GRECCAR 8: Primary Tumor Resection in Rectal Cancer With Unresectable Metastasis

Study Overview
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Brief Summary
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A prospective, open, multicenter, randomized III trial with two arms: Arm A: Primary tumor resection , followed by chemotherapy Arm B: Chemotherapy alone. Compare overall 2-year survival rates in patients treated for resectable rectal adenocarcinoma with unresectable metastasis, treated either with the primary tumor resection with chemotherapy +/- target therapy, or with chemotherapy (+/- target therapy) alone.

Official Title
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GRECCAR 8 : Impact on Survival of the Primary Tumor Resection in Rectal Cancer With Unresectable Synchronous Metastasis a Randomized Multicenter Study

Conditions
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Rectal Adenocarcinoma

Intervention / Treatment
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* Procedure: Primary tumor resection + chemotherapy
* Drug: Oxaliplatin/irinotecan + capecitabine, 5-FUI ± bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Non-complicated primary tumor (i.e. tumor without obstruction, bleeding, abscess or perforation requiring emergency surgery and/or contra-indicating first-line chemotherapy) Unresectable synchronous metastases ECOG performance status 0-1 Rectal adenocarcinoma (<15 cm from the anal verge) with few or no symptoms and unresectable metastasis (assessed by the investigator) unsuitable for curative treatment No known unresectable primary tumor (with clear margin >1mm) on CT-scan and MRI No disease progression under chemotherapy (for at least 4 cycles); Assessment of KRAS status before randomization (wild type or mutated); Life expectancy without cancer >2 years White blood cell count ≥ 3 x 109/L, with neutrophils ≥ 1,5 x 109/L, platelet count ≥ 100 x 109/L, hemoglobin°≥ 9 g/dL (5,6 mmol/l) Total bilirubin ≤ 1.5 x ULN (upper limit of normal), ASAT and ALAT ≤ 2.5 x ULN, alkaline phosphatase°≤°1.5°x ULN, serum creatinine ≤ 1.5 x ULN; Age ≥ 18 years ≤ 75 years Patients with childbearing potential should use effective contraception during the study and up 6 months after the end of chemotherapy Covered by a Health System where applicable, and/or in compliance with the recommendations of the national laws in force relating to biomedical research; Signed written informed consent obtained prior to any study-specific screening procedures Exclusion Criteria: Rectal tumor operated before inclusion Symptoms related to the rectal tumor requiring first intention rectal surgery (appreciated by investigator) Contra-indication for surgery Resectable metastases Complicated (obstruction, bleeding, abscess, perforation) primary tumor requiring emergency surgery and/or contra-indicating first line-chemotherapy Non-resectable primary tumor (with wild margin) Age > 75 years < 18 years ECOG performance status > 2 Under nutrition (albumin < 30 g/l) Peritoneal carcinomatosis Disease progression under chemotherapy (RECIST 1.1 criteria) Known hypersensitivity reaction or specific contraindications to any of the components of study treatments Clinically relevant coronary artery disease or history of myocardial infarction in the last 12 months, or high risk of uncontrolled arrhythmia Pregnancy (absence to be confirmed by ß-hCG test) or breast-feeding; Previous malignancy in the last 5 years Medical, geographical, sociological, psychological or legal conditions that would prevent the patient from completing the study or signing the informed consent; in the investigator's opinion Any significant disease which, in the investigator's opinion, excludes the patient from the study Under an administrative or legal supervision.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

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: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: A Primary tumor resection + chemotherapy<br>PT resection + systemic chemotherapy +/- target therapy | Procedure: Primary tumor resection + chemotherapy<br>* Step 1: Primary Tumor (PT) resection Within 3 weeks after randomization Immunonutrition given 7 days prior to PT resection Mechanical bowel preparation performed before surgery according to the local practices Performed by laparoscopy (recommended) or by laparotomy (at the investigator's discretion) Step 2: postoperative CT-scan Must be performed within 4 weeks after surgery CT-scan/MRI with the same criteria as pre-treatment evaluation Step 3: Chemotherapy +/- target therapy Within 4 weeks after the surgery Chemotherapy administered according to the usual scheme for the chosen protocol All validated and/or registered perioperative rectal cancer treatments authorized The duration of one treatment cycle depending on the type of treatment administered Radiotherapy is allowed after randomization if indicated<br>|
| Other: B Oxaliplatin/irinotecan + capecitabine, 5-FUI ± bevacizumab<br>Chemotherapy (+/- target therapy) | Drug: Oxaliplatin/irinotecan + capecitabine, 5-FUI ± bevacizumab<br>* Treatment will start within 3 weeks after randomization; Chemotherapy will be administered according to the regimen in the chosen protocol and validated by the MDOC of each center. If complications occur, emergency surgery can be performed according to the local practices of each investigator center. Radiotherapy is allowed after randomization if indicated (MDOC).<br>* Other names: EGFR antibodies panitumumad and cetuxiamb in case of KRAS wild-type tumors.;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival, defined as the time interval between the date of randomization and the date of death, with a 24 months' follow-up, in both treatment arms. | up to 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression free survival | Progression free survival will be assessed every 3 months during follow-up and will be estimated at 24 months. | up to 2 years | 
| Quality of life | Quality of life will be assessed at the time of randomization and then every 3 months in both treatment arms. The EORTC QLQ-C30, QLQ-CR29 questionnaires will be used. | Up to 2 years | 
| Toxicity of chemotherapy (Common Toxicity Criteria for Adverse Events (NCI-CTC-AE V4.0) | Chemotherapy toxicity will be graded according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTC-AE V4.0) in both treatment arms | Up to 2 years | 
| Response of the metastatic disease to systemic chemotherapy (RECIST 1.1 criteria) | The response rate of the metastatic disease will be evaluated in both treatment arms by CT scan and analyzed using the RECIST 1.1 criteria | up to2 years | 
| Time to disease progression | Time to disease progression is defined as the lapse of time between the date of randomization and the first date of progression (clinical or imaging) of the metastatic disease in both treatment arms, or of the primary rectal tumor in the chemotherapy arm (Arm B) | up to 2 years | 
| Post-operative morbidity | The evaluation of post-operative morbidity and mortality will be assessed in the primary tumor resection arm (Arm A) and in the chemotherapy arm (Arm B) for patients who require emergency surgery. The post-operative complications will be evaluated according to the Clavien-Dindo Classification of Surgical Complication and graded 0 to V. | within 30 days after surgical intervention | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rectal adenocarcinoma, unresectable, surgery, chemotherapy