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Uterine Neoplasms

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Genital Diseases

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Cisplatin

Standard chemo-radiotherapy and brachytherapy according to EMBRACE II and ESGO/ESTRO recommendations.

Standard treatment: Control arm

Pre-therapeutic para-aortic lymphadenectomy followed by tailored chemo-radiotherapy and brachytherapy.

Experimental arm

Guillaume BABIN

Pierre-François DUPRE

Jennifer UZAN

Hélène COSTAZ

Carlos MARTINEZ GOMEZ

Yohan KERBAGE

Tristan GAUTHIER

Guillaume BLACHE

Pierre-Emmanuel COLOMBO

Catherine FERRER

Bruno BORGHESE

Anne-Sophie BATS

Cyrille HUCHON

Catherine UZAN

Enora LAAS

Witold GERTYCH

Agathe CROUZET

Cécile LOAEC

Chérif AKLADIOS

Alejandra MARTINEZ

Lobna OULDAMER

Sébastien GOUY

Nicolo BIZZARRI

Berta DIAZ-FEIJOO

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.

A cost-utility study will be performed in patients included in France. Other countries could be involved in this specific study. It will assess the incremental cost-utility ratio (cost per QALY gained) of para-aortic lymphadenectomy followed by tailored chemo-radiation in patients with positive PALN compared to patients staged with PET/CT only followed by chemo-radiation.

This study also has ancillary objectives:

* Biologic: To study T cell exhaustion, immune changes during chemoradiation, HPV ctDNA dynamic evolution, and the par-aortic lymph node as a premetastatic niche.
* Radiomics: To study the contribution of radiomics and FDG-PET/CT metabolic parameters to predict para-aortic lymph node involvement and clinical outcome.
* Senti-PAROLA: To evaluate the accuracy (Sensitivity, specificity, positive and negative predictive value) of the para-aortic sentinel lymph node (SPA) for PALN staging, and to evaluate the prognostic value of low volume metastasis of SPA.

PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer

DFS is defined as the time from randomization until first relapse (local, regional, or distant), or death from any cause. Patients still alive at the time of analysis without documented event (including lost to follow-up) will be censored at the last valid disease assessment.

OS is defined by the delay between randomization and death from any cause. Patients still alive at the time of analysis (including lost of follow-up) will be censored at the last known alive date.

CSS is defined by the delay between randomization and death from cancer. Patients still alive at the time of analysis (including lost of follow-up) or death from other cause will be censored at the last known alive date and date of death, respectively.

MFS is defined as the time from randomization until first distant relapse, or death from any cause. Patients still alive at the time of analysis (including loss of follow-up) without appearance of distant relapse will be censored at the last valid disease assessment.

PAFS is defined as the time from randomization until para-aortic recurrence, or death from any cause. Patients still alive at the time of analysis (including loss of follow-up) without appearance of para-aortic recurrence will be censored at the last valid disease assessment.

The QLQ-C-30 response options are a 4-point Likert scale from "not at all" to "very much" or a seven-point Likert scale from "very poor" to "excellent."The QLQ-CX24 consists of 24 questions including symptom items and sexuality items. The scores/dimensions are: Body image, symptom experience, Sexual/Vaginal Functioning, Lymphedema, Peripheral Neuropathy, Menopausal Symptoms, Sexual Worry, Sexual Activity, sexual enjoyment.The EQ-5D-5L has a descriptive component (composed of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and a visual analogue scale (EQ-VAS). The EQ-5D-5L is translated and validated in French with a utility function calculated on the basis of revealed preferences of French population. The utility-preference approach of the EQ-5D-5L provides a scale with cardinal properties to calculate quality-adjusted life years (QALYs) that are uses in cost-utility analyses.

Cost per QALYs gained at 3 year and 5-year follow-up:

* QALYs gained estimated as the area between the quality-adjusted survival curves of both groups.
* Utilities are derived from the EQ-5D-5L questionnaire using French weights.

False-negative rate of PET/CT and optional ultrasonography for PALN (Para-Aortic Lymph Node) staging is defined as the ratio of the number of patients PALN+ on para-aortic lymphadenectomy (surgical staging) among the number of patients randomized in the experimental arm (in the overall population and in the subgroup of patients with equivocal lymph nodes).

Spots Global Cancer Trial Database for standard treatment: control arm