Reducing Salivary Toxicity with Adaptive Radiotherapy (ReSTART): A Randomized Controlled Trial comparing conventional IMRT to adaptive IMRT in head and neck Squamous Cell Carcinomas

Abstract

Abstract Objectives: The utility of Adaptive Radiation Therapy (ART) in Head and Neck Squamous Cell Carcinoma (HNSCC) remains to be ascertained. While multiple retrospective and single-arm prospective studies have demonstrated its efficacy in decreasing parotid doses and reducing xerostomia, there is a lack of adequate randomized evidence. Methods and Analysis: ReSTART is an ongoing phase III randomized trial of patients with previously untreated, locally advanced HNSCC of the oropharynx, larynx, and hypopharynx. Patients are randomized in a 1:1 ratio to the standard Intensity Modulated Radiation Therapy (IMRT) arm {Planning Target Volume (PTV) margin 5 mm} vs. ART arm (standard IMRT with a PTV margin 3 mm, two planned adaptive planning at 10th and 20th fractions). The stratification factors include the primary site and nodal stage. The RT dose prescribed is 66Gy in 30 fractions for high-risk PTV and 54Gy in 30 fractions for low-risk PTV over five weeks, along with concurrent chemotherapy. The primary endpoint is to compare salivary toxicity between arms using salivary scintigraphy 12 months’ post-radiation. To detect a 25% improvement in the primary endpoint at 12 months in the ART arm with a two-sided 5% alpha value and a power of 80% (and 10% attrition ratio), a sample size of 130 patients is required (65 patients in each arm). The secondary endpoints include acute and late toxicities, locoregional control, disease-free survival, overall survival, quality of life, and xerostomia scores between the two arms. Discussion: The ReSTART trial aims to answer an important question in Radiation Therapy for HNSCC, particularly in a resource-limited setting. The uniqueness of this trial, compared to other ongoing randomized trials, includes the PTV margins and the xerostomia assessment by scintigraphy at 12 months as the primary endpoint. Ethics and dissemination: This trial was approved by the Institutional Ethical Committee of Tata Memorial Hospital, Mumbai, on 3rd February 2017. Trial Registration Number: The trial is prospectively registered with the Clinical Trial Registry of India (CTRI) (Reg no: CTRI/2018/08/ 015531).