Long-Term Risk of Carotid Stenosis and Cerebrovascular Disease after Radiation Therapy for Head and Neck Cancer

Abstract

<h3>Purpose/Objective(s)</h3> The incidence of asymptomatic carotid artery stenosis (CAS) in the general population is ∼5%. CAS is a known toxicity of radiation therapy (RT) for head and neck cancer (HNC). CAS screening is not routinely performed after RT despite the increased risk of cerebrovascular disease (CVD) in this population. Here we report long-term incidence and associated risk factors for CAS and CVD after RT for HNC. <h3>Materials/Methods</h3> Records were retrospectively identified for all patients undergoing carotid ultrasound (U/S) screening following RT for HNC at a single institution between November 2000 and October 2020. Exclusion criteria included CAS or CVD prior to RT. Carotid U/S screening was obtained within 24 months of RT completion, then every three years in the absence of CAS or annually following CAS diagnosis. Asymptomatic CAS was defined as radiographic luminal narrowing ≥50%; CVD was defined as stroke or transient ischemic attack, and composite CAS was defined as asymptomatic CAS and/or CVD. Cumulative incidence estimates (CIE) of asymptomatic CAS, CVD, and composite CAS were estimated. Univariate and multivariable (MVA) Cox proportional hazards regression was used to study potential associations between clinical parameters and the CVD and composite CAS outcomes. <h3>Results</h3> Among 628 patients, median follow-up was 4.8 years (IQR 2.6 - 8.3 yr) with 97 patients followed beyond 10 yr. Median age was 61 yo. 56% of patients had a history of smoking. 61% had an oropharyngeal primary tumor (64% p16+). Squamous cell carcinoma was the most common histology (94%). 57% patients completed 70 Gy over 35 fractions, 69% received concurrent chemotherapy, and 28% were treated post-operatively. Asymptomatic CAS was identified in 111 (18%) with 50 (45%) prescribed CAS-related medication and 24 (22%) undergoing carotid endarterectomy or stenting. 5, 10, and 12-year CIE for asymptomatic CAS were 19.8%, 37.1%, and 50.2%, respectively. MVA showed that a history of peripheral arterial disease ([PAD]; HR 4.5, 95% CI 1.7 - 11.8) and myocardial infarction ([MI]; HR 3.3; 95% CI 1.1 - 9.8) were predictive of time to asymptomatic CAS. CVD events were observed in 45 (7.2%) patients, of whom 27 (60%) were found to have asymptomatic CAS. 5, 10, and 12-year CIE for CVD were 5.4%, 12.4%, and 21.7%, respectively. On MVA, male sex (HR 3.3, 95% CI 1.1 - 10) and type 2 diabetes mellitus ([DM2]; HR 2.3, 95% CI 1.2 - 4.6) were significantly associated with CVD. 5, 10, and 12-year CIE for composite CAS were 17.5%, 32.3%, and 43.6%, respectively. On MVA, male sex (HR 2.0, 95% CI 1.1 – 3.3), PAD (HR 3.1, 95% CI 1.2 - 7.8), and MI (HR 2.5, 95% CI 1.1 - 5.9) were significantly associated with composite CAS. <h3>Conclusion</h3> Long-term follow up shows a steady increase in the risk of asymptomatic CAS and CVD following RT for HNC. It is independently associated with sex, PAD, MI, and DM2. Ongoing analyses include dosimetric analysis of CAS and CVD per carotid artery and cost-effectiveness of carotid ultrasound screening.