Vaios, Eugene

Abstract Background Multi-modality therapy has improved survival for many patients with brain metastases. However, neurocognitive sequelae remain a challenge. While advances in radiotherapy have reduced toxicity, the potential interaction with targeted therapy and immunotherapy and the consequent impact on neurocognitive outcomes remain poorly defined. We appraised the current evidence on neurocognitive outcomes in the era of modern combined-modality therapy. Methods This systematic review adhered to PRISMA guidelines and included clinical trials reporting neurocognitive outcomes in patients with brain metastases receiving radiotherapy ± concurrent systemic therapies. Studies published through December 31, 2024 were identified through PubMed/Medline, EMBASE, and Web of Science using pre-defined MeSH term-based search strings. Results 39 studies from 1997-2024 involving 6,617 patients met inclusion criteria (n = 27 whole-brain radiotherapy [WBRT]; n = 12 radiosurgery), including six studies evaluating combined-modality therapy in 1,161 patients. Baseline cognitive evaluation was performed inconsistently, but neurocognitive deficits were frequently observed prior to treatment. Most randomized trials reported improved cognitive outcomes and quality of life with advanced radiotherapy techniques (e.g., hippocampal avoidance, radiosurgery) vs WBRT. Among 20 randomized trials comparing radiotherapy with or without a concurrent investigational systemic therapy, only four included neurocognitive assessments. There was no evidence of cognitive sequelae with combined-modality therapy, though evaluable trials were limited due to inconsistent reporting of neurocognitive functioning. Conclusion As survival improves in patients with brain metastases, preserved cognition is an important outcome measure. The lack of neurocognitive endpoints in pivotal brain metastasis trials represents a critical evidence gap. The interaction between radiotherapy and novel systemic therapies, and their combined effects on neurocognition, remain unknown. To address this, we recommend 1) integrating sensitive, pragmatic, and tailored neurocognitive assessments into oncology trials to quantify additive toxicity, 2) early and systematically incorporating neuropsychology into care pathways, 3) expanding radiation dose-sparing and radioprotective strategies, and 4) evaluating the utility of cognitive rehabilitation programs.

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.