Risk Stratification For Relapse In Human Papillomavirus-Unrelated Oropharyngeal Carcinoma Treated With Definitive Radiation Therapy With Or Without Chemotherapy

To determine the profile for risk of disease relapse following definitive radiation therapy/chemotherapy (RT/CRT) in human papillomavirus-unrelated (HPV[-]) oropharyngeal cancer (OPC) patients (pts). All newly diagnosed p16-confirmed HPV(-) OPC pts treated with RT/CRT from 2000 to 2012 were included. Overall survival (OS), relapse-free survival (RFS), locoregional control (LRC), distant control (DC), and grade 3–4 late toxicity (LT) were estimated using Kaplan-Meier or competing risk method. Multivariable analysis (MVA) identified predictors for RFS. Recursive partitioning analysis (RPA) derived low and high RFS risk groups. A total of 314 HPV(–) (stage I, II, III, and IV: 13, 39, 51, and 211) pts were identified, including 231 (74%) males with median age of 65 years (range, 33–89 years). Primary tumors originated from tonsil or tongue base in 230 (73%) cases. Two hundred and ten (67%) cases were treated with RT alone, 87 (28%) with concurrent cisplatin (100 mg/m2 x 3 on days 1, 22, and 43), and 17 (5%) with cetuximab. Median follow-up was 3.9 years. Relapse occurred in 112 cases (57 locoregional only, 33 distant only, 22 locoregional-distant). At 5 years, OS, RFS, LRC, DC, and LT were 45%, 64%, 74%, 83%, and 25%, respectively. MVA identified the N2b–3 category as a predictor for disease relapse (hazard ratio [HR] 2.6 95% CI: 1.7–4.1, P < .01); age (HR = 1.03, P = .06), T3–4 (HR = 1.4, P = .09), and RT alone (HR = 1.4, P = .13) were marginally predictive; smoking pack-years was nonpredictive (P = .94). RPA stratified the entire cohort into low (T1–2N0–2a, n = 77) and high (T3–4 or N2b–3, n = 237) relapse risk groups with 5-year RFS of 86% and 56%, respectively. In the low-risk group, 74 of 77 (96%) pts received RT alone, and their 5-year RFS was 86% (95% CI: 74–92). For the high-risk group, the RT alone (n = 136) subgroup had a lower RFS compared to the CRT (n = 84) or RT + cetuximab (n = 17) subgroups (51% vs 63%, P = .03). Locoregional failure is the main form of treatment failure for the HPV(–) OPC population. A low-relapse-risk subgroup, defined as T1–T2N0–N2a, may be appropriately treated with RT alone. High-relapse-risk HPV(-) OPC pts have a poor prognosis, and while intensified treatment schedules (e.g., high dose cisplatin) appear to suggest benefit in this subgroup, further research on novel treatment strategies is warranted.