Induction chemotherapy for locally advanced OPSCC: real-world evidence and HPV-dependent prognostic value of treatment response

BACKGROUND: The clinical value of induction chemotherapy (IC) in stage III-IV oropharyngeal squamous cell carcinoma (OPSCC) remains controversial. While randomized trials have shown limited survival benefit in unselected populations, it remains unclear whether IC provides benefit in high-risk subgroups and whether early treatment response to IC can serve as a prognostic and stratification tool. METHODS: We conducted a two-center retrospective real-world cohort study of 496 patients with stage III-IV OPSCC treated with definitive radiotherapy with or without IC. Inverse probability of treatment weighting (IPTW) was used to balance baseline characteristics, adjusting for age, sex, smoking, alcohol use, T/N stage (AJCC 7th), tumor subsite, HPV status, clinical extranodal extension (cENE), and use of concurrent chemoradiotherapy. Overall survival (OS), progression-free survival (PFS), distant metastasis-free survival (DMFS), and locoregional recurrence-free survival (LRFS) were compared using Kaplan-Meier and Cox proportional hazards models. A clinical nomogram was developed to predict individual DMFS and estimate IC benefit. In IC-treated patients, analyses were stratified by HPV status and IC response further stratified prognosis across endpoints. RESULTS: In IPTW-weighted multivariable Cox analysis, IC was independently associated with improved DMFS (HR = 0.60, 95% CI: 0.43-0.83, p = 0.016) and PFS (HR = 0.66, 95% CI: 0.49-0.90, p = 0.041). Subgroup analysis revealed reduced distant metastasis with IC in N3 patients (HR = 0.43, 95% CI: 0.20-0.93, p = 0.033). The nomogram (C-index = 0.697) suggested IC-associated benefit in patients with higher baseline risk. Among IC-treated patients, treatment response further stratified prognosis in an HPV-dependent manner. In the HPV-negative subgroup, patients achieving a complete or partial response (CR/PR) to IC experienced significantly improved OS compared with non-responders (p = 0.019). In multivariable analysis, IC response (CR/PR) was independently associated with superior PFS and LRFS, whereas no response-associated survival benefit was observed in HPV-positive patients. CONCLUSION: In this real-world cohort of locally advanced OPSCC, IC was not associated with an overall survival benefit after adjustment, but was associated with improved distant metastasis-free survival, particularly in selected high-risk patients. Early IC response further identified a favorable-risk subgroup among HPV-negative patients. Given the retrospective design and treatment heterogeneity, these findings should be considered hypothesis-generating and require prospective validation.