Surgery for the Treatment of HPV-Negative Oropharyngeal Squamous Cell Carcinoma-A Systematic Review and Meta-Analysis

Human papillomavirus (HPV) negative oropharyngeal squamous cell carcinoma (OPSCC) is associated with worse survival when compared to HPV-positive OPSCC. Primary surgery is one option to intensify therapy in this high-risk group of patients. Unfortunately, the only randomized trial to explore this approach (RTOG 1221) failed to accrue and the role of primary surgery in the treatment of HPV-negative OPSCC remains unanswered.

A systematic review and meta-analysis were performed to examine the outcomes of surgery in the treatment of HPV-negative OPSCC. We used the PRISMA statement for reporting and queried Pubmed, Web of Science and the Cochrane databases for studies examining the use of primary surgery in the treatment of HPV-negative OPSCC. Excluded from analysis were reviews, commentaries, case series with fewer than 10 patients, and studies that included HPV-negative head and neck cancers of mixed sites. Our primary outcomes were 2-year and 5-year overall survival (OS) and disease-free survival (DFS). OS and DFS were pooled using meta-analysis of proportions.

A total of 15 studies were included in qualitative synthesis and 11 were included in the meta-analysis. There were 923 patients total included. Eight studies including 483 patients reported staging of HPV negative disease, of which 81.6% had T1/T2 tumors and 41.4% had N0 nodal disease. The average rate of positive margins was 12.6%. The average rate of patients who underwent risk-stratified adjuvant RT was 30.7% and CRT was 29.5%. The average follow-up was 32.7 months (SD = 12.47 months). Only two studies reported survival outcomes for HPV-negative disease based on overall staging: 5-year OS was improved for stage III versus stage IV and early versus late stage disease. The pooled 2- and 5-year OS were 84% (95% CI 77%-91%, I ² = 52.4%; 5 studies) and 72% (95% CI 46%-92%, I ² = 95.5%; 4 studies), respectively. The pooled 2- and 5-year DFS for the entire population were 77% (95% CI 66%-86%, I ² = 55%; 6 studies) and 59% (95% CI 50%-69%, I ² = 0%; 3 studies). Of the subgroup undergoing TOS alone, the pooled 2- and 5-year OS were 87% (95% CI 79%-93%, I ² = 46.8%; 4 studies) and 82% (95% CI 69%-92%, I ² = 74.2%; 3 studies). The pooled 2- and 5-year DFS for the subgroup of patients undergoing TOS alone were 78% (95% CI 63%-90%, I ² = 56%; 4 studies) and 59% (95% CI 47%-71%, I ² = undetermined; 2 studies).

The two- and five-year OS for patients with HPV-negative OPSCC treated with any surgical approach and pathology-directed adjuvant therapy is 84% and 72%, respectively. The two- and five-year OS for HPV-negative OPCSCC treated with transoral surgery and pathology-directed adjuvant therapy is 87% and 82%, respectively.