Tobacco smoking and increased risk of death and progression for patients with p16-positive and p16-negative oropharyngeal cancer

Abstract

Purpose: Tobacco smoking is associated with oropharynx cancer survival, but to what extent cancer progression or death increases with increasing tobacco exposure is unknown.

Patients and methods: Patients with oropharynx cancer enrolled onto a phase III trial of radiotherapy from 1991 to 1997 (Radiation Therapy Oncology Group [RTOG] 9003) or of chemoradiotherapy from 2002 to 2005 (RTOG 0129) were evaluated for tumor human papillomavirus status by a surrogate, p16 immunohistochemistry, and for tobacco exposure by a standardized questionnaire. Associations between tobacco exposure and overall survival (OS) and progression-free survival (PFS) were estimated by Cox proportional hazards models.

Results: Prevalence of p16-positive cancer was 39.5% among patients in RTOG 9003 and 68.0% in RTOG 0129. Median pack-years of tobacco smoking were lower among p16-positive than p16-negative patients in both trials (RTOG 9003: 29 v 45.9 pack-years; P = .02; RTOG 0129: 10 v 40 pack-years; P < .001). After adjustment for p16 and other factors, risk of progression (PFS) or death (OS) increased by 1% per pack-year (for both, hazard ratio [HR], 1.01; 95% CI, 1.00 to 1.01; P = .002) or 2% per year of smoking (for both, HR, 1.02; 95% CI, 1.01 to 1.03; P < .001) in both trials. In RTOG 9003, risk of death doubled (HR, 2.19; 95% CI, 1.46 to 3.28) among those who smoked during radiotherapy after accounting for pack-years and other factors, and risk of second primary tumors increased by 1.5% per pack-year (HR, 1.015; 95% CI, 1.005 to 1.026).

Conclusion: Risk of oropharyngeal cancer progression and death increases directly as a function of tobacco exposure at diagnosis and during therapy and is independent of tumor p16 status and treatment.

Fig 1.

CONSORT diagram for Radiation Therapy Oncology Group (RTOG) 9003. AFX-C, accelerated fractionation with concomitant boost radiotherapy; AFX-S, accelerated fractionation with split radiotherapy; HFX, hyperfractionation radiotherapy; RT, radiotherapy; SFX, standard fractionation radiotherapy.

Fig 2.

CONSORT diagram for Radiation Therapy Oncology Group (RTOG) 0129. AFX-C, accelerated fractionation with concomitant boost radiotherapy; RT, radiotherapy; SFX, standard fractionation radiotherapy.

Fig 3.

Survival outcomes for patients with oropharyngeal carcinoma (OPC) with known p16 status in Radiation Therapy Oncology Group (RTOG) 9003. Kaplan-Meier curves for overall survival (OS) for OPC with known p16 status enrolled in RTOG 9003 (A) overall, (B) stratified by p16 status, (C) smoking exposure, and (D) smoking during radiotherapy. (A) Median follow-up among surviving patients was 9.3 years (range, 0.3 to 13.2 years) and the 5-year OS was 31.0% (95% CI, 24.3% to 37.7%). (B) Patients with p16-positive OPC had significantly better OS when compared with patients with human papillomavirus –negative OPC (log-rank test P < .001). An absolute benefit in OS of 29.5% (95% CI, 15.8% to 43.2%) was observed at 5 years. (C) Patients with ≤ 10 pack-years had significantly better OS when compared with patients with more than 10 pack-years (log-rank test P < .001). An absolute benefit in OS of 30.0% (95% CI, 6.9% to 53.1%) was observed at 5 years. (D) OS stratified by smoking during radiotherapy. Patients who did not smoke during radiotherapy had significantly better OS compared with patients who did smoke during radiotherapy (HR, 2.48; 95% CI, 1.70 to 3.60; log-rank test P < .001). An absolute benefit in OS of 24.6% (95% CI, 5.9% to 43.3%) was observed at 5 years. Gold lines indicate 95% CIs for the survival estimates. HR, hazard ratio.

Fig 4.

Survival outcomes for patients with oropharyngeal carcinoma with known p16 status in Radiation Therapy Oncology Group (RTOG) 0129. Kaplan-Meier curves for overall survival (OS) for oropharyngeal carcinoma with known p16 status enrolled onto RTOG 0129 (A) overall and (B) stratified by smoking exposure. (A) Median follow-up among surviving patients was 4.9 years (range, 1.6 to 6.4 years), and the 5-year OS was 66.8% (95% CI, 61.4% to 72.1%). (B) Patients with ≤ 10 pack-years had significantly better OS when compared with patients with more than 10 pack-years (log-rank test P < .001). An absolute benefit in OS of 25.9% (95% CI, 10.3% to 41.5%) was observed at 5 years. HR, hazard ratio.