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.

Applicability and limitations of a recently-proposed prognostic grading metric, initial brain metastasis velocity, for brain metastasis patients undergoing stereotactic radiosurgery.

PURPOSE: This study, based on our brain metastasis (BM) patients undergoing stereotactic radiosurgery (SRS) procedures, aimed to validate whether the recently-proposed prognostic grading system, initial brain metastasis velocity (iBMV, scoring the cumulative number of BMs at the time of SRS divided by time [years] since the initial primary cancer diagnosis), is generally applicable. METHODS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 3498 patients who underwent SRS for BMs during the 19.5-year-period between July, 1998 and December, 2017. We excluded four lost to follow-up, 24 for whom the day of primary cancer diagnosis was not available, 665 with synchronous presentation and 651 with pre-SRS radiotherapy and/or surgery, ultimately studying 2150 patients. Patients were categorized into two classes by iBMV scores, i.e., < 2.00 and ≥ 2.00. RESULTS: In a multivariable model, iBMV was directly associated with a higher risk of death (p < 0.0001). The median survival time of patients with iBMV scores < 2.00, 10.0 (95% CI; 9.2-10.9) months, was longer than that of patients with iBMV scores ≥ 2.00, 6.3 (5.6-6.7) months, showing a significant difference between the two groups (HR 1.599, 95% CI 1.458-1.753, p < 0.0001). The same results were obtained in patients with non-small cell lung, breast, kidney or other cancers. Among 608 patients who underwent repeat SRS for newly-developed BMs, iBMV score categories correlated well with brain metastasis velocity risk groups (p < 0.0001). CONCLUSIONS: Our present results support the validity of iBMV for predicting survival after SRS.

Long-term follow-up results of stereotactic radiosurgery for vestibular schwannomas larger than 8 cc.

BACKGROUND: Accumulated stereotactic radiosurgery (SRS) experience for large vestibular schwannomas (VSs) based on over 5 years of follow-up are as yet insufficient, and chronological volume changes have not been documented. METHOD: Among 402 patients treated between 1990 and 2015, tumor volumes exceeded 8 cc in 30 patients. We studied 19 patients with follow-up for more than 36 post-SRS months or until an event. Median tumor volume was 11.5 cc (range; 8.0 to 30.6). The target volume was basically covered with 12.0 Gy. RESULTS: The median magnetic resonance imaging and clinical follow-up periods were both 98 months (range 49 to 204). Tumor shrinkage was documented in 13 patients (72%), no change in 2 (11%), and growth in the other 3 (17%). Therefore, the crude growth control rate was 83%. All three patients with tumor enlargement needed salvage treatment. Thus, the crude clinical control rate was 84%. Actuarial further procedure-free rates were 91%, 83% and 76%, at the 60th, 120th, and 180th post-SRS month. Among six patients followed chronologically, transient tumor expansion was observed in three (43%) and two cystic VSs showed rapid tumor growth. Transient trigeminal neuropathy occurred in two patients (11%). No patients experienced facial nerve palsy. None of the six patients with useful hearing pre-SRS maintained serviceable hearing. Ventricular-peritoneal shunt placement was required in three patients. CONCLUSIONS: Long-term tumor control with SRS was moderately acceptable in large VSs. In terms of functional outcome, trigeminal neuropathies and facial palsies were rare. However, hearing preservation remains a challenge. In the long term, chronological tumor volumes were generally decreased after SRS. However, caution is required regarding rapid increases in tumor size, especially for cystic type VSs. Further studies are needed to optimize clinical positioning of SRS for large VSs.

A case-matched study of stereotactic radiosurgery for patients with brain metastases: comparing treatment results for those with versus without neurological symptoms.

We aimed to reappraise whether post-stereotactic radiosurgery (SRS) results for brain metastases differ between patients with and without neurological symptoms. This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 2825 consecutive BM patients undergoing gamma knife SRS alone during the 15-year period since July 1998. The 2825 patients were divided into two groups; neurologically asymptomatic [group A, 1374 patients (48.6 %)] and neurologically symptomatic [group B, 1451 (51.4 %)]. Because there was considerable bias in pre-SRS clinical factors between groups A and B, a case-matched study was conducted. Ultimately, 1644 patients (822 in each group) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival. Competing risk analysis was applied to estimate cumulative incidences of neurological death, neurological deterioration, local recurrence, re-SRS for new lesions and SRS-induced complications. Post-SRS median survival times (MSTs) did not differ between the two groups; 7.8 months in group A versus 7.4 months in group B patients (HR 1.064, 95 % CI 0.963-1.177, p = 0.22). However, cumulative incidences of neurological death (HR 1.637, 95 % CI 1.174-2.281, p = 0.0036) and neurological deterioration (HR 1.425, 95 % CI 1.073-1.894, p = 0.014) were significantly lower in the group A than in the group B patients. Neurologically asymptomatic patients undergoing SRS for BM had better results than symptomatic patients in terms of both maintenance of good neurological state and prolonged neurological survival. Thus, we conclude that screening computed tomography/magnetic resonance imaging is highly beneficial for managing cancer patients.

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

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

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.

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.

A Cohort Study of Stereotactic Radiosurgery Results for Patients With 5 to 15 Versus 2 to 4 Brain Metastatic Tumors.

PURPOSE: The role of stereotactic radiosurgery (SRS) alone for patients with ≥5 brain metastases is not fully understood. The objective of the study was to compare SRS-alone treatment results for 2 to 4 versus 5 to 15 tumors. METHODS AND MATERIALS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 1150 patients with 2 to 4 tumors and 939 with 5 to 15 tumors who underwent Gamma Knife SRS during a 20-year period (1998-2018). The Kaplan-Meier method was used to determine post-SRS survival times, and competing risk analyses were applied to estimate cumulative incidences of the secondary endpoints. RESULTS: The post-SRS median survival time was slightly longer in the group with 2 to 4 tumors (8.1 months) than in that with 5 to 15 tumors (7.2 months, P = .0010). Median survival time differences were statistically significant for non-small cell lung cancer, gastrointestinal tract cancer, and others but not for small cell lung cancer, breast cancer, and kidney cancer. Multivariable analysis demonstrated female sex, better Karnofsky Performance Status score, non-small cell lung cancer (vs gastrointestinal tract cancer), younger age, controlled primary cancer, and no extracerebral metastases to be significant predictors of a longer survival period in both tumor number groups. Crude and cumulative incidences of salvage whole brain radiation therapy were significantly higher in the group with 5 to 15 tumors than in that with 2 to 4 tumors, although those of other secondary endpoints were similar to or lower in the 5 to 15 tumor number group than those in the group with 2 to 4 tumors. CONCLUSIONS: We conclude that carefully selected patients with ≥5 to 15 tumors are not unfavorable candidates for SRS alone.

Signal intensity increases in dentate nucleus/globus pallidus/pulvinar on unenhanced T1WI MR images after multiple examinations with gadodiamide.

BACKGROUND AND PURPOSE: Elevated signal intensity (SI) in the dentate nucleus (DN), globus pallidus (GP) and pulvinar (PUL) was reportedly observed on unenhanced T1-weighted (T1WI) magnetic resonance (MR) images in patients receiving multiple enhanced MR examinations. We aimed to clarify whether this phenomenon influences the long-term neurological status of patients. MATERIALS AND METHODS: We studied 196 radiosurgically treated patients undergoing ≥10 MR examinations using a single dose of gadodiamide and the same 1.5 Tesla MR unit. SI ratios were calculated by referencing the brainstem (BS) for the DN and the thalamus (TH) for the GP and PUL. We compared the SI ratios at the first, fifth, and 10th, and at the most recent examinations. The neurological symptoms of all 196 patients were assessed at each MR examination by one of the authors (MY). RESULTS: The DN/BS and GP/TH SI ratios were significantly increased at the fifth examination ( p < .0001, p = 0.0094) and, thereafter, gradually increased. Although the PUL/TH SI ratio was not significantly increased at the fifth examination ( p = 0.2515), a significant increase was noted at the 10th examination ( p < .0001). There were no significant predictive factors for DN/BS SI increases. Younger age, no brain metastasis, and normal estimated glomerular filtration rate were related to GP/TH SI ratio increases ( p = 0.0308, p = 0.0001, p = 0.0306). Higher age and total bilirubin level were related to an increased PUL/TH SI ratio ( p = 0.0276, p = 0.0097). No patients experienced gadodiamide-related health problems. CONCLUSIONS: Although the SI ratios rose as numbers of gadodiamide administrations increased, no adverse health effects have developed to date.

Gamma Knife Radiosurgery For Brain Vascular Malformations: Current Evidence And Future Tasks.

Gamma Knife radiosurgery (GKRS) has long been used for treating brain vascular malformations, including arteriovenous malformations (AVMs), dural arteriovenous fistulas (DAVFs), and cavernous malformations (CMs). Herein, current evidence and controversies regarding the role of stereotactic radiosurgery for vascular malformations are described. 1) It has already been established that GKRS achieves 70-85% obliteration rates after a 3-5-year latency period for small to medium-sized AVMs. However, late radiation-induced adverse events (RAEs) including cyst formation, encapsulated hematoma, and tumorigenesis have recently been recognized, and the associated risks, clinical courses, and outcomes are under investigation. SRS-based therapeutic strategies for relatively large AVMs, including staged GKRS and a combination of GKRS and embolization, continue to be developed, though their advantages and disadvantages warrant further investigation. The role of GKRS in managing unruptured AVMs remains controversial since a prospective trial showed no benefit of treatment, necessitating further consideration of this issue. 2) Regarding DAVFs, GKRS achieves 41-90% obliteration rates at the second post-GKRS year with a hemorrhage rate below 5%. Debate continues as to whether GKRS might serve as a first-line solo therapeutic modality given its latency period. Although the post-GKRS outcomes are thought to differ among lesion locations, further outcome analyses regarding DAVF locations are required. 3) GKRS is generally accepted as an alternative for small or medium-sized CMs in which surgery is considered to be too risky. The reported hemorrhage rates ranged from 0.5-5% after GKRS. Higher dose treatments (>15 Gy) were performed during the learning curve, while, with the current standard treatment, a dose range of 12-15 Gy is generally selected, and has resulted in acceptable complication rates (< 5%). Nevertheless, further elucidation of long-term outcomes is essential.

Stereotactic Radiosurgery for Patients with 10 or More Brain Metastases.

The JLGK0901 study showed the non-inferiority of stereotactic radiosurgery (SRS) alone as the initial treatment for 5-10 as compared to 2-4 brain metastases (BM) in terms of overall survival and most secondary endpoints [Lancet Oncol 2014;15:387-395]. A trend for patients with 5-10 tumors to undergo SRS alone has since become apparent. The next step is to reappraise whether results of SRS treatment alone for tumor numbers ≥10 differ from those for 2-9 tumors. During the past 2 decades, several retrospective studies have demonstrated the SRS alone treatment strategy to have certain benefits for carefully selected patients with ≥10 BM, i.e., a sufficiently long survival period with lower incidences of neurological death, neurological deterioration, local recurrence, and SRS-related complications. Herein, we introduce our Mito experiences with SRS for ≥10 BM, employing a case-matched study on 934 patients, 467 each in groups with 2-9 BM and ≥10 BM. Post-SRS treatment results, i.e., median survival time, neurological death-free survival time and cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-related complications, were not inferior for patients with ≥10 BM as compared to those with 2-9 BM. We conclude that patients with ≥10 tumors are not unfavorable candidates for SRS alone.

Postsurgical Salvage Radiosurgery for Nonfunctioning Pituitary Adenomas Touching/Compressing the Optic Chiasm: Median 13-Year Postirradiation Imaging Follow-up Results.

BACKGROUND: There is little information on long-term outcomes after salvage treatment by either surgery or stereotactic radiosurgery (SRS) for patients with recurrent/residual nonfunctioning pituitary adenomas (NFPAs). OBJECTIVE: To reappraise the efficacy and safety of SRS for patients with NFPAs touching/compressing the optic apparatus (OA). METHODS: We studied 27 patients (14 females, 13 males; mean age: 61 [range, 19-85] yr) who underwent SRS between 1998 and 2008 for NFPAs with such condition. The median tumor volume was 4.9 (range, 1.8-50.8) cc. To avoid excess irradiation to the OA, the lower part of the tumor was covered with a 50% or a 60% isodose gradient, ie 49% to 98% (mean, 84%; median, 88%) of the entire tumor received the selected doses. Median doses at the tumor periphery/OA were 7.6/11.0 (interquartile range [IQR], 5.8-9.1/10.1-11.8) Gy. RESULTS: Seven patients (26%) were confirmed to be deceased due to unrelated diseases at a median post-SRS period of 149 (IQR, 83-158) mo. Follow-up magnetic resonance imaging (MRI) showed tumor growth in 2 patients (7%) at the 11th and 134th post-SRS month; the former underwent surgery and the other SRS. Excluding these 2 patients, the latest follow-up MRI examinations, performed 13 to 238 (median: 168, IQR: 120-180) mo after SRS, showed no size changes in 5 (19%) and shrinkage in 20 (74%) patients. Cumulative incidences of tumor growth control were 96.3% and 91.8% at the 120th and 180th post-SRS month. None of our patients developed subjective symptoms suggesting SRS-induced optic neuropathy or endocrinological impairment. CONCLUSION: In patients with NFPAs touching/compressing the OA, SRS achieves good long-term results.

Validity of a Recently Proposed Prognostic Grading Index, Brain Metastasis Velocity, for Patients With Brain Metastasis Undergoing Multiple Radiosurgical Procedures.

PURPOSE: This study of our patients with brain metastasis who underwent multiple stereotactic radiosurgery (SRS) procedures aimed to validate whether the recently proposed prognostic grading system, brain metastasis velocity (BMV), is generally applicable. The BMV scores the cumulative number of new brain metastases that developed after the first SRS divided by time (years) since the initial SRS. Patients were categorized into 3 classes by their BMV scores (ie, ≤3, 4-13, and ≥14). METHODS AND MATERIALS: This retrospective cohort study was approved by the Tokyo Women's Medical University Institutional Review Board (number 1981). We used our prospectively accumulated database, which included 833 patients who underwent a second SRS procedure for newly detected lesions, using a gamma knife, for brain metastases. Patients who had whole-brain radiation therapy were excluded. The procedures took place during the 19-year period between July 1998 and June 2017. Furthermore, among the 833 patients, 250 underwent a third SRS procedure, and 88 had a fourth SRS procedure. RESULTS: The median survival times (MSTs) after the second SRS were 12.9 months (95% confidence interval [CI], 10.2-17.1) for the BMV group with a score of ≤3; 7.5 months (CI, 6.5-9.0) for the group scoring 4 to 13, and 5.1 months (CI, 4.0-5.6) for the group scoring ≥14 (P = .0001). The corresponding MSTs after the third SRS were 13.2 months (95% CI, 9.1-21.6), 8.0 months (CI, 6.2-11.2), and 5.7 months (CI, 4.8-7.8; P = .0001). Respective MSTs after the fourth SRS were 13.2 months (95% CI, 9.1-21.6), 8.0 months (CI, 6.2-11.2), and 5.7 months (CI, 4.8-7.8; P < .0001). The mean BMV score of patients with small cell lung cancer, 24.8, was significantly higher than that of patients with non-small cell lung cancer, 17.7 (P = .032). CONCLUSIONS: Our present results support the validity of BMV for predicting survival not only after the second SRS but also after the third and fourth SRS.

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

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.

Complications after stereotactic radiosurgery for brain metastases: Incidences, correlating factors, treatments and outcomes.

BACKGROUND AND PURPOSE: Complications after stereotactic radiosurgery (SRS) for brain metastases (BMs) were analyzed in detail using our database including nearly 3000 BM patients. MATERIALS AND METHODS: This was an institutional review board-approved, retrospective cohort study using our prospectively accumulated database including 3271 consecutive patients who underwent gamma knife SRS for BMs during the 1998-2016 period. Excluding four patients lost to follow-up, 112 with three-staged treatment and 189 with post-operative irradiation, 2966 who underwent a single-session of SRS only as radical irradiation were studied. RESULTS: The overall median survival time after SRS was 7.8 (95% CI; 7.4-8.1) months. Post-SRS complications occurred in 86 patients (2.9%) 1.9-211.4 (median; 24.0, IQR; 12.0-64.6) months after treatment. RTOG neurotoxicity grades were 2, 3 and 4 in 58, 25 and 3 patients, respectively. Cumulative incidences determined with a competing risk analysis were 1.4%, 2.2%, 2.4%, 2.6% and 2.9% at the 12th, 24th, 36th, 48th and 60th post-SRS month, respectively. Among various pre-SRS clinical factors and radiosurgical parameters, multivariable analyses demonstrated solitary tumor (Adjusted HR; 0.584, 95% CI; 0.381-0.894, p = 0.0133), controlled primary cancer (Adjusted HR; 2.595, 95% CI; 1.646-4.091, p < 0.0001), no extra-cerebral metastases (Adjusted HR; 1.608, 95% CI; 1.028-2.514, p = 0.0374), KPS ≥80% (Adjusted HR; 2.715, 95% CI; 1.245-5.924, p = 0.0121) and largest tumor volume ≥3.3 cc (Adjusted HR; 0.516, 95% CI; 0.318-0.836, p = 0.0072) to be independently significant predictors of a higher incidence of complications. CONCLUSION: The post-SRS complication incidence is acceptably low (2.9%). Meticulous long-term follow-up after SRS is crucial for all patients.

Stereotactic radiosurgery for brain metastases: a case-matched study comparing treatment results for patients 80 years of age or older versus patients 65-79 years of age.

OBJECT: Recently, an increasing number of patients with brain metastases, even patients over 80 years of age, have been treated with stereotactic radiosurgery (SRS). However, there is little information on SRS treatment results for patients with brain metastases 80 years of age and older. The authors undertook this study to reappraise whether SRS treatment results for patients 80 years of age or older differ from those of patients who are 65-79 years old. METHODS: This was an institutional review board-approved, retrospective cohort study. Among 2552 consecutive brain metastasis patients who underwent SRS during the 1998-2011 period, we studied 165 who were 80 years of age or older (Group A) and 1181 who were age 65-79 years old (Group B). Because of the remarkable disproportion in patient numbers between the 2 groups and considerable differences in pre-SRS clinical factors, the authors conducted a case-matched study using the propensity score matching method. Ultimately, 330 patients (165 from each group, A and B) were selected. For time-to-event outcomes, the Kaplan-Meier method was used to estimate overall survival and competing risk analysis was used to estimate other study end points, as appropriate. RESULTS: Although the case-matched study showed that post-SRS median survival time (MST, months) was shorter in Group A patients (5.3 months, 95% CI 3.9-7.0 months) than in Group B patients (6.9 months, 95% CI 5.0-8.1 months), this difference was not statistically significant (HR 1.147, 95% CI 0.921-1.429, p = 0.22). Incidences of neurological death and deterioration were slightly lower in Group A than in Group B patients (6.3% vs 11.8% and 8.5% vs 13.9%), but these differences did not reach statistical significance (p = 0.11 and p = 0.16). Furthermore, competing risk analyses showed that the 2 groups did not differ significantly in cumulative incidence of local recurrence (HR 0.830, 95% CI 0.268-2.573, p = 0.75), rates of repeat SRS (HR 0.738, 95% CI 0.438-1.242, p = 0.25), or incidence of SRS-related complications (HR 0.616, 95% CI 0.152-2.495, p = 0.49). Among the Group A patients, post-SRS MSTs were 11.6 months (95% CI 7.8-19.6 months), 7.9 months (95% CI 5.2-10.9 months), and 2.8 months (95% CI; 2.4-4.6 months) in patients whose disease status was modified-recursive partitioning analysis (RPA) Class(es) I+IIa, IIb, and IIc+III, respectively (p < 0.001). CONCLUSIONS: Our results suggest that patients 80 years of age or older are not unfavorable candidates for SRS as compared with those 65-79 years old. Particularly, even among patients 80 years and older, those with modified-RPA Class I+IIa or IIb disease are considered to be favorable candidates for more aggressive treatment of brain metastases.

Validity of prognostic grading indices for brain metastasis patients undergoing repeat radiosurgery.

OBJECTIVES: We tested the validity of 5 prognostic indices, Recursive Partitioning Analysis (RPA), Score Index for Radiosurgery (SIR), Basic Score for Brain Metastases (BSBM), Graded Prognostic Assessment (GPA), and Modified-RPA, for patients who underwent repeat stereotactic radiosurgery (re-SRS). METHODS: For this study, we used our database, which included 804 patients who underwent gamma knife re-SRS during the period 1998-2013. RESULTS: There were statistically significant survival differences among patients stratified into 3 or 4 groups based on the 5 systems (P < 0.001). With RPA, SIR, BSBM, and the Modified-RPA, there were statistically significant median survival time (MST) differences between any 2 pairs within the 3/4 groups. With the GPA system, however, the MST difference between the GPA 3.5-4.0 and GPA 3.0 groups did not reach statistical significance (P = 0.48). There were large patient number discrepancies among the 3/4 groups in the RPA, SIR, BSBM, and GPA whereas patient numbers were very similar among the 3 Modified-RPA system groups. Our present results show the RPA and BSBM systems to reflect changes less well, with 86%-95% of patients remaining in the same categories between the first and second SRS procedures. However, with SIR, GPA, and the Modified-RPA, 25%-31% of patients were categorized into different subclasses, either better or worse. With the modified-RPA system, such categorical change correlated well with post-re-SRS MSTs. CONCLUSIONS: Among the 5 systems, based on patient number proportions, MST separation among the 3/4 groups, and/or detailed reflection of status changes, the Modified-RPA system was shown to be most applicable to re-SRS patients.

Long-term side effects of radiosurgery for arteriovenous malformations.

In this report, our experiences with 181 consecutive patients who underwent Gamma Knife radiosurgery (GKRS) for arteriovenous malformations (AVMs) during an approximately quarter century period from 1978 to 2002 will be summarized along with much of what we have learned from a wealth of already published data. During the mean post-GKRS follow-up period of 10.2 years (range, 5.4-30.6), 15 (8.3%) of our 181 patients experienced stereotactic radiosurgery-related, symptomatic complications. Among these 15 patients, 12 manifested complications 5 years or more after GKRS. Furthermore, in 5 of these 12, the complications were seen 10 or more years after GKRS. In the present series, the actuarial complication rates computed using the Kaplan-Meier method were 2.3% at the fifth, 8.2% at the tenth, 15.2% at the fifteenth and 31.1% at the twentieth post-GKRS year. AVM volumes, Pollock-Flickinger AVM scores, the initial presentation of bleeding and centrally located AVMs were demonstrated to be significantly associated with the risk of delayed complications after GKRS (p<0.05). There was a significant difference in complication rates between two patient groups, based on whether dose planning was performed using the older (Kula) or the modern (Gamma Plan) system (18.0 vs. 4.6%, χ2 p=0.0002). Although GKRS is undoubtedly an alternative to microsurgical resection for appropriately selected AVMs, we must weigh treatment results against complication risks which are not negligibly low.

Delayed complications in patients surviving at least 3 years after stereotactic radiosurgery for brain metastases.

PURPOSE: Little is known about delayed complications after stereotactic radiosurgery in long-surviving patients with brain metastases. We studied the actual incidence and predictors of delayed complications. PATIENTS AND METHODS: This was an institutional review board-approved, retrospective cohort study that used our database. Among our consecutive series of 2000 patients with brain metastases who underwent Gamma Knife radiosurgery (GKRS) from 1991-2008, 167 patients (8.4%, 89 women, 78 men, mean age 62 years [range, 19-88 years]) who survived at least 3 years after GKRS were studied. RESULTS: Among the 167 patients, 17 (10.2%, 18 lesions) experienced delayed complications (mass lesions with or without cyst in 8, cyst alone in 8, edema in 2) occurring 24.0-121.0 months (median, 57.5 months) after GKRS. The actuarial incidences of delayed complications estimated by competing risk analysis were 4.2% and 21.2% at the 60th month and 120th month, respectively, after GKRS. Among various pre-GKRS clinical factors, univariate analysis demonstrated tumor volume-related factors: largest tumor volume (hazard ratio [HR], 1.091; 95% confidence interval [CI], 1.018-1.154; P=.0174) and tumor volume≤10 cc vs >10 cc (HR, 4.343; 95% CI, 1.444-12.14; P=.0108) to be the only significant predictors of delayed complications. Univariate analysis revealed no correlations between delayed complications and radiosurgical parameters (ie, radiosurgical doses, conformity and gradient indexes, and brain volumes receiving >5 Gy and >12 Gy). After GKRS, an area of prolonged enhancement at the irradiated lesion was shown to be a possible risk factor for the development of delayed complications (HR, 8.751; 95% CI, 1.785-157.9; P=.0037). Neurosurgical interventions were performed in 13 patients (14 lesions) and mass removal for 6 lesions and Ommaya reservoir placement for the other 8. The results were favorable. CONCLUSIONS: Long-term follow-up is crucial for patients with brain metastases treated with GKRS because the risk of complications long after treatment is not insignificant. However, even when delayed complications occur, favorable outcomes can be expected with timely neurosurgical intervention.

A case-matched study of stereotactic radiosurgery for patients with multiple brain metastases: comparing treatment results for 1-4 vs ≥ 5 tumors: clinical article.

OBJECT: Although stereotactic radiosurgery (SRS) alone for patients with 4-5 or more tumors is not a standard treatment, a trend for patients with 5 or more tumors to undergo SRS alone is already apparent. The authors' aim in the present study was to reappraise whether SRS results for ≥ 5 tumors differ from those for 1-4 tumors. METHODS: This institutional review board-approved retrospective cohort study used the authors' database of prospectively accumulated data that included 2553 consecutive patients who underwent SRS, not in combination with concurrent whole-brain radiotherapy, for brain metastases (METs) between 1998 and 2011. These 2553 patients were divided into 2 groups: 1553 with tumor numbers of 1-4 (Group A) and 1000 with ≥ 5 tumors (Group B). Because there was considerable bias in pre-SRS clinical factors between Groups A and B, a case-matched study was conducted. Ultimately, 1096 patients (548 each in Groups A and B) were selected. The standard Kaplan-Meier method was used to determine post-SRS survival and the post-SRS neurological death-free survival times. Competing risk analysis was applied to estimate cumulative incidences of local recurrence, repeat SRS for new lesions, neurological deterioration, and SRS-induced complications. RESULTS: The post-SRS median survival time was significantly longer in the 548 Group A patients (7.9 months, 95% CI 7.0-8.9 months) than in the 548 Group B patients (7.0 months 95% [CI 6.2-7.8 months], HR 1.176 [95% CI 1.039-1.331], p = 0.01). However, incidences of neurological death were very similar: 10.6% in Group A and 8.2% in Group B (p = 0.21). There was no significant difference between the groups in neurological death-free survival intervals (HR 0.945, 95% CI 0.636-1.394, p = 0.77). Furthermore, competing risk analyses showed that there were no significant differences between the groups in cumulative incidences of local recurrence (HR 0.577, 95% CI 0.312-1.069, p = 0.08), repeat SRS (HR 1.133, 95% CI 0.910-1.409, p = 0.26), neurological deterioration (HR 1.868, 95% CI 0.608-1.240, p = 0.44), and major SRS-related complications (HR 1.105, 95% CI 0.490-2.496, p = 0.81). In the authors' cohort, age ≤ 65 years, female sex, a Karnofsky Performance Scale score ≥ 80%, cumulative tumor volume ≤ 10 cm(3), controlled primary cancer, no extracerebral METs, and neurologically asymptomatic status were significant factors favoring longer survival equally in both groups. CONCLUSIONS: This retrospective study suggests that increased tumor number is an unfavorable factor for longer survival. However, the post-SRS median survival time difference, 0.9 months, between the two groups is not clinically meaningful. Furthermore, patients with 5 or more METs have noninferior results compared to patients with 1-4 tumors, in terms of neurological death, local recurrence, repeat SRS, maintenance of good neurological state, and SRS-related complications. A randomized controlled trial should be conducted to test this hypothesis.