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.

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 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.

Growth potential of small residual tumors after vestibular schwannoma surgery: comparison between remnants and the natural history of small tumors.

OBJECTIVE: Due to the heterogeneous definitions of tumor regrowth and various tumor volume distributions, the nature of small remnants after vestibular schwannoma (VS) surgery and the appropriate timing of adjuvant stereotactic radiosurgery for these remnants remain unclear. In this study, the growth potential of small remnants (< 1 cm3) after VS surgery was compared with that of treatment-naïve (TN) small VSs. METHODS: This retrospective single-center study included 44 patients with VS remnants following subtotal resection (STR) of a large VS (remnant group) and 75 patients with TN VS (< 1 cm3; TN group). A 20% change in tumor volume over the imaging interval indicated radiographic progression or regression. Tumor progression-free survival (TPFS) rates were estimated using the Kaplan-Meier method. RESULTS: In the remnant group, the mean preoperative tumor volume was 13.8 ± 9.0 cm3 and the mean tumor resection rate was 95% ± 5%. The mean tumor volume at the start of the observation period did not differ significantly between the two groups (remnant vs TN: 0.41 ± 0.29 vs 0.34 ± 0.28 cm3, p = 0.171). The median periods until tumor progression was detected were 15.1 (range 4.9-76.2) months and 44.7 (range 12.6-93.2) months in the TN and remnant groups, respectively. In the remnant group, the TPFS rates were 74% and 70% at 3 and 5 years after the surgery, respectively, compared with 59% and 47% in the TN group. The log-rank test demonstrated a significant difference (p = 0.008) in the TPFS rates between the two groups. Furthermore, 42 patients each from the remnant and TN groups were matched based on tumor volume. TPFS was significantly longer in the remnant group than in the TN group (3-year rates, 77% vs 62%; 5-year rates, 73% vs 51%; p = 0.02). In the remnant group, 18% of the tumor remnants demonstrated regression during follow-up, compared with 9% in the TN group, but this intergroup difference was not significant (p = 0.25). CONCLUSIONS: This study demonstrated that the growth potential of small VS remnants was lower than that of TN tumors. Observing for small remnants may be appropriate after STR of a large VS. Given the risk of tumor regrowth, careful observation using MRI should be mandatory during follow-up.

A Practical Grading Scale for Predicting Outcomes of Radiosurgery for Dural Arteriovenous Fistulas: JLGK 1802 Study.

BACKGROUND AND PURPOSE: To assess the long-term outcomes of intracranial dural arteriovenous fistula (DAVF) treated with stereotactic radiosurgery (SRS) alone or embolization and SRS (Emb-SRS) and to develop a grading system for predicting DAVF obliteration. METHODS: This multi-institutional retrospective study included 200 patients with DAVF treated with SRS or Emb-SRS. We investigated the long-term obliteration rate and obliteration-associated factors. We developed a new grading system to estimate the obliteration rate. Additionally, we compared the outcomes of SRS and Emb-SRS by using propensity score matching. RESULTS: The 3- and 4-year obliteration rates were 66.3% and 78.8%, respectively. The post-SRS hemorrhage rate was 2%. In the matched cohort, the SRS and Emb-SRS groups did not differ in the rates of obliteration (P=0.54) or post-SRS hemorrhage (P=0.50). In multivariable analysis, DAVF location and cortical venous reflux (CVR) were independently associated with obliteration. The new grading system assigned 2, 1, and 0 points to DAVFs in the anterior skull base or middle fossa, DAVFs with CVR or DAVFs in the superior sagittal sinus or tentorium, and DAVFs without these factors, respectively. Using the total points, patients were stratified into the highest (0 points), intermediate (1 point), or lowest (≥2 points) obliteration rate groups that exhibited 4-year obliteration rates of 94.4%, 71.3%, and 60.4%, respectively (P<0.01). CONCLUSIONS: SRS-based therapy achieved DAVF obliteration in more than three-quarters of the patients at 4 years of age. Our grading system can stratify the obliteration rate and may guide physicians in treatment selection.

Gamma Knife radiosurgery for metastatic brain tumors from ovarian cancer: histopathological analysis of survival and local control. A Japanese multi-institutional cooperative and retrospective cohort study.

OBJECTIVE: Brain metastasis is rare in ovarian cancer patients. The results of Gamma Knife radiosurgery (GKRS) for the treatment of patients with brain metastases from ovarian cancer were retrospectively analyzed to derive the efficacy and prognostic factors for survival and local tumor control. Further histopathological analysis was also performed. METHODS: The authors retrospectively reviewed the medical records of 118 patients with 566 tumors who had undergone GKRS at the 10 GKRS institutions in Japan. RESULTS: After the initial GKRS, the median overall survival time was 18.1 months. Multivariate analysis showed that uncontrolled primary cancer (p = 0.003) and multiple intracranial metastases (p = 0.034) were significant unfavorable factors. Ten patients died of uncontrolled brain metastases at a median of 17.1 months. The 6-, 12-, and 24-month neurological death rates were 3.2%, 4.6%, and 11.9%, respectively. The 6-, 12-, and 24-month neurological deterioration rates were 7.2%, 13.5%, and 31.4%, respectively. The 6-, 12-, and 24-month distant brain control failure rates were 20.6%, 40.2%, and 42.3%, respectively. Median tumor volume was 1.6 cm3 and marginal dose was 20 Gy. The 6-, 12-, and 24-month local tumor control rates were 97.6%, 95.2%, and 88.0%, respectively. Peritumoral edema (p = 0.043), more than 7-cm3 volume (p = 0.021), and prescription dose less than 18 Gy (p = 0.014) were factors that were significantly correlated in local tumor control failure. Eight patients had symptomatic radiation injury. The 6-, 12-, and 24-month GKRS-related complication rates were 3.3%, 7.8%, and 12.2%, respectively. Primary ovarian cancer was histopathologically diagnosed for 313 tumors in 69 patients. Serous adenocarcinoma was found in 37 patients and other types in 32 patients. Median survival times were 32.3 months for the serous type and 17.4 months for other types after initial GKRS. Patients with serous-type tumors survived significantly longer than patients with other types (p = 0.039). The 6-, 12-, and 24-month local tumor control rates were 100%, 98.8%, and 98.8%, respectively. Serous-type tumors were a significantly good prognosis factor for local tumor control after GKRS (p = 0.005). CONCLUSIONS: This study established a relationship between the efficacy of GKRS treatment for brain metastases and the histological type of primary ovarian cancer. GKRS for ovarian cancer brain metastasis can provide satisfactory survival and local control, especially in cases of serous adenocarcinoma.

Stereotactic radiosurgery results for brain metastasis patients with renal cancer: A validity study of Renal Graded Prognostic Assessment and proposal of a new grading index (JLGK2101 Study).

BACKGROUND AND PURPOSE: The Renal Graded Prognostic Assessment (GPA) is relatively new and has not been sufficiently validated using a different dataset. We thus developed a new grading index, the Renal Brain Metastasis Score (Renal-BMS). MATERIALS AND METHODS: Using our dataset including 262 renal cancer patients with brain metastases (BMs) undergoing stereotactic radiosurgery (SRS) (test series), we validity tested the Renal-GPA. Next, we applied clinical factor-survival analysis to the test series and thereby developed the Renal-BMS. This system was then validated using another series of 352 patients independently undergoing SRS at nine gamma knife facilities in Japan (verification series). RESULTS: Using the test series, with the Renal-GPA, 95% confidence intervals (CIs) of the post-SRS median survival times (MSTs) overlapped between pairs of neighboring subgroups. Among various pre-SRS clinical factors of the test series, six were highly associated with overall survival. Therefore, we assigned scores for six factors, i.e., "KPS ≥ 80%/<80% (0/3)", "tumor numbers 1-4/≥5 (score; 0/2)", "controlled primary cancer/not (0/2)", "existing extra-cerebral metastases/not (0/3)", "blood hemoglobin ≥ 11.0/<11.0 g/dl (0/1)" and "interval from primary cancer to SRS ≥ 5/<5 years (0/1)". Patients were categorized into three subgroups according to the sum of scores, i.e., 0-4, 5-8 and 9-12. In the test and verification series, post-SRS MSTs differed significantly (p < 0.0001) with no overlaps of 95% CIs among the three subgroups. CONCLUSIONS: The Renal BMS has the potential to be very useful to physicians selecting among aggressive treatment modalities for renal cancer patients with BMs.

Non-small cell lung cancer with multiple brain metastases remains relapse-free for more than 13 years: A case report.

Brain metastasis (BM) in patients with non-small cell lung cancer (NSCLC) is usually associated with a poor prognosis. A 55-year-old Japanese man visited Tokyo Dental College Ichikawa General Hospital with complaints of motor aphasia and fatigue. Enhanced magnetic resonance imaging of the brain revealed multiple tumors. The patient's medical history included lung cancer surgery performed at another hospital 3 months prior to his visit to our hospital. Total resection of the left frontal tumor revealed BM from lung adenocarcinoma. Stereotactic radiosurgery (SRS) was performed for the remaining three BMs. At 9 months after SRS, another new BM was discovered, and SRS was again performed. More than 13 years have elapsed since the last SRS was performed, and the patient has remained relapse-free. To the best of our knowledge, this is the first case report describing a patient with NSCLC with multiple BMs who has remained relapse-free for >13 years with no neurological dysfunction, including cognitive deficit.

Stereotactic Radiosurgery Results for Patients With Brain Metastases From Gastrointestinal Cancer: A Retrospective Cohort Study of 802 Patients With GI-GPA Validity Test.

PURPOSE: The role of stereotactic radiosurgery (SRS) alone for patients with gastrointestinal (GI) cancer has yet to be established based on a large patient series. We analyzed post-SRS treatment results and reappraised whether either the GI graded prognostic assessment (GPA) system or modified-recursive partitioning assessment (M-RPA) system was applicable to our 802 SRS-treated patients with GI cancer with brain metastases. METHODS AND MATERIALS: This was an institutional review board approved retrospective cohort study 2 database comprising 802 patients with GI cancer treated with gamma-knife SRS by 2 experienced neurosurgeons during the 1998 to 2018 period. The Kaplan-Meier method was applied to determine post-SRS survival times, and competing risk analyses were used to estimate cumulative incidences of the secondary endpoints. RESULTS: The median survival time (MST; months) after SRS was 5.7. With the GI GPA system, MSTs were 3.5/6.1/7.7/11.0 in the 4 subgroups, that is, 0 to 1.0/1.5 to 2.0/2.5 to 3.0/3.5 to 4.0, respectively (stratified P < .0001). However, there was no significant MST difference between 2 of the subgroups, GI-GPA 1.5 to 2.0 and 2.5 to 3.0 (P = .073). In contrast, using the M-RPA system, 3 plot lines corresponding to the 3 subgroups showed no overlap and the MST differences between the subgroups with M-RPA were 1 + 2a versus 2b (P < .0001) and 2b versus 2c + 3 (P < .0001). Better Karnofsky performance status score, solitary tumor, well-controlled primary cancer, and the absence of extracerebral metastases were shown by multivariable analysis to be significant predictors of longer survival. The crude and cumulative incidences of neurologic death, neurologic deterioration, local recurrence, salvage whole brain radiation therapy, and SRS-related complications did not differ significantly between the 2 patient groups, with upper and lower GI cancers. CONCLUSIONS: This study clearly demonstrated the usefulness of the GI GPA. Patients with GI GPA 1.5 to 2.0 or better or M-RPA 2b or better are considered to be favorable candidates for treatment with SRS alone.

Predicting Potential of Rapid Tumor Growth in Small to Medium Vestibular Schwannomas on the Basis of Sway Assessed Using Posturography.

OBJECTIVE: The relationship between quantitative posturography results and growth of vestibular schwannomas (VSs) during conservative management has not been studied. We aimed to clarify the relationship between the presence of disequilibrium based on posturographic measurement and VS growth. METHODS: This retrospective, single-center study included 53 patients with VSs (Koos stage I or II) managed conservatively after initial diagnosis. Radiographic progression was considered present if 20% volumetric growth was observed over the imaging interval. Posturography was performed at initial diagnosis, and sway velocity (SV) and sway area were calculated. Tumor growth-free survival was estimated using the Kaplan-Meier method. RESULTS: Mean follow-up period was 2.87 ± 2.58 years, up to tumor growth detection or last follow-up magnetic resonance imaging. Tumor growth incidence was 40.8% and 61.2% at 2 and 5 years, respectively. Cerebellopontine angle extension and SV with eyes open were related to tumor growth. Tumor growth-free survival of patients with cerebellopontine angle extension and patients with intracanalicular tumor at 2 years was 37.3% and 76.4%, respectively. Tumor growth-free survival of patients with SV >2.06 cm/second and patients with SV ≤2.06 cm/second at 2 years was 30.8% and 68.9%, respectively. The Cox hazard model demonstrated a significant risk for future tumor growth with SV >2.06 cm/second (relative risk, 2.475; 95% confidence interval, 1.11-5.37, P = 0.027). CONCLUSIONS: We demonstrated a positive correlation between SV with eyes open and future tumor growth. Posturographic data are objective and quantitative; thus, SV may be a potential predictor of future growth of VSs.

An aberrant venous channel mimicking the perilabyrinthine cells in the petrous bone of a patient with vestibular schwannoma: illustrative case.

BACKGROUND: Anatomical variations, such as high jugular bulbs and air cell development in the petrosal bone, should be evaluated before surgery. Most bone defects in the internal auditory canal (IAC) posterior wall are observed in the perilabyrinthine cells. An aberrant vascular structure passing through the petrous bone is rare. OBSERVATIONS: A 48-year-old man presented with a right ear hearing disturbance. Magnetic resonance imaging revealed a 23-mm contrast-enhancing mass in the right cerebellopontine angle extending into the IAC, consistent with a right vestibular schwannoma. Preoperative bone window computed tomographic scans showed bone defects in the IAC posterior wall, which ran farther posteroinferiorly in the petrous bone, reaching the medial part of the jugular bulb. The tumor was accessed via a lateral suboccipital approach. There was no other major vein in the cerebellomedullary cistern, except for the vein running from the brain stem to the IAC posterior wall. To avoid complications due to venous congestion, the authors did not drill out the IAC posterior wall or remove the tumor in the IAC. LESSONS: Several aberrant veins in the petrous bone are primitive head sinus remnants. Although rare, their surgical implication is critical in patients with vestibular schwannomas.

A graded prognostic model for patients surviving 3 years or more (GPM ≥ 3Ys) after stereotactic radiosurgery for brain metastasis.

BACKGROUND AND PURPOSE: As more cancer patients with brain metastases (BMs) are surviving longer due to recent advancements in various treatment modalities, we developed a grading system for stereotactic radiosurgery (SRS)-treated BM patients with long survival. This is a Graded Prognostic Model for Patients Surviving 3 Years or More (GPM ≥ 3Ys). MATERIALS AND METHODS: First, using clinical factor-survival time analysis of 3237 patients in whom gamma knife (GK) SRS was performed by the second author (test cohort), we developed the GPM ≥ 3Ys based on survival ≥3 years as the objective variable. The validity of this model was then tested using another series of 3317 patients independently undergoing GK SRS performed by the third author (verification cohort). Number of patients surviving 3 years or more were 289 (8.9%) and 348 (10.5%), respectively. RESULTS: Using the test series, among various pre-SRS clinical factors, noted below, five were shown to be highly correlated with survival of ≥3 years. Therefore, we assigned scores for these five factors, i.e., "tumor numbers 1/2-4/≥5 (score; 6/1/0)", "female/male (5/0)", "KPS ≥80%/<80% (5/0)", "primary cancers of breast/lung/gastrointestinal tract/other (score; 1/0/3/0)", "controlled primary cancer/not (8/0)" and "existing extra-cerebral metastases/not (5/0). Patients were categorized into four grades according to the sum of scores, i.e., 0-9, 10-19, 20-29 and 30-36. Post-SRS mean survival times (MSTs) differed significantly (p < 0.0001) with no overlapping of 95% confidence intervals (CIs) among the four grades. Also, in the verification series, MSTs differed significantly (p < 0.0001) with no overlapping of 95% CI among the four grades of the GPM ≥ 3Ys system. CONCLUSION: Although this was a retrospective study, the GPM ≥ 3Ys system was shown to be very useful to physicians selecting among more aggressive treatment modalities for patients in whom longer survival can be expected.

Stereotactic Radiosurgery Results for Patients with 5-10 versus 11-20 Brain Metastases: A Retrospective Cohort Study Combining 2 Databases Totaling 2319 Patients.

OBJECTIVE: The treatment of patients with ≥11 brain metastases (BMs) with stereotactic radiosurgery (SRS) alone has yet to be established. The aim of this study was to compare results of SRS alone in patients with 5-10 BMs versus 11-20 BMs. METHODS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 1515 patients with 5-10 tumors and 804 patients with 11-20 tumors treated with Gamma Knife SRS by 2 experienced neurosurgeons between 1998 and 2018. The Kaplan-Meier method was applied to determine post-SRS survival times, and competing risk analyses were used to estimate cumulative incidences of the secondary end points. RESULTS: The post-SRS median survival time was slightly longer in the group with 5-10 tumors (7.7 months) than in the group with 11-20 tumors (6.5 months) (P < 0.0001). Median survival time differences were statistically significant for patients with lung cancers but not for patients with breast, gastrointestinal tract, kidney, and other cancers. Multivariable analysis revealed female sex, better Karnofsky performance scale score, controlled primary cancer, and absence of extracerebral metastases to be statistically significant predictors of longer survival in the 2 patient cohorts. Crude and cumulative incidences of local recurrences were significantly lower in the group with 11-20 tumors than in the group with 5-10 tumors, while those of other secondary end points were similar to or lower in the group with 11-20 tumors than in the group with 5-10 tumors. Post-SRS outcomes were relatively poor in patients with 11-20 tumors from kidney or other cancers. CONCLUSIONS: Carefully selected patients with 11-20 BMs are not unfavorable candidates for SRS alone.

Stereotactic radiosurgery for brain metastases: A retrospective cohort study comparing treatment results between two lung cancer patient age groups, 75 years or older vs 65-74 years.

BACKGROUND: There is little information on stereotactic radiosurgery (SRS) results for brain metastases (BMs) in lung cancer patients ≥75 years of age. We aimed to reappraise whether SRS results for patients ≥75 (very elderly) differ from those of patients with 65-74 years old (elderly). METHODS: This IRB-approved retrospective cohort study was based on our prospectively-accumulated database including 7351 consecutive patients undergoing gamma knife (GK) SRS performed for BMs by two highly experienced neurosurgeons during the 1998-2018 period. We selected a total of 2915 elderly patients (age ≥65 years, 39.7 % of the 7351) with lung cancers (902 females, 2013 males, median age; 72 [maximum; 96] years, 2441 NSCLCs, 474 SCLCs) for this study. RESULTS: Post-SRS median survival times (MSTs, months) differed significantly between the two lung cancer types, NSCLC (9.0) and SCLC (7.2, p < 0.0001). In NSCLC patients, post-SRS MSTs were significantly shorter in the very elderly (9.7) than those in the elderly (7.8) group (p < 0.0001). However, in SCLC patients, there were no significant MST differences (7.3 vs 6.9, p = 0.52) between the two age groups. In both NSCLC and SCLC patients, neither crude nor cumulative incidences of secondary endpoints in the very elderly group, i.e., neurological death, neurological deterioration, local recurrence, repeat SRS, salvage whole brain radiotherapy and SRS-related complications, were shown to be unfavorable to those in the elderly group. CONCLUSIONS: Our results suggest that carefully-selected patients ≥75 years of age are not poor candidates for SRS as compared to those 65-74 years old.

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.

Evaluation of First-line Radiosurgery vs Whole-Brain Radiotherapy for Small Cell Lung Cancer Brain Metastases: The FIRE-SCLC Cohort Study.

Importance: Although stereotactic radiosurgery (SRS) is preferred for limited brain metastases from most histologies, whole-brain radiotherapy (WBRT) has remained the standard of care for patients with small cell lung cancer. Data on SRS are limited. Objective: To characterize and compare first-line SRS outcomes (without prior WBRT or prophylactic cranial irradiation) with those of first-line WBRT. Design, Setting, and Participants: FIRE-SCLC (First-line Radiosurgery for Small-Cell Lung Cancer) was a multicenter cohort study that analyzed SRS outcomes from 28 centers and a single-arm trial and compared these data with outcomes from a first-line WBRT cohort. Data were collected from October 26, 2017, to August 15, 2019, and analyzed from August 16, 2019, to November 6, 2019. Interventions: SRS and WBRT for small cell lung cancer brain metastases. Main Outcomes and Measures: Overall survival, time to central nervous system progression (TTCP), and central nervous system (CNS) progression-free survival (PFS) after SRS were evaluated and compared with WBRT outcomes, with adjustment for performance status, number of brain metastases, synchronicity, age, sex, and treatment year in multivariable and propensity score-matched analyses. Results: In total, 710 patients (median [interquartile range] age, 68.5 [62-74] years; 531 men [74.8%]) who received SRS between 1994 and 2018 were analyzed. The median overall survival was 8.5 months, the median TTCP was 8.1 months, and the median CNS PFS was 5.0 months. When stratified by the number of brain metastases treated, the median overall survival was 11.0 months (95% CI, 8.9-13.4) for 1 lesion, 8.7 months (95% CI, 7.7-10.4) for 2 to 4 lesions, 8.0 months (95% CI, 6.4-9.6) for 5 to 10 lesions, and 5.5 months (95% CI, 4.3-7.6) for 11 or more lesions. Competing risk estimates were 7.0% (95% CI, 4.9%-9.2%) for local failures at 12 months and 41.6% (95% CI, 37.6%-45.7%) for distant CNS failures at 12 months. Leptomeningeal progression (46 of 425 patients [10.8%] with available data) and neurological mortality (80 of 647 patients [12.4%] with available data) were uncommon. On propensity score-matched analyses comparing SRS with WBRT, WBRT was associated with improved TTCP (hazard ratio, 0.38; 95% CI, 0.26-0.55; P < .001), without an improvement in overall survival (median, 6.5 months [95% CI, 5.5-8.0] for SRS vs 5.2 months [95% CI, 4.4-6.7] for WBRT; P = .003) or CNS PFS (median, 4.0 months for SRS vs 3.8 months for WBRT; P = .79). Multivariable analyses comparing SRS and WBRT, including subset analyses controlling for extracranial metastases and extracranial disease control status, demonstrated similar results. Conclusions and Relevance: Results of this study suggest that the primary trade-offs associated with SRS without WBRT, including a shorter TTCP without a decrease in overall survival, are similar to those observed in settings in which SRS is already established.

Gamma Knife Surgery for Brain Metastases from Uterine Malignant Tumor.

BACKGROUND: Uterine malignant tumors (uterine cervical carcinoma [UCC], uterine endometrial carcinoma, and uterine sarcoma) are common in women. Brain metastases from uterine malignant tumors are rare, but its incidence has been increasing. The present study aimed to investigate the characteristics of brain metastases from uterine malignant tumors, evaluate predictive factors, and assess the efficacy of Gamma Knife surgery (GKS) for metastases from uterine malignant tumors. METHODS: We retrospectively reviewed the records of patients with brain metastases from uterine malignant tumors treated at Tokyo Gamma Unit Center from 2005 to 2017. RESULTS: We identified 37 patients: 16 had UCC, 12 had uterine endometrial carcinoma, and 9 had uterine sarcoma. Their median age at diagnosis of brain metastases was 54.0 years. The median interval from diagnosis of uterine malignant tumor to brain metastases was 21.0 months, the median number of brain metastases was 3.0, and the median Karnofsky Performance Status at first GKS was 80%. The median survival after first GKS was 6.0 months. All patients had other metastases. Six-month and 1-year survival after first GKS were 48.9% and 32.6%, respectively, and the tumor control rate at 6 months after GKS was 90.8%. Brain metastases from UCC were significantly correlated with good tumor control (P = 0.024). Multivariate analysis determined that Karnofsky Performance Status was significantly associated with patient survival (P = 0.001). CONCLUSIONS: The results of our study suggest that GKS is an acceptable choice for controlling brain metastases from uterine malignant tumors. In particular, GKS provides excellent local control for metastases from UCC.

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.