Publications by authors named "Toru Serizawa"

62 Publications

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

World Neurosurg 2021 04 11;148:e406-e414. Epub 2021 Jan 11.

Departments of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

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.
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http://dx.doi.org/10.1016/j.wneu.2020.12.175DOI Listing
April 2021

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

Radiother Oncol 2021 03 27;156:29-35. Epub 2020 Nov 27.

Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Japan.

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.
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http://dx.doi.org/10.1016/j.radonc.2020.11.024DOI Listing
March 2021

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

World Neurosurg 2021 02 16;146:e479-e491. Epub 2020 Nov 16.

Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.wneu.2020.10.124DOI Listing
February 2021

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.

Lung Cancer 2020 11 18;149:103-112. Epub 2020 Aug 18.

Katsuta Hospital Mito GammaHouse, Hitachi-naka, Japan.

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.
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http://dx.doi.org/10.1016/j.lungcan.2020.07.037DOI Listing
November 2020

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

Breast Cancer Res Treat 2020 Nov 1;184(1):149-159. Epub 2020 Aug 1.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

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.
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http://dx.doi.org/10.1007/s10549-020-05835-8DOI Listing
November 2020

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

JAMA Oncol 2020 07;6(7):1028-1037

Department of Neurosurgery, New York University Langone Medical Center, New York.

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.
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http://dx.doi.org/10.1001/jamaoncol.2020.1271DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7273318PMC
July 2020

Gamma Knife Surgery for Brain Metastases from Uterine Malignant Tumor.

World Neurosurg 2020 07 16;139:e363-e372. Epub 2020 Apr 16.

Department of Neurological Surgery, Nihon University School of Medicine, Tokyo, Japan.

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.
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http://dx.doi.org/10.1016/j.wneu.2020.03.225DOI Listing
July 2020

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

J Neurooncol 2020 Mar 5;147(1):237-246. Epub 2020 Feb 5.

Department of Neurological Surgery, Chiba University Graduate School of Medicine, Chiba, Japan.

Purpose: Stereotactic radiosurgery (SRS) is typically considered for patients who cannot undergo surgical resection for large (> 10 cm) 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.
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http://dx.doi.org/10.1007/s11060-020-03421-yDOI Listing
March 2020

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

J Neurooncol 2020 Mar 27;147(1):177-184. Epub 2020 Jan 27.

Katsuta Hospital Mito GammaHouse, 5125-2 Nakane, Hitachi-naka, Hitachinaka, Ibaraki, 312-0011, Japan.

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.
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http://dx.doi.org/10.1007/s11060-020-03412-zDOI Listing
March 2020

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

J Neurooncol 2020 Mar 13;147(1):67-76. Epub 2020 Jan 13.

Department of Human Health Sciences, School of Medicine, Kyoto University, Kyoto, Japan.

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.
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http://dx.doi.org/10.1007/s11060-020-03397-9DOI Listing
March 2020

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).

J Neurooncol 2019 Oct 5;145(1):151-157. Epub 2019 Sep 5.

Department of Radiology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.

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.
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http://dx.doi.org/10.1007/s11060-019-03282-0DOI Listing
October 2019

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

J Neurooncol 2019 Sep 23;144(2):393-402. Epub 2019 Jul 23.

Department of Radiology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.

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.
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http://dx.doi.org/10.1007/s11060-019-03242-8DOI Listing
September 2019

Function-Preserving Multimodal Treatment for Jugular Foramen Meningiomas.

J Neurol Surg B Skull Base 2019 Jun 21;80(3):239-243. Epub 2018 Aug 21.

Department of Neurosurgery, Seikei-kai Chiba Medical Center, Chiba, Japan.

 Despite being pathologically benign, jugular foramen meningioma (JFM) may be locally aggressive and spread in three compartments. Because of the complex anatomical location, radical removal of JFM usually causes serious morbidity through lower cranial nerve (LCN) deficits. To accomplish long-standing tumor control with good functional outcomes, we report function-preserving multimodal treatment (FMT) for JFM, comprising the combination of intradural tumor removal with the preservation of LCN function and stereotactic radiosurgery (RS) for the residual tumor.  This study investigated six JFM patients (five women, one man). Preoperatively, five patients showed no LCN sign.  All patients underwent function-preserving retrosigmoid intradural tumor removal, and no patient developed new LCN deficit. Three patients underwent RS for the residual tumor at 8 to 12 months after surgery. After RS, all three tumors were controlled. No patients showed tumor recurrence or new LCN deficits in the follow-up period (2 months to 8 years).  FMT for JFMs can accomplish long-standing tumor control with excellent functional outcomes.
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http://dx.doi.org/10.1055/s-0038-1668137DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534742PMC
June 2019

Local tumor progression treated with Gamma Knife radiosurgery: differences between patients with 2-4 versus 5-10 brain metastases based on an update of a multi-institutional prospective observational study (JLGK0901).

J Neurosurg 2019 Apr 26;132(5):1480-1489. Epub 2019 Apr 26.

10Department of Neurosurgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Objective: The Japanese Leksell Gamma Knife (JLGK)0901 study proved the efficacy of Gamma Knife radiosurgery (GKRS) in patients with 5-10 brain metastases (BMs) as compared to those with 2-4, showing noninferiority in overall survival and other secondary endpoints. However, the difference in local tumor progression between patients with 2-4 and those with 5-10 BMs has not been sufficiently examined for this data set. Thus, the authors reappraised this issue, employing the updated JLGK0901 data set with detailed observation via enhanced MRI. They applied sophisticated statistical methods to analyze the data.

Methods: This was a prospective observational study of 1194 patients harboring 1-10 BMs treated with GKRS alone. Patients were categorized into groups A (single BM, 455 cases), B (2-4 BMs, 531 cases), and C (5-10 BMs, 208 cases). Local tumor progression was defined as a 20% increase in the maximum diameter of the enhanced lesion as compared to its smallest documented maximum diameter on enhanced MRI. The authors compared cumulative incidence differences determined by competing risk analysis and also conducted propensity score matching.

Results: Local tumor progression was observed in 212 patients (17.8% overall, groups A/B/C: 93/89/30 patients). Cumulative incidences of local tumor progression in groups A, B, and C were 15.2%, 10.6%, and 8.7% at 1 year after GKRS; 20.1%, 16.9%, and 13.5% at 3 years; and 21.4%, 17.4%, and not available at 5 years, respectively. There were no significant differences in local tumor progression between groups B and C. Local tumor progression was classified as tumor recurrence in 139 patients (groups A/B/C: 68/53/18 patients), radiation necrosis in 67 (24/31/12), and mixed/undetermined lesions in 6 (1/5/0). There were no significant differences in tumor recurrence or radiation necrosis between groups B and C. Multivariate analysis using the Fine-Gray proportional hazards model revealed age < 65 years, neurological symptoms, tumor volume ≥ 1 cm3, and prescription dose < 22 Gy to be significant poor prognostic factors for local tumor progression. In the subset of 558 case-matched patients (186 in each group), there were no significant differences between groups B and C in local tumor progression, nor in tumor recurrence or radiation necrosis.

Conclusions: Local tumor progression incidences did not differ between groups B and C. This study proved that tumor progression after GKRS without whole-brain radiation therapy for patients with 5-10 BMs was satisfactorily treated with the doses prescribed according to the JLGK0901 study protocol and that results were not inferior to those in patients with a single or 2-4 BMs.Clinical trial registration no.: UMIN000001812 (umin.ac.jp).
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http://dx.doi.org/10.3171/2019.1.JNS183085DOI Listing
April 2019

The Tethered Effect of Vestibular Schwannoma Tumor Shrinkage Following Stereotactic Radiosurgery in Secondary Trigeminal Neuralgia.

World Neurosurg 2019 Mar 12;123:136-141. Epub 2018 Dec 12.

Department of Neurosurgery, Seikei-kai Chiba Medical Center, Chiba, Japan.

Background: Compression of the trigeminal nerve by vessels and tumors causes trigeminal neuralgia. However, a tethering effect, provoking an abnormal root-stretching force, has been previously reported to play a role in trigeminal nerve hyperexcitability. We report 2 patients with vestibular schwannomas treated by stereotactic radiosurgery (SRS) who presented with typical manifestations of trigeminal neuralgia after tumor shrinkage. Furthermore, we discuss the mechanisms of trigeminal neuralgia.

Case Description: Two patients without a history of trigeminal dysfunction, including trigeminal neuralgia, underwent SRS for vestibular schwannomas. Both patients demonstrated tumor shrinkage after transient tumor expansion following SRS. Neither patient presented with facial pain or dysesthesia at the time of peak tumor volume. However, trigeminal neuralgia occurred after tumor shrinkage. One patient underwent surgery, as the neuralgia was refractory to medical treatment; although the trigeminal nerve was adhered and tethered to the tumor, no neurovascular conflict was identified between the tumor and the nerve. We removed the tumor partially, dissecting between the nerve and the tumor, and relieved the tethered effect. Trigeminal neuralgia was relieved without medication after surgery.

Conclusions: The present cases demonstrate a tethered effect of tumor shrinkage after SRS, which was considered to play a role in trigeminal neuralgia. Surgical dissection surrounding the nerve root is effective for medically resistant neuralgia, even if the tumor shrinks. Partial tumor removal is adequate in such cases, as the tumor has been controlled by radiosurgery.
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http://dx.doi.org/10.1016/j.wneu.2018.12.002DOI Listing
March 2019

Prognostic grading system specifically for elderly patients with brain metastases after stereotactic radiosurgery: a 2-institution study.

J Neurosurg 2018 12;129(Suppl1):95-102

2Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo.

OBJECTIVEWith the aging of the population, increasing numbers of elderly patients with brain metastasis (BM) are undergoing stereotactic radiosurgery (SRS). Among recently reported prognostic grading indexes, only the basic score for brain metastases (BSBM) is applicable to patients 65 years or older. However, the major weakness of this system is that no BM-related factors are graded. This prompted the authors to develop a new grading system, the elderly-specific (ES)-BSBM.METHODSFor this IRB-approved, retrospective cohort study, the authors used their prospectively accumulated database comprising 3267 consecutive patients undergoing Gamma Knife SRS for BMs during the 1998-2016 period at the Mito GammaHouse. Among these 3267 patients, 1789 patients ≥ 65 years of age were studied (Yamamoto series [Y-series]). Another series of 1785 patients ≥ 65 years of age in whom Serizawa and colleagues performed Gamma Knife SRS during the same period (Serizawa series [S-series]) was used for validity testing of the ES-BSBM.RESULTSTwo factors were identified as strongly impacting longer survival after SRS by means of multivariable analysis using the Cox proportional hazard model with a stepwise selection procedure. These factors are the number of tumors (solitary vs multiple: HR 1.450, 95% CI 1.299-1.621; p < 0.0001) and cumulative tumor volume (≤ 15 cm3 vs > 15 cm3: HR 1.311, 95% CI 1.078-1.593; p = 0.0067). The new index is the addition of scores 0 and 1 for these 2 factors to the BSBM. The ES-BSBM system is based on categorization into 3 classes by adding these 2 scores to those of the original BSBM. Each ES-BSBM category has 2 possible scores. For the category ES-BSBM 4-5, the score is either 4 or 5; for ES-BSBM 2-3, the score is either 2 or 3; and for ES-BSBM 0-1, the score is either 0 or 1. In the Y-series, the median survival times (MSTs, months) after SRS were 17.5 (95% CI 15.4-19.3) in ES-BSBM 4-5, 6.9 (95% CI 6.4-7.4) in ES-BSBM 2-3, and 2.8 (95% CI 2.5-3.6) in ES-BSBM 0-1 (p < 0.0001). Also, in the S-series, MSTs were, respectively, 20.4 (95% CI 17.2-23.4), 7.9 (95% CI 7.4-8.5), and 3.2 (95% CI 2.8-3.6) (p < 0.0001). The ES-BSBM system was shown to be applicable to patients with all primary tumor types as well as to those 80 years or older.CONCLUSIONSThe authors found that the addition of the number of tumors and cumulative tumor volume as scoring factors to the BSBM system significantly improved the prognostic value of this index. The present study is strengthened by testing the ES-BSBM in a different patient group.
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http://dx.doi.org/10.3171/2018.7.GKS181458DOI Listing
December 2018

Three-stage Gamma Knife treatment for metastatic brain tumors larger than 10 cm3: a 2-institute study including re-analyses of earlier results using competing risk analysis.

J Neurosurg 2018 12;129(Suppl1):77-85

2Department of Neurosurgery, Tokyo Women's Medical University Medical Center East, Tokyo.

OBJECTIVEThe results of 3-stage Gamma Knife treatment (3-st-GK-Tx) for relatively large brain metastases have previously been reported for a series of patients in Chiba, Japan (referred to in this study as the C-series). In the current study, the authors reappraised, using a competing risk analysis, the efficacy and safety of 3-st-GK-Tx by comparing their experience with that of the C-series.METHODSThis was a retrospective cohort study. Among 1767 patients undergoing GK radiosurgery for brain metastases at Mito Gamma House during the 2005-2015 period, 78 (34 female, 44 male; mean age 65 years, range 35-86 years) whose largest tumor was > 10 cm3, treated with 3-st-GK-Tx, were studied (referred to in this study as the M-series). The target volumes were covered with a 50% isodose gradient and irradiated with a peripheral dose of 10 Gy at each procedure. The interval between procedures was 2 weeks. Because competing risk analysis had not been employed in the published C-series, the authors reanalyzed the previously published data using this method.RESULTSThe overall median survival time after 3-st-GK-Tx was 8.3 months (95% CI 5.6-12.0 months) in the M-series and 8.6 months (95% CI 5.5-10.6 months) in the C-series (p = 0.41). Actuarial survival rates at the 6th and 12th post-3-st-GK-Tx months were, respectively, 55.1% and 35.2% in the M-series and 62.5% and 26.4% in the C-series (HR 1.175, 95% CI 0.790-1.728, p = 0.42). Cumulative incidences at the 12th post-3-st-GK-Tx, determined by competing risk analyses, of neurological deterioration (14.2% in C-series vs 12.8% in M-series), neurological death (7.2% vs 7.7%), local recurrence (4.8% vs 6.2%), repeat SRS (25.9% vs 18.0%), and SRS-related complications (2.3% vs 5.1%) did not differ significantly between the 2 series.CONCLUSIONSThere were no significant differences in post-3-st-GK-Tx results between the 2 series in terms of overall survival times, neurological death, maintained neurological status, local control, repeat SRS, and SRS-related complications. The previously published results (C-series) are considered to be validated by the M-series results.
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http://dx.doi.org/10.3171/2018.7.GKS181392DOI Listing
December 2018

Multiinstitutional prospective observational study of stereotactic radiosurgery for patients with multiple brain metastases from non-small cell lung cancer (JLGK0901 study-NSCLC).

J Neurosurg 2018 12;129(Suppl1):86-94

11Department of Radiology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.

OBJECTIVEPrevious Japanese Leksell Gamma Knife Society studies (JLGK0901) demonstrated the noninferiority of stereotactic radiosurgery (SRS) alone as the initial treatment for patients with 5-10 brain metastases (BMs) compared with those with 2-4 BMs in terms of overall survival and most secondary endpoints. The authors studied the aforementioned treatment outcomes in a subset of patients with BMs from non-small cell lung cancer (NSCLC).METHODSPatients with initially diagnosed BMs treated with SRS alone were enrolled in this prospective observational study. Major inclusion criteria were the existence of up to 10 tumors with a maximum diameter of less than 3 cm each, a cumulative tumor volume of less than 15 cm3, and no leptomeningeal dissemination in patients with a Karnofsky Performance Scale score of 70% or better.RESULTSAmong 1194 eligible patients, 784 with NSCLC were categorized into 3 groups: group A (1 tumor, n = 299), group B (2-4 tumors, n = 342), and group C (5-10 tumors, n = 143). The median survival times were 13.9 months in group A, 12.3 months in group B, and 12.8 months in group C. The survival curves of groups B and C were very similar (hazard ratio [HR] 1.037; 95% CI 0.842-1.277; p < 0.0001, noninferiority test). The crude and cumulative incidence rates of neurological death, deterioration of neurological function, newly appearing lesions, and leptomeningeal dissemination did not differ significantly between groups B and C. SRS-induced complications occurred in 145 (12.1%) patients during the median post-SRS period of 9.3 months (IQR 4.1-17.4 months), including 46, 54, 29, 11, and 5 patients with a Common Terminology Criteria for Adverse Events v3.0 grade 1, 2, 3, 4, or 5 complication, respectively. The cumulative incidence rates of adverse effects in groups A, B, and C 60 months after SRS were 13.5%, 10.0%, and 12.6%, respectively (group B vs C: HR 1.344; 95% CI 0.768-2.352; p = 0.299). The 60-month post-SRS rates of neurocognitive function preservation were 85.7% or higher, and no significant differences among the 3 groups were found.CONCLUSIONSIn this subset analysis of patients with NSCLC, the noninferiority of SRS alone for the treatment of 5-10 versus 2-4 BMs was confirmed again in terms of overall survival and secondary endpoints. In particular, the incidence of neither post-SRS complications nor neurocognitive function preservation differed significantly between groups B and C. These findings further strengthen the already-reported noninferiority hypothesis of SRS alone for the treatment of patients with 5-10 BMs.
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http://dx.doi.org/10.3171/2018.7.GKS181378DOI Listing
December 2018

Prognostic Importance of Cumulative Intracranial Tumor Volume in Patients with Gastrointestinal Brain Metastasis Treated with Stereotactic Radiosurgery.

World Neurosurg 2019 Jan 9;121:e747-e754. Epub 2018 Oct 9.

Department of Neurosurgery, University of Minnesota Medical School, Minneapolis, Minnesota, USA. Electronic address:

Background: The disease-specific Graded Prognostic Assessment (ds-GPA) for patients with gastrointestinal (GI) tract cancer brain metastases (BM) suggests Karnofsky Performance Status (KPS) as the only pertinent prognostic factor. We evaluated the prognostic importance of cumulative intracranial tumor volume (CITV).

Methods: KPS, CITV, and overall survival were collected from consecutive patients with stereotactic radiosurgery-treated GI BM. Patients were grouped into 2 independent cohorts for development and validation of the model (termed "exploratory" and "validation" cohorts). Analyses were performed using logistic regression, Cox proportional hazards models, Net Reclassification Index (NRI >0), integrated discrimination improvement (IDI >0), and Akaike information criterion.

Results: In univariable logistic regression models, both CITV and KPS were independently associated with patient survival. The association between CITV and overall survival remained robust after controlling for KPS (P < 0.001) in a multivariable Cox proportional hazards model. Based on NRI analysis of the exploratory cohort, we found that a CITV cutoff of 12 cm best augments the prognostic accuracy of GI-ds-GPA. In this analysis, incorporation of CITV (as < or ≥12 cm) improved prognostication of the GI-specific GPA model by NRI >0 of 0.397 (95% confidence interval [CI], 0.165-0.630; P < 0.001) and IDI of 0.019 (95% CI, 0.004-0.033; P = 0.013). We confirmed the prognostic usefulness of the CITV-incorporated GI-ds-GPA in an independent validation cohort, in which CITV incorporation improved prognostic usefulness with an NRI >0 of 0.478 (95% CI, 0.257-0.699; P < 0.001) and IDI of 0.028 (95% CI, 0.014-0.043; P < 0.001).

Conclusions: CITV is an important prognostic variable in patients with stereotactic radiosurgery-treated GI BM and augments the prognostic accuracy of the GI-ds-GPA index.
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http://dx.doi.org/10.1016/j.wneu.2018.09.209DOI Listing
January 2019

Comparison of treatment results between 3- and 2-stage Gamma Knife radiosurgery for large brain metastases: a retrospective multi-institutional study.

J Neurosurg 2018 Sep;131(1):227-237

21Department of Neurosurgery, National Cerebral and Cardiovascular Center, Suita, Japan.

Objective: In order to obtain better local tumor control for large (i.e., > 3 cm in diameter or > 10 cm3 in volume) brain metastases (BMs), 3-stage and 2-stage Gamma Knife surgery (GKS) procedures, rather than a palliative dose of stereotactic radiosurgery, have been proposed. Here, authors conducted a retrospective multi-institutional study to compare treatment results between 3-stage and 2-stage GKS for large BMs.

Methods: This retrospective multi-institutional study involved 335 patients from 19 Gamma Knife facilities in Japan. Major inclusion criteria were 1) newly diagnosed BMs, 2) largest tumor volume of 10.0-33.5 cm3, 3) cumulative intracranial tumor volume ≤ 50 cm3, 4) no leptomeningeal dissemination, 5) no more than 10 tumors, and 6) Karnofsky Performance Status 70% or better. Prescription doses were restricted to between 9.0 and 11.0 Gy in 3-stage GKS and between 11.8 and 14.2 Gy in 2-stage GKS. The total treatment interval had to be within 6 weeks, with at least 12 days between procedures. There were 114 cases in the 3-stage group and 221 in the 2-stage group. Because of the disproportion in patient numbers and the pre-GKS clinical factors between these two GKS groups, a case-matched study was performed using the propensity score matching method. Ultimately, 212 patients (106 from each group) were selected for the case-matched study. Overall survival, tumor progression, neurological death, and radiation-related adverse events were analyzed.

Results: In the case-matched cohort, post-GKS median survival time tended to be longer in the 3-stage group (15.9 months) than in the 2-stage group (11.7 months), but the difference was not statistically significant (p = 0.65). The cumulative incidences of tumor progression (21.6% vs 16.7% at 1 year, p = 0.31), neurological death (5.1% vs 6.0% at 1 year, p = 0.58), or serious radiation-related adverse events (3.0% vs 4.0% at 1 year, p = 0.49) did not differ significantly.

Conclusions: This retrospective multi-institutional study showed no differences between 3-stage and 2-stage GKS in terms of overall survival, tumor progression, neurological death, and radiation-related adverse events. Both 3-stage and 2-stage GKS performed according to the aforementioned protocols are good treatment options in selected patients with large BMs.
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http://dx.doi.org/10.3171/2018.4.JNS172596DOI Listing
September 2018

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

Int J Clin Oncol 2019 Feb 11;24(2):161-167. Epub 2018 Aug 11.

Tokyo Gamma Unit Center, Tsukiji Neurological Clinic, Tokyo, Japan.

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.
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http://dx.doi.org/10.1007/s10147-018-1339-7DOI Listing
February 2019

Modern management for brain metastasis patients using stereotactic radiosurgery: literature review and the authors' gamma knife treatment experiences.

Cancer Manag Res 2018 5;10:1889-1899. Epub 2018 Jul 5.

Katsuta Hospital Mito Gamma House, Hitachi-Naka, Japan,

Historically, whole brain radiotherapy was administered to most patients with brain metastases. However, over the past three decades, stereotactic radiosurgery (SRS), targeted at individual cranial lesions, has been accepted widely. In this study, based on the authors' experiences along with published data, recent trends in SRS for brain metastases are discussed. This article focuses on the following issues: 1) How many tumors can or should be treated with SRS? 2) Two-/three-staged SRS for relatively large tumors, 3) post- or preoperative SRS, and 4) repeat SRS.
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http://dx.doi.org/10.2147/CMAR.S116718DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6038887PMC
July 2018

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

Stereotact Funct Neurosurg 2018 3;96(3):162-171. Epub 2018 Jul 3.

Gamma Center Kagoshima, Atsuchi Neurosurgical Hospital, Kagoshima, Japan.

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.
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http://dx.doi.org/10.1159/000489948DOI Listing
April 2019

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

Acta Neurochir (Wien) 2018 05 2;160(5):997-1003. Epub 2018 Mar 2.

Department of Neurological Surgery, Nihon University School of Medicine, 30-1 Oyaguchi-Kamimachi, Itabashi-ku, Tokyo, 173-8610, Japan.

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.
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http://dx.doi.org/10.1007/s00701-018-3504-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5897455PMC
May 2018

A Multi-institutional Prospective Observational Study of Stereotactic Radiosurgery for Patients With Multiple Brain Metastases (JLGK0901 Study Update): Irradiation-related Complications and Long-term Maintenance of Mini-Mental State Examination Scores.

Int J Radiat Oncol Biol Phys 2017 09 7;99(1):31-40. Epub 2017 Aug 7.

Department of Radiology, Niigata University Graduate School of Medicine and Dental Sciences, Niigata, Japan.

Purpose: The JLGK0901 study showed the noninferiority of stereotactic radiosurgery (SRS) alone as initial treatment of 5 to 10 brain metastases (BMs) compared with 2 to 4 BMs in terms of overall survival and most secondary endpoints (Lancet Oncol 2014;15:387-95). However, observation periods were not long enough to allow confirmation of the long-term safety of SRS alone in patients with 5 to 10 BMs.

Methods And Materials: This was a prospective observational study of Gamma Knife SRS-treated patients with 1 to 10 newly diagnosed BMs enrolled at 23 facilities between March 1, 2009, and February 15, 2012.

Results: The 1194 eligible patients were categorized into the following groups: group A, 1 tumor (n=455); group B, 2 to 4 tumors (n=531); and group C, 5 to 10 tumors (n=208). Cumulative rates of Mini-Mental State Examination (MMSE) score maintenance (MMSE score decrease <3 from baseline) determined with a competing risk analysis of groups A, B, and C were 93%, 91%, and 92%, respectively, at the 12th month after SRS; 91%, 89%, and 91%, respectively, at the 24th month; 89%, 88%, and 89%, respectively, at the 36th month; and 87%, 86%, and 89%, respectively, at the 48th month (hazard ratio [HR] of group A vs group B, 0.719; 95% confidence interval [CI], 0.437-1.172; P=.18; HR of group B vs group C, 1.280; 95% CI, 0.696-2.508; P=.43). During observations ranging from 0.3 to 67.5 months (median, 12.0 months; interquartile range, 5.8-26.5 months), as of December 2014, 145 patients (12.1%) had SRS-induced complications. Cumulative complication incidences by competing risk analysis for groups A, B, and C were 7%, 8%, and 6%, respectively, at the 12th month after SRS; 10%, 11%, and 11%, respectively, at the 24th month; 11%, 11%, and 12%, respectively, at the 36th month; and 12%, 12%, and 13%, respectively, at the 48th month (HR of group A vs group B, 0.850; 95% CI, 0.592-1.220; P=.38; HR of group B vs group C, 1.052; 95% CI, 0.666-1.662, P=.83). Leukoencephalopathy occurred in 12 of the 1074 patients (1.1%) with follow-up magnetic resonance imaging and was detected after salvage whole-brain radiation therapy in 11 of these 12 patients. In these 11 patients, leukoencephalopathy was detected by magnetic resonance imaging 5.2 to 21.2 months (median, 11.0 months; interquartile range, 7.0-14.4 months) after whole-brain radiation therapy.

Conclusions: Neither MMSE score maintenance nor post-SRS complication incidence differed among groups A, B, and C. This longer-term follow-up study further supports the already-reported noninferiority hypothesis of SRS alone for patients with 5 to 10 BMs versus 2 to 4 BMs.
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http://dx.doi.org/10.1016/j.ijrobp.2017.04.037DOI Listing
September 2017

Improving the Prognostic Value of Disease-Specific Graded Prognostic Assessment Model for Renal Cell Carcinoma by Incorporation of Cumulative Intracranial Tumor Volume.

World Neurosurg 2017 Dec 25;108:151-156. Epub 2017 Jul 25.

Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address:

Background: We tested the prognostic value of cumulative intracranial tumor volume (CITV) in the context of a disease-specific Graded Prognostic Assessment (ds-GPA) model for renal cell carcinoma (RCC) patients with brain metastasis (BM) treated with stereotactic radiosurgery (SRS).

Methods: Patient and tumor characteristics were collected from RCC cohorts with new BM who underwent SRS. Univariable and multivariable logistic regression model was used to test the prognostic value of CITV, Karnofsky Performance Score (KPS), and the number of BM. Net reclassification index (NRI) and integrated discrimination improvement (IDI) were used to assess whether CITV improved the prognostic utility of RCC ds-GPA.

Results: In univariable logistic regression models, CITV, KPS, and the number of BM were independently associated with RCC patient survival. In a multivariable Cox proportional hazard model, the association between CITV and survival remained robust after controlling for KPS and the number of BM (P = 0.042). The incorporation of the CITV into the RCC ds-GPA model (consisting of KPS and number of BM) improved prognostic accuracy with NRI >0 of 0.3156 (95% confidence interval [CI], 0.0883-0.5428; P = 0.0065) and IDI of 0.0151 (95% CI, 0.0036-0.0277; P = 0.0183). These findings were validated in an independent cohort of 107 SRS-treated RCC BM patients.

Conclusion: CITV is an important prognostic variable in SRS-treated RCC patients with BM. The prognostic value of the ds-GPA scale for RCC brain metastasis was enhanced by the incorporation of CITV.
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http://dx.doi.org/10.1016/j.wneu.2017.07.109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5705321PMC
December 2017

Survival Patterns of 5750 Stereotactic Radiosurgery-Treated Patients with Brain Metastasis as a Function of the Number of Lesions.

World Neurosurg 2017 Nov 19;107:944-951.e1. Epub 2017 Jul 19.

Center for Translational and Applied Neuro-Oncology, Department of Neurosurgery, University of California, San Diego, La Jolla, California, USA; Department of Neurosurgery, University of Minnesota, Minneapolis, Minnesota, USA. Electronic address:

Background: The number of brain metastases (BMs) plays an important role in the decision between stereotactic radiosurgery (SRS) and whole-brain radiation therapy.

Methods: We analyzed the survival of 5750 SRS-treated patients with BM as a function of BM number. Survival analyses were performed with Kaplan-Meier analysis as well as univariate and multivariate Cox proportional hazards models.

Results: Patients with BMs were first categorized as those with 1, 2-4, and 5-10 BMs based on the scheme proposed by Yamamoto et al. (Lancet Oncology 2014). Median overall survival for patients with 1 BM was superior to those with 2-4 BMs (7.1 months vs. 6.4 months, P = 0.009), and survival of patients with 2-4 BMs did not differ from those with 5-10 BMs (6.4 months vs. 6.3 months, P = 0.170). The median survival of patients with >10 BMs was lower than those with 2-10 BMs (6.3 months vs. 5.5 months, P = 0.025). In a multivariate model that accounted for age, Karnofsky Performance Score, systemic disease status, tumor histology, and cumulative intracranial tumor volume, we observed a ∼10% increase in hazard of death when comparing patients with 1 versus 2-10 BMs (P < 0.001) or 10 versus >10 BMs (P < 0.001). When BM number was modeled as a continuous variable rather than using the classification by Yamamoto et al., we observed a step-wise 4% increase in the hazard of death for every increment of 6-7 BM (P < 0.001).

Conclusions: The contribution of BM number to overall survival is modest and should be considered as one of the many variables considered in the decision between SRS and whole-brain radiation therapy.
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http://dx.doi.org/10.1016/j.wneu.2017.07.062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654648PMC
November 2017

Superior Prognostic Value of Cumulative Intracranial Tumor Volume Relative to Largest Intracranial Tumor Volume for Stereotactic Radiosurgery-Treated Brain Metastasis Patients.

Neurosurgery 2018 04;82(4):473-480

Department of Neurosurgery, Center for Translational and Applied Neuro-Oncology, University of California, San Diego, La Jolla, California.

Background: Two intracranial tumor volume variables have been shown to prognosticate survival of stereotactic-radiosurgery-treated brain metastasis patients: the largest intracranial tumor volume (LITV) and the cumulative intracranial tumor volume (CITV).

Objective: To determine whether the prognostic value of the Scored Index for Radiosurgery (SIR) model can be improved by replacing one of its components-LITV-with CITV.

Methods: We compared LITV and CITV in terms of their survival prognostication using a series of multivariable models that included known components of the SIR: age, Karnofsky Performance Score, status of extracranial disease, and the number of brain metastases. Models were compared using established statistical measures, including the net reclassification improvement (NRI > 0) and integrated discrimination improvement (IDI). The analysis was performed in 2 independent cohorts, each consisting of ∼3000 patients.

Results: In both cohorts, CITV was shown to be independently predictive of patient survival. Replacement of LITV with CITV in the SIR model improved the model's ability to predict 1-yr survival. In the first cohort, the CITV model showed an NRI > 0 improvement of 0.2574 (95% confidence interval [CI] 0.1890-0.3257) and IDI of 0.0088 (95% CI 0.0057-0.0119) relative to the LITV model. In the second cohort, the CITV model showed a NRI > 0 of 0.2604 (95% CI 0.1796-0.3411) and IDI of 0.0051 (95% CI 0.0029-0.0073) relative to the LITV model.

Conclusion: After accounting for covariates within the SIR model, CITV offers superior prognostic value relative to LITV for stereotactic radiosurgery-treated brain metastasis patients.
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http://dx.doi.org/10.1093/neuros/nyx225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745302PMC
April 2018

Robustness of the neurological prognostic score in brain metastasis patients treated with Gamma Knife radiosurgery.

J Neurosurg 2017 Nov 2;127(5):1000-1006. Epub 2016 Dec 2.

Department of Radiology, Graduate School of Medical Sciences and Medical School, Nagoya City University, Nagoya, Japan.

OBJECTIVE The neurological prognostic score (NPS) was recently proposed as a means for predicting neurological outcomes, such as the preservation of neurological function and the prevention of neurological death, in brain metastasis patients treated with Gamma Knife radiosurgery (GKRS). NPS consists of 2 groups: Group A patients were expected to have better neurological outcomes, and Group B patients were expected to have poorer outcomes. NPS robustness was tested in various situations. METHODS In total, 3040 patients with brain metastases that were treated with GKRS were analyzed. The cumulative incidence of the loss of neurological function independence (i.e., neurological deterioration) was estimated using competing risk analysis, and NPS was compared between Groups A and B by employing Gray's model. NPS was tested to determine if it can be applied to 5 cancer categories-non-small cell lung cancer, small cell lung cancer, gastrointestinal tract cancer, breast cancer, and other cancers-as well as if it can be incorporated into the 5 major grading systems: recursive partitioning analysis (RPA), score index for stereotactic radiosurgery (SIR), basic score for brain metastases (BSBM), graded prognostic assessment (GPA), and modified-RPA (M-RPA). RESULTS There were 2263 patients in NPS Group A and 777 patients in Group B. Neurological deterioration was observed in 586 patients (19.2%). The cumulative incidences of neurological deterioration were 9.5% versus 21.0%, 14.1% versus 25.4%, and 17.6% versus 27.8% in NPS Groups A and B at 1, 2, and 5 years, respectively. Significant differences were detected between the NPS groups in all cancer categories. There were significant differences between NPS Groups A and B for all classes in terms of the BSBM, GPA, and M-RPA systems, but the differences failed to reach statistical significance in terms of RPA Class I and SIR Class 0 to 3. CONCLUSIONS The NPS was verified as being highly applicable to all cancer categories and almost all classes for the 5 grading systems in terms of neurological function independence. This NPS system appears to be quite robust in various situations for brain metastasis patients treated with GKRS.
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http://dx.doi.org/10.3171/2016.8.JNS16528DOI Listing
November 2017

Gamma Knife radiosurgery for brain metastases from pulmonary large cell neuroendocrine carcinoma: a Japanese multi-institutional cooperative study (JLGK1401).

J Neurosurg 2016 12;125(Suppl 1):11-17

Department of Neurosurgery, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto.

OBJECTIVE In 1999, the World Health Organization categorized large cell neuroendocrine carcinoma (LCNEC) of the lung as a variant of large cell carcinoma, and LCNEC now accounts for 3% of all lung cancers. Although LCNEC is categorized among the non-small cell lung cancers, its biological behavior has recently been suggested to be very similar to that of a small cell pulmonary malignancy. The clinical outcome for patients with LCNEC is generally poor, and the optimal treatment for this malignancy has not yet been established. Little information is available regarding management of LCNEC patients with brain metastases (METs). This study aimed to evaluate the efficacy of Gamma Knife radiosurgery (GKRS) for patients with brain METs from LCNEC. METHODS The Japanese Leksell Gamma Knife Society planned this retrospective study in which 21 Gamma Knife centers in Japan participated. Data from 101 patients were reviewed for this study. Most of the patients with LCNEC were men (80%), and the mean age was 67 years (range 39-84 years). Primary lung tumors were reported as well controlled in one-third of the patients. More than half of the patients had extracranial METs. Brain metastasis and lung cancer had been detected simultaneously in 25% of the patients. Before GKRS, brain METs had manifested with neurological symptoms in 37 patients. Additionally, prior to GKRS, resection was performed in 17 patients and radiation therapy in 10. A small cell lung carcinoma-based chemotherapy regimen was chosen for 48 patients. The median lesion number was 3 (range 1-33). The median cumulative tumor volume was 3.5 cm, and the median radiation dose was 20.0 Gy. For statistical analysis, the standard Kaplan-Meier method was used to determine post-GKRS survival. Competing risk analysis was applied to estimate GKRS cumulative incidences of maintenance of neurological function and death, local recurrence, appearance of new lesions, and complications. RESULTS The overall median survival time (MST) was 9.6 months. MSTs for patients classified according to the modified recursive partitioning analysis (RPA) system were 25.7, 11.0, and 5.9 months for Class 1+2a (20 patients), Class 2b (28), and Class 3 (46), respectively. At 12 months after GKRS, neurological death-free and deterioration-free survival rates were 93% and 87%, respectively. Follow-up imaging studies were available in 78 patients. The tumor control rate was 86% at 12 months after GKRS. CONCLUSIONS The present study suggests that GKRS is an effective treatment for LCNEC patients with brain METs, particularly in terms of maintaining neurological status.
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http://dx.doi.org/10.3171/2016.7.GKS161459DOI Listing
December 2016
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