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

<b>Background/Objectives</b>: 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. <b>Methods</b>: 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. <b>Results</b>: 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. <b>Conclusions</b>: 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.