Survival Outcomes in Human Papillomavirus-Associated Nonoropharyngeal Squamous Cell Carcinomas: A Systematic Review and Meta-analysis

Importance: Although the survival impact of human papillomavirus (HPV) in oropharyngeal squamous cell carcinoma (OPSCC) is well known, there has been conflicting and scarce evidence on the role of HPV in non-OPSCC. Objective: To undertake a Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant systematic review and meta-analysis of all published studies on the association between HPV status and survival outcomes in patients with non-OPSCC, analyzing each site separately. Data Sources: PubMed, CINAHL, and Embase were searched from 1946 to December 16, 2019, for English-language articles. Study Selection: Analysis comprised randomized clinical trials or observational studies that each included at least 10 patients with non-OPSCC in which the presence of HPV was analyzed, survival outcomes were reported, and a clinical follow-up of 1 year or more was performed. Studies excluded were those in which data on OPSCC and non-OPSCC were not distinguished between both cohorts and studies on patients with distant metastatic tumors at diagnosis. Final analysis included outcomes that were analyzed in at least 3 studies. Data Extraction and Synthesis: Two reviewers independently abstracted the data. Risk of bias was estimated with the Newcastle-Ottawa Scale. Meta-analysis was performed using the random-effects model. Main Outcomes and Measures: The primary end point was overall survival (OS); secondary end points were disease-specific survival (DSS) and disease-free survival (DFS). Results: Of the 3947 articles screened, a total of 22 observational and 2 randomized clinical trials were included in the analysis, representing 24854 patients. In oral cavity locations, OS was not significantly associated with HPV positivity (hazard ratio [HR], 1.16; 95% CI, 0.83-1.61; I²= 71%); however, HPV-positive tumors showed worse DFS (HR, 1.81; 95% CI, 1.12-2.91; I²= 47%). Laryngeal and hypopharyngeal HPV-positive tumors were associated with improved OS (HR, 0.71; 95% CI, 0.54-0.92; I²= 38% and HR, 0.60; 95% CI, 0.47-0.76; I²= 0%), respectively, whereas, in nasopharyngeal locations HPV was not associated with OS (HR, 0.82; 95% CI, 0.49-1.38; I²= 46%) or DSS (HR, 0.55; 95% CI, 0.22-1.42; I²= 65%). Conclusions and Relevance: In this meta-analysis of 24 studies, HPV was associated with improved OS in laryngeal and hypopharyngeal locations but not in the oral cavity and the nasopharynx. This information may be useful for future clinical studies of laryngeal and hypopharyngeal tumors and whether HPV status should be incorporated in prognostication of patients with these cancers..