Therapeutic options for human papillomavirus-positive tonsil and base of tongue cancer.

The incidences of human papillomavirus-positive (HPV+) tonsillar and base tongue squamous cell carcinomas (TSCC and BOTSCC) have increased in recent decades. Notably, HPV+ TSCC and BOTSCC have a significantly better prognosis than their HPV-negative counterparts when treated with current surgical options, radiotherapy, or intensified chemoradiotherapy. However, a cure is not achieved in 20% of patients with HPV+ TSCC/BOTSCC. Meanwhile, cured patients often present with severe chronic side effects. This necessitates novel tailored alternatives, such as targeted therapy, immune checkpoint inhibitors (ICIs), and treatment de-escalation, together with better follow-up. Current precision medicine therefore focuses on detecting predictive and driver cancer genes to better stratify patient treatment, provide those with poor prognostic markers targeted therapy, and select those with favorable markers for de-escalated therapy. Moreover, detecting cell-free HPV DNA (cfHPV DNA) in plasma before and after treatment has been attempted to improve follow-up. In this context, this perspective discusses the significance of optimally defining HPV+ status, which requires HPV DNA and p16INKa overexpression, using prognostic markers, such as high CD8+ T-cell counts and HPV E2 mRNA expression, tumor size, and following cfHPV DNA for patient selection for specific therapies. Clinical trials with ICI with/without chemotherapy, targeted therapy with specific inhibitors-such as phosphoinositide 3-kinase and fibroblast growth factor receptor inhibitors-or immune therapy with various HPV-based vaccines for treating recurrences have yielded promising results.