# Neoadjuvant Chemotherapy for Oropharyngeal Cancer Treatment De-Escalation: From Historical Failures to Contemporary HPV-Driven Paradigms

## TL;DR

This paper explores using chemotherapy before main treatment to reduce oropharyngeal cancer tumors and allow less aggressive follow-up treatments, potentially improving quality of life.

## Contribution

The study provides a narrative synthesis of neoadjuvant chemotherapy outcomes in HPV-driven oropharyngeal cancer, highlighting its potential for treatment de-escalation.

## Key findings

- Neoadjuvant chemotherapy in HPV-positive oropharyngeal cancer shows high pathologic complete response rates and improved survival.
- NAC followed by surgery or chemoradiotherapy may reduce complications and feeding-tube dependence.
- Emerging evidence suggests NAC could enable de-escalation of treatment while maintaining oncologic outcomes.

## Abstract

Oropharyngeal cancer is becoming more common in individuals with fewer comorbidities. Traditional therapies, which include surgery, radiation, and chemotherapy, can control cancer but may have serious side effects, such as problems with swallowing. This study examines existing data on using chemotherapy before the primary treatment (neoadjuvant chemotherapy) to reduce tumors and make subsequent treatments less aggressive. By synthesizing the findings from several trials, we investigate whether this approach could keep optimal survival while enhancing quality of life. The findings suggest that neoadjuvant chemotherapy could help in the selection of individuals for a more conservative surgery or radiation, thus decreasing complications and maintaining function. Further clinical trials are needed to validate these advantages and determine which patients will benefit the most.

Background/Objectives: Oropharyngeal squamous cell carcinoma (OPSCC) management has shifted following recognition of HPV-driven disease. Neoadjuvant chemotherapy (NAC) has historically failed to improve overall survival (OS) in mixed head and neck cohorts, although contemporary HPV-stratified series suggest NAC may enable treatment de-escalation. We aimed to narratively synthesize OPSCC-specific evidence on NAC focusing on primary and nodal response, pathologic complete response (pCR), survival, and functional outcomes. Methods: We conducted a narrative review of PubMed, selecting primary studies in which OPSCC outcomes were reported separately (surgery- or chemoradiotherapy [CRT]-based strategies; HPV status when available). We extracted study design, treatment regimens, response outcomes, survival, and toxicity data. Results: Pre-HPV studies showed variable responses and no consistent OS advantage over locoregional therapy. In the HPV era, non-comparative cohorts of NAC followed by transoral surgery reported substantial downstaging and high pCR rates at both the primary site and regional nodes, with 3–5-year OS frequently ≥80%. NAC+CRT paradigms demonstrated high clinical CR rates and OS exceeding 80–90%, and lower feeding-tube dependence and reduced swallowing morbidity in de-escalated regimens. Comparative retrospective series suggest NAC + surgery may be associated with lower rates of distant metastases and feeding-tube use compared with CRT or upfront surgery, although interpretation is limited by selection bias, regimen heterogeneity, and small sample sizes. Conclusions: While randomized trials have not established an OS advantage for NAC over standard CRT in head and neck cancer overall, HPV-positive OPSCC shows emerging evidence that systemic intensification with NAC may enable surgical and/or radiation de-escalation with promising oncologic and functional outcomes.