PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer

Study Overview
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Brief Summary
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This is an international, multicenter and randomized open-label phase III study designed to demonstrate, in patients with stage IIIC1 cervical cancer, whether para-aortic lymphadenectomy followed by tailored chemoradiation is associated with increased disease-free survival compared to patients staged with FDG-PET/CT only followed by chemoradiation. The planned sample size is 510; including 200 patients in France. In this trial, patients will be assigned in one of the two following treatments arms: Arm A (control arm): Standard chemo-radiotherapy and brachytherapy according to EMBRACE II and ESGO/ESTRO recommendations. Arm B (experimental arm): Pretherapeutic para-aortic lymphadenectomy followed by tailored chemo-radiotherapy and brachytherapy. Each patient will be followed up for 5 years.

Official Title
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PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer

Conditions
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Cervical Carcinoma, Adenocarcinoma, Adenosquamous Carcinoma

Intervention / Treatment
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* Other: Standard treatment: Control arm
* Procedure: Experimental arm


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 18 years at time of study entry Newly diagnosed histologically proven cervical squamous carcinoma, adenocarcinoma, or adenosquamous tumor FIGO stage IIIC1 (FIGO 2018) cervical cancer with FDG-PET/CT showing FDG-positive pelvic nodes and FDG-negative PALN including equivocal lymph nodes in the common iliac and para-aortic regions. The highest positive lymph node must be located inferior to the common iliac bifurcation in both sides (anatomical level 1). Patients with TNM T stage I-IIIB. FIGO stage IIIC1 cervical cancer by positive pelvic sentinel lymph node from surgical staging (either intraoperative assessment (frozen section) or from final histology - patients are not eligible after radical hysterectomy, and FDG-negative common iliac of para-aortic lymph node on PET/CT (performed before or after SLN procedure) Patient eligible for pelvic radiotherapy and cisplatin-based chemotherapy with a curative intent as confirmed by a multidisciplinary board ECOG performance status < 2 i.e. 0 or 1 Life expectancy more than 12 months Pretherapeutic imaging FDG-PET/CT images should be available for central review Prior validation of the surgeon's participation in the study by the Quality Assurance Comity Women should be post-menopaused or willing to accept the use of an effective contraceptive regimen during the treatment period. All non-menopaused women should have a negative pregnancy test within 72 hours prior to study entry. Patient is willing and able to comply with the protocol for the duration of the study including undergoing treatment and scheduled visits and examinations including follow up Patient participating to other clinical trials including immunotherapy strategies or additional chemotherapy is also eligible for the study Signed informed consent Patient affiliated to a Social Health Insurance in France (French patients only). Exclusion Criteria: Unequivocal positive common iliac or para-aortic lymph nodes at pretherapeutic imaging FDG-PET/CT Negative or equivocal pelvic lymph nodes at pretherapeutic imaging FDG-PET/CT Metastatic disease confirmed by FDG-PET/CT Other histologies than adenocarcinoma, squamous cell carcinoma and adenosquamous carcinoma Contraindication for cisplatin-based chemotherapy Women who received any prior treatment for cervical cancer Prior surgery for the cervical cancer, except for cone procedure and pelvic lymph node staging Previous pelvic radiotherapy History of another primary malignancy except for: Malignancy treated with curative intent and with no known active disease after 5 years, adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease, adequately treated carcinoma in situ (any location) without evidence of disease. Any psychological, familial, geographic or social situation, according to the judgment of investigator, potentially preventing the provision of informed consent or compliance to study procedure Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice).

Ages Eligible for Study
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Minimum Age: 18 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 |
| --- | --- |
| Other: Arm A<br>Control arm | Other: Standard treatment: Control arm<br>* Standard chemo-radiotherapy and brachytherapy according to EMBRACE II and ESGO/ESTRO recommendations.<br>|
| Experimental: Arm B<br>Experimental arm | Procedure: Experimental arm<br>* Pre-therapeutic para-aortic lymphadenectomy followed by tailored chemo-radiotherapy and brachytherapy.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival (DFS) defined as the time from randomization until first relapse (local, regional, or distant), or death from any cause. |  | 5 years for each patient | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival defined by the delay between randomization and death from any cause. |  | 5 years for each patient | 
| Metastasis Free Survival (MFS) defined as the time from randomization until first distant relapse, or death from any cause. |  | 5 years for each patient | 
| Morbidity assessed by the toxicity grading of the National Cancer Institute (NCI-CTCAE v 5.0). |  | 5 years for each patient | 
| Quality of life will evaluated by the EORTC QLQ-C-30 questionnaire. | This questionnaire is a cancer-specific, multi-dimensional core QOL instrument. Response options are a four-point Likert scale from not at all to very much or a seven-point Likert scale from very poor to excellent. | 5 years for each patient | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Locally advanced cervical cancer, HPV 16+, Stage IIIC1, Radiation therapy, Cisplatin, Para-aortic lymphadenectomy