Risk Stratification for Relapse in Human Papillomavirus–Unrelated Oropharyngeal Carcinoma Treated With Definitive Radiation Therapy With or Without Chemotherapy

Abstract

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). Materials/Methods: 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 3e4 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. Results: A total of 314 HPV(e) (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, 33e89 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/m 2 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 N2be3 category as a predictor for disease relapse (hazard ratio [HR] 2.6 95% CI: 1.7e4.1, P < .01); age (HR Z 1.03, P Z .06), T3e4 (HR Z 1.4, P Z .09), and RT alone (HR Z 1.4, P Z .13) were marginally predictive; smoking pack-years was nonpredictive (P Z .94). RPA stratified the entire cohort into low (T1e2N0e2a, n Z 77) and high (T3e4 or N2be3, n Z 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: 74e92). For the highrisk group, the RT alone (n Z 136) subgroup had a lower RFS compared to the CRT (n Z 84) or RT + cetuximab (n Z 17) subgroups (51% vs 63%, P Z .03). Conclusion: Locoregional failure is the main form of treatment failure for the HPV(e) OPC population. A low-relapse-risk subgroup, defined as T1eT2N0eN2a, may be appropriately treated with RT alone. Highrelapse-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.