Radiation Therapy Dose-Volume Correlates Predict Videofluoroscopy-Detected Dysphagia Per DIGEST after IMRT for Oropharyngeal Carcinoma: Results of a Prospective Registry

Abstract

Our primary aim was to prospectively validate retrospectively studied dosimetric parameters predictive of radiation-associated dysphagia (RAD) after intensity modulated radiation therapy (IMRT) for oropharyngeal cancer (OPC). The secondary aim was to validate grade ≥2 dichotomization of a published videofluoroscopic dysphagia grade (Dynamic Imaging Grade for Swallowing Toxicity, DIGEST) as a radiation dose-sensitive cutoff for RAD. Ninety-seven patients with stage I-IV OPC underwent videofluoroscopy pre- and 3-6 months after IMRT per an IRB-approved prospective registry protocol. Dysphagia severity was graded per DIGEST criteria (dichotomized grade≥2 as moderate/severe RAD). Multivariate regression analysis identified clinical and dosimetric predictors of RAD. Dose-volume histogram (DVH) of superior/ middle/inferior pharyngeal constrictors (S/M/IPC), intrinsic tongue muscle (ITM), geniohyoid muscle (GHM), genioglossus muscle (GGM), mylohyoid muscle (MHM), anterior digastric muscle (ADM), and glottic, supraglottic areas were calculated. Recursive partitioning analysis (RPA) and Bayesian Information Criteria (BIC) were used to identify dose-volume effects associated with moderate/severe RAD. The median age was 61 (range: 35–86) years and 47% were current/former smokers. The majority of tumors (47%) originated from the base of the tongue; 27% and 48% of the patients presented with advanced T (i.e., T3-4) and N2 disease, respectively. HPV/p16 status was positive in 95% of tumors. Concurrent chemotherapy (CRT) was delivered in 23%. Median RT dose was 69.96 (range: 50-70) Gy. At 3-6 months after IMRT, 70% had MBS-evident RAD (DIGEST grade ≥1) and 31% had moderate/severe dysphagia (i.e. DIGEST grade ≥2). Intensified treatment modalities (induction+CRT), advanced T stage, in addition to higher RT mean dose of GHM and GGM (p=0.004 and 0.0089, respectively) were significantly associated with moderate/severe RAD in multivariate analysis. RPA identified GHM V61 ≥ 18.57% (LogWorth 7.3, p<0.0001), SPC V55 ≥ 97.46% (LogWorth 3.8, p=0.0001) and supraglottic V23 ≥92.54% (LogWorth 2.8, p=0.001) as dose-volume thresholds for moderate/severe RAD (AUC 0.9 and 0.7 across training and validation sets, respectively). V61 ≥ 18.57% of GHM had the optimal model performance for prediction of DIGEST grade ≥2 in the subsequent multivariate analysis. The findings from this prospective longitudinal study validate prior observations that dose to submental musculature predicts increased burden of dysphagia after oropharyngeal IMRT. Findings also support dichotomization of DIGEST grade ≥2 as a dose-dependent split for use in endpoint reporting or predictive dose-response analysis of videofluoroscopy results.