Tobacco exposure as a major modifier of oncologic outcomes in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma

Abstract

Background: 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. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients.

Methods: We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing 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 define tobacco exposure associated with survival (p < 0.05).

Results: Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (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- patients (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.

Conclusions: Tobacco exposure 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.

Keywords: Human papillomavirus; Oropharyngeal carcinoma; Radiotherapy; Tobacco.

Fig. 1

Heavy tobacco exposure decreases overall and disease free survival for patients with HPV + OPC. Kaplan-Meier curves of overall survival ‘OS’ (a) and disease-free survival ‘DFS’ (b) for the entire cohort stratified by human papillomavirus (HPV) status; and OS (c) and DFS (d) for the entire cohort stratified by HPV status and tobacco exposure. Kaplan-Meier survival curves confidence intervals are represented by shades of the corresponding group color

Fig. 2

Heavy tobacco exposure decreases HPV + OPC overall survival across AJCC stages. Kaplan-Meier overall survival (OS) curves for HPV + OPSCC AJCC (8th edition) stages I-III. Solid lines denote survival curves for each individual stage in the absence of heavy tobacco exposure; dotted lines denote survival for each individual stage in the presence of heavy tobacco exposure

Fig. 3

Competing risks models for causes of death in subpopulations stratified by human papillomavirus (HPV) and tobacco exposure: (a) HPV- & pack-years (PY) ≤30; (b) HPV- & PY > 30; (c) HPV+ & PY ≤30; and (d) HPV+ & PY > 30. Lines are curves fitting all cause death events (black), cancer-specific death events (red) and non-cancer death events (blue)

Fig. 4

Competing risks models for causes of relapse in subpopulations stratified by human papillomavirus (HPV) and tobacco exposure: (a) HPV- & pack-years (PY) ≤30; (b) HPV- & PY > 30; (c) HPV+ & PY ≤30; and (d) HPV+ & PY > 30. Lines are curves fitting all cause relapse events (black), loco-regional relapse events (green) and distant metastasis events (red)