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Among patients with index oropharyngeal cancer, second primary malignancies (SPMs) may be less common in cases of human papillomavirus (HPV)-associated tumors than HPV-negative tumors. Further modification of these SPM risks by smoking has not been reported.SPM outcomes of 356 patients with incident oropharyngeal cancer were analyzed using Cox proportional hazards and Kaplan–Meier models. SPM risk and SPM-free survival were compared in HPV-seronegative patients, HPV-seropositive never smokers, and HPV-seropositive ever smokers.HPV-seropositive patients had a lower 5-year SPM rate than HPV-seronegative patients (5.6% vs 14.6%;p= .051). Compared to HPV-seronegative patients, HPV-seropositive never smokers had a 73% reduced SPM risk, and HPV-seropositive ever smokers had a 27% reduced SPM risk (trendp= .028). Although HPV-seronegative patients had SPMs in traditional locations, 70% of SPMs among HPV-seropositive patients were outside typical tobacco-related sites.HPV serologic status and smoking may stratify patients with index oropharyngeal cancers in terms of risk and location of SPMs.