Executive summary of American Radium Society's appropriate use criteria for the postoperative management of lower grade gliomas.

Postoperative management of lower grade gliomas (grade 2 and 3) is heterogeneous. The American Radium Society's brain malignancies panel systematically reviewed and evaluated the literature to develop consensus guidelines addressing timing of postoperative therapy, monotherapy versus combined modality therapy, type of chemotherapy used with radiotherapy, and radiotherapy dose. Thirty-six studies were included. Using consensus methodology (modified Delphi), the panel voted upon representative case variants using a 9-point appropriateness scale to address key questions. Voting results were collated to develop summarized recommendations. Following gross-total surgical resection, close surveillance is appropriate for well-selected grade 2, IDH-mutant oligodendrogliomas or astrocytomas with low-risk features. For grade 2 gliomas with high-risk features or any grade 3 glioma, immediate adjuvant therapy is recommended. When postoperative therapy is administered, radiation and planned chemotherapy is strongly recommended over monotherapy. For grade 2 and 3 IDH-mutant oligodendrogliomas and astrocytomas, either adjunctive PCV (procarbazine, lomustine, vincristine) or temozolomide is appropriate. For grade 3 IDH-mutant astrocytomas, radiotherapy followed by temozolomide is strongly recommended. The recommended radiotherapy dose for grade 2 gliomas is 45-54 Gy/1.8-2.0 Gy, and for grade 3 gliomas is 59.4-60 Gy/1.8-2.0 Gy. While multiple appropriate treatment options exist, these consensus recommendations provide an evidence-based framework to approach postoperative management of lower grade gliomas.

Executive summary from American Radium Society's appropriate use criteria on neurocognition after stereotactic radiosurgery for multiple brain metastases.

BACKGROUND: The American Radium Society (ARS) Appropriate Use Criteria brain malignancies panel systematically reviewed (PRISMA [Preferred Reporting Items for Systematic Reviews and Meta-Analyses]) published literature on neurocognitive outcomes after stereotactic radiosurgery (SRS) for patients with multiple brain metastases (BM) to generate consensus guidelines. METHODS: The panel developed 4 key questions (KQs) to guide systematic review. From 11 614 original articles, 12 were selected. The panel developed model cases addressing KQs and potentially controversial scenarios not addressed in the systematic review (which might inform future ARS projects). Based upon quality of evidence, the panel confidentially voted on treatment options using a 9-point scale of appropriateness. RESULTS: The panel agreed that SRS alone is usually appropriate for those with good performance status and 2-10 asymptomatic BM, and usually not appropriate for >20 BM. For 11-15 and 16-20 BM there was (between 2 case variants) agreement that SRS alone may be appropriate or disagreement on the appropriateness of SRS alone. There was no scenario (among 6 case variants) in which conventional whole-brain radiotherapy (WBRT) was considered usually appropriate by most panelists. There were several areas of disagreement, including: hippocampal sparing WBRT for 2-4 asymptomatic BM; WBRT for resected BM amenable to SRS; fractionated versus single-fraction SRS for resected BM, larger targets, and/or brainstem metastases; optimal treatment (WBRT, hippocampal sparing WBRT, SRS alone to all or select lesions) for patients with progressive extracranial disease, poor performance status, and no systemic options. CONCLUSIONS: For patients with 2-10 BM, SRS alone is an appropriate treatment option for well-selected patients with good performance status. Future study is needed for those scenarios in which there was disagreement among panelists.

Frequent Use of Local Therapy Underscores Need for Multidisciplinary Care in the Management of Patients With Melanoma Brain Metastases Treated With PD-1 Inhibitors.

PURPOSE: An increasing number of clinical trials are studying immunotherapy for the treatment of brain metastases. The role of local therapy in this setting has not been well described. METHODS AND MATERIALS: Twenty-three melanoma patients with brain metastases were treated with pembrolizumab in a prospective phase 2 trial, NCT02085070, and included in this secondary analysis. Patients had at least 1 untreated or progressive brain metastasis, 5 to 20 mm in size, without any associated neurologic symptoms. Local therapy (stereotactic radiosurgery, surgery, or laser interstitial thermal therapy) was used to treat concerning lesions immediately before trial enrollment and was also allowed on trial in patients whose brain metastases were progressing, but who were otherwise deriving benefit. RESULTS: In total, 13 out of 23 patients (57%) received local therapy immediately before or during the trial-4 patients received local therapy before the trial owing to lesion size or location in sensitive areas; 6 during the trial because of tumor growth, hemorrhage, or radiation necrosis/cystic changes; and 3 both before and during the trial. Of the 10 patients who did not receive local therapy immediately before or during the trial, 8 patients (35%) did not later receive local therapy owing to rapid disease progression, and only 2 patients (9%) lived for 2 years without requiring any local therapy. CONCLUSIONS: Local therapy continues to play an important role in the management of melanoma patients with brain metastases being treated with immunotherapy. These patients should be closely monitored via serial brain imaging, with a multidisciplinary team involved in clinical decision making to ensure each patient's neurologic safety.

Consensus Contouring Guidelines for Postoperative Completely Resected Cavity Stereotactic Radiosurgery for Brain Metastases.

PURPOSE: To propose contouring guidelines based on consensus contours generated by 10 international experts for cavity stereotactic radiosurgery (SRS), an emerging treatment option after surgical resection of brain metastases. No guidelines for contouring the surgical cavity volume have been previously reported. METHODS AND MATERIALS: Ten postoperative completely resected cases with varying clinical scenarios and locations within the brain were selected. For each case, 10 experts independently contoured the surgical cavity clinical target volume (CTV). All the contours were analyzed, and agreement was calculated using the simultaneous truth and performance level estimation (STAPLE) with the kappa statistic. A follow-up survey was also completed by each investigator to summarize their contouring rationale for a number of different clinical scenarios. The results from the survey and the consensus STAPLE contours were both summarized to establish contouring guidelines. RESULTS: A high level of agreement was found between the expert CTV contours (mean sensitivity 0.75, mean specificity 0.98), and the mean kappa was 0.65. The agreement was statistically significant at P<.001 for all cases. From these results and analyses of the survey answers, the recommendations for CTV include fusion of the preoperative magnetic resonance imaging scan to aid in volume delineation; contouring the entire surgical tract regardless of the preoperative location of the tumor; extension of the CTV 5 to 10 mm along the dura overlying the bone flap to account for microscopic disease extension in cases with preoperative dural contact; and a margin of ≤5 mm into the adjacent sinus when preoperative venous sinus contact was present. CONCLUSIONS: Consensus contouring guidelines for postoperative completely resected cavity SRS treatment were established using expert contours and clinical practice. However, in the absence of clinical data supporting these recommendations, these guidelines serve as a baseline for further study and refinement.

Stereotactic radiosurgery of early melanoma brain metastases after initiation of anti-CTLA-4 treatment is associated with improved intracranial control.

BACKGROUND: Numerous studies suggest that radiation can boost antitumor immune response by stimulating release of tumor-specific antigens. However, the optimal timing between radiotherapy and immune checkpoint blockade to achieve potentially synergistic benefits is unclear. MATERIAL AND METHODS: Multi-institutional retrospective analysis was conducted of ninety-nine metastatic melanoma patients from 2007 to 2014 treated with ipilimumab who later received stereotactic radiosurgery (SRS) for new brain metastases that developed after starting immunotherapy. All patients had complete blood count acquired before SRS. Primary outcomes were intracranial disease control and overall survival (OS). RESULTS: The median follow-up time was 15.5months. In the MD Anderson cohort, patients who received SRS after 5.5months (n=20) of their last dose of ipilimumab had significantly worse intracranial control than patients who received SRS within 5.5months (n=51) (median 3.63 vs. 8.09months; hazard ratio [HR] 2.07, 95% confidence interval [CI] 1.03-4.16, p=0.041). OS was not different between the two arms. The improvement in intracranial control was confirmed in an independent validation cohort of 28 patients treated at Yale-New Haven Hospital. Circulating absolute lymphocyte count before SRS predicted for treatment response as those with baseline counts >1000/µL had reduced risk of intracranial recurrence compared with those with ≤1000/µL (HR 0.46, 95% CI 0.0.23-0.94, p=0.03). CONCLUSIONS: In this multi-institutional study, patients who received SRS for new brain metastases within 5.5months after ipilimumab therapy had better intracranial disease control than those who received SRS later. Moreover, higher circulating lymphocyte count was associated with improved intracranial disease control.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram.

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients' DBF risk within the validation dataset (c-index = 0.631) and Heller's explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

Comparing available criteria for measuring brain metastasis response to immunotherapy.

The response assessment in neuro-oncology (RANO) working group recently proposed standardized response criteria for brain metastases (RANO-BM). We sought to compare RANO-BM to other criteria in an ongoing brain metastasis trial. The first 36 patients enrolled on NCT02085070, an ongoing trial of pembrolizumab for patients with untreated brain metastases, were included in this analysis. As RANO-BM had not been proposed when the protocol was written, response on trial was assessed using an institutional modification of RECIST 1.1 (mRECIST), wherein minimum target brain lesion size was 5 mm in longest diameter and up to five target brain lesions were followed. We here additionally assessed response using standard RECIST 1.1, RANO high-grade glioma (RANO-HGG), and RANO-BM. Comparison between the four criteria sets using cases eligible across the board revealed excellent concordance (kappa statistic > 0.8), with only one discordant case. However, compared to RECIST 1.1 or RANO-BM, using a 5 mm threshold for target brain lesions in mRECIST allowed enrollment of 13 additional patients, five of whom had durable responses. Compared to RANO-HGG, 19 additional patients were enrolled using mRECIST, eight of whom had durable responses. Consequently, this resulted in response rates ranging from 12% with RANO-HGG to 28% with mRECIST. This study supports using a 5 mm threshold for target brain lesions when using high resolution MRI with ≤2 mm slices to facilitate accrual to similar clinical trials and provide earlier access to novel therapies for brain metastasis patients. Concordance among the four criteria studied was otherwise very high.

Timing and type of immune checkpoint therapy affect the early radiographic response of melanoma brain metastases to stereotactic radiosurgery.

BACKGROUND: Growing evidence suggests that immunotherapy and radiation therapy can be synergistic in the treatment of cancer. This study was performed to determine the effect of the relative timing and type of immune checkpoint therapy on the response of melanoma brain metastases (BrMets) to treatment with stereotactic radiosurgery (SRS). METHODS: Seventy-five melanoma patients with 566 BrMets were treated with both SRS and immune checkpoint therapy between 2007 and 2015 at a single institution. Immunotherapy and radiosurgery treatment of any single lesion were considered concurrent if SRS was administered within 4 weeks of immunotherapy. The impact of the timing and type of immunotherapy on the lesional response was determined with the Wilcoxon rank-sum test, which was used to compare the median percent lesion volume change 1.5, 3, and 6 months after SRS treatment, with significance determined by P = .0167 according to the Bonferroni correction for multiple comparisons. RESULTS: Concurrent use of immunotherapy and SRS resulted in a significantly greater median percent reduction in the lesion volume at 1.5 (-63.1% vs -43.2%, P < .0001), 3 (-83.0% vs -52.8%, P < .0001), and 6 months (-94.9% vs -66.2%, P < .0001) in comparison with nonconcurrent therapy. The median percent reduction in the lesion volume was also significantly greater for anti-programmed cell death protein 1 (anti-PD-1) than anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) at 1.5 (-71.1% vs -48.2%, P < .0001), 3 (-89.3% vs -66.2%, P < .0001), and 6 months (-95.1% vs -75.9%, P = .0004). CONCLUSIONS: The administration of immunotherapy within 4 weeks of SRS results in an improved lesional response of melanoma BrMets in comparison with treatment separated by longer than 4 weeks. Anti-PD-1 therapy also results in a greater lesional response than anti-CTLA-4 after SRS. Cancer 2016;122:3051-3058. © 2016 American Cancer Society.

Demonstration of differential radiosensitivity based upon mutation profile in metastatic melanoma treated with stereotactic radiosurgery.

BACKGROUND: Metastatic melanoma often involves the brain. Radiotherapy is an important treatment of melanoma brain metastases, although melanoma radiosensitivity is considered heterogeneous. Thus, identifying subsets with differential radiosensitivity is essential. MATERIALS AND METHODS: Patients with metastatic melanoma were identified in a prospective stereotactic radiosurgery (SRS) database. Tumor were tested for alterations in B-RAF, N-RAS, and c-KIT. Standardized imaging following SRS was reviewed for recurrence. Differences in local and distant failure were determined using modified Cox proportional hazards models. RESULTS: 102 patients and 1,028 brain metastases were included. N-RAS mutated patients were significantly less likely to develop local recurrence after SRS than wild type patients (HR 0.17, 95% CI 0.04-0.72, p=0.017). B-RAF and c-KIT mutations were not associated with altered rates of local recurrence. Lower local recurrence rates for N-RAS mutated tumors persisted on multivariate analysis (HR 0.18, 95% CI 0.04-0.84p=0.029). CONCLUSIONS: N-RAS mutation is associated with improved local control following SRS. Local recurrence is more common in wild type patients and those with B-RAF or c-KIT mutations. Further research is needed to validate these findings and integrate into practice.

Characterization of PD-L1 Expression and Associated T-cell Infiltrates in Metastatic Melanoma Samples from Variable Anatomic Sites.

PURPOSE: Programmed death ligand-1 (PD-L1) tumor expression represents a mechanism of immune escape for melanoma cells. Drugs blocking PD-L1 or its receptor have shown unprecedented activity in melanoma, and our purpose was to characterize tumor PD-L1 expression and associated T-cell infiltration in metastatic melanomas. EXPERIMENTAL DESIGN: We used a tissue microarray (TMA) consisting of two cores from 95 metastatic melanomas characterized for clinical stage, outcome, and anatomic site of disease. We assessed PD-L1 expression and tumor-infiltrating lymphocyte (TIL) content (total T cells and CD4/CD8 subsets) by quantitative immunofluorescence. RESULTS: High PD-L1 expression was associated with improved survival (P = 0.02) and higher T-cell content (P = 0.0005). Higher T-cell content (total and CD8 cells) was independently associated with improved overall survival; PD-L1 expression was not independently prognostic. High TIL content in extracerebral metastases was associated with increased time to developing brain metastases (P = 0.03). Cerebral and dermal metastases had slightly lower PD-L1 expression than other sites, not statistically significant. Cerebral metastases had less T cells (P = 0.01). CONCLUSIONS: T-cell-infiltrated melanomas, particularly those with high CD8 T-cell content, are more likely to be associated with PD-L1 expression in tumor cells, an improved prognosis, and increased time to development of brain metastases. Studies of T-cell content and subsets should be incorporated into trials of PD-1/PD-L1 inhibitors to determine their predictive value. Furthermore, additional studies of anatomic sites with less PD-L1 expression and T-cell infiltrate are needed to determine if discordant responses to PD-1/PD-L1 inhibitors are seen at those sites.

Gamma knife stereotactic radiosurgical thalamotomy for intractable tremor: a systematic review of the literature.

Tremor markedly reduces quality of life and causes a significant psychological burden for patients who are severely affected by this movement disorder. Pharmacologic and surgical treatments for tremor exist, but for patients who have failed medical therapy and are not surgical candidates, stereotactic radiosurgery is the only available treatment option. Of available stereotactic radiosurgical techniques for intractable tremor, the authors chose to evaluate the safety and efficacy of gamma knife stereotactic radiosurgical thalamotomy. In order to qualitatively synthesize available data a systematic review was conducted by searching MEDLINE (OvidSP 1946-January Week 1 2014) and Embase (OvidSP 1974-2014 January). The search strategy was not limited by study design or language of publication. All searches were conducted on January 7, 2014. Treatment efficacy, adverse outcomes, and patient deaths were reviewed and tabulated. Complications appeared months to years post procedure and most commonly consisted of mild contralateral numbness and transient hemiparesis. Rarely, more severe complications were reported, including dysphagia and death. Though no data from randomized controlled trials are available, our analysis of the literature indicates that unilateral gamma knife thalamotomy using doses from 130 to 150Gy appears safe and well tolerated.

Gamma Knife radiosurgery for sellar and parasellar meningiomas: a multicenter study.

OBJECT: Parasellar and sellar meningiomas are challenging tumors owing in part to their proximity to important neurovascular and endocrine structures. Complete resection can be associated with significant morbidity, and incomplete resections are common. In this study, the authors evaluated the outcomes of parasellar and sellar meningiomas managed with Gamma Knife radiosurgery (GKRS) both as an adjunct to microsurgical removal or conventional radiation therapy and as a primary treatment modality. METHODS: A multicenter study of patients with benign sellar and parasellar meningiomas was conducted through the North American Gamma Knife Consortium. For the period spanning 1988 to 2011 at 10 centers, the authors identified all patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were also required to have a minimum of 6 months of imaging and clinical follow-up after GKRS. Factors predictive of new neurological deficits following GKRS were assessed via univariate and multivariate analyses. Kaplan-Meier analysis and Cox multivariate regression analysis were used to assess factors predictive of tumor progression. RESULTS: The authors identified 763 patients with sellar and/or parasellar meningiomas treated with GKRS. Patients were assessed clinically and with neuroimaging at routine intervals following GKRS. There were 567 females (74.3%) and 196 males (25.7%) with a median age of 56 years (range 8-90 years). Three hundred fifty-five patients (50.7%) had undergone at least one resection before GKRS, and 3.8% had undergone prior radiation therapy. The median follow-up after GKRS was 66.7 months (range 6-216 months). At the last follow-up, tumor volumes remained stable or decreased in 90.2% of patients. Actuarial progression-free survival rates at 3, 5, 8, and 10 years were 98%, 95%, 88%, and 82%, respectively. More than one prior surgery, prior radiation therapy, or a tumor margin dose < 13 Gy significantly increased the likelihood of tumor progression after GKRS. At the last clinical follow-up, 86.2% of patients demonstrated no change or improvement in their neurological condition, whereas 13.8% of patients experienced symptom progression. New or worsening cranial nerve deficits were seen in 9.6% of patients, with cranial nerve (CN) V being the most adversely affected nerve. Functional improvements in CNs, especially in CNs V and VI, were observed in 34% of patients with preexisting deficits. New or worsened endocrinopathies were demonstrated in 1.6% of patients; hypothyroidism was the most frequent deficiency. Unfavorable outcome with tumor growth and accompanying neurological decline was statistically more likely in patients with larger tumor volumes (p = 0.022) and more than 1 prior surgery (p = 0.021). CONCLUSIONS: Gamma Knife radiosurgery provides a high rate of tumor control for patients with parasellar or sellar meningiomas, and tumor control is accompanied by neurological preservation or improvement in most patients.

Secondary neoplasms after stereotactic radiosurgery.

OBJECTIVE: The use of medical radiation has increased 6-fold in the past 30 years. Within neurosurgery, the advent of stereotactic radiosurgery (SRS) has significantly altered the treatment paradigm for both benign and malignant central nervous system diseases. With this increased reliance on radiation has come a responsibility to identify the long-term risks, including the potential development of radiation-induced neoplasms. Although the data regarding traditional radiation exposure and its subsequent risks are well-defined, the data for SRS is less developed. METHODS: We reviewed the published literature to more accurately define the risk of developing secondary neoplasms after stereotactic radiosurgery. RESULTS: A total of 36 cases of SRS-induced neoplasms were identified. More than half of the cases had an initial diagnosis of vestibular schwannoma. Overall, the risk of developing an SRS-induced neoplasm is approximately 0.04% at 15 years. CONCLUSION: The risk of developing an SRS-induced neoplasm is low but not zero. Thus, long-term surveillance imaging is advised for patients treated with SRS.

Role of stereotactic radiosurgery in patients with more than four brain metastases.

For patients presenting with brain metastases, two methods of radiation treatment currently exist: stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT). SRS is a minimally invasive to noninvasive technique that delivers a high dose of ionizing radiation to a precisely defined focal target volume, whereas WBRT involves multiple smaller doses of radiation delivered to the whole brain. Evidence exists from randomized controlled trials for SRS in the treatment of patients with one to four brain metastases. Patients with more than four brain metastases generally receive WBRT, which can effectively treat undetected metastases and protect against intracranial relapse. However, WBRT has been associated with an increased potential for toxic neurocognitive side effects, including memory loss and early dementia, and does not provide 100% protection against relapse. For this reason, physicians at many medical centers are opting to use SRS as first-line treatment for patients with more than four brain metastases, despite evidence showing an increased rate of intracranial relapse compared with WBRT. In light of the evolving use of SRS, this review will examine the available reports on institutional trials and outcomes for patients with more than four brain metastases treated with SRS alone as first-line therapy.

Management of brain metastases: surgery, radiation, or both?

A significant number of cancer patients will develop intracranial metastases. In general, treatment of these lesions uses a combination of surgery and radiation. However, over the past several decades the specifics of this treatment paradigm have evolved significantly. This article describes the current standard of care with respect to intracranial metastases, highlighting the latest therapeutic developments.

Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival.

OBJECT: A prospectively collected cohort of 77 patients who underwent definitive radiosurgery between 2002 and 2010 for melanoma brain metastases was retrospectively reviewed to assess the impact of ipilimumab use and other clinical variables on survival. METHODS: The authors conducted an institutional review board-approved chart review to assess patient age at the time of brain metastasis diagnosis, sex, primary disease location, initial radiosurgery date, number of metastases treated, performance status, systemic therapy and ipilimumab history, whole-brain radiation therapy (WBRT) use, follow-up duration, and survival at the last follow-up. The Diagnosis-Specific Graded Prognostic Assessment (DSGPA) score was calculated for each patient based on performance status and the number of brain metastases treated. RESULTS: Thirty-five percent of the patients received ipilimumab. The median survival in this group was 21.3 months, as compared with 4.9 months in patients who did not receive ipilimumab. The 2-year survival rate was 47.2% in the ipilimumab group compared with 19.7% in the nonipilimumab group. The DS-GPA score was the most significant predictor of overall survival, and ipilimumab therapy was also independently associated with an improvement in the hazard for death (p = 0.03). CONCLUSIONS: The survival of patients with melanoma brain metastases managed with ipilimumab and definitive radiosurgery can exceed the commonly anticipated 4-6 months. Using ipilimumab in a supportive treatment paradigm of radiosurgery for brain oligometastases was associated with an increased median survival from 4.9 to 21.3 months, with a 2-year survival rate of 19.7% versus 47.2%. This association between ipilimumab and prolonged survival remains significant even after adjustment for performance status without an increased need for salvage WBRT.

Radiosurgery alone for 5 or more brain metastases: expert opinion survey.

OBJECT: Oligometastatic brain metastases may be treated with stereotactic radiosurgery (SRS) alone, but no consensus exists as to when SRS alone would be appropriate. A survey was conducted at 2 radiosurgery meetings to determine which factors SRS practitioners emphasize in recommending SRS alone, and what physician characteristics are associated with recommending SRS alone for ≥ 5 metastases. METHODS: All physicians attending the 8th Biennial Congress and Exhibition of the International Stereotactic Radiosurgery Society in June 2007 and the 18th Annual Meeting of the Japanese Society of Stereotactic Radiosurgery in July 2009 were asked to complete a questionnaire ranking 14 clinical factors on a 5-point Likert-type scale (ranging from 1 = not important to 5 = very important) to determine how much each factor might influence a decision to recommend SRS alone for brain metastases. Results were condensed into a single dichotomous outcome variable of "influential" (4-5) versus "not influential" (1-3). Respondents were also asked to complete the statement: "In general, a reasonable number of brain metastases treatable by SRS alone would be, at most, ___." The characteristics of physicians willing to recommend SRS alone for ≥ 5 metastases were assessed. Chi-square was used for univariate analysis, and logistic regression for multivariate analysis. RESULTS: The final study sample included 95 Gamma Knife and LINAC-using respondents (54% Gamma Knife users) in San Francisco and 54 in Sendai (48% Gamma Knife users). More than 70% at each meeting had ≥ 5 years experience with SRS. Sixty-five percent in San Francisco and 83% in Sendai treated ≥ 30 cases annually with SRS. The highest number of metastases considered reasonable to treat with SRS alone in both surveys was 50. In San Francisco, the mean and median numbers of metastases considered reasonable to treat with SRS alone were 6.7 and 5, while in Sendai they were 11 and 10. In the San Francisco sample, the clinical factors identified to be most influential in decision making were Karnofsky Performance Scale score (78%), presence/absence of mass effect (76%), and systemic disease control (63%). In Sendai, the most influential factors were the size of the metastases (78%), the Karnofsky Performance Scale score (70%), and metastasis location (68%). In San Francisco, 55% of respondents considered treating ≥ 5 metastases and 22% considered treating ≥ 10 metastases "reasonable." In Sendai, 83% of respondents considered treating ≥ 5 metastases and 57% considered treating ≥ 10 metastases "reasonable." In both groups, private practitioners, neurosurgeons, and Gamma Knife users were statistically significantly more likely to treat ≥ 5 metastases with SRS alone. CONCLUSIONS: Although there is no clear consensus for how many metastases are reasonable to treat with SRS alone, more than half of the radiosurgeons at 2 international meetings were willing to extend the use of SRS as an initial treatment for ≥ 5 brain metastases. Given the substantial variation in clinicians' approaches to SRS use, further research is required to identify patient characteristics associated with optimal SRS outcomes.