Prophylactic Para Aortic Irradiation vs Pelvic Radiotherapy in Pelvic node-positive Carcinoma Cervix in the setting of concurrent chemoradiation: A phase II Open-label Multi centric Randomized Controlled Trial (PRO-PARA)

Abstract

AbstractBackgroundEMBRACE and Retro EMBRACE studies have shown that excellent local control and pelvic control could be achieved with concurrent chemoradiation and MRI-based brachytherapy in carcinoma cervix. Now para aortic nodal failure and distant metastasis are the predominant modes of failure. Paraaortic nodal failure rates are higher in pelvic node-positive cases as compared to pelvic node-negative cases as demonstrated in EMBRACE studies. The current study aims to find out the benefit of adding prophylactic para-aortic node irradiation in patients of carcinoma cervix who have involved pelvic nodes on volumetric imaging.MethodThis will be a two-arm, parallel group, phase II open-label multicenter randomized controlled trial. Patients will be enrolled in a phase II trial where the primary endpoint will be demonstration of reduction in the risk of para-aortic recurrence.If the primary endpoint is met, a phase III trial will be initiated using the same trial design and intervention. Patients in arm A(control arm) will receive pelvic radiotherapy covering the common iliac nodes with Intensity Modulated Radiotherapy (IMRT) to a dose of 45 Gy/25 fractions over five weeks. Radiologically involved lymph nodes will be boosted to a dose of 55 Gy/25 fractions with simultaneous integrated boost(SIB).Patients in arm B (Experimental arm)will receive pelvic and elective para-aortic radiotherapy up to the lower border of the renal vein (IMRT) to dose of 45 Gy/25 fractions over five weeks.Radiologically involved lymph nodes will be boosted to a dose of 55 Gy/25 fractions with simultaneous integrated boost(SIB). Concurrent chemotherapy with cisplatin 40mg/m2 weekly will be given during external beam radiotherapy in both the arms. After completion of concurrent chemoradiation, high dose rate (HDR) intracavitary or intracavitary +interstitial brachytherapy will be performed in both the arms.With a one sided type I error of 5% and a power of 80%, a total of 9 para-aortic recurrences is required to demonstrated that addition of prophylactic para-aortic nodal recurrence reduces the the risk of a para-aortic nodal failure from 10% in the control arm to 2% or less in the test arm. Without a substantial reduction in the risk of para-aortic nodal failure, an improvement in overall survival cannot be expected. 224 patients will need to be accrued over a period of 2 years with a minimum follow up of 12 months to demonstrate this number of para-aortic nodal recurrences for the phase II trial.For the current study we will assume that the 5 year overall survival is 70% in the control arm and that use of prophylactic EFRT will translate into an absolute improvement of 9% in the overall survival. This implies that the test arm will have a 5 year overall survival of about 79%. This corresponds to a hazard ratio of 0.75 which is a conservative estimate of the possible relative benefit of extended field radiotherapy. With a two sided type I error of 5% and a power of 80%, a total of 143 events is required to demonstrate an improvement in the overall survival corresponding to the hazard ratio of 0.75. This would need a total accrual duration of 5 years, and a minimum follow up duration of 4 years (such that the total trial duration of 9 years), a total of 462 patients (equal allocation) need to be accrued. Assuming a 15% loss to follow up, a total sample size of 530 patients is needed corresponding to an annual accrual of 106 patients..DiscussionThis trial will demonstrate the efficacy of prophylactic para aortic radiation in pelvic node positive carcinoma cervix. It also gives an opportunity to standardize and assess the quality-assurance radiotherapy practices in carcinoma cervix across multiple premier institutes of the nation at the same time.The safety of this intervention in advanced pelvic node-positive disease requiring prophylactic para aortic radiation will be established.Trial RegistrationThe trial has been registered at the Clinical Trial Registry of India (CTRI) vide registration number: CTRI/2023/08/057075(30th August 2023)