PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer

Adenocarcinoma Clinical Trial

— PAROLA  

Official title:

PARa-aOrtic LymphAdenectomy in Locally Advanced Cervical Cancer

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05581121
• Other study ID #: 22GENF08
• Status: Recruiting
• Phase: Phase 3
• Start date: December 20, 2023
• Est. completion date: December 2033

Study information

• Verified date: May 2024
• Source: Institut Claudius Regaud
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 510
• Est. completion date: December 2033
• Est. primary completion date: December 2031
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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. 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).

Related Conditions & MeSH terms

• Adenocarcinoma
• Adenosquamous Carcinoma
• Carcinoma
• Carcinoma, Adenosquamous
• Cervical Carcinoma
• Uterine Cervical Neoplasms

Intervention

Other:
• Standard treatment: Control arm
Standard chemo-radiotherapy and brachytherapy according to EMBRACE II and ESGO/ESTRO recommendations.

Procedure:
• Experimental arm
Pre-therapeutic para-aortic lymphadenectomy followed by tailored chemo-radiotherapy and brachytherapy.

Locations

Country	Name	City	State
France	Institut Bergonié	Bordeaux
France	CHU Brest	Brest
France	Centre Hospitalier Intercommunal de Créteil	Créteil
France	Centre Georges François Leclerc	Dijon
France	Centre Oscar Lambret	Lille
France	CHRU Lille	Lille
France	CHU Limoges	Limoges
France	Institut Paoli Calmettes	Marseille
France	ICM Val d'Aurelle	Montpellier
France	CHU Nîmes	Nîmes
France	Hôpital Cochin	Paris
France	Hôpital Européen Georges Pompidou	Paris
France	Hôpital Lariboisière Saint Louis	Paris
France	Hôpital Pitié-Salpêtrière	Paris
France	Institut Curie	Paris
France	Hôpital Lyon Sud	Pierre-Bénite
France	Centre Henri Becquerel	Rouen
France	Institut de Cancérologie de l'Ouest	Saint-Herblain
France	CHRU Strasbourg - ICANS	Strasbourg
France	Institut Universitaire du Cancer Toulouse - Oncopole	Toulouse
France	Chru Tours	Tours
France	Institut Gustave Roussy	Villejuif
Italy	Policlinico Universitario Agostino Gemelli	Roma
Spain	Hospital Clinic Barcelona	Barcelona

Sponsors (11)

Lead Sponsor

Collaborator

Institut Claudius Regaud

ARCAGY/ GINECO GROUP, Belgian Gynaecological Oncology Group, European Network of Gynaecological Oncological Trial Groups (ENGOT), Grupo Español de Investigación en Cáncer de Ovario, Gynecologic Cancer Intergroup (GCIG), Hellenic Cooperative Oncology Group, Institute of Cancer Research, United Kingdom, Multicenter Italian Trials in Ovarian cancer and gynecologic malignancies, Swiss GO Trial Group, The Central and Eastern European Gynecologic Oncology Group

Countries where clinical trial is conducted

France,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Disease Free Survival (DFS)	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.	5 years for each patient
Secondary	Overall survival (OS)	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.	5 years for each patient
Secondary	Cancer Specific survival (CSS)	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.	5 years for each patient
Secondary	Metastasis Free Survival (MFS)	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.	5 years for each patient
Secondary	Para-aortic Free Survival (PAFS)	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.	5 years for each patient
Secondary	Morbidity and adverse events assessed by the toxicity grading of the National Cancer Institute (NCI-CTCAE v 5.0).		5 years for each patient
Secondary	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.	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.	5 years for each patient
Secondary	Cost-utility analysis	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.	5 years for each patient
Secondary	False-negative rate of PET/CT and optional ultrasonography	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).	3 months post-CRT (Chemo-radiotherapy and brachytherapy) treatment for each patient