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Salvage Stereotactic Radiosurgery Effectively Treats Recurrences From Whole-brain Radiation Therapy Samuel T. Chao, MD1,2 Gene H. Barnett, MD2,3 Michael A. Vogelbaum, MD, PhD2,3 Lilyana Angelov, MD2,3 Robert J. Weil, MD2,3 Gennady Neyman, PhD1 Alwyn M. Reuther, MPH1 John H. Suh, MD1,2

BACKGROUND. The purpose of the current study was to examine overall survival (OS) and time to local failure (LF) in patients who received salvage stereotactic radiosurgery (SRS) for recurrent brain metastases (BM) after initial management that included whole-brain radiation therapy (WBRT).

METHODS. The records of 1789 BM patients from August 1989 to November 2004 were reviewed. Of these, 111 underwent WBRT as part of their initial management and SRS as salvage. Patients were stratified by Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis class, primary disease, dimension of the largest metastases and number of BM at initial diagnosis, and time to first

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brain recurrence after WBRT. Overall survival, survival after SRS, and time to local

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RESULTS. The median OS from the initial diagnosis of BM was 17.7 months. Me-

Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio. Brain Tumor and Neuro-Oncology Center, Cleveland Clinic, Cleveland, Ohio. 3

Department of Neurosurgery, Cleveland Clinic, Cleveland, Ohio.

and distant failure were analyzed. dian survival after salvage SRS for the entire cohort was 9.9 months. Median survival after salvage SRS was 12.3 months in patients who had their first recurrence >6 months after WBRT versus 6.8 months for those who developed disease recurrence 6 months after (P 5 .0061). Primary tumor site did not appear to affect survival after SRS. Twenty-eight patients (25%) developed local recurrence after their first SRS with a median time of 5.2 months. A dose 2 cm were found to be predictive of local failure.

CONCLUSIONS. In this study, patients who recurred after WBRT and were treated with salvage SRS were found to have good local control and survival after SRS. WBRT provided good initial control, as 45% of these patients failed >6 months after WBRT. Those with a longer time to failure after WBRT had significantly longer survival after SRS. Cancer 2008;113:2198–204.  2008 American Cancer Society.

KEYWORDS: brain metastases, whole-brain radiation therapy, stereotactic radiosurgery, gamma knife, salvage.

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Address for reprints: Samuel T. Chao, MD, Brain Tumor and Neuro-Oncology Center/Department of Radiation Oncology, T28, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH 44195; Fax: (216) 445-1068; E-mail: [email protected] Received February 12, 2008; revision received June 3, 2008; accepted June 6, 2008.

ª 2008 American Cancer Society

rain metastasis (BM) is the most common neurologic complication of cancer.1 The incidence of BM has been increasing because patients are living longer after the diagnosis of their primary disease. Typically, patients present with neurologic deficits and headaches that can be disabling. The diagnosis of BM usually carries a poor prognosis, with a median survival of approximately 4 months.2 Prognosis is influenced by multiple factors, which include histology, generalized performance status, age, control of primary disease, and lack of extracranial metastases. These factors constitute the Radiation Therapy Oncology Group (RTOG) recursive partitioning analysis (RPA) classification described by Gaspar et al.2 Prognosis is also influenced by therapy, which may include whole-brain radiation therapy (WBRT), surgical resection, or stereotactic radiosurgery (SRS). In a study by Patchell et al3 for single BM, the addition of surgery to WBRT improved overall survival and

DOI 10.1002/cncr.23821 Published online 8 September 2008 in Wiley InterScience (www.interscience.wiley.com).

Salvage Stereotactic Radiosurgery/Chao et al

decreased local recurrence. The omission of WBRT after surgery, however, increases the risk of local and distant brain recurrence.4 Although there was no statistically significant difference in overall survival between the 2 groups, that study was not powered to detect the difference. SRS is an alternative modality that may improve local control after WBRT. A prospective, randomized controlled trial was completed for patients with 1 to 3 BM comparing WBRT with WBRT with SRS boost. With the addition of the SRS boost, local control increased from 71% to 82% (P 5 .0132).5 Those undergoing SRS boost were more likely to have stable or improved Karnofsky performance status (KPS) at 6 months. There was also a modest improvement in survival, particularly in patients who were RPA class 1 (with a mean survival of 11.6 months) or possessed a favorable histology, defined as squamous or nonsmall cell histology, usually observed in lung cancer (with a mean survival of 5.6 months). Another study assessed the role of SRS in addition to WBRT for 2 to 4 BM and found that the rate of local failure at 1 year was 100% after WBRT alone, but only 8% for those patients who received an SRS boost.6 Survival did not differ between the 2 groups, but the study was not powered for survival. These 2 studies established the role of SRS boost. To our knowledge, the optimal dose for SRS boost has not been determined prospectively. The RTOG standard of 24 grays (Gy) for tumors measuring 2 cm was based on toxicity, not efficacy, for patients in whom planned WBRT was not used.7 This was assessed retrospectively at the University of Kentucky.8 An SRS dose >20 Gy did not improve local control when compared with a dose of 20 Gy. There was a trend toward an increased risk of grade 3 or 4 neurotoxicity with doses >20 Gy versus 20 Gy (5.9% vs 1.9%; P 5 .078). The authors concluded that 20 Gy is the optimal dose for SRS boost for metastases measuring 2 cm when combined with WBRT. In a Japanese study, patients were randomized to SRS with WBRT or SRS alone.9 There was no difference in survival noted between the 2 arms, but there was a 46.8% recurrence rate in SRS with WBRT arm versus 76.4% for SRS alone (P < .001). Local control and distant brain control were improved (P < .002 for local control and P < .003 for distant control). Salvage was less frequent in the SRS with WBRT treatment arm (P < .001). Despite the results, because the SRS alone arm did not result in neurologic death, SRS alone is an option. However, arguably the addition of WBRT from this study improves control and can be considered for all patients.

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Despite good control rates from WBRT, especially with the addition of aggressive local therapy such as surgical resection or SRS, recurrences continue to occur locally and elsewhere in the brain. Repeat WBRT may cause neurotoxicity and is typically reserved for patients with poor prognoses.10 This leaves surgical resection and SRS as the remaining options. Of these 2 options, SRS may be an ideal option because it may be better than surgery at controlling the microscopic disease at the tumor margin that may be left behind after a resection.11 In addition, patients who have had BM are followed closely with serial imaging studies and therefore are more likely to have new metastases discovered when they are small and produce little or no mass effect. These lesions are ideal for SRS. Surgery, conversely, is often reserved for patients with neurologic deficits or symptoms and signs related to mass effect.11 In the current study, we retrospectively reviewed our series of patients who received WBRT as part of their initial management and who later developed recurrences that were treated with SRS.

MATERIALS AND METHODS The records of 1789 patients with BM diagnosed from August 1989 to November 2004 were reviewed and entered into an Institutional Review Boardapproved database. The presence of BM was confirmed by computed tomography (CT) and/or magnetic resonance imaging (MRI). Of these, 148 (8%) patients had WBRT as part of their initial management and subsequently developed a recurrence treated with SRS. After excluding cases because of incomplete records, in which all the relevant treatment information and/or follow-up information were not attainable, 111 (75%) of the 148 patients comprised the study sample; the remaining 25% had inadequate information to be a part of this study. These patients may have been treated with surgery and/or SRS as part of their initial management. Recurrence was either local or distant within the brain. We did not include patients treated for persistent disease. Patients had demonstrated progression in size or a new distant BM. SRS was LINAC-based from 1989 to 1997, after which gamma knife (Elekta, Stockholm, Sweden) SRS was used. All but 1 patient received gamma knife SRS for salvage. SRS was typically dosed as per the RTOG 90-05 protocol.7 Per this protocol, doses were based on the maximal dimension (metastases measuring 2 cm received 24 Gy to the tumor margin, metastases measuring >2 cm but 3 cm received 18 Gy, and metastases measuring >3 cm received 15

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Gy). In some cases, a lower dose was prescribed when the lesion was in the brainstem or next to a critical structure (as low as 9.6 Gy). Occasionally, a higher dose was given for smaller lesions at the discretion of the treating physician (as high as 25.4 Gy). Metastases measuring >4 cm were rarely treated because of concerns for radiation necrosis, but when they were treated a lower dose was given (approximately 12 Gy). No additional margins were used in treatment. Both CT and MRI data were used in planning. During planning, attempts were made to keep the conformality index and homogeneity index to 2. To study which factors were prognostic for overall survival, survival after SRS, and time to local and distant failure, patients were stratified by RTOG RPA class, primary disease, dimension of the largest and number of BM at the time of initial diagnosis, and time to first brain recurrence after WBRT. Primary disease was categorized into breast cancer, nonsmall cell lung cancer, melanoma, renal cell carcinoma, and other. Dimension of the largest BM was categorized into 2 cm to 3 cm, >3 cm to 4 cm, and >4 cm. The number of BM was categorized into 1, 2, 3, or >3. Time to first recurrence was stratified as 3 months, >3 to 6 months, >6 months to 12 months, and >12 months. Local failure was defined as any growth from previous MRI after SRS. If radiation necrosis was suspected, additional imaging in the form of positron emission tomography, single–photon emission CT, or serial follow-up MRI scans were used to establish a diagnosis. Ten patients had histologic confirmation of local disease recurrence. Distant failure was defined as new brain lesions that developed after SRS. Follow-up scans were usually performed at 2– month to 3-month intervals after SRS. Time to diagnosis of BM and survival were calculated from the date of the first MRI or CT scan documenting BM. Survival was also measured from the date of salvage SRS. The time to distant brain recurrence was defined as the time to neuroimaging evidence of a new BM elsewhere in the brain. Time to local disease recurrence was defined as time to progression of a treated BM on neuroimaging. The Kaplan-Meier method was used to test differences in overall survival, and time to local and distant recurrence after SRS. Analyses were performed using StatView software (version 5.0; SAS Institute Inc, Cary, NC) and S1.

RESULTS The median follow-up after SRS was 7.1 months (range, 0.0-57.8 months). The median age of the

TABLE 1 Median Overall Survival From Imaging Diagnosis of Brain Metastases Stratification RPA Class 1 (n524) Class 2 (n580) Class 3 (n57) Time to first recurrence. mo 3 (n531) >3-6 (n530) >6-12 (n528) >12 (n522)

Median OS, Mo

P .16

24.6 17.6 10.2 3 to 6 months, 28 (25%) developed disease recurrence >6 to 12 months, and 22 (20%) developed disease recurrence >12 months after WBRT. Some patients recurred as little as 0.4 months after WBRT; these were confirmed to be true recurrences with growth of lesions noted on MRI. All patients received gamma knife for salvage, except 1 patient who received LINAC-based SRS. The median dose was 23.6 Gy (range, 9.6-25.4 Gy). The median overall survival (OS) from the initial diagnosis of BM was 17.7 months. The median OS for the various stratifications are summarized in Table 1. RPA class (P 5 .16), primary disease (P 5 .28), size of the largest BM (P 5 .74), and number of BM (P 5 .92) did not appear to affect OS. The time to

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TABLE 2 Median Overall Survival From Date of SRS Stratification Primary Nonsmall cell lung (n553) Breast (n525) Melanoma (n510) Renal cell (n59) Other (n514) Time to first recurrence, mo 3 (n531) >3-6 (n530) >6-12 (n528) >12 (n522)

Median OS, Mo

P .61

8.2 12.8 2.3 6.0 6.9 .05 7.1 6.8 9.9 12.8

SRS indicates stereotactic radiosurgery; OS overall survival.

FIGURE 2. Kaplan-Meier curve of survival from time of salvage stereotactic radiosurgery by location of disease recurrence.

TABLE 3 Median Time to Local Failure After Salvage SRS Stratification Primary Nonsmall cell lung (e512) Breast (e59) Melanoma (e51) Renal cell (e52) Other (e54) Time to first recurrence, mo 3 (e56) >3-6 (e510) >6-12 (e58) >12 (e54)

FIGURE 1. Kaplan-Meier curve of survival from time of salvage stereotac-

Median Time to LF, Mo

P .49

15.3 10.7 NR NR 8.4 .14 NR 15.4 15.3 NR

SRS indicates stereotactic radiosurgery; LF, local failure; NR, not reached; e, number of failure events.

tic radiosurgery by time to disease recurrence.

first disease recurrence after WBRT did significantly influence OS (P < .0001, univariate analysis). Because none of the other variables were found to affect OS, survival from time of salvage SRS was calculated for time to recurrence after WBRT. The median survival after salvage SRS was 9.9 months in all patients. The median survivals after SRS when stratified by histology and time to first disease recurrence are summarized in Table 2. The median survival was 12.3 months in patients who had their first recurrence >6 months versus 6.8 months for those who developed disease recurrence 6 months after WBRT (P 5 .0061). The Kaplan-Meier survival curve is shown in Figure 1. The location of the disease recurrence, whether it was a local recurrence or distant recurrence that occurred after WBRT, did not appear to affect survival after SRS. The Kaplan-Meier survival curve is

shown in Figure 2. The median survival after SRS was 10.4 months for patients with local only recurrence, 12.9 months for distant only recurrence, and 7.3 months for those who fail locally and distantly after WBRT. Twenty-eight (25%) of the patients developed a local failure (LF) at a site of their first salvage SRS, at a median of 5.2 months. The local control rate at 1 year was 68% and that at 2 years was 59%. Table 3 compares median time to LF stratified by histology and time to first disease recurrence (which includes censoring for patients who did not fail). Histology (P 5 .49) or time to first disease recurrence after WBRT (P 5 .14) did not affect time to LF. The size of the metastasis and SRS dose were examined for each lesion. A total of 243 metastases were treated, of which 31 failed. With regard to size, 91% of the metastatic lesions measuring 2 cm were controlled

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FIGURE 3. Kaplan-Meier curve of time to local failure of metastasis by

FIGURE 4. Kaplan-Meier curve for time to local failure of metastasis by

lesion size.

salvage stereotactic radiosurgery dose. Gy indicates Grays.

at 12 months versus 62% of the lesions measuring >2 cm (P < .0001) (Fig. 3). As for dose, 92% of the metastatic lesions receiving 22 Gy were controlled at 12 months versus 72% for those receiving 3-6 (e58) >6-12 (e510) >12 (e511)

Median Time to DF, Mo

P .57

27.3 22.5 14.5 35.9 13.2 .74 20.2 14.5 27.3 22.5

SRS indicates stereotactic radiosurgery; DF, distant failure; e, number of failure events.

severe fatigue after SRS and slept >12 hours per day. No other major toxicities were noted.

DISCUSSION SRS may be used in the upfront setting to improve local control and survival or in a salvage setting after failure from other therapy, including WBRT and surgery. In the salvage setting when WBRT was given upfront, the remaining options are often SRS or surgery. Surgery may be selected in cases in which there is only 1 recurrent lesion or the lesion is large or symptomatic, and in patients with good functional status and prognosis. Alternatively, SRS has the benefit of being a minimally invasive, outpatient procedure without the use of general anesthesia. Other advantages include minimal recovery time, less risk

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TABLE 5 Review of Selected Series Evaluating the Outcomes of Patients Undergoing Salvage SRS After WBRT Series

No. of Patients

Median Survival After SRS, Mo

Prognostic Factors for Survival

Inclusion

Alexander 199514 Noel 200116 Current study

182 54 111

9.4 7.8 9.9

No active systemic disease, age