Multicenter Phase 2 Trial: a Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR4)

A Randomized Multicenter Phase 2 Study: a Tailored Strategy for Locally Advanced Rectal Carcinoma

The purpose of this study is to determine whether the tailored management of locally advanced rectal carcinoma can improve the oncologic and functional outcome.

Study Overview

• Status: Completed
• Conditions: Rectal Carcinoma; Locally Advanced Malignant Neoplasm
• Intervention / Treatment: Other: Early tumor response evaluation by MRI volumetry; Procedure: Radical proctectomy with total mesorectal excision; Drug: Induction trichemotherapy - FOLFIRINOX regimen; Radiation: Radiochemotherapy Cap 50; Radiation: Radiochemotherapy Cap 60

Detailed Description

Locally advanced rectal carcinoma raise the issue of both the oncological control, local and general, and the therapeutic morbidity. Surgery alone can cure only one out of two patients, radiochemotherapy improves the local control but the metastatic risk remains about 30% with enhanced postoperative morbidity and poor functional results. The tumor response to preoperative treatment is the major prognostic factor which revealed the aggressiveness of the tumor. To this day, there are no biologic predictive markers for tumor response.

The purpose of this trial is to tailor the management according to the early tumoral response after short and intensive induction trichemotherapy. MRI volumetric tumor response will be used to distinguish between good responders and bad responders.

"Very good" responders will be randomized to either immediate surgery or radiochemotherapy followed by surgery (Standard arm: Cap 50). "Good or bad" responders will be randomized between two arms: intensive radiochemotherapy (Cap 60) or the standard arm (Cap 50).

This tailored management should result in a better oncologic prognosis with a lower rate of post therapeutic functional disorders.

• Study Type: Interventional
• Enrollment (Actual): 150
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Montpellier, France, 34298
    • CRLC Val d'Aurelle-Paul Lamarque

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed rectal carcinoma

• Primary tumor evaluated by pelvic MR Imaging:

  i) iT3 ≥c tumors, with MRI showing a predictive CRM ≤ 2 mm or a EMS (Extra Mural Spread) ≥ 5 mm

ii) Resectable iT4 tumors (only randomized within the "poor responders" group)

iii) Any T tumors with MRI showing a predictive CRM ≤ 1 mm

• No detectable metastases: Thorax-abdomen-pelvic CT-scan
• Patient ≥ 18 years
• ECOG Performance Status 0-1-2
• Patient information and written informed consent form signed
• Patient who can receive radiotherapy and chemotherapy
• Negative pregnancy test in women of childbearing potential
• Patient covered by a Social Security system
• Hematology : Haemoglobin ≥ 9 g/dL, WBC ≥ 4000/mm3, neutrophils ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L
• Hepatic function : total bilirubin ≤ 1.5 x ULN, AST and ALT ≤ 3 x ULN, Alkaline phosphatases ≤ 3 x ULN
• Renal function : creatinine ≤ 1.25 x ULN or creatinine clearance ≥ 60 ml/min

Exclusion Criteria:

• Indication for immediate surgery
• Primary tumor not measured at the MRI before inclusion
• Previous pelvic radiotherapy
• Contraindication to radiotherapy and/or chemotherapy
• Severe renal or liver impairment
• Cardiac and/or coronary disease which could contraindicate 5-Fu administration
• Active infectious disease
• Peripheral sensitive neuropathy
• History of prior cancer (except if it was cured more than 5 years ago, and if complete remission)
• Patient (male or female) of reproductive potential not using an effective contraceptive method during the whole treatment and up to 6 months after the completion of treatment
• Concurrent participation in any other clinical trial likely to interfere with the therapeutic schedule
• Fertile female patient not using adequate contraception, or breast-feeding woman

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A: immediate rectal surgery; "Very good" responder patients will be randomly assigned to proctectomy within 2-4 weeks after the end of the induction chemotherapy.	Other: Early tumor response evaluation by MRI volumetry; Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.; Procedure: Radical proctectomy with total mesorectal excision; The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.; Drug: Induction trichemotherapy - FOLFIRINOX regimen; A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).
Other: Arm B: RCT Cap 50 and then rectal surgery; "Very good" responder patients will be randomly assigned to receive chemoradiotherapy combining the administration of oral capecitabine (1600 mg/m2/day, BID) and radiotherapy at a total dose of 50 grays (2Gy/day, 5 days a week, 5 weeks, boost 6 Gy).	Other: Early tumor response evaluation by MRI volumetry; Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.; Procedure: Radical proctectomy with total mesorectal excision; The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.; Drug: Induction trichemotherapy - FOLFIRINOX regimen; A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).; Radiation: Radiochemotherapy Cap 50; RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or IMRT (2 Gy per fraction, 5 fractions per week during 5 weeks / 44 Gy in mini pelvis, and boost 6 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of RT treatment (2 daily intake).
Other: Arm C: RCT Cap 50 and then rectal surgery; "Good or poor" responder patients will be randomly assigned to receive chemoradiotherapy combining the administration of oral capecitabine (1600 mg/m2/day, BID) and radiotherapy at a total dose of 50 grays (2Gy/day, 5 days a week, 5 weeks, boost 6 Gy).	Other: Early tumor response evaluation by MRI volumetry; Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.; Procedure: Radical proctectomy with total mesorectal excision; The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.; Drug: Induction trichemotherapy - FOLFIRINOX regimen; A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).; Radiation: Radiochemotherapy Cap 50; RCT Cap 50 will combine radiotherapy at a dose of 50 Gy by either conventional 3D or IMRT (2 Gy per fraction, 5 fractions per week during 5 weeks / 44 Gy in mini pelvis, and boost 6 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of RT treatment (2 daily intake).
Experimental: Bras D: RCT Cap 60 and then rectal surgery; "Good or poor" responder patients will be randomly assigned to receive chemoradiotherapy combining the administration of oral capecitabine (1600 mg/m2/day, BID) and radiotherapy at a total dose of 60 grays (2Gy/day, 5 days a week, 6 weeks, boost 14 Gy).	Other: Early tumor response evaluation by MRI volumetry; Two weeks after the CT completion, the tumor volume will be measured by MRI with specific software which automatically borders the tumor so as to determine the early tumor response. A centralized reassessment of all MRI exams will be systematically performed by two radiologists of the coordinator center.; Procedure: Radical proctectomy with total mesorectal excision; The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.; Drug: Induction trichemotherapy - FOLFIRINOX regimen; A short (4 cycles) and intensive trichemotherapy combinig irinotecan 180 mg/m2, oxaliplatin 85 mg/m2, elvorin 200 mg/m2, 5-Fu (bolus 400 mg/m2, followed by a 46-hour continuous infusion 2,400 mg/m2) will be delivered for 8 weeks (D1=D15).; Radiation: Radiochemotherapy Cap 60; RCT Cap 60 will combine radiotherapy at a dose of 60 Gy by either conventional 3D or IMRT (2 Gy per fraction, 5 fractions per week during 6 weeks / 44 Gy in mini pelvis, and boost 16 Gy on reduced peritumoral volume) with concomitant oral capecitabine at 1600 mg/m2 per day delivered the days of RT treatment (2 daily intake)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ro resection rate	To confirm the feasibility of a tailored management with a 90% R0 resection rate achieved for all arms.	Within 15 days after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological complete response rate	To assess the pathological complete response rate (ypT0N0)	Within 15 days after surgery
Sphincter-saving surgery rate	To assess the impact of the therapeutic strategy on the rate of sphincter-saving surgery.	Up to 2 months after the end of the neoadjuvant treatment
Efficiency of MRI for prognosis	To specify the efficiency of MRI for prognosis in terms of volumetry, downstaging, downsizing and CRM measurement after completion of the induction trichemotherapy.	Within 15 days after the surgery
Compliance rate with neoadjuvant treatment schedule	To measure the compliance rate to the whole neoadjuvant schedule (induction CT + radiochemotherapy)	Within 4 months after the start of treatment
Acute and late toxicity of neoadjuvant treatments	To evaluate overall toxicity of neoadjuvant treatments (induction trichemotherapy + radiochemotherapy) according to the Common Terminology Criteria for Adverse Events v4.0 (NCI CTC v4.0).	For the duration of treatment, as expexcted to be up to 4 months and within the 5-year follow-up
Tumor regression grade (TRG)	To assess at pathologic examination the tumor regression grade (TRG) according to the Dworak classification.	Within 15 days after surgery
Perioperative and postoperative morbidity	To assess the impact of the therapeutic strategy on perioperative and postoperative morbidity.	Within 6 weeks after surgery and during the 5-year follow-up
Functional outcome	To assess the long-term digestive,urinary and sexual functional results of tailored strategy	For a 5-year follow-up
Quality of life	To assess the impact of treatments on quality of life according to the EORTC QLQ-C30.	For a 5-year follow-up
Local recurrence rate	To measure the local recurrence rate in each treatment arm.	For a 5-year follow-up
Incidence of metastases	To measure the incidence of distant metastases (liver, pulmonary, peritoneal, ganglionnary or any others) in each treatment arm.	For a 5-year follow-up

Collaborators and Investigators

• Sponsor: Institut du Cancer de Montpellier - Val d'Aurelle
• Investigators: Principal Investigator: Philippe ROUANET, MD, Ph D, CRLC Val d'Aurelle-Paul Lamarque

Publications and helpful links

General Publications

• Rouanet P, Rullier E, Lelong B, Maingon P, Tuech JJ, Pezet D, Castan F, Nougaret S; GRECCAR Study Group*. Tailored Strategy for Locally Advanced Rectal Carcinoma (GRECCAR 4): Long-term Results From a Multicenter, Randomized, Open-Label, Phase II Trial. Dis Colon Rectum. 2022 Aug 1;65(8):986-995. doi: 10.1097/DCR.0000000000002153. Epub 2022 Jul 5.
• Rouanet P, Rullier E, Lelong B, Maingon P, Tuech JJ, Pezet D, Castan F, Nougaret S; and the GRECCAR Study Group. Tailored Treatment Strategy for Locally Advanced Rectal Carcinoma Based on the Tumor Response to Induction Chemotherapy: Preliminary Results of the French Phase II Multicenter GRECCAR4 Trial. Dis Colon Rectum. 2017 Jul;60(7):653-663. doi: 10.1097/DCR.0000000000000849.

Study record dates

Study Major Dates

• Study Start: May 1, 2011
• Primary Completion (Actual): September 1, 2014
• Study Completion (Actual): September 1, 2014

Study Registration Dates

• First Submitted: April 8, 2011
• First Submitted That Met QC Criteria: April 11, 2011
• First Posted (Estimate): April 12, 2011

Study Record Updates

• Last Update Posted (Actual): August 21, 2017
• Last Update Submitted That Met QC Criteria: August 16, 2017
• Last Verified: August 1, 2017

More Information

Terms related to this study

• Keywords: locally advanced rectal carcinoma; Tailored treatment strategy; MRI volumetry; Early tumor response
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Neoplasms; Carcinoma; Rectal Neoplasms; Antineoplastic Agents; Folfirinox
• Other Study ID Numbers: GRECCAR 4; 2010-023546-73 (EudraCT Number)