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Radiosurgery for intracranial malignancies
Radiosurgery for Intracranial Malignancies Jay s. Loejfler, Dennis C. Shrieve, Patrick Y. Wen, Howard A. Fine, Hanne M. Kooy, Anthony E. Addesa, PeterMcL. Black, and Eben Alexander III Radiosurgery was historically designed as a technology to be used for the treatment of functional disorders, benign tumors, and vascular malformations. In the last 5 years, malignant lesions have become an increasingly common target for the radiosurgeon. In fact, by 1994 the most common disease treated with radiosurgery in the United States was metastatic disease. Published data suggest that radiosurgery offers excellent local control for intracraniai metastatic lesions regardless of location or histology with the majority of patients demonstrating an improved quality of life. Recent information from the Joint Center for Radiation Therapy suggests that radio-
surgery compares favorably with interstitial brachytherapy for both recurrent as well as in newly diagnosed patients with malignant gliomas in terms of improved survival and the need of surgery and steroid support for symptomatic radiation changes. Prospective studies (Phase I through III) are ongoing to determine the ultimate role of radiosurgery in the management of patients with newly diagnosed and recurrent malignant giiomas, recurrent pediatric brain tumors disease, and patients with single or multiple intracranial metastases. Copyright 9 1995 by W.B. Saunders Company
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thera W have significant b" fewer recurrences at the initial metastatic site compared with those receiving whole brain radiotherapy alone; they also have significantly increased survival and improved quality of life. 2,3 This is particularly true for younger patients and patients without evidence of progressive systemic disease. 3 So far, systemic chemotherapy has not been demonstrated to significantly influence outcome. Patients with extracranial metastases from melanoma or renal cell carcinoma who might otherwise qualify for promising therapies with biologic response modifiers are usually excluded if brain metastases are present. The biological and physical characteristics of metastases (Table 1) appear to make them ideal radiosurgery targets. The potential advantages of radiosurgery, as well as those of surgery,, are listed in Table 2. A summary, of results obtained by various groups treating metastases with radiosurge D' indicates local control is obtained in 73% to 98% of patients, with median follow-up of 5 to 26 months (Table 3). Flickinger et al 4 recently reported the results from a multi-institutional trial (Gamma Knife [I~skell G a m m a Unit; Elekta Radiosurgery, Inc, Atlanta, GA] Users Group) involving ! 16 patients treated with g a m m a knife radiosurgery for single brain metastasis. With a mean minimum dose of 17.5 Gy, local tumor control was obtained in 99 patients (85%). The 2-year actuarial tumor control rates for the whole group was 67% -+ 8% with a plateau in the curve at 18 months suggesting that local control rates are durable in the majority of patients. In a multivariate analysis, better local control was obtained in patients who received whole brain radiotherapy in addition to radiosurgery and in those patients with "radioresistant" histologies (mela-
adiosurgery was originally described as a technique to deliver a large single fraction of highly focal radiation to treat functional disorders (pain, movement disorders, psychiatric disorders, etc.) and later to treat arteriovenous malformations and benign tumors. 1Malignant lesions were not considered appropriate targets for radiosurgery mainly because of their invasiveness and large volumes. Over the last 6 years, there has been a growing interest in the use of radiosurgery in the treatment of primary, and metastatic brain tumors. This article reviews the results and complications associated with the use of radiosurgery in the treatment of both metastatic disease and malignant glioma as part of initial management and for recurrence.
Metastases Patients with symptomatic brain metastases have a median survival of about I month if left untreated and 3 to 6 months if whole brain radiation therapy is delivered, without significant differences between various conventional radiotherapy fractionation schemes. Patients undergoing surgery and radio-
From The Brain Tumor Center of the Brigham and Women'sHospital, Children's Hospital, Dana-Fa~er CancerInstitute, Joint Centerfor Radiation Therapy; and the Departments of Radiation Oncology, Neurology. Medicine, and Neurosurgery, Harvard Medical School, Boston, MA. Supported in part by National Imtitutes of Health Grants No. P2ONS3110 (JSL, PMB), KllCAOt496 (PYW), and KllCAOI467 (HAF). Address reprint requests to Jay S. Loeffter, MD, Joint Centerfor Radiation Therapy, 75Francis Street, Boston, MA 02115. Copyright 9 1995 by W.B. Saunders Company 1053-4296/95/0503-0008505.00/0
Seminars in Radiation Oncolog), Vol 5, No 3 (July), 1995:pp 225-234
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Table 1. Characteristics of Metastases: Ideal Radiosurgery Targets Often nearly spherical and radiographically distinct UsuaIly relatively small ( < 30 ram) at presentation Displace normal brain parenchyma circumferentially beyond the target volume which reduces risk of normal tissue injury Minimally invasive (entire extent of disease usually encompassed within target volume) Data from Loeffieret al.5 noma and renal cell carcinoma). The paradoxical finding of better control in histologies that are known to be radioresistant to fractionated radiotherapy has been reported by others. 5 Median survival measured from the time of radiosurgery was 11 months with patients with breast cancer having the best survival. These encouraging results have led to the design of prospective, randomized studies to be conducted by this group for patients with single or multiple brain metastases (Table 4). Alexander et al. 6 recently reviewed and reported their 7-year experience from the Joint Center for Radiation Therapy (JCRT) for patients with intracranial metastases treated with radiosurgery. The authors treated 421 metastatic lesions in 248 patients between May 1986 and May 1993. Sixty patients were treated as a planned boost following whole brain radiotherapywhereas 188 patients were treated at the time of recurrence. At the time of radiosurgery, 77 patients had no evidence of systemic disease whereas 171 patients had stable systemic disease. O f the lesions treated, 126 were classified as "radioresistant" (melanoma, renal cell carcinoma, and sarcoma) based on their response to conventionally fractionated radiotherapy with the remaining 295 lesions representing all other histologies. A single lesion was treated in 177 patients, 52 patients were treated for two lesions, and 19 patients were treated for three or more lesions. The median minimum
Table 2. Surgery Versus Radiosurgery for Metastases Advantages of surgery Provides immediate resolution of mass effect Provides diagnostic information if required Avoids risk of radiation necrosis Advantages of radiosurgery Links treatment directly to 3-D tumor visualization (reduces chances of "marginal miss") Requires minimal hospitalization (reduced costs) Avoids risk of hemorrhage, infection, and tumor seeding Data from Loeffleret al.27
dose was 15 Gy with a median tumor volume of 3.0 mL. With a median observation period of 26 months, 48/421 (11%) lesions have progressed within the radiosurgery volume. The actuarial l-, 2-, and 3-year local control rates were 85%, 65%, and 65%, respectively. Radioresistant histologies had equivalent control rates compared with other lesions. In a multivariate analysis, the two factors that predicted for improved local control were supratentorial versus infratentorial location (r.r. 2.31,P = .0087) and treatment for primary tumor versus recurrence (r.r. 4.622, P = .0345). The median survival for the whole group was 9.4 months measured from the radiosurgery treatment. In a multivariate analysis, the absence of systemic disease (r.r. 4.4, P = .0001) and age less than 60 years (r.r. 1.6, P = .002) were factors associated with improved survival. Eighteen patients (7%) required surgery for the development of symptomatic mass effect from 1 to 22 months following radiosurgery. These patients were considered treatment failures and were classified as local failures for the sake of this analysis. At the time of reoperation, 9 patients were found to have necrosis only, whereas the remaining patients had necrosis and "treated" tumor seen at pathology. Although the median peripheral dose varies from one institution to another and does not appear to be correlated with outcome, no clear dose-response relationship has been demonstrated at individual institutions, within the narrow ranges of doses commonly used for radiosurgery. In general, most institutions use lower doses for larger target volumes to minimize risks of complications. Therefore the response rate can be expected to depend on target size. For example, Mehta et al 7 reported complete response (CR) in 78% of tumor volumes smaller than 2 mL and in 50% of tumor volumes equal to or larger than 10 mL. In addition, response durability appeared to correlate with degree of response: only 4% of CRs subsequently progressed whereas 20% of partial responses (PRs) subsequently progressed. An example of a long-term radiosurgery response is seen in Fig I. Alexander et al. ~ found that tumor volume greater than 3 mL was associated with higher rates of local failure in a univariate analysis, although in a multivariate analysis it was of borderline significance (P = .06). Some groups have observed that whole brain radiotherapy in addition to radiosurgery results in a more favorable outcome. Fuller et al 8 found that subsequent brain failure (either in the radiosurgery
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Table 3. Radiosurgery for Brain Metastases
Institution
Technique
Patients Treated
Harvard6 Heidelberg~ Stanford8 Wisconsin7 GKUG 4 Karolinska3~
linac linac linac linac gamma knife gamma knife
248 71 27 40 116 300
Lesions Treated
Dose* (Gy)
Local Control (%)
Median FU (months)
421 124 47 58 116 200
15 17 24.6 18.3 17.5 29
89 94 88 73 85 94
26t 7 5 6.5 9
*Median dose to tumor periphery. 1"Medianfollow-upfor survivors. GKUG, Gamma Knife Users Group. Data from l.~effleret al.28
volume or elsewhere in the brain) was significantly more frequent in patients receiving radiosurgery alone than in those receiving radiosurgery plus whole brain radiotherapy, although this was not reflected as a survival benefit. Flickinger et al 4 found that failure at the radiosurgery site itself was also significantly reduced in patients receiving whole brain radiotherapy in addition to radiosurgery. All groups report clinical improvement and decreased steroid requirements in the majority of patients following radiosurgery, and only 11% to 25% of patients are reported to eventually succumb to neurologic death. 7,8 It has not been established whether patients with multiple brain metastases benefit from radiosurgery. Alexander et al 6 have shown that patients treated for one or two lesions had equal opportunity for survival, but that patients treated for three or more lesions had statistically inferior survival rates ( P - . 0 1 ) with
most of these patients dying of progressive central nervous system disease (secondary to new lesions or carcinomatous meningitis). Several ongoing randomized studies compare the results of radiosurgery to surgery in the t r e a t m e n t of patients with single brain metastases. The study that started more than 2 years ago at t h e J C R T has very poorly accrued patients because of physician or patient preference for either surgery or radiosurgery in individual circumstances. 9 In September of 1994, a decision was made to conduct the protocol through the Radiation T h e r a p y Oncology G r o u p (RTOG) and its m e m b e r s in order to improve accrual. Until this and other studies are completed, it cannot be scientifically stated that these two modalities are equivalent in the t r e a t m e n t of patients with a single brain metastasis. However, retrospective comparison of radiosurgery and surgical series suggest that these
T a b l e 4. Ongoing or Proposed Radiosurgery Studies for Intracranial Malignancies O~ease
Institution(s)
Disease
Status
Study design
Phase
RTOG RTOG RTOG POG GKUG GKUG GKUG JCRT JCRT Kentucky Wisconsin
Malignant glioma Metastatic or primary Metastatic or primary Metastatic or primary Ocular melanoma Multiple mets Single or multiple mets Two mets Single met Single met Single met
New Recurrent Recurrent Recurrent New New/Recurrent New/Recurrent Recurrent Newt New~ New
RS + RT v RT* RS + SR-2508 RS RS RS RS + RT v RT RS + RT v RS RS v RS + SR-2508 RS + RT v surgery + RT RS + RT v RT RT + RS v RT + RS + Fluosoi
HI II I Pilot II I~ IH In IH HI Ill
*Both arms receiveBCNU. tOperable lesion. :[:Inoperablelesion. RTOG, Radiation Therapy Oncologygroup; POG, Pediatric OncologyGroup; GKUG, Gamma Knife User Group;JCRT,Joint Center for Radiation therapy; RS, radiosurgery;RT, radiotherapy; SR-2508,etanidazole.
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treatments appear to produce similar results (Table 5). Other ongoing prospective studies of radiosurgery for brain metastases are listed in Table 4. Considerations in the interpretation of radiosurgery results for brain metastases include: 1. Local control rates, in general, are reported as crude rather than actuarial numbers. Because
2.
3.
4.
5.
most patients die of extracranial disease progression, long-term results are only infrequently available. Local control is measured as "lack of progression" on radiographic studies. The pathological and radiographic complete response rates are relatively low ( < 50%). Adequate quality of life studies following radiosurgery have not been done. Most studies report change in performance status, steroid requirements, and reoperation rates as a measurement of quality of life. The lack of completed randomized trials prevents an adequate comparison of radiosurgery versus surgery or radiotherapy as treatment modalities for patients with single or multiple brain metastases. In an era of health care reform and cost containment, cost analysis and effectiveness studies of radiosurgery are needed.
Malignant Gliomas Despite the ability of surgery, radiotherapy, and chemotherapy to prolong survival in patients with glioblastoma multiform, most patients succumb to their disease, usually as a result of local tumor growth and invasion. Since the original demonstration of a dose-effect relationship of external beam radiation and survival] ~ further attempts at dose escalation using conventional radiation techniques have failed to show an improvement in survival. I1 Conventional fractionated radiotherapy dose is limited to about 60 Gy to avoid unacceptable risks of -brain necrosis.12 Stereotactic radiation techniques (brachytherapy and radiosurgery) have been recently incorporated
F i g u r e 1. (A) Stereotactic CT scan with contrast of a 27-year-old man with a solitary melanoma metastasis centered in the left external capsule. Patient experienced a brief episode of expressive aphasia that led to obtaining a CT scan. He underwent surgery for a Clark Level 4 melanoma of his left forearm 18 years earlier at the age of 9 years. Whole brain radiotherapy was not given due to the long interval from initial diagnosis to the development of this solitary lesion. He was treated with radiosurgery using a 22.5-mm collimator delivering 20 Gy normalized to the 90% isodose distribution. (B) CT scan with contrast obtained 2 years following radiosurgery. The diameter of the enhancement is unchanged, but the central region of the lesion has become necrotic. Despite the increase in surrounding edema, the patients remains asymptomatic and does not require steroids.
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T a b l e 5. Comparison of Radiosurgical and Surgical Treated Patients With a Single Brain Metastasis
Institution
Number of Patients
Leiden 3 Kentucky2 Wisconsin 31 Harvard 6
32 25 19 47
Treatment
Median Survival (weeks)
Median KPS 70 (weeks)
% Local Failure
% Neurological Deaths
Surgery Surgery Radiosurgery Radiosurgery
43 40 40 49
34 38 36 36
NS 20 I1 I1
33 29 17 18
NOTE. The patients in the two radiosurge~" studies fit the eligibilitycriteria of those used b.vthe Universityof Kentucky stud','.NS, not stated. as "boost" techniques to full dose external beam radiation ( ~ 60 Gy) to focally escalate the total dose of radiation to areas of greatest t u m o r cell density (enhancing regions on computed tomography [CT] and magnetic resonance imaging [MRI]) without irradiating significant volumes of normal brain tissue immediately outside the target volume) 3 Intuitively, any focal treatment cannot be expected to ultimately control nonfocal or infiltrating disease processes) 4 Uncontrolled prospective studies (Table 6) from the University of California, San Francisco (UCSF), and the J C R T suggest that high activity ~25I brachytherapy results in significantly improved survival. 15,16 Further evidence to support the use ofbrachytherapy in the initial m a n a g e m e n t of patients with malignant glioma was recently presented by the Brain T u m o r Cooperative Group (BTCG). Green et a117 presented the results of the B T C G trial 8701 that randomized more than 250 patients (87% of the patients had the diagnosis of glioblastoma) to brachytherapy (60 Gy) and external beam radiotherapy (60.2 Cry) and BCNU versus radiotherapy and BCNU alone. Both groups underwent a second operation following treatment if clinical or radiographic "failure" was suspected. The median survival for those patients undergoing brachytherapy (125) was 16 months compared with the 13 months for the 131 patients not receiving brachytherapy (P = .02). The reoperation rates for the two groups were 50% and 42%, respectively.
The encouraging results from the brachytherapy experiences of UCSF, JCRT, and BTCG mentioned above have lead some to consider radiosurgery as a technique for focal dose escalation for malignant glioma patients) ~ Because the close distribution of radiosurge~' and brachythera W are similar, it would therefore appear to have the same potential for improving survival. The potential advantages of radiosurgery boost, as well as those of brachytherapy boost, are listed in Table 7. A summary of results of each boost technique is presented in Table 6 and shows that median survivals measured from time of diagnosis are 1! to 22 months. With the exception of the radiosurgery study from the University of Wisconsin, 19 institutional protocols required that patients have unifocal, well-demarcated enhancing lesions on C T and MRI; have Karnofsky performance status (liPS) of at least 70%; have m a x i m u m target dimension of 5 cm (brachytheraw) or 4 cm (radiosurgery); and receive conventional external beam radiotherapy to approximately 60 Gy in 33 fractions before having boost treatment. Reoperation to remove symptomatic radiation necrosis, recurrent tumor, or both was often required for either boost techniqueJ ~ Brachytherapy doses were prescribed according to institutional protocois and were not dependent on target volume; radiosurger3" doses were prescribed according to
T a b l e 6. Stereotactic Radiation Boost for Primary Glioblastoma Muitiforme (GBM)
Institution
Boost Technique
Boost Dose* (Gy)
UCSF 15 BTCGt 7t Harvard 16 Wisconsin 19 Harvard 24
125Ibrachytherapy 125Ibrachytherapy l~5Ibrachytherapy Radiosurgery Radiosurgery
52.9 60 50.0 12.0 12.0
*Median dose to tumor periphe~'. "t"87%of patients GBM.
Patients
Median Survival (months)
Reoperation Rate ('/,)
106 125 56 50 69
22 16 18 11 19.7
38 50 64 I0 38
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Table 7.
Brachytherapy Boost Versus Radiosurgery Boost for Malignant Glioma Advantages of Brachytherapy Biological advantage of continuous irradiation for hypoxic tumors Opportunity to obtain tissue for biological and pathological correlation Allows simultaneous use of radiation modifiers delivered over several days Extensive experience both in North America and Europe Advantages of Radiosurgery Biological advantage of large fraction for radioresistant tumors Requires minimal hospitalization (reduced costs) Avoids risk of hemorrhage, infection, and tumor seeding Data fromLarsonet al.32 protocol and were based on lesion location and volume.
Recurrent Glioblastoma Radiosurgery and brachytherapy have also been used in patients with recurrent glioblastoma and the results are summarized in Table 8. We have recently completed an analysis of 118 patients with recurrent glioblastoma treated with either brachytherapy32 or radiosurgery 86 at t h e J C R T between December 1985 and July 1993.21 Patient characteristics were similar in both groups with the exception of tumor volume. Median tumor volumes were 10.1 mL and 29 mL for radiosurgery and brachytherapy, respectively. Initially, brachytherapy represented standard therapy for these recurrent tumors with radiosurgery being reserved for smaller tumor volumes, tumors in nonimplantable sites (deep grey structures, brainstem, or eloquent cortex) or patients who were believed to be at increased risk for brachytherapy-related complications. However, with further experience, radiosurgery became the preferred treatment, except in cases of larger or irregularly shaped volumes. Twentyone patients (24%) treated with stereotactic radiosur-
Table 8.
gery (SRS) were alive with median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with radiosurgery was 10.2 months, with 12 months and 24 months survivals being 45% and 19%, respectively. Younger age and smaller tumor volume were predictive of better outcome. Tumor dose, interval from initial diagnosis, and need for reoperation were not predictive of outcome following radiosurgery. Five patients (16%) treated with brachytherapy were alive with median follow-up of 43.3 months. Median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals at 12 and 24 months were 44% and 17%, respectively. Patient age, but not tumor volume, interval from initial diagnosis, or tumor dose was predictive of outcome in these patients. Comparison of results between patients treated with radiosurgery and brachytherapy indicated similar survival. Nineteen patients (22%) required reoperation following radiosurgery compared with 14 (44%) in the brachytherapy group. Actuarial risk for reoperation was 33% at 12 months and 48% at 24 months following radiosurgery compared with 54% and 65%, respectively, following brachytherapy (P = . 195). Patients undergoing reoperation following brachytherapy survived longer than similar patients not undergoing reoperation. Outcome following SRS was independent of need for reoperation. An example of the radiographic results following radiosurgery for a recurrent glioblastoma is shown in Fig 2.
Newly Diagnosed Malignant Gliomas The interpretation of the results from radiosurgery or brachytherapy is difficult because the patients selected for such procedures represent a subgroup of patients with a relatively good prognosis, even with standard therapy. This appears to be confirmed in several retrospective analyses of outcome in protocol eligible or ineligible patients, none of whom received
Stereotactic Radiation for Recurrent Glioblastoma Multiforme
Institution
Boost Technique
Dose (Gy)*
Harvard21 UCSF 15 Harvard21
125Ibrachytherapy 125Ibrachytherapy Radiosurgery
50 64.4 13.0
*Mediandose to tumor periphery.
Patients
Median Survival (months)
Reoperation Rate(%)
32 66 86
11.5 12 10
44 38 22
Radiosurgeryfor IntracranialMalignancies
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P a t i e n t had ~i~Hitic~ml c • ttl~ta,~si~ at tl~i- ~imc. "Fhr h,.i,m ~,,~- IFt'Al,'(] \xil}l A -)~'.-)-llllli t't)]]iil/tlll)l" ;lnti rrt cixcd 15 G \ n ( w m a l i z c d 1o l}w ~{()% isodosc <[isuibtad~m. (B) ( : T scaa ~,it}l (i)illltt.~l ~) I11()11[}1~ lilll()\x[l'l~ rtidi(~ur~cl-) Ql<)\~ila~ till c n l a r ~ i n ~ m a s s w i t h central iaccrosis ar~c{ incvc~scci ccicma. l ' h c [):/liClll I t'(ltlil't'(] ]~i II]~ (It dCX~lH1Cl}]zl:4olIc [)~I cltt.) ~.P.(t \~.~l~, d e v e l o p i n g a mild righ~ }'~emipai-csis. Rcopcrati
232
Loejtter et al
boost therapy. 22,23Florell et a123 reported a significant increase in median survival rate from 9.3 months to 16.6 months (P = .0001) for brachytherapy ineligible versus brachytherapy eligible glioblastoma and anaplastic astrocytoma patients treated with external beam radiotherapy alone. In a similar designed study, Curran et a122 reviewed the results from the R T O G 83-02 trial and reported an improvement in survival for radiosurgery eligible patients compared with ineligible patients using the criteria established by our group at theJCRT. The radiosurgery eligible patients had a median survival of 14.4 months versus 11.7 months (P = .04) for boost ineligible patients. Typically, patients considered "eligible" for radiosurgery boost protocols have a KPS > 70%, radiographically discrete tumors measuring < 4 cm in greatest diameter, and no evidence of subependymal spread. Unfortunately, in our experience only 10% to 20% of patients with newly diagnosed glioblastoma meet the eligibility criteria for boost protocols involving radiosurgery or brachytherapy. Recently, the experience at the J C R T using radiosurgery as an adjunct treatment to surgery and full-dose external beam radiotherapy was reviewed. 24 Between May 1988 and April 1994, 69 patients (median tumor volume 9.3 mL) with glioblastoma treated were using radiosurgery (median dose 12 Gy) within 4 weeks of external beam radiotherapy (54.9 Gy in 33 fractions). To be eligible, patients had to have a KPS of 70% or greater, a tumor volume < 4 cm, and no evidence of multifocality or subependymal spread. Chemotherapy was not a part of the formal protocol, although six patients received postradiosurgery chemotherapy at the referring physician's request. These 69 patients represented approximately 20% of the glioblastoma patients evaluated for the protocol. Patients were followed-up at 3-month intervals with complete neurological examinations and CT or MRI studies. If a question of recurrence or radiation necrosis was suspected from these morphological radiographic examinations, patients underwent functionai MRI or dual isotope single photon emission computed tomography (SPECT) studies. The median survival for the whole group measured from the time of pathological diagnosis was 19.7 months (range 6 to 60+ months). Reoperation was required for progressive symptomatic mass effect in 38% of patients. At the time of reoperation, most patients were found to have a combination of "treated" tumor cells and necrosis. In a multivariate analysis, younger age ( P = .011) and higher dose (P = .045) were the only factors predicting for pro-
longed survival. Patients who underwent a reoperation for symptomatic mass effect enjoyed an improved quality of life and were, in general, maintained on a lower dose of steroid support. However, reoperation did not confer an improvement in survival (P = .952).
In contrast to these favorable results, the University of Wisconsin recently reported their experience in 31 patients with glioblastoma treated in a similar fashion. Between January 1989 and December 1992, 31 patients were treated with a radiosurgery boost (median dose, 12 Gy) following full-dose external beam radiotherapy (median dose, 54 Gy). These patients represented 61% of the total patients evaluated for the protocol compared with the 20% rate from the JCRT. The median tumor volume of this group of patients was 17.4 mL compared with 9.3 cc for the J C R T patients. The median KPS was 70% with a range from as low as 20% to 90%. The overall actuarial median survival of the entire group was 42 weeks, with the 1- and 2-year actuarial rates being 38% and 28%. In a multivariate analysis, only age ( < 55 years v > 55 years) bordered on significance with a P value of.051. Based solely on clinical criteria of deteriorating symptoms and increasing steroid dependence, 26 of 31 (84%) patients were considered to progress. However, with the use of functional radiographic studies (positron emission tomography, SPECT, MR spectroscopy), it was determined that no patient failed to respond within the radiosurgery treatment volume. Peripheral failures (within 2 cm from the radiosurgery volume) accounted for 79% of the recurrences whereas distant failure (greater than 2 cm from the radiosurgery volume) occurred in 17% of the patients. Although the median survival in this study was similar to that seen in patients treated with conventional radiotherapy techniques, the 2-year survival rate of 28% and the lack of central recurrences (within the radiosurgery volume) were encouraging. It is quite obvious that difficulties are encountered in the comparison ofradiosurgery trials performed at different institutions using different eligibility criteria. In the two largest experiences using radiosurgery in the initial therapy of patients with glioblastoma discussed above, the results are quite disparate despite similar treatment schedules. The identification of appropriate historical control groups is strongly dependent on pretreatment prognostic factors. The RTOG has recently published a nonparametric recursive partitioning analysis of three previous external beam radiotherapy trials where patients were strati-
RadiosurgeryforIntracranialMalignancies
fled into six prognostic classes based on a combination of prognostic and treatment variables. 25 It has been postulated that stratification of patients with this schema may be advantageous in evaluating the outcome of patients treated with radiosurgery in order to control for the multitude of possible prognostic factors. A study was recently reported that compared the results of patients treated with radiosurgery and external beam radiotherapy as part of the initial therapy in patients with malignant gliomas. 26 In order to create a large data base, three institutions (Universities of Wisconsin and Florida, and the JCRT) combined their data and collected 115 patients treated in a similar fashion all using radiosurgery as part of the initial therapy. These I t5 patients were stratified into prognostic classes as described by the investigators from the RTOG. These prognostic classes were determined by a nonparametric recursive partitioning analysis of the results from three previous R T O G studies. The statistical technique of recursive partitioning analysis results in the stratification of patients into classes based on a decision tree formed from the determination of the relative importance of various prognostic classes (1 through 6) with class 1 having the best prognosis and class 6 having the worse. The actuarial survival at 2 years for the entire cohort of patients with GBM was 38% with a median survival of 91 weeks. Stratification of patients by prognostic groups revealed a significant difference in overall survival by class (P < .001). The overall survival for patients treated with radiosurgery appears superior to the results reported by the RTOG. There was a minimal difference in survival for class l patients from either group, whereas classes 3 through 5/6, the radiosurgery patients, appeared to have a superior 2-year and median survival. The differences in outcome for class 5 patients was striking with a median survival of 13.1 months and 2-year survival of 21% for the radiosurgery patients compared with 9 months and 6%, respectively, for the R T O G patients. In contrast to the radiosurgery patients with a marked decreased in survival classes 3 and 4, the survival for the R T O G patients decreased earlier with a marked difference in survival between the class 2 and 3 patients. In summary, the treatment of patients with malignant gliomas with combination full-dose external beam radiotherapy and a radiosurgery boost appears to results in a superior overall median and 2-year survival in comparison to published results of pa-
2,33
tients with similar prognostic features treated with external beam radiotherapy alone. In addition, the results of radiosurgery appear similar to those reported from the BTCG, UCSF, and t h e J C R T using msI brachytherapy with less-attendant morbidity. Based on the encouraging results discussed above, R T O G is beginning a prospective, randomized study evaluating the role of radiosurgery in the initial management of patients with malignant gliomas. R T O G 9305 will randomize patients with supratentorial malignant gliomas who are > 18 years old with K ~ of > 60 and postoperative residual disease of _<4 cm in greatest diameter to radiosurgery ( 15 to 21 Gy) followed by radiothera W (60 Gy) and BCNU compared with radiotherapy and BCNU alone. Eventual randomized trials will be required to determine which boost technique provides a more favorable outcome, either for primary or recurrent glioblastoma. In summary, radiosurgery and brachytherapy produce similar survival rates in recurrent and newly diagnosed patients with glioblastoma. 2~ The development of symptomatic radiation necrosis requiring prolonged steroid support, and reoperation appears to be the same for both stereotactic radiation techniques. Thus, radiosurgery is a more appealing technique in the management of highly focal malignant gliomas than brachytherapy because it is a noninvasire, single-day procedure.
References 1. Lunsford LD, Alexander E III, LoefflerJS:General introduction: Histoq"of radiosurgery, in E Alexander III,JS l_,oeffler, LD Lunsford (eds):StereotacticRadiosurgery.NewYork, NY, McGraw-Hill, 1993,pp 1-4. 2. Patchell RA,Tibbs PA, WalshJW, et al: A randomized trial of surge~" in the treatment of single metastases to the brain. N EnglJ Med 322:494-500,1990 3. NoordijkEM, Vecht CJ, Haaxma-Reiche H, et al: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys29:711-717,1994 4. FlickengerJC, Kondziolka D, Lunsford LD, et al: A multiinstitutional experience ~ith stereotactic radiosurgeD" for solitary brain metastasis. IntJ Radiat Oncol Biol Phys 28:797802, 1994 5. LoefflerJS,AlexanderE II/:Radiosurgeryfor the treatmentof intracranial metastases, in EI Alexander, JS Loemer, LD Lunsford (eds): Stereotactic radiosurgery. New York, NY, McGraw-Hill, 1993,pp 197-206 6. Alexander E III, Moriarty TM, Davis R.B,et al: Stereotactic radiosurgery for the definitive, noninvasivetreatment ofbrain metastases.J Natl Cancer Inst 87:34-40, 1995 7. Mehta MP, RozentalJM, LeninAB, et al: Defining the role of
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radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 24:619-625, 1992 8. Fuller BG, Kaplan ID, AdlerJ, et al: Stereotaxic radiosurgery for brain metastases: The importance of adjuvant whole brain radiotherapy. IntJ Radiat Oncol Biol Phys 23:413-418, 1992 9. Loeffler JS, Shrieve DC: What is appropriate therapy for a patient with a single brain metastasis. IntJ Radiat Oncol Biol Phys 29:915-917, 1994 10. Walker MD, Strike TA, Sheline GE: An analysis of dose-effect relationship in radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5:1725-1731, 1979 11. Chang C, Horton J, Schoenfeld D, et al: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the muhidic-sciplinary management of malignant gliomas. Cancer 52:997, 1983 12. Sheline GE, Wara WM, Smith V: Therapeutic irradiation and brain injury. IntJ Radiat Oncol Biol Phys 6:1215, 1980 13. Leibel SA, Scott CB, LoefiterJS: Contemporary approaches to the treatment of malignant gliomas with radiation therapy. Semin Oncol 21:198-219, 1994 14. Halperin EC, Burger PC, Bullard DE: The fallacy of the localized malignant glioma. I n t J Radiat Oncol Biol 15:505509, 1988 15. Scharfen CO, Sneed PK, Wara WM, et al: High activity iodine-125 implant for gliomas. Int J Radiat Oncol Biol Phys 24:583-591, 1992 16. Wen PY, Mexander E III, Black PM, et al: Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas. Cancer 73:3029-3036, 1994 17. Green SB, Shapiro WR, Burger PC, et al: A randomized trial of interstitial radiotherapy (RT) boost for newly diagnosed malignant glioma: Brain Tumor Cooperative Group (BTCG) Trial 8701. Proceedings of the American Society of Clinical Oncology, Dallas, TX, 1994, p 174 18. LoefflerJ, Alexander E IlI, Shea M, et al: Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Onco110:1379-1385, 1992 19. Mehta MP, Massciopinto J, Rozental J, et al: Stereotactic radiosurgery for glioblastoma multiforme: Report of a prospective study evaluating prognostic factors and analyzing longterm survival advantage. IntJ Radiat Oncol Biol Phys 30:541549, 1994 20. Alexander E III, Black P, Wen PY, et al: Results of radiosurgery versus brachytherapy for malignant gliomas, in AAF DeSalles, SJ Goetsch (eds): Stereotactic Surgery and Radiosurgery. Madison, WI, Medical Physics Publishing, 1993, pp 455-461
21. Shrieve DC, Alexander E llI, Wen PY, et ah Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36:275284, 1995 22. Curran WJ, Scott CB, Weinstein AS, et al: Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: A report of Radiation Therapy Oncology Group 83-02.J Clin Oncol 11:857-862, 1993 23. Florell RC, MacDonald DR, Irish WD, et al: Selection bias, survival and brachytherapy for glioma. J Neurosurg 76:179183, 1992 24. Addesa AE, Shrieve DC, Alexander E BI, et al: Longterm results of radiosurgery for newly diagnosed patients with glioblastoma. (submitted for publication) 25. Curran WJ, Scott CB, HortonJ, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials.J Natl Cancer Inst 85:704-710, 1993 26. Sarkaria JN, Mehta MP, Loemer JS, et al: Stereotactic radiosurgery improves survival in malignant gliomas compared with the RTOG recursive partitioning analysis. Int J Radiat Oncol Biol Phys 30:164, 1995 27. LoeflterJS, Larson DA: Radiosurgery in the management of intracranial lesions: A radiation oncology prospective, in WC Dewey, M Edington, RJM Fry, et al (eds): Radiation Research: A Twentieth-Century Perspective. San Diego, CA, Harcourt Brace Jovanovich, 1992, pp 535-540 28. Loeffler JS, Larson DA, Shrieve DC, et al: Radiosurgery for the treatment of intracranial lesions, in VT DeVita, S Hellman, SA Rosenberg (eds): Yearbook of Oncology. Philadelphia, PA,J.B. Lippincott, 1994 29. Engenhart R, Kimmig B, Hover K, et al: Long term follow-up for brain metastases treated percutaneous single high dose radiation. Cancer 71:1353-1361, 1993 30. Kihlstrom L, Karlsson B, Lindquist C: Stereotactic radiosurgery for single and multiple cerebral metastases. Acta Neurochirurgia 122:158, 1993 31. Mehta M: Radiosurgery for brain metastases, in DeSalles AF, SJ Goetsch (eds): Stereotactic Surgery and Radiosurgery. Madison, WI, Medical Physics, 1993, pp 353-368 32. Larson DA, Flickinger JC, LoefflerJS: Stereotactic radiosurgery: Techniques and results, in VT DeVita S Hellman, SA Rosenberg (eds): Cancer: Principle and Practice of Oncology Updates. Philadelphia, Lippincott, 1993, pp 1-19
surgery compares favorably with interstitial brachytherapy for both recurrent as well as in newly diagnosed patients with malignant gliomas in terms of improved survival and the need of surgery and steroid support for symptomatic radiation changes. Prospective studies (Phase I through III) are ongoing to determine the ultimate role of radiosurgery in the management of patients with newly diagnosed and recurrent malignant giiomas, recurrent pediatric brain tumors disease, and patients with single or multiple intracranial metastases. Copyright 9 1995 by W.B. Saunders Company
R
thera W have significant b" fewer recurrences at the initial metastatic site compared with those receiving whole brain radiotherapy alone; they also have significantly increased survival and improved quality of life. 2,3 This is particularly true for younger patients and patients without evidence of progressive systemic disease. 3 So far, systemic chemotherapy has not been demonstrated to significantly influence outcome. Patients with extracranial metastases from melanoma or renal cell carcinoma who might otherwise qualify for promising therapies with biologic response modifiers are usually excluded if brain metastases are present. The biological and physical characteristics of metastases (Table 1) appear to make them ideal radiosurgery targets. The potential advantages of radiosurgery, as well as those of surgery,, are listed in Table 2. A summary, of results obtained by various groups treating metastases with radiosurge D' indicates local control is obtained in 73% to 98% of patients, with median follow-up of 5 to 26 months (Table 3). Flickinger et al 4 recently reported the results from a multi-institutional trial (Gamma Knife [I~skell G a m m a Unit; Elekta Radiosurgery, Inc, Atlanta, GA] Users Group) involving ! 16 patients treated with g a m m a knife radiosurgery for single brain metastasis. With a mean minimum dose of 17.5 Gy, local tumor control was obtained in 99 patients (85%). The 2-year actuarial tumor control rates for the whole group was 67% -+ 8% with a plateau in the curve at 18 months suggesting that local control rates are durable in the majority of patients. In a multivariate analysis, better local control was obtained in patients who received whole brain radiotherapy in addition to radiosurgery and in those patients with "radioresistant" histologies (mela-
adiosurgery was originally described as a technique to deliver a large single fraction of highly focal radiation to treat functional disorders (pain, movement disorders, psychiatric disorders, etc.) and later to treat arteriovenous malformations and benign tumors. 1Malignant lesions were not considered appropriate targets for radiosurgery mainly because of their invasiveness and large volumes. Over the last 6 years, there has been a growing interest in the use of radiosurgery in the treatment of primary, and metastatic brain tumors. This article reviews the results and complications associated with the use of radiosurgery in the treatment of both metastatic disease and malignant glioma as part of initial management and for recurrence.
Metastases Patients with symptomatic brain metastases have a median survival of about I month if left untreated and 3 to 6 months if whole brain radiation therapy is delivered, without significant differences between various conventional radiotherapy fractionation schemes. Patients undergoing surgery and radio-
From The Brain Tumor Center of the Brigham and Women'sHospital, Children's Hospital, Dana-Fa~er CancerInstitute, Joint Centerfor Radiation Therapy; and the Departments of Radiation Oncology, Neurology. Medicine, and Neurosurgery, Harvard Medical School, Boston, MA. Supported in part by National Imtitutes of Health Grants No. P2ONS3110 (JSL, PMB), KllCAOt496 (PYW), and KllCAOI467 (HAF). Address reprint requests to Jay S. Loeffter, MD, Joint Centerfor Radiation Therapy, 75Francis Street, Boston, MA 02115. Copyright 9 1995 by W.B. Saunders Company 1053-4296/95/0503-0008505.00/0
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Table 1. Characteristics of Metastases: Ideal Radiosurgery Targets Often nearly spherical and radiographically distinct UsuaIly relatively small ( < 30 ram) at presentation Displace normal brain parenchyma circumferentially beyond the target volume which reduces risk of normal tissue injury Minimally invasive (entire extent of disease usually encompassed within target volume) Data from Loeffieret al.5 noma and renal cell carcinoma). The paradoxical finding of better control in histologies that are known to be radioresistant to fractionated radiotherapy has been reported by others. 5 Median survival measured from the time of radiosurgery was 11 months with patients with breast cancer having the best survival. These encouraging results have led to the design of prospective, randomized studies to be conducted by this group for patients with single or multiple brain metastases (Table 4). Alexander et al. 6 recently reviewed and reported their 7-year experience from the Joint Center for Radiation Therapy (JCRT) for patients with intracranial metastases treated with radiosurgery. The authors treated 421 metastatic lesions in 248 patients between May 1986 and May 1993. Sixty patients were treated as a planned boost following whole brain radiotherapywhereas 188 patients were treated at the time of recurrence. At the time of radiosurgery, 77 patients had no evidence of systemic disease whereas 171 patients had stable systemic disease. O f the lesions treated, 126 were classified as "radioresistant" (melanoma, renal cell carcinoma, and sarcoma) based on their response to conventionally fractionated radiotherapy with the remaining 295 lesions representing all other histologies. A single lesion was treated in 177 patients, 52 patients were treated for two lesions, and 19 patients were treated for three or more lesions. The median minimum
Table 2. Surgery Versus Radiosurgery for Metastases Advantages of surgery Provides immediate resolution of mass effect Provides diagnostic information if required Avoids risk of radiation necrosis Advantages of radiosurgery Links treatment directly to 3-D tumor visualization (reduces chances of "marginal miss") Requires minimal hospitalization (reduced costs) Avoids risk of hemorrhage, infection, and tumor seeding Data from Loeffleret al.27
dose was 15 Gy with a median tumor volume of 3.0 mL. With a median observation period of 26 months, 48/421 (11%) lesions have progressed within the radiosurgery volume. The actuarial l-, 2-, and 3-year local control rates were 85%, 65%, and 65%, respectively. Radioresistant histologies had equivalent control rates compared with other lesions. In a multivariate analysis, the two factors that predicted for improved local control were supratentorial versus infratentorial location (r.r. 2.31,P = .0087) and treatment for primary tumor versus recurrence (r.r. 4.622, P = .0345). The median survival for the whole group was 9.4 months measured from the radiosurgery treatment. In a multivariate analysis, the absence of systemic disease (r.r. 4.4, P = .0001) and age less than 60 years (r.r. 1.6, P = .002) were factors associated with improved survival. Eighteen patients (7%) required surgery for the development of symptomatic mass effect from 1 to 22 months following radiosurgery. These patients were considered treatment failures and were classified as local failures for the sake of this analysis. At the time of reoperation, 9 patients were found to have necrosis only, whereas the remaining patients had necrosis and "treated" tumor seen at pathology. Although the median peripheral dose varies from one institution to another and does not appear to be correlated with outcome, no clear dose-response relationship has been demonstrated at individual institutions, within the narrow ranges of doses commonly used for radiosurgery. In general, most institutions use lower doses for larger target volumes to minimize risks of complications. Therefore the response rate can be expected to depend on target size. For example, Mehta et al 7 reported complete response (CR) in 78% of tumor volumes smaller than 2 mL and in 50% of tumor volumes equal to or larger than 10 mL. In addition, response durability appeared to correlate with degree of response: only 4% of CRs subsequently progressed whereas 20% of partial responses (PRs) subsequently progressed. An example of a long-term radiosurgery response is seen in Fig I. Alexander et al. ~ found that tumor volume greater than 3 mL was associated with higher rates of local failure in a univariate analysis, although in a multivariate analysis it was of borderline significance (P = .06). Some groups have observed that whole brain radiotherapy in addition to radiosurgery results in a more favorable outcome. Fuller et al 8 found that subsequent brain failure (either in the radiosurgery
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Table 3. Radiosurgery for Brain Metastases
Institution
Technique
Patients Treated
Harvard6 Heidelberg~ Stanford8 Wisconsin7 GKUG 4 Karolinska3~
linac linac linac linac gamma knife gamma knife
248 71 27 40 116 300
Lesions Treated
Dose* (Gy)
Local Control (%)
Median FU (months)
421 124 47 58 116 200
15 17 24.6 18.3 17.5 29
89 94 88 73 85 94
26t 7 5 6.5 9
*Median dose to tumor periphery. 1"Medianfollow-upfor survivors. GKUG, Gamma Knife Users Group. Data from l.~effleret al.28
volume or elsewhere in the brain) was significantly more frequent in patients receiving radiosurgery alone than in those receiving radiosurgery plus whole brain radiotherapy, although this was not reflected as a survival benefit. Flickinger et al 4 found that failure at the radiosurgery site itself was also significantly reduced in patients receiving whole brain radiotherapy in addition to radiosurgery. All groups report clinical improvement and decreased steroid requirements in the majority of patients following radiosurgery, and only 11% to 25% of patients are reported to eventually succumb to neurologic death. 7,8 It has not been established whether patients with multiple brain metastases benefit from radiosurgery. Alexander et al 6 have shown that patients treated for one or two lesions had equal opportunity for survival, but that patients treated for three or more lesions had statistically inferior survival rates ( P - . 0 1 ) with
most of these patients dying of progressive central nervous system disease (secondary to new lesions or carcinomatous meningitis). Several ongoing randomized studies compare the results of radiosurgery to surgery in the t r e a t m e n t of patients with single brain metastases. The study that started more than 2 years ago at t h e J C R T has very poorly accrued patients because of physician or patient preference for either surgery or radiosurgery in individual circumstances. 9 In September of 1994, a decision was made to conduct the protocol through the Radiation T h e r a p y Oncology G r o u p (RTOG) and its m e m b e r s in order to improve accrual. Until this and other studies are completed, it cannot be scientifically stated that these two modalities are equivalent in the t r e a t m e n t of patients with a single brain metastasis. However, retrospective comparison of radiosurgery and surgical series suggest that these
T a b l e 4. Ongoing or Proposed Radiosurgery Studies for Intracranial Malignancies O~ease
Institution(s)
Disease
Status
Study design
Phase
RTOG RTOG RTOG POG GKUG GKUG GKUG JCRT JCRT Kentucky Wisconsin
Malignant glioma Metastatic or primary Metastatic or primary Metastatic or primary Ocular melanoma Multiple mets Single or multiple mets Two mets Single met Single met Single met
New Recurrent Recurrent Recurrent New New/Recurrent New/Recurrent Recurrent Newt New~ New
RS + RT v RT* RS + SR-2508 RS RS RS RS + RT v RT RS + RT v RS RS v RS + SR-2508 RS + RT v surgery + RT RS + RT v RT RT + RS v RT + RS + Fluosoi
HI II I Pilot II I~ IH In IH HI Ill
*Both arms receiveBCNU. tOperable lesion. :[:Inoperablelesion. RTOG, Radiation Therapy Oncologygroup; POG, Pediatric OncologyGroup; GKUG, Gamma Knife User Group;JCRT,Joint Center for Radiation therapy; RS, radiosurgery;RT, radiotherapy; SR-2508,etanidazole.
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treatments appear to produce similar results (Table 5). Other ongoing prospective studies of radiosurgery for brain metastases are listed in Table 4. Considerations in the interpretation of radiosurgery results for brain metastases include: 1. Local control rates, in general, are reported as crude rather than actuarial numbers. Because
2.
3.
4.
5.
most patients die of extracranial disease progression, long-term results are only infrequently available. Local control is measured as "lack of progression" on radiographic studies. The pathological and radiographic complete response rates are relatively low ( < 50%). Adequate quality of life studies following radiosurgery have not been done. Most studies report change in performance status, steroid requirements, and reoperation rates as a measurement of quality of life. The lack of completed randomized trials prevents an adequate comparison of radiosurgery versus surgery or radiotherapy as treatment modalities for patients with single or multiple brain metastases. In an era of health care reform and cost containment, cost analysis and effectiveness studies of radiosurgery are needed.
Malignant Gliomas Despite the ability of surgery, radiotherapy, and chemotherapy to prolong survival in patients with glioblastoma multiform, most patients succumb to their disease, usually as a result of local tumor growth and invasion. Since the original demonstration of a dose-effect relationship of external beam radiation and survival] ~ further attempts at dose escalation using conventional radiation techniques have failed to show an improvement in survival. I1 Conventional fractionated radiotherapy dose is limited to about 60 Gy to avoid unacceptable risks of -brain necrosis.12 Stereotactic radiation techniques (brachytherapy and radiosurgery) have been recently incorporated
F i g u r e 1. (A) Stereotactic CT scan with contrast of a 27-year-old man with a solitary melanoma metastasis centered in the left external capsule. Patient experienced a brief episode of expressive aphasia that led to obtaining a CT scan. He underwent surgery for a Clark Level 4 melanoma of his left forearm 18 years earlier at the age of 9 years. Whole brain radiotherapy was not given due to the long interval from initial diagnosis to the development of this solitary lesion. He was treated with radiosurgery using a 22.5-mm collimator delivering 20 Gy normalized to the 90% isodose distribution. (B) CT scan with contrast obtained 2 years following radiosurgery. The diameter of the enhancement is unchanged, but the central region of the lesion has become necrotic. Despite the increase in surrounding edema, the patients remains asymptomatic and does not require steroids.
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T a b l e 5. Comparison of Radiosurgical and Surgical Treated Patients With a Single Brain Metastasis
Institution
Number of Patients
Leiden 3 Kentucky2 Wisconsin 31 Harvard 6
32 25 19 47
Treatment
Median Survival (weeks)
Median KPS 70 (weeks)
% Local Failure
% Neurological Deaths
Surgery Surgery Radiosurgery Radiosurgery
43 40 40 49
34 38 36 36
NS 20 I1 I1
33 29 17 18
NOTE. The patients in the two radiosurge~" studies fit the eligibilitycriteria of those used b.vthe Universityof Kentucky stud','.NS, not stated. as "boost" techniques to full dose external beam radiation ( ~ 60 Gy) to focally escalate the total dose of radiation to areas of greatest t u m o r cell density (enhancing regions on computed tomography [CT] and magnetic resonance imaging [MRI]) without irradiating significant volumes of normal brain tissue immediately outside the target volume) 3 Intuitively, any focal treatment cannot be expected to ultimately control nonfocal or infiltrating disease processes) 4 Uncontrolled prospective studies (Table 6) from the University of California, San Francisco (UCSF), and the J C R T suggest that high activity ~25I brachytherapy results in significantly improved survival. 15,16 Further evidence to support the use ofbrachytherapy in the initial m a n a g e m e n t of patients with malignant glioma was recently presented by the Brain T u m o r Cooperative Group (BTCG). Green et a117 presented the results of the B T C G trial 8701 that randomized more than 250 patients (87% of the patients had the diagnosis of glioblastoma) to brachytherapy (60 Gy) and external beam radiotherapy (60.2 Cry) and BCNU versus radiotherapy and BCNU alone. Both groups underwent a second operation following treatment if clinical or radiographic "failure" was suspected. The median survival for those patients undergoing brachytherapy (125) was 16 months compared with the 13 months for the 131 patients not receiving brachytherapy (P = .02). The reoperation rates for the two groups were 50% and 42%, respectively.
The encouraging results from the brachytherapy experiences of UCSF, JCRT, and BTCG mentioned above have lead some to consider radiosurgery as a technique for focal dose escalation for malignant glioma patients) ~ Because the close distribution of radiosurge~' and brachythera W are similar, it would therefore appear to have the same potential for improving survival. The potential advantages of radiosurgery boost, as well as those of brachytherapy boost, are listed in Table 7. A summary of results of each boost technique is presented in Table 6 and shows that median survivals measured from time of diagnosis are 1! to 22 months. With the exception of the radiosurgery study from the University of Wisconsin, 19 institutional protocols required that patients have unifocal, well-demarcated enhancing lesions on C T and MRI; have Karnofsky performance status (liPS) of at least 70%; have m a x i m u m target dimension of 5 cm (brachytheraw) or 4 cm (radiosurgery); and receive conventional external beam radiotherapy to approximately 60 Gy in 33 fractions before having boost treatment. Reoperation to remove symptomatic radiation necrosis, recurrent tumor, or both was often required for either boost techniqueJ ~ Brachytherapy doses were prescribed according to institutional protocois and were not dependent on target volume; radiosurger3" doses were prescribed according to
T a b l e 6. Stereotactic Radiation Boost for Primary Glioblastoma Muitiforme (GBM)
Institution
Boost Technique
Boost Dose* (Gy)
UCSF 15 BTCGt 7t Harvard 16 Wisconsin 19 Harvard 24
125Ibrachytherapy 125Ibrachytherapy l~5Ibrachytherapy Radiosurgery Radiosurgery
52.9 60 50.0 12.0 12.0
*Median dose to tumor periphe~'. "t"87%of patients GBM.
Patients
Median Survival (months)
Reoperation Rate ('/,)
106 125 56 50 69
22 16 18 11 19.7
38 50 64 I0 38
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Table 7.
Brachytherapy Boost Versus Radiosurgery Boost for Malignant Glioma Advantages of Brachytherapy Biological advantage of continuous irradiation for hypoxic tumors Opportunity to obtain tissue for biological and pathological correlation Allows simultaneous use of radiation modifiers delivered over several days Extensive experience both in North America and Europe Advantages of Radiosurgery Biological advantage of large fraction for radioresistant tumors Requires minimal hospitalization (reduced costs) Avoids risk of hemorrhage, infection, and tumor seeding Data fromLarsonet al.32 protocol and were based on lesion location and volume.
Recurrent Glioblastoma Radiosurgery and brachytherapy have also been used in patients with recurrent glioblastoma and the results are summarized in Table 8. We have recently completed an analysis of 118 patients with recurrent glioblastoma treated with either brachytherapy32 or radiosurgery 86 at t h e J C R T between December 1985 and July 1993.21 Patient characteristics were similar in both groups with the exception of tumor volume. Median tumor volumes were 10.1 mL and 29 mL for radiosurgery and brachytherapy, respectively. Initially, brachytherapy represented standard therapy for these recurrent tumors with radiosurgery being reserved for smaller tumor volumes, tumors in nonimplantable sites (deep grey structures, brainstem, or eloquent cortex) or patients who were believed to be at increased risk for brachytherapy-related complications. However, with further experience, radiosurgery became the preferred treatment, except in cases of larger or irregularly shaped volumes. Twentyone patients (24%) treated with stereotactic radiosur-
Table 8.
gery (SRS) were alive with median follow-up of 17.5 months. Median actuarial survival, measured from the time of treatment for recurrence, for all patients treated with radiosurgery was 10.2 months, with 12 months and 24 months survivals being 45% and 19%, respectively. Younger age and smaller tumor volume were predictive of better outcome. Tumor dose, interval from initial diagnosis, and need for reoperation were not predictive of outcome following radiosurgery. Five patients (16%) treated with brachytherapy were alive with median follow-up of 43.3 months. Median actuarial survival for all patients treated with brachytherapy was 11.5 months. Survivals at 12 and 24 months were 44% and 17%, respectively. Patient age, but not tumor volume, interval from initial diagnosis, or tumor dose was predictive of outcome in these patients. Comparison of results between patients treated with radiosurgery and brachytherapy indicated similar survival. Nineteen patients (22%) required reoperation following radiosurgery compared with 14 (44%) in the brachytherapy group. Actuarial risk for reoperation was 33% at 12 months and 48% at 24 months following radiosurgery compared with 54% and 65%, respectively, following brachytherapy (P = . 195). Patients undergoing reoperation following brachytherapy survived longer than similar patients not undergoing reoperation. Outcome following SRS was independent of need for reoperation. An example of the radiographic results following radiosurgery for a recurrent glioblastoma is shown in Fig 2.
Newly Diagnosed Malignant Gliomas The interpretation of the results from radiosurgery or brachytherapy is difficult because the patients selected for such procedures represent a subgroup of patients with a relatively good prognosis, even with standard therapy. This appears to be confirmed in several retrospective analyses of outcome in protocol eligible or ineligible patients, none of whom received
Stereotactic Radiation for Recurrent Glioblastoma Multiforme
Institution
Boost Technique
Dose (Gy)*
Harvard21 UCSF 15 Harvard21
125Ibrachytherapy 125Ibrachytherapy Radiosurgery
50 64.4 13.0
*Mediandose to tumor periphery.
Patients
Median Survival (months)
Reoperation Rate(%)
32 66 86
11.5 12 10
44 38 22
Radiosurgeryfor IntracranialMalignancies
:231
P a t i e n t had ~i~Hitic~ml c • ttl~ta,~si~ at tl~i- ~imc. "Fhr h,.i,m ~,,~- IFt'Al,'(] \xil}l A -)~'.-)-llllli t't)]]iil/tlll)l" ;lnti rrt cixcd 15 G \ n ( w m a l i z c d 1o l}w ~{()% isodosc <[isuibtad~m. (B) ( : T scaa ~,it}l (i)illltt.~l ~) I11()11[}1~ lilll()\x[l'l~ rtidi(~ur~cl-) Ql<)\~ila~ till c n l a r ~ i n ~ m a s s w i t h central iaccrosis ar~c{ incvc~scci ccicma. l ' h c [):/liClll I t'(ltlil't'(] ]~i II]~ (It dCX~lH1Cl}]zl:4olIc [)~I cltt.) ~.P.(t \~.~l~, d e v e l o p i n g a mild righ~ }'~emipai-csis. Rcopcrati
232
Loejtter et al
boost therapy. 22,23Florell et a123 reported a significant increase in median survival rate from 9.3 months to 16.6 months (P = .0001) for brachytherapy ineligible versus brachytherapy eligible glioblastoma and anaplastic astrocytoma patients treated with external beam radiotherapy alone. In a similar designed study, Curran et a122 reviewed the results from the R T O G 83-02 trial and reported an improvement in survival for radiosurgery eligible patients compared with ineligible patients using the criteria established by our group at theJCRT. The radiosurgery eligible patients had a median survival of 14.4 months versus 11.7 months (P = .04) for boost ineligible patients. Typically, patients considered "eligible" for radiosurgery boost protocols have a KPS > 70%, radiographically discrete tumors measuring < 4 cm in greatest diameter, and no evidence of subependymal spread. Unfortunately, in our experience only 10% to 20% of patients with newly diagnosed glioblastoma meet the eligibility criteria for boost protocols involving radiosurgery or brachytherapy. Recently, the experience at the J C R T using radiosurgery as an adjunct treatment to surgery and full-dose external beam radiotherapy was reviewed. 24 Between May 1988 and April 1994, 69 patients (median tumor volume 9.3 mL) with glioblastoma treated were using radiosurgery (median dose 12 Gy) within 4 weeks of external beam radiotherapy (54.9 Gy in 33 fractions). To be eligible, patients had to have a KPS of 70% or greater, a tumor volume < 4 cm, and no evidence of multifocality or subependymal spread. Chemotherapy was not a part of the formal protocol, although six patients received postradiosurgery chemotherapy at the referring physician's request. These 69 patients represented approximately 20% of the glioblastoma patients evaluated for the protocol. Patients were followed-up at 3-month intervals with complete neurological examinations and CT or MRI studies. If a question of recurrence or radiation necrosis was suspected from these morphological radiographic examinations, patients underwent functionai MRI or dual isotope single photon emission computed tomography (SPECT) studies. The median survival for the whole group measured from the time of pathological diagnosis was 19.7 months (range 6 to 60+ months). Reoperation was required for progressive symptomatic mass effect in 38% of patients. At the time of reoperation, most patients were found to have a combination of "treated" tumor cells and necrosis. In a multivariate analysis, younger age ( P = .011) and higher dose (P = .045) were the only factors predicting for pro-
longed survival. Patients who underwent a reoperation for symptomatic mass effect enjoyed an improved quality of life and were, in general, maintained on a lower dose of steroid support. However, reoperation did not confer an improvement in survival (P = .952).
In contrast to these favorable results, the University of Wisconsin recently reported their experience in 31 patients with glioblastoma treated in a similar fashion. Between January 1989 and December 1992, 31 patients were treated with a radiosurgery boost (median dose, 12 Gy) following full-dose external beam radiotherapy (median dose, 54 Gy). These patients represented 61% of the total patients evaluated for the protocol compared with the 20% rate from the JCRT. The median tumor volume of this group of patients was 17.4 mL compared with 9.3 cc for the J C R T patients. The median KPS was 70% with a range from as low as 20% to 90%. The overall actuarial median survival of the entire group was 42 weeks, with the 1- and 2-year actuarial rates being 38% and 28%. In a multivariate analysis, only age ( < 55 years v > 55 years) bordered on significance with a P value of.051. Based solely on clinical criteria of deteriorating symptoms and increasing steroid dependence, 26 of 31 (84%) patients were considered to progress. However, with the use of functional radiographic studies (positron emission tomography, SPECT, MR spectroscopy), it was determined that no patient failed to respond within the radiosurgery treatment volume. Peripheral failures (within 2 cm from the radiosurgery volume) accounted for 79% of the recurrences whereas distant failure (greater than 2 cm from the radiosurgery volume) occurred in 17% of the patients. Although the median survival in this study was similar to that seen in patients treated with conventional radiotherapy techniques, the 2-year survival rate of 28% and the lack of central recurrences (within the radiosurgery volume) were encouraging. It is quite obvious that difficulties are encountered in the comparison ofradiosurgery trials performed at different institutions using different eligibility criteria. In the two largest experiences using radiosurgery in the initial therapy of patients with glioblastoma discussed above, the results are quite disparate despite similar treatment schedules. The identification of appropriate historical control groups is strongly dependent on pretreatment prognostic factors. The RTOG has recently published a nonparametric recursive partitioning analysis of three previous external beam radiotherapy trials where patients were strati-
RadiosurgeryforIntracranialMalignancies
fled into six prognostic classes based on a combination of prognostic and treatment variables. 25 It has been postulated that stratification of patients with this schema may be advantageous in evaluating the outcome of patients treated with radiosurgery in order to control for the multitude of possible prognostic factors. A study was recently reported that compared the results of patients treated with radiosurgery and external beam radiotherapy as part of the initial therapy in patients with malignant gliomas. 26 In order to create a large data base, three institutions (Universities of Wisconsin and Florida, and the JCRT) combined their data and collected 115 patients treated in a similar fashion all using radiosurgery as part of the initial therapy. These I t5 patients were stratified into prognostic classes as described by the investigators from the RTOG. These prognostic classes were determined by a nonparametric recursive partitioning analysis of the results from three previous R T O G studies. The statistical technique of recursive partitioning analysis results in the stratification of patients into classes based on a decision tree formed from the determination of the relative importance of various prognostic classes (1 through 6) with class 1 having the best prognosis and class 6 having the worse. The actuarial survival at 2 years for the entire cohort of patients with GBM was 38% with a median survival of 91 weeks. Stratification of patients by prognostic groups revealed a significant difference in overall survival by class (P < .001). The overall survival for patients treated with radiosurgery appears superior to the results reported by the RTOG. There was a minimal difference in survival for class l patients from either group, whereas classes 3 through 5/6, the radiosurgery patients, appeared to have a superior 2-year and median survival. The differences in outcome for class 5 patients was striking with a median survival of 13.1 months and 2-year survival of 21% for the radiosurgery patients compared with 9 months and 6%, respectively, for the R T O G patients. In contrast to the radiosurgery patients with a marked decreased in survival classes 3 and 4, the survival for the R T O G patients decreased earlier with a marked difference in survival between the class 2 and 3 patients. In summary, the treatment of patients with malignant gliomas with combination full-dose external beam radiotherapy and a radiosurgery boost appears to results in a superior overall median and 2-year survival in comparison to published results of pa-
2,33
tients with similar prognostic features treated with external beam radiotherapy alone. In addition, the results of radiosurgery appear similar to those reported from the BTCG, UCSF, and t h e J C R T using msI brachytherapy with less-attendant morbidity. Based on the encouraging results discussed above, R T O G is beginning a prospective, randomized study evaluating the role of radiosurgery in the initial management of patients with malignant gliomas. R T O G 9305 will randomize patients with supratentorial malignant gliomas who are > 18 years old with K ~ of > 60 and postoperative residual disease of _<4 cm in greatest diameter to radiosurgery ( 15 to 21 Gy) followed by radiothera W (60 Gy) and BCNU compared with radiotherapy and BCNU alone. Eventual randomized trials will be required to determine which boost technique provides a more favorable outcome, either for primary or recurrent glioblastoma. In summary, radiosurgery and brachytherapy produce similar survival rates in recurrent and newly diagnosed patients with glioblastoma. 2~ The development of symptomatic radiation necrosis requiring prolonged steroid support, and reoperation appears to be the same for both stereotactic radiation techniques. Thus, radiosurgery is a more appealing technique in the management of highly focal malignant gliomas than brachytherapy because it is a noninvasire, single-day procedure.
References 1. Lunsford LD, Alexander E III, LoefflerJS:General introduction: Histoq"of radiosurgery, in E Alexander III,JS l_,oeffler, LD Lunsford (eds):StereotacticRadiosurgery.NewYork, NY, McGraw-Hill, 1993,pp 1-4. 2. Patchell RA,Tibbs PA, WalshJW, et al: A randomized trial of surge~" in the treatment of single metastases to the brain. N EnglJ Med 322:494-500,1990 3. NoordijkEM, Vecht CJ, Haaxma-Reiche H, et al: The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int J Radiat Oncol Biol Phys29:711-717,1994 4. FlickengerJC, Kondziolka D, Lunsford LD, et al: A multiinstitutional experience ~ith stereotactic radiosurgeD" for solitary brain metastasis. IntJ Radiat Oncol Biol Phys 28:797802, 1994 5. LoefflerJS,AlexanderE II/:Radiosurgeryfor the treatmentof intracranial metastases, in EI Alexander, JS Loemer, LD Lunsford (eds): Stereotactic radiosurgery. New York, NY, McGraw-Hill, 1993,pp 197-206 6. Alexander E III, Moriarty TM, Davis R.B,et al: Stereotactic radiosurgery for the definitive, noninvasivetreatment ofbrain metastases.J Natl Cancer Inst 87:34-40, 1995 7. Mehta MP, RozentalJM, LeninAB, et al: Defining the role of
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radiosurgery in the management of brain metastases. Int J Radiat Oncol Biol Phys 24:619-625, 1992 8. Fuller BG, Kaplan ID, AdlerJ, et al: Stereotaxic radiosurgery for brain metastases: The importance of adjuvant whole brain radiotherapy. IntJ Radiat Oncol Biol Phys 23:413-418, 1992 9. Loeffler JS, Shrieve DC: What is appropriate therapy for a patient with a single brain metastasis. IntJ Radiat Oncol Biol Phys 29:915-917, 1994 10. Walker MD, Strike TA, Sheline GE: An analysis of dose-effect relationship in radiotherapy of malignant gliomas. Int J Radiat Oncol Biol Phys 5:1725-1731, 1979 11. Chang C, Horton J, Schoenfeld D, et al: Comparison of postoperative radiotherapy and combined postoperative radiotherapy and chemotherapy in the muhidic-sciplinary management of malignant gliomas. Cancer 52:997, 1983 12. Sheline GE, Wara WM, Smith V: Therapeutic irradiation and brain injury. IntJ Radiat Oncol Biol Phys 6:1215, 1980 13. Leibel SA, Scott CB, LoefiterJS: Contemporary approaches to the treatment of malignant gliomas with radiation therapy. Semin Oncol 21:198-219, 1994 14. Halperin EC, Burger PC, Bullard DE: The fallacy of the localized malignant glioma. I n t J Radiat Oncol Biol 15:505509, 1988 15. Scharfen CO, Sneed PK, Wara WM, et al: High activity iodine-125 implant for gliomas. Int J Radiat Oncol Biol Phys 24:583-591, 1992 16. Wen PY, Mexander E III, Black PM, et al: Long term results of stereotactic brachytherapy used in the initial treatment of patients with glioblastomas. Cancer 73:3029-3036, 1994 17. Green SB, Shapiro WR, Burger PC, et al: A randomized trial of interstitial radiotherapy (RT) boost for newly diagnosed malignant glioma: Brain Tumor Cooperative Group (BTCG) Trial 8701. Proceedings of the American Society of Clinical Oncology, Dallas, TX, 1994, p 174 18. LoefflerJ, Alexander E IlI, Shea M, et al: Radiosurgery as part of the initial management of patients with malignant gliomas. J Clin Onco110:1379-1385, 1992 19. Mehta MP, Massciopinto J, Rozental J, et al: Stereotactic radiosurgery for glioblastoma multiforme: Report of a prospective study evaluating prognostic factors and analyzing longterm survival advantage. IntJ Radiat Oncol Biol Phys 30:541549, 1994 20. Alexander E III, Black P, Wen PY, et al: Results of radiosurgery versus brachytherapy for malignant gliomas, in AAF DeSalles, SJ Goetsch (eds): Stereotactic Surgery and Radiosurgery. Madison, WI, Medical Physics Publishing, 1993, pp 455-461
21. Shrieve DC, Alexander E llI, Wen PY, et ah Comparison of stereotactic radiosurgery and brachytherapy in the treatment of recurrent glioblastoma multiforme. Neurosurgery 36:275284, 1995 22. Curran WJ, Scott CB, Weinstein AS, et al: Survival comparison of radiosurgery-eligible and -ineligible malignant glioma patients treated with hyperfractionated radiation therapy and carmustine: A report of Radiation Therapy Oncology Group 83-02.J Clin Oncol 11:857-862, 1993 23. Florell RC, MacDonald DR, Irish WD, et al: Selection bias, survival and brachytherapy for glioma. J Neurosurg 76:179183, 1992 24. Addesa AE, Shrieve DC, Alexander E BI, et al: Longterm results of radiosurgery for newly diagnosed patients with glioblastoma. (submitted for publication) 25. Curran WJ, Scott CB, HortonJ, et al: Recursive partitioning analysis of prognostic factors in three Radiation Therapy Oncology Group malignant glioma trials.J Natl Cancer Inst 85:704-710, 1993 26. Sarkaria JN, Mehta MP, Loemer JS, et al: Stereotactic radiosurgery improves survival in malignant gliomas compared with the RTOG recursive partitioning analysis. Int J Radiat Oncol Biol Phys 30:164, 1995 27. LoeflterJS, Larson DA: Radiosurgery in the management of intracranial lesions: A radiation oncology prospective, in WC Dewey, M Edington, RJM Fry, et al (eds): Radiation Research: A Twentieth-Century Perspective. San Diego, CA, Harcourt Brace Jovanovich, 1992, pp 535-540 28. Loeffler JS, Larson DA, Shrieve DC, et al: Radiosurgery for the treatment of intracranial lesions, in VT DeVita, S Hellman, SA Rosenberg (eds): Yearbook of Oncology. Philadelphia, PA,J.B. Lippincott, 1994 29. Engenhart R, Kimmig B, Hover K, et al: Long term follow-up for brain metastases treated percutaneous single high dose radiation. Cancer 71:1353-1361, 1993 30. Kihlstrom L, Karlsson B, Lindquist C: Stereotactic radiosurgery for single and multiple cerebral metastases. Acta Neurochirurgia 122:158, 1993 31. Mehta M: Radiosurgery for brain metastases, in DeSalles AF, SJ Goetsch (eds): Stereotactic Surgery and Radiosurgery. Madison, WI, Medical Physics, 1993, pp 353-368 32. Larson DA, Flickinger JC, LoefflerJS: Stereotactic radiosurgery: Techniques and results, in VT DeVita S Hellman, SA Rosenberg (eds): Cancer: Principle and Practice of Oncology Updates. Philadelphia, Lippincott, 1993, pp 1-19