Importance: Brain tumor patients have the highest stroke mortality rates among all cancer types, but the factors associated with fatal stroke in brain tumor remain unknown. Objective: We aimed to examine to what extent brain tumor grade, a marker of biological aggressiveness, tumor size and cancer treatment each associated with stroke mortality in glioma. Gliomas include the most common malignant types of brain cancer. Design, setting, participants: A retrospective, observational cohort study using the US National Cancer Institute Surveillance Epidemiology and End Results program. We identified adult patients with a primary diagnosis of malignant gliomas in 2000 to 2018 (N=72,252). The primary outcome of interest was death from cerebrovascular disease. Adjusted hazard ratio (aHR) and 95% confidence interval (CI) were calculated using cause-specific Cox regression model to determine associations with tumor characteristics: grades II-IV, tumor size and cancer treatment (surgery, radiotherapy, chemotherapy) associated with stroke mortality after adjustment for age, sex, race, marital status and calendar years. Results: In patients with glioma, increased risk for stroke mortality was observed in patients with higher grade (Grade III: aHR=1.19, 95% CI=0.88-1.61, p>0.05; Grade IV: aHR=1.94, 95% CI=1.39-2.71 compared to Grade II, p<0.001), and those with larger brain tumours (size=3-6 cm: aHR=1.93, 95%CI 1.31 -2.85, p<0.001, size>9cm: aHR=2.07, 95% CI=1.40-3.06, p<0.001 compared to size < 3cm). Having treatment was associated with decreased risk: surgery (yes VS no: aHR= 0.65; p<0.01), radiation (yes VS no: aHR= 0.66, p<0.01), chemotherapy (yes VS no: aHR=0.49, p<0.001). Conclusions Higher grade and tumor size are strongly associated with increased stroke mortality. This implicates tumor biology and/or the systemic tumor response which require further investigation in prospective studies to determine strategies to mitigate this risk.

The authors have declared no competing interest.

KJ and MTCP are funded by Cancer Research UK Brain Cancer Centre of Excellence Award (C157/A27589). Cancer Research UK did not play a role in study design, analysis, interpretation, or submission of this article.

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