Clinical trial NCT05581121: PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer
Official title: PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Cervical Carcinoma
Adenocarcinoma
Adenosquamous Carcinoma
Keywords: Locally advanced cervical cancer
HPV 16+
Stage IIIC1
Radiation therapy
Cisplatin
Para-aortic lymphadenectomy
INTERLACE
KEYNOTE-A18
Lead sponsor: Institut Claudius Regaud
Sponsor class: OTHER
Collaborators: name: ARCAGY/ GINECO GROUP
name: European Network of Gynaecological Oncological Trial Groups (ENGOT)
name: Gynecologic Cancer Intergroup (GCIG)
name: Grupo Español de Investigación en Cáncer de Ovario
name: Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies
name: Belgian Gynaecological Oncology Group
name: Swiss GO Trial Group
name: Institute of Cancer Research, United Kingdom
name: The Central and Eastern European Gynecologic Oncology Group
name: Hellenic Cooperative Oncology Group
First posted: 2022-10-14
Enrollment: 510
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Considering the changing standard treatment landscape of locally advanced cervical cancer, both arms (control arm and experimental arm) may also be treated according to the INTERLACE and KEYNOTE-A18 studies, if applicable, at the discretion of the attending physician.

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.


Eligibility criteria: Inclusion Criteria:

1. Age ≥ 18 years at time of study entry
2. Newly diagnosed histologically proven cervical squamous carcinoma, adenocarcinoma, or adenosquamous tumor
3. 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).
4. Patients with TNM T stage I-IIIB.
5. 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)
6. Patient eligible for pelvic radiotherapy and cisplatin-based chemotherapy with a curative intent as confirmed by a multidisciplinary board
7. ECOG performance status \< 2 i.e. 0 or 1
8. Life expectancy more than 12 months
9. Pretherapeutic imaging FDG-PET/CT images should be available for central review
10. Prior validation of the surgeon's participation in the study by the Quality Assurance Comity
11. 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.
12. 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
13. Not applicable since protocol revision V4. Patient participating to other clinical trials including immunotherapy strategies or adjuvant chemotherapy is also eligible for the study. Adjuvant treatment must be decided prior to randomization
14. Signed informed consent
15. Patient affiliated to a Social Health Insurance in France (French patients only).

Exclusion Criteria:

1. Unequivocal positive common iliac or para-aortic lymph nodes at pretherapeutic imaging FDG-PET/CT
2. Negative or equivocal pelvic lymph nodes at pretherapeutic imaging FDG-PET/CT
3. Metastatic disease confirmed by FDG-PET/CT
4. Other histologies than adenocarcinoma, squamous cell carcinoma and adenosquamous carcinoma
5. Contraindication for cisplatin-based chemotherapy
6. Women who received any prior treatment for cervical cancer
7. Prior surgery for the cervical cancer, except for cone procedure and pelvic lymph node staging
8. Previous pelvic radiotherapy
9. 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.
10. 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
11. Patient who has forfeited his/her freedom by administrative or legal award or who is under legal protection (curatorship and guardianship, protection of justice).

Primary outcomes:
measure: Disease Free Survival (DFS)
timeFrame: 5 years for each patient
Secondary outcomes:
measure: Overall survival (OS)
timeFrame: 5 years for each patient
measure: Cancer Specific survival (CSS)
timeFrame: 5 years for each patient
measure: Metastasis Free Survival (MFS)
timeFrame: 5 years for each patient
measure: Para-aortic Free Survival (PAFS)
timeFrame: 5 years for each patient
measure: Morbidity and adverse events assessed by the toxicity grading of the National Cancer Institute (NCI-CTCAE v 5.0).
timeFrame: 5 years for each patient
measure: Quality of life will evaluated by the EORTC QLQ-C-30 questionnaire and its cervical cancer module (CXC-24) and the EQ-5D-5L questionnaire.
timeFrame: 5 years for each patient
measure: Cost-utility analysis
timeFrame: 5 years for each patient
measure: False-negative rate of PET/CT and optional ultrasonography
timeFrame: 3 months post-CRT (Chemo-radiotherapy and brachytherapy) treatment for each patient
Other outcomes:
Locations:
city: Angers
country: France
facility: Institut de Cancérologie de l'Ouest
city: Bordeaux
country: France
facility: Institut Bergonié
city: Brest
country: France
facility: CHU Brest
city: Créteil
country: France
facility: Centre Hospitalier Intercommunal de Créteil
city: Dijon
country: France
facility: Centre Georges François Leclerc
city: Lille
country: France
facility: Centre Oscar Lambret
city: Lille
country: France
facility: CHRU Lille
city: Limoges
country: France
facility: CHU Limoges
city: Lyon
country: France
facility: Centre Léon Bérard
city: Marseille
country: France
facility: Institut Paoli Calmettes
city: Montpellier
country: France
facility: ICM Val d'Aurelle
city: Nîmes
country: France
facility: CHU Nîmes
city: Paris
country: France
facility: Hôpital Cochin
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou
city: Paris
country: France
facility: Hôpital Lariboisière Saint Louis
city: Paris
country: France
facility: Hôpital Pitié-Salpêtrière
city: Paris
country: France
facility: Institut Curie
city: Pierre-Bénite
country: France
facility: Hôpital Lyon Sud
city: Rouen
country: France
facility: Centre Henri Becquerel
city: Saint-Herblain
country: France
facility: Institut de Cancérologie de l'Ouest
city: Strasbourg
country: France
facility: CHRU Strasbourg - ICANS
city: Toulouse
country: France
facility: Institut Universitaire du Cancer Toulouse - Oncopole
city: Tours
country: France
facility: Chru Tours
city: Villejuif
country: France
facility: Institut Gustave Roussy
city: Roma
country: Italy
facility: Policlinico Universitario Agostino Gemelli
city: Barcelona
country: Spain
facility: Hospital Clinic Barcelona
Study officials:
References: