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Radiotherapy has an important role in the treatment of brain metastases (BrM) but carries risk of short and/or long-term toxicity, termed radiation-induced neurotoxicity (RIN). As the diagnosis of RIN is crucial for correct pa-tient management, there is an unmet need for reliable biomarkers for RIN. The aim of this proof-of concept study was to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as RIN biomarkers. Twenty-four patients with BrM were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. During follow-up nine RIN events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RIN correlated with de-crease in BncfDNA. Changes in BncfDNA were independent of tumor response. Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy, further research is needed to establish BncfDNA as a novel plasma-based biomarker for RIN.

Purpose: To examine the applicability and efficacy of Cognitive Retraining and Functional Treatment (CRAFT) combining remote computerized cognitive training (CCT) and occupation-based treatment in adults with cancer-related cognitive impairment (CRCI). Methods: Three-armed randomized controlled trial including 74 individuals with CRCI, randomized into 12 weeks of either CRAFT, CCT alone, or treatment-as-usual. Assessments evaluating participation in daily life, perceived cognition, cognitive performance, quality-of-life, and treatment satisfaction were administered at baseline, post-intervention and 3-month follow up. Results: Significant time X group interactions in favor of the CRAFT and CCT groups were found for participation in daily life (F2,34=5.31, p=.01, eta=.238), perceived cognition (F2,34=4.897, p=.014, eta=.224) and cognitive performance on speed of processing test (F=5.678, p=.009, eta=.289). CRAFT group demonstrated significantly larger clinically meaningful gains on participation in daily life (Chi-square= 6.91, p=.032) and significantly higher treatment satisfaction. All treatment gains were maintained at a 3-month follow-up (n=32). Conclusions: CCT and CRAFT were found to have a positive impact on participation and cognitive outcomes among individuals with CRCI. The CRAFT showed an additional advantage in improving self-chosen occupation-based goals suggesting that a combination of cognitive training with occupation-based intervention has a positive synergistic effect resulting in ‘real world’ health benefits. Implications for Cancer Survivors: A combination of cognitive training with occupation-based intervention has a positive effect resulting in clinically meaningful improvements in participation in daily life, objective cognitive performance, and subjective cognitive impairment. Clinical Trial Registration: ClinicalTrials.gov NCT04210778, December 26, 2019, retrospectively registered.