State of the Art of Systemic Therapy in HPV-Positive Oropharyngeal Squamous Cell Carcinoma: A Scoping Review

TL;DR

This review summarizes current and emerging systemic treatments for HPV-positive oropharyngeal cancer, focusing on reducing treatment intensity and using immunotherapy.

Contribution

The paper provides a comprehensive overview of evolving systemic therapy strategies and highlights the potential of immunotherapy in HPV-positive oropharyngeal cancer.

Findings

Cisplatin-based chemoradiation remains the standard for locally advanced HPV-positive OPSCC.

PD-1 inhibitors show durable responses in advanced disease and are being tested in earlier stages.

De-escalation strategies may be feasible for low-risk patients but replacing cisplatin with cetuximab reduces survival.

Abstract

Objectives: To synthesize current evidence and emerging data on systemic treatment strategies for early-stage and locally advanced human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC), with emphasis on treatment de-escalation and the integration of immunotherapy. Data Sources: We searched PubMed/MEDLINE, Scopus, and EMBASE for English-language studies published from 2010 to 2025 using terms related to HPV-positive disease, oropharyngeal carcinoma, de-escalation, chemoradiation, and immunotherapy. Review Methods: Peer-reviewed clinical trials, meta-analyses, and key translational studies addressing systemic therapy, biomarkers, and immunotherapeutic strategies in HPV-positive OPSCC were included. Emphasis was placed on phase II–III trials evaluating cisplatin-sparing regimens, cetuximab substitution, radiation dose reduction, and early-phase immunotherapy combinations. Evidence was synthesized qualitatively. Results: Cisplatin-based concurrent chemoradiation remains the standard of care for locally advanced HPV-positive OPSCC. De-intensification trials suggest that reduced-intensity regimens may be feasible in carefully selected low-risk patients; however, replacing cisplatin with cetuximab results in inferior survival. PD-1 inhibitors (e.g., pembrolizumab, nivolumab) provide durable responses in recurrent/metastatic disease and are under active evaluation in earlier stages and in combination with therapeutic vaccines, bispecific antibodies, and viral-vector platforms. Conclusions: Systemic therapy for HPV-positive OPSCC is moving toward biomarker-informed personalization. Cisplatin-based chemoradiation remains the curative backbone, while rational de-escalation and immunotherapy integration may preserve high cure rates while reducing long-term toxicity. Ongoing phase III trials will clarify which patient subsets are most suitable for de-intensified or immunotherapeutic approaches, guiding future standards of care.

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