General info

The role of adjuvant (chemo)radiotherapy in intermediate risk (IR) cervical cancer patients is controversial, supported by a single randomised study performed more than 20 years ago (GOG 92 study, 1999). The intermediate-risk group is defined as lymph-node-negative but with a combination of negative prognostic factors (tumour size >2 cm, lymphovascular space invasion, deep stromal invasion >2/3). Recent retrospective studies showed excellent local control in intermediate-risk group patients after radical surgery with no additional adjuvant treatment.

The CERVANTES trial is designed to bring level A evidence on the role of adjuvant treatment in IR patients in an international, prospective, randomised study. Patients will be registered into the trial before surgery and randomised after surgery if the final pathology report has confirmed IR group and other inclusion criteria into ARM A, with no additional treatment, and ARM B, receiving adjuvant (chemo)radiotherapy. The quality assurance program will be in place for both radical surgery and adjuvant treatment. Accrual is expected to last for 5 years, with an additional 3 years of follow-up for primary endpoint analysis. If the primary analysis shows a positive outcome, the study will continue for 3 further years to evaluate overall survival as a secondary endpoint.

The objective of the trial is to evaluate if adjuvant (chemo)radiation is associated with a disease-free survival benefit after radical surgery in patients with IR cervical cancer. The primary endpoint of the study is disease-free survival from the day of randomisation. A total of 514 patients (including an expected drop-out rate of 10%) are required to achieve 80% power on 5% significance level with non-inferiority margin of 5% to test the difference between the arms using the Cox proportional hazards model. The maximal tolerated margin for non-inferiority in 2-year DFS is 5%.

Overview

Arm

ARM A: Surgery only

Radical hysterectomy, sentinel lymph node biopsy and systematic pelvic lymphadenectomy (PLND)*. No futher treatment will be administered.

*PLND can be avoided in patients with tumours <4cm

ARM B: Surgery + radiotherapy

Radical hysterectomy, sentinel lymph node biopsy and systematic pelvic lymphadenectomy (PLND)*, followed by adjuvant treatment.

*PLND can be avoided in patients with tumours <4cm

Intervention / treatment

ARM A:

Radiation: No adjuvant therapy

Patient will not receive any type of adjuvant therapy.

ARM B:

Radiation: Adjuvant therapy

Patient will receive adjuvant treatment composed of either pelvic radiotherapy external beam radiotherapy ± brachytherapy or concomitant chemoradiotherapy (pelvic radiotherapy + chemotherapy)

Arms and interventions

Primary endpoint

Disease-free survival

Calculated as an interval from the day of randomisation until diagnosis of recurrence:

unequivocal finding on imaging by subjective radiological assessment;

suspicious recurrence on imaging either confirmed by biopsy or supported by other signs (disease progression on imaging or progression of symptoms);
physical examination supported by clinical evidence (i.e., symptoms or progression); or
death caused by disease or death of unknown cause.

Key secondary endpoint

Overall survival:

In case of a positive outcome of the primary DFS analysis, the trial will continue for a further 3 years to evaluate overall survival.