Prognostic Impact of HPV-Associated p16 Expression and Smoking Status on Outcomes Following Radiation Therapy for Oropharyngeal Cancer: the MARCH-HPV Project

Abstract

To evaluate the prognostic and predictive impact of HPV-associated p16-expression and to assess the combined prognostic impact of p16 and smoking on altered fractionated radiation therapy (RT) for oropharyngeal cancer (OPC) within the frames of the update of the Meta-Analysis of Radiotherapy in Carcinomas of Head and neck (MARCH). Patients with OPC, known tumor p16 status, and smoking history were identified from the MARCH update, resulting in a dataset of 815 patients from four randomized trials (RTOG9003, DAHANCA6&7, RTOG0129, ARTSCAN). HPV status was determined according to p16 immunohistochemistry. Analysis was performed using a Cox model stratified by trial and adjusted on gender, age, T stage, N stage, type of radiation therapy fractionation, p16 status, and smoking. Primary endpoint was progression-free survival (PFS). In total, 465 patients (57%) of the patients had p16-positive tumors and 350 (43%) p16-negative. Patients with p16-positive tumors were significantly younger (mean: 56 vs 59 years, P = .0002), in better performance (PS = 0: 74% vs 50%, P < .0001), had smaller tumors (T1-2: 46% vs 33%, P < .0001) and more advanced N stage (N+: 87% vs 76%, P <. 0001) compared with the p16-negative subgroup. p16-positive patients had significantly better PFS (HR = 0.42 [95% CI 0.34-0.51], 28.9% absolute increase at 10 years) and OS (HR = 0.40 [0.32-0.49], 32.1% absolute increase at 10 years) than patients with p16-negative tumors. No interaction between p16-status and fractionation schedule was detected. Smoking negatively impacted outcome; in the p16-positive subgroup, never smokers had significantly better PFS than former/current smokers (HR = 0.49 [0.33-0.75], 24.2% survival benefit at 10 years). The strong prognostic impact of p16-status was confirmed and especially p16-positive never smoking patients have superior outcome after RT.