Takao Koiso

Cumulative Intracranial Tumor Volume (CITV) Enhances the Prognostic Value of the Lung-Specific Graded Prognostic Assessment (GPA) Model.

BACKGROUND Management of patients afflicted with brain metastasis requires tailoring of therapeutic strategies based on survival expectations. Therefore, the development of prognostic indices is of critical importance in this patient population. OBJECTIVE To determine whether the cumulative intracranial tumor volume (CITV) of brain metastasis augments the prognostic value of the lung-specific Graded Prognostic Assessment (GPA) index. METHODS Patient data were derived from 365 lung cancer patients with brain metastasis who were consecutively treated with stereotactic radiosurgery at the University of California, San Diego/San Diego Gamma Knife Center. CITV was analyzed to determine the volume cutoff that maximized sensitivity and specificity for 1-year survival. Multivariate Cox proportional hazard modeling was performed, and overall survival was estimated by the Kaplan-Meier method risk stratifying with or without this optimal CITV. The prognostic value of these models (lung-specific GPA ± CITV) was quantitatively compared with the use of net reclassification improvement (>0) and integrated discrimination improvement. RESULTS For the University of California, San Diego/San Diego Gamma Knife Center cohort, the CITV cutoff that had the greatest survival discrimination at 1 year was 4 cm. The addition of CITV to the lung-specific GPA indexes significantly improved the prognostic value of lung-specific GPA, with net reclassification improvement >0 of 0.430 (95% confidence interval, 0.228-0.629) and integrated discrimination improvement of 0.029 (95% confidence interval, 0.004-0.073). These findings were validated in an independent cohort of 1638 lung cancer patients with brain metastasis who were treated with stereotactic radiosurgery at the Katsuta Hospital Mito Gamma House in Japan. CONCLUSION In independent cohorts, the addition of CITV to the lung-specific GPA index significantly improved the prognostic value of this index. ABBREVIATIONS AUC, area under the receiver-operating characteristic curveBM, brain metastasisCITV, cumulative intracranial tumor volumeds-GPA, disease-specific Graded Prognostic AssessmentGPA, Graded Prognostic AssessmentIDI, integrated discrimination improvementKHMGH, Katsuta Hospital Mito Gamma HouseKPS, Karnofsky Performance StatusNRI, net reclassification improvementROC, receiver-operating characteristic curveSRS, stereotactic radiosurgeryUCSD/SDGKC, University of California, San Diego/San Diego Gamma Knife Center.

Follow-up results of brain metastasis patients undergoing repeat Gamma Knife radiosurgery

OBJECTIVE Stereotactic radiosurgery (SRS) without upfront whole-brain radiotherapy (WBRT) has influenced recent treatment recommendations for brain metastasis patients. However, in brain metastasis patients who undergo SRS alone, new brain metastases inevitably appear with relatively high incidences during post-SRS follow-up. However, little is known about the second SRS results. The treatment results of second SRS were retrospectively reviewed, mainly for newly developed or, uncommonly, for recurrent brain metastases in order to reappraise the efficacy of this treatment strategy with a special focus on the maintenance of neurological status and safety. METHODS This was an institutional review board-approved, retrospective cohort study that used a prospectively accumulated database, including 3102 consecutive patients with brain metastases who underwent SRS between July 1998 and June 2015. Among these 3102 patients, 859 (376 female patients; median age 64 years; range 21-88 years) who underwent a second SRS without WBRT were studied with a focus on overall survival, neurological death, neurological deterioration, local recurrence, salvage SRS, and SRS-induced complications after the second SRS. Before the second SRS, the authors also investigated the clinical factors and radiosurgical parameters likely to influence these clinical outcomes. For the statistical analysis, the standard Kaplan-Meier method was used to determine post-second SRS survival and neurological death. A competing risk analysis was applied to estimate post-second SRS cumulative incidences of local recurrence, neurological deterioration, salvage SRS, and SRS-induced complications. RESULTS The post-second SRS median survival time was 7.4 months (95% CI 7.0-8.2 months). The actuarial survival rates were 58.2% and 34.7% at 6 and 12 months after the second SRS, respectively. Among 789 deceased patients, the causes of death could not be determined in 24 patients, but were confirmed in the remaining 765 patients to be nonbrain diseases in 654 (85.5%) patients and brain diseases in 111 (14.5%) patients. The actuarial neurological death-free survival rates were 94.4% and 86.6% at 6 and 12 months following the second SRS. Multivariable analysis revealed female sex, Karnofsky Performance Scale score of 80% or greater, better modified recursive partitioning analysis class, smaller tumor numbers, and higher peripheral dose to be significant predictive factors for longer survival. The cumulative incidences of local recurrence were 11.2% and 14.9% at 12 and 24 months after the second SRS. The crude incidence of neurological deterioration was 7.1%, and the respective cumulative incidences were 4.5%, 5.8%, 6.7%, 7.2%, and 7.5% at 12, 24, 36, 48, and 60 months after the second SRS. SRS-induced complications occurred in 25 patients (2.9%) after a median post-second SRS period of 16.8 months (range 0.6-95.0 months; interquartile range 5.6-29.3 months). The cumulative incidences of complications were 1.4%, 2.0%, 2.4%, 3.0%, and 3.0% at 12, 24, 36, 48, and 60 months after the second SRS, respectively. CONCLUSIONS Carefully selected patients with recurrent tumors-either new or locally recurrent-are favorable candidates for a second SRS, particularly in terms of neurological status maintenance and the safety of this treatment strategy.

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

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 models 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.

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.

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.

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

OBJECTIVEIn 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.METHODSThis 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.RESULTSIn 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.CONCLUSIONSThis 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.

339 Comparative Prognostic Value of the Cumulative Intracranial Tumor Volume and Score Index for Radiosurgery in Brain Metastasis.

INTRODUCTION There are 2 published prognostic scales for brain metastasis (BM) patients undergoing radiosurgery that take into consideration the volume of the tumor treated. The score index for radiosurgery (SIR) inputs the largest tumor volume treated as a survival predictor, while the cumulative intracranial tumor volume (CITV) inputs the total cumulative volume of the tumors treated. It remains unclear whether 1 scale is superior in terms of predicting survival. METHODS We compared the sensitivity and specificity of SIR and CITV scales in predicting 1-year survival using standard measures of continuous data: Net Reclassification Index (NRI > 0) and Integrated Discrimination Improvement (IDI). The analysis was performed in 2 independent cohorts: 3020 BM patients treated at either the University of California San Diego (UCSD) or the Katsuta Hospital Mito Gamma House (KHMGH), and a second cohort of 3040 patients treated at Chiba/Tsukiji (CT) hospital. RESULTS In both cohorts, models incorporating age, Karnofsky performance score, presence of extracranial disease, number of metastases, and CITV performed better than models where CITV was replaced with the largest tumor volume. In the first cohort, models incorporating CITV showed a Net Reclassification Index ([NRI] >0) improvement 0.2416 (95% confidence interval [CI], 0.1637-0.3194) and Integrated Discrimination Improvement (IDI) of 0.0029 (95% CI, 0.0001-0.0064) relative to models incorporating the largest lesion size. Similar results were observed in the second cohort (NRI > 0 of 0.2431 [95% CI, 0.1692-0.3171] and IDI of 0.0068 [95% CI, 0.0003-0.0011]). CONCLUSION In both cohorts, models incorporating age, Karnofsky performance score, presence of extracranial disease, number of metastases, and CITV performed better than models where CITV was replaced with the largest tumor volume. In the first cohort, models incorporating CITV showed a Net Reclassification Index (NRI > 0) improvement 0.2416 (95% CI, 0.1637-0.3194) and, IDI of 0.0029 (95% CI, 0.0001-0.0064) relative to models incorporating the largest lesion size. Similar results were observed in the second cohort (NRI >0 of 0.2431 [95% CI, 0.1692-0.3171] and IDI of 0.0068 [95% CI, 0.0003-0.0011]).METHODS: Under ACUC approval, 32 mice underwent implantation of 130 000 GL261 cells in the left striatum using a stereotactic frame. The presence of tumor was confirmed by bioluminescence imaging at day 7. Mice were randomly assigned to 4 groups: Control, FLT3 (courtesy of Celldex) treatment, Poly IC treatment, and FLT31Poly IC treatment. Survival was assessed using log-rank analysis and described using Kaplan-Meier curves.