Association between up-front surgery and risk of stroke in U.S. veterans with oropharyngeal squamous cell carcinoma.
Authors: Sun Lova , Brody Robert , Candelieri Danielle , Anglin-Foote Tori , Lynch Julie Ann , Hausler Ryan , Maxwell Kara Noelle , Damrauer Scott , Ojerholm Eric , Lukens John Nicholas , Cohen Roger B. , Getz Kelly D. , Hubbard Rebecca A. , Ky Bonnie 
Published: June 2022

6057

Background: Cardiovascular disease and stroke are important causes of long-term morbidity and mortality in patients with oropharyngeal squamous cell carcinoma (OPSCC). Cancer treatments including radiotherapy to the neck and chemotherapy have been associated with increased risk of stroke. In the era of treatment de-intensification for OPSCC, up-front surgical treatment has been proposed as one strategy that allows for de-escalation or avoidance of (chemo)radiotherapy. We sought to quantify the cumulative incidence of stroke in patients treated for non-metastatic OPSCC, and then evaluate whether patients receiving up-front surgery for OPSCC have decreased risk of stroke compared to those undergoing non-surgical treatment. Methods: We identified a cohort of 10,436 United States veterans diagnosed with non-metastatic OPSCC from 2000-2020, of whom 2,717 received up-front surgery (with or without perioperative radiotherapy or chemoradiotherapy) and 7,719 received non-surgical therapy (definitive radiotherapy or chemoradiotherapy). We estimated the cumulative incidence of stroke in this population, accounting for death as a competing risk. To assess the association between up-front surgery and risk of stroke, we generated a propensity score for the probability of receiving surgical treatment and used inverse probability weighting to construct pseudo-populations balanced on all potential confounders. Cox regression models of the inverse probability weighted population were used to estimate the cause-specific hazard ratio of stroke associated with surgical vs non-surgical treatment. Results: The 10-year cumulative incidence of stroke was 12.5% (95% CI 11.8-13.23) and death was 57.3% (95% CI 56.2-58.4). Up-front surgical patients who underwent perioperative (chemo)radiotherapy had shorter radiation and chemotherapy courses compared to non-surgical patients, suggestive of lower treatment intensity. Propensity score generation and inverse probability weighting yielded good overlap and covariate balance between surgical and non-surgical treatment groups. The inverse probability weighted cause-specific hazard ratio of stroke associated with up-front surgical treatment was 0.77 (95% CI 0.66-0.91, p = 0.002). This association was consistent across subgroups defined by age ( > /≤65 years) and baseline cardiovascular risk factors (hypertension, hyperlipidemia, diabetes). Conclusions: In over 10,000 US veterans with OPSCC, cumulative incidence of stroke was 12.5% at 10 years. Up-front surgical treatment was associated with a 23% reduced risk of stroke compared to definitive (chemo)radiotherapy. These findings present an important additional risk-benefit consideration to factor into treatment decisions and patient counseling, and should motivate future studies to examine cardiovascular events in this high-risk population.