Abstract Body: Introduction
Previous studies have observed an increased risk of stroke in head and neck cancer (HNC) survivors. However, whether this risk is amplified with exposure to various treatment modalities including radiotherapy is less certain, as are any potential mechanisms by which this increase in risk is mediated. This study aims to investigate the risk of stroke in patients with HNC and whether cancer type and treatment modalities have varying effects.

Methods
This PRISMA-adherent systematic review involved a systematic search of PubMed, SCOPUS and Embase for studies reporting stroke incidence in patients with HNC and without prior strokes since inception to April 25,2024. The study protocol was registered prospectively on PROSPERO. The hazard ratios extracted from the studies were pooled for meta-analyses. Random effects meta-analyses and meta-regressions were used for primary analysis. Subgroup analyses and meta-regression were performed to determine if key categorical and hierarchical variables influenced the results. Risk of bias was performed using the Newcastle Ottawa Scale.

Results
22 studies [EL1] with 5,093,445 patients were included. The meta-analyses of nine studies showed that the risk of stroke was increased in patients with HNC compared to healthy controls (HR=1.45; 95%CI: 1.27-1.65, I2: 20%). Subgroup analyses demonstrated that the risk of stroke was significantly increased in HNC patients treated with radiotherapy alone compared to those treated with surgery alone (HR=1.66; 95%CI: 1.35-2.03, I2: 0%). Subgroup analyses also revealed an increased risk of stroke in HNC patients who had undergone any radiotherapy compared to HNC patients who had not undergone radiotherapy in the past (HR=1.47; 95%CI: 1.29-1.68, I2: 60%).
Additionally, HNC patients who had undergone definitive chemoradiotherapy had increased risk of stroke compared to HNC patients who had undergone definitive surgery with or without adjuvant chemoradiotherapy (HR=1.28; 95%CI: 1.09-1.49, I2: 86%).

Conclusion
We report an increased risk of stroke in HNC patients, which is consistently raised when compared with the general population. This risk is more significant in patients who had undergone radiotherapy. Future research should aim to understand the pathogenesis of stroke in HNC patients and the effect of different treatment modalities on stroke risk to develop effective preventive strategies, thereby guiding the management for patients with HNC.