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Background The historic standard of care for adult medulloblastoma has been considered surgery and radiation, while chemotherapy is increasingly being prescribed. This study reviewed 20-year chemotherapy trends at a high-volume center, as well as overall and progression free-survival. Methods Adults with medulloblastoma treated at an academic center from January 1, 1999 to –December 31, 2020 were reviewed. Patient baseline data were summarized and Kaplan–Meier estimators were used for survival. Results Forty-nine patients were included; median age was 30 years and male: female ratio was 2:1. Desmoplastic and classical histologies were most common. Of all patients, 23 (47%) were high risk and 7 (14%) metastatic at diagnosis. Only 10 (20%) received initial chemotherapy, of which 70% were high risk and 30% metastatic, with most treated from 2010 to 2020. Forty percent of initial chemotherapy patients received salvage chemotherapy for recurrence or metastases (of all patients, 49% required salvage). Initial chemotherapy regimens were mainly cisplatin/lomustine/vincristine, and at recurrence cisplatin/etoposide. Median overall survival was 8.6 years (95% CI 7.5–∞), with 1-, 5-, and 10-year survival at 95.8%, 72%, and 46.7%. Median overall survival for those who did not receive initial chemotherapy was 12.4 years and 7.4 years for those who did (P-value .2). Conclusions Twenty years of adult medulloblastoma treatment was reviewed. Initial chemotherapy patients, most of whom were high risk, trended towards worse survival, but this was nonsignificant. The ideal timing and choice of chemotherapy for adult medulloblastoma is unknown—challenges of administering chemotherapy following photon craniospinal irradiation may have prevented it from becoming routine.

Background We sought to identify variates correlating with overall survival (OS) in patients treated with surgery (S) plus adjuvant stereotactic radiosurgery (SRS) versus definitive SRS for large (>4 cc) brain metastases (BrM). Methods We used univariate (UVA) and multivariate analyses (MVA) to identify survival correlates among eligible patients identified from a prospective registry and compared definitive SRS to S+ adjuvant SRS cohorts using propensity score-matched analysis (PSMA). Secondary outcomes were measured using the cumulative incidence (CI) method. Results We identified 364 patients; 127 and 237 were treated with S+SRS and definitive SRS, respectively. On UVA, SRS alone [HR1.73 (1.35,2.22) P < .001), BrM quantity [HR 1.13 (1.06–1.22) (P < .001)]; performance status (PS) [HR 2.78 (1.73–4.46) (P < .001)]; extracranial disease (ECD) [HR 1.82 (1.37,2.40) (P < .001)]; and receipt of systemic treatment after BrM therapy, [HR 0.58 (0.46–073) (P < .001)] correlated with OS. On MVA, SRS alone [HR 1.81 (1.19,2.74) (P < .0054)], SRS target volume [HR 1.03 (1.01,1.06) (P < .0042)], and receipt of systemic treatment [HR 0.68 (0.50,0.93) (P < .015)] correlated with OS. When PSMA was used to balance ECD, BrM quantity, PS, and SRS target volume, SRS alone remained correlated with worsened OS [HR 1.62 (1.20–2.19) (P = 0.0015)]. CI of local failure requiring resection at 12 months was 3% versus 7% for S+SRS and SRS cohorts, respectively [(HR 2.04 (0.89–4.69) (P = .091)]. CI of pachymeningeal failure at 12 months was 16% versus 0% for S+SRS and SRS. Conclusion SRS target volume, receipt of systemic therapies, and treatment with S+SRS instead of definitive SRS correlated with improved survival in patients with large BrM.

BACKGROUND We aimed to identify factors predicting survival following treatment to large (>4cc) BrM. METHODS From a prospective registry database, we identified 364 adult patients treated for brain metastases (BrM) or surgical cavities larger than >4 cc: 127 and 237 treated with surgery plus stereotactic radiosurgery (S+SRS) and SRS alone, respectively. We compared the 2 treatment arms using propensity score-matched (PSMA) and multivariate analyses (MVA). P values RESULTS Median target volume was 6.6cc (4-36.9cc) for intact BrM and 15cc (4-54) for cavities. Median OS was 19 and 12 months for the S+SRS and SRS groups, respectively [HR 1.73 (1.35-2.22) (P CONCLUSION Reduced SRS target volume, treatment with systemic therapy following BrM treatment, and surgical resection prior to SRS correlate with survival in patients with large BrM. PMSA supports the hypothesis that surgery prior to SRS improves survival in patients with large BrM.

PURPOSE Neurocognitive dysfunction is common in patients with advanced metastatic cancer. The contribution of brain metastases (BrMets) to neurocognitive outcomes is uncertain. We examined the impact of BrMets on cognitive outcomes before CNS-directed treatment and compared findings to patients with advanced metastatic cancer without BrMets. Here we present results from an ongoing prospective, longitudinal study. METHODS English-speaking adults followed at the brain metastases and lung cancer clinics underwent neurocognitive testing using a standardized battery (prior to cranial radiotherapy, if applicable), with follow-up assessments 3, 6, 9, 12, 18, and 24 months later. We calculated z-scores and impairment rates for composite neurocognitive function and memory, attention/working memory, processing speed and executive function domains. Impairment was defined according to International Cancer and Cognition Task Force criteria. RESULTS 78 patients with BrMets (50% female; mean age (SD):61(11) years) and 28 patients with metastatic non-small cell lung cancer (mNSCLC) with no known BrMets (71% female; age 67(9) years) were included. Baseline neurocognitive composite scores were impaired in both groups (BrMets: 61.5%; nonBrMets: 60.7%). Impairment rates varied between groups and across domains (BrMets vs nonBrMets: memory: 35.9%vs25.0%; attention/working memory: 35.8%vs21.4%; processing speed: 10.3%vs7.1%; executive function: 44.0%vs35.7%). Subgroup comparisons between BrMets patients with mNSCLC (N=29) and mNSCLC patients without BrMets, none of whom had targetable mutations, revealed no differences in impairment rates, but BrMets patients had slower processing speed than nonBrMets patients (mean(SD): -0.6(1.4) vs -0.1(1.9); Wilcoxon signed-rank test, p = 0.043). CONCLUSION Neurocognitive impairment in patients with advanced cancers is common. Our preliminary findings demonstrate no clear difference in cognitive outcomes between patients with BrMets and those with advanced metastatic disease not involving the brain. Our work examining how neurocognitive outcomes evolve over time in patients with and without BrMets, and demographic, disease, and treatment variables associated with those outcomes, is ongoing.

Background Having multiple brain lesions has been considered a negative prognostic factor in patients with brain metastases. The role of surgery in the management of these patients remains a matter of debate. Methods We retrospectively reviewed our patients who underwent surgical resection of brain metastases from January 2018 to December 2019, and examined outcomes including overall survival (OS), progression free survival (PFS) and rates of local failure. Results We identified 130 patients who underwent surgical resection as the primary treatment modality of brain metastases. At the time of surgery, 117 patients harbored 1–3 lesions, 13 had more than 3 lesions. Overall survival at two years for our entire cohort was 46%. The difference in OS between patients with > 3 metastases (21%) and 1–3 metastases (49%) was not statistically significant (HR=1.34, 95% CI: 0.67–2.68, p=0.41). Similarly, 27% of patients had PFS at two years, with 25% in the multiple metastases group and 28% in the comparison group (HR=1.19, 95% CI: 0.63–2.23, p=0.59). Additionally, 32% of patients overall experienced local failure at two years and there was no significant difference between patients with >3 metastases (15%) and those with fewer (33%) (HR=0.68, 95% CI: 0.21–2.19, p=0.52). A multivariate regression model examining multiple preoperative features revealed large tumor volume to be the only independent predictor of limited OS (p = 0.017) and PFS (p = 0.023), and local failure (p = 0.031). Conclusions In carefully selected patients, surgical resection is a reasonable management option for patients with multiple brain metastases.

INTRODUCTION The effect of stereotactic radiosurgery (SRS) dose-rate on tumor control for acoustic neuroma (AN, or vestibular schwannoma) is unclear. METHODS This was a retrospective study of all patients treated for AN with frame-based cobalt-60 SRS at the Toronto Western Hospital between 2005-2019. Dose rates on the day of SRS were calculated from the calibration dose-rate while accounting for the cobalt-60 half-life of 5.2713 years. Local failure was defined as continued tumor growth >36 months post-SRS, tumor resection for LF, or use of any repeat SRS for LF. Cumulative incidence of LF was reported after accounting for competing risks of death, on a per-lesion basis. Comparisons of actuarial LF were made using Gray’s test. Multivariable analysis of LF was performed using a proportional hazards model. RESULTS A total of 607 patients were treated for 617 acoustic neuromas. Median follow-up was 5.0 years. 158 tumors (26%) were cystic. 71 tumors (12%) had previous resection. Nine patients received 10-11 Gy due to large tumor size; all remaining patients received 12 Gy to approximately the 50% isodose line. Median dose rate was 2.4 Gy/min (range, 1.3-3.7). There was no association between dose rate and LF (≥ 2.4 Gy/min vs. < 2.4 Gy/min, 6.07% vs. 6.12% at 5-year follow-up, p = 0.75). The adjusted local failure-specific hazard ratio (HR) for dose rate (per Gy/min) was 1.2 (95% CI 0.69-2.1, p = 0.52). Patients with previous surgery had higher LF, with a HR of 3.6 (95% CI 1.7-7.8, p = 0.0012), after adjusting for presence of cysts (HR 0.27, p = 0.034) and maximum tumor diameter (HR 1.055 per cm, p = 0.071). CONCLUSIONS In a large cohort of patients with acoustic neuromas, radiosurgery dose-rate was not associated with tumor control. Previous resection was a strong risk factor for local failure after SRS.

BACKGROUND: Glioblastoma is the most common adult malignant glioma, with poor prognosis and adverse neurological sequelae. Physical activity improves outcomes in patients with other cancers, but has not been evaluated in GBM. This prospective, single-arm intervention trial examines feasibility and preliminary efficacy of exercise on progression-free survival (PFS), cognition and quality of life (QOL) in newly diagnosed GBM patients. METHOD: Participants are English-speaking GBM patients scheduled for concurrent chemo-radiation at the Princess Margaret Cancer Centre, 18–65 years old, ECOG 2. The 3-month home-based exercise program, prescribed by a physiotherapist, includes aerobic and resistance training, tailored to prior fitness level, current physical status, and individual interests. Assessments of physical and neurocognitive functions, mood, fatigue, sleep, and QOL, occur within 2 weeks of starting chemo-radiation, and approximately 3, 6, 12, and 18 months later, or until tumor progression. Feasibility will be assessed by accrual, retention, and adherence rates. Outcomes include PFS (RANO criteria), change in cognition, physical activity and sleep (actigraphy, self-report questionnaires). Time-to-event outcomes will be estimated (Kaplan-Meier), and mixed modelling will explore individual and disease variables that contribute to outcomes. RESULTS: During the first seven months of recruitment, 51 newly diagnosed GBM patients scheduled to be treated at our institution were screened, 25 met eligibility criteria, and 16 consented. Four participants did not complete the exercise program; 3 withdrew consent, 1 refused concurrent chemoradiation. Two participants died after the intervention and one other progressed. No exercise-related serious adverse events occurred. Updated accrual and feasibility details will be presented at the meeting. DISCUSSION: Exercise appears feasible for GBM patients. Preliminary efficacy in terms of survival, performance status, cognition, sleep, mood, and QOL are under study. Results may guide physical activity recommendations in GBM, lay the groundwork for a larger randomized controlled trial, and generate avenues for translational research.

PURPOSE/OBJECTIVE(S): Melanoma commonly metastasizes to the brain and is radioresistant. Stereotactic radiosurgery (SRS) confers durable local control of brain metastases (BM) while maintaining neurocognitive function. These advantages are increasingly important as survival among these patients improves secondary to advances in systemic therapies. This study investigated the local control (LC), intracranial PFS (iPFS), freedom from radionecrosis (FFRN), and overall survival (OS) among melanoma patients receiving SRS for BM. MATERIALS/METHODS: We retrospectively reviewed clinical outcomes of melanoma patients with brain metastases treated with SRS between October 2008 and January 2017 in a large academic centre. Post-SRS, patients were followed in a multidisciplinary clinic with clinical examination and brain MRI every 3 months. Survival outcomes were estimated using the Kaplan-Meier method. RESULTS: In total, 97 patients with 283 brain metastases (including 12 surgical cavities) treated with SRS were identified. Median age was 60.5 (24.4–90.7). Median follow-up was 9.6 (2.2–74.7) months after first SRS. Median prescription dose was 21 (10–24) Gy delivered in a single fraction. Thirty (30.9%) patients had WBRT post-SRS, 36 (37.1%) patients had BRAF-positive disease. Per lesion (N=283), 1-year LC and FFRN were 84.4%, and 90.1%, respectively; medians were not achieved for either LC or FFRN. Radionecrosis (RN) occurred in 20 (7.1%) lesions. Per patient (N=97), median OS and iPFS were 16.0 and 5.3 months, respectively; 1-year OS and iPFS rates were 62.0%, and 30.1%, respectively. CONCLUSION: SRS resulted in excellent rates of LC, with a low risk of RN. However, most patients developed intracranial progression within 1 year. Further analyses to establish correlates (lesion size, SRS dose, and molecular status) to LC, FFRN, OS, and iPFS will be performed prior to the final presentation.

BACKGROUND: Accurate survival stratification in early-stage non–small cell lung cancer (NSCLC) could inform the use of adjuvant therapy. We developed a clinically implementable mortality risk score incorporating distinct tumor microenvironmental gene expression signatures and clinical variables. METHODS: Gene expression profiles from 1106 nonsquamous NSCLCs were used for generation and internal validation of a nine-gene molecular prognostic index (MPI). A quantitative polymerase chain reaction (qPCR) assay was developed and validated on an independent cohort of formalin-fixed paraffin-embedded (FFPE) tissues (n = 98). A prognostic score using clinical variables was generated using Surveillance, Epidemiology, and End Results data and combined with the MPI. All statistical tests for survival were two-sided. RESULTS: The MPI stratified stage I patients into prognostic categories in three microarray and one FFPE qPCR validation cohorts (HR = 2.99, 95% CI = 1.55 to 5.76, P < .001 in stage IA patients of the largest microarray validation cohort; HR = 3.95, 95% CI = 1.24 to 12.64, P = .01 in stage IA of the qPCR cohort). Prognostic genes were expressed in distinct tumor cell subpopulations, and genes implicated in proliferation and stem cells portended poor outcomes, while genes involved in normal lung differentiation and immune infiltration were associated with superior survival. Integrating the MPI with clinical variables conferred greatest prognostic power (HR = 3.43, 95% CI = 2.18 to 5.39, P < .001 in stage I patients of the largest microarray cohort; HR = 3.99, 95% CI = 1.67 to 9.56, P < .001 in stage I patients of the qPCR cohort). Finally, the MPI was prognostic irrespective of somatic alterations in EGFR, KRAS, TP53, and ALK. CONCLUSION: The MPI incorporates genes expressed in the tumor and its microenvironment and can be implemented clinically using qPCR assays on FFPE tissues. A composite model integrating the MPI with clinical variables provides the most accurate risk stratification.