Human papillomavirus and survival of patients with oropharyngeal cancer

Abstract

Background: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown.

Methods: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer.

Results: The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage.

Conclusions: Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)

Figure 1. Kaplan–Meier Estimates of Survival among the Study Patients with Oropharyngeal Cancer, According to Tumor HPV Status or p16-Expression Status

Data on overall survival and progression-free survival are shown according to stratification on the basis of tumor HPV status (Panels A and B, respectively) or p16-expression status (Panels C and D, respectively). The Kaplan–Meier curves are shown in black, and the associated 95% confidence intervals in gray. Patients with HPV-positive tumors had significantly better overall survival and progression-free survival than did patients with HPV-negative tumors (P<0.001 for both comparisons by the two-sided log-rank test). The 3-year rates of overall survival were 82.4% (95% CI, 77.2 to 87.6) in the HPV-positive subgroup and 57.1% (95% CI, 48.1 to 66.1) in the HPV-negative subgroup (Panel A), and the 3-year rates of progression-free survival were 73.7% (95% CI, 67.7 to 79.8) and 43.4% (95% CI, 34.4 to 52.4), respectively (Panel B). The 3-year absolute benefit of HPV-positive status for overall survival was 25 percentage points (95% CI, 11 to 40), and the absolute benefit for progression-free survival was 30 percentage points (95% CI, 15 to 45). The results were similar with stratification according to p16-expression status. The 3-year rates of overall survival were 83.6% (95% CI, 78.7 to 88.6) in the subgroup that was positive for p16 expression and 51.3% (95% CI, 41.5 to 61.0) in the subgroup that was negative for p16 expression (P<0.001) (Panel C), and the 3-year rates of progression-free survival were 74.4% (95% CI, 68.5 to 80.2) and 38.4% (95% CI, 28.9 to 47.9), respectively (P<0.001) (Panel D).

Figure 2. Classification of the Study Patients into Risk-of-Death Categories and Kaplan–Meier Estimates of Overall Survival According to Those Categories

Recursive-partitioning analysis was used to identify prognostic factors with the most influential predictive significance in a proportional-hazards model of overall survival and to classify patients into categories of low, intermediate, or high risk of death. The prognostic factors in the analysis were age, tumor stage, nodal stage, race, smoking status, HPV status, anemia status, performance status, treatment assignment, and sex. Panel A shows the resulting classifications. Panel B shows data for overall survival in the classified patients. The Kaplan–Meier curves are shown in black, and the associated 95% confidence intervals in gray. The 3-year rates of overall survival were 93.0% (95% CI, 88.3 to 97.7) in the low-risk group, 70.8% (95% CI, 60.7 to 80.8) in the intermediate-risk group, and 46.2% (95% CI, 34.7 to 57.7) in the high-risk group. Hazard ratios for death among the 266 patients for whom the risk classification could be made on the basis of the recorded data and among all 433 patients with oropharyngeal cancer (after missing data on HPV status and number of pack-years were estimated with the use of statistical imputation) were as follows: 3.54 (95% CI, 1.91 to 6.57) and 2.67 (95% CI, 1.54 to 4.62), respectively, in the intermediate-risk group versus the low-risk group; and 7.16 (95% CI, 3.97 to 12.93) and 5.23 (95% CI, 3.14 to 8.73), respectively, in the high-risk group versus the low-risk group.