De-Escalation Strategies of (Chemo)Radiation for Head-and-Neck Squamous Cell Cancers-HPV and Beyond

Simple Summary HPV-related oropharyngeal squamous cell carcinoma patients have a very good prognosis but are often suffering from long-term treatment-induced toxicities. Therefore, a plethora of de-escalation trials is examining whether treatment for HPV-induced oropharyngeal carcinoma can be de-escalated without compromising the favorable outcomes. The purpose of this review was to present and critically discuss the published as well as the ongoing de-escalation trials in head-and-neck squamous cell carcinoma, in particular for HPV-related oropharyngeal carcinoma. De-escalation studies are using several approaches such as radiotherapy dose reduction, target volume reduction, omission of concomitant chemotherapy, replacement of cisplatin through less toxic systemic agents, omission of adjuvant (chemo)radiation after primary surgery and selection of suitable patients by induction chemotherapy or peritherapeutic hypoxia imaging. Although many promising results have been obtained from several Phase I and II trials, the two Phase III de-escalation trials failed to show the equivalence of the de-escalated treatment arm, so that so far, no treatment de-escalation can be recommended outside of clinical trials. Oncological outcomes for head-and-neck squamous cell carcinoma (HNSCC) patients are still unsatisfactory, especially for advanced tumor stages. Besides the moderate survival rates, the prevalence of severe treatment-induced normal tissue toxicities is high after multimodal cancer treatments, both causing significant morbidity and decreasing quality of life of surviving patients. Therefore, risk-adapted and individualized treatment approaches are urgently needed for HNSCC patients to optimize the therapeutic gain. It has been a well-known fact that especially HPV-positive oropharyngeal squamous cell carcinoma (OSCC) patients exhibit an excellent prognosis and may therefore be subject to overtreatment, resulting in long-term treatment-related toxicities. Regarding the superior prognosis of HPV-positive OSCC patients, treatment de-escalation strategies are currently investigated in several clinical trials, and HPV-positive OSCC may potentially serve as a model for treatment de-escalation also for other types of HNSCC. We performed a literature search for both published and ongoing clinical trials and critically discussed the presented concepts and results. Radiotherapy dose or volume reduction, omission or modification of concomitant chemotherapy, and usage of induction chemotherapy are common treatment de-escalation strategies that are pursued in clinical trials for biologically selected subgroups of HNSCC patients. While promising data have been reported from various Phase II trials, evidence from Phase III de-escalation trials is either lacking or has failed to demonstrate comparable outcomes for de-escalated treatments. Therefore, further data and a refinement of biological HNSCC stratification are required before deescalated radiation treatments can be recommended outside of clinical trials.

Automated summary

HPV-positive oropharyngeal squamous cell carcinoma patients have a good prognosis but may suffer from long-term treatment-related toxicities. Many de-escalation trials have been conducted to explore reducing treatment for this type of cancer without compromising outcomes. Although promising results have been seen in Phase I and II trials, Phase III trials have not shown equivalence for de-escalated treatments yet, indicating that further research is needed before de-escalation can be recommended outside of clinical trials.