Selection Criteria for De-Escalated Chemoradiotherapy for HPV-Related Oropharyngeal Cancer Based on Prognostic Biomarkers or Early Tumor Response to Therapy: A Narrative Review

<b>Backgrounds</b>: Single-arm studies evaluating reduced intensity (de-escalated) therapy for low-risk Human Papillomavirus-related oropharyngeal cancer (HPV+OPC) patients demonstrated high cure rates and reduced toxicity compared with historical results of standard of care (SOC). However, randomized studies demonstrated that the outcomes of de-escalated therapies were inferior to standard therapy, suggesting that a minority of patients may not benefit from de-escalation. <b>Objectives</b>: to review strategies and prognostic biomarkers before or early during therapy to identify low-risk HPV+OPC patients who may require SOC and who should be excluded from de-escalation trials to avoid compromising outcomes. <b>Methods</b>: A comprehensive narrative literature review between January 2000 and August 2025 was performed to identify prognostic biomarkers in HPV+OPC, as well as studies reporting early-response indicators with prognostic potential in clinically defined good-prognosis HPV+OPC treated with chemo-irradiation. Preclinical studies were excluded unless their findings had implications for clinical outcomes. Data were synthesized qualitatively in this narrative report due to the substantial heterogeneity of the clinical and methodological aspects of the reviewed studies. The risk of bias in non-randomized studies was assessed using the Newcastle-Ottawa Scale (NOS) for cohort studies. <b>Results</b>: Multiple candidate prognostic biomarkers were identified, including molecular, histopathological, imaging, and clinical factors. Almost all studies were retrospective, included small cohorts and lacked internal or external validation, and had poor NOS scores, mostly due to lack of sufficient follow-up and lack of information about loss to follow-up, thereby precluding most biomarkers from current clinical utilization. Response-based selection based on induction chemotherapy is effective but limited by its added toxicity. Early tumor responses assessed by hypoxia, metabolic imaging, and circulating HPV DNA kinetics show encouraging preliminary results that need to be validated. <b>Conclusions</b>: Current evidence indicates major methodological limitations in most studies of prognostic biomarkers in clinically defined good-prognosis HPV+OPC. Early tumor response-based selection strategies are promising and warrant comparison with SOC in multi-center randomized trials.