% 71%
Hokkaido, & fixed (0.3–4.0) hydrocephalous
Stereotactic Radiotherapy for Vestibular Schwannoma

Japan10 requiring shunt
Selch/University of 48 54 1.8 mask- arcs 2.2* 100% 36 2.1% 2.2% 93%
California Los & fixed (0.6–4.0)
Angeles11
Combs/ 106 57.6 1.8 mask- 3.9 93% 48.5 2.3% 3.4% 94.5%
Heidelberg mmlc (2.7–30.7)
Germany12 fixed
Chan/ 70 54 1.8 GTC–arcs 2.4* 98% 45.3 1% 4% 84%
Massachusetts (0.05–21.1)
General13
Horan/ 95 50 1.66 Mask/ 2.0* 97% 18.6 3.2% 0% 100%
Addenbrookes, GTC–arc (1.0–4.0)
Cambridge14 & fixed
Koh/Princess 60 50 2 GTC– arcs 4.9 96% 31.9 0% 0% GBM 77.3%
Margaret15 (0.3–49)
Thomas/British 34 45 1.8 Mask–arcs 2.25 96% 36.5 7% 0% 2- hydrocephalous 63%
Columbia16 & fixed (0.3–17.93)
McClelland III/ 20 54 1.8 GTC–arcs 2.1* 100% 22 0% 10% 100%
Minnesota17 (1.1–3.4)
Abbreviations: Gy, gray; mmlc, mini-multi-leaf collimator; GTC, gill-thomas-cosman frame; Local Ctrl, local control; Median f/u (mos), median follow-up in months;
CN, cranial nerve; hydroceph, hydrocephalus; GBM, glioblastoma multiforme; NF2, neurofibromatosis, type II; no diff, no difference in outcome; hearing pres (%),
proportion of patients with preservation of hearing after treatment.
* maximal diameter in cm instead of volume measurements.
659
660
Sweeney et al
Table 2
Hypofractionated stereotactic radiotherapy
Complications
Fraction Local Median Cranial Cranial
First Author/Institution Number of Dose Size Tumor Size Control Follow- Nerve Nerve Hearing
(Reference) Patients (Gy) (Gy) Technique (Range) cm3 (%) up (mo) VII V Other Pres (%)
Lederman/Staten Island, 38 20 4/5 6.9 100% 28 0% 0%
New York19 (0.1–32)
Kalapurakal/Philadelphia20 19 30 5/6 GTC-arcs 3.5* 100% 54
(2.3–4.9)
Williams/Hopkins, Baltimore21 111 25 5 Mask 1.4 100% 21.6 0% 0% 72%
14 30 3 8.1 100% 21.6 0% 0%
Meijer/VU, Amsterdam22 80 20/25 4/5 GTC–arcs 2.5* 100% 33 3% 2% 61%
(0.8–3.8)
Chang/Stanford23 61 21/18 7/6 Cyberknife 1.8* 98% 48 0% 0% 74%
(0.5–3.2)
Abbreviations: GTC, Gill-Thomas-Cosman frame; hearing pres (%), proportion of patients with preservation of hearing after treatment.
* maximal diameter in cm instead of volume measurements.
placement8,10,16 and the rare development of second malignancies.8,15 With respect

to hearing preservation, all the studies demonstrate that greater than two thirds of
patients can preserve useful hearing, although there is trend for hearing preservation
rates to decline with longer follow-up. The hearing preservation rates for SRT are
similar to those reported for SRS.6,7 An exception to this is the report of the group
from Thomas Jefferson University (Philadelphia, Pennsylvania), which compared
Gamma Knife radiosurgery patients treated at the authors’ institution with those
treated with SRT.9 These authors reported a statistically significant improvement in
hearing preservation in those treated with SRT compared with those treated with
Gamma Knife.9 This study was limited, however, by a small number of patients who
underwent prospective testing and a short follow-up interval. Recent data from
Thomas Jefferson University by Werner-Wasik, and colleagues,18 with a median follow
up of 69 months, has suggested that lowering the total radiation dose from 50.4 Gy to
46.8 Gy with conventional fractionation may be associated with higher hearing pres-
ervation rates without changing local control.
Table 2 shows a summary of the series treating vestibular schwannoma patients
with hypofractionated SRT.19–23 The first report in the literature from Lederman and
colleagues19 in 1997 was with four or five weekly fractions to a total dose of 20 Gy.
They described 100% tumor control with no permanent cranial neuropathies. Similarly
good results have been reported from the Stanford group.23 The Stanford group’s
initial experience with hypofractionation for vestibular schwannoma was with the rigid
fixation of an SRS frame with three fractions spaced 8 hours apart to a total dose of 21
Gy.24 With this technique, the Stanford group reported 97% tumor control with a 77%
hearing preservation rate at a median follow-up interval of 24 months. In recent years,
Stanford has been using the frameless Cyberknife system to deliver SRT. With this
technique, they are treating with three 6 Gy fractions delivered on consecutive days
to a total dose of 18 Gy. With a minimum follow-up of 36 months, they have reported
similar rates of local control, complication risk, and hearing preservation as their earlier
experience.23 The latest results from Stanford using the Cyberknife are reported in the
article by Sakamoto and colleagues, elsewhere in this issue. Thus it would appear that
hypofractionated SRT, like conventionally fractionated SRT, leads to similar outcomes
in vestibular schwannoma patients as single-fraction SRS.
SUMMARY
The optimal dose and fractionation schedule for vestibular schwannoma SRT remain
to be determined. It is clear that the tumor control rates for both conventionally frac-
tionated and hypofractionated SRT are similar to SRS. In addition, the risk of cranial
neuropathies is low for SRT and SRS. The posited advantage of fractionation for
acoustic schwannomas over single-fraction radiosurgery is preservation of hearing.
Most current data, however, do not show an advantage of hearing preservation
when using either conventionally or hypofractionated SRT when compared with
SRS. The exception to this are the data from Thomas Jefferson University that appear
to show that conventionally fractionated SRT leads to better hearing preservation
when compared with single-fraction SRS.9 This study, however, is limited by a small
number of patients and a short follow-up interval. In addition, data from Stanford using
the Cyberknife have demonstrated a 74% hearing preservation rate at 2 years of
follow-up (see the article concerning Cyberknife radiotherapy for vestibular schwan-
noma, by Sakamoto and colleagues, elsewhere in this issue).
Flickinger 25 has noted that because of the high success rate in controlling vestibular
schwannomas with SRS and SRT, it is unlikely that reliable radiobiologic parameters
662 Sweeney et al
will be extracted from dose–response data. He notes that tumor control rates were not
changed as the doses of SRS were lowered from 16 Gy to 20 Gy to the current level of
11 Gy to 13 Gy. Morbidity has decreased, however, as dosages were reduced. It is
likely that a similar lowering of total dose and fraction sizes for SRT will continue to
lead to excellent tumor control. The impact on cranial neuropathies and hearing pres-
ervation will require lengthy follow-up and large case series.
As a practical matter, fractionated SRT, as opposed to SRS, would appear to be
more suitable for larger lesions or those that are adherent to, or compressing, the
brainstem. Although the optimal dose and fraction size are not known, it would
seem that conventional SRT would be most useful in those radiotherapy departments
without the ability to image patients on a daily basis before treatment (IGRT), thus
requiring larger safety margins and leading to a larger volume of normal tissue in
the radiated volume. The tolerance of the normal brain to radiation, although not
understood completely, is related partly to the volume irradiated and to fraction
size.26 Partial inclusion of the brainstem in the target volume receiving a full dose
with conventional fractionation should be tolerated well. Hypofractionated SRT prob-
ably should be used in those departments with IGRT capability where prospective
imaging of the target allows for smaller margins of normal tissue and thus the minimi-
zation of brainstem in the treated volume. Small vestibular tumors can be treated
effectively with any of these stereotactic techniques.
REFERENCES
1. Pollock BE, Lunsford DL, Noren G. Vestibular schwannoma management in the

next century: a radiosurgcal perspective. Neurosurgery 1998;43(3):475–81.
2. Verhey LJ, Smith V. The physics of radiosurgery. Semin Radiat Oncol 1995;5(3):
175–91.
3. Kooy HM, Dunbar SF, Tarbell NJ, et al. Adaptation and verification of the relocat-
able Gill-Thomas-Cosman frame in stereotactic radiotherapy. Int J Radiat Oncol
Biol Phys 1994;30(3):685–91.
4. Hall E, Giaccia A. Time, dose and fractionation in radiotherapy. In: Hall E,
Giaccia, editors. Radiobiology for the radiologist. 5th edition. Philidelphia:
Lippincott Wilkins & Williams; 2000. p. 397–418.
5. Linskey ME, Martinez AJ, Kondziolka D, et al. The radiobiology of human acoustic
schwannoma xenografts after stereotactic radiosurgery evaluated in the subrenal
capsule of athymic mice. J Neurosurg 1993;78(4):645–53.
6. Chopra R, Kondziolka D, Niranjan A, et al. Long-term follow-up of acoustic
schwannoma radiosurgery with marginal doses of 12 to 13 Gy. Int J Radiat Oncol
Biol Phys 2007;68(3):845–51.
7. Friedman WA, Bradshaw P, Myers A, et al. Linear accelerator radiosurgery for
vestibular schwannomas. J Neurosurg 2006;105(5):657–61.
8. Maire JP, Huchet A, Milbeo Y, et al. Twenty years ’ experience in the treatment of
acoustic neuromas with fractionated radiotherapy: a review of 45 cases. Int J
comparative observation of 125 patients treated at one institution. Int J Radiat
Oncol Biol Phys 2001;50(5):1265–78.
10. Sawmura Y, Shirato H, Sakamoto T, et al. Management of vestibular schwannoma
by fractionated stereotactic radiotherapy and associated cerebrospinal fluid
malabsorption. J Neurosurg 2003;99(4):685–92.
11. Selch MT, Pedroso A, Lee SP, et al. Stereotactic radiotherapy for the treatment of
acoustic neuromas. J Neurosurg 2004;101(Suppl 3):362–72.
treated at a single institution. Int J Radiat Oncol Biol Phys 2005;63(1):75–81.
13. Chan A, Black PM, Ojemann RG, et al. Stereotactic radiotherapy for vestibular
schwannomas: favorable outcome with minimal toxicity. Neurosurgery 2005;
57(1):60–70.
14. Horan G, Whitfield GA, Burton KE, et al. Fractionated conformal radiotherapy in
vestibular schwannoma: early results from a single center. Clin Oncol 2007;
19(7):517–22.
15. Koh ES, Millar BA, Menard C, et al. Fractionated stereotactic radiotherapy for
acoustic neuroma: single institution experience at princess Margaret hospital.
Cancer 2007;109(6):1203–10.
of cochlear dose. J Neurosurg 2007;107(5):917–26.
17. McClelland S III, Gerbi BJ, Higgins PD, et al. Safety and efficacy of fractionated
stereotactic radiotherapy for acoustic neuromas. J Neurooncol 2008;86(2):191–4.
18. Werner-Wasik W, Curran WJ, Evans J, et al. Improved hearing preservation with
deescalated dose of fractionated stereotactic radiotherapy (SRT) in patients with
acoustic schwannomas: 50.4 Gy vs. 48.6 Gy. Int J Radiat Oncol Biol Phys 2006;
66(3):S241.
19. Lederman G, Lowry J, Wertheim S, et al. Acoustic neuroma: potential benefits of
fractionated stereotactic radiosurgery. Stereotact Funct Neurosurg 1997;69:
175–82.
20. Kalapurakal JA, Silverman CL, Akhtar N, et al. Improved trigeminal and facial
nerve tolerance following fractionated stereotactic radiotherapy for large acoustic
neuromas. Br J Radiol 1999;72(864):1202–7.
21. Williams JA. Fractionated stereotactic radiotherapy for acoustic neuromas. Int
J Radiat Oncol Biol Phys 2002;54(2):500–4.
22. Meijer OWM, Vandertop WP, Baayen JC, et al. Single-fraction vs. fractionated
linac-based radiosurgery for vestibular schwannomas: a single-institution study.
Int J Radiat Oncol Biol Phys 2003;56(5):1390–6.
23. Chang SD, Gibbs IC, Sakamoto GT, et al. Staged stereotactic irradiation for
acoustic neuroma. Neurosurgery 2005;56(6):1254–63.
report. Neurosurgery 1999;45(6):1299–307.
25. Flickinger JC. What is the optimal dose and fractionation for stereotactic irradia-
tion of acoustic neuromas? Int J Radiat Oncol Biol Phys 2002;54(2):311–2.
26. Marks JE, Baglan RJ, Prassad SC, et al. Cerebral radionecrosis: incidence and
risk in relation to dose, time, fractionation, and volume. Int J Radiat Oncol Biol
Phys 1981;7(2):243–52.
Cyb erknife
Radiotherapy for
Vestibular
Schwa nnoma
GordonT. Sakamoto, MDa,*, Nikolas Blevins, MDb, Iris C. Gibbs, MDc
KEYWORDS
Stereotactic radiosurgery Vestibular schwannomas
Cyberknife Fractionation
Most vestibular schwannomas are benign and slow-growing. Based on that fact,
conservative management with serial imaging is a viable alternative.1 For patients
who undergo treatment because of tumor growth, progressive symptoms, or personal
preference, options include serial observation, microsurgical resection, fractionated
stereotactic radiotherapy, and stereotactic radiosurgery. There remains some debate
as to how best to manage these tumors. Historically, vestibular schwannomas have
been treated with microsurgical resection. Loss of hearing and facial nerve injury,
however, are not uncommon microsurgical complications. Fractionated radiotherapy
was used initially as an adjunct to microsurgery in patients who had undergone
subtotal resection, and demonstrated the overall effectiveness of radiation for treating
vestibular schwannomas.2 Over the last few decades, stereotactic radiosurgery has
emerged as a safe and effective treatment modality for vestibular schwannomas.3–11
Owing mainly to the unknown risks of secondary tumors and possible late effects of
stereotactic radiation, stereotactic radiosurgery initially was reserved for patients
who were poor microsurgical candidates, or as an adjuvant treatment for residual or
recurrent tumor. The long-term data of stereotactic radiosurgery now support the effi-
cacy of this treatment modality. Historical reviews also suggest that secondary tumors
are rare after radiosurgery.12 For these reasons, stereotactic radiosurgery has
emerged as the preferred treatment modality, as it offers lower morbidity than surgical
resection and excellent long-term tumor control.4,7,13,14
Traditionally, stereotactic radiosurgery required the use of rigid immobilization using
a stereotactic frame to achieve treatment precision and accuracy. The Cyberknife
(Accuray, Incorporated, Sunnyvale, California), which was introduced in 1994, does
a
Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, USA
b
Department of Otolaryngology, Stanford University School of Medicine, Stanford, CA, USA
c
Radiation Oncology, Stanford University School of Medicine, Stanford, CA, USA
E-mail address: gtsaka@yahoo.com (G.T. Sakamoto).

666 Sakamoto et al
not require the use of rigid immobilization. Although the Cyberknife does not require
the use of a stereotactic frame, its accuracy is comparable to frame-based radiosur-
gery.15 Additionally, because the Cyberknife does not employ a rigid frame, it is prac-
tical to fractionate or stage Cyberknife treatments over several days to decrease the
risk of radiation injury to adjacent critical structures, such as the brainstem or cochlea.
THE CYBERKNIFE
Stereotactic radiosurgery is a radiation technique that can deliver therapeutic doses of

radiation with submillimeter accuracy and a rapid dose fall-off at the periphery of the
target. Leksell first conceived the concept of radiosurgery in the 1950s16 and created
the Gamma Knife, which used multiple cobalt sources to treat a target as defined on
pretreatment imaging data. Since then, stereotactic radiosurgery has advanced with
technologic improvements in computing and imaging. For three decades, stereotactic
targeting that required rigid skeletal fixation to provide registration between pretreat-
ment plan and target anatomy was at the center of all radiosurgical systems, espe-
cially the gold standard Gamma Knife. In the 1990s, John Adler, however, created
the CyberKnife, a robotic frameless radiotherapy system that uses real-time acquisi-
tion of the patient’s bony anatomy for image-guidance.17
The Cyberknife is a frameless, image-guided, robotic radiotherapy system. Thera-
peutic radiation is emitted from a compact 6 MV linear accelerator mounted on
a robotic arm (Fig. 1). The arm is programmed to move the linear accelerator sequen-
tially through a predetermined series of locations. At each location, radiation is deliv-
ered to the target volume. The trajectory and dose delivered at each location are
calculated so that their cumulative effect optimizes the coverage of the target volume
while minimizing the exposure of adjacent tissues. The Cyberknife can generate
beams from more than 1200 directions. This allows for nonisocentric radiation plan-
ning that can optimize dose conformality and homogeneity. The need for rigid fixation
is circumvented by real-time image guidance. For intracranial targets, patients are
relatively immobilized with an Aquaplast mask (WFR/Aquaplast Company, Wyckoff,
New Jersey) (Fig. 2). Flat- panel radiograph detectors are mounted on either side of
Fig. 1. The Cyberknife is a linear accelerator mounted on a robotic arm that employs image
guidance to eliminate the need for a stereotactic frame.
Fig. 2. A custom-fit Aquaplast mask is shown attached to the treatment table.
the treatment table and obtain orthogonal radiograph images in real time during the
treatment. These images are referenced to digitally reconstructed radiographs
(DRRs) that are created from CT datasets obtained during treatment planning. The
patient’s position is verified by his or her own bony anatomy. The image guidance soft-
ware compares differences in three translational and three rotational axes, and adjust-
ments are made with the treatment couch and robotic arm. This process is updated
throughout the radiotherapy treatment to maintain accuracy.15
RADIOSURGERY FOR VESTIBULAR SCHWANNOMA
Leksell pioneered the use of stereotactic radiosurgery for treating vestibular schwan-
nomas in 1969. He later published his initial experience with vestibular schwannoma
radiosurgery using the Gamma Knife in 1971.18 Since then, stereotactic radiosurgery
has proven to be a safe and effective treatment option for managing vestibular
schwannomas. Numerous radiosurgical series exist in the literature detailing excellent
tumor control rates ranging from 92% to 100% in the first several years after treatment
using the Gamma Knife.4,7–9,13,19,20 Additionally, many studies have confirmed excel-
lent longer-term control rates at 5 and 10 years after treatment.7,13,19,20
Over the last decade, attention has been directed to improving the hearing preser-
vation rates following radiosurgery and reducing other treatment-related morbidities.
Initial radiosurgery series reported hearing preservation rates that ranged from 51% to
60%7–9 with significant rates of facial weakness and numbness.7 Improvements in
conformal radiation treatment delivery and use of lower marginal prescription doses,
however, have improved steadily the 3- to 5-year hearing preservation rate to between
68% and 77% while also reducing rates of facial weakness and numbness.4,10,11,13,19
Despite improved Gamma Knife radiosurgical techniques and lower marginal doses,
a recent report has shown a somewhat disappointing 10-year actuarial hearing pres-
ervation rate of 44.5%, with hearing loss developing as much as 6 years after
treatment.13
668 Sakamoto et al
Studies have demonstrated that the total radiation dose to the cochlea is a critical
factor in hearing preservation.21,22 Fractionation of the total dose, or staging, however,
also may play a fundamental role. Staging radiation treatments long has been
proposed as a means to reduce the risk of injury to adjacent critical structures such
as the brainstem, cranial nerves, and cochlea.23–28 Fractionation of the prescribed
dose takes advantage of radiobiologic principles to reduce toxicity and maintain tumor
control.28,29 The authors’ initial experience with staged frame-based radiotherapy
using 21 Gy in three fractions and a 12-hour interfraction interval showed a 77%
hearing preservation rate at 2 years.26 Experience, however, with dose staging using
an interfraction interval of 24 hours was limited, as frame-based radiotherapy tech-
niques would require that the patient remain hospitalized while wearing a stereotactic
frame continuously over the course of several days.
Based on the proof of principle established in the authors’ staged framed-based
study and the introduction of the Cyberknife, it became possible to accurately deliver
highly conformal radiation to vestibular schwannomas and fractionate the prescribed
dose in an attempt to spare the adjacent brainstem and cochlea. The treatment of the
first vestibular schwannoma with the Cyberknife occurred in 1999. Since then, over
350 vestibular schwannomas have been treated at Stanford using the Cyberknife em-
ploying a standard 3-day staging protocol.
PATIENT SELECTION
A team that consists of a neurosurgeon or otolaryngologist and a radiation oncologist

experienced in the treatment of vestibular schwannomas evaluates all patients treated
with Cyberknife radiosurgery. All treatment options, including conservative manage-
ment and microsurgical resection, are considered by the team.
Cyberknife radiosurgery is offered to patients with unilateral or bilateral vestibular
schwannomas that are less than 3 cm in diameter within the cerebellopontine angle.
The Cyberknife also can be used to treat residual vestibular schwannomas after
a planned subtotal microsurgical resection or those that recur despite apparent gross
total removal. Patients demonstrating tumor growth following radiotherapy or radio-
surgical treatment also can be considered for retreatment. Retreatment is considered
no sooner than 1 year after radiotherapy treatment. Patients who are not microsurgical
candidates because of advanced age or other risk factors or patients who do not wish
to undergo microsurgical treatment may be candidates for Cyberknife treatment.
Additionally, patients who have neurofibromatosis type II (NF2) are also candidates
for Cyberknife treatment, although as a group this population does not seem to
respond as well to treatment as do patients who have sporadic unilateral tumors.30
PRETREATMENT EVALUATION
A pretreatment gadolinium-enhanced MRI is obtained in all patients within the 3

months before treatment. The tumor is measured in three orthogonal dimensions.
The intracanalicular portion (if any) is included in the maximal transverse diameter
when calculating measurements.
Pretreatment audiograms are obtained within 3 months before treatment to docu-
ment baseline hearing unless anacusis has been documented previously. The word
recognition score and pure tone average in decibels are recorded. Hearing is graded
on the Gardner-Robertson (G-R) scale.31
Clinical evaluation of the patient’s neurologic status is performed before treatment.
Special attention is given to the fifth, seventh, and eighth cranial nerve examination,
and any baseline deficits or palsies are noted. Trigeminal nerve function is graded
on a semiquantitative scale as normal sensation, decreased sensation, or no sensa-

tion. Facial nerve function is graded on the House-Brackmann (H-B) scale.32
TREATMENT PLANNING AND RADIOSURGERY DELIVERY
All patients initially are fitted with a custom made Aquaplast mask and thin foam head-
rest to ensure consistent positioning from the acquisition of the imaging studies
through the radiotherapy treatment. While in the mask, a thin slice (1.25 mm) high-
resolution (CT) scan of the entire head is obtained with a GE Light Speed 8i Scanner
(Milwaukee, Wisconsin) after the intravenous administration of 125 mL of Omnipaque
contrast (iohexol, 350 mg I/mL; Nycomed, Incorporated, Princeton, New Jersey). The
acquired images then are transferred to the Cyberknife treatment planning worksta-
tion. When the tumor is identified readily on the CT, with morphology and dimensions
consistent with those of the pretreatment MRI, target planning can be done using CT
imaging alone. In the authors’ experience, nearly all vestibular schwannomas can be
delineated accurately with the high-resolution, thin-slice contrast CT imaging alone.
In the rare instance that CT imaging is not optimal, or if a patient cannot tolerate
iodinated contrast used during acquisition of the CT, a thin slice (2 mm) gadolinium-
enhanced T1 weighted MRI is obtained. This MRI then is fused to the CT using the
Cyberknife treatment planning software to create a composite image for tumor local-
ization. This method helps define the extent of smaller tumors and can help further
define intracanalicular lesions. Additionally, most digital imaging and communication
in medicine (DICOM) format imaging studies can be imported and fused to the stan-
dard CT image. The high-resolution, thin-slice CT scan is always necessary to provide
the skeletal anatomy used for real-time patient tracking during treatment.
The treating surgeon then manually defines the tumor volumes and critical struc-
tures on the axial images (Fig. 3). Although the axial images normally are used for
treatment planning, it is possible to delineate structures on the either the coronal or
sagittal images. It is usually necessary to adjust the windows and levels of the treat-
ment planning CT dataset to optimize clarity of the bone of the internal auditory canal
to improve definition of the tumor margins. In addition, the cochlea is defined better
Fig. 3. Right-sided intracanalicular vestibular schwannoma outlined as the radiotherapy

target with the cochlea and brainstem outline as critical structures.
670 Sakamoto et al
when CT window levels are set for bone visualization. It should be emphasized that
target definition can be a complex process in recurrent or postoperative lesions,
and in rare circumstances, it may require the input of an experienced neuroradiologist.
Once the tumor and critical structures are delineated, nonisocentric, inverse plan-
ning using the Cyberknife treatment planning software helps to achieve a highly
conformal radiotherapy dose that minimizes dose to the adjacent critical structures
(Fig. 4). Nonisocentric planning allows the beams of radiation to originate from
many different points in space to create an even dose distribution to nonspherical
lesions. This differs from isocentric planning, in which one or more spherical dose
distributions are used to cover the tumor shape. The Cyberknife can do both isocentric
and nonisocentric planning; however, for irregularly shaped tumors, such as vestibular
schwannomas, nonisocentric planning is used. Inverse planning allows the physician
to input specific treatment criteria and dose tolerances. Then the treatment planning
software selects the beams and beam weights to compute a radiotherapy plan that
meets the treatment criteria. This is in contrast to forward planning, in which the
user manually selects the beams and beam weights to be used. The treatment plan
is evaluated by the treating surgeon and the radiation oncologist. The treatment
plan is evaluated and selected based on an analysis of the volumetric dose and the
dose–volume histograms of the target volume and the adjacent critical structures.
The number of paths and beams used for each patient varies and is determined by
the selected individual treatment plan.
Fig. 4. Treatment plan for a left-sided vestibular schwannoma involving the left internal
auditory canal and cerebellopontine angle cistern treated with 18 Gy delivered in three
equal fractions. The dose distribution is contoured to minimize irradiation of the cochlea
and brainstem. The tumor volume is depicted as well as the 50% and 25% isodose lines
in three planes.
Once the treatment plan has been created and approved by the treating physicians,
the patient is brought back and placed supine on the treatment couch. The Aquaplast
mask then is put on the patient and affixed to the treatment couch to ensure consistent
positioning throughout the treatment. The treatment couch is adjusted as necessary to
align the patient with the previously generated DRRs. Once the patient is aligned prop-
erly, treatment begins. Each fraction lasts between 30 and 45 minutes. Following each
radiotherapy fraction, patients are treated with an oral dose of 4 mg of dexamethasone
for prophylaxis of acute radiation toxicity.
POST-TREATMENT FOLLOW-UP
For the first 2 years after radiosurgery, a thin slice (2 to 3 mm) gadolinium-enhanced
MRI is obtained every 6 months. MR images are obtained annually after the first 2
years. Tumor size is measured in three orthogonal dimensions on each follow-up
scan and compared with the pretreatment measurements. Tumors then are catego-
rized as stable, smaller, or larger than the pretreatment dimensions.
For the first 2 years after radiosurgery, audiograms are obtained every 6 months.
After the first 2 years, pure-tone audiograms and word recognition scores are obtained
annually or if a hearing change is reported. Whenever possible, patients obtain audio-
grams at the same center to minimize discrepancies related to technique. Directed
neurologic examination and testing of the fifth, seventh, and eighth cranial nerves is
performed every 6 months for the first 2 years. Neurologic testing occurs annually
thereafter.
STANFORD UNIVERSITY CYBERKNIFE EXPERIENCE
Between 1999 and 2001, 61 patients who had unilateral vestibular schwannomas
underwent tri-fractionated Cyberknife radiosurgery at Stanford University using the
protocol outlined previously.33 Mean patient age was 54 years (range 27 to 79 years),
and 31 (51%) of the vestibular schwannomas were located on the right side, while 30
were located on the left side. Eight patients had a prior microsurgical resection on the
treated side. These eight patients either demonstrated residual tumor on postopera-
tive scans or a new recurrence on follow-up scans. None of the patients in this series
carried the diagnosis of NF2.
The mean pretreatment maximal tumor dimension was 18.5 mm (range 5 to 32 mm).
The initial treatment dose was 21 Gy over 3 days for the first 14 patients. This dose was
based on the authors’ prior experience with frame-based radiosurgery and selected
based on the radiobiological equivalence to a single 14 Gy dose.26 Based on excellent
tumor control and evidence that a reduced dose could maintain tumor control rates
while improving hearing preservation,10,34 the dose was lowered to 18 Gy delivered
in three equal fractions delivered on consecutive days (18 Gy in three fractions is
approximately equal to 11.5 Gy in one single treatment session). The treatment
dose was prescribed to the 70% to 80% isodose contour line at the periphery of
the tumor. In every case, the total dose was given in equal fractions over the course
of 3 consecutive days. After each fraction was delivered, 4 mg of dexamethasone
was administered orally.
All patients received an MRI, audiogram, and clinical follow up every 6 months for
the first 2 years. After the first 2 years, the patients were followed with annual MRIs,
audiograms, and clinic visits. Mean clinical and radiological follow-up for this series
was 48 months (range 36 to 62) months.
Radiologically, 29 of 61 tumors decreased in size, and 31 tumors had no change in
size, producing a tumor control rate of 98% (Fig. 5). The loss of central enhancement
672 Sakamoto et al
Fig. 5. (A) Axial T1 weighted gadolinium-enhanced MRI of a right-sided vestibular schwan-

noma before Cyberknife radiosurgery. (B) Follow-up axial T1 weighted gadolinium-
enhanced MRI taken 6 years after Cyberknife radiosurgery demonstrating no evidence of
tumor progression.
within the tumor was noted routinely between 6 and 12 months after radiosurgery. One
patient was noted to have an increase in tumor size 4 years after treatment. The tumor
dimensions all increased by 50%. At 3 years after treatment, the tumor was minimally
larger than pretreatment dimensions. The patient did not develop new neurologic
symptoms with tumor growth. This patient ultimately underwent a microsurgical
resection.
Of the 61 patients in this series, 13 patients had no hearing (G-R grade 5) before
treatment. These patients were not followed with serial audiograms. The remaining
48 patients all had some degree of hearing (G-R grade 1 to 3) before treatment. Of
the 48 patients with hearing before treatment, 43 (90%) retained hearing (G-R grade
1 to 3) at last follow-up. Thirty-five patients had G-R grade 1 to 2 hearing before treat-
ment, and 26 (74%) of these patients maintained this level of hearing at last follow-up.
Two patients’ hearing actually improved after treatment with the Cyberknife. One
patient’s hearing improved from a G-R grade 2 to a grade 1, and the other patient
improved from a G-R grade 3 to a grade 1.
No patient treated with the Cyberknife developed a new facial weakness. One
patient had a H-B grade 3 facial weakness before treatment that remained stable after
radiosurgery. Two patients had transient facial twitching within the first 12 months
after radiosurgery. One patient’s twitching resolved in 3 months, and the other
resolved in 5 months.
Trigeminal function was assessed at each follow up using a semiquantitative scale.
Trigeminal dysfunction usually is seen in association with larger tumors. Smaller
tumors and intracanalicular tumors are relatively distant from the trigeminal nerve. In
this series, no patients experienced trigeminal nerve deficits after radiosurgery,
regardless of tumor size.
One patient who had undergone previous microsurgical resection developed symp-
toms from brainstem edema within the first 12 months after radiotherapy. Five months
after radiotherapy, the patient experienced left lower extremity sensory loss. Imaging
demonstrated a T2 signal change along the lateral brainstem. The patient’s symptoms
resolved over a period of 3 months and the imaging abnormalities fully resolved on
subsequent studies.
In summary, this series demonstrated excellent short tumor control rates with good
hearing preservation and few cranial nerve deficits. A recent Gamma Knife study
suggests that cranial nerve deficits after radiosurgery can occur up to 5 years after
treatment.35 Additionally, another recent Gamma Knife study reported that the hearing
preservation rate continues to decline even 6 years after treatment.13 Therefore, addi-
tional studies with longer follow-up after Cyberknife radiosurgery are underway to
determine if fractionation of the radiotherapy dose can improve upon previously re-
ported Gamma Knife results.
SUMMARY
Vestibular schwannomas are benign tumors, which are amenable to both microsur-
gical and radiotherapy or radiosurgical treatments. For patients with small- to
medium-sized tumors, who are poor microsurgical candidates or who do not wish
to undertake the risks associated with microsurgical resection, Cyberknife stereo-
tactic radiotherapy offers excellent tumor control and hearing preservation with
minimal facial and trigeminal morbidity. Further studies with longer follow-up are
needed and underway. Based on the Stanford University experience, fractionated
Cyberknife radiotherapy appears to be a safe and effective primary treatment for
vestibular schwannomas.
REFERENCES
1. Smouha EE, Yoo M, Mohr K, et al. Conservative management of acoustic

neuroma: a meta-analysis and proposed treatment algorithm. Laryngoscope
2005;115:450–4.
2. Wallner KE, Sheline GE, Pitts LH, et al. Efficacy of irradiation for incompletely
excised acoustic neurilemomas. J Neurosurg 1987;67:858–63.
3. Bertalanffy A, Dietrich W, Aichholzer M, et al. Gamma knife radiosurgery of
acoustic neurinomas. Acta Neurochir (Wien) 2001;143:689–95.
2001;94:1–6.
5. Flickinger JC, Lunsford LD, Coffey RJ, et al. Radiosurgery of acoustic neurino-
mas. Cancer 1991;67:345–53.
acoustic tumors: multivariate analysis of four-year results. Radiother Oncol
1993;27:91–8.
7. Kondziolka D, Lunsford LD, McLaughlin MR, et al. Long-term outcomes after ra-
diosurgery for acoustic neuromas. N Engl J Med 1998;339:1426–33.
8. Linskey ME, Lunsford LD, Flickinger JC. Radiosurgery for acoustic neurinomas:
early experience. Neurosurgery 1990;26:736–44 [discussion: 44–5].
9. Lunsford LD, Linskey ME. Stereotactic radiosurgery in the treatment of patients
with acoustic tumors. Otolaryngol Clin North Am 1992;25:471–91.
10. Niranjan A, Lunsford LD, Flickinger JC, et al. Dose reduction improves hearing
preservation rates after intracanalicular acoustic tumor radiosurgery. Neurosur-
gery 1999;45:753–62 [discussion: 62–5].
11. Spiegelmann R, Gofman J, Alezra D, et al. Radiosurgery for acoustic neurinomas
(vestibular schwannomas). Isr Med Assoc J 1999;1:8–13.
12. Rowe J, Grainger A, Walton L, et al. Risk of malignancy after gamma knife stereo-
tactic radiosurgery. Neurosurgery 2007;60:60–5 [discussion: 65–6].
13. Chopra R, Kondziolka D, Niranjan A, et al. Long-term follow-up of acoustic
schwannoma radiosurgery with marginal tumor doses of 12 to 13 Gy. Int J Radiat
674 Sakamoto et al
14. Pollock BE, Lunsford LD, Kondziolka D, et al. Outcome analysis of acoustic
neuroma management: a comparison of microsurgery and stereotactic radiosur-
gery. Neurosurgery 1995;36:215–24 [discussion: 24–9].
15. Chang SD, Main W, Martin DP, et al. An analysis of the accuracy of the Cyber-
knife: a robotic frameless stereotactic radiosurgical system. Neurosurgery
2003;52:140–6 [discussion: 46–7].
16. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand
1951;102:316–9.
17. Adler JR Jr, Chang SD, Murphy MJ, et al. The Cyberknife: a frameless robotic
system for radiosurgery. Stereotact Funct Neurosurg 1997;69:124–8.
18. Leksell L. A note on the treatment of acoustic tumours. Acta Chir Scand 1971;
137:763–5.
surgery 2005;57:257–65 [discussion: 57–5].
20. Hasegawa T, Kida Y, Kobayashi T, et al. Long-term outcomes in patients with
vestibular schwannomas treated using gamma knife surgery: 10-year follow up.
J Neurosurg 2005;102:10–6.
21. Massager N, Nissim O, Delbrouck C, et al. Irradiation of cochlear structures
during vestibular schwannoma radiosurgery and associated hearing outcome.
J Neurosurg 2007;107:733–9.
of cochlear dose. J Neurosurg 2007;107:917–26.
23. Flickinger JC. An integrated logistic formula for prediction of complications from
radiosurgery. Int J Radiat Oncol Biol Phys 1989;17:879–85.
24. Lederman G, Lowry J, Wertheim S, et al. Acoustic neuroma: potential benefits of
fractionated stereotactic radiosurgery. Stereotact Funct Neurosurg 1997;69:
175–82.
25. Lo YC, Ling CC, Larson DA. The effect of setup uncertainties on the radiobiolog-
ical advantage of fractionation in stereotaxic radiotherapy. Int J Radiat Oncol Biol
Phys 1996;34:1113–9.
report. Neurosurgery 1999;45:1299–305 [discussion: 305–07].
27. Varlotto JM, Shrieve DC, Alexander E 3rd, et al. Fractionated stereotactic radio-
therapy for the treatment of acoustic neuromas: preliminary results. Int J Radiat
28. Williams JA. Fractionated stereotactic radiotherapy for acoustic neuromas. Int J
Radiat Oncol Biol Phys 2002;54:500–4.
comparative observations of 125 patients treated at one institution. Int J Radiat
30. Mathieu D, Kondziolka D, Flickinger JC, et al. Stereotactic radiosurgery for vestib-
ular schwannomas in patients with neurofibromatosis type 2: an analysis of tumor
control, complications, and hearing preservation rates. Neurosurgery 2007;60:
460–8 [discussion: 68–70].
31. Gardner G, Robertson JH. Hearing preservation in unilateral acoustic neuroma
surgery. Ann Otol Rhinol Laryngol 1988;97:55–66.
32. House JW, Brackmann DE. Facial nerve grading system. Otolaryngol Head Neck
Surg 1985;93:146–7.
33. Chang SD, Gibbs IC, Sakamoto GT, et al. Staged stereotactic irradiation for
acoustic neuroma. Neurosurgery 2005;56:1254–61 [discussion: 61–3].
34. Spiegelmann R, Lidar Z, Gofman J, et al. Linear accelerator radiosurgery for
vestibular schwannoma. J Neurosurg 2001;94:7–13.
195–9.
Stere ot ac tic
Radiosurger y
a nd Stere ot actic
Radiotherapy in the
Treatment of Skull
Bas e Meningiomas
John M. McGregor, MD*, Atom Sarkar, MD, PhD
KEYWORDS
Stererotactic Radiosurgery Fractionated Radiotherapy
Skull base Meningioma Gamma Knife Particle therapy
LINAC
Meningiomas are the most common of the nonglial brain tumors. They account for
approximately 20% of primary brain tumors. They tend to be slow growing, tend
to be benign, and often can reach substantial sizes before becoming symptomatic.
Complete surgical resection of intracranial meningiomas, including the dura of origin
and infiltrated bone, remains the treatment of choice when able to be accomplished
safely. Extent of resection has been shown to be a predictor of recurrence.1,2 Addi-
tional prognostic factors for recurrence after surgical resection include the World
Health Organization (WHO) pathologic grade and the tumor cell proliferation
rate.3,4 Location of a meningioma within the cranial vault may make a complete
surgical resection unlikely, and tumors arising from the dura of the skull base are
particularly challenging in this regard. Advances in radiation therapy, including
stereotactic techniques, expand the options for treatment available in these situa-
tions. They may be used as adjuncts to surgery or as alternative modalities in the
treatment of these complex tumors. The therapy for these patients can be individu-
alized depending on several factors, including clinical presentation, patient comor-
bidities, tumor progression, tumor location, and involvement of adjacent
neurovascular structures.
Department of Neurological Surgery, The Ohio State University College of Medicine, 410 West
10th Avenue, Columbus, OH 43212, USA
E-mail address: john.mcgregor@osumc.edu (J.M. McGregor).

678 McGregor & Sarkar
SKULL BASE MENINGIOMAS
One of the most difficult areas in which to achieve complete resection is the basal
skull. This region includes tumors that arise from the dura of the clivus and petrous
bone; dura of the cavernous sinus and tentorium; sphenoid bone, including sella tur-
cica; and the olfactory groove; and the optic nerve sheath. Approximately 20% of
intracranial meningiomas reside at these regions of the skull base.5,6 In these locations
they tend to present clinically with symptoms due to the proximity of adjacent vascular
and cranial nerve structures or due to mass effect on intracranial contents.
Treatments of meningiomas of the skull base often have to be tailored to the local
environment in which the tumor arises and the surrounding structures that find them-
selves involved in tumor. Because of the location of the tumor, treatment options must
be weighed against the sensitivity of normal adjacent structures and by the morbidity
associated with the treatment approaches required and the natural history of the
tumor itself. Complexities in the clinical decision making regarding treatment for skull
base meningiomas center around the risk for morbidity and from intervention and
expectant management. These tumors tend to be benign and slow growing although
they can be aggressive clinically and histologically.
The natural history and the tolerance of surrounding neural tissues must be consid-
ered when treatments are discussed. Bindal and colleagues addressed the issue of
natural history of skull base meningiomas. They reviewed 40 patients who were diag-
nosed with skull base meningiomas based on radiographic studies and who were fol-
lowed without treatment over a mean of nearly 7 years. Twenty-seven percent
progressed neurologically, all with worsening cranial nerve deficit. No new strokes
or brainstem symptoms developed. On serial follow-up imaging studies, 18% showed
some degree of growth. The 2-, 5-, and 10-year radiologic evaluations showed their
tumors were progression free on serial imaging at rates of 97%, 80%, and 42%,
respectively. Forty percent of their patients eventually underwent some form of radio-
surgical or surgical treatment.7 These observations need to be considered when
recommendations for treatment are made. They also need to be considered when
trying to assess the results of various treatment modalities. Still, with the threefold
advances of imaging capabilities, microsurgical techniques, and focused radiation
delivery systems, the options to individualize therapy, taking into account tumor-
and patient-specific variables, have never been as great.
SURGERY FOR SKULL BASE MENINGIOMAS
Microsurgery for meningiomas of the skull base remains a viable and in many cases an
optimal treatment of this condition. The abilities of a surgeon to affect complete
removal, obtain tissue diagnosis, and affect an immediate decompression of compro-
mised neural structures with minimal new neurologic sequelae are important points in
the decision-making process. Yet the ability to accomplish those goals surgically must
be assessed on a case-by-case basis. Every tumor and every patient has unique char-
acteristics that affect a decision for surgery.
Microsurgery of the skull base has been shown effective, yet there are risks for adja-
cent structures and there are recurrences. Current microsurgical techniques have
advanced the abilities of surgeons to perform aggressive resections in the skull
base area with minimal morbidity and mortality and prolongation of progression-free
survivals. Complete surgical resection in all cases of skull base meningiomas with
minimal morbidity remains, however, elusive. In addition, several reports evaluating
pathologic specimens of skull base meningiomas have demonstrated that tumor infil-
tration can be seen into neurovascular structures adjacent to tumor, suggesting that
Skull Based Meningiomas 679
there are limits to which microsurgery can achieve complete resection.8–10 De Jesus
and colleagues,11 in the analysis of their series of 119 patients who had cavernous
sinus meningiomas at a mean of 2.5 years follow-up, identified a recurrence rate of
10% in patients initially believed to have complete resection and a progression rate
of 15% in patients who had initial subtotal resection. DeMonte and colleagues12
observed, in their 41 patients followed over a mean 45 months, 7% mortality, 7%
morbidity, 10% new cranial nerve deficit, and 10% recurrence rate for patients who
had complete resection. O’Sullivan and colleagues reviewed 89 patients, over
a mean of 2 years, who had cavernous meningiomas of varying histologic grade.
They reported a 12% incidence of new cranial nerve deficit with surgery. They were
able to attain a complete resection in 8 patients who had WHO grade I tumors who
had no recurrence during the follow-up period. The progression rate for the patients
who had subtotal resection was 6%.13
Surgery for resection of skull base meningiomas of the petroclival region involves
a particularly difficult area. Natarajan and colleagues reported on the long-term results
of 150 patients evaluated at a mean of 102 months after microsurgery for skull base
meningiomas in this area. They reported new neurologic deficits in 20% of patients.
Gross total resection was accomplished in 40% of patients. Recurrence developed
in 4% of patients who had complete resection and 5% of patients who had incomplete
resection. They reviewed the literature on surgery in this area and reported a range of
total or gross total resection rates of between 40% and 79% with recurrence/progres-
sion rates reported as 0 to 36%. Follow-up times for the other reports are compara-
tively shorter, however (14–73 months).14
RADIATION THERAPY FOR SKULL BASE MENINGIOMA
Historically, radiation therapy has been shown a reasonable adjunct to surgical resec-
tion, providing enhanced local control of tumor growth for benign meningiomas.
Barbaro and colleagues15 in 1987 reviewed their series, which included all types
and grades of meningiomas, and showed an improvement in progression-free survival
at 6.5 years with external-beam fractionated radiotherapy after subtotal resection
when compared with subtotal resection alone (68% versus 40%).
In the ensuing years, advancements in imaging and improvements in radiation
delivery methods have enhanced abilities to conform the dose of radiation ever
more precisely to tumor, have allowed for more intense tumor dosing, and have
allowed for reduction in radiation to nontumor structures. These concepts have
been particularly advantageous for tumors that arise at the skull base. The proximity
of important radiosensitive neurovascular structures, brainstem, and pituitary gland
to tumor margins requires that radiation to skull base lesions be delivered in a way
that provides therapeutic benefit while maintaining enhanced margins of safety for
adjacent tissues. Further improvements in conformality have been achieved with the
introduction of focused radiation techniques, including stereotactic radiosurgery
(SRS) and stereotactic radiotherapy (SRT); each may be delivered by gamma photons,
x-ray photons, or charged particle beam therapy.
Stereotactic therapy is the term used to identify treatment modalities that use high-
dose radiation, delivered from multiple beam locations, to precise targets registered
within a defined 3-D space. Stereotactic localization uses high-quality imaging to iden-
tify tumor, tumor margins, critical neurovascular structures, and identifiable fiducial
points, which then are digitally processed to register a patient and anatomy into
a defined 3-D space. Stereotactic therapy includes a mechanism of radiation accuracy
assurance during treatment. Repetitive image localization during treatment or fixation
of a patient and target throughout the treatment are used as methods to confirm the
accuracy of the radiation dose delivered.
Radiation Sources
The radiation sources for SRS or SRT that are used most commonly in clinical practice
are the gamma photons generated from the decay of cobalt-60 or the x-ray photons
generated from a linear accelerator (linac). Cobalt-60 decays with the release of two
gamma photons. The isotope is housed in such a way as to allow the release of only
those photons emitted in a predetermined direction. A series of cobalt sources are ar-
ranged to deliver multiple gamma photons to a single convergent point. Targeting then
is accomplished by adjusting a patient’s position so as to place the tumor into the point
of convergence. The isotope has a half-life of 5.28 years. The sources typically are re-
placed every 5 to 8 years because the treatment times increase as the sources age.
Linear Accelerators
Linear accelerators can generate x-ray photons by the collision of accelerated elec-
trons and a target metal. The resulting photon beam exits the generator following
a linear path. The beam then can be directed by moving the accelerator into the proper
position. Targeting is accomplished by positioning the accelerator to allow the beam
to pass through the target site from multiple entrance trajectories. These radiation
beams, gamma radiation and x irradiation, are characterized by having high enough
energy to penetrate the cranial tissues allowing for treatment of the intracranial
contents. Additionally, they deposit radiation over the entire length of the beam,
including both target tissue and nontarget tissue proximal and distal to the target.
By arranging multiple portals for the delivery of these radiation beams and having
them all converge on the exact same target point, the target can accumulate signifi-
cant radiation exposure while the dose delivered to nontarget tissues is minimized.
A steep gradient of radiation dosage is generated with a substantial falloff of the
dose measured at distances adjacent to and distal to the target. In addition to varying
the location of beam delivery, current delivery systems allow gamma photon beams
and x-ray photon beams to be varied in their intensity along each particular delivery
path, providing variable dosing per exposure and greater opportunities for dose con-
touring. These techniques add to the ability to minimize the dose to nontarget tissues
while maintaining the planned target dose accumulation.16
Particle Therapy
Particle therapy refers generally to beams of heavier charged particles used as radia-
tion sources. These particles include protons (hydrogen nuclei), helium nuclei, and
carbon nuclei. Using a cyclotron, these beam sources are generated by the stripping
of the underlying atoms of their electrons and accelerating the charged nuclei to a vari-
able exiting energy level. The particle beam then is released in the intended direction
of the target. As with photon-based therapies, particle therapies vary the direction and
the intensity of the beam entering the patient to improve conformality of the dose to
the tumor. Because the particles have mass and charge, they can be focused magnet-
ically. Most importantly, particle beams release their energy essentially completely at
a single interaction point at a predetermined depth within the target tissue. This char-
acteristic is known as the Bragg peak effect. By varying the intensity of the beam as it
leaves the cyclotron, the distance the particle beam travels in tissue before discharg-
ing its energy can be varied. Because so little energy is delivered beyond the length of
the Bragg peak, the radiation exposure is decreased to the surrounding nontarget
tissues. This allows for increased conformality of the radiation dose and provides
a theoretically improved radiobiologic profile.6,17
FOCUSED RADIATION AND FRACTIONATION
SRS, then, is a radiation delivery method that uses multiple radiation beams focused in
a 3-D manner within a defined target space (stereotactically) to a single target. Typi-
cally, the term, radiosurgery, refers to treatment performed in a single fraction,
although up to five fractions may be considered radiosurgery according to convention.
The radiation may be generated from fixed sources, such as the gamma knife unit. In
this unit, 201 fixed, cobalt-60, gamma ray–emitting sources housed in cast iron are
preset in a spherical array focused to the unit’s isocenter. A series of tungsten helmet
collimators are used to further focus the individual sources. Patients are immobilized in
a rigid titanium stereotactic frame applied to the skull in four-point pin fixation. The
pins secure the frame with tension applied to the outer table of the skull. A fiducial
box is attached to the frame, and the patient then undergoes stereotactic MRI or
CT scanning or both for localization of the target and adjacent structures. Other rele-
vant images (positron emission tomography, functional MRI, or diffusion tensor
imaging) may be merged to the stereotactic images as necessary. Once targets are
identified and digitized and a treatment plan optimized, the patient is attached via
the rigid frame to the gamma knife unit in such a manner as to place the patient’s
target in the machine’s isocenter. The table then moves the patient into the focal point
of the sources and the radiation for that isocenter is delivered. Depending on the
complexity of the plan, the patient may require several isocenter exposures to
complete the treatment plan. Once the treatment plan is completed, the head frame
is removed.
The radiation output for SRS also may be generated as x rays from a nonfixed linac.
In this instance electrons are accelerated and then collide with a metal target gener-
ating a beam of x-ray photons. The photon source then is rotated in multiple arcs
around the patient lying on the treatment table, positioning the x-ray beam in multiple
orientations focused to a fixed isocenter. This method generates a spherical distribu-
tion at the isocenter. Tertiary collimators can be added to the beam to adjust the dose
at each position, allowing for a nonuniform, or shaped, isocenter. For 3-D localization,
the patient may be immobilized by a stereotactic rigid frame applied to the skull,
implanted with attached fiducials, or registered with a frameless system in which
repeated x-ray imaging confirms patient position throughout the treatment. A high-
resolution, stereotactic MRI or CT is performed with an attached fiducial reference
frame. The images are used for target localization and treatment planning. Depending
on the complexity of the tumor and the plan, there may be a single isocenter used to
treat the tumor or multiple isocenters. In the treatment paradigms that use rigid fixa-
tion, the radiation dose delivered can be contoured to the margin of the tumor itself.
No additional treatment beyond the margin is needed.
STEREOTACTIC RADIOTHERAPY
SRT is a variation of the stereotactic focused radiation that combines the benefits of
stereotactic localization and the advantages of radiation fractionation. It allows for
focused radiation to be delivered over several sessions instead of a single session.
This method uses the precision of the stereotactic localization in 3-D space of
a patient, target, nontarget structures and delivery methods that include multiple-
beam entry points targeting the isocenter in a repeatable, accurate manner. Accuracy
is assured over multiple treatment sessions using frameless head holders, face masks,
or bite blocks; with repetitive imaging during treatment; or by the use of skull mounted
implanted anchors to provide repeatable accurate positioning at each treatment
session.18 Because of the ability of normal tissue to affect repair between fractions,
SRT is considered beneficial in the treatment of larger lesions that likely would expose
surrounding central nervous system tissues to a higher dose if treated in a single frac-
tion and in the treatment of those tumors adjacent to critical radiation sensitive struc-
tures. Patients undergo stereotactic MRI or CT imaging with or without additional
image merging, followed by 3-D registration and dose planning. Treatment then is per-
formed over a series of repeat sessions, in a conventional fashion with 25 to 30 frac-
tions (fractionated SRT) or over a much fewer number of fractions (hypofractionated
SRT [HSRT]).5
TISSUE TOLERANCES
Microsurgical resection currently remains the gold standard in the treatment of skull
base meningiomas to which all new therapies are compared. The use of radiosurgery
in these treatments has evolved over time as improvements in imaging, tumor identi-
fication, tolerance of the cranial structures, and minimal effective dosing schemes
were identified. Radiosurgery initially was reserved for those lesions that were recur-
rent, more malignant, or identified in patients who had associated medical conditions
that precluded surgery. The ability to incorporate MRI into dose planning has allowed
improved accuracy by better identifying tumor margins and cranial nerves. The initial
marginal doses used for the treatment of skull base meningiomas were derived from
effective doses used in other central nervous system malignancies. Over time, the
identification of tolerances of the cranial nerve structures has led to modification of
doses with good results. Current therapeutic dosing for meningiomas of the skull
base has allowed for reasonable therapeutic benefits and minimal cranial nerve
complications.
OPTIC NERVE CONSIDERATIONS
In planning anterior skull base radiosurgery, the critical structure to be addressed is

the optic apparatus. Its tolerance to single-fraction radiosurgery has been shown to
be less than 10 Gy,19 although some investigators have observed radiation-induced
optic neuropathy at doses greater than 9 Gy20 and greater than 8 Gy.21 Leber and
colleagues, in reviewing their series of 50 patients treated with gamma knife radiosur-
gery, identified no radiation-induced optic neuropathy when the dose to the optic
apparatus was kept below 10 Gy. They reported, however, a 26% incidence when
the optic nerve received doses of between 10 and 15 Gy and a 77% incidence at
doses greater than 15 Gy after a mean follow-up of 40 months.19 Kondziolka and
colleagues22 recommend keeping the dose to the optic nerve at less than 8 Gy and
have observed radiation-induced optic neuropathy in only 1 of 78 patients (1.3%)
from 2001 to 2008. Alternatively, Morita and colleagues,23 in their series of 88 patients
who had skull base meningiomas, observed over a median follow-up period of 35
months, reported no incidence of optic nerve deterioration in which only short
segments (9–12 mm) of the apparatus were exposed to doses of 12 to 16 Gy. They
did not include tumors that had distorted or elevated the optic nerves and chiasm.
Stafford and colleagues24 reported a 1.1% incidence of significant radiation-induced
optic neuropathy in their series of 218 patients treated for mixed anterior skull base
tumor types who received 12 Gy or less and were followed for a median of 40 months.
CRANIAL NERVE CONSIDERATIONS
The cranial nerves of the cavernous sinus seem to tolerate relatively higher doses than
the optic apparatus. Morita and colleagues23 observed trigeminal nerve dysfunction in
13% of their 88 patients who had Meckel’s cave doses of greater than 19 Gy but in
only 7% of their patients who received less than 19 Gy. They reported only one patient
who had abducens palsy and one who had an oculomotor deficit among their 88
patients. Leber and colleagues,19 in their series of 50 patients, observed no new
trigeminal nerve deficits (dose range of 6–20 Gy) and no new deficits in cranial nerve
3, 4, or 6 (dose range 5–30 Gy).
PITUITARY GLAND CONSIDERATIONS
The pituitary gland function is also at risk from radiosurgery to the skull base; however,
although the incidence reported is much lower than that seen in the treatment of pitu-
itary adenomas, the actual safe dose to the hypophysis is not known. Vladyka and
colleagues studied pituitary dose tolerance in their series of 63 patients who had
adenoma and were evaluated at a median of 5 years after gamma knife radiosurgery.
They observed a 60% risk for gonadotropic dysfunction at a mean dose to the
hypophysis of greater than 17 Gy, a 15% risk at a mean dose of less than 17 Gy,
and no hypofunction at a mean dose of 15 Gy or less. They observed an 85% risk
for hypothyroidism when the mean dose was greater than 17 Gy, a 15% risk if the
mean dose was less than 17 Gy, and no dysfunction if the mean dose was 15 Gy or
less. They observed corticotropic hypofunction in 85% of patients receiving a mean
dose of greater than 20 Gy, a 10% risk if the dose was less than 20 Gy, and no
observed corticotropic hypofunction if the dose was less than 18 Gy.25
TREATMENT RESULTS FOR SKULL BASE MENINGIOMAS

Stereotactic Radiosurgery Results
Initially used to treat postoperative recurrences and medically unsuitable surgical
candidates, radiosurgery has evolved in its application as a treatment modality of value
in the care of patients who have these difficult lesions. Currently, radiation is considered
useful as primary treatment and as an adjunct to surgical therapy. Several investigators
have reported their rates of tumor control and progression after radiosurgery for skull
base meningiomas and, recently, long-term data have been reviewed. Kreil and
colleagues reviewed the results of their 200 patients who had benign skull base menin-
giomas evenly divided between postsurgical radiosurgery and primary radiosugery
treatments to a median marginal dose of 12 Gy (range 10–20), with a median follow-
up period of 95 months. They reported a 10-year progression-free survival of 97%.
They observed a neurologic deterioration in 4.5% of patients.26 Zachenhofer and
colleagues evaluated their series of 36 patients who had cranial base meningiomas
and were treated with gamma knife radiosurgery with or without previous surgery. Their
follow-up period was a mean of 103 months. They prescribed a mean marginal dose of
17 Gy. They reported a long-term tumor control rate of 94% (31 of 33 patients) with size
reduction in 70%. One patient developed late pituitary dysfunction, and one patient
developed progressive cranial nerve palsy. In addition, they reviewed the literature
on results of gamma knife radiosurgery on skull base meningiomas with mean
follow-up of 15 to 82 months. They reported tumor control rates of 82% to 100%
and new neurologic deficits in 0 to 27%.4 Iwai and colleagues27 evaluated their 108
patients after lower-dose gamma knife radiosurgery at a mean of 86 months after giving
a median marginal dose of 12 Gy (range 8–12 Gy). They reported a 10-year progression
free survival of 86% and adverse neurologic sequelae in 6%.
Comparable studies using linac-based radiosurgery units to treat skull base menin-
giomas generally indicate similar tumor control rates of 92% to 100% over median
follow-up periods of 23 to 48 months using median marginal doses of 14.6 to 18
Gy. More recent studies identified neurologic dysfunction post treatments of 4.7%
to 24%.26,28,29
Stereotactic Radiotherapy Results

Fractionated SRT techniques have been applied with success to meningiomas of the
skull base. Lo and colleagues published a retrospective comparison of SRS and frac-
tionated SRT for the treatment of intracranial meningiomas, which included 30 skull
base lesions in 53 patients. They reported similar control rates of 92% for each group
at 3 years, using median tumor marginal doses of 14 Gy in single fraction and a median
dose of 54 Gy at the 88% isodose given over a median of 30 fractions. They suggest
that larger tumors and those closer to sensitive neural structures, such as the optic
apparatus, would benefit from fractionation.30 Hamm and colleagues reviewed their
224 patients who had skull base meningiomas alone and underwent radiosurgery,
fractionated SRT, or HSRT. Those patients who had the largest tumor volumes or
those in the closest proximity to the optic apparatus (<2 mm) underwent the more
conventional fractionated SRT with a median dose of 55.8 Gy at the 90% to 95%
isodose (1.8–2.0 Gy per fraction). HSRT consisted of doses of 4 to 5 Gy per fraction.
Single-fraction radiosurgery used a marginal dose of 12.8 to 18 Gy. Their median
follow-up was 3 years. They reported a local control rate of 96.9% and a 4.4% neuro-
logic deterioration but no differences between the three types of focused radiation. In
their review of published studies, they observed similar control rates for gamma knife
radiosurgery, linac radiosurgery, and SRT (92%–100% overall) at the various centers
over the median follow-up periods (19–82 months), and similar mean deterioration
rates were 6%–7% for the three treatment modalities.29
Gorman and colleagues examined their results from HSRT for 38 patients who had
skull base meningiomas who had a median follow-up of 47 months. They treated with
a median dose of 37.5 Gy to the 80% isodose in 15 fractions. They reported no tumor
progression on imaging in this early follow-up period and 11% new cranial nerve
dysfunction.5 Milker-Zabel and colleagues published their long-term follow-up results
(median 78 months) for their 57 patients who had cavernous sinus meningiomas
treated with linac-based fractionated SRT using a median dose of 57.6 Gy to the
90% isodose, 1.8 Gy per fraction, with a median of 32 fractions. Their 5- and 10-
year local tumor control rates were 100%, with a 7% new cranial nerve dysfunction,
and no pituitary dysfunction.31
Fractionated SRT has been shown safe and effective in the treatment of skull base
meningiomas with low rates of neurotoxicity comparable to those of radiosurgery.
Although those patients whose tumors were treated with single-fraction radiosurgery
tended to have smaller tumors that were located farther from sensitive structures,
such as the brainstem and optic apparatus, compared with those patients treated
with fractionated SRT, the tumor control rates and neurologic toxicities were
comparable.
Proton Beam Results

Although fewer total data have been accumulated and published using protons than
either LINAC based x-ray or Cobalt-60 based Gamma radiation, several investigators
have described their results in treating meningiomas of the skull base with proton beam
fractionated SRT. Weber and colleagues reviewed their series of 16 patients who had
meningiomas that were pathologically confirmed or highly suggestive based on
imaging characteristics. Thirteen of these were skull base lesions. All were treated
with proton beam therapy. The investigators targeted the tumor, dural tail, and a 4-
to 6-mm margin. The median tumor volume was 17.5 cm3. The median dose
prescribed was 56 cobalt gray equivalents (CGE 5 proton Gy 1.1). The median
follow-up time was 34.1 months. Their 3-year local control rate was 91.7% with
a 19% overall late neurologic complication rate consisting of one case each of optic
neuropathy, retinopathy, and radiation-induced cortical injury.32
Vernimmen and colleagues reviewed their 23 patients who underwent proton beam
therapy for skull base meningiomas. Five were treated with SRT (>15 fractions) and 18
patients were treated with a hypofractionated therapy (HSRT) (3 fractions). Their mean
target volumes were 15.6 cm3 and the mean single-fraction dose equivalent (sfe) in the
HSRT group was 20.3 sfe/CGE. In the SRT group, the dose ranged from 54 CGE in 27
fractions to 61.6 CGE in 16 fractions. Vernimmen and colleagues demonstrated for the
HSRT group a radiologic response rate of 88% and 29% regressed partially or
completely. Clinically, 89% improved or remained the same. The SRT group all re-
mained stable on MRI and stable or improved clinically. The mean follow-up time
was 40 months in the two groups combined. They reported 11% late side effects con-
sisting of an eighth nerve palsy and one new case of temporal lobe epilepsy.33
SUMMARY
Skull base meningiomas remain a difficult clinical condition with several options for
management. Surgery provides the gold standard for therapy when complete resec-
tion can be accomplished with minimal neurologic risk. Focused radiation techniques
have become more important as an adjunct to surgical therapy and as a primary treat-
ment in selected individual cases. SRS in a single fraction or SRT in full- or hypofrac-
tionated delivery systems offers the opportunity for tumor control with reasonable risk
profiles. The source of radiation may be provided by gamma photons, x-ray photons,
or charged nuclei particles, such as protons, each with clinical and practical advan-
tages and disadvantages; however, the complexity of the anatomy of the skull base
does not eliminate the risk for surrounding neurovascular structures with any of these
modalities. Additionally, the natural history of these tumors needs to be considered
when the decision to move forward with treatment is made. There has been a move
toward more individualized recommendations regarding the application of therapy
for these conditions.
Focused radiation techniques and microsurgery have evolved as complementary
tools in the treatment of meningiomas of the skull base. Patients should be considered
appropriate for microsurgery in those clinical situations in which complete surgical
resection can be achieved and a minimum of acceptable morbidity is likely. Patients
should be considered for SRT or SRS in situations in which surgery is not desired,
is not deemed safe, or is unlikely to accomplish complete resection without significant
morbidity. Additionally, surgery and focused radiation techniques can be used in
a complementary fashion. When tumor is purposefully left behind at surgery or tumor
progresses on follow-up after surgery, SRT or SRS may afford better tumor control.
Certain clinical conditions also arise where anatomic reduction of tumor from critical
structures, such as the brain, brainstem, or the optic apparatus, is required for
symptom relief, and as such a reduction may improve the ability to subsequently
deliver optimal focused radiation to the residual tumor with the least risk for neurologic
complications.
Finally, although complete surgical resection continues to be the result with the best
long-term outcome, in situations where this approach is not possible or the risks for
surrounding central nervous system tissues and vessels are too great, surgery can
be reasonably modified to the point where a surgeon resects as much as is considered
acceptable, preserving neurovascular structures as best as possible, and addressing
residual tumor with focused radiation techniques. Heros has an excellent review of
these issues in which he describes his current surgical approaches to cranial menin-
giomas at various locations throughout the skull base and his application of radiosur-
gery in practice.34
Focused stereotactic radiation techniques continued to evolve. They currently can
make a significant contribution to the care of the patients who have skull base menin-
giomas. The particular care and direction of treatment of these patients can be individ-
ualized based on accurate anatomy identified on ever-improving imaging techniques
and on expected biologic behavior given a combination of clinical conditions, patho-
logic identification, and sequential image analysis. There are limits to accurate deci-
sion making as these are slow growing tumors with a potentially long natural history,
and the lengths of follow-up analyses published on the various modalities are relatively
short. The best long-term outcomes for patients will be obtained when all the options
available for each patient are considered, the risks of the various treatment modalities
are addressed, and the likely outcomes are reviewed in light of the natural history of
these tumors. Although the treatment of these tumors remains an exceptional clinical
therapeutic challenge, focused radiation techniques, such as SRS and SRT, offer
considerable help in the application of treatment options for individual patients.
REFERENCES
1. Simpson D. The recurrence of intracranial meningiomas after surgical treatment.

J Neurol Neurosurg Psychiatr 1957;20(1):22–39.
2. Adegbite AB, Khan MI, Paine KW, et al. The recurrence of intracranial meningi-
omas after surgical treatment. J Neurosurg 1983;1:51–6.
3. Commins DL, Atkinson RD, Burnett ME. Review of meningioma histopathology.
Neurosurg Focus 2007;23(4):E3 [review].
4. Zachenhofer I, Wolfsberger S, Aichholzer M, et al. Gamma-knife radiosurgery for
cranial base meningiomas: experience of tumor control, clinical course, and
morbidity in a follow-up of more than 8 years. Neurosurgery 2006;58(1):28–36
[discussion: 28–36].
5. Gorman L, Ruben J, Myers R, et al. Role of hypofractionated stereotactic radio-
therapy in treatment of skull base meningiomas. J Clin Neurosci 2008;15(8):
856–62 [Epub 2008 Jun 12].
6. Elia AE, Shih HA, Loeffler JS. Stereotactic radiation treatment for benign meningi-
omas. Neurosurg Focus 2007;23(4):E5 [review].
7. Bindal R, Goodman JM, Kawasaki A, et al. The natural history of untreated skull
base meningiomas. Surg Neurol 2003;59(2):87–92.
8. Shaffrey M, Dolenc V, Lanzino G, et al. Invasion of the internal carotid artery by
cavernous sinus meningiomas. Surg Neurol 1999;53:167–71.
9. Sen C, Hague K. Meningiomas involving the cavernous sinus: histological factors
affecting the degree of resection. J Neurosurg 1997;87(4):535–43.
10. Larson J, van Loveren H, Balko M, et al. Evidence of meningioma infiltration into
cranial nerves: clinical implications for cavernous sinus meningiomas. J Neuro-
surg 1995;83(4):596–9.
11. De Jesus O, Sekhar LN, Parikh HK, et al. Long-term follow-up of patients with
meningiomas involving the cavernous sinus: recurrence, progression, and quality
of life. Neurosurgery 1996;39(5):915–9 [discussion: 919–20].
12. DeMonte F, Smith HK, al-Mefty O. Outcome of aggressive removal of cavernous
sinus meningiomas. J Neurosurg 1994;81(2):245–51.
13. O’Sullivan MG, van Loveren HR, Tew JM Jr. The surgical resectability of meningi-
omas of the cavernous sinus. Neurosurgery 1997;40(2):238–44 [discussion:
245–47].
14. Natarajan SK, Sekhar LN, Schessel D, et al. Petroclival meningiomas: multimodal-
ity treatment and outcomes at long-term follow-up. Neurosurgery 2007;60(6):
965–79.
15. Barbaro N, Gutin P, Wilson C, et al. Radiation therapy in the treatment of partially
resected meningiomas. Neurosurgery 1987;20(4):525–8.
16. Kondziolka D, Lunsford LD, Flickinger JC. The application of stereotactic radio-
surgery to disorders of the brain. Neurosurgery 2008;62(Suppl 2):707–19
[discussion: 719–20] [review].
17. Chen CC, Chapman P, Petit J, et al. Proton radiosurgery in neurosurgery. Neuro-
surg Focus 2007;23(6):E5 [review].
18. Ammirati M, Bernardo A, Ramsinghani N, et al. Stereotactic radiotherapy of
central nervous system and head and neck lesions, using a conformal inten-
sity-modulated radiotherapy system (Peacock system). Skull Base 2001;11(2):
109–19.
19. Leber KA, Berglöff J, Pendl G. Dose-response tolerance of the visual pathways
and cranial nerves of the cavernous sinus to stereotactic radiosurgery. J Neuro-
surg 1998;88(1):43–50.
20. Duma CM, Lunsford LD, Kondziolka D, et al. Stereotactic radiosurgery of
cavernous sinus meningiomas as an addition or alternative to microsurgery.
Neurosurgery 1993;32(5):699–704 [discussion: 704–5].
21. Tishler RB, Loeffler JS, Lunsford LD, et al. Tolerance of cranial nerves of the
cavernous sinus to radiosurgery. Int J Radiat Oncol Biol Phys 1993;27(2):
215–21.
22. Kondziolka D, Flickinger JC, Lunsford LD. The principles of skull base radiosur-
gery. Neurosurg Focus 2008;24(5):E11 [review].
23. Morita A, Coffey RJ, Foote RL, et al. Risk of injury to cranial nerves after gamma
knife radiosurgery for skull base meningiomas: experience in 88 patients. J Neu-
rosurg 1999;90(1):42–9.
24. Stafford SL, Pollock BE, Leavitt JA, et al. A study on the radiation tolerance of the
optic nerves and chiasm after stereotactic radiosurgery. Int J Radiat Oncol Biol
Phys 2003;55(5):1177–81.
25. Vladyka V, Liscak R, Novotný J Jr, et al. Radiation tolerance of functioning pitui-
tary tissue in gamma knife surgery for pituitary adenomas. Neurosurgery 2003;
52(2):309–16 [discussion: 316–17].
26. Kreil W, Luggin J, Fuchs I, et al. Long term experience of gamma knife radiosur-
gery for benign skull base meningiomas. J Neurol Neurosurg Psychiatr 2005;
76(10):1425–30.
27. Iwai Y, Yamanaka K, Ikeda H. Gamma knife radiosurgery for skull base menin-
gioma: long-term results of low-dose treatment. J Neurosurg 2008;109(5):
804–10.
28. Deinsberger R, Tidstrand J, Sabitzer H, et al. LINAC radiosurgery in skull base
meningiomas. Minim Invasive Neurosurg 2004;47(6):333–8.
29. Hamm K, Henzel M, Gross MW, et al. Radiosurgery/stereotactic radiotherapy in

the therapeutical concept for skull base meningiomas. Zentralbl Neurochir
2008;69(1):14–21.
30. Lo SS, Cho KH, Hall WA, et al. Single dose versus fractionated stereotactic radio-
therapy for meningiomas. Can J Neurol Sci 2002;29(3):240–8.
31. Milker-Zabel S, Zabel-du Bois A, Huber P, et al. Fractionated stereotactic radiation
therapy in the management of benign cavernous sinus meningiomas: long-term
experience and review of the literature. Strahlenther Onkol 2006;182(11):635–40
[review].
32. Weber DC, Lomax AJ, Rutz HP, et al. Swiss Proton Users Group. Spot-scanning
proton radiation therapy for recurrent, residual or untreated intracranial meningi-
omas. Radiother Oncol 2004;71(3):251–8.
33. Vernimmen FJ, Harris JK, Wilson JA, et al. Stereotactic proton beam therapy of
skull base meningiomas. Int J Radiat Oncol Biol Phys 2001;49(1):99–105.
34. Heros RC. Effect of modern radiation techniques on the surgery of nonmalignant
intracranial tumors. Neurosurg Focus 2008;24(5):1–5.
Radiosurger y
for Glomus
Jugulare Tumor s
Jonathan P. Miller, MDa, Maroun T. Semaan, MDb,
Robert J. Maciunas, MD, MPHa,c, Douglas B. Einstein, MD, PhDc,
Cliff A. Megerian, MDa,b,*
KEYWORDS
Glomus jugulare tumor Gamma knife radiosurgery
CyberKnife radiosurgery LINAC radiosurgery
Minimally invasive glomas jugulare surgery
Paragangliomas (glomus tumors) are slow-growing, usually benign, highly vascular

tumors of paraganglionic tissue. During embryogenesis, paraganglionic tissue is
derived from the migration of neural crest cells in close association with the sympathetic
nervous system. Within the head and neck these cell rests are predominantly distrib-
uted throughout the middle ear in close association with the Jacobson nerve (branch
of cranial nerve [CN] IX) and the Arnold nerve (branch of CN X), the jugular foramen, va-
gus nerve, and carotid body. Tumors arising from paraganglionic tissue can be divided
into adrenal paraganglioma (pheochromocytoma) and extra-adrenal paraganglioma.
The term ‘‘branchiomeric paraganglioma’’ is used to describe extra-adrenal tumors
arising from head and neck paraganglionic tissue.1 The presence of paraganglionic
tissue associated with the Jacobson nerve was recognized as early as 1840.2 Guild
coined the term ‘‘glomic tissue’’ to describe the vascularized ganglionic tissue along
the adventitia of the jugular bulb and promontory.3 In 1945, Rosenwasser4 successfully
removed a middle ear paraganglioma that he called a carotid body of the middle ear.
Although frequently used, the term glomus is a misnomer and denotes the previously
believed origin from specialized pericytes within arteriovenous complexes (glomus).
Carotid and aortic bodies are the only two paraganglia known to function as chemore-
ceptors. Hence, the term chemodectoma is improperly used to designate paraganglio-
mas. The most common head and neck paraganglioma is the carotid body tumor.
a
Department of Neurological Surgery, Case Western Reserve University and University
Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA
b
Department of Otolaryngology–Head and Neck Surgery, Case Western Reserve University and
University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA
c
Department of Radiation Oncology, Case Western Reserve University and University Hospitals
of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106, USA
* Corresponding author. Department of Neurological Surgery, Case Western Reserve University
and University Hospitals of Cleveland, 11100 Euclid Avenue, Cleveland, OH 44106.
E-mail address: cliff.megerian@uhhospitals.org (C.A. Megerian).

690 Miller et al
Within the temporal bone two types of paragangliomas exist: glomus tympanicum and
glomus jugulare or jugulotympanic paraganglioma (JTP). Glomus tympanicum arises
from rests of paraganglionic tissue associated with Jacobson and Arnold nerves.
Glomus jugulare is believed to arise from similar paraganglionic rests within the adven-
titia of the jugular bulb, intimately associated with CNs IX, X, and XI. The incidence of
paragangliomas is estimated at 0.012%.5 No racial predilection has been noted and
they commonly occur in the fourth and fifth decades of life.6 Multicentricity is seen in
3% to 10%.7,8 Familial paraganglioma, inherited as an autosomal dominant disorder
with genetic imprinting through paternal transmission, occurs in 1/30,000 head and
neck tumors.9 In contrast to the sporadic type, individuals affected by this rare condition
develop multiple paragangliomas, often bilateral and at an earlier age. Multicentricity is
seen in 30% of cases of familial paragangliomas. The most common association is
a carotid body tumor and ipsilateral glomus tympanicum.8 Recent genetic studies
found linkage to two distinct chromosomal loci, 11q13.1 (PGL 2) and 11q22.3-q23
(PGL 1).9–11 Germline mutations in the genes encoding for the three subunits of the mito-
chondrial complex II or succinate dehydrogenase (SDHD) (an essential component of
Krebs cycle), SDHB, SDHC, and SDHD, have been recently found.12–14 Some reports
suggested that the same pattern of mutations may be found in sporadic cases and other
have disputed a common genetic alteration.14,15
Paragangliomas spread through pathways of least resistance: air cell tracts,
vascular channels, naturally occurring fissures, and foramina. Different patterns of
intracranial spread, ‘‘dangerous triangles,’’ have been described.16 Paragangliomas
can travel through the peritubal air cells into the petrous apex, petrous carotid artery,
and middle cranial fossa, or through the hypotympanic air cell tract between the
jugular bulb and carotid artery into the posterior fossa.
Malignant paragangliomas are rare and reported in 5% of cases.17 The diagnosis of
malignancy is based on the confirmed presence of distant metastasis. Cellular criteria
and invasiveness has not been established as a prerequisite for making the diagnosis
of malignant paragangliomas. Paragangliomas may originate in the temporal bone and
invade into the cerebellopontine angle (CPA).18,19
PATHOLOGY
Paragangliomas contain two cell types: the chief cells and sustentacular cells. The
chief cells possess secretory granules that contain catecholamines. They are deriva-
tives of neural crest cells and belong to the diffuse neuroendocrine system (DNES).20
Cells that are members of the DNES are capable of secreting neurotransmitters and
have similar cell receptors.
Despite the detection of catecholamine precursors in most paragangliomas, only
1% to 3% of head and neck paragangliomas excrete norepinephrine. Unlike adrenal
paragangliomas (pheochromocytoma), extra-adrenal paragangliomas rarely produce
epinephrine, because the rate-converting enzyme phenylethanolamine-N-methyl
transferase is absent.20,21
On light microscopy, chief cells form clusters (zellballen) embedded with support
cells (sustentacular cells) within an abundant vascular stroma. Mitosis and capsular
invasion have been described in the benign variant and are not considered determi-
nant of malignant behavior. Unmyelinated nerve fibers may be seen.6
CLINICAL MANIFESTATIONS
Paragangliomas may be sporadic or part of an inherited syndrome with an autosomal

dominant mode of transmission with genetic imprinting. The hereditary form is
characterized by a higher incidence of multicentricity and associated tumors.22 The

genetic imprinting through paternal transmission seen in these tumors is reflected
by the absence of phenotypic expression in offspring of females carrying the mutated
gene, whereas inheriting a mutated copy from the father results in phenotypic expres-
sion with high penetrance.10,11
Early-stage paragangliomas present with symptoms related to involvement of the
middle ear cleft. Pulsatile tinnitus and conductive hearing loss are seen in 98% and
63%, respectively.23 Glomus tympanicum tends to spread through pathways of least
resistance along the peritubal air cells, intrapetrous carotid artery, and petrous apex.
Glomus jugulare presents with pulsatile tinnitus and cranial neuropathy. These
neoplasms tend to spread trough the hypotympanic air cells tract, around the jugular
bulb, inferior petrosal sinus, and carotid artery into the jugular foramen and posterior
fossa. The jugular foramen syndrome may be seen in 50% of tumors.18 Involvement of
CN IX has been reported in 4% to 43% of cases, CN X in 5% to 57%, CN XI in 4% to
43%, and CN XII in 7% to 43%.6,18,24,25 Glomus tympanicum is seen as a retrotym-
panic red mass on the promontory. Glomus jugulare presents as a middle ear mass
when it erodes into the floor of the hypotympanum, and as an aural polyp if erosion
of the tympanic membrane has occurred. Invasion of the middle ear results in conduc-
tive hearing loss. Of interest, paragangliomas encroach onto the ossicles but do not
cause ossicular erosion.26 Pulsatile tinnitus is an indicator of the tumor hypervascular-
ity. Brown sign (tumor blanching with positive pressure using pneumatoscopy) or
Aquino sign (cessation of pulsations with compression of the ipsilateral carotid artery)
may be seen. As tumor invades into deeper structures, additional lower cranial
neuropathies, sensorineural hearing loss, vertigo, and pain may ensue. Extension of
the tumor through the facial recess and retrofacial air cells may result in encasement
of the facial nerve. Facial nerve involvement is present in 21% to 33%.25–27 In large
tumors, Horner syndrome, facial hypesthesia, and diplopia may be seen due to exten-
sion into the carotid artery and intradural or extradural involvement of CN VI.25,26 In
one study,18 posterior fossa involvement was seen in 50% of cases with jugular
foramen syndrome and in 75% of cases with CN XII neuropathy.
It is prudent not to biopsy a vascular middle ear mass, because this may result in
profuse bleeding or exsanguination if not properly controlled. An aberrant carotid
artery or high-riding, dehiscent jugular bulb may present as a reddish or bluish
mass in the hypotympanum and possibly masquerade as a glomus tumor.
In cases in which multicentricity is seen, an appropriate workup should include
screening for other adrenal and extra-adrenal tumors and for familial type paraganglio-
mas. A 24-hour urinary vanillylmandelic acid (VMA), plasma catecholamines, and
urinary beta-metanephrine and normetanephrine may be obtained as part of the
biochemical screening workup.28 History suggestive of labile hypertension, attacks
of headache, anxiety, sweating, and flushing may suggest a catecholamine-producing
tumor. Because of the rarity of functional head and neck paragangliomas, elevated
plasma catecholamines should prompt the search for a pheochromocytoma, and peri-
operative alpha blockade may be indicated to avoid catecholaminergic crisis. Genetic
screening is not widely available as a screening tool and remains confined to the
research laboratory. A gadolinium-enhanced MRI of the head and neck is the gold
standard modality to screen for multicentric paragangliomas.
DIAGNOSIS
The role of neuroradiology in determining the origin, extent, and nature of the tumor is
of paramount importance. Its role is not limited to the characterization of the lesion
692 Miller et al
itself, but is essential in differentiating these lesions from vascular anomalies or

temporal bone malignant neoplasms and in screening for other contralateral or ipsilat-
eral lesions in cases of familial paragangliomas.
On high-resolution CT of the temporal bone, glomus tympanicum in its early phases
appears as a well-circumscribed soft tissue mass localized on the promontory. The
differential diagnosis of a soft tissue density confined to the promontory includes
congenital cholesteatoma, persistent stapedial artery, and aberrant carotid artery.29
Radiographically, glomus jugulare tumors are associated with an irregular erosive
enlargement of the jugular plate (floor of the hypotympanum) and the jugulocarotid
spine, a pattern that is described as ‘‘moth-eaten.’’ Depending on their origin, these
neoplasms extend through the skull base to involve the jugular foramen in its neural
and vascular compartment and eventually progress intracranially through intra or ex-
tradural pathways or extracranially through cervical extension.30
MR weighted images are superior to evaluate tumor vascularity, extension along
neural foramina, and multicentricity.31 In addition, MR venography is helpful in
ensuring intraluminal patency of the jugular vein and retrograde involvement of the
venous system and the status of the contralateral venous system. On T1-weighted
images, paragangliomas appear hypointense with a speckled appearance. On gado-
linium-enhanced T1 images, early and pronounced enhancement is seen witnessing
the hypervascular nature of the neoplasm. On T2-weighted images, paragangliomas
are hyperintense, and when larger then 2 cm the serpentine flow void pattern is
described as a ‘‘salt and pepper’’ appearance.31,32
Paragangliomas exhibit an intense blush or a ‘‘bag of worm’’ appearance on angi-
ography. MR angiography may substitute for four-vessel angiography as a tool to eval-
uate the vascularity of skull base tumors. Small vascular anomalies and blood feeders
are better seen on conventional angiography, however.33 Four-vessel angiography is
indicated if preoperative embolization is planned. The latter may decrease intraoper-
ative blood loss and operative time.34
TREATMENT
Classification Schemes
Different classification schemes have been described. The scheme advised by Fisch
divides these lesions into four categories:35 type A, tumors limited to the middle ear;
type B, tumors limited to the tympanomastoid compartment; type C, tumors
involving the infralabyrinthine air cells tract and intrapetrous carotid canal and ex-
tending into the petrous apex; and type D, tumors with intracranial extension. The
scheme described by Jackson and colleagues36 divides JTPs into four types: type
I, small tumors involving the jugular bulb, middle ear, and mastoid; type II, tumors
extending under the internal auditory canal that may have an intracranial extension;
type III, tumors extending into the petrous apex with or without intracranial extension;
and type IV, tumors extending beyond the petrous apex into the clivus or infratem-
poral fossa. The House ear group adopted the classification devised by Antonio
De La Cruz.23 JTPs are considered tympanic when tumors are entirely confined to
the mesotympanum, tympanomastoid when they extend beyond the limits of the
mesotympanum without eroding the jugular plate, jugular bulb when the tumors
are confined to the jugular foramen without involvement of the carotid artery or
extension intracranially, carotid artery when the tumor involves the intrapetrous
carotid artery, and transdural when the tumor extends intracranially. These classifica-
tions help guide the surgeon in the selection of the most appropriate approach to
eradicate the disease.
Operative Management
Tympanic tumors may be completely excised by a transcanal approach. To ensure
adequate exposure, the tympanic annulus is elevated circumferentially and left
attached to the manubrium. The tumor is excised using cup forceps and hemostasis
is obtained with hemostatic sealant or absorbable gelatin foam (Gelfoam). Tympano-
mastoid tumors are removed by a classic mastoidectomy with an extended facial
recess approach. This approach can at times obviate the need to elevate a tympano-
meatal flap. For jugular bulb tumors the mastoid-neck approach is used. Only after
preoperative embolization has been achieved is a mastoidectomy performed. The
mastoid tip is taken down along with the insertion of the sternocleidomastoid muscle.
The posterior belly of the digastric is dissected free and reflected anteriorly to expose
the great vessels. The jugular vein is ligated in the neck. The proximal sigmoid sinus is
packed extraluminally and the anterior wall of the segment involved by the tumor is
excised preserving the posterior dural surface of the vein intact. Bleeding from the
inferior petrosal sinus is controlled by packing and the remainder of the tumor is
removed. Some centers perform preoperative embolization of the inferior petrosal
sinus to minimize intraoperative bleeding and facilitate neural microdissection.37
Facial nerve rerouting can often be avoided if a fallopian bridge technique is used to
access the tumor.24 This technique involves the removal of the retrofacial and infrala-
byrinthine air cell tracts. Anatomic factors, such as an anteriorly displaced jugular
bulb, may limit exposure. For carotid artery tumors the infratemporal fossa
approaches described by Fisch38 provide adequate access. Detailing the surgical
technique is beyond the scope of this discussion. Transdural involvement is ad-
dressed by different posterior fossa approaches. Paragangliomas involving the CPA
are often extensive, and their treatment involves a combined extradural and intradural
approach, which may or may not be a staged procedure.39 The transpetrous approach
may be performed for complete tumor excision, with or without facial nerve rerouting,
with or without a transcochlear approach, and with additional craniotomies designed
as dictated by tumor extension.40 For tumors extending into the CPA without violating
the otic capsule, a transsigmoid, retrolabyrinthine approach may provide adequate
exposure of the upper compartment of the CPA. For lesions with inferior extension,
a retrosigmoid approach, which may be combined with a far-lateral approach, may
be needed. Lesions extending to the middle cranial fossa with preserved hearing
may be removed using the subtemporal-retrolabyrinthine approach.41 These exten-
sive operations are often associated with significant morbidity and increased opera-
tive time.
CONVENTIONAL RADIOTHERAPY
Conventional fractionated external beam radiotherapy represents an alternative to

surgery for paragangliomas and has been used as primary treatment in patients for
whom surgery is contraindicated because of advanced age or other comorbidities.
Radiotherapy has also been used as an adjuvant to surgery for patients who have
large or unresectable tumors and as salvage treatment for residual disease.42,43
Glomus tumors are relatively radioresistant and tend to persist after radiotherapy,
although control of tumor growth has been demonstrated.44–46 The effect of radiation
on paraganglioma tissue is not well understood. Postirradiation histopathologic
studies demonstrate variable amounts of perivascular fibrosis45,47 and increase in
stromal connective tissue,48,49 but there is minimal effect on tumor cells themselves
or catecholamine secretion after radiation.46 Nevertheless, long-term control of tumor
growth can be obtained using radiotherapy.
694 Miller et al
Tumor control seems to be related to dose, with frequent recurrence reported at

lower radiation doses.50–56 At higher doses, multiple studies have shown tumor
control comparable to that obtained by surgery, with only rare progression,54,57–61
and similar or even lower rate of complication.62 One retrospective review of studies
from 1965 to 1988 demonstrated long-term control rates after surgery alone, surgery
and radiotherapy, and radiotherapy alone to be 86%, 90%, and 93%, respectively,
with lowest complication rates in the radiotherapy group.63 Another review that
included 582 patients from 24 series comparing surgery and radiotherapy demon-
strated recurrence in 7% versus 8% and death in 2.5% versus 6%.64
Unfortunately, radiotherapy is associated with risk for several significant long-term
complications. To obtain an adequate dose of radiation to the tumor, normal tissue of
the upper neck and skull base must be included in the radiation field. The temporal
bone itself is exquisitely radiosensitive and is susceptible to osteoradionecro-
sis.59,61,65 Other reported complications of radiotherapy for glomus tumors include
radiation-induced otitis, mastoiditis, altered taste sensation, alopecia, mucositis,
dermatitis, cranial nerve palsy (such as facial weakness or hearing loss), brain
necrosis, radiation-induced secondary malignancy, metastasis, cerebrospinal fluid
leakage, and insufficiency of pituitary or hypothalamic function.54,59,61,66–71 For this
reason, radiotherapy is not commonly used to treat glomus tumors. Elderly patients
or patients for whom extensive surgery is contraindicated may benefit from a limited
surgical procedure with adjuvant radiotherapy.72
RADIOSURGERY
Over the past several years, radiosurgical techniques have emerged as a promising
alternative to other therapeutic strategies for treatment of glomus jugulare tumors.
Developed by Lars Leksell in 1951, radiosurgery is a refinement of traditional radio-
therapy in which a large number of intersecting beams of radiation are focused directly
on the tumor.73,74 This method allows for a steep drop-off in radiation dose around the
tumor margin so that a large dose of radiation can be provided to the tumor while mini-
mizing radiation exposure to adjacent tissues. Although glomus tumors are relatively
radioresistant, they are otherwise ideal candidates for radiosurgical treatment,
because they are well-demarcated on MRI, rarely invade the brain, are usually fairly
small, and lie close to vital structures.75 Because the volume of irradiated tissue adja-
cent to the tumor is small, the rate of complications is also significantly lower than for
conventional radiotherapy.75,76 Several studies have documented stability or reduc-
tion in tumor size after radiosurgery without new neurologic deficits.76–89 There are
currently three techniques available for radiosurgery: gamma knife, linear accelerator
(LINAC), and CyberKnife. A schematic of each of these is shown in Fig. 1, and photo-
graphs of a gamma knife and a CyberKnife machine are shown in Fig. 2.
GAMMA KNIFE RADIOSURGERY
The most widely studied technique for radiosurgical treatment of glomus tumors is
gamma knife, in which convergent beams of gamma radiation from 201 separate
cobalt-60 sources are focused on a point into which the patient is moved.74 Before
treatment, an MRI is obtained while the patient is wearing a stereotactic head frame,
and the tumor is then carefully analyzed by a neurosurgeon and radiation oncologist
using a computer to identify a treatment plan that will effectively treat the tumor and
avoid adjacent tissue. The patient is placed into the machine so that the tumor remains
at the focal point of radiation for the precise amount of time to receive the appropriate
dose of radiation. Positioning of the patient within the machine can be then be slightly
Fig. 1. Three types of radiosurgery. All use the intersection of many beams of radiation to
produce a high dose to the tumor with low dose to adjacent tissues. (A) Gamma knife radio-
surgery. A total of 201 separate cobalt-60 sources are arranged in a hemisphere, each behind
a column of lead that produces beams that converge. The tumor is placed at the location of
the convergence to provide radiation. (B) Conventional LINAC radiosurgery. Convergent
high-voltage x-ray beams are produced by a gantry that rotates and pivots around the
tumor. (C) CyberKnife radiosurgery. A LINAC is mounted on a robotic arm and aims x-ray
beams at the tumor from different directions.
altered and the process repeated several times to provide treatment to an irregular
volume. The entire process takes only a few hours and can be performed in an outpa-
tient setting.
Gamma knife radiosurgery to treat glomus jugulare tumors was first reported in
1995 in a case series of skull base tumors.77 Two glomus jugulare tumors were
included, and there was no radiographic or clinical progression 19 months after treat-
ment. Two years later, Foote and colleagues76 reported a study of 9 patients designed
to evaluate complications of radiosurgery for glomus tumors; they noted control of
tumor growth in 8 of 9 and no apparent complications. A subsequent study from
the same authors added 16 patients for a total of 25 and demonstrated no radio-
graphic progression and only one complication (vertigo) after 25 months.78 Multiple
other studies have shown high rates of tumor control with rare and transient compli-
cations. In 1999, Eustacchio and colleagues79 reported 10 patients who had glomus
jugulare, among whom 7 were receiving primary treatment, and noted 40% had
696 Miller et al
Fig. 2. Photographs of radiosurgical devices. (A) Gamma knife. The patient’s head is immo-
bilized in a stereotactic head frame that is attached to the metal hemisphere, and the entire
table moves into the machine so that the tumor is precisely placed at the intersection of the
beams of radiation. (B) CyberKnife. The patient lies on the table and two orthogonal x-rays
(visible at the top of the image) continuously check patient position and adjust the plan
accordingly. The robotic arm moves the LINAC device around the patient, allowing for radi-
ation to be delivered to the tumor from many directions, sparing adjacent tissue.
decrease in tumor size after median of 37.6 months with no evidence of clinical or
radiographic progression in any patient. In a subsequent publication, 9 more patients
were added for a total of 19 (10 treated primarily), with similar results.80 Meanwhile,
Liscak and colleagues81,82 reported a multicenter experience including 66 glomus jug-
ulare tumors, of whom 30 were primarily treated, and all patients had stabilization or
decrease in tumor size with decreased vascularity seen on angiography at median
24 months. Jordan and colleagues83 reported 8 patients who were ineligible for
surgery who all underwent gamma knife as primary treatment with no radiographic
progression over 27 months and only one complication (vertigo). Saringer and
colleagues75 reported 13 patients treated with gamma knife who had no tumor growth
at 5 years and transient cranial nerve complications in 2 patients.
More recently, Sheehan and colleagues84 reported 8 patients who had recurrent,
residual, or unresectable glomus tumors; all 8 had no clinical or radiographic progres-
sion over median 32 months, and tumor shrinkage occurred in 3 of these patients.
Gerosa and colleagues85 treated 20 patients and noted shrinkage in nearly half.
Among patients in this study, symptoms remained stable in 13, improved in 5, and
worsened (hearing loss) in 2. A radiologic volumetric analysis of 15 patients who
had glomus tumors treated with gamma knife radiosurgery discovered transient
increase in the size of tumors in 7 but sustained enlargement in only 4, with 8
decreasing in size and 5 unchanged.86 In summary, gamma knife radiosurgery has
been shown to be effective to control growth in the vast majority of cases.
LINEAR ACCELERATOR AND CYBERKNIFE
LINAC radiosurgery is performed using a particle accelerator mounted on a gantry that

is able to rotate around the patient’s head. CyberKnife is a special type of LINAC in
which a compact linear accelerator is mounted on a robotic arm that moves freely
around the patient to irradiate the tumor from multiple directions. Conventional LINAC
radiosurgery requires placement of a frame before imaging and planning, but Cyber-
Knife radiosurgery is performed without a frame, because there are x-ray devices that
repeatedly check patient position and reregister orientation in case of patient

movement.
In contrast to gamma knife, there are only a few reports of LINAC or CyberKnife
used for glomus jugulare tumors, but the results seem similar to those obtained using
gamma knife. Maarouf and colleagues87 reported 14 patients with glomus jugulare
tumors treated with LINAC; none had progression, and 8 reported symptomatic
improvement. Lim and colleagues88 reported 13 patients with 16 tumors treated
with LINAC (5 patients) or CyberKnife (8 patients). Dosage ranged from 18 to 25 Gy
using one to three fractions, with no evidence of growth in any patient through
a mean follow-up period of 44 months. Subsequently, Lim and colleagues89 reported
21 tumors treated with LINAC or CyberKnife with a mean follow-up of 60 months,
including 8 patients followed for at least 10 years. Two patients had transient hearing
loss and tongue weakness, but no patient at last follow-up had any signs of radio-
graphic or clinical progression.
COMBINED SURGERY-RADIOSURGERY
Radiosurgery has repeatedly been shown to be a safe and effective alternative to

surgery and radiotherapy. Most published series indicate that radiosurgery often
does not lead to improvement of symptoms, however, especially tinnitus, otalgia,
and hearing loss. Liscak and colleagues82 reported improvement in tinnitus in only
12 of 53 patients and improvement in hearing loss in 1 of 40 patients. Eusatacchio
and colleagues80 treated 10 patients who had tinnitus, and only 4 reported improve-
ment. Gerosa and colleagues85 noted improvement in tinnitus in 2 patients out of 4.
Varma and colleagues86 treated 17 patients and noted tinnitus improved in 4, otalgia
in 2, and hearing in 1; 7 patients had unchanged symptoms. Results from 9 recent
studies with respect to tumor control and clinical outcome are shown in Table 1. Alto-
gether, of 175 patients reported to have been treated with gamma knife radiosurgery
alone, the vast majority (93%) had no evidence of tumor growth, but fewer than half
(42%) had any improvement in symptoms. Radiosurgery also does not allow for
a tissue diagnosis, and it is remotely possible that what radiographically appears to
be a glomus tumor is in fact another type of tumor that requires more aggressive
treatment.90
To effectively deal with a symptomatic glomus jugulare tumor without the risk of
total surgical excision, it is possible to combine a limited tailored surgical resection
with radiosurgery. Originally reported by Willen and colleagues91 in 2005, this para-
digm combines the advantages of both techniques to produce a better outcome
than is obtainable by either alone. Use of planned postoperative radiosurgery allows
the surgical procedure to be completed in an outpatient setting without dissection
of the entire jugular bulb where neurologic injury often occurs. Evacuation of tumor
from the middle ear, mastoid, and dome of the jugular bulb produces immediate
improvement of symptoms caused by tumor in that area, and it displaces radiosurgical
targeting away from the highly radiosensitive tympanic portion of the temporal bone.
Both are relatively conservative methods that are easily tolerated by elderly patients in
poor health. Finally, this paradigm allows for tissue diagnosis, which can be important
to exclude other masses in the region of the jugular foramen that might masquerade as
glomus jugulare tumors.
The approach for the tailored surgical resection consists of transcanal resection of
mesotympanic tumor or posterior auricular/transmastoid resection of middle ear or
mastoid tumor using the extended facial recess approach. Tumor is dissected from
the undersurface of the tympanic membrane and then dissected from the ossicular
698 Miller et al
Table 1
Summary of major series in which gamma knife radiosurgery alone was used to treat glomus jugulare
tumors
Radiographic Response Clinical Outcome
No.
Series Patients Larger Stable Smaller Unknown Better Stable Worse Unknown
Eustacchio et al, 13 0 6 4 3 5 5 0 3
199979
Liscak et al, 52 0 31 21 0 15 34 3 0
199982
Jordan et al, 8 0 3 4 1 7 1 0 0
200083
Saringer et al, 13 0 10 3 0 6 7 0 0
200175
Eustacchio et al, 19 1 11 7 0 10 8 1 0
200280
Foote et al, 25 0 17 8 0 15 9 1 0
200278
Sheehan et al, 8 0 3 4 1 3 5 0 0
200584
Gerosa et al, 20 8 11 1 0 5 13 2 0
200685
Varma et al, 17 4 5 8 0 7 8 2 0
200686
Total 175 13 97 60 5 73 90 9 3
chain. At this point no attempt is made to remove tumor from the jugular bulb or to
reroute the facial nerve. The tumor is dissected from the facial nerve as far as the
mastoid tip using facial nerve monitoring. A diagram of the surgical site after exposure
and resection of the tumor is shown in Fig. 3. The surgical procedure is relatively
Fig. 3. Transmastoid posterior auricular approach to glomus jugulare tumor after exposure
(A) and removal (B) of tumor. The tumor is resected from the middle ear and hypotympa-
num without altering the course of the facial nerve. Tumor in the main portion of jugular
bulb is left for radiosurgical treatment after removal of tumor in the hypotympanum and
dome of the bulb. EFR, extended facial recess; FN, facial nerve; GJ, glomus jugulare tumor;
I, incus; ISJ, incudostapedial joint; M, malleus; RFC, retrofacial air cells; SCC, semicircular
canals; SS, sigmoid sinus.
straightforward and can be performed as an outpatient. After a few weeks, gamma

knife radiosurgery is performed. The frame is placed low and shifted toward the
side of the tumor to place the tumor as close as possible to the center of the frame.
The plan is then developed in such a way as to minimize radiation exposure to the
internal auditory canal and cochlea. An example of a representative gamma knife
plan is shown in Fig. 4.
To date, five patients have been treated using this paradigm. Patient characteristics
and treatment results after median 29 months of follow-up (range, 11–40 months) are
shown in Table 2. All patients had immediate improvement or resolution of pulsatile
tinnitus or ear pain, and one patient had complete resolution of both symptoms.
Four patients had hearing preoperatively, and all four had improved hearing after treat-
ment. Audiogram results for these patients are shown in Fig. 5. One patient who had
preoperative facial nerve palsy experienced improvement from House grade IV to
grade II, and one patient who had baseline CN XI weakness did not experience any
change postoperatively. The only treatment complication was transient facial palsy
in one patient that appeared approximately 2 weeks after surgery, but it fully resolved
before radiosurgery and did not recur. Postoperative MR imaging revealed stable
tumor size in two patients and a decrease by at least 20% in net tumor volume in three
patients. There were no immediate or delayed complications due to radiosurgery.
This novel paradigm combining outpatient tailored microsurgical and radiosurgical
treatment of glomus jugulare tumors in the symptomatic patient appears to be safe,
improving tinnitus, otalgia, and hearing loss while controlling tumor growth. Extended
follow-up reveals that control of tumor size and clinical symptoms persists for years
after treatment (J.P. Miller, unpublished data, 2009).
Fig. 4. Axial contrast-enhanced T1-weighted MR image demonstrating radiosurgical treat-

ment plan for glomus tumor in axial (A), coronal (B), and sagittal (C) section. 30% (9 Gy),
40% (12 Gy), and 50% (15 Gy) isodose curves are noted.
700
Miller et al
Table 2
Baseline characteristics, treatment parameters, and neurologic response for patients treated with combined surgery/radiosurgery
Tumor/
Dose Matrix
Surgical Time to (50%/100% Volume Follow- Clinical Clinical
Age/sex Stage (Fisch) Approach GKRS (mo) isodose) (cm3) Conformality Up (mo) Presentation Outcome Tumor Response
61/F D1 Transmastoid 3.2 15 Gy/30 Gy 4.0/6.8 1.7 11 Dead ear Hearing No change
Otalgia unchanged
Otalgia
improved
73/F C3 Transcanal 2.3 15 Gy/30 Gy 2.7/5.6 2.1 40 Pulsatile Tinnitus No change
tinnitus improved
73/F D1 Transmastoid 3.6 15 Gy/30 Gy 6.8/10.3 1.5 36 Pulsatile Tinnitus Reduced size
tinnitus resolved
Otalgia Otalgia
resolved
78/F D1 Transmastoid 4.9 15 Gy/30 Gy 2.5/4.0 1.6 21 Pulsatile Tinnitus Reduced size
tinnitus improved
Otalgia Otalgia
Grade IV resolved
facial palsy Grade II
facial palsy
63/F C3 Transmastoid 4.0 15 Gy/30 Gy 4.7/7.6 1.6 35 Pulsatile Tinnitus Reduced size
tinnitus improved
Otalgia Otalgia
Cranial improved
nerve No change
XI palsy in CN XI
Abbreviation: GKRS, Gamma knife radiosurgery.

Fig. 5. Audiogram results for four patients who had hearing at presentation. Each patient
was noted to have improvement in hearing threshold (pure-tone average).
SUMMARY
Glomus jugulare tumors represent a treatment challenge because of their location

near many vital structures. Traditional surgical resection can be performed but is
sometimes associated with significant morbidity, and radiotherapy is fraught with
complications. Radiosurgery represents a promising alternative to surgery or radio-
therapy, because it allows for control of tumor growth without significant side effects.
It can also be combined with a limited surgical resection to produce immediate allevi-
ation of symptoms without the risk for an extensive gross total resection. Although
long-term data are not yet available, results have so far been promising, and radiosur-
gical techniques will likely become even more important in the treatment of glomus
jugulare tumors in the future.
REFERENCES
1. Glenner G, Grimley P. Tumors of the extra-adrenal paraganglion system

(including chemoreceptors). Atlas of tumor pathology. 2nd series, fascicle 9.
Washington, DC: Armed Forces Institute of Pathology; 1974.
2. Valentin G. Ueber eine gangliose Anschwellung in der Jacobsonchen Anasto-
mose des Menschen. Arch Anat Physiol Wissensch Medicin 1840;89:287–90.
3. Guild SR. The glomus jugulare, a nonchromaffin paraganglion, in man. Ann Otol
Rhinol Laryngol 1953;62(4):1045–71.
4. Rosenwasser H. Carotid body tumor of the middle ear and mastoid. Arch Otolar-
yngol 1945;41:64–7.
702 Miller et al
5. Lack EE, Cubilla AL, Woodruff JM, et al. Paragangliomas of the head and neck
region: a clinical study of 69 patients. Cancer 1977;39(2):397–409.
6. Alford BR, Guilford FR. A comprehensive study of tumors of the glomus jugulare.
Laryngoscope 1962;72:765–805.
7. Zacks SI. Chemodectomas occurring concurrently in the neck (carotid body),
temporal bone (glomus jugulare) and retroperitoneum; report of a case with histo-
chemical observations. Am J Pathol 1958;34(2):293–309.
8. Spector GJ, Ciralsky R, Maisel RH, et al. Multiple glomus tumors in the head and
neck. Laryngoscope 1975;85(6):1066–75.
9. Mariman EC, van Beersum SE, Cremers CW, et al. Fine mapping of a puta-
tively imprinted gene for familial non-chromaffin paragangliomas to chromo-
some 11q13.1: evidence for genetic heterogeneity. Hum Genet 1995;95(1):
56–62.
10. Heutink P, van der Mey AG, Sandkuijl LA, et al. A gene subject to genomic
imprinting and responsible for hereditary paragangliomas maps to chromosome
11q23-qter. Hum Mol Genet 1992;1(1):7–10.
11. Milunsky J, DeStefano AL, Huang XL, et al. Familial paragangliomas: linkage to
chromosome 11q23 and clinical implications. Am J Med Genet 1997;72(1):
66–70.
12. Milunsky JM, Maher TA, Michels VV, et al. Novel mutations and the emergence of
a common mutation in the SDHD gene causing familial paraganglioma. Am
J Med Genet 2001;100(4):311–4.
13. Astuti D, Hart-Holden N, Latif F, et al. Genetic analysis of mitochondrial complex II
subunits SDHD, SDHB and SDHC in paraganglioma and phaeochromocytoma
susceptibility. Clin Endocrinol (Oxf) 2003;59(6):728–33.
14. Mhatre AN, Li Y, Feng L, et al. SDHB, SDHC, and SDHD mutation screen in
sporadic and familial head and neck paragangliomas. Clin Genet 2004;66(5):
461–6.
15. Bikhazi PH, Messina L, Mhatre AN, et al. Molecular pathogenesis in sporadic
head and neck paraganglioma. Laryngoscope 2000;110(8):1346–8.
16. Spector GJ, Sobol S, Thawley SE, et al. Panel discussion: glomus jugulare tumors
of the temporal bone. Patterns of invasion in the temporal bone. Laryngoscope
1979;89(10 Pt 1):1628–39.
17. Manolidis S, Shohet JA, Jackson CG, et al. Malignant glomus tumors. Laryngo-
scope 1999;109(1):30–4.
18. Spector GJ, Ciralsky RH, Ogura JH. Glomus tumors in the head and neck: III.
Analysis of clinical manifestations. Ann Otol Rhinol Laryngol 1975;84(1 Pt 1):73–9.
19. Kinney SE. Glomus jugulare tumor surgery with intracranial extension. Otolaryngol
Head Neck Surg 1980;88(5):531–5.
20. Gulya AJ. The glomus tumor and its biology. Laryngoscope 1993;103(11 Pt 2
Suppl 60):7–15.
21. Myssiorek D. Head and neck paragangliomas: an overview. Otolaryngol Clin
North Am 2001;34(5):829–36.
22. McCaffrey TV, Myssiorek D, Marrinan M. Familial paragangliomas of the head and
neck. Arch Otolaryngol Head Neck Surg 1994;120(11):1211–6.
23. Green JD Jr, Brackmann DE, Nguyen CD, et al. Surgical management of previ-
ously untreated glomus jugulare tumors. Laryngoscope 1994;104(8 Pt 1):917–21.
24. Pensak ML, Jackler RK. Removal of jugular foramen tumors: the fallopian bridge
technique. Otolaryngol Head Neck Surg 1997;117(6):586–91.
25. Spector GJ, Gado M, Ciralsky R, et al. Neurologic implications of glomus tumors
in the head and neck. Laryngoscope 1975;85(8):1387–95.
26. Brown LA. Glomus jugulare tumor of the middle ear; clinical aspects. Laryngo-
scope 1953;63(4):281–92.
27. Jackson CG, Harris PF, Glasscock ME III, et al. Diagnosis and management of
paragangliomas of the skull base. Am J Surg 1990;159(4):389–93.
28. Schwaber MK, Glasscock ME, Nissen AJ, et al. Diagnosis and management of
catecholamine secreting glomus tumors. Laryngoscope 1984;94(8):1008–15.
29. Lo WW, Solti-Bohman LG. High-resolution CT of the jugular foramen: anatomy and
vascular variants and anomalies. Radiology 1984;150(3):743–7.
30. Lo WW, Solti-Bohman LG, Lambert PR. High-resolution CT in the evaluation of
glomus tumors of the temporal bone. Radiology 1984;150(3):737–42.
31. Olsen WL, Dillon WP, Kelly WM, et al. MR imaging of paragangliomas. AJR Am
J Roentgenol 1987;148(1):201–4.
32. Weber AL, McKenna MJ. Radiologic evaluation of the jugular foramen. Anatomy,
vascular variants, anomalies, and tumors. Neuroimaging Clin N Am 1994;4(3):
579–98.
33. Rodgers GK, Applegate L, De la Cruz A, et al. Magnetic resonance angiography:
analysis of vascular lesions of the temporal bone and skull base. Am J Otol 1993;
14(1):56–62.
34. Murphy TP, Brackmann DE. Effects of preoperative embolization on glomus jug-
ulare tumors. Laryngoscope 1989;99(12):1244–7.
35. Jenkins HA, Fische U. Glomus tumors of the temporal region. Technique of
surgical resection. Arch Otolaryngol 1982;107(4):209–14.
36. Jackson CG, Glasscock ME III, Nissen AJ, et al. Glomus tumor surgery: the
approach, results, and problems. Otolaryngol Clin North Am 1982;15(4):
897–917.
37. Lustig LR, Jackler RK. The variable relationship between the lower cranial nerves
and jugular foramen tumors: implications for neural preservation. Am J Otol 1996;
17(4):658–68.
38. Fisch U. Infratemporal fossa approach for extensive tumors of the temporal bone
and base of the skull. In: Silverstein H, Norell H, editors. Neurological surgery of
the ear. Birmingham (AL): Aesculapius; 1977. p. 34–53.
39. Sanna M, Jain Y, De Donato G, et al. Management of jugular paragangliomas: the
Gruppo Otologico experience. Otol Neurotol 2004;25(5):797–804.
40. Blevins NH, Jackler RK, Kaplan MJ, et al. Combined transpetrosal-subtemporal
craniotomy for clival tumors with extension into the posterior fossa. Laryngoscope
1995;105(9 Pt 1):975–82.
41. Daspit CP, Spetzler RF, Pappas CT. Combined approach for lesions involving the
cerebellopontine angle and skull base: experience with 20 cases—preliminary
report. Otolaryngol Head Neck Surg 1991;105(6):788–96.
42. Pemberton LS, Swindell R, Sykes AJ. Radical radiotherapy alone for glomus jug-
ulare and tympanicum tumours. Oncol Rep 2005;14(6):1631–3.
43. Krych AJ, Foote RL, Brown PD, et al. Long-term results of irradiation for paragan-
glioma. Int J Radiat Oncol Biol Phys 2006;65(4):1063–6.
44. Spector GJ, Compagno J, Perez CA, et al. Glomus jugulare tumors: effects of
radiotherapy. Cancer 1975;35(5):1316–21.
45. Hawthorne MR, Makek MS, Harris JP, et al. The histopathological and clinical
features of irradiated and nonirradiated temporal paragangliomas. Laryngoscope
1988;98(3):325–31.
46. Schwaber MK, Gussack GS, Kirkpatrick W. The role of radiation therapy in the
management of catecholamine-secreting glomus tumors. Otolaryngol Head
Neck Surg 1988;98(2):150–4.
704 Miller et al
47. Brackmann DE, House WF, Terry R, et al. Glomus jugulare tumors: effect of irra-
diation. Trans Am Acad Ophthalmol Otolaryngol 1972;76(6):1423–31.
48. Spector GJ, Maisel RH, Ogura JH. Glomus tumors in the middle ear. I. An anal-
ysis of 46 patients. Laryngoscope 1973;83(10):1652–72.
49. Spector GJ, Maisel RH, Ogura JH. Glomus jugulare tumors. II. A clinicopatho-
logic analysis of the effects of radiotherapy. Ann Otol Rhinol Laryngol 1974;
83(1):26–32.
50. Spector GJ, Fierstein J, Ogura JH. A comparison of therapeutic modalities of
glomus tumors in the temporal bone. Laryngoscope 1976;86(5):690–6.
51. Gibbin KP, Henk JM. Glomus jugulare tumours in South Wales—a twenty-year
review. Clin Radiol 1978;29(6):607–9.
52. Kim JA, Elkon D, Lim ML, et al. Optimum dose of radiotherapy for chemodecto-
mas of the middle ear. Int J Radiat Oncol Biol Phys 1980;6(7):815–9.
53. Simko TG, Griffin TW, Gerdes AJ, et al. The role of radiation therapy in the treat-
ment of glomus jugulare tumors. Cancer 1978;42(1):104–6.
54. Sharma PD, Johnson AP, Whitton AC. Radiotherapy for jugulo-tympanic paragan-
gliomas (glomus jugulare tumours). J Laryngol Otol 1984;98(6):621–9.
55. Powell S, Peters N, Harmer C. Chemodectoma of the head and neck: results of
treatment in 84 patients. Int J Radiat Oncol Biol Phys 1992;22(5):919–24.
56. Mukherji SK, Kasper ME, Tart RP, et al. Irradiated paragangliomas of the head
and neck: CT and MR appearance. AJNR Am J Neuroradiol 1994;15(2):
357–63.
57. Larner JM, Hahn SS, Spaulding CA, et al. Glomus jugulare tumors. Long-term
control by radiation therapy. Cancer 1992;69(7):1813–7.
58. Boyle JO, Shimm DS, Coulthard SW. Radiation therapy for paragangliomas of the
temporal bone. Laryngoscope 1990;100(8):896–901.
59. Hinerman RW, Mendenhall WM, Amdur RJ, et al. Definitive radiotherapy in the
management of chemodectomas arising in the temporal bone, carotid body,
and glomus vagale. Head Neck 2001;23(5):363–71.
60. Elshaikh MA, Mahmoud-Ahmed AS, Kinney SE, et al. Recurrent head-and-neck
chemodectomas: a comparison of surgical and radiotherapeutic results. Int J
61. Hu K, Persky MS. The multidisciplinary management of paragangliomas of the
head and neck, Part 2. Oncology (Williston Park) 2003;17(8):1143–53.
62. Wang ML, Hussey DH, Doornbos JF, et al. Chemodectoma of the temporal bone:
a comparison of surgical and radiotherapeutic results. Int J Radiat Oncol Biol
Phys 1988;14(4):643–8.
63. Springate SC, Haraf D, Weichselbaum RR. Temporal bone chemodectomas—
comparing surgery and radiation therapy. Oncology (Williston Park) 1991;5(4):
131–7.
64. Carrasco V, Rosenman J. Radiation therapy of glomus jugulare tumors. Laryngo-
scope 1993;103(Suppl 60):23–7.
65. Wang CC, Doppke K. Osteoradionecrosis of the temporal bone—consideration of
nominal standard dose. Int J Radiat Oncol Biol Phys 1976;1(9–10):881–3.
66. Cole DJ. Glomus jugulare tumours seen in Oxford 1960–1984. Clin Radiol 1988;
39(1):83–6.
67. Springate SC, Weichselbaum RR. Radiation or surgery for chemodectoma of the
temporal bone: a review of local control and complications. Head Neck 1990;12:
303–7.
68. Lalwani AK, Jackler RK, Gutin PH. Lethal fibrosarcoma complicating radiation
therapy for benign glomus jugulare tumor. Am J Otol 1993;14(4):398–402.
69. Pluta RM, Ram Z, Patronas NJ, et al. Long-term effects of radiation therapy for
a catecholamine-producing glomus jugulare tumor. Case report. J Neurosurg
1994;80:1091–4.
70. Gabriel EM, Sampson JH, Dodd LG, et al. Glomus jugulare tumor metastatic to
the sacrum after high-dose radiation therapy: case report. Neurosurgery 1995;
37:1001–5.
71. Mumber MP, Greven KM. Control of advanced chemodectomas of the head and
neck with irradiation. Am J Clin Oncol 1995;18(5):389–91.
72. Maniglia AJ, Sprecher RC, Megerian CA, et al. Inferior mastoidectomy-hypotym-
panic approach for surgical removal of glomus jugulare tumors: an anatomical
and radiologic study emphasizing distances between critical structures. Laryn-
goscope 1992;102(4):407–14.
73. Leksell L. The stereotaxic method and radiosurgery of the brain. Acta Chir Scand
1951;102(4):316–9.
74. Lunsford LD, Flickinger J, Lindner G, et al. Stereotactic radiosurgery of the brain
using the first United States 201 cobalt-60 source gamma knife. Neurosurgery
1989;24(2):151–9.
75. Saringer W, Khayal H, Ertl A, et al. Efficiency of gamma knife radiosurgery in the
treatment of glomus jugulare tumors. Minim Invasive Neurosurg 2001;44(3):
141–6.
76. Foote RL, Coffey RJ, Gorman DA, et al. Stereotactic radiosurgery for glomus jug-
ulare tumors: a preliminary report. Int J Radiat Oncol Biol Phys 1997;38(3):491–5.
77. Kida Y, Kobayashi T, Tanaka T, et al. [A new strategy for the treatment of jugular
foramen tumors using radiosurgery] [article in Japanese]. No Shinkei Geka 1995;
23(8):671–5.
78. Foote RL, Pollock BE, Gorman DA, et al. Glomus jugulare tumor: tumor control
and complications after stereotactic radiosurgery. Head Neck 2002;24(4):
332–8.
79. Eustacchio S, Leber K, Trummer M, et al. Gamma knife radiosurgery for glomus
jugulare tumours. Acta Neurochir (Wien) 1999;141(8):811–8.
80. Eustacchio S, Trummer M, Unger F, et al. The role of gamma knife radiosurgery in
the management of glomus jugular tumours. Acta Neurochir Suppl 2002;84:91–7.
81. Liscak R, Vladyka V, Simonova G, et al. Leksell gamma knife radiosurgery of the
tumor glomus jugulare and tympanicum. Stereotact Funct Neurosurg 1998;
70((Suppl 1):152–60.
82. Liscak R, Vladyka V, Wowra B, et al. Gamma knife radiosurgery of the glomus jug-
ulare tumour - early multicentre experience. Acta Neurochir (Wien) 1999;141(11):
1141–6.
83. Jordan JA, Roland PS, McManus C, et al. Stereotactic radiosurgery for glomus
jugulare tumors. Laryngoscope 2000;110(1):35–8.
84. Sheehan J, Kondziolka D, Flickinger J, et al. Gamma knife surgery for glomus jug-
ulare tumors: an intermediate report on efficacy and safety. J Neurosurg 2005;
102(Suppl):241–6.
85. Gerosa M, Visca A, Rizzo P, et al. Glomus jugulare tumors: the option of gamma
knife radiosurgery. Neurosurgery 2006;59(3):561–9.
86. Varma A, Nathoo N, Neyman G, et al. Gamma knife radiosurgery for glomus jug-
ulare tumors: volumetric analysis in 17 patients. Neurosurgery 2006;59(5):
1030–6.
87. Maarouf M, Voges J, Landwehr P, et al. Stereotactic linear accelerater-based
radiosurgery for the treatment of patients with glomus jugulare tumors. Cancer
2003;97(4):1093–8.
706 Miller et al
88. Lim M, Gibbs IC, Adler JR Jr, et al. Efficacy and safety of stereotactic radiosur-
gery for glomus jugulare tumors. Neurosurg Focus 2004;17(2):68–72.
89. Lim M, Bower R, Nangiana JS, et al. Radiosurgery for glomus jugulare tumors.
Technol Cancer Res Treat 2007;6(5):419–24.
90. Megerian CA, McKenna MJ, Nadol JB Jr. Non-paraganglioma jugular foramen
lesions masquerading as glomus jugulare tumors. Am J Otol 1995;16(1):94–8.
91. Willen SN, Einstein DB, Maciunas RJ, et al. Treatment of glomus jugulare tumors
in patients with advanced age: planned limited surgical resection followed by
staged gamma knife radiosurgery: a preliminary report. Otol Neurotol 2005;
26(6):1229–34.
Microsurger y
Af ter Radiosurger y
or Radiotherapy
for Vestibular
Schwa nnomas
William H. Slattery III, MD
KEYWORDS
Radiation therapy Tumor changes Surgical excision cases
House clinic surgical excision data Tumor pathology
Malignant transformation surgery
Vestibular schwannomas (VS) are benign neoplasms of the eighth cranial nerves.
Vestibular schwannomas usually present with symptoms associated with the eighth
cranial nerve including hearing loss, tinnitus, or dizziness. Historically, microsurgery
has been the mainstay of therapy. Complete tumor removal has been the goal of treat-
ment. Since the early 1990s, radiosurgery and radiotherapy have developed as alter-
natives to microsurgical excision of vestibular schwannomas in the United States. The
goals of microsurgery and radiation therapy are very different. The goal of microsur-
gical excision is complete tumor removal with preservation of the cranial nerves.
The goal of radiosurgery or radiotherapy is tumor control or prevention of tumor
growth, with preservation of cranial nerve function.
There are several modalities by which radiation may be used to treat vestibular
schwannomas. Treatment types may include a single-session treatment, used with
gamma knife radiosurgery, or fractionated therapy that is performed over several
sessions. Fractionated radiotherapy is more common with the linear particle acceler-
ator (LINAC) system such as Cyberknife (Accuray, Sunnyvale, California). The use of
a head frame or facial mask may be used for stereotactic computer localization of
the tumor to guide radiation localization to the tumor. All of these therapies have
a significant tumor control rate as defined by lack of tumor growth. Approximately
2% to 10% of tumors continue to grow, however, and cause symptoms despite treat-
ment with radiosurgery or radiotherapy.
Clinical Studies, House Ear Institute, House Ear Clinic, University of Southern California, 2100
West Third Street, Los Angeles, CA 90057, USA
E-mail address: DrSlattery@hei.org

708 Slattery
ADVANTAGES OF RADIATION THERAPY
The indications for radiation therapy for vestibular schwannomas have evolved over
the years. The initial indications for radiation therapy for vestibular schwannomas
included elderly patients, patients who had significant medical conditions precluding
microsurgery, or patients who refused microsurgical removal. Recently, the indica-
tions for radiation therapy have expanded to include all patients who wish to have ra-
diosurgery or radiotherapy for their vestibular schwannoma. Although some
physicians will treat all vestibular schwannomas with radiation therapy, others recom-
mend that there should be documented tumor growth before radiosurgery or radio-
therapy. Because the goal of radiation therapy is to stop tumor growth, these
physicians believe that the tumor should demonstrate growth before having the risk
associated with radiation therapy. Many vestibular schwannomas do not grow and,
therefore, a watch-and-wait policy can be recommended before undergoing radiation
therapy.
The main advantage of radiation therapy is that it is less invasive compared with
microsurgery. Radiosurgery or radiotherapy is considered less invasive, as the treat-
ment usually is performed as an outpatient procedure, or requires only a one-night
hospital stay. The patient may return back to work much faster following this type of
treatment when compared with microsurgery. Radiosurgery or radiotherapy often
results in preservation of facial nerve function, although facial nerve paralysis can
occur. The risks of significant immediate adverse effects are low. Radiation therapy
offers the ability to preserve hearing in tumors whose size normally would be consid-
ered a contraindication for a hearing preservation type of microsurgery. As an
example, tumors larger than 2 cm in size have a poor prognosis for hearing preserva-
tion with microsurgery. The possibility of preserving hearing can be considered with
radiation for tumors larger than 2 cm. Hearing preservation after microsurgery and
radiation therapy will be discussed later in this article.
DISADVANTAGES OF RADIATION THERAPY
The main disadvantage of radiation therapy for vestibular schwannoma is that the
tumor is still present after treatment and, therefore, the long-term control rate is
unknown. As long as the tumor is still present there is always the possibility for tumor
growth. Patients treated with radiation therapy must undergo routine MRI scans for the
remainder of their lives. It is known that tumors swell initially after radiation therapy
and, therefore, a size limit of 2.5 to 3.0 cm is recommended as the maximum treatment
size. Tumors larger than 2.5 to 3.0 cm can swell, causing the patient to have significant
intracranial complications such as brainstem compression requiring medical or micro-
surgical intervention. Therefore, most centers will not treat patients who have tumors
larger than 2.5 to 3.0 cm in size. Radiation treatment also includes a risk to the cranial
nerve’s seventh and eighth complexes. This risk includes partial or complete loss of
hearing. Most studies have demonstrated that hearing may be preserved in the imme-
diate months following radiation treatment; however, there is a definite decrease in the
rate of hearing preservation the longer the patient is followed. Facial nerve complica-
tions can include temporary or permanent paralysis.
Facial nerve spasm is also a symptom that is associated with postradiation treat-
ment. Patients can have significant hemifacial spasm that can be quite disabling. In
some cases, the hemifacial spasm is severe enough to warrant microsurgical excision
of the tumor. Botox therapy also may be used to treat the hemifacial spasm. New-
onset or worsening preexisting dizziness or ataxia may develop following radiation
treatment. Vestibular rehabilitation with physical therapy may help in some cases,
Microsurgery After Radiosurgery 709
but in other cases, the dizziness or ataxia can be so severe that the patient is at signif-
icant risk of falls. Two percent to 10% of patients treated with radiation therapy have
tumors that continue to grow and that may require microsurgical treatment. Microsur-
gical treatment may consist of insertion of a ventricular peritoneal shunt for hydro-
cephalus or microsurgical excision of the tumor.
The long-term effects of radiation therapy for vestibular schwannomas are not
known. The earliest reported series from within the United States used a higher
dose of radiation to treat vestibular schwannomas than is used currently. This higher
rate of radiation was associated with a higher rate of radiation-induced complications;
therefore the total dose to the tumor has been reduced over the past 10 years. The
long-term effect of lowering the treatment dose with respect to tumor control will be
assessed only with time. There are very few reports on the long-term effects after
15 years from stereotactic radiation treatment. Radiation poses the risk of possible
malignant transformation of the tumor or the risk of inducing additional tumor forma-
tion within the radiation field. This risk of malignancy associated with stereotactic radi-
ation has been estimated to be approximately 1%. More information regarding
malignancy risk is available elsewhere in this issue. Other radiation treatment modal-
ities have been associated with an increase incidence of tumor formation 15 to 30
years after treatment. The risk of subsequent tumor formation is thought to be higher
for younger patients, as they have a longer life expectancy following radiation treat-
ment and therefore have more time to develop additional tumors. Meningioma forma-
tion and vestibular schwannoma have been associated in patients who have
experienced external beam radiation therapy 15 to 30 years before the presentation
and diagnosis of these tumors.
TUMOR CHANGES AFTER RADIATION
There are consistent changes that occur following radiation therapy for vestibular
schwannomas. These changes include an increase in size of the tumor 6 to 9 months
after treatment and loss of central MRI enhancement. Pollock and colleagues1 found
in 208 patients that the median time for tumor enlargement was 9 months. The median
volume was increased by 75%. A loss of MRI central enhancement was noted in 93%
of tumors at the time of tumor expansion. The increase in size of the tumor is
presumed to be caused by swelling of tumor tissue. The tumors typically increase in
size 6 to 12 months following treatment and then decrease in size over the 12 to 24
months following treatment. Reduction of MRI signal intensity and the time it takes
for the tumor to reach maximum swelling following treatment have been associated
with the total tumor dose. The higher tumor dose is associated with a more rapid
swelling and more central MRI changes.
Pollock1 describes three types of growth patterns that may occur following stereo-
tactic radiosurgery for vestibular schwannomas. Type 1 is seen most commonly. The
vestibular schwannoma usually will enlarge by several millimeters within 9 to 12
months after stereotactic radiotherapy. This enlargement is followed by a volume
reduction that reverts back to the initial tumor size. The type 2 pattern includes tumors
that enlarge and remain larger than the size before radiosurgery. This occurs in
approximately 30% of cases. Although these tumors may be larger, they do not cause
any additional symptoms. The type 3 pattern consists of vestibular schwannomas that
progressively grow in serial imaging. These are usually the tumors that require treat-
ment when symptoms change or develop.
Long-term follow-up of type 1 tumors reveals that they are very stable. The type 2
tumors require long-term follow-up, because these tumors may continue to grow
710 Slattery
and fall into the type 3 category. It is possible that the increase in size and stabilization
of type 2 tumors may represent the natural history of the benign tumor that has spon-
taneous periods of growth arrest.
Tumor size may increase after radiation therapy because of three factors: (1) solid
expansion of the tumor, (2) tumor necrosis, or (3) tumor cyst formation.
Tumor cyst formation may result from increased extracellular proteins that leak from
the blood vessel walls in the tumor. This can result in a multiseptated cyst associated
with the tumor. Cyst formation following radiation therapy is not uncommon. This
theory of cyst formation is supported by the fact that cerebrospinal fluid (CSF) protein
levels are higher in patients who have tumor enlargement requiring ventriculo–perito-
neal (VP) shunts after radiation therapy of their vestibular schwannomas.
In the early experience of stereotactic radiation therapy for vestibular schwanno-
mas, the swelling found after treatment was thought to represent tumor growth, indi-
cating the radiation did not work; therefore microsurgery was undertaken for the
growth. This resulted in some patients undergoing microsurgery, which was probably
unnecessary. In addition, in the early use of stereotactic radiation therapy for vestib-
ular schwannomas, larger tumors were treated. Unfortunately, many of the patients
with these large tumors had normal swelling that occurred following radiation therapy,
and they developed hydrocephalus or brainstem compression. This has led to size
constraints for patients who are candidates for radiation therapy.
SURGICAL INDICATIONS FOR VESTIBULAR SCHWANNOMA REMOVAL

AFTER RADIATION THERAPY
Microsurgery following radiation therapy is relatively uncommon, as most cases of

stereotactic radiation therapy for vestibular schwannomas have good short-term
tumor control rates. As a result of the good short-term tumor control rate, there are
few large series of microsurgery following radiation cases. The degree of increased
microsurgical technical difficulties between nonradiated and radiated tumors has
been discussed, although conclusions regarding the relative difficulty of tumor dissec-
tion following radiation therapy have not been settled. Surgical treatment after radia-
tion therapy may include insertion of VP shunt, excision of tumor-associated cyst,
subtotal tumor resection, or total tumor resection.
It is advisable to avoid surgery during the first 2 years after radiation therapy
unless there are significant complications associated with tumor growth or radia-
tion. The rationale for avoiding surgery during this time is twofold. First, the cranial
nerves are more susceptible to damage from surgical manipulation during the first
year. Second, differentiation of long-term tumor growth from expected tumor
swelling during this first 2 years is difficult. Radiation-induced cranial neuropathy
is known to occur during the first year after routine radiation therapy. Cranial
neuropathy associated paralysis is unusual after the first year. Tumor swelling
usually occurs during the first year after radiation therapy, and this effect may
extend into the second year. Therefore, it is recommended to observe the tumor
for 2 years after radiation therapy before considering a surgical intervention unless
serve tumor-related symptoms develop. These severe tumor-related symptoms are
usually brainstem compression or hydrocephalus.
REVIEW OF PUBLISHED CASES OF SURGICAL EXCISION
Most centers have only one or two cases of microsurgery following stereotactic radi-
ation therapy for vestibular schwannomas. Many of these cases have not been
reported in the literature. There are several small case series that report on the micro-
surgical results following stereotactic radiation therapy for vestibular schwannomas,
and these are reviewed here.
In 1998, Pollock and colleagues2 described 13 patients who underwent microsur-
gery at a median time of 27 months after they had undergone radiosurgery. This
represents a 2.9% failure rate for their series of gamma knife radiosurgery proce-
dures. Tumor enlargement was the indication in five patients who had stable symp-
toms; tumor enlargement with new or increased symptoms occurred in five patients,
and increased symptoms without evidence of tumor growth occurred in three. Gross
total resection was achieved in seven patients, and a near gross total resection was
achieved in four patients. The authors found the microsurgery was more difficult in 8
of 13 patients, easier in 1, and no different in 4, relative to microsurgery without prior
radiation treatment. All patients had lost hearing as a result of their tumors. Three
patients required VP shunts for progressive symptoms of hydrocephalus despite
the tumor removal. Three patients’ postoperative course required persistent care-
givers. One patient in the series died of metastatic tumor progression following
radiosurgery.
Kwon and colleagues3 reported the results of Korea’s gamma knife unit in 1999.
They reported a 91% control rate of their vestibular schwannomas followed over 6
months with a mean of 55 months. They had seven patients whose tumor increased
significantly in size during the follow-up. Three of these were observed as the patients
had no symptoms. Four patients underwent microsurgical excision, as the tumor was
solid and increased in size. One patient developed brainstem compression, and
despite microsurgery was left in a persistent vegetative state. Three patients devel-
oped multiseptated cysts that caused brainstem compression. Loss of central MRI
enhancement was seen in all three of these tumors despite the cysts. The cysts
were associated with tumors that were larger than 3.0 cm in size before radiation.
The time for microsurgical intervention following radiation was 5, 10, 34, and 64
months. The histopathology of the tumors was typical for routine vestibular schwan-
nomas. The authors stated the facial nerve was preserved in all cases; however,
they noted 50% of the patients had some degree of postoperative facial nerve paral-
ysis. The authors stated, ‘‘all tumors were relatively easy to remove.’’ They further
stated the tumor was avascular and that they had a shorter operating time removing
the previously radiated tumors. They additionally stated the facial nerve was not any
different to dissect than other nonradiated cases. The authors failed to explain why
the facial nerve outcome in these postradiated cases, if it was so easy to remove,
was so significantly poor in 50% of the cases.
In 2000, Battista4 sent a survey to the American Neurotology Society requesting
surgeons experienced with treating vestibular schwannomas to describe their
experience in treating patients microsurgically who previously had undergone
stereotactic radiotherapy. The survey response was 36% and described 12
patients who had tumor resection following stereotactic radiation therapy. The
mean time to microsurgery was 35 months after radiotherapy (range 3 to 72
months). Seven of the 12 tumors were larger than 3.0 cm at the time of microsur-
gery, and four had had prior microsurgical resection before radiation therapy. Nine
of 12 surgeons believed the microsurgery was more difficult than microsurgery
without prior radiation therapy, as no plane was found between the tumor and
the facial nerve. This survey study concluded that microsurgery was more difficult
following radiation therapy.
In 2003, Lee5 reported on the Johns Hopkins (Baltimore, Maryland) experience of
four patients who had undergone previous gamma knife or fractionated stereotactic
712 Slattery
radiotherapy (FRT). Tumor resection was performed by means of the retrosigmoid

approach. Indications for treatment for the four cases included
Facial spasm without tumor growth at 12 months following radiotherapy
Tumor growth with left-sided tongue and oral numbness 2 years after FRT
Progressive facial spasms 2 years after FRT
Facial spasm with tumor growth
Tumor growth varied from 2 to 5 mm from the time of radiation therapy until micro-
surgical resection. The time between radiation and microsurgery was an average of
1.6 years, (range, 1 to 2 years). Intraoperatively, capsular fibrosis was seen with scar-
ring of the tumor capsule in all cases. This made microsurgical dissection of the facial
nerve and other cranial nerves more difficult. Anatomic facial nerve preservation was
achieved in all cases, but it is thought to be more difficult to dissect along the facial
nerve compared with cases without prior radiation therapy. One patient developed
a House-Brackmann (H-B) grade 6 facial paralysis, while the remaining three patients
varied from H-B grade 1 to 2. After microsurgery, the facial spasm resolved in the first
case, but the outcome of facial spasm was not reported in cases three and four. Histo-
logically, elongated bipolar cells were seen in all cases. The tumors were moderately
cellular, but no real findings of radiation were noted.
Iwai and colleagues6 published their results from Japan in 2007 of 265 patients
treated over a 10-year period (1994 to 2004) with gamma knife therapy. They had
seven patients who failed to respond to radiation therapy and who required microsur-
gical removal. Five were performed at Osaka City Hospital in Osaka, Japan, and two
were reported from other institutions. There were five patients who had unilateral
tumors and one patient who had NF2. The size of the tumors at radiation therapy
was an average diameter of 27.5 mm (19.4 to 45.9 mm). The average radiation dose
was 11 Gy (10 to 12.5 Gy). The indications for microsurgery were cerebellar ataxia
with increased intracranial pressure and worsening neurologic status. The mean
interval between microsurgery and radiation therapy was 28 months (4 to 74 months).
The size of the tumor at microsurgery averaged 30.6 mm, with a range of 28.5 to 58.5
mm. All microsurgical procedures were done by means of the retrosigmoid approach.
The authors did not open the internal auditory canal and left tumor on the brainstem;
thus, a subtotal or partial resection was performed in all cases. Findings at the time of
microsurgery included thickening of the arachnoid with increased bleeding relative to
microsurgery without prior radiation therapy. Histopathology findings included normal
tumor cells with foamy macrophages.
In 2008, Shuto and colleagues7 reported their postradiation microsurgical experi-
ence in 12 patients from a total of 559 patients who underwent gamma knife therapy.
These 12 patients had microsurgical removal of the tumor. The time between gamma
knife and microsurgery was 29 months (range, 6.6 to 120 months). Four patients had
undergone previous microsurgery. The median gamma knife dose was 12.3 Gy. The
indications for microsurgical excision included tumor enlargement without deteriora-
tion of symptoms in three patients. Tumor enlargement with new symptoms was
seen in nine patients. All patients had lost hearing by the time they underwent micro-
surgical excision. The microsurgery was performed by means of the suboccipital
approach, and tumor was removed subtotally except around the internal auditory
canal, which was left in place. Adhesion to the brainstem was very severe in seven
patients, and identification of the facial nerve was easy in five patients and difficult
in seven. The surgeons found dissection of the facial nerve difficult because of the
severe adhesions or lack of color change between the facial nerve and the tumor.
Severe adhesions between the trigeminal nerve were observed in two patients. Facial
nerve function was unchanged in 7 of 12 patients, improved in 2, and deteriorated in 3.

The brainstem compression symptoms were improved after tumor removal in all
symptomatic patients. It appeared from the cases presented that debulking the tumor
was the main objective in most of these cases.
The pathology demonstrated typical features of vestibular schwannomas such as
bipolar cells and nuclear palisading. Hyalinization of the tumor vessels was found in
most cases. It was thought the hyalinization was the result of radiation. There were
no malignant changes found in any tumor specimens.
REVIEW OF HOUSE EAR CLINIC MICROSURGICAL EXCISION DATA
The initial House Ear Clinic experience with microsurgery following stereotactic radi-
ation therapy for vestibular schwannomas was published in 1995.8 This report con-
sisted of five cases that had undergone previous radiation therapy—three with
gamma knife and two with proton beam. All five patients had lost all hearing preoper-
atively and had significant facial weakness preoperatively. The symptoms initiating
microsurgery included:
Progressive facial weakness in one patient 12 years after gamma knife therapy
Brainstem compression symptoms in two patients, 8 months and 2 years after
treatment
Increase in tumor size in two patients, 2 and 2.5 years following treatment
All patients had an increase in tumor size during their time of follow-up after radia-
tion before microsurgery. During microsurgery, the normal plane between the facial
nerve and tumor was difficult to determine in three cases and completely lost in the
remaining two. The histopathology examination demonstrated viable tumor cells
consistent with schwannoma. The classic interweaving bundles of spindle-shaped
cells with nuclei palisading was seen. Two tumors had thrombosed blood vessels in
the area of fibrotic necrosis. Viable tumor cells were seen in all five cases. As a result
of this initial study, the microsurgical approach for tumor removal at the House Ear
Clinic has become much more conservative in regards to facial nerve dissection in
patients who previously have undergone radiation therapy.
The most recent published update of the House Ear Clinic experience with micro-
surgical salvage after radiation therapy was published in 2005.9 This is the largest pub-
lished series to date, with 44 patients having undergone microsurgery after previous
irradiation. Six of the 44 patients had previous microsurgery and radiation therapy
before presentation to the House Ear Clinic and therefore were excluded from the
analysis. The remaining 38 patients treated with microsurgery following radiation treat-
ment were compared with a matched random sample of 38 patients who underwent
primary microsurgery alone. The most common type of radiation therapy was gamma
knife, which occurred in 22 patients. LINAC was the second most common type of
radiation, used in nine patients, and proton beam therapy was used in four patients.
The mean time from irradiation to microsurgical treatment was 3.3 years (range 5.2
months to 15.8 years). Tumor growth was the indication for microsurgery in most
patients.
Patients who had undergone radiation therapy were more likely to have moderate-
to-severe adhesions of the tumor to the facial nerve when compared with the nonirra-
diated microsurgical control group. Brainstem adherence also was increased
significantly with the radiation group. Total tumor resection is the goal at the House
Ear Clinic for cases without prior irradiation. Over 97% of microsurgically treated
vestibular schwannoma patients achieved total tumor removal in those cases without
714 Slattery
prior irradiation. In the group with previous irradiation, the number of patients with total
tumor removal has dropped to 79%. This decrease in total tumor removal in previously
irradiated patients represents a change in treatment philosophy at the House Ear
Clinic. This change in approach was because of the earlier microsurgical experience
where severe adhesions of the tumor to the facial nerve were found in the irradiated
patients. The irradiated facial nerve did not recover from microsurgical trauma when
compared with the nonirradiated facial nerve. The facial nerve was lost in a greater
group of previously irradiated microsurgical patients compared with the nonirradiated
group. There were no significant differences in operative complications other than the
adherence to the facial nerve and facial nerve results. Histopathology in this larger
group of published patients again demonstrated signs of typical vestibular
schwannomas.
Since the 2005 report, the author’s experience has increased to include 62 patients
with tumors undergoing microsurgery following radiotherapy. The incidence of
patients who have growing tumors following irradiation is increasing. This probably
represents the larger number of patients who have opted for radiosurgery or radio-
therapy as the initial treatment. The time from radiation to microsurgery averages
approximately 3.1 years. The average size of the tumor is approximately 3.1 cm in
linear direction. Almost all procedures are performed through the translabyrinthine
approach, as the chance of preserving hearing in a patient who has undergone radi-
ation therapy is very poor. In fact, hearing preservation from microsurgery in a previ-
ously irradiated patient has not yet been reported. The author has become less
aggressive at obtaining complete tumor removal because of the significant adhesions
that found between the facial nerve and the tumor. Approximately 87% of patients still
have moderate-to-severe adhesion of the tumor to the facial nerve. This is similar to
the earlier House Ear Clinic study that demonstrated an increased risk with this
group.9 At present, there are not enough data to comment on the long-term outcome
of those patients who have undergone subtotal excision during revision microsurgery
after irradiation.
PATHOLOGY OF TUMORS
The histopathology of tumors following radiation therapy has been very similar to
tumors that have not been radiated. Some authors who have investigated this have
reported tumor fibrosis with loss of the peri-tumor arachnoid plane. There is thickening
of the arachnoid membrane with adjacent scarring. There are changes in the vascu-
larity, with increased scarring of the anterior–inferior cerebellar artery to tumor.
MALIGNANT TRANSFORMATION SURGERY
Malignant vestibular schwannomas may occur sporadically or be induced by radia-

tion.10–12 (More information is available elsewhere in this issue.) Malignant tumors
require more aggressive microsurgery than benign tumors. Usually the tumor plane
with the facial nerve is lost, and sacrifice of the facial nerve is required for total tumor
removal. The planes between the other intracranial components can vary, as some are
very scarred, and others separate from the brainstem much more easily.
SUMMARY
The House Ear Clinic experience with microsurgery after irradiation has demonstrated
that the facial nerve is different once it has been radiated. An irradiated facial nerve’s
regeneration potential is diminished, and the recovery from microsurgical trauma is
not as robust. It is recommended that patients who require microsurgical excision

following radiosurgery or radiotherapy have a subtotal or near total resection per-
formed as opposed to a gross total resection. A gross total resection may be
performed if the facial nerve planes are pristine. If the planes are not pristine, then
near-total resection should be performed with some tumor left on the facial nerve.
The long-term results of these tumor remnants will require further follow-up.
REFERENCES
1. Pollock BE. Management of vestibular schwannomas that enlarge after stereo-

tactic radiosurgery: treatment recommendations based on a 15-year experience.
Neurosurgery 2006;58(2):241–8.
2. Pollock BE, Lunsford LD, Kondziolka D, et al. Vestibular schwannoma manage-
ment: part II—failed radiosurgery and the role of delayed microsurgery. J Neuro-
surg 1998;89:949–55.
3. Kwon Y, Khang SK, Kim CJ, et al. Radiologic and histopathologic changes after
gamma knife radiosurgery for acoustic schwannoma. Stereotact Funct Neurosurg
1999;72(Suppl 1):2–10.
4. Battista RA, Wiet RJ. Stereotactic radiosurgery for acoustic neuromas: survey of
the American Neurotology Society. Am J Otol 2000;21:371–81.
5. Lee DJ, Westra WH, Staecker H, et al. Clinical and histopathologic features of
recurrent vestibular schwannomas (acoustic neuroma) after stereotactic radiosur-
gery. Otol Neurotol 2003;24:650–60.
6. Iwai Y, Yamanaka K, Yamagata K, et al. Surgery after radiosurgery for acoustic
neuromas: Surgical strategy and histological findings. Neurosurgery 2007;60:
75–82.
7. Shuto T, Inomori S, Matsunaga S, et al. Microsurgery for vestibular schwannoma
after gamma knife radiosurgery. Acta Neurochir (Wien) 2008;150(3):229–34.
8. Slattery WH III, Brackmann DE. Results of surgery following stereotactic irradia-
tion for acoustic neuromas. Am J Otol 1995;16:315–21.
9. Friedman RA, Brackmann DE, Hitselberger WE, et al. Surgical salvage after failed
irradiation for vestibular schwannoma. Laryngoscope 2005;115:1827–32.
10. Cahan WG, Woodard HQ, Higinbotham NL, et al. Sarcoma arising in irradiated
bone: report of eleven cases, 1948. Cancer 1998;82:8–34.
11. Hanabusa K, Morikawa A, Murata T, et al. Acoustic neuroma with malignant trans-
formation: case report. J Neurosurg 2001;95:518–21.
12. Shin M, Ueki K, Kurita H, et al. Malignant transformation of a vestibular schwan-
noma after gamma knife radiosurgery. Lancet 2002;360:309–10.
Ne oplastic
Tra ns formation
Af ter Radiosurger y
or Radiotherapy :
Risk a nd Realities
Ajay Niranjan, MBBS, MCha,c,*, Douglas Kondziolka, MDa,b,c,
L. Dade Lunsford, MDa,b,c
KEYWORDS
Malignant transformation Radiation-induced tumor
Radiosurgery Radiation therapy Gamma Knife
The risk of a radiation-induced tumor is a controversial topic. Patients who undergo

radiosurgery or fractionated radiation therapy may be at an increased risk for develop-
ment of a second tumor. The role of concomitant environmental and genetic risk
factors is not known.1 Radiation-induced oncogenesis is a special a concern when
radiation is used to manage benign tumors where prolonged survival is expected.2
Typically, radiation-induced tumors occur several years after radiation exposure.
The concept of radiation oncogenesis was established in 1948 by Cahan and
colleagues,3 who observed 11 patients who had sarcomas that developed after radio-
therapy was administered for bone tumors and breast cancer. They outlined the
following criteria that must be met for a tumor to be designated as a radiation-induced
tumor:
A certain latency interval is required between delivery of the radiation and tumor
development.
The new tumor must arise in the irradiated region.
The new tumor must be histologically distinct from the original irradiated tumor.
There must be imaging evidence that the second tumor was not present at the time
of irradiation.
The patient must not have a genetic predisposition for developing cancer.
a
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA
b
Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA
c
The Center for Image-Guided Neurosurgery, University of Pittsburgh Medical Center,
Pittsburgh, PA 15213, USA
* Corresponding author. Suite B-400, University of Pittsburgh Medical Center Presbyterian, 200
Lothrop Street, Pittsburgh, PA 15213.
E-mail address: niranjana@upmc.edu (A. Niranjan).

718 Niranjan et al
SECOND TUMOR AFTER FRACTIONATED RADIATION THERAPY
Several large studies have documented an increased incidence of a second tumor in

the body after radiation therapy. Brenner and colleagues4 reported data from the
National Cancer Institute’s Surveillance Epidemiology and End Result (SEER)
program, which contained information on 51,584 men who had prostate cancer
treated by radiotherapy and 70,539 treated by surgery. The risk of a second tumor
was found to be higher by about 6% in the radiotherapy group. Boice and colleagues5
studied the risk of a second malignancy in various organs in 150,000 patients who had
carcinoma of uterine cervix treated with either surgery or radiotherapy. The overall
conclusion of this study was that an increased cancer risk was associated with radi-
ation therapy compared with surgery. Bhatia and colleagues6 reported that 17 of 483
women treated with radiation for Hodgkin’s disease later developed breast cancer.
There is evidence establishing radiation as a carcinogen in animal and human
studies.3,7–13 Since Cahan’s publication, radiation-induced neoplasms affecting the
central nervous system (CNS) after fractionated radiotherapy have been documented.
The risk of developing a radiation-induced tumor after fractionated radiation therapy to
the CNS is estimated to be 1% to 3%.7,10,14 Most of these tumors are meningiomas,
but gliomas, sarcomas, and schwannomas have been reported.7,8,10,12–16 The term
‘‘radiation-induced,’’ however, seems inappropriate, because it implies that there is
definitive evidence at a molecular level that radiation was the causative factor. Such
information has not been reported definitely.17 Perhaps ‘‘radiation-associated’’ may
be a better term.
Published data on the risks of oncogenesis after fractionated radiotherapy delivered
to the brain suggests that even very low doses (less than 2 Gy) have been associated
with development of a second tumor. Between 1948 and 1960, 10,834 children in
Israel received scalp irradiation to induce alopecia as part of the management of tinea
capitis.10 Mean doses to the brain in these children were estimated to be 1.5 Gy for the
entire cohort. The relative risk of tumor formation at 30 years compared with the
general population was 18.8 for schwannomas, 9.5 for meningiomas, and 2.6 for
gliomas. A clear-cut dose–response effect was observed, with the relative risk
approaching 20 after doses of approximately 2.5 Gy. The mean latency interval was
histology-dependent. In this study, the mean latency interval was 21 years for menin-
giomas, 15 years for schwannomas, and 14 years for gliomas.
In a study of radiation-associated second tumors, Sadetzki and colleagues18
described 253 patients who developed meningiomas after radiation for tinea capitis.
The mean time from exposure to meningioma diagnosis was 36 years (range 12 to
49 years). The authors found a higher incidence of multiple lesions, a younger age
at diagnosis, and a higher percentage of calvarial lesions in this group of patients
compared with those who developed meningiomas without previous exposure to
ionizing radiation. Dalton and colleagues19 reported on 1597 children who were
treated with or without 28 Gy of prophylactic whole-brain irradiation as part of
management for acute lymphoblastic leukemia. Thirteen second tumors were
reported in this group, with a median follow-up period of 7.6 years. Five second
tumors were in the CNS (four astrocytomas and one meningioma). The median latency
interval for astrocytoma development was 9 years compared with 16.6 years for
meningioma detection. Among the irradiated children, there was a 0.085 incidence
per 100 patient years of developing second tumors compared with 0 incidence for
those not receiving cranial irradiation.
Brada and colleagues20 reported the risk of second brain tumor formation in 334
patients treated for pituitary tumors with surgery and fractionated small-field
Risk and Realities 719
irradiation therapy using 45 Gy. Five patients developed second tumors (two astrocy-
tomas, two meningiomas, and one meningeal sarcoma) in long-term follow-up. The
latency period for the second tumor was 6 to 21 years, with malignant tumors devel-
oping earlier than benign tumors. The cumulative risk of developing second brain
tumors was 1.3% at 10 years and 1.9% at 20 years. The relative risk of a second brain
tumor was 9.38 compared with the normal population. In these patients, the irradiated
volumes were typically small. On the basis of this experience, it seems that the relative
risk of second tumor formation is substantially less than that seen in patients treated
with larger-volume radiation. Balasubramaniam and colleagues21 reported a radia-
tion-associated glioblastoma multiforme (GBM) in the temporal lobe 5 years after
stereotactic fractionated radiation therapy (25 fractions) for a vestibular schwannoma.
The area where the GBM developed had received between 1.45 to 6.94 Gy.
SECOND BRAIN TUMORS AFTER RADIOSURGERY
Physicians have speculated for years that second tumor formation would be a risk for
patients after radiosurgery. It also was thought, however, that the risk would be quite
low, for the following reasons:
The irradiated volume is very small compared with traditional radiotherapy
techniques.
The high single doses of radiation given to the target volume during radiosurgery
would lead to cytotoxicity and not mutagenicity, which is required for tumor
formation.
Volumes and doses of radiation along the entrance and exit pathways in radiosur-
gery are so small that the likelihood of second tumors would be less.22
Nonetheless, there have been case reports of second tumor detection after radio-
surgery. Currently, the number of patients worldwide who have received radiosurgery
is now likely in excess of 500,000. Reported cases of a second tumor after radiosur-
gery can be grouped under the following three categories.
Radiosurgery-Associated Malignant Tumors

At present, five case reports (Table 1) of new malignant tumors after radiosurgery
meet Cahan’ criteria for radiation-induced neoplasm.23–27 Each of these cases is
summarized. The new malignant tumors were discovered from 5.3 to 9 years after
radiosurgery. Each of the secondary tumors were high-grade gliomas.
Case report 1
A 63-year-old woman underwent gamma knife radiosurgery for an imaging-defined
meningioma.27 She received 20 Gy to the tumor margin, with a maximal dose of 40
Gy. Two years later, she underwent tumor resection because of persistent neurolog-
ical symptoms and edema. The final pathological finding was a benign meningioma
with adjacent radiation necrosis. Seven years after radiosurgery and 5 years after
microsurgical resection, she was found to have an enhancing lesion in her left occipital
lobe. Surgical resection revealed a GBM. It was estimated that the site at which the
GBM originated had received 5 to 10 Gy at the time of radiosurgery 7 years earlier.
Case report 2
A 57-year-old woman underwent gamma knife radiosurgery for a left-sided vestibular
schwannoma.26 She was treated with 11 Gy to margin of an 8.6-cm3 tumor. Six-month
follow-up MRI showed cystic degeneration of the lesion with mass effect on the brain-
stem. The patient underwent microsurgical resection. Pathological study
720
Niranjan et al
Table 1
Radiosurgery-associated malignant tumors
Author,Year Patient Age/Sex Original Diagnosis Margin Dose Postradiosurgery Management Duration New Tumor
Yu, 200027 63/F Meningioma 20 Gy Resection 2 years later 7 years GBM
Shamisa, 200126 57/F Vestibular Schwannoma 11 Gy Resection 6 months later 7.5 years GBM
Kaido, 200124 14/M Arteriovenous malformation 20 Gy None 6 years GBM
McIver, 200425 43.F Malignant Melanoma Metastases 15 Gy Whole-brain radiation therapy 5.25 years Anaplastic astrocytoma
Berman, 200723 34/F Arteriovenous malformation 15 Gy None 9 years GBM
Abbreviations: Duration, time between original treatment and diagnosis of malignant tumor; GBM, glioblastoma multiforme.
demonstrated a benign schwannoma. Seven and one-half years later, she presented
with progressive headaches, confusion, and left hemiparesis. She was found to have
a large cystic, enhancing lesion in the left temporal lobe. Microsurgery was performed.
Histology showed a GBM. The site at which the second tumor arose had received 4 Gy
(14% of the maximum dose of 27.5 Gy) at the time of the radiosurgical treatment 7.5
years earlier.
Case report 3
A 14-year-old boy underwent gamma knife radiosurgery for a right parietal arteriove-
nous malformation (AVM).24 He received 20 Gy to the tumor margin and 40 Gy
maximum dose. Two years after radiosurgery, angiography confirmed that the AVM
had been obliterated. The patient developed headaches and vomiting 6 years after ra-
diosurgery and was found to have a new lesion in the previous area of radiosurgery.
Surgery was performed, and a GBM was discovered. The tumor seemed to arise
within the full-dose region of his AVM radiosurgical treatment.
Case report 4
A 43-year-old woman underwent radiosurgery for three brain metastases from malig-
nant melanoma.25 Following radiosurgery, she underwent whole-brain radiotherapy
(37.5 Gy). Twenty-two months later, a second radiosurgical procedure was performed
for a recurrent right temporal lobe metastasis. Five years and 4 months after initial ra-
diosurgery, the patient was diagnosed with a cerebellar anaplastic astrocytoma. The
area of cerebellum where the glioma developed had received a maximum dose of 7.7
Gy and 1.5 Gy during the previous two radiosurgery procedures, respectively. The
additional role of fractionated radiation therapy in the development of astrocytoma
is not clear.
Case report 5
A 34-year-old woman underwent embolization followed by radiosurgery for a 4.5 3.0
cm 3.0 cm AVM located in the pineal region.23 A margin dose of 15 Gy at 70%
isodose line was delivered using linear accelerator linear accelerator (LINAC) radiosur-
gery. The patient was lost to follow-up after treatment until she presented with
a change in mental status, nausea, headaches, and a generalized seizure 9 years later.
MRI demonstrated a 55 mm 45 mm enhancing, heterogenous mass in the splenium
of the corpus callosum. Maximal debulking was performed. Pathological examination
demonstrated an infiltrating glial neoplasm consistent with a GBM.
Radiosurgery-Associated Benign Tumors

Only four cases of new benign tumors after radiosurgery are reported (Table 2) in the
literature that meet Cahan’s criteria for radiation-induced neoplasms.17,28
Case report 1
A 41-year-old man was diagnosed with acromegaly associated with a pituitary macro-
adenoma.17 After trans-sphenoidal surgery, he underwent non-Bragg peak proton ra-
diosurgery in Moscow, receiving 87 Gy by means of 25 separate 10 mm beams. The
beams were centered on the sella, where the prescription dose was delivered. Sixteen
years after radiosurgery, he was evaluated for decreased vision, and repeat MRI
confirmed a Tuberculum sellae meningioma. Partial resection of a benign meningioma
was performed. The lesion was at the immediate periphery of the previous full-dose
irradiated volume. The site at which the tumor arose was estimated to have received
30% to 50% of the prescribed radiation dose.
722 Niranjan et al
Table 2
Radiosurgery-associated benign tumors
Author, Patient Original

Year Age/Sex Diagnosis Margin Dose Duration New Tumor
Loeffler 41/male Growth hormone- 87 Gy via 25 16 years Tuberculum sellae
200317 secreting separate beams meningioma
pituitary using non-Bragg
adenoma peak proton
radiosurgery
Loeffler 53/male Growth hormone- 104 Gy via 12 fields 19 years Vestibular
200317 secreting using Bragg schwannoma
pituitary peak proton
adenoma radiosurgery
Sheehan 7/male Arteriovenous 20 Gy using 12 years Meningioma
200728 malformation gamma knife
Sheehan 12/ Arteriovenous 25 Gy using 10 years Meningioma
200728 female malformation gamma knife
Abbreviation: Duration, time between original treatment and diagnosis of malignant tumor.
Case report 2
A 53-year-old man underwent resection of a pituitary adenoma associated with
acromegaly.17 Bragg peak proton radiosurgery followed. He received a peak dose
of 104 Gy by means of 12 separate fields. Nineteen years later, MRI disclosed a left
vestibular schwannoma. The second tumor site had received 4.4 Gy during proton ra-
diosurgery. A CT scan performed in 1979 showed no evidence of a soft tissue mass
within the posterior fossa or any widening of the internal auditory canal. Although
this case meets the criteria for a radiation-associated second tumor, one might argue
that if an MRI scan had been performed in 1979, a small intracanicular schwannoma
might have been detected.
Case report 3
A seven-year-old boy underwent gamma knife radiosurgery in May of 1990 using
a margin dose of 15 Gy (maximum dose of 30 Gy) to treat a right basal ganglia
arteriovenous malformation.28 He underwent a second radiosurgery for persistent
nidus in 1995 with a margin dose of 20 G (maximum, 40 Gy). Follow-up MRI in 2002
showed a small dural-based tumor consistent with meningioma. This area received
0.6 Gy and 0.25 Gy during first and second radiosurgery procedures.
Case report 4
A 12-year-old girl underwent gamma knife radiosurgery in November of 1992 using
a margin dose of 25 Gy (maximum dose of 28 Gy) to treat a 1.2 cc right temporal
arteriovenous malformation.28 She underwent a second radiosurgery for persistent
nidus in 1995 with a margin dose of 20 G (maximum, 40 Gy). Follow-up MRI 10 years
after radiosurgery showed a mass consistent with meningioma in the previously
treated area, which had received 25 Gy.
Radiosurgery-Associated Tumor Dedifferentiation

Spontaneous malignant transformation of tumors has been described in the literature,
especially for glioma. There have been few case reports of malignant transformation
after radiosurgery, but such transformation is considered tumor dedifferentiation and

does not meet Cahan’s criteria for a radiation-induced tumor. These tumors differ from
radiation-associated tumors in that the tumor was not induced by radiation but rather
showed evidence of malignant progression that involves the cellular evolution of
a benign lesion to malignancy (Table 3). Kubo and colleagues29 in their report
contended that detailed histology prior to radiosurgery is essential, as biologically
aggressive schwannomas are encountered in 0.14% of cases. These tumors exhibit
local invasiveness, frequent recurrences, and systemic dissemination. If not identified
before radiosurgery, an erroneous diagnosis of radiation-associated malignancy can
be made easily.
Of the 11 reported cases (see Table 3; Table 4) of tumor dedifferentiation, prior
histology was available only in five. On the other hand, even if the tumor exhibits unam-
biguous histological proof of a benign pattern, its malignant progression after radio-
surgery is not caused by irradiation necessarily. In fact, after incomplete surgical
resection, radiosurgery frequently is used only if residual neoplasm shows radiologi-
cally confirmed regrowth. By itself, however, tumor growth after prior resection may
result in malignant transformation of the initially benign tumor, either spontaneous,
or even induced by microsurgery. Hanabusa and collegues30 reported on a patient
who had tumor recurrence 4 years after initial microsurgical resection for a vestibular
schwannoma (pathologically proven from the first operation). The patient underwent
radiosurgery for the recurrence. Six months later, a second microsurgical resection
was performed. At reoperation, the tumor was found to be a malignant schwanno-
ma.30 Whether the malignant transformation occurred because of radiosurgery or
was a result the natural history of malignant phenotype change is unclear. It is
common for a surgeon to resect a benign meningioma, only to find at a second resec-
tion for recurrence that the tumor is now atypical or even malignant.
The histological diagnosis of radiation-induced malignant transformation may
represent a significant challenge. In some reports, the aggressive locus was histolog-
ically identifiable against a background of the benign tumor.31 In other reports, the
entire recurrent tumor exhibited a malignant pattern.30,32,33 In the absence of specific
clinical and histological criteria for identifying the irradiation-induced malignant trans-
formation of the initially benign intracranial neoplasm, the pretreatment evaluation of
the tumor proliferative potential seems to be extremely important.
RISK OF RADIOSURGERY-ASSOCIATED TUMORS
Prediction of the relative risk of radiation-associated second tumors in patients under-

going radiosurgery is a challenging task. It is impossible to make an accurate assess-
ment of the magnitude of radiosurgery-associated tumors because of lack of
systematic long term follow-up of all cases and lack of knowledge of total number
of cases treated with radiosurgery. Approximately 80,000 patients in the United States
were treated with gamma knife radiosurgery for AVMs, benign tumors, and functional
disorders up to 1996 (to allow 12 years of follow-up). It is this population that forms the
large denominator of treated patients that will be needed to accurately estimate the
risk of radiation-associated carcinogenesis.
A recent study of patients followed for up to 19 years after radiosurgery found no
increased risk of malignancies when compared with national mortality and cancer
registries.34 An accurate estimation of the probability that individual patients have of
developing delayed tumors is the most critical issue left to be determined in radiosur-
gery. Information from the studies on scalp irradiation for tinea capitis may be extrap-
olated to provide an estimate of this risk.10,18 These articles showed that tissue
724
Niranjan et al
Table 3
Radiosurgery-associated tumor dedifferentiation for sporadic vestibular schwannoma
Author, Year Patient Age/Sex CP Angle Tumor Histology Margin Dose Duration Final Histology
Comey, 199831 50/male Sporadic No 14.4 Gy 5 years Triton tumor
Harada, 200340 7/male Sporadic VS RT 27 Gy 2 years Malignant schwannoma
Wilkinson, 200441 53/male Sporadic VS RT 7 years Malignant schwannoma
Hanabusa, 200130 51/female Sporadic VS 15 Gy 6 months Malignant schwannoma
Shin, 200232 26/female Sporadic VS 17 Gy 6 years Malignant schwannoma
Kubo et al, 200429 51/male Sporadic VS 14 Gy 8 months Malignant schwannoma
Abbreviations: Duration, time between original treatment and diagnosis of malignant tumor (all cases were treated with gamma knife radiosurgery unless other-
wise noted); RT, fractionated radiation therapy; VS, vestibular schwannoma.
Table 4
Radiation therapy-associated tumor dedifferentiation for neurofibromatosis type 2 (NF2)
Patient Cerebello-Pontine Margin Final

AuthorYear Age/Sex AngleTumor Histology Dose Duration Histology
Noren, 18/female NF2 No 20 Gy 5 years Triton tumor
199842
Bari, 200243 28/female NF2 No 15 Gy 3.5 years Malignant
schwannoma
Thomsen, 19/female NF2 No 12 Gy 6 years Meningosarcoma
200033
McEvoy, 22/male NF2 No 15 Gy 2 years Not known
200344
Ho, 200245 14/female NF2 No RT 18 Gy 7 months Death
All cases were treated with Gamma Knife radiosurgery unless otherwise noted.
Abbreviations: Duration, time between original treatment and diagnosis of malignant tumor;
NF2, neurofibromatosis type 2.
receiving doses as low as 1 Gy are at increased risk for the development of second
tumors. Phantom studies based on the technique of irradiation used demonstrated
that tissues up to 2 cm from the scalp were exposed to this level of radiation. Thus,
the volume of tissue at risk was approximately 900 cm3. By comparison, the total
volume of adjacent tissue receiving 1 Gy or more during radiosurgery for a 1.5 cm
vestibular schwannoma is approximately 120 cm3. Consequently, the tissue volume
at risk for later tumor formation after radiosurgery is less than 15% of the volume
irradiated for tinea capitis. Because the 30-year cumulative risk of radiation-induced
tumors after scalp irradiation was 0.8%, it can be predicted that the long-term risk
after radiosurgery should be approximately 1 in 1000.
Many argue that the numerator (five malignant and four benign radiation-associated
tumors reported) may not be reflective of the overall number of radiation-associated
tumors because of under-reporting or failure to recognize this complication. Still,
the incidence must be relatively low when one considers a denominator of more
than 80,000 patients treated with radiosurgery worldwide up to 1996. Although it
will require 10 to 20 years of open-ended follow-up to determine the actual risk of
second tumor formation as a result of radiosurgery, enough information is available
to state that the relative risk is very low (1 in 1000 to 1 in 20,000 patients).
MECHANISM OF RADIATION-ASSOCIATED CARCINOGENESIS
The mechanism of radiation-associated carcinogenesis is multifaceted and not under-

stood well. Radiation modulates various interdependent factors such as cell growth,
apoptosis, mutations, repair, and genetic instability. Radiation-induced oncogenesis
is thought to be secondary to sublethal nuclear damage of a tumor suppressor
gene or a proto-oncogene, which is unable to be repaired. Subsequent acquired
environmental carcinogens then can produce oncogenesis. The time to acquire the
subsequent genetic defects is expressed as the latency between initial radiation expo-
sure and carcinogenesis. This hypothesis is supported by the long-term follow-up
study published by Rowe and colleagues,35 in which only one new primary intracranial
tumor was reported among 4877 patients treated by radiosurgery. The age-matched
population would have expected 2.47 cases.
The efficiency of tumor induction varies inversely with repair capacity, which in turn
depends on the integrity of cell cycle checkpoints.36 The general form of the dose-
726 Niranjan et al
response curve for radiation-associated second tumors is not clear, but several exper-
iments on small animals suggest that the incidence increases with dose up to a maximum
usually occurring between 3 and 10 Gy (delivered in a single dose), followed by a subse-
quent decrease. Clinical evidence supports this biphasic relationship.37 There are also
studies reporting that the highest incidence of radiation-associated second tumors
occurs at field peripheries, where the dose is less than at the field center.36
There are no radiographic or histopathological features to differentiate between
spontaneous and radiation-induced gliomas. It has been postulated that radiation
may result in genetic alterations that differ from those seen in spontaneous tumors.
Genetic alterations that have been described include a three-base pair homozygous
deletion in exon 7 of the p53 gene,38 activating K-ras mutations,39 epidermal growth
factor receptor amplification, p16 deletions, pentaerythritol tetranitrate mutations,
and p53 mutations.
There is also growing evidence that second tumors are more likely after combined
modality treatment (radiation and chemotherapy), which is increasingly common. The
risk of radiation-associated cancer varies considerably with age at the time of irradi-
ation. In some cases, younger patients may be especially vulnerable because of
a developmental window of opportunity for second tumor development.17
LESSONS LEARNED
Lessons learned include:

Radiation-associated tumors can occur within the full-dose region and in very
low-dose peripheral regions.
The risk is substantially lower with radiosurgery than that seen in patients treated
with larger-volume radiation.
The latency period after radiosurgery is similar to what has been seen with fraction-
ated therapy in the 6- to 20-year range, and malignant tumors occur earlier than
their benign tumor counterparts.
Long-term follow-up should be obtained for all patients who undergo radiosurgery
for benign brain lesions.
The current practice standards for radiosurgery should not be modified because of
this very low risk of radiation-associated tumors.
FINAL THOUGHTS ON RADIOSURGERY OR RADIOTHERAPY FOR BENIGN TUMORS
In recent years there has been a dramatic increase in the number of patients selecting
radiosurgery or radiotherapy as preferred management for benign tumors. Full disclo-
sure of the risks and consequences of radiation and surgery is of paramount impor-
tance in truly providing informed consent. All patients should be informed about the
risk of radiation-associated tumors. They also should be aware that this risk remains
significantly lower than that associated with the potential mortality after craniotomy
and tumor resection (ie, from pulmonary embolus, myocardial infarction, meningitis,
or some other adverse event). At the authors’ institution, all patients who undergo
radiosurgery or radiation therapy with curative intent are informed about the risk for
developing a second tumor. Radiosurgery patients are told that this risk can occur
5 to 30 years after the procedure. The authors estimate this risk to be low, less than
1 in 1000, which is less than 10% of the risk for fractionated large-field irradiation.
Currently, the authors have not seen such a case in their practice, which extends to
over 9000 radiosurgery cases. Patients must weigh all of these factors as they
make educated decisions regarding their care.
REFERENCES
1. Hall EJ. Radiation carcinogenesis. Philadelphia: Lippincott Williams & Wilkins;

2000.
2. Heros RC, Korosue K. Radiation treatment of cerebral arteriovenous malforma-
tions. N Engl J Med 1990;323:127–9.
3. Cahan WG, Woodard HQ, Higinbotham NL, et al. Sarcoma arising in irradiated
bone: report of eleven cases. Cancer 1948;82:8–34.
4. Brenner DJ, Curtis RE, Hall EJ, et al. Second malignancies in prostate carcinoma
patients after radiotherapy compared with surgery. Cancer 2000;88:398–406.
5. Boice JD Jr, Engholm G, Kleinerman RA, et al. Radiation dose and second cancer
risk in patients treated for cancer of the cervix. Radiat Res 1988;116:3–55.
6. Bhatia S, Robison LL, Oberlin O, et al. Breast cancer and other second
neoplasms after childhood Hodgkin’s disease. N Engl J Med 1996;334:745–51.
7. al-Mefty O, Kersh JE, Routh A, et al. The long-term side effects of radiation
therapy for benign brain tumors in adults. J Neurosurg 1990;73:502–12.
8. Liwnicz BH, Berger TS, Liwnicz RG, et al. Radiation-associated gliomas: a report
of four cases and analysis of postradiation tumors of the central nervous system.
Neurosurgery 1985;17:436–45.
9. Modan B, Baidatz D, Mart H, et al. Radiation-induced head and neck tumours.
Lancet 1974;1:277–9.
10. Ron E, Modan B, Boice JD Jr, et al. Tumors of the brain and nervous system after
radiotherapy in childhood. N Engl J Med 1988;319:1033–9.
11. Salvati M, Artico M, Caruso R, et al. A report on radiation-induced gliomas.
Cancer 1991;67:392–7.
12. Shapiro S, Mealey J Jr, Sartorius C. Radiation-induced intracranial malignant
gliomas. J Neurosurg 1989;71:77–82.
13. Simmons NE, Laws ER Jr. Glioma occurrence after sellar irradiation: case report
and review. Neurosurgery 1998;42:172–8.
14. Tsang RW, Laperriere NJ, Simpson WJ, et al. Glioma arising after radiation
therapy for pituitary adenoma. A report of four patients and estimation of risk.
Cancer 1993;72:2227–33.
15. Sznajder L, Abrahams C, Parry DM, et al. Multiple schwannomas and meningi-
omas associated with irradiation in childhood. Arch Intern Med 1996;156:1873–8.
16. Dweik A, Maheut-Lourmiere J, Lioret E, et al. Radiation-induced meningioma.
Childs Nerv Syst 1995;11:661–3.
17. Loeffler JS, Niemierko A, Chapman PH. Second tumors after radiosurgery: tip of
the iceberg or a bump in the road? Neurosurgery 2003;52:1436–40 [discussion:
1440–432].
18. Sadetzki S, Flint-Richter P, Ben-Tal T, et al. Radiation-induced meningioma:
a descriptive study of 253 cases. J Neurosurg 2002;97:1078–82.
19. Kimball Dalton VM, Gelber RD, Li F, et al. Second malignancies in patients treated
for childhood acute lymphoblastic leukemia. J Clin Oncol 1998;16:2848–53.
20. Brada M, Ford D, Ashley S, et al. Risk of second brain tumour after conservative
surgery and radiotherapy for pituitary adenoma. BMJ 1992;304:1343–6.
21. Balasubramaniam A, Shannon P, Hodaie M, et al. Glioblastoma multiforme after
stereotactic radiotherapy for acoustic neuroma: case report and review of the
literature. Neuro Oncol 2007;9:447–53.
22. Larson DA, Flickinger JC, Loeffler JS. The radiobiology of radiosurgery. Int
J Radiat Oncol Biol Phys 1993;25:557–61.
728 Niranjan et al
23. Berman EL, Eade TN, Brown D, et al. Radiation-induced tumor after stereotactic
radiosurgery for an arteriovenous malformation: case report. Neurosurgery 2007;
61:E1099 [discussion: E1099].
24. Kaido T, Hoshida T, Uranishi R, et al. Radiosurgery-induced brain tumor. Case
report. J Neurosurg 2001;95:710–3.
25. McIver JI, Pollock BE. Radiation-induced tumor after stereotactic radiosurgery
and whole-brain radiotherapy: case report and literature review. J Neurooncol
2004;66:301–5.
26. Shamisa A, Bance M, Nag S, et al. Glioblastoma multiforme occurring in a patient
treated with gamma knife surgery. Case report and review of the literature.
J Neurosurg 2001;94:816–21.
27. Yu JS, Yong WH, Wilson D, et al. Glioblastoma induction after radiosurgery for
meningioma. Lancet 2000;356:1576–7.
28. Sheehan J, Yen CP, Steiner L. Gamma knife surgery-induced meningioma.
Report of two cases and review of the literature. J Neurosurg 2006;105:325–9.
29. Kubo O, Chernov M, Izawa M, et al. Malignant progression of benign brain
tumors after gamma knife radiosurgery: is it really caused by irradiation? Minim
Invasive Neurosurg 2005;48:334–9.
30. Hanabusa K, Morikawa A, Murata T, et al. Acoustic neuroma with malignant
transformation. Case report. J Neurosurg 2001;95:518–21.
31. Comey CH, McLaughlin MR, Jho HD, et al. Death from a malignant cerebellopon-
tine angle triton tumor despite stereotactic radiosurgery. Case report. J Neuro-
surg 1998;89:653–8.
32. Shin M, Ueki K, Kurita H, et al. Malignant transformation of a vestibular schwan-
noma after gamma knife radiosurgery. Lancet 2002;360:309–10.
33. Thomsen J, Mirz F, Wetke R, et al. Intracranial sarcoma in a patient with
neurofibromatosis type 2 treated with gamma knife radiosurgery for vestibular
schwannoma. Am J Otol 2000;21:364–70.
34. Rowe J, Grainger A, Walton L, et al. Risk of malignancy after gamma knife stereo-
tactic radiosurgery. Neurosurgery 2007;60:60–5 [discussion: 65–6].
35. Rowe J, Grainger A, Walton L, et al. Safety of radiosurgery applied to conditions
with abnormal tumor suppressor genes. Neurosurgery 2007;60:860–4 [discus-
sion: 860–64].
36. Epstein R, Hanham I, Dale R. Radiotherapy-induced second cancers: are we
doing enough to protect young patients? Eur J Cancer 1997;33:526–30.
37. Boice JD Jr, Land CE, Shore RE, et al. Risk of breast cancer following low-dose
radiation exposure. Radiology 1979;131:589–97.
38. Tada M, Sawamura Y, Abe H, et al. Homozygous p53 gene mutation in a radia-
tion-induced glioblastoma 10 years after treatment for an intracranial germ cell
tumor: case report. Neurosurgery 1997;40:393–6.
39. Brustle O, Ohgaki H, Schmitt HP, et al. Primitive neuroectodermal tumors after
prophylactic central nervous system irradiation in children. Association with an
activated K-ras gene. Cancer 1992;69:2385–92.
40. Harada K, Nishizaki T, Adachi N, et al. Pediatric acoustic schwannoma showing
rapid regrowth with high proliferative activity. Childs Nerv Syst 2000;16:134–7.
41. Wilkinson JS, Reid H, Armstrong GR. Malignant transformation of a recurrent
vestibular schwannoma. J Clin Pathol 2004;57:109–10.
ular schwannomas. Stereotact Funct Neurosurg 1998;70(Suppl 1):65–73.
43. Bari ME, Forster DM, Kemeny AA, et al. Malignancy in a vestibular schwannoma.
Report of a case with central neurofibromatosis, treated by both stereotactic
radiosurgery and surgical excision, with a review of the literature. Br J Neurosurg

2002;16:284–9.
44. McEvoy AW, Kitchen ND. Rapid enlargement of a vestibular schwannoma
following gamma knife treatment. Minim Invasive Neurosurg 2003;46:254–6.
45. Ho SY, Kveton JF. Rapid growth of acoustic neuromas after stereotactic
radiotherapy in type 2 neurofibromatosis. Ear Nose Throat J 2002;81:831–3.

OCNA Sept 2009 Radiosurgery and Radiotherapy For Benign Skull Base Tumors

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Radiosurgery and Radiotherapy for Benign Skull Base Tumors

The History of Stereotactic Radiosurgery and Radiotherapy 593

Basic Principles of Radiobiology Applied to Radiosurgery and Radiotherapy

Radiation Effects on the Auditory and Vestibular Systems 623

Gama Knife Radiosurgery for Vestibular Schwannoma 635

Stereotactic Radiotherapy for Vestibular Schwannoma 655

Cyberknife Radiotherapy for Vestibular Schwannoma 665

Stereotactic Radiosurgery and Stereotactic Radiotherapy in the Treatment

Radiosurgery for Glomus Jugulare Tumors 689

Microsurgery After Radiosurgery or Radiotherapy for Vestibular Schwannomas 707

Neoplastic Transformation After Radiosurgery or Radiotherapy: Risk and Realities 717

Otolaryngol Clin N Am 42 (2009) xiii–xiv

Finally, a note regarding terminology used throughout the book:

FO RTHCOM I NG ISSUES RECENT ISSUES

Neuroimaging Clinics, May 2009

THE C LI N ICS ARE NOW AVA I L ABLE ONL I NE!

Otolaryngol Clin N Am 42 (2009) e1

Stereotactic radiosurgery evolved from the pioneering work reported in 1908 by

Otolaryngol Clin N Am 42 (2009) 593–599

1940s. The medical community and patients have a well-founded combination of

TYPES OF IONIZING RADIATION

Otolaryngol Clin N Am 42 (2009) 601–621

BASIC PRINCIPLES OF RADIOBIOLOGY

Depth Dose Distribution in Water

Mammalian Cell Survival Curves

where SF is the fraction of cells surviving a dose, D, of radiation expressed in Gy.5 a is

Radiobiology of Fractionated Radiotherapy

where F is a fractionation factor

A Total Dose Required to Acheive BED B Relative BED of Fractionated vs Single-

Application of the Linear-Quadratic Equation to Benign Brain Tumors

by setting BED1 5 BED2, the unknown a/b is calculated as follows

Acoustic Neuroma Local Control

decision to fractionate or use single-dose radiosurgery for vestibular schwannomas is

Time Interval Required for Maximal Repair Between Fractions

Model Predicting Tumor Control Probability Based on Cell Survival

Probability of Tumor Cure

NORMAL TISSUE TOLERANCES

D1 =D2 5 ða=b1d2 Þ=ða=b1d1 Þ

Dose constraint is a maximum unless otherwise specified.

Structure Single Fraction Dose Constraint Reference #

Dose constraint is a maximum unless otherwise specified.

Neuret 5 D N0:44 T0:06

the risk of radionecrosis. With standard fractionated whole-brain radiotherapy, they

ED 5 DðcGyÞ N0:377 T0:058

in 25 fractions were described as safe. Similar regimens retrospectively evaluated by

Optic ret 5 D N0:53

Extraocular Nerves (Cranial Nerves III, IV & VI)

Trigeminal (Cranial Nerve V)

Facial Nerve (Cranial Nerve VII)

Cranial Nerve VIII

symptoms of vertigo or gait ataxia persisted in less than 5% of subjects regardless of

Cranial Nerves IX to XII

79. Massager N, Nissim O, Delbrouck C, et al. Role of intracanalicular volumetric

A comprehensive discussion of the tissue effects of radiation is beyond the scope of

Otolaryngol Clin N Am 42 (2009) 623–634

effect. The Compton mass attenuation coefficient is independent of the atomic

RADIATION AND THE EAR

The entire auditory-vestibular system is vulnerable to RT injury. Nearly half of all

Measurement or scoring of ototoxicity after fractionated RT for head and neck

Grade 1 Grade 2 Grade 3 Grade 4

Grade 1 Grade 2 Grade 3 Grade 4

RADIATION THERAPY FOR VESTIBULAR SCHWANNOMA