Involved nodal versus elective neck radiotherapy (INVERT) for head and neck squamous cell carcinoma: a prospective phase II randomized controlled trial protocol

BACKGROUND: Definitive chemoradiotherapy for head and neck squamous cell carcinomas (HNSCC) carries significant long-term toxicities, with elective neck irradiation (ENI) serving as a major contributor to integral dose and the irradiation of critical organs-at-risk. Involved nodal radiotherapy (INRT) is a novel investigational approach that omits ENI and only treats involved and suspicious lymph nodes, holding the potential to improve short- and long-term morbidity and reduce RT-induced immunosuppression. Although single arm trials have demonstrated a low risk of elective nodal recurrences with INRT, it has never been directly compared to ENI. This study aims to compare INRT and ENI in a randomized controlled trial. METHODS: This phase II randomized controlled trial will enroll 80 patients with oropharynx, larynx and hypopharynx HNSCC (AJCC stage I-IVB, ECOG 0-2). Patients will be randomized 1:1 to receive either ENI (56 Gy) or INRT to the neck, along with standard radiotherapy or chemoradiotherapy to the primary disease. All patients will receive 70 Gy in 35 fractions to gross disease and 63 Gy in 35 fractions to suspicious lymph nodes. For patients on the INRT arm, additional suspicious nodes will be identified by our previously validated in-house AI radiomics model and receive 56 Gy to the node(s) only. The primary endpoint is the probability of solitary elective volume recurrence at 2 years. Secondary endpoints include grade 2 + acute dermatitis, grade 3 + acute dysphagia, and MD Anderson Dysphagia Index scores at 2 years. DISCUSSION: This trial is the first randomized study comparing INRT and ENI approaches in HNSCC and will provide important information on whether INRT is non-inferior to ENI with respect to disease control. TRIAL REGISTRATION: Registered on ClinicalTrials.gov (NCT06477692).