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Evidence-Based Review of the Role of Radiosurgery for Brain Metastasis

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 Int. J. Radiation Oncology Biol. Phys., Vol. 63, No. 1, pp. 37– 46, 2005
Copyright © 2005 American Society for Therapeutic Radiology and Oncology. Published by Elsevier Inc.
Printed in the USA. All rights reserved
0360-3016/05/$–see front matter

doi:10.1016/j.ijrobp.2005.05.023

ASTRO REPORT

THE AMERICAN SOCIETY FOR THERAPEUTIC RADIOLOGY AND

ONCOLOGY (ASTRO) EVIDENCE-BASED REVIEW OF THE ROLE OF
RADIOSURGERY FOR BRAIN METASTASES

MINESH P. MEHTA, M.D., MAY N. TSAO, M.D., TIMOTHY J. WHELAN, M.D., DAVID E. MORRIS, M.D.,
JAMES A. HAYMAN, M.D., JOHN C. FLICKINGER, M.D., MICHAEL MILLS, PH.D.,
C. LELAND ROGERS, M.D., AND LUIS SOUHAMI, M.D.
The American Society for Therapeutic Radiology and Oncology, Fairfax, VA

Purpose: To systematically review the evidence for the use of stereotactic radiosurgery in adult patients with
brain metastases.
Methods: Key clinical questions to be addressed in this evidence-based review were identified. Outcomes
considered were overall survival, quality of life or symptom control, brain tumor control or response and toxicity.
MEDLINE (1990 –2004 June Week 2), CANCERLIT (1990 –2003), CINAHL (1990 –2004 June Week 2), EM-
BASE (1990 –2004 Week 25), and the Cochrane library (2004 issue 2) databases were searched using OVID. In
addition, the Physician Data Query clinical trials database, the proceedings of the American Society of Clinical
Oncology (ASCO) (1997–2004), ASTRO (1997–2004), and the European Society of Therapeutic Radiology and
Oncology (ESTRO) (1997–2003) were searched. Data from the literature search were reviewed and tabulated.
This process included an assessment of the level of evidence.
Results: For patients with newly diagnosed brain metastases, managed with whole-brain radiotherapy alone vs.
whole-brain radiotherapy and radiosurgery boost, there were three randomized controlled trials, zero prospec-
tive studies, and seven retrospective series (which satisfied inclusion criteria). For patients with up to three (<4
cm) newly diagnosed brain metastases (and in one study up to four brain metastases), radiosurgery boost with
whole-brain radiotherapy significantly improves local brain control rates as compared with whole-brain radio-
therapy alone (Level I-III evidence). In one large randomized trial, survival benefit with whole-brain radiother-
apy was observed in patients with single brain metastasis. In this trial, an overall increased ability to taper down
on steroid dose and an improvement in Karnofsky performance status was seen in patients who were treated with
radiosurgery boost as compared with patients treated with whole-brain radiotherapy alone. However, Level I
evidence regarding overall quality of life outcomes using a validated instrument has not been reported. All
randomized trials showed improved local control with the addition of radiosurgery to whole-brain radiotherapy.
For patients with multiple brain metastases, there is no overall survival benefit with the use of radiosurgery boost
to whole-brain radiotherapy (Level I-III evidence). Radiosurgery boost is associated with a small risk of early or
late toxicity. In patients treated with radiosurgery alone (withholding whole-brain radiotherapy) as initial
treatment, there were 2 randomized trials, 2 prospective cohort studies, and 16 retrospective series. There is
Level I to Level III evidence that the use of radiosurgery alone does not alter survival as compared to the use of
whole-brain radiotherapy. However, there is Level I to Level III evidence that omission of whole-brain
radiotherapy results in poorer intracranial disease control, both local and distant (defined as remaining brain,
outside the radiosurgery field). Quality of life outcomes have not been adequately reported. Radiosurgery is
associated with a small risk of early or late toxicity. Radiosurgery as salvage for patients with brain metastases
was reported in zero randomized trials, one prospective study, and seven retrospective series.
Conclusions: Based on Level I-III evidence, for selected patients with small (up to 4 cm) brain metastases (up to
three in number and four in one randomized trial), the addition of radiosurgery boost to whole-brain radio-

Reprint requests to: The American Society for Therapeutic care Policy and Economics, and Government Relations Commit-
Radiology and Oncology, 12500 Fair Lakes Circle, Suite 375, tees for their thoughtful reviews of earlier versions of this evi-
Fairfax, VA 22033. Tel: (703) 502-1550; Fax: (703) 502-7873; dence-based review. ASTRO wishes to acknowledge McMaster
E-mail: [email protected] University’s Program in evidence-based Care for carrying out the
Supplementary data associated with this article can be found in systematic review used in the development of these recommenda-
the online version at doi:10.1016/j.ijrobp.2005.05.023. tions. Further acknowledgments are extended to Alex Chambers
Note: To access the supplementary materials accompanying this (Research Coordinator, Program in Evidence-based Care, McMas-
article, visit this month’s issue of International Journal of Radia- ter University, Hamilton, Ontario, Canada), and Jennifer Padberg,
tion Oncology ● Biology ● Physics at www.redjournal.org. M.P.H., (Director of Research, American Society for Therapeutic
Acknowledgments—The expert panel wishes to express its grati- Radiology and Oncology (ASTRO)).
tude to Drs. Jay Loeffler, Roy A. Patchell, Michael A. Vogelbaum, Received May 20, 2005. Accepted for publication May 20,
and the members of the ASTRO Health Services Research, Health- 2005.

37
38 I. J. Radiation Oncology ● Biology ● Physics Volume 63, Number 1, 2005

therapy improves brain control as compared with whole-brain radiotherapy alone. In patients with a single brain
metastasis, radiosurgery boost with whole-brain radiotherapy improves survival. There is a small risk of toxicity
associated with radiosurgery boost as compared with whole-brain radiotherapy alone. In selected patients treated
with radiosurgery alone for newly diagnosed brain metastases, overall survival is not altered. However, local and
distant brain control is significantly poorer with omission of upfront whole-brain radiotherapy (Level I-III
evidence). Whether neurocognition or quality of life outcomes are different between initial radiosurgery alone vs.
whole-brain radiotherapy (with or without radiosurgery boost) is unknown, because this has not been adequately
tested. There was no statistically significant difference in overall toxicity between those treated with radiosurgery
alone vs. whole-brain radiotherapy and radiosurgery boost based on an interim report from one randomized
study. There is insufficient evidence as to the clinical benefit/risks radiosurgery used in the setting of recurrent
or progressive brain metastases, although radiographic responses are well-documented. © 2005 American
Society for Therapeutic Radiology and Oncology. Published by Elsevier Inc.

Brain metastases, Radiosurgery, Evidence-based medicine.

INTRODUCTION intent was to provide a variety of different perspectives in

an attempt to minimize bias (Table 1).
As the use of radiosurgery becomes widespread for the
management of certain intracranial lesions, the American Process overview
Society for Therapeutic Radiology And Oncology (AS- In evaluating the evidence regarding the role of radiosur-
TRO) Health Services Research Committee concluded that gery for brain metastases, a systematic search of the litera-
an evidence-based review of the evidence for the use of ture was performed. The process included an assessment of
stereotactic radiosurgery in adult patients with brain metas- the level of evidence (Table 2).
tases would be useful. It should be noted that Level I data are not necessarily the
ultimate requirement for a proposed treatment to be en-
dorsed as reasonable and necessary. The unique nature of
Evidence-based medicine
the practice of oncology often precludes the opportunity to
Evidence-based medicine is the conscientious, explicit,
perform level I studies. Many treatments are considered
and judicious use of current best evidence in making deci-
appropriate, in some cases essential, based solely on Level
sions about the care of individual patients (1). The practice
II or Level III data. As previously noted, it is the judgment
of evidence-based medicine means integrating individual
of the treating physician that ultimately determines which
clinical expertise with the best available external clinical
therapy is indicated.
evidence from systematic research and patient choice. Sys-
tematic research refers to reviews that appraise critically,
Review of the available data
summarize, and attempt to reconcile the published evidence
Pertinent information from the published literature was
concerning a particular problem (2). External clinical evi-
retrieved and reviewed for the creation of these recommen-
dence can inform, but can never replace, individual clinical
dations. A detailed account of the methods used to obtain
expertise, and it is this expertise that decides whether the
this information, including the inclusion/exclusion criteria,
external evidence applies to the individual patient at all and,
databases searched, time periods covered by the search and
if so, how it should be integrated into a clinical decision (1).
the search criteria used can be found in Appendix B (online
The final determinant of what treatment should be rec-
only).
ommended rests with the oncologist. It is based on his or her
clinical impression of the individual case, his or her under-
Consensus based on the evidence
standing of the relevant circumstances, and sound medical
The expert panel identified several key clinical questions
judgment. ASTRO fully recognizes this and considers ad-
to be addressed in this review (Appendix B). The expert
herence to these recommendations voluntary. Rather, this
evidence-based review is intended to summarize the current
medical literature and identify important questions for fur- Table 1. Causal pathway: A graphical representation of a
ther research. These recommendations do not apply to fur- “causal pathway” is shown below
ther research in clinical trials. Patient population Intervention Outcomes

Adult patients with Radiosurgery (as 1. Brain tumor

brain metastases primary control or response
METHODOLOGY treatment, boost
with whole-brain 2. Overall survival
Expert panel selection radiotherapy, or
The expert panel was assembled by the Health Services at the time of 3. Quality of life or
Research Committee of ASTRO and is composed of experts salvage after symptom control
in radiation oncology, physics, clinical research, and out- whole brain
comes/health services research. A full list of expert panel radiotherapy 4. Toxicity
failure)
members is listed in Appendix A (online only). The primary
 ASTRO evidence-based review of the role of radiosurgery for brain metastases ● M. P. MEHTA et al. 39

Table 2. Level of evidence although the most common primary sites are lung, breast,
colorectum, melanoma, or kidney (5, 6).
Strength of the evidence: The effectiveness of radiosurgery
(tumor control/response, survival, quality of life or symptom Whole-brain radiotherapy and steroids represent the
control) in the treatment of brain metastases was graded mainstay of management for patients with a diagnosis of
according to the quality of evidence obtained (3) brain metastases. For selected patients with single brain
metastases, survival is improved with the addition of resec-
Level I Evidence obtained from at least one properly
designed randomized controlled trial tion of the single brain metastasis followed by whole-brain
Level II-1 Evidence obtained from well-designed radiotherapy as compared with whole-brain radiotherapy
controlled trials without randomization. alone (7, 8). Whole-brain radiotherapy added to surgical
Level II-2 Evidence obtained from well-designed cohort or resection of a single brain metastasis, in selected patients,
case-control analytic studies, preferably from improves intracranial control as compared with surgery
more than one center or research group
Level II-3 Evidence obtained from comparisons between alone (9). This effect was less evident for patients with poor
times or places with or without the performance status or active extracranial disease (10). How-
intervention. ever, only a minority of patients with brain metastases are
Level III Opinions of respected authorities, based on eligible for craniotomy to resect single brain metastasis
clinical experience, descriptive studies or (11). No randomized studies have been reported that address
reports of expert committees.
the use of surgery for removal of two or more brain metas-
Data from Woolf et al. (3). tases or for the management of recurrent brain metastases.
For progressive brain metastases after initial manage-
ment, repeat whole-brain radiotherapy has been reported in
panel convened on numerous occasions in person and via small case series (12, 13). This approach is used on a limited
conference call to discuss and formulate the recommenda- basis because of the possible neurologic/neurocognitive se-
tions. Drafts were developed and circulated in several iter- quelae that may occur (11, 14).
ations and all members of the expert panel had an oppor- Radiosurgery has emerged as a common treatment modality
tunity to comment. for brain metastases. When used as initial therapy, radiosur-
The expert panel did not attempt to codify established gery is applied either as boost with whole-brain radiotherapy or
practice. The experts reviewed the available evidence and as sole therapy without whole-brain radiation. The intent of
added their best clinical judgment to make final recommen- radiosurgery when used as boost is to improve local brain
dations. The content was peer-reviewed by the ASTRO control. This may translate into survival benefit in selected
Health Services Research, Healthcare Policy and Econom- patients in whom the predominant problem is brain metastases
ics, and Government Relations Committees as well as sev- as compared with extracranial tumor activity. The putative
eral external reviewers not involved in the development of rationale for radiosurgery when used alone is to achieve brain
the document. The ASTRO board of directors reviewed and control without the possible side effects (e.g., potential neuro-
approved the document before its dissemination. cognitive sequelae) of whole-brain radiotherapy. Radiosurgery
has also been used as salvage for progressive intracranial
disease after whole-brain radiotherapy relapse.
Revisions/updating Stereotactic radiosurgery is a specialized radiation technique
Evidence-based documents are living documents, which in which a single dose of highly collimated radiation is deliv-
reflect the best practice at a particular point in time and ered to one or more intracranial targets with submillimeter
include the most up-to-date evidence available. They re- precision. Three types of devices have commonly been used
quire regular revision to cope with changing medical prac- for delivering radiosurgery, the multisource cobalt unit known
tice, advances in technology, and changes in the environ- as the “gamma knife,” specially modified linear accelerators,
ment. This requires commitment to resources to monitor the or charged-particle irradiators.
emerging literature so that decisions as to whether or not a As the use of radiosurgery for the management of brain
document should be revised, or if it has become obsolete metastases becomes more widespread, the ASTRO Health
can be made. Therefore, at regular intervals, this document Services Research Committee determined that an evidence-
will be reviewed and a determination made as to whether or based review of this radiation modality was relevant and im-
not an update should be undertaken, or if the document portant. The aim of this evidence-based project was to provide
should be retired. a clear presentation of the key clinical questions related to the
use of stereotactic radiosurgery in the management of brain
metastases and to assess the published evidence for the effec-
RADIOSURGERY FOR BRAIN METASTASES
tiveness (benefits and harms) of radiosurgery in patients with
Background brain metastases.
Brain metastases represent a significant clinical problem.
It is estimated that approximately half of patients dying Results
from cancer are found to have brain metastases at autopsy Because of the limited power and methodologic weak-
(4). Brain metastases may originate from any primary site, ness of small retrospective series and to reduce the number
40 I. J. Radiation Oncology ● Biology ● Physics Volume 63, Number 1, 2005

of studies to a manageable size, arbitrarily, any nonrandom- randomized and the results were reported for 14 patients
ized series with fewer than 100 patients with newly diag- treated with whole-brain radiotherapy alone and 13 patients
nosed brain metastases were excluded. treated with whole-brain radiotherapy and radiosurgery
A priori, it was expected that the number of studies boost. The two groups were well balanced with respect to
obtained from the literature search for recurrent or progres- age, sex, tumor type, number of tumors, and extent of
sive brain metastases would be fewer in number. As such, extracranial disease.
studies with any sample size were included in this category. The Chougule et al. trial (15) was published in abstract
Appendix C, Tables 3–9 (only online) list the studies that form and the data remain to be fully published and peer-
met predefined inclusion criteria. Two additional random- reviewed. Patients with one to three brain metastases with
ized controlled trials (15, 16) have not yet been fully pub- tumor volume ⱕ30 cc and minimum life expectancy of 3
lished in the peer reviewed literature. Information for these months were included. The randomization arms were
studies was obtained from abstracts, meeting presentations, gamma knife radiosurgery alone (30 Gy to the tumor mar-
and direct communication with the primary investigators, gin), whole brain radiotherapy (30 Gy in 10 fractions) plus
including access to submitted manuscripts. Although ab- gamma knife boost (20 Gy to the tumor margin), and
stracts of randomized trials are included in this report, it is whole-brain radiotherapy alone (30 Gy in 10 fractions).
recognized that the quality of randomized trials reported in Overall median survival was 7, 5, and 9 months for the
abstracts but lacking peer-reviewed publications is difficult arms, respectively (not significant).
to assess. Abstract data from randomized trials were con- All three randomized trials (15, 17, 18) detected an im-
sidered preliminary, with less impact as compared with provement in local brain control in patients treated with
peer-reviewed fully published manuscripts. whole-brain and radiosurgery boost as compared with
whole-brain radiotherapy alone. In RTOG 95-08 (18), local
NEWLY DIAGNOSED BRAIN METASTASES brain control was defined as unchanged or improved serial
posttreatment MRI scans judged as either a complete re-
Radiosurgery as boost with whole-brain radiotherapy
sponse, partial response, or stable disease. Posttreatment
Interpretative summary
MRI scans were sent for central review and read by one
Key clinical question #1: Does the use of radiosurgery
neuroradiologist. Progressive disease was defined as an
boost with whole-brain radiotherapy improve brain con-
increase in the size of any lesion, the development of new
trol/tumor response as compared with whole-brain ra-
intracranial lesions, or stable disease with deterioration of
diotherapy alone in patients with brain metastases?
the neurologic examination. Local brain control was not
There have been three randomized trials examining the
defined in the Chougule abstract (15). Kondziolka et al. (17)
use of whole-brain radiotherapy plus radiosurgery boost as
defined local brain control as no tumor growth based on
compared with whole-brain radiotherapy alone in selected
MRI scans and no increase in clinical symptoms associated
patients with brain metastases. Two of these trials have been
reported in the peer-reviewed published literature (17), and with the lesion. Serial scans were read by an independent
one has only been reported in abstract form with the final blinded observer. For these three randomized trials, local
report pending (15). brain control at 1 year ranged from 82% to 92% in the
The strongest evidence comes from the Radiation Ther- radiosurgery boost arm vs. 0% to 71% in the whole-brain
apy Oncology Group (RTOG) 95-08 trial (18), which ran- alone arm. The study by Kondziolka et al. (17) also reported
domized 164 patients to whole-brain radiotherapy and ra- superior intracranial control with the use of radiosurgery,
diosurgery boost vs. 167 patients randomized to whole- but the rather small patient numbers raise methodologic and
brain radiotherapy alone. Patients with one to three newly interpretative questions. The study by Chougule et al. (15)
diagnosed brain metastases were included. The brain me- is difficult to analyze because it included patients with
tastases could be a maximum diameter of 4 cm for the multiple lesions and some of these had been surgically
largest lesion and the additional lesions could not exceed 3 removed.
cm (based on contrast-enhanced magnetic resonance imag- The retrospective series report a range of local brain
ing [MRI]). The arms of the trial were well balanced for control rates or tumor response rates at variable time points.
baseline characteristics known to affect survival such as Because of the retrospective nature of these studies, heter-
age, Karnofsky performance status (KPS) and status of ogeneity of patient, and treatment characteristics, conclu-
extracranial metastases. The study was powered to establish sions regarding the impact of radiosurgery boost on brain
possible differences in outcome stratified for number of control or tumor response as compared with patients man-
brain metastases (one vs. two to three) and extent of ex- aged with whole-brain radiotherapy alone cannot be made.
tracranial disease (none vs. present). In addition, there were various dosing strategies, which may
Kondziolka et al. (17) reported on patients with two to potentially account for differences in control rates. Because
four brain metastases all ⱕ25 mm. Patients were random- of heterogeneity, it was not possible to examine the effect of
ized to whole-brain radiotherapy alone (30 Gy in 12 frac- dose on tumor control rates.
tions) or whole-brain radiotherapy plus radiosurgery. The Key clinical question #2: Does radiosurgery used as
study was stopped at 60% accrual. Only 27 patients were boost with whole-brain radiotherapy improve survival
 ASTRO evidence-based review of the role of radiosurgery for brain metastases ● M. P. MEHTA et al. 41

as compared with whole-brain radiotherapy alone, in therapy and radiosurgery boost for newly diagnosed patients
patients with brain metastases? with brain metastases. These studies were heterogeneous in
RTOG 95-08 (18) reported that overall mean survival terms of patient inclusion characteristics. Age ranged from
time did not differ between the two groups (6.5 months for 23 to 88 years, and KPS ranged from ⬍70 to 100. Some
whole-brain radiotherapy alone vs. 5.7 months for whole- studies included patients with radiosensitive tumors such as
brain radiotherapy and radiosurgery boost, p ⫽ 0.1356). lymphoma or small-cell lung cancer to radioresistant tumor
In Kondziolka et al.’s study (17), median survival was histologies such as renal cell or melanoma. Although Sang-
not statistically different between the two arms, 7.5 months havi et al. (21) found survival to be increased in patients
for those receiving whole-brain radiotherapy alone vs. 11 treated with radiosurgery boost as compared with those
months for those receiving whole-brain radiotherapy and treated with whole-brain radiotherapy based on RPA
radiosurgery boost (p ⫽ 0.22). Survival was dependent on classes, the group of patients treated with radiosurgery boost
the extent of extracranial disease (p ⫽ 0.02), but was not may represent a subgroup within each RPA class who have
dependent on histology or number of tumors. better inherent prognosis as compared with those who may
All three trials (15, 17, 18) report no statistically signif- not be radiosurgery eligible but classified in the same RPA
icant improvement in overall survival with the use of radio- group treated with whole-brain radiotherapy. Because of the
surgery boost as compared with whole-brain radiotherapy retrospective nature of these studies, heterogeneity of pa-
alone. Median survivals for the whole-brain radiotherapy tient inclusion and heterogeneity of treatment characteris-
alone arm ranged from 5.7 to 7.5 months. Median survivals tics, definitive conclusions regarding survival data, and
for the whole-brain radiotherapy and radiosurgery boost treatment effect cannot be made. Survival results from all
arm ranged from 5 to 11 months. retrospective series may be influenced by baseline prognos-
The objectives of the RTOG recursive partitioning anal- tic factors (age, performance status, and status of extracra-
ysis (RPA) of prognostic factors (19) were to analyze the nial disease), thereby reducing the class strength of such
relative contributions of pretreatment variables to the sur- data. One putative advantage of the retrospective analysis
vival of patients with brain metastases treated with whole- may be that the majority of patients selected for radiosur-
brain radiotherapy and to identify subgroups of patients gery boost might be those who have completed whole-brain
with homogeneous prognostic characteristics predictive of radiotherapy remain neurologically and functionally stable
survival. Three classes were devised: Class I, patients with and may have limited relatively indolent extracranial dis-
KPS ⱖ70, ⬍ 60 years of age with controlled primary, and ease. It remains speculative whether these highly selected
no extracranial metastases; Class III, KPS ⬍70; and Class patients represent the group of patients who benefit the most
II, all others. From this historic database, the best survival from radiosurgery boost.
was seen in Class I patients (median, 7.1 months). The worst Key clinical question #3: Does radiosurgery used as
survival was seen in Class III patients (median, 2.3 months). boost with whole-brain radiotherapy improve quality of
Class II patients had intermediate survival (median, 4.2 life or symptom control as compared with whole-brain
months). It was proposed that these classes could be used to radiotherapy alone in patients with brain metastases?
compare outcomes of new interventions such as radiosur- Of the three randomized trials, only RTOG 95-08 (18)
gery in homogeneous brain metastases patients based on reported KPS outcomes. Patients in the radiosurgery boost
RPA class. group were more likely to have a stable or improved KPS at
One trial, RTOG 95-08 (18), explored survival outcomes 6 months follow-up than patients allocated to whole brain
in certain subsets of patients. By multivariate analysis, radiotherapy alone (43% vs. 27%, respectively, p ⫽ 0.03).
whole-brain radiotherapy and radiosurgery boost improved At 6 months, steroid use decreased in 41 of 76 patients
survival in RPA Class I patients (p ⬍ 0.0001) and in treated with radiosurgery boost as compared with 25/75
patients with favorable histologic status, squamous cell, or patients treated with whole-brain radiotherapy alone (p ⫽
non–small-cell lung tumors (p ⫽ 0.0121). However, the 0.0158). No difference in Mini-Mental Status Examination
RPA class analysis and the histologic status analysis were results was observed.
not prospectively defined endpoints and the variables in the Only one retrospective study (20) reported on quality of
multivariate analysis were not corrected for the effect of life or symptom control outcomes. In the Auchter series
multiple comparisons. (20), the median time in which the KPS was sustained ⱖ70
RTOG 95-08 (18) included a predefined hypothesis to was 44 weeks for patients treated with whole-brain radio-
detect a 75% median survival time improvement (80% therapy and radiosurgery. However, no comparisons were
statistical power) in patients with single brain metastasis made with a similar group of patients treated with whole-
(deemed unresectable or the patients were inoperable). Me- brain radiotherapy alone.
dian survival was 6.5 months in patients with single brain Key clinical question #4: Does the use of radiosurgery
metastasis treated with radiosurgery boost as compared with boost with whole-brain radiotherapy increase toxicity?
4.9 months in patients with single brain metastasis treated Of the three randomized trials, only two (17, 18) report
with whole brain radiotherapy alone, p ⫽ 0.0393. on toxicity. The Kondziolka et al. (17) trial reported “no
Seven retrospective series, with sample sizes greater than neurologic or systemic morbidity related to (radiosurgery).”
100, (20 –26) reported on the results of whole-brain radio- Andrews et al. (18) reported higher toxicities with the
42 I. J. Radiation Oncology ● Biology ● Physics Volume 63, Number 1, 2005

radiosurgery boost arm as compared with the whole-brain There is Level I evidence that, for patients with multiple
radiotherapy arm. Grades 3 and 4 acute toxicities were 0% brain metastases, radiosurgery boost does not improve over-
in the whole brain alone arm vs. 3% in the radiosurgery all survival as compared with whole-brain radiotherapy
boost arm. For acute Grade 3 toxicities, 1 patient had alone. Patients eligible for radiosurgery boost in these trials
nausea/vomiting, 2 patients had central neurologic toxicity, had brain metastases ⱕ4 cm, KPS ⱖ70, and up to four brain
and 1 patient had peripheral neurologic toxicity in the metastases.
radiosurgery boost arm. There was 1 patient who suffered One trial (18) reported that the ability to taper down on
acute Grade 4 central neurologic toxicity in the radiosurgery steroid dose and improvement of KPS was statistically
boost arm. Grades 3 and 4 late toxicities occurred in 3% of better in the radiosurgery arm at 6 months. There is a
patients in the whole-brain alone arm vs. 6% in the radio- statistically nonsignificant increase in the risk of toxicity
surgery boost arm. Late Grade 3 and 4 toxicities ranged with radiosurgery boost, which was reported as 3% acute
from nausea/vomiting, hearing loss, and central neurologic Grades 3 and 4 toxicity and 6% late Grades 3 and 4
symptoms. Two patients developed late Grade 4 “other” toxicities in this trial (18).
toxicities in the radiosurgery boost arm vs. 1 patient who However, overall quality of life using a validated instru-
developed late Grade 4 central toxicity in the whole-brain ment was not measured in any of these trials.
radiotherapy arm. These toxicity differences did not reach
statistical significance because of the low event rate.
RADIOSURGERY ALONE AS INITIAL THERAPY
Conclusion Interpretative summary
All three randomized trials (two fully published and one Key clinical question #1: Does the use of radiosurgery
in abstract form) found a significantly improved local brain alone as initial therapy alter whole-brain tumor control
control rate with the use of radiosurgery boost as compared as compared with whole-brain radiotherapy?
with whole-brain radiotherapy alone for patients with up to One randomized trial compared the use of radiosurgery
four metastases. This constitutes Level I evidence in favor vs. whole-brain radiotherapy as initial therapy in selected
of reduced intracranial failure with radiosurgery boost. patients with brain metastases. Results were presented as an
There is Level I evidence (based on one high-quality interim report in abstract form (16). The data from this trial
trial) to indicate that radiosurgery boost with whole-brain represent preliminary results. Mature data from this trial
radiotherapy improves survival in selected patients with a have not yet been published in a peer-reviewed manner. In
single brain metastasis. The analysis of survival benefit in this Japanese trial, JROSG 99-1, patients with KPS of at
patients with single brain metastasis in the Andrews et al. least 70, four or fewer brain metastases with size 3 cm or
study (18) was part of the original protocol design as an less were randomized to radiosurgery alone vs. whole-brain
independent prospective measure, with built-in and planned radiotherapy and radiosurgery. Radiosensitive histologies
statistical analysis and hence constitutes Level I evidence were excluded. Patients were stratified by number of lesions
for a beneficial survival effect. In contrast, the subset anal- (one vs. two to four), primary tumor (lung vs. other), and
ysis of survival benefit in other subgroups such as RPA extracranial disease (present or absent/stable). The planned
class I patients was performed after study completion with- accrual for each arm was 85 patients. An interim report,
out statistically correcting for multiple comparisons and after early closure of the trial, was presented at American
should therefore be regarded as hypothesis generating. Society of Clinical Oncology meeting in 2004 (16). The
Both Andrews et al. (18) and Chougule et al. (15) in- results of 61 patients randomized in the radiosurgery alone
cluded patients with single brain metastasis. However, sur- arm and 59 patients in the radiosurgery and whole-brain
vival comparison for the subset of patients with single brain radiotherapy arm were presented. Median follow-up dura-
metastasis was not reported in the Chougule et al. (15) tion was 6 months (range, 1– 40 months). The radiosurgery
abstract. The data on the benefit of radiosurgery boost for dose was lowered by 25% in the whole-brain radiotherapy
patients with single brain metastasis reported in RTOG arm.
95-08 (18) are analogous with the surgical randomized JROSG 99-1 (16) reported actuarial 6-month freedom
trials, which have examined the use of whole-brain radio- from new brain metastases to be 48% in the radiosurgery
therapy with or without surgical excision (7, 8). Noordijk et alone arm and 82% in the radiosurgery and whole-brain
al. (7) and Patchell et al. (8) found that the addition of radiotherapy arm (log–rank, p ⫽ 0.003). Actuarial 1-year
surgical excision of a single brain metastasis improved brain tumor control rate for the lesions treated with radio-
survival and brain control in selected patients as compared surgery was 70% in the radiosurgery alone arm and 86% in
with similar patients managed with whole-brain radiother- the radiosurgery and whole-brain radiation arm (log–rank, p
apy alone. However, the trials examining the use of radio- ⫽ 0.019).
surgery boost were not designed to address the question as Another randomized trial was reported in abstract form
to whether or not radiosurgery can replace surgery in the (15). This trial by Chougule et al. (15) randomized patients
management of patients with single brain metastasis, and, in to gamma knife radiosurgery alone vs. whole-brain radio-
fact, patients enrolled on RTOG 95-08 were either inoper- therapy and gamma knife radiosurgery vs. whole-brain ra-
able or had unresectable lesions. diotherapy alone. The local brain control rate was higher in
 ASTRO evidence-based review of the role of radiosurgery for brain metastases ● M. P. MEHTA et al. 43

the two radiosurgery arms (87% for gamma knife radiosur- arm and 39% in the radiosurgery and whole-brain radiation
gery alone and 91% for gamma knife radiosurgery and arm (log–rank, p ⫽ 0.58).
whole-brain radiotherapy) as compared with 62% in the In Chougule et al.’s abstract, (15) median survivals were
whole-brain radiotherapy only arm. 7, 5, and 9 months for gamma knife radiosurgery alone vs.
A prospective, single arm, multi-institutional ECOG whole-brain radiotherapy and gamma knife radiosurgery vs.
Phase II study of radiosurgery alone for “radioresistant” whole-brain radiotherapy, respectively. Survival was re-
histologies (melanoma, sarcoma, renal cell carcinoma) in ported as not different among the three arms.
patients with one to three brain metastases has also been The ECOG Phase II trial (reported in abstract form) (27)
reported in abstract form (27). Inclusion criteria were one to of radiosurgery alone for radioresistant histologies found
three newly diagnosed brain metastases with a maximum median survival to be 8.2 months (95% CI, 7.4 –12.2
diameter of 4 cm. In patients with multiple lesions and any months) in their cohort of patients.
lesion ⬎3 cm, all remaining lesions had to be ⱕ3 cm. Of 36 Another prospective study (28) reported on the use of
patients accrued, 31 were eligible and evaluable, 14 with radiosurgery alone for the initial management of brain me-
melanoma, 14 with renal cell carcinoma, and 3 with sar- tastases. However, no survival comparisons were made with
coma. Three of 31 (10%) of patients had partial response, 10 patients treated with whole brain radiotherapy.
of 31 (32%) had stable disease, 14 of 31 (42%) had pro- Sixteen retrospective studies have reported on the use of
gressive disease, and 4 of 31 (14%) were not evaluable. At radiosurgery alone as initial management of selected pa-
6 months, 39.2% failed within the radiosurgery volume and tients with brain metastases (22–26, 29 –39). Survival out-
39.4% failed outside the radiosurgery volume. comes ranged from 8 to 15 months. Chidel et al. (29)
In the prospective study by Lutterbach et al. (28), the reported the median survival of patients treated with radio-
1-year overall brain failure free progression rate with the surgery alone as 10.5 months compared with 6.4 months in
use of radiosurgery alone as initial treatment was only 51%. patients treated with radiosurgery boost and whole-brain
Five retrospective studies (22, 24, 29 –31) compared local radiotherapy (p value not stated). Sneed et al. (31) reported
brain control rates between those patients receiving initial that the median survival of patients treated initially with
radiosurgery alone vs. those receiving whole-brain radio- radiosurgery alone was 11.3 months, which was not statis-
therapy. Chidel et al. (29) found a statistically significant tically different from the survival of patients treated with
improvement in 2-year brain control with the use of whole- whole-brain radiotherapy and radiosurgery boost (11.1
brain radiotherapy in addition to radiosurgery boost, 80% months). Wang et al. (22) reported 15 months’ median
vs. 52% in patients treated with radiosurgery alone (p ⫽ survival in patients treated with radiosurgery alone vs. 20
0.034). Pirzkall et al. (30) found 1-year local control rates to months in patients treated with whole-brain radiotherapy
be inferior with the radiosurgery alone group, 89% vs. 92% and radiosurgery boost vs. 8.5 months for patients treated
in the whole-brain radiotherapy and radiosurgery boost with whole-brain radiotherapy alone (p value not stated).
group. Shehata et al. (24) reported that patients who had Pirzkall et al. (30) found no difference in overall survival
whole-brain radiotherapy had superior local tumor control for 236 patients treated with radiosurgery alone (n ⫽ 158)
rates, 97%, as compared with patients treated with radio- or radiosurgery and whole-brain radiotherapy (n ⫽ 78);
surgery alone 87% (p ⫽ 0.0001). Sneed et al. (31) reported however, in the subset of patients without extracranial dis-
on a statistically significant improvement in 1-year brain ease, omitting whole-brain radiotherapy resulted in a sur-
freedom from progression rate in those patients treated with vival decrement from 15.4 months to 8.3 months.
whole-brain radiotherapy and radiosurgery boost, 69% as The largest retrospective review (38) of data collected
compared with those patients treated with initial radiosur- from 10 institutions was specifically undertaken to compare
gery only, 28%. It was commented that the 1-year brain the survival probabilities of patients with newly diagnosed
control rate allowing for salvage (using whole-brain radio- brain metastases managed initially with radiosurgery alone
therapy or serial radiosurgery) at first failure was not sta- vs. radiosurgery and whole-brain radiotherapy. Survival
tistically different between those treated with initial whole- times were compared using the Cox proportional hazards
brain radiotherapy and radiosurgery boost (73%) vs. those model to adjust for known prognostic factors or RTOG RPA
treated initially with radiosurgery alone (62%). However, class. Of the 569 evaluable patients, 268 had radiosurgery
whether the study had enough power to detect a difference alone initially (24% of whom ultimately had salvage whole-
in ultimate brain control (allowing for salvage) is unknown. brain radiotherapy) and 301 had radiosurgery and up-front
Wang et al. (22) found that the local brain control rate of whole-brain radiotherapy. The median survival times for
patients treated with radiosurgery alone was 93.3% vs. patients treated with radiosurgery initially vs. radiosurgery
95.6% in patients treated with whole-brain radiotherapy and and whole-brain radiotherapy were 14.0 vs. 15.2 months for
radiosurgery boost. RPA Class 1, 8.2 vs. 7.0 months for Class 2, and 5.3 vs. 5.5
Key clinical question #2: Does the use of radiosurgery months for Class 3. With adjustment by RPA class, there
alone as initial therapy alter survival as compared with was no survival difference comparing radiosurgery alone
whole-brain radiotherapy? initially with radiosurgery and up-front whole-brain radia-
The Japanese trial reported in abstract form (16) found tion (p ⫽ 0.33; hazard ratio ⫽ 1.09).
actuarial 1-year survival to be 26% in the radiosurgery alone Level I evidence from the Japanese trial (16) remains to
44 I. J. Radiation Oncology ● Biology ● Physics Volume 63, Number 1, 2005

be published fully. Thus there is published Level II-3 evi- omission of whole brain radiation is unlikely to affect
dence that omission of up-front whole-brain radiotherapy survival.
appears to result in comparable length of survival in patients These data are analogous the surgical randomized study
treated with up-front radiosurgery alone for patients with by Patchell et al. (9). Patients with single brain metastasis
newly diagnosed brain metastases (reserving whole-brain were randomized to surgical excision alone vs. surgical
radiotherapy for salvage). excision and whole-brain radiotherapy. There was no sig-
Key clinical question #3: Does the use of radiosurgery nificant difference in survival between the two arms. How-
alone improve quality of life or symptom control as ever, there was a statistically significant difference in brain
compared with whole-brain radiotherapy? tumor recurrence, 70% in those patients treated with surgery
No formal comparisons between radiosurgery alone vs. alone vs. 18% in those patients treated with surgery and
competing options of management such as whole-brain whole-brain radiotherapy.
radiotherapy have been made in terms of quality of life or Firm conclusions cannot be made as to whether the
symptom control among the studies. omission of whole-brain radiotherapy has a significant or
The only study that has reported KPS outcomes has been measurable impact on neurocognition, because adequate
the Japanese randomized trial presented in abstract form evaluation of this issue has not been undertaken.
(16). Actuarial 1-year KPS preservation rate (KPS ⱖ70) Therefore, it is reasonable to conclude that omission of
was 25% in the radiosurgery alone arm and 37% in the whole brain radiotherapy may perhaps not affect survival,
whole-brain radiotherapy and radiosurgery arm (log–rank, p but it is most likely to negatively impact intracranial control
⫽ 0.54). No formal neurologic functional tests were pro- and, therefore, the treating physician must weigh the sig-
spectively performed. nificance of these two endpoints when making the decision
However, validated quality of life outcomes have not to omit or include whole-brain radiotherapy.
been reported in any of these studies examining the use of
radiosurgery alone (without whole-brain radiotherapy) as
up-front treatment for brain metastases.
RECURRENT OR PROGRESSIVE BRAIN
Key clinical question #4: Is the use of radiosurgery
METASTASES
alone associated with toxicity?
In the randomized Japanese trial (16), there was no sta- Radiosurgery as Salvage (40 – 45)
tistically significant difference in any grade of either acute Interpretative summary
or late radiation toxicities between the radiosurgery alone Key clinical question #1: Does the use of radiosurgery at
arm and the radiosurgery and whole-brain arm. In the the time of progressive brain metastases improve brain
ECOG trial (27), two Grade 3 events in 31 patients (one local control or brain tumor response?
seizure and one fatigue) were thought to be possibly related There is lack of Level I evidence as to whether radiosur-
to radiosurgery. gery at the time of progressive brain metastases improves
The prospective study by Lutterbach et al. (28) reported local brain control or brain tumor response. There is Level
13% of patients experiencing complications with radiosur- II-2 and Level II-3 evidence that the use of radiosurgery at
gery alone as initial treatment for brain metastases. Nine the time of salvage is associated with tumor response.
percent were acute toxicities and 4% were late toxicities. However, the studies are too small and heterogenous in
Varying degrees of toxicities were reported in the retro- patient characteristics and treatment methods to allow for
spective series examining the outcomes of patients treated definitive conclusions.
with radiosurgery alone. Key clinical question #2: Does the use of radiosurgery
at the time of progressive brain metastases improve
survival as compared to other competing management
CONCLUSION
strategies?
There is Level I evidence (abstract form) that omission of Level I evidence is not available to indicate whether the
whole-brain radiotherapy results in significant deterioration use of radiosurgery at the time of progressive brain metas-
in intracranial disease control, both at the site of radiosur- tases improves survival as compared to other competing
gery and also in the remaining untreated brain. Level II-1 strategies. There is Level II-2 and Level II-3 evidence that
and Level II-3 evidence further support this observation. radiosurgery at the time of progressive brain metastases
There is Level I (abstract form) to Level II-3 evidence (after previous whole brain radiotherapy) is associated with
that the use of radiosurgery alone as initial therapy (with 1 year survivals ranging from 26% to 40% in selected
whole-brain radiation used as salvage) does not alter sur- patients. It is unclear whether such survival outcomes are
vival as compared with the use of whole-brain radiation directly related to radiosurgery treatment or simply reflect
with or without radiosurgery boost. The multi-institutional the natural history of selected patients with relatively good
report by Sneed et al. (38) provides Level II-2 evidence that prognoses.
lend further support to this evidence. Several other reports Key clinical question #3: Does the use of radiosurgery
constitute Level II-3 evidence refuting this observation. at the time of progressive brain metastases improve
However, based on the relative strength of the studies, quality of life or symptom control?
 ASTRO evidence-based review of the role of radiosurgery for brain metastases ● M. P. MEHTA et al. 45

None of the studies reported on quality of life or symp- partial or whole brain external beam radiotherapy versus steroid
tom control outcomes. use alone for patients with recurrent multiple brain metastases is
Key clinical question #4: Is the use of radiosurgery at needed with outcomes of interest including overall survival, brain
the time of progressive brain metastases associated with control, quality of life, neurologic function, neurocognitive func-
toxicity? tion and symptom control. However, accrual to such a trial may be
The retrospective nature, small size and heterogeneity of difficult as there may be lack of clinical equipoise due to strong
the reported studies; as well as the lack of randomized data physician or patient preferences.
and lack of large prospective cohort studies make conclu-
sions regarding toxicity not possible.
ONGOING TRIALS
Conclusion The Eastern Cooperative Oncology Group (ECOG) re-
Evidence regarding the benefits and risks of radiosurgery cently completed a phase II trial in patients with melanoma,
for salvage at the time of progressive brain metastases renal cell carcinoma and sarcoma with 1-3 brain metastases
previously treated with whole brain radiotherapy is weak. treated with radiosurgery alone. Results are pending.
There is Level II-2 and Level II-3 evidence that the use of The American College of Surgeons Oncology Group
radiosurgery is associated with brain tumor response and (ACOSOG) is conducting a phase III randomized study
1-year survivals ranging from 26% to 40%. The studies in (Z0300) of radiosurgery with or without WBRT in patients
the literature are small and heterogenous in terms of patient with one to three cerebral metastases.
characteristics, treatment details and outcome measures. It The Radiation Therapy Oncology Group (RTOG) is
is not possible to discern whether outcomes are directly about to open a three arm phase III study (BR-0320) of
related to radiosurgery versus inherent patient prognostic whole brain radiotherapy and radiosurgery, or the same
factors. The options available for patients in this scenario, treatment with either Iressa or temozolomide for patients
however are limited. Until stronger evidence becomes avail- with non-small cell lung cancer with up to 3 brain metas-
able, the use of radiosurgery for salvage may be considered tases.
an option in selected patients. Additionally, several single-institution trials are ongoing
A randomized trial of radiosurgery for salvage versus repeat or planned.

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