Background: EMBRACE 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. Method This 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.. Discussion: This 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.

The authors have declared no competing interest.

CTRI/2023/08/057075

Funded by Indian Council of Medical Research

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Tata Medical Center/Institutional Review Board

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

The full protocol as well as the statistical analysis plan is available within the manuscript. There are no plans to make patient-level data available publically during the study recruitment, but we will consider the same once primary reporting of the outcomes is completed or as mandated by regulations.