Human papillomavirus in oropharyngeal cancer in Canada: analysis of 5 comprehensive cancer centres using multiple imputation

Abstract

Background: The incidence of oropharyngeal cancer has risen over the past 2 decades. This rise has been attributed to human papillomavirus (HPV), but information on temporal trends in incidence of HPV-associated cancers across Canada is limited.

Methods: We collected social, clinical and demographic characteristics and p16 protein status (p16-positive or p16-negative, using this immunohistochemistry variable as a surrogate marker of HPV status) for 3643 patients with oropharyngeal cancer diagnosed between 2000 and 2012 at comprehensive cancer centres in British Columbia (6 centres), Edmonton, Calgary, Toronto and Halifax. We used receiver operating characteristic curves and multiple imputation to estimate the p16 status for missing values. We chose a best-imputation probability cut point on the basis of accuracy in samples with known p16 status and through an independent relation between p16 status and overall survival. We used logistic and Cox proportional hazard regression.

Results: We found no temporal changes in p16-positive status initially, but there was significant selection bias, with p16 testing significantly more likely to be performed in males, lifetime never-smokers, patients with tonsillar or base-of-tongue tumours and those with nodal involvement (p < 0.05 for each variable). We used the following variables associated with p16-positive status for multiple imputation: male sex, tonsillar or base-of-tongue tumours, smaller tumours, nodal involvement, less smoking and lower alcohol consumption (p < 0.05 for each variable). Using sensitivity analyses, we showed that different imputation probability cut points for p16-positive status each identified a rise from 2000 to 2012, with the best-probability cut point identifying an increase from 47.3% in 2000 to 73.7% in 2012 (p < 0.001).

Interpretation: Across multiple centres in Canada, there was a steady rise in the proportion of oropharyngeal cancers attributable to HPV from 2000 to 2012.

Figure 1:

Receiver operating characteristic curves for prediction of p16 status using clinical and demographic variables. The area under the curve is represented by the C statistic (with 95% confidence interval). The base model included age at diagnosis, sex, anatomic cancer subsite, tumour stage and nodal stage. Social habits included smoking status (current, former, never), smoking pack-years and alcohol consumption (none/light, moderate/heavy). Note: BMI = body mass index, CCI = Charlson comorbidity index. *Model also includes province.

Figure 2:

Overall survival, by p16 status, in Toronto, Alberta (Edmonton and Calgary combined) and Halifax.

Figure 3:

Overall survival by p16 status after multiple imputation. (A) For analysis of the entire cohort (n = 3643), the imputed population (n = 2361) was compared with the population having known p16 status (n = 1282). For the imputed population, the probability of p16-positive status, or Pr(p16+), was categorized into quintiles (Q5 = most likely to be p16-positive, Q1 = least likely to be p16-positive) and compared with patients with known p16 status. (B) The analysis was restricted to the validation subset (patients with known p16 status only; n = 1282). Overall survival is presented by Pr(p16+) dichotomized with 85% sensitivity, where Pr(p16+) = 68.7%, and compared with the actual (i.e., tested) p16 status.

Figure 4:

Change in p16-associated oropharyngeal cancer, following multiple imputation (n = 3643). (A) Probability and proportion of patients deemed positive for human papillomavirus (HPV), for all of Canada. Probability of p16-positive status, or Pr(p16+), was retained as a continuous probability or dichotomized with 85% sensitivity. The Pr(p16+) that resulted in 85% sensitivity was 68.7%. (B) Probability of patients deemed HPV-positive, as mean continuous probability Pr(p16+) over time, stratified by cancer centre. (C) Proportion of patients deemed HPV-positive using a cut point with 85% sensitivity, stratified by cancer centre. (D) Probability and proportion of patients deemed HPV-positive, for all of Canada. The Pr(p16+) over time is shown with various cut points, and the data for “continuous probability” from Figure 4A superimposed for comparison. The optimal cut point resulted in a sensitivity of 71% and a specificity of 81%.