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A proposal for risk‐based and strategy‐adapted de‐escalation in human papillomavirus‐positive oropharyngeal squamous cell carcinoma

INTRODUCTION Treatment deescalation for patients with human papillomavirus (HPV)associated oropharyngeal squamous cell carcinoma (OPSCC) is now a critically important research goal in head and neck oncology. The clinical rationale for deescalation is well accepted among physicians; current standardofcare (SOC) treatment was developed for HPVnegative cancers and is highly morbid, with a negative impact on longterm quality of life (QoL). Patients with HPVpositive OPSCC have a significantly better response to therapy and prognosis than those with HPVnegative disease. Many will survive for decades, and a meaningful fraction will even die from overtreatment. Currently, deescalation remains entirely investigational; the initial results of deescalation studies are promising for both survival outcomes and sideeffect profiles. However, when longterm data are published, the head and neck community will face several important challenges. First, multiple trials have included only patients with very early stage disease and minimal smoking histories, limiting deescalation to a small fraction of the larger HPVpositive population. Defining an optimal cohort has been limited because the clinical and molecular biomarkers that prognosticate HPVpositive OPSCC are still largely unknown. Furthermore, multiple approaches to deescalation have been examined, including reduction in dose and/or volume of radiotherapy (RT) and omission, reduction, and substitution of cisplatin in the definitive setting, after minimally invasive surgery, and after induction chemotherapy. There is also significant heterogeneity within these strategies, such as differences in induction regimens and radiation dosing. This lack of meaningful inclusion criteria and stratification for patients and coordination of the selection of therapies for phase 3 trials has significantly impeded progress. In this commentary, we propose a strategy to address this situation in the form of several adequately powered, stratified, coordinated, multicenter, and multidisciplinary randomized controlled trials (RCTs) that compare rationally selected deescalation strategies in well defined risk groups. In our schema, surgical and concurrent chemoradiation (CCRT) approaches are compared in patients who have lower risk disease, whereas sequential therapy is used and compared with SOC CCRT in patients who have advanced and higher risk disease.