De-escalation of head-and-neck cancer radiotherapy: balancing cure and side effects

Potential treatment-related side effects of radiotherapy for head and neck squamous cell carcinoma are substantial and affect long-term quality-of-life. This narrative review discusses de-escalation strategies aimed at reducing side effects without compromising oncologic outcomes. Four categories of radiotherapy de-escalation strategies are discussed. First, elective neck dose- and volume de-escalation have shown very low rates of isolated regional recurrence in prospective and retrospective cohorts, however clinical benefits in unselected patient cohorts remain modest. Personalized dose and volume-de-escalation is currently under investigation, e.g. in risk-adapted elective neck volume-reduction based on lymphatic drainage mapping. Second, in HPV-related oropharyngeal cancer, unselected de-escalation strategies seemed to be inferior in terms of cure and survival, however risk-stratified approaches for post-operative radiotherapy or response-guided radiotherapy after neoadjuvant systemic therapy are promising, especially in intermediate-risk patients. Phase III randomized trials are currently recruiting patients in this matter. Third, adaptive radiotherapy can correct anatomical changes during treatment, but prospective trials are now needed to demonstrate its clinical benefits and safety in case of reducing volumes of targets. Fourth, proton therapy offers substantial dosimetric sparing and reduced acute toxicity in oropharynx, nasopharynx and nasal cavity and paranasal sinus cancer patients, however broad implementation is still limited by cost and access.