Retarded Surgery Following Neoadjuvant Chemotherapy in Advanced Ovarian Cancer

Study Overview
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Brief Summary
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The aim of CHRONO trial is to compare the DFS when surgery is performed after 3 courses of NACT, or after 6 courses of NACT, in a prospective multi institutional randomized setting,considering only patients initially unsuitable for primary surgery.

Official Title
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CHRONO - Retarded Surgery Following Neoadjuvant Chemotherapy in Advanced Ovarian Cancer

Conditions
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Ovarian Cancer Stage IV, Ovarian Cancer Stage IIIC, Ovarian Cancer Stage IIIb

Intervention / Treatment
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* Procedure: Retarded IDS (Interval Debulking Surgery)
* Procedure: Standard IDS (Interval Debulking Surgery)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Female patients ≥18 years. Histologically confirmed epithelial ovarian cancer, fallopian tube carcinoma or primary peritoneal carcinoma, high grade serous or endometrioïd, with the exception of mucinous, clear cell and carcinosarcoma histologies. Performance status < 2 (see Appendix 2). Documented International Federation of Gynecologic Oncology (FIGO 2014, Appendix 1) stage IIIB-IIIC-IVa unsuitable for complete primary cytoreductive surgery (confirmed by open laparoscopy or by laparotomy [not mandatory for stage IVA]). Patient must be judged resectable after 3 courses of Neoadjuvant chemotherapy Adequate bone marrow, liver and renal function to receive chemotherapy and subsequently to undergo surgery: White blood cells (WBC) >3x109/L, absolute neutrophil count (ANC) ≥1,5x109/L, platelets (PLT) ≥100x109/L, hemoglobin (Hb) ≥9 g/dL, Serum creatinine <1.25 x upper normal limit (UNL) or creatinine clearance ≥ 30 mL/min according to Cockroft-Gault formula or to local lab measurement, serum bilirubin <1.25 x UNL, AST(SGOT) and ALT(SGPT) <2.5 x UNL. Signed informed consent obtained prior to any study-specific procedures. Patient affiliated to, or a beneficiary of, a social security category Exclusion Criteria: Mucinous, clear cell , carcinosarcoma and low grade serous carcinomahistologies. Synchronous or previous other malignancies within 3 years prior to starting study treatment, with the exception of adequately treated non-melanomatous skin cancer or carcinoma in situ (of the cervix or breast or other sites). Patients with brain metastases, seizure not controlled with standard medical therapy, or history of cerebrovascular accident (CVA, stroke) or transient ischemic attack (TIA) or subarachnoid hemorrhage before 6 months from the enrollment on this study. Any other concurrent medical conditions contraindicating surgery or chemotherapy that could compromise the adherence to the protocol (including but not limited to impaired cardiac function or clinically significant cardiac diseases, active or uncontrolled infections, HIV-positive patients on antiretroviral therapy, uncontrolled diabetes, cirrhosis, chronic active or persistent hepatitis, impaired respiratory function requiring oxygen-dependence, serious psychiatric disorders). Pregnant or breastfeeding women.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 99 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 |
| --- | --- |
| Active Comparator: Interval Debulking Surgery (IDS)<br>Complete surgery after 3 courses of neoadjuvant chemotherapy (NACT) | Procedure: Standard IDS (Interval Debulking Surgery)<br>* Patient will receive 3 courses of i.v carboplatine and paclitaxel every 3 weeks followed by IDS (Interval Debulking Surgery) within 6 weeks from C3D1. After surgery patient will undergo 5 more courses of carboplatine and paclitaxel chemotherapy. Treatment accepted : Paclitaxel and carboplatin could will be administred according to the site practice and Saint-Paul-de-Vence recommendation (Joly et al, 2017): paclitaxel 175 mg/m² + carboplatin AUC 5-6, D1=D21 or paclitaxel 80 mg/m² at J1-J8-J15 + carboplatin AUC 5-6, D1=D21 or paclitaxel 60 mg/m² D1-D8-D15 + carboplatin AUC2 D1-D8-D15, D1= D21 Adjuvant therapy and maintenance (optional)according to national recommendations (Saint Paul de Vence)<br>|
| Experimental: Retarded Interval Debulking Surgery (IDS)<br>Complete surgery after 6 courses of neoadjuvant chemotherapy (NACT) | Procedure: Retarded IDS (Interval Debulking Surgery)<br>* Patient will receive 6 courses of i.v carboplatine and paclitaxel every 3 weeks followed by IDS (Interval Debulking Surgery) within 6 weeks from C6D1. After surgery patient will undergo 2 more courses of carboplatine and paclitaxel chemotherapy Treatment accepted : Paclitaxel and carboplatin could will be administred according to the site practice and Saint-Paul-de-Vence recommendation (Joly et al, 2017): paclitaxel 175 mg/m² + carboplatin AUC 5-6, D1=D21 or paclitaxel 80 mg/m² at J1-J8-J15 + carboplatin AUC 5-6, D1=D21 or paclitaxel 60 mg/m² D1-D8-D15 + carboplatin AUC2 D1-D8-D15, D1= D21 Adjuvant therapy and maintenance (optional)according to national recommendations (Saint Paul de Vence)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Disease Free Survival | Disease free survival (DFS) defined as the time interval between randomization and physical or radiographic evidence of recurrence (local/distant) or second cancer or death (all causes) whichever occur first | From date of randomisation until the date of second cancer or death, which ever occurs earlier, assessed up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| EORTC QLQ-C30 | Health related quality of life of the patient | through study completion, up to 2 years | 
| Pathological complete response (PCR) | Pathological response will be established using the grading system called chemotherapy response score (CRS). The response will be assessed based on the omentum microscopic review. | through study completion, up to 2 years | 
| Overall survival (OS) | Overall survival (OS) defined as time interval between randomization and death (all causes); alive patients will be censored at the last date of news | from date of randomisation to death, assessed up to 5 years | 
| Time for first subsequent treatment (TFST) |  | up to 5 years | 
| Post-operative mortality | Post operative mortality defined as the interval between the date of debulking surgery and the date of death due to any cause occurring within the 30 day post-surgery | up to 5 months | 
| Post-operative morbidity | Surgical morbidity defined as the interval between the date of debulking surgery and any events occurring within the 30 day post-surgery (All grades ≥ 3 according to the CTCAE v4.03 & All grades ≥ 3 according to Clavien Dindo classification) | up to 5 months | 
| Fagotti laparoscopic score | Disease extension assessed by Fagotti score at the time of diagnosis https://www.ncbi.nlm.nih.gov/pubmed/16791447 | diagnosis | 
| CTC-AE version 4.03 adverse events | safety assessment | 30 days after last treatment intake, up to 1 year | 
| questionnaire OV28 | Physical, abdominal/gastrointestinal (GI), fatigue | through study completion, up to 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ovarian cancer, retarded surgery, neoadjuvant chemotherapy