Quantifying the Interplay Between Smoking and Human Papillomavirus in Risk Stratification of Patients with Oropharyngeal Cancer Undergoing Radiotherapy

Abstract

The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. (Gillison M, et al. J Natl Cancer Inst. 2008) Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-viral mediated (HPV-) OPSCC, the improvement is not uniform. (Vadwa N, et al. Int J Radiat Oncol Biol Phys. 2019) We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. We sought to integrate smoking into current staging system after statistically identifying a threshold value for smoking pack-years (PY) that is associated with worse survival. We also aimed at modeling the differential competing risks of treatment failure and death in HPV+ heavy and non-heavy smokers. We performed a retrospective review of patients with OPSCC treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to statistically define tobacco exposure associated with survival (p<0.05). We identified 611 OPSCC patients with concordant p16 and HPV testing results. Eighty-nine percent of patients were HPV+; 50% of whom were non-smokers compared to only 20% of HPV- patients. Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p=0.002, p=0.003 respectively). RPA identified 30 PY as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ >30 PY patients didn’t differ significantly from HPV- group (p= 0.72, p= 0.27, respectively). HPV+ >30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p= 0.03, 76% vs 88.3%; p= 0.07, and 52.3% vs 74%; p= 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. A competing risk analysis of modes of failure and causes of death showed a higher risk of loco-regional failure and non-cancer deaths among HPV+ >30 PY patients compared to HPV+ ≤30 PY patients. Tobacco exposure beyond 30 PY can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV+OPSCC smokers should be avoided.