Intermediate Risk Cervical Cancer: Radical Surgery +/- Adjuvant Radiotherapy

Study Overview
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Brief Summary
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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 intermediate risk cervical cancer. The primary endpoint of the study is the disease-free survival from the day of randomisation. A total of 514 patients are required to achieve 80% power on 5% significance level with non-inferiority margin of 5% to test the difference between the ARMs using Cox proportional hazards model. The maximal tolerated margin for non-inferiority in 2-year DFS is 5% (including expected drop-out rate of 10%).

Detailed Description
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The role of adjuvant (chemo)radiotherapy in intermediate risk (IR) cervical cancer patients is controversial, supported by single randomised GOG 92 study performed more than 20 years ago. 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. 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 the final pathology report has been received into ARM A, with no additional treatment, and ARM B, receiving adjuvant (chemo)radiotherapy. Quality assurance program will be in place for both, radical surgery and adjuvant treatment.

Official Title
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An International Randomised Trial of Radical Surgery Followed by Adjuvant (Chemo)Radiation Versus no Further Treatment in Patients With Early-stage, Intermediate-risk Cervical Cancer Patients

Conditions
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Cervical Cancer

Intervention / Treatment
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* Radiation: No adjuvant therapy
* Radiation: Adjuvant radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathologically confirmed invasive cervical cancer FIGO IB1-IIA Squamous cell cancer or HPV-related adenocarcinoma Presence of tumour-related risk factors as follows: tumour ≥4 cm OR tumour>2 cm <4 cm AND lymphovascular space invasion OR tumour >2 cm <4 cm AND tumour free distance <3 mm OR tumour >2 cm <4 cm AND deep stromal invasion (>2/3) No evidence of suspicious pelvic lymph nodes or distant metastases on imaging (by radiological subjective assessment before surgery and negative pelvic LN on final pathology) ECOG performance status 0-1 Deemed suitable and fit for radical surgery followed by adjuvant radiotherapy Negative pregnancy test (if applicable) Negative HIV test (only performed in high-risk countries or patients who have moved from those countries within the past 10 years) Exclusion Criteria: Adenosquamous cancer or adenocarcinoma unusual type (non-HPV related - such as: mucinous, clear cell, mesonephric) or other rare tumour types (those not listed in the inclusion criteria) Inconclusive primary site of disease Unequivocally positive lymph node by imaging (by radiological subjective assessment) FIGO <IB1 / >IIA Previous pelvic malignancy History of second primary cancer outside pelvis if ≤ 3 years complete clinical remission (CCR) Previous pelvic radiotherapy Neoadjuvant chemotherapy prior surgical treatment Low likelihood of patient compliance to the follow-up

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A: Surgery only<br>Radical hysterectomy, sentinel lymph node biopsy and systematic pelvic lymphadenectomy (PLND)*. No further treatment will be administered. *PLND can be avoided in patients with tumours < 4cm | Radiation: No adjuvant therapy<br>* Patients will not receive any type of adjuvant therapy.<br>|
| Experimental: B: Surgery + radiothrerapy<br>Radical hysterectomy, sentinel lymph node biopsy and systematic pelvic lymphadenectomy (PLND)*, followed by adjuvant treatment. *PLND can be avoided in patients with tumours < 4cm | Radiation: Adjuvant radiotherapy<br>* Patients will receive adjuvant treatment composed of either pelvic radiotherapy external beam radiotherapy ± brachytherapy or concomitant chemoradiotherapy (pelvic radiotherapy + chemotherapy).<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease-free survival | Calculated as an interval from the day of randomisation until diagnosis of recurrence: (a) unequivocal finding on imaging by subjective radiological assessment; b) suspicious recurrence on imaging either confirmed by biopsy or supported by other signs (disease progression on imaging or progression of symptoms); (c) physical examination supported by clinical evidence (i.e., symptoms or progression); or (d) death caused by disease or death of unknown cause. | Analysed 3 years after randomization of the last patient. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival |  | Analysed 6 years after randomization of the last patient. | 
| Pelvic disease-free survival |  | Analysed 3 years after randomization of the last patient. | 
| Health-related quality of life based questionnaire | The analysis will be made based on EORTC validated questionnaires and developed qualitative CERVANTES questionnaire. | Analysed 3 years after randomization of the last patient. | 
| Treatment-related adverse events based on Common Terminology Criteria for Adverse Events v5.0 |  | Analysed 3 years after randomization of the last patient. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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intermediate risk cervical cancer, adjuvant radiotherapy, disease free survival