A phase II multi-center, open-label, randomized, parallel-group, superiority study to compare the acute toxicity of Hypofractionated dOse Painted External radiotherapy versus conventional external radiotherapy in patients with carcinoma cervix stage I - IIB. (HOPE)

Introduction Trials investigating hypofractionated radiotherapy in carcinoma cervix have demonstrated an increased risk of acute gastrointestinal toxicity. Patients with node negative disease have a very low risk of pelvic nodal relapse, a dose painting approach integrating differential doses to the primary and elective nodal clinical target volumes may allow safe hypofractionated radiotherapy by reducing the acute gastro-intestinal toxicity. Methods and Analysis Patients with Human Papillomavirus (HPV) associated squamous cell carcinoma who have no pelvic nodal involvement as documented on PET CT and MRI will be eligible. Patients will be randomly allocated to receive standard whole pelvic radiotherapy (CRT) covering the primary clinical target volume (CTVp) and the nodal clinical target volume (CTVn) to a dose of 45 Gy (25 fractions, 1.8 Gy per fraction) with concurrent weekly cisplatin at a dose of 40 mg/m2 weekly for five cycles. In the experimental arm (HDRT), a dose of 42.5 Gy (2.125 Gy per fraction) and 36 Gy (1.8 Gy per fraction) will be delivered in 20 fractions to the CTVp and CTVn respectively. Concurrent cisplatin will be delivered at a dose of 50 mg/m2 weekly for four cycles. The primary objective will be to compare the proportion of patients with grade 2 or higher acute gastrointestinal toxicity (nausea, vomiting and diarrhea). Secondary outcomes will include disease free survival, quality of life and late toxicity. The primary statistical analysis will be reported on the intention-to-treat population. The primary outcome will be analysed using a covariate adjusted log binomial model to compare the relative risk of grade 2 or higher acute gastrointestinal toxicity. We assume that HDRT will reduce the toxicity rate from 35% to 21% (14% absolute risk reduction). Using an asymmetric two-sided group sequential design with three planned interim analyses, the target sample size is 274 patients for 80% power with a 5% (1-sided) type I error. Ethics and dissemination The trial will be initiated at the participating centers after institutional review board approval at the respective centers. All patients will provide written informed consent. The results will be presented in peer reviewed literature as well as academic conferences. Trial Registration The trial has been prospectively registered in the clinical trial registry of India.