PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer

Обзор

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.

Вмешательства

• Другое Standard treatment: Control arm
  Standard chemo-radiotherapy and brachytherapy according to EMBRACE II and ESGO/ESTRO recommendations.
• Процедура Experimental arm
  Pre-therapeutic para-aortic lymphadenectomy (by minimally invasive approach) followed by tailored chemo-radiotherapy and brachytherapy. Both traditional laparoscopy or robotically assisted laparoscopy approaches are accepted in the study.

Первичные конечные точки

• Disease Free Survival (DFS) [Срок оценки: 5 years for each patient]

Вторичные конечные точки (8)

• Overall survival (OS) [Срок оценки: 5 years for each patient]
• Cancer Specific survival (CSS) [Срок оценки: 5 years for each patient]
• Metastasis Free Survival (MFS) [Срок оценки: 5 years for each patient]
• Para-aortic Free Survival (PAFS) [Срок оценки: 5 years for each patient]
• Morbidity and adverse events assessed by the toxicity grading of the National Cancer Institute (NCI-CTCAE v 5.0). [Срок оценки: 5 years for each patient]
• 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. [Срок оценки: 5 years for each patient]
• Cost-utility analysis [Срок оценки: 5 years for each patient]
• False-negative rate of PET/CT and optional ultrasonography [Срок оценки: 3 months post-CRT (Chemo-radiotherapy and brachytherapy) treatment for each patient]

Критерии участия

Критерии включения

• 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
• 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
• Signed informed consent
• Patient affiliated to a Social Health Insurance in France (French patients only).

Критерии исключения

• 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).

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Франция · 28 центров

• Institut de Cancérologie de l'Ouest — Angers
• Institut Bergonié — Bordeaux
• CHU Brest — Brest
• Centre François Baclesse — Caen
• Centre Hospitalier Intercommunal de Créteil — Créteil
• Centre Georges François Leclerc — Dijon
• Centre Oscar Lambret — Lille
• CHRU Lille — Lille
• … и ещё 20 центров

Испания · 5 центров

• H.U. Vall d'Hebron — Barcelona
• Hospital Clinic i Provincial de Barcelona — Barcelona
• H. Josep Trueta — Girona
• H. Clínico San Carlos / Madrid — Madrid
• H.U. La Paz / Madrid — Madrid

Чехия · 3 центра

• UH Ostrava - FNO — Ostrava
• UH Plzeň — Pilsen
• General UH in Prague - VFN — Prague

Италия · 1 центр

• Policlinico Universitario Agostino Gemelli — Roma

Публикации

• Martinez A, Lecuru F, Bizzarri N, Chargari C, Ducassou A, Fagotti A, Fanfani F, Scambia G, Cibula D, Diaz-Feijoo B, Gil Moreno A, Angeles MA, Muallem MZ, Kohler C, Luyckx M, Kridelka F, Rychlik A, Gerestein KG, Heinzelmann V, Ramirez PT, Frumovitz M, Ferron G, Betrian S, Filleron T, Fotopoulou C, Querleu D; PAROLA Study group. PARa-aOrtic LymphAdenectomy in locally advanced cervical cancer (PAROLA PMID 36717163

Идентификаторы

NCT: NCT05581121 · 22GENF08

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗