Impact of breast cancer subtype on clinical outcomes after Gamma Knife radiosurgery for brain metastases from breast cancer: a multi-institutional retrospective study (JLGK1702).

INTRODUCTION: Brain metastasis (BM) is one of the most important issues in the management of breast cancer (BC), since BMs are associated with neurological deficits. However, the importance of BC subtypes remains unclear for BM treated with Gamma Knife radiosurgery (GKS). Thus, we conducted a multicenter retrospective study to compare clinical outcomes based on BC subtypes, with the aim of developing an optimal treatment strategy. METHODS: We studied 439 patients with breast cancer and 1-10 BM from 16 GKS facilities in Japan. Overall survival (OS) was analyzed by the Kaplan-Meier method, and cumulative incidences of systemic death (SD), neurologic death (ND), and tumor progression were estimated by competing risk analysis. RESULTS: OS differed among subtypes. The median OS time (months) after GKS was 10.4 in triple-negative (TN), 13.7 in Luminal, 31.4 in HER2, and 35.8 in Luminal-HER2 subtype BC (p < 0.0001). On multivariate analysis, poor control of the primary disease (hazard ratio [HR] = 1.84, p < 0.0001), active extracranial disease (HR = 2.76, p < 0.0001), neurological symptoms (HR 1.44, p = 0.01), and HER2 negativity (HR = 2.66, p < 0.0001) were significantly associated with worse OS. HER2 positivity was an independent risk factor for local recurrence (p = 0.03) but associated with lower rates of ND (p = 0.03). TN histology was associated with higher rates of distant brain failure (p = 0.03). CONCLUSIONS: HER2 positivity is related to the longer OS after SRS; however, we should pay attention to preventing recurrence in Luminal-HER2 patients. Also, TN patients require meticulous follow-up observation to detect distant metastases and/or LMD.

Comparison of two-stage Gamma Knife radiosurgery outcomes for large brain metastases among primary cancers.

PURPOSE: Stereotactic radiosurgery (SRS) is typically considered for patients who cannot undergo surgical resection for large (> 10 cm3) brain metastases (BMs). Staged SRS requires adaptive planning during each stage of the irradiation period for improved tumor control and reduced radiation damage. However, there has been no study on the tumor reduction rates of this method. We evaluated the outcomes of two-stage SRS across multiple primary cancer types. METHODS: We analyzed 178 patients with 182 large BMs initially treated with two-stage SRS. The primary cancers included breast (BC), non-small cell lung (NSCLC), and gastrointestinal tract cancers (GIC). We analyzed the overall survival (OS), neurological death, systemic death (SD), tumor progression (TP), tumor recurrence (TR), radiation necrosis (RN), and the tumor reduction rate during both stages. RESULTS: The median survival time after the first Gamma Knife surgery (GKS) procedure was 6.6 months. Compared with patients with BC and NSCLC, patients with GIC had shorter OS and a higher incidence of SD. Compared with patients with NSCLC and GIC, patients with BC had significantly higher tumor reduction rates in both sessions. TP rates were similar among primary cancer types. There was no association of the tumor reduction rate with tumor control. The overall cumulative incidence of RN was 4.2%; further, the RN rates were similar among primary cancer types. CONCLUSIONS: Two-stage SRS should be considered for BC and NSCLC if surgical resection is not indicated. For BMs from GIC, staged SRS should be carefully considered and adapted to each unique case given its lower tumor reduction rate and shorter OS.

Three-institution study on applicability of initial brain metastasis velocity for breast cancer brain metastasis patients undergoing stereotactic radiosurgery.

PURPOSE: This study aimed to validate whether the recently-proposed prognostic grading system, initial brain metastasis velocity (iBMV), is applicable to breast cancer patients receiving stereotactic radiosurgery (SRS). We focused particularly on whether this grading system is useful for patients with all molecular types, i.e., positive versus negative for EsR, PgR and HER2. METHODS AND MATERIALS: This was an institutional review board-approved, retrospective cohort study using our database, prospectively accumulated at three gamma knife institutes, during the 20-year-period since 1998. We excluded patients for whom the day of primary cancer diagnosis was not available, had synchronous presentation, lacked information regarding molecular types, and/or had received pre-SRS radiotherapy and/or surgery. We ultimately studied 511 patients categorized into two classes by iBMV scores, i.e., < 2.00 and ≥ 2.00. RESULTS: The median iBMV score for the entire cohort was 0.97 (IQR 0.39-2.84). Median survival time (MST) in patients with iBMV < 2.00, 15.9 (95% CI 13.0-18.6, IQR 7.5-35.5) months, was significantly longer than that in patients with iBMV ≥ 2.00, 8.2 (95% CI 6.8-9.9, IQR 3.9-19.4) months (HR 1.582, 95% CI: 1.308-1.915, p < 0.0001). The same results were obtained in patients with EsR (-), PgR (-), HER2 (+) and HER2 (-) cancers, while MSTs did not differ significantly between iBMV < 2.00 vs ≥ 2.00 in patients with EsR (+) and PgR (+) cancers. CONCLUSIONS: This system was clearly shown to be applicable to breast cancer patients with SRS-treated BMs. However, this system is not applicable to patients with hormone receptor (+) breast cancer.

Salvage gamma knife radiosurgery for active brain metastases from small-cell lung cancer after whole-brain radiation therapy: a retrospective multi-institutional study (JLGK1701).

PURPOSE: To evaluate the efficacy of gamma knife radiosurgery (GKS) for brain metastases (BMs) from small-cell lung cancer after whole-brain radiotherapy (WBRT). METHODS: We retrospectively analyzed the usefulness and safety of GKS in 163 patients from 15 institutions with 1-10 active BMs after WBRT. The usefulness and safety of GKS were evaluated using statistical methods. RESULTS: The median age was 66 years, and 79.1% of patients were men. The median number and largest diameter of BM were 2.0 and 1.4 cm, respectively. WBRT was administered prophylactically in 46.6% of patients. The median overall survival (OS) was 9.3 months, and the neurologic mortality was 20.0%. Crude incidences of local control failure and new lesion appearance were 36.6% and 64.9%, respectively. A BM diameter ≥ 1.0 cm was a significant risk factor for local progression (hazard ratio [HR] 2.556, P = 0.039) and neurologic death (HR 4.940, P = 0.031). Leukoencephalopathy at the final follow-up was more prevalent in the therapeutic WBRT group than in the prophylactic group (P = 0.019). The symptom improvement rate was 61.3%, and neurological function was preserved for a median of 7.6 months. Therapeutic WBRT was not a significant risk factor for OS, neurological death, local control, or functional deterioration (P = 0.273, 0.490, 0.779, and 0.560, respectively). Symptomatic radiation-related adverse effects occurred in 7.4% of patients. CONCLUSIONS: GKS can safely preserve neurological function and prevent neurologic death in patients with 1-10 small, active BMs after prophylactic and therapeutic WBRT.

The impact of EGFR-TKI use on clinical outcomes of lung adenocarcinoma patients with brain metastases after Gamma Knife radiosurgery: a propensity score-matched analysis based on extended JLGK0901 dataset (JLGK0901-EGFR-TKI).

PURPOSE: Recent advances in targeted therapy have prolonged overall survival (OS) for patients with lung cancer. The impact of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI) on brain metastases (BM) treated with stereotactic radiosurgery (SRS) has not, however, been fully elucidated. We investigated the influence of post-SRS EGFR-TKI use on the efficacy and toxicity of SRS for BM from lung adenocarcinoma. METHODS: We used the updated dataset of the Japanese Leksell Gamma Knife (JLGK) 0901 study, which proved the efficacy of Gamma Knife SRS in patients with BM. Propensity score matching (PSM) analysis was employed to determine the impact of concurrent or post-SRS EGFR-TKI use on OS, neurological death, intracranial disease recurrence and SRS-related adverse events. RESULTS: Among 1194 patients registered in the JLGK0901 study, 608 eligible lung adenocarcinoma patients were identified and 238 (39%) had received EGFR-TKI concurrently or during the post-SRS clinical course. After PSM, there were 200 patient pairs with/without post-SRS EGFR-TKI use. EGFR-TKI use was associated with longer OS (median 25.5 vs. 11.0 months, HR 0.60, 95% CI 0.48-0.75, p < 0.001), although the long-term OS curves eventually crossed. Distant intracranial recurrence was more likely in patients receiving EGFR-TKI (HR 1.45, 95% CI 1.12-1.89, p = 0.005). Neurological death, local recurrence and SRS-related adverse event rates did not differ significantly between the two groups. CONCLUSIONS: Although patients receiving EGFR-TKI concurrently or after SRS had significantly longer OS, the local treatment efficacy and toxicity of SRS did not differ between patients with/without EGFR-TKI use.

Stereotactic radiosurgery in elderly patients with brain metastases: comparison with non-elderly patients using database of a multi-institutional prospective observational study (JLGK0901-Elderly).

PURPOSE: Stereotactic radiosurgery (SRS) has been increasingly used for elderly patients with brain metastases (BMs). However, no studies based on a large sample size have been reported. To compare SRS treatment results between elderly and non-elderly patients, we performed a subset study of elderly patients using our prospectively-accumulated multi-institution study database (JLGK0901 Study, Lancet Oncol 15:387-395, 2014). METHODS: During the 2009-2011 period, 1194 eligible patients undergoing gamma knife SRS alone for newly diagnosed BMs were enrolled in this study from 23 gamma knife facilities in Japan. Observation was discontinued at the end of 2013. The 1194 patients were divided into the two age groups, 693 elderly ( ≥ 65 years) and 501 non-elderly ( < 65 years) patients. Our study protocol neither set an upper age limit nor required dose de-escalation. RESULTS: Median post-SRS survival time was significantly shorter in the elderly than in the non-elderly patient group (10.3 vs 14.3 months, HR 1.380, 95% CI 1.218-1.563, p < 0.0001). However, regarding all secondary endpoints including neurological death, neurological deterioration, SRS-related complications, leukoencephalopathy, local recurrence, newly-developed tumors, meningeal dissemination, salvage SRS, whole brain radiotherapy and surgery and decreased mini-mental state examination scores, the elderly patient group was not inferior to the non-elderly patient group. In the 693 elderly patients, there was no post-SRS median survival time difference between those with 5-10 versus 2-4 tumors (10.8 vs 8.9 months, HR 0.936, 95% CI 0.744-1.167, p = 0.5601). CONCLUSIONS: We conclude that elderly BM patients are not unfavorable candidates for SRS alone treatment.

Low-dose Gamma Knife radiosurgery plus whole-brain radiation therapy for patients with 5 or more brain metastases with or without meningeal dissemination.

PURPOSE/OBJECTIVE(S): Radiosurgery plus whole-brain radiotherapy (WBRT) has been reported to be useful for patients with ≤ 4 brain metastases (BM), but we hypothesized that similar treatment may be applicable to patients with ≥ 5 BM with or without meningeal dissemination. The purpose of this study was to evaluate the efficacy and toxicity of low-dose Gamma Knife (GK) followed by WBRT for patients with advanced BM. MATERIALS/METHODS: Major eligibility criteria for this phase II study were: (1) ≥ 5 BM with or without meningeal dissemination and (2) the largest tumor diameter ≤ 4 cm. During 2013-2016, 40 patients (13 men and 27 women) entered the study. Nineteen had meningeal dissemination. The GK dose was 12 Gy at the periphery when the longest diameter was 3-4 cm and 14 Gy when it was < 3 cm. The WBRT dose to the isocenter was 30 Gy in 10 fractions, or 37.5 Gy in 15 fractions for two patients, with an expected survival of > 12 months. The median number of target BM was 17.5. RESULTS: After GK plus WBRT for 40 patients, 31 did not develop further intracranial recurrence until death or last follow-up, whereas 9 developed recurrence. With a follow-up period up to 24 months, the overall survival rate was 36% at 12 months and median survival time was 8 months. The cumulative incidence of intracranial recurrence was 25% at 12 months. Toxicity was considered acceptable. CONCLUSION: Treatment with low-dose GK followed by WBRT for advanced-stage BM appeared to contribute to local control.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Malignant Melanomas: A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study (JLGK1501).

BACKGROUND: The incidences of metastatic brain tumors from malignant melanomas have increased and survival has been prolonged by novel molecular targeted agents and immunotherapy. However, malignant melanomas are uncommon in Asian populations. OBJECTIVES: We retrospectively analyzed treatment efficacy and identified prognostic factors impacting tumor control and survival in Japanese melanoma patients with brain metastases treated with gamma knife radiosurgery (GKRS). METHODS: We retrospectively reviewed the medical records of 177 patients with 1,500 tumors who underwent GKRS for brain metastases from malignant melanomas. This study was conducted by the Japanese Leksell Gamma Knife Society (JLGK1501). RESULTS: Six and 12 months after GKRS, the cumulative incidences of local tumor recurrence were 9.2 and 13.8%. Intratumoral hemorrhage (p < 0.0001) and larger tumor volume (p = 0.001) in GKRS were associated with significantly poorer local control outcomes. The use of immune checkpoint inhibitors before GKRS was significantly associated with symptomatic adverse events (p = 0.037). The median overall survival time after the initial GKRS was 7.3 months. Lower Karnofsky performance status scores (p = 0.016), uncontrolled primary cancer (p < 0.0001), and multiple brain metastases (p = 0.014) significantly influenced unfavorable overall survival outcomes. The cumulative incidences of neurological death 6 and 12 months after GKRS were 9.7 and 17.4%, those of neurological deterioration were 14.2 and 19.6%, and those of new tumor appearance were 34.5 and 40.5%. CONCLUSIONS: The results of the present multicenter study suggest that GKRS is a relatively effective and safe modality for control of tumor progression in Japanese patients with brain metastases from malignant melanomas.

Clinical features of brain metastases from hepatocellular carcinoma using gamma knife surgery.

BACKGROUND: Brain metastases from hepatocellular carcinoma (HCC) are rare, but their incidence is increasing because of developments in recent therapeutic advances. The purpose of this study was to investigate the characteristics of brain metastases from HCC, to evaluate the predictive factors, and to assess the efficacy of gamma knife surgery (GKS). METHOD: A retrospective study was performed on patients with brain metastases from HCC who were treated at Tokyo Gamma Unit Center from 2005 to 2014. RESULTS: Nineteen patients were identified. The median age at diagnosis of brain metastases was 67.0 years. Fifteen patients were male and four patients were female. Six patients were infected with hepatitis B virus (HBV). Two patients were infected with hepatitis C virus (HCV). Eleven patients were not infected with HBV or HCV. The median interval from the diagnosis of HCC to brain metastases was 32.0 months. The median number of brain metastases was two. The median Karnofsky performance score at first GKS was 70. The median survival time following brain metastases was 21.0 weeks. Six-month and 1-year survival rates were 41.2 and 0%, respectively. One month after GKS, no tumor showed progressive disease. The HBV infection (positive vs. negative) was significantly associated with survival according to univariate analysis (p = 0.002). CONCLUSIONS: The patients having brain metastases from HCC had poor prognosis and low performance state. Therefore, GKS is an acceptable option for controlling brain metastases from HCC because GKS is noninvasive remedy and local control is reasonable.

Gamma knife radiosurgery in movement disorders: Indications and limitations.

Functional radiosurgery has advanced steadily during the past half century since the development of the gamma knife technique for treating intractable cancer pain. Applications of radiosurgery for intracranial diseases have increased with a focus on understanding radiobiology. Currently, the use of gamma knife radiosurgery to ablate deep brain structures is not widespread because visualization of the functional targets remains difficult despite the increased availability of advanced neuroimaging technology. Moreover, most existing reports have a small sample size or are retrospective. However, increased experience with intraoperative neurophysiological evaluations in radiofrequency thalamotomy and deep brain stimulation supports anatomical and neurophysiological approaches to the ventralis intermedius nucleus. Two recent prospective studies have promoted the clinical application of functional radiosurgery for movement disorders. For example, unilateral gamma knife thalamotomy is a potential alternative to radiofrequency thalamotomy and deep brain stimulation techniques for intractable tremor patients with contraindications for surgery. Despite the promising efficacy of gamma knife thalamotomy, however, these studies did not include sufficient follow-up to confirm long-term effects. Herein, we review the radiobiology literature, various techniques, and the treatment efficacy of gamma knife radiosurgery for patients with movement disorders. Future research should focus on randomized controlled studies and long-term effects. © 2016 International Parkinson and Movement Disorder Society.

Fractionated stereotactic radiotherapy for metastatic brain tumors that recurred after gamma knife radiosurgery results in acceptable toxicity and favorable local control.

BACKGROUND: To treat local recurrence of brain metastases after gamma knife radiosurgery (GKS), we have used fractionated stereotactic radiotherapy (SRT). The purpose of this study was to evaluate the efficacy and toxicity of SRT in these patients. METHODS: Fifty locally recurrent metastatic brain tumors in 47 patients were treated with SRT. The median prescribed dose of GKS was 20 Gy at the periphery. The median interval between the GKS (the last session in cases in which multiple GKS procedures were performed) and recurrence was 7.5 (range 1-33) months. Several dose-fractionation protocols were used for SRT, depending on the size and location of the tumor and previous GKS dose. The median prescribed dose of the SRT at the isocenter was 30 Gy with a median of ten fractions. RESULTS: Among the 50 lesions treated with SRT, 26 did not recur locally before the patient's death or the last follow-up examination, and 24 recurred locally. The median follow-up period for the surviving patients was 24 months after the first GKS procedure, and the overall survival rate was 80% at 1 year and 57% at 2 years. The median time to local re-recurrence after the SRT (16 months) was significantly longer than the median interval between the last GKS and recurrence (7.5 months; P < 0.001). Only two patients developed ≥grade 2 radiation necrosis. CONCLUSIONS: Stereotactic radiotherapy appeared to be an effective treatment for recurrent metastatic brain tumors and yielded relatively good local control. The associated adverse events were generally acceptable.

Stereotactic radiosurgery in combination with up-front high-dose methotrexate as a first-line treatment for newly diagnosed primary central nervous system lymphoma.

The efficacy of stereotactic radiosurgery (SRS) instead of whole brain radiotherapy (WBRT) following high-dose methotrexate (HD-MTX) for primary central nervous system lymphoma (PCNSL) is unclear. To clarify whether SRS in combination with up-front HD-MTX supplements the effect of HD-MTX in remaining or refractory lesions after initial HD-MTX treatment. The authors conducted a retrospective review for newly diagnosed PCNSL patients who underwent SRS after HD-MTX as a first-line treatment. The local control (LC), the progression-free survival (PFS), the recurrence patterns, the salvage treatments, the overall survival (OS), the Karnofsky Performance Status (KPS), the activities of daily living (ADL) were analyzed as well as radiosurgical parameters. Twenty patients underwent SRS for 51 lesions with the median volume of 0.45 cm(3). The median age at SRS was 67 (range 37-82). The median KPS at SRS was 90. The LC rate at 2 years was 86.0 %, the median PFS after SRS was 17 months, necessitating additional SRS and chemotherapy. The median OS was 52 months. No significant side effects related to SRS were observed. During follow-up period, the good ADL preservation was achieved for 13 months from SRS. Patients with KPS ≥ 90 at SRS demonstrated longer ADL preservation (32 months from SRS). SRS following up-front HD-MTX without WBRT provided excellent LC, acceptable OS and the long ADL preservation period. These benefits may be more emphasized especially in patients with good KPS, but should be validated in a large patient population.

Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study.

BACKGROUND: We aimed to examine whether stereotactic radiosurgery without whole-brain radiotherapy (WBRT) as the initial treatment for patients with five to ten brain metastases is non-inferior to that for patients with two to four brain metastases in terms of overall survival. METHODS: This prospective observational study enrolled patients with one to ten newly diagnosed brain metastases (largest tumour <10 mL in volume and <3 cm in longest diameter; total cumulative volume ≤15 mL) and a Karnofsky performance status score of 70 or higher from 23 facilities in Japan. Standard stereotactic radiosurgery procedures were used in all patients; tumour volumes smaller than 4 mL were irradiated with 22 Gy at the lesion periphery and those that were 4-10 mL with 20 Gy. The primary endpoint was overall survival, for which the non-inferiority margin for the comparison of outcomes in patients with two to four brain metastases with those of patients with five to ten brain metastases was set as the value of the upper 95% CI for a hazard ratio (HR) of 1·30, and all data were analysed by intention to treat. The study was finalised on Dec 31, 2012, for analysis of the primary endpoint; however, monitoring of stereotactic radiosurgery-induced complications and neurocognitive function assessment will continue for the censored subset until the end of 2014. This study is registered with the University Medical Information Network Clinical Trial Registry, number 000001812. FINDINGS: We enrolled 1194 eligible patients between March 1, 2009, and Feb 15, 2012. Median overall survival after stereotactic radiosurgery was 13·9 months [95% CI 12·0-15·6] in the 455 patients with one tumour, 10·8 months [9·4-12·4] in the 531 patients with two to four tumours, and 10·8 months [9·1-12·7] in the 208 patients with five to ten tumours. Overall survival did not differ between the patients with two to four tumours and those with five to ten (HR 0·97, 95% CI 0·81-1·18 [less than non-inferiority margin], p=0·78; pnon-inferiority<0·0001). Stereotactic radiosurgery-induced adverse events occurred in 101 (8%) patients; nine (2%) patients with one tumour had one or more grade 3-4 event compared with 13 (2%) patients with two to four tumours and six (3%) patients with five to ten tumours. The proportion of patients who had one or more treatment-related adverse event of any grade did not differ significantly between the two groups of patients with multiple tumours (50 [9%] patients with two to four tumours vs 18 [9%] with five to ten; p=0·89). Four patients died, mainly of complications relating to stereotactic radiosurgery (two with one tumour and one each in the other two groups). INTERPRETATION: Our results suggest that stereotactic radiosurgery without WBRT in patients with five to ten brain metastases is non-inferior to that in patients with two to four brain metastases. Considering the minimal invasiveness of stereotactic radiosurgery and the fewer side-effects than with WBRT, stereotactic radiosurgery might be a suitable alternative for patients with up to ten brain metastases. FUNDING: Japan Brain Foundation.

Validity test of small cell lung cancer (SCLC) graded prognostic assessment and proposal of a new index for patients with brain metastases from SCLC.

Background and purpose: We performed a validity test of a recently-reported, small cell lung cancer (SCLC) graded prognostic assessment (GPA) system for SCLC patients with brain metastases (BMs). Thereafter, we created a new prognostic index, the SCLC Grade, for such patients. Materials and methods: We studied 508 SCLC patients selected from among nearly 7000 consecutive patients undergoing gamma knife SRS for BMs since 1998. Results: In the SCLC GPA, there were no median survival time (MST) differences among pairs of the neighboring subgroups. Therefore, the 508 patients were randomly divided into the two series, i.e., a test (340 patients) and a validity (168) series. In the test series, five factors were identified by univariable analyses as favoring longer survival (rounded lower 95 % CI of the HR was at least 1.3): Sex, Karnofsky Performance Status, tumor numbers, primary tumor status and extracerebral metastases. This new index is the sum of scores (0 and 1) of these five factors: SCLC-Grade 4-6 (score of 4, 5 or 6), 2-3 (2 or 3), and 0-1 (0 or 1). This new system showed highly statistically significant MST differences among subclasses. Next, this SCLC-Grade was applied to the verification series. Consistent results were obtained, i.e., there were highly statistically significant MST differences among subclasses. Conclusions: Our validity test results for the SCLC GPA demonstrated this system to not precisely reflect the outcomes of SCLC patients with BMs. Our results suggest the herein-proposed SCLC-Grade to have superior prognostic value.

Validity of two recently-proposed prognostic grading indices for lung, gastro-intestinal, breast and renal cell cancer patients with radiosurgically-treated brain metastases.

We tested the validity of two prognostic indices for stereotactic radiosurgically (SRS)-treated patients with brain metastases (BMs) from five major original cancer categories. The two indices are Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) and our Modified Recursive Partitioning Analysis (RPA). Forty-six hundred and eight BM patients underwent gamma knife SRS during the 1998-2011 period. Primary cancer categories were non-small cell lung cancer (NSCLC, 2827 patients), small cell lung cancer (SCLC, 460), gastro-intestinal cancer (GIC, 582), breast cancer (BC, 547) and renal cell cancer (RCC, 192). There were statistically significant survival differences among patients stratified into four groups based on the DS-GPA systems (p < 0.001) in all five original cancer categories. In the NSCLC category, there were statistically significant mean survival time (MST) differences (p < 0.001) among the four groups without overlapping of 95 % confidence intervals (CIs) between any two pairs of groups with the DS-GPA system. However, among the SCLC, GIC, BC and RCC categories, MST differences between some pairs of groups failed to reach statistical significance with this system. There were, however, statistically significant MST differences (p < 0.001) among the three groups without overlapping of 95 % CIs between any two pairs of groups with the Modified RPA system in all five categories. The DS-GPA system is applicable to our set of patients with NSCLC only. However, the Modified RPA system was shown to be applicable to patients with five primary cancer categories. This index should be considered when designing future clinical trials involving BM patients.

Efficacy and limitations of salvage gamma knife radiosurgery for brain metastases of small-cell lung cancer after whole-brain radiotherapy.

BACKGROUND: The efficacy and limitations of salvage gamma knife surgery (GKS) have not been thoroughly described. This study evaluated the efficacy of GKS for treating brain metastases associated with small-cell lung cancer (SCLC) after whole-brain radiotherapy (WBRT) as the first-line radiation therapy. METHODS: Forty-four patients with recurrent or new SCLC-associated brain metastases underwent GKS after receiving WBRT (median age, 62 years; median duration between WBRT and first GKS, 8.8 months). The median Karnofsky performance status (KPS) score was 100 (range, 40-100), and the median number of brain metastases at the first GKS was five. Ten patients who partially or completely responded to chemotherapy received prophylactic cranial irradiation (PCI) for limited disease. RESULTS: The median prescribed dose and number of lesions treated with the initial GKS were 20.0 Gy and 3.5, respectively, and the tumor control rate was 95.8 % (median follow-up period, 4.0 months). The 6-month new lesion-free survival, functional preservation rates, and overall survival were 50.0 %, 94.7 %, and 5.8 months, respectively. Neurological death occurred in 17.9 % of cases. The poor prognostic factors for new lesion-free survival time and functional preservation were >5 brain metastases and carcinomatous meningitis, respectively. Poor prognostic factors for survival time were KPS <70, >10 brain metastases, diameter of the largest tumor >20 mm, and carcinomatous meningitis. Median overall survival time from brain metastasis diagnosis was 16.9 months. CONCLUSIONS: GKS may be an effective option for controlling SCLC-associated brain metastases after WBRT and for preventing neurological death in patients without carcinomatous meningitis.

Long-Term Outcomes of Hearing Preservation After Retrosigmoid Removal of Large Vestibular Schwannoma.

Background: Hearing preservation after large vestibular schwannoma (VS) removal is challenging and the long-term outcomes of postoperatively preserved hearing have not been elucidated. Objective: We aimed to clarify long-term outcomes of hearing preservation after the retrosigmoid large VS removal and to recommend a strategy for treating large VS. Materials and Methods: Hearing preservation with total/nearly total (T/NT) tumor removal was accomplished in six of 129 patients who underwent retrosigmoid large VS (≥3 cm) removal. We evaluated the long-term outcomes of these six patients. Results: Preoperative hearing of these six patients was 15-68 dB by pure tone audiometry (PTA) (Class I: 2, II: 3, and III: 1 by the Gardner-Robertson (GR) classification). Postoperatively, magnetic resonance imaging (MRI) with gadolinium administration confirmed T/NT removal, the preserved hearing was 36-88 dB (Class II: 4 and III: 2), and no facial palsy occurred. After long-term follow-up (8-16 [median: 11.5] years), five patients maintained hearing of 46-75 dB (Class II: 1 and III: 4) while one lost hearing. Three patients showed small tumor recurrence on MRI; two recurrences were controlled by gamma knife (GK) and one showed minimal change only by observation. Conclusions: Hearing preserved after T/NT removal of large VS is maintained for a long time (>10 years), though tumor recurrence on MRI is somewhat common. Detecting small recurrence early, and regular MRI follow-up contributes to the long-term maintenance of hearing. Hearing preservation with tumor removal is a challenging yet worthwhile strategy in large VS patients with preoperative hearing.

Gamma Knife Radiosurgery for Metastatic Brain Tumors from Uterine Cervical and Endometrial Carcinomas: Histopathological Analysis of Survival and Local Control. A Japanese Multi-Institutional Cooperative and Retrospective Cohort Study.

OBJECTIVE: A retrospective comparative analysis of the outcomes of gamma knife radiosurgery (GKRS) for brain metastases from uterine cervical carcinoma (CC) and endometrial carcinoma (EC), investigated the efficacy and prognostic factors for survival and local tumor control. Histopathological analysis was also performed. METHODS: The authors retrospectively reviewed 61 patients with 260 tumors of CC and 73 patients with 302 tumors of EC who had undergone GKRS. RESULTS: The survival times after GKRS had no difference between CC and EC. Uncontrolled primary cancer was significant unfavorable factor. CC resulted in significantly higher neurological death and post-GKRS neurological deterioration. New lesions appeared intracranially after GKRS, with no significant difference between CC and EC. Local tumor control rates at 6, 12, and 24 months after GKRS were 90.0%, 86.6%, and 78.0% for CC and 92.2%, 87.9%, and 86.4% for EC. Primary cancer of CC, more than 7 cm3 volume, and prescription dose less than 20 Gy were significantly correlated in control failure. Local tumor control rates were significantly lower for squamous cell carcinoma in CC. No significant differences were found between histopathological subtypes of EC. CONCLUSIONS: This study established a relationship between the efficacy of GKRS for CC and EC brain metastases and the histopathological. Though, survival time after GKRS has no difference between CC and EC, CC was significantly higher neurogenic death and neurological deterioration after GKRS. Squamous cell carcinoma had a significantly lower rate of local tumor control among all CC, thereby resulting in CC having lower local tumor control than EC.

Comparison of first-line radiosurgery for small-cell and non-small cell lung cancer brain metastases (CROSS-FIRE).

INTRODUCTION: Historical reservations regarding stereotactic radiosurgery (SRS) for small-cell lung cancer (SCLC) brain metastases include concerns for short-interval and diffuse central nervous system (CNS) progression, poor prognoses, and increased neurological mortality specific to SCLC histology. We compared SRS outcomes for SCLC and non-small cell lung cancer (NSCLC) where SRS is well established. METHODS: Multicenter first-line SRS outcomes for SCLC and NSCLC from 2000 to 2022 were retrospectively collected (n = 892 SCLC, n = 4785 NSCLC). Data from the prospective Japanese Leksell Gamma Knife Society (JLGK0901) clinical trial of first-line SRS were analyzed as a comparison cohort (n = 98 SCLC, n = 814 NSCLC). Overall survival (OS) and CNS progression were analyzed using Cox proportional hazard and Fine-Gray models, respectively, with multivariable adjustment for cofactors including age, sex, performance status, year, extracranial disease status, and brain metastasis number and volume. Mutation-stratified analyses were performed in propensity score-matched retrospective cohorts of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) positive NSCLC, mutation-negative NSCLC, and SCLC. RESULTS: OS was superior for patients with NSCLC compared to SCLC in the retrospective dataset (median OS = 10.5 vs 8.6 months; P < .001) and in the JLGK0901 dataset. Hazard estimates for first CNS progression favoring NSCLC were similar in both datasets but reached statistical significance in the retrospective dataset only (multivariable hazard ratio = 0.82, 95% confidence interval = 0.73 to 0.92, P = .001). In the propensity score-matched cohorts, there were continued OS advantages for NSCLC patients (median OS = 23.7 [EGFR and ALK positive NSCLC] vs 13.6 [mutation-negative NSCLC] vs 10.4 months [SCLC], pairwise P values < 0.001), but no statistically significant differences in CNS progression were observed in the matched cohorts. Neurological mortality and number of lesions at CNS progression were similar for NSCLC and SCLC patients. Leptomeningeal progression was increased in patients with NSCLC compared to SCLC in the retrospective dataset only (multivariable hazard ratio = 1.61, 95% confidence interval = 1.14 to 2.26, P = .007). CONCLUSIONS: After SRS, SCLC histology was associated with shorter OS compared to NSCLC. CNS progression occurred earlier in SCLC patients overall but was similar in patients matched on baseline factors. SCLC was not associated with increased neurological mortality, number of lesions at CNS progression, or leptomeningeal progression compared to NSCLC. These findings may better inform clinical expectations and individualized decision making regarding SRS for SCLC patients.

Gamma knife surgery for brain metastases from ovarian cancer.

BACKGROUND: Brain metastases from ovarian cancer are rare, but their incidence is increasing. The purpose of this study was to investigate the characteristics of brain metastases from ovarian cancer, and to assess the efficacy of treatment with gamma knife surgery (GKS). METHODS: A retrospective review was performed of patients with brain metastases from ovarian cancer who were treated at the Tokyo Gamma Unit Center from 2006 to 2010. RESULTS: Sixteen patients were identified. Their median age at diagnosis of brain metastases was 56.5 years, the median interval from diagnosis of ovarian cancer to brain metastases was 27.5 months, and the median number of brain metastases was 2. The median Karnofsky Performance Score (KPS) at the first GKS was 80. The median survival following diagnosis of brain metastases was 12.5 months, and 6-month and 1-year survival rates were 75 % and 50 %, respectively. The tumor control rate was 86.4 %. The KPS (<80 vs ≥80) and total volume of brain metastases (<10 cm(3) vs ≥10 cm(3)) were significantly associated with survival according to a univariate analysis (p = 0.004 and p = 0.02, respectively). CONCLUSIONS: The results of this study suggest that GKS is an effective remedy and acceptable choice for the control of brain metastases from ovarian cancer.