Abstract
IMPORTANCE: Hypoglossal (CN XII) neuropathy is a debilitating latent toxic effect in survivors of oropharyngeal cancer (OPC), which is often underdiagnosed due to its delayed onset and subtle early signs and symptoms. There is no established patient-reported outcome tool to aid early detection. OBJECTIVE: To evaluate selected MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) symptom items for predicting CN XII neuropathy risk and derive a composite symptom-based nerve score (MDASI-HN-NERVE) with an optimal threshold for early risk stratification. DESIGN, SETTING, AND PARTICIPANTS: This retrospective analysis used data from a prospective cohort study of 1297 patients with OPC who were treated with curative intent at MD Anderson Cancer Center between March 2015 and December 2023. Eligible patients completed symptom assessments at baseline and regular follow-up intervals for up to 5 years. CN XII neuropathy status was classified based on documented clinical signs through a structured health record review. Data were analyzed in June 2025. MAIN OUTCOMES AND MEASURES: Symptom trajectories of 6 MDASI-HN items (chewing/swallowing, choking, speech/voice, mucus, fatigue, and dry mouth) were analyzed using spaghetti plots and piecewise linear mixed-effects models. A MDASI-HN-NERVE score was derived from these items to quantify CN XII neuropathy-associated symptom burden. Time-dependent Cox models and Kaplan-Meier analyses were used to assess the risk of developing CN XII neuropathy, and optimal cut-off values were identified. RESULTS: Of 1297 participants, 141 (10.9%) were female and 1156 (89.1%) were male; the mean (SD) age was 65.9 (9.2) years. Higher MDASI-HN-NERVE scores were associated with an increased risk of CN XII neuropathy (hazard ratio, 1.35; 95% CI, 1.18-1.54). An optimal threshold of 3.4 at baseline and 3.5 at 3 to 6 months posttreatment distinguished high-risk vs low-risk groups with significantly different CN XII neuropathy-free survival. Single-item MDASI speech/voice scores at baseline and 3 to 6 months also discriminated latent CN XII neuropathy risk. CONCLUSIONS AND RELEVANCE: The results of this cohort study suggest that MDASI-HN speech/voice symptoms and the MDASI-HN-NERVE score may provide a practical, patient-centered approach to aid early detection and monitoring of CN XII neuropathy risk. These findings provide early evidence to support the clinical use of MDASI-HN-based surveillance in oropharyngeal cancer survivorship care.