Roberge, David

PURPOSE Survival for patients with melanoma has recently improved. The propensity of melanoma to metastasize to the brain remains a common and serious feature of this disease. The purposes of this study were to evaluate prognostic factors for patients with newly diagnosed melanoma brain metastases (MBMs) in a large cohort treated with modern multimodal therapies, compare those results with those in prior eras, and update the Melanoma Graded Prognostic Assessment (GPA). METHODS Univariable and multivariable (MVA) analyses of prognostic factors and treatments associated with survival were performed on 1,796 patients with newly diagnosed MBM treated between January 01, 2015, and December 31, 2021, using a multi-institutional retrospective database. Multiple imputation was used to address missingness of potential predictors. Significant variables in combined MVA were used to update the Melanoma GPA. Comparisons were made with legacy cohorts. RESULTS Median survivals for cohorts A (1985-2007, n = 481), B (2006-2015, n = 823), and C (2015-2021, n = 1,796) were 6.7, 9.8, and 16.6 months and median follow-up times were 40.1, 43.6, and 48.8 months, respectively. In combined MVA, significant prognostic factors for survival were higher Karnofsky Performance Status, fewer MBMs, absence of extracranial metastases, lower serum lactate dehydrogenase, and no immunotherapy before MBM. These factors were incorporated into the updated Melanoma GPA. The combined median and 3-year survivals for patients with GPA 0-1, 1.5-2, and 2.5-4.0 were 5.4, 13.2, and 43.2 months and 12.4%, 28.8%, and 51.6%, respectively. CONCLUSION Prognostic factors have changed and survival has improved for patients with MBM but varies widely by GPA. The updated Melanoma GPA calculator (BrainMetGPA), available free online, can be used to estimate survival, individualize treatment, stratify clinical trials, guide surveillance, and augment clinical trial eligibility. Multidisciplinary treatment is essential. Trials are needed to elucidate the optimal sequencing of various therapeutic modalities.

OBJECTIVE Many patients recruited in the Treatment of Brain Arteriovenous Malformations Study (TOBAS) are managed conservatively. The aim of this study was to monitor what happened to those patients. METHODS TOBAS comprises two randomized controlled trials and multiple prospective registries. All patients with brain arteriovenous malformations (AVMs) can participate. This report concerns patients selected for conservative management. The primary trial outcome measure is related death or dependency (modified Rankin Scale [mRS] score > 2) at 10 years. Secondary outcomes include intracranial hemorrhages, nonhemorrhagic neurological events, and serious adverse events (SAEs). For this report, outcome results are presented using patient-years, Kaplan-Meier survival curves, and Cox log-rank tests. There was no blinding. RESULTS From June 2014 to May 2021, 1010 patients were recruited, of whom 498 (49%) were proposed the prospective observation registry. After exclusions, 434 (87%) patients remained for analysis. The majority of patients had unruptured AVMs (378/434 [87%]), of which 195 (52%) were low grade (Spetzler-Martin grade I or II). During a mean follow-up period of 3.2 years (total 1368 patient-years), the primary outcome occurred in 23 of 434 (5%) patients, corresponding to an incidence of 1.7 (95% CI 1.1–2.5) per 100 patient-years. For unruptured AVMs the incidence was 1.1 (95% CI 0.7–1.9) per 100 patient-years, and for low-grade unruptured AVMs it was 0.6 (95% CI 0.2–1.7) per 100 patient-years. Poor outcomes were more frequent in patients with a history of rupture (HR 5.6 [95% CI 2.4–13.0], p < 0.001), infratentorial AVMs (HR 2.9 [95% CI 1.1–7.3], p = 0.027), and age ≥ 55 years (HR 3.2 [95% CI 1.4–7.6], p = 0.007). Major intracranial hemorrhage occurred in 35 of 434 (8%) patients (incidence of 2.6 [95% CI 1.9–3.6] per 100 patient-years; 2.0 [95% CI 1.3–2.9] per 100 patient-years for unruptured AVMs and 1.3 [95% CI 0.6–2.6] per 100 patient-years for low-grade unruptured AVMs). Major AVM hemorrhages were more frequent in ruptured (HR 4.4 [95% CI 2.1–8.9], p < 0.001), large (HR 2.6 [95% CI 1.1–6.6], p = 0.039), and high-grade (HR 2.5 [95% CI 1.2–5.3], p = 0.013) AVMs and those with deep venous drainage (HR 2.1 [95% CI 1.1–4.2], p = 0.032). SAEs occurred in 48 of 434 (11%) patients (incidence of 3.6 [95% CI 2.7–4.8] per 100 patient-years). For unruptured AVMs the incidence was 2.8 (95% CI 2.0–4.0) per 100 patient-years, and for low-grade unruptured AVMs it was 1.8 (95% CI 1.0–3.2) per 100 patient-years. CONCLUSIONS Nearly half of TOBAS participants were observed. Rates of untoward neurological events were within expected boundaries.

2008 Background: For non-small cell lung cancer (NSCLC) with brain metastases (BM) stereotactic radiosurgery (SRS) is the current preferred therapy. Due to frequent intracranial failures, there is a high unmet need for salvage therapies. Whole brain radiotherapy (WBRT) reduces intracranial failure but used less frequently due to cognitive consequences. Tumor Treating Fields (TTFields) are electric fields that disrupt cancer cell division and have shown improved survival and safety in patients with glioblastoma and metastatic NSCLC. Phase 3 METIS trial [NCT02831959] aimed to evaluate the efficacy and safety of TTFields therapy in NSCLC patients with BM treated with SRS, specifically in terms of lengthening time to intracranial progression without cognitive decline. Methods: Mutation negative (M-) NSCLC patients with 1–10 BM were randomized 1:1 to receive stereotactic radiosurgery (SRS) followed by Tumor Treating Fields (TTFields; 150 kHz) therapy with best supportive care (BSC) or SRS followed by BSC. Patients with Karnofsky Performance Status (KPS) ≥70, newly diagnosed with one inoperable or 2–10 supra-/infratentorial brain metastases suitable for SRS and receiving optimal extracranial disease therapy were included. Exclusions were prior WBRT and single operable or recurrent brain metastases. Primary endpoint was time to first intracranial progression (RANO-BM) based on cumulative risk. Patients were followed every two months until second intracranial progression. Cognition and patient quality of life (QoL) were evaluated. Results: Between July 2016 and September 2022, 298 patients were randomized. Baseline characteristics were balanced: median age was 63.5 (range 37-84) years, 37.6% females, majority of patients had a KPS ≥ 80, median time from initial NSCLC diagnosis was 1.8 months (range: 0.2-55.7), 77% had adenocarcinoma. Median treatment duration of TTFields was 16 weeks, with a median usage time of 67%. Primary endpoint, time to intracranial progression from SRS, was significantly prolonged with SRS followed by TTFields therapy with BSC vs. BSC alone arm (median of 21.9 vs. 11.3 months); HR=0.67 [0.48-0.93], p=0.02. TTFields-related AEs were mainly dermatological, and Grade ≤2. TTFields therapy also improved deterioration-free survival of global health status, physical functioning, and fatigue according to QoL, and did not negatively impact cognition. Conclusion: METIS study met its primary endpoint, demonstrating that TTFields therapy following SRS in mutation negative NSCLC patients with BM, significantly prolongs time to intracranial progression and could postpone WBRT, without QoL and cognition decline. Clinical trial information: NCT02831959 .

Abstract INTRODUCTION: TTFields are electric fields that disrupt processes necessary for cancer cell survival and can stimulate an antitumor immune response in preclinical NSCLC models. TTFields therapy is a noninvasive and locoregional treatment approved for glioblastoma, which has recently demonstrated a survival benefit when applied to the thorax with standard of care (SOC) systemic therapy in patients with metastatic NSCLC that progressed on/after platinum. Here we describe the pivotal METIS study (EF-25, NCT02831959) evaluating the efficacy and safety of TTFields therapy applied to brain metastases from NSCLC. TRIAL DESIGN: Patients (270) with 1–10 brain metastases from NSCLC will receive stereotactic radiosurgery (SRS), followed by 1:1 randomization to TTFields (NovoTTF-200M [150 kHz] applied to the head ≥ 18 h/day) with best SOC, or best SOC alone. Key inclusion criteria are life expectancy ≥ 3 months, a new diagnosis of 1 inoperable or 2–10 supra and/or infratentorial brain metastases from NSCLC, that are amenable to SRS. Patients who had prior whole brain radiotherapy, or have single operable, leptomeningeal, or recurrent brain metastases, certain genetic mutations, or severe comorbidities or contraindications, are not eligible. The primary endpoint is time to first intracranial progression. Secondary endpoints include time to neurocognitive failure, overall survival, radiological response rate, time to second intracranial progression, time to first/second intracranial progression by modified RECIST v1.1, rate of intracranial progression, time to distant progression, rate of cognitive decline, quality of life, neurocognitive failure-free survival, and safety. The study is powered at 80% (2-sided alpha of 0.05) to detect a hazard ratio of 0.57. In July 2021, an independent Data Monitoring Committee reviewed the study data and recommended continuation. The study includes 128 sites in Europe, Israel, mainland China, North America, and Hong Kong. The final patient was enrolled in March 2023.

Abstract PURPOSE Previous analysis of NRG-CC001 suggested pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggested patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not standard-WBRT. The current analysis examined the relationship between changes in MR-determined WMI and NCF 6-months following WBRT+memantine+/-HA. METHODS NCF-testing was performed at baseline, 2, 4, 6, and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR-volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (met vol) (FLAIR-volume/(whole brain volume–met-vol). Pearson correlation coefficients were used to assess the correlation between pre-treatment WMI and change from baseline to 6-months for each standardized NCF score. RESULTS Of the 518 randomized patients, 443 (217 patients WBRT+Memantine and 226 HA-WBRT+Memantine) had WMI data available at baseline, and of those, 162 patients (89 patients WBRT+Memantine and 73 HA-WBRT+Memantine) had both baseline and 6-month imaging available. For these patients, there was only a trend toward significance for change in corrected FLAIR-volume from baseline to 6-months (p = 0.174) but no significant change in met-vol (p = 0.438) or whole brain volume (p = 0.977). The change in standardized TMT Part A and B and the change in composite 6-month change scores were moderately correlated with change in corrected FLAIR volume adjusted for met-vol but only in the WBRT+Memantine arm (rho=-0.35, -0.34, -0.39 and p-value = 0.003, 0.006, 0.001). CONCLUSIONS Despite an increase in post-WBRT MR-WMI at 6-months, analysis did not show strong correlation between NCF and MR-WMI as determined by FLAIR-volume change between baseline and 6-months. Similar analyses are underway for the NRG-CC003 imaging data.

Abstract PURPOSE Hippocampal volume (HV) is a predictor of neurocognitive function (NCF) in neurodegenerative disease. The role of patient-specific anatomic variables has not been well investigated in patients with brain metastases. This work aimed to evaluate HV at baseline and 6 months as a predictor of NCF and differential benefit from HA-WBRT for patients enrolled on CC001. MATERIALS HV was calculated at baseline and 6 months. HV at baseline and 6 months were correlated with baseline and 2, 4, and 6-month NCF scores (HVLT-R Total and Delayed Recall, Delayed Recognition, TMT Parts A and B, and COWA) using Pearson correlation. Correlation was defined as weak if ρ ≤0.35. A cox proportional hazards model was used to determine the impact of baseline HV on time to NCF failure. RESULTS Of 518 patients randomized on CC001, 277 had baseline imaging, and 135 had 6-month imaging. However, only 87 patients were analyzable at both baseline and 6-month periods. At baseline, HV was not significantly associated with NCF score for any measure (p-value range: 0.06-0.72). Additionally, there was no association between baseline HV and time to NCF failure (p = 0.16). Additionally, the impact of treatment arm allocation on HV was examined but found to be non-significant (p = 0.06). Lastly, baseline HV and NCF scores were noted to have weak correlation at 2, 4, 6, and 12 month timepoints (ρ: range, -0.17-0.15; P-value range, 0.04-0.98). At 6 months, the correlation between HV, baseline NCF change, and 6 month standardized NCF change were also noted to be weak (ρ: range, 0.05-0.16; P-value range, 0.06-0.76). CONCLUSIONS Radiotherapy is known to have deleterious effects on neurocognition. In neurodegenerative disease, HV and rate of HV change are known predictors for NCF. However, baseline HV is not an independent predictor of neurocognitive changes after WBRT or HA-WBRT for patients with brain metastases.

AbstractBackgroundA recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline.MethodsIn this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment.ResultsThe APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P &lt; .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014).ConclusionsPatients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Abstract BACKGROUND The assessment of BM response to WBRT and its impact on NCF in clinical trials has been limited by lack of standardized imaging protocols. NRG-CC001 is a randomized clinical trial requiring pre-specified MRI protocols at baseline and 6-months, providing a uniform dataset to investigate if RR correlates with NCF changes. METHODS NRG-CC001 randomized patients with BM to hippocampal avoidance WBRT (HA-WBRT) or WBRT. NCF was analyzed using 6-month standardized change scores and deterioration, defined using the reliable change index. Chi-square and t-tests were used for pretreatment characteristic comparisons. Inter-rater reliability between central and institutional assessment of RR was assessed with weighted kappa, κ. Linear regression was used to test trends in NCF change scores across types of response and multivariable logistic regression was used to test the association of RR to NCF deterioration. RESULTS 149 and 135 patients were evaluable for RR and NCF assessment, respectively. Pretreatment characteristics were well-balanced, except for post-high school education (70.6% HA-WBRT vs. 52.5% WBRT, p=0.023). Inter-rater reliability between central and institutional assessment of RR was fair (κ=0.36). There was no difference between arms in RR (p=0.41) with overall rates of 14.1% CR, 42.2% PR, 17% SD, and 26.7% PD. Patients with CR had improved 6-month NCF change as measured by HVLT-R Total Recall (p=0.0005), HVLT-R Delayed Recall (p=0.0003), HVLT-R Delayed Recognition (p=0.011), TMT-B (p=0.033), COWA (p=0.016), and Clinical Trial Battery Composite score (p=0.0011). Multivariable analysis demonstrated less deterioration in HVLT-R Delayed Recall for CR (p=0.019) and PR (p=0.0086) vs. SD/PD and HVLT-R Recognition for PR (p=0.031) vs. SD/PD. CONCLUSIONS HA-WBRT and WBRT result in similar RR at 6-months. CR or PR is associated with better NCF preservation. This suggests investigation into treatment escalation for patients with SD/PD may provide further NCF benefit along with HA-WBRT and memantine.Grant support from NCI-UG1CA189867 and U24CA180803.

Importance Long-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases. Objective To determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases. Design, Setting, and Participants This secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017. Interventions Stereotactic radiosurgery or WBRT. Main Outcomes and Measures Intracranial tumor control, toxic effects, cognitive deterioration, and QOL. Results Fifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, −40.7; 95% CI, −68.1% to −13.4%), respectively. Data were first analyzed in February 2017. Conclusions and Relevance The use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population. Trial Registration ClinicalTrials.gov Identifier: NCT01372774 ; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group)

Abstract PURPOSE Previous secondary analysis of NRG/RTOG 0933 provided hypothesis-generating data supporting a relationship between larger volumes of MR-determined pre-treatment WMI and developing neurocognitive decline following HA-WBRT. The current study examines the relationship between pre-treatment WMI and neurocognitive function (NCF) following WBRT+memantine +/-HA in a substantially larger cohort. METHODS NCF testing was performed at baseline,2,4,6,and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (FLAIR/(whole brain volume – metastasis FLAIR volume). Pearson correlation coefficients were used to assess association between pre-treatment WMI and change from baseline for each standardized NCF score. RESULTS Of 518 randomized patients, 442 (217,WBRT+Memantine; 225,HA-WBRT+Memantine) had WMI data and were included. In the entire cohort, mean FLAIR volume was 9.3cc (0.1-68.2cc), mean metastases FLAIR volume was 61.5cc (0-423.5cc), mean Whole Brain volume was 1336.4cc (949.4-2397.8cc). At 2 months, there were no significant correlations between neurocognitive test change scores and pre-treatment WMI volume. However, at 4 months, both HVLT-R Total Recall and TMT Part B change score and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.22 p=0.042 and ρ=-0.27, p=0.013). At 12 months, both TMT Part A and TMT Part B change scores and pre-treatment WMI volume were significantly negatively correlated on the HA-WBRT+Memantine arm (ρ=-0.30, p=0.046 and ρ=-0.53, p&lt; 0.001). CONCLUSIONS Pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggests patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not following standard WBRT. Dose heterogeneity inherent to HA-WBRT delivery may contribute to these findings and are hypothesis generating.