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

Primary Purpose

Locally Advanced Malignant Neoplasm, Rectal Carcinoma

Status

Completed

Phase

Phase 2

Locations

France

Study Type

Interventional

Intervention

Induction trichemotherapy - FOLFIRINOX regimen

Early tumor response evaluation by MRI volumetry

Radiochemotherapy Cap 50

Radiochemotherapy Cap 60

Radical proctectomy with total mesorectal excision

About this trial

This is an interventional treatment trial for Locally Advanced Malignant Neoplasm focused on measuring locally advanced rectal carcinoma, Tailored treatment strategy, MRI volumetry, Early tumor response

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

CRLC Val d'Aurelle-Paul Lamarque

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Other

Experimental

Arm Label

Arm A: immediate rectal surgery

Arm B: RCT Cap 50 and then rectal surgery

Arm C: RCT Cap 50 and then rectal surgery

Bras D: RCT Cap 60 and then rectal surgery

Arm Description

"Very good" responder patients will be randomly assigned to proctectomy within 2-4 weeks after the end of the induction chemotherapy.

"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).

"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).

"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).

Outcomes

Primary Outcome Measures

Ro resection rate

To confirm the feasibility of a tailored management with a 90% R0 resection rate achieved for all arms.

Secondary Outcome Measures

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.

Compliance rate with neoadjuvant treatment schedule

To measure the compliance rate to the whole neoadjuvant schedule (induction CT + radiochemotherapy)

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).

Pathological complete response rate

To assess the pathological complete response rate (ypT0N0)

Tumor regression grade (TRG)

To assess at pathologic examination the tumor regression grade (TRG) according to the Dworak classification.

Perioperative and postoperative morbidity

To assess the impact of the therapeutic strategy on perioperative and postoperative morbidity.

Sphincter-saving surgery rate

To assess the impact of the therapeutic strategy on the rate of sphincter-saving surgery.

Functional outcome

To assess the long-term digestive,urinary and sexual functional results of tailored strategy

Quality of life

To assess the impact of treatments on quality of life according to the EORTC QLQ-C30.

Local recurrence rate

To measure the local recurrence rate in each treatment arm.

Incidence of metastases

To measure the incidence of distant metastases (liver, pulmonary, peritoneal, ganglionnary or any others) in each treatment arm.

Full Information

NCT ID

NCT01333709

First Posted

April 8, 2011

Last Updated

August 16, 2017

Sponsor

Institut du Cancer de Montpellier - Val d'Aurelle

1. Study Identification

Unique Protocol Identification Number

NCT01333709

Brief Title

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

Acronym

GRECCAR4

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2017

Overall Recruitment Status

Completed

Study Start Date

May 2011 (undefined)

Primary Completion Date

September 2014 (Actual)

Study Completion Date

September 2014 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Institut du Cancer de Montpellier - Val d'Aurelle

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Locally Advanced Malignant Neoplasm, Rectal Carcinoma

Keywords

locally advanced rectal carcinoma, Tailored treatment strategy, MRI volumetry, Early tumor response

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

150 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Arm A: immediate rectal surgery

Arm Type

Experimental

Arm Description

"Very good" responder patients will be randomly assigned to proctectomy within 2-4 weeks after the end of the induction chemotherapy.

Arm Title

Arm B: RCT Cap 50 and then rectal surgery

Arm Type

Other

Arm Description

Arm Title

Arm C: RCT Cap 50 and then rectal surgery

Arm Type

Other

Arm Description

Arm Title

Bras D: RCT Cap 60 and then rectal surgery

Arm Type

Experimental

Arm Description

"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).

Intervention Type

Drug

Intervention Name(s)

Induction trichemotherapy - FOLFIRINOX regimen

Intervention Description

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).

Intervention Type

Other

Intervention Name(s)

Early tumor response evaluation by MRI volumetry

Intervention Description

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.

Intervention Type

Radiation

Intervention Name(s)

Radiochemotherapy Cap 50

Intervention Description

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).

Intervention Type

Radiation

Intervention Name(s)

Radiochemotherapy Cap 60

Intervention Description

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)

Intervention Type

Procedure

Intervention Name(s)

Radical proctectomy with total mesorectal excision

Intervention Description

The proctectomy can be performed by laparoscopic surgery or conventional laparotomy.

Primary Outcome Measure Information:

Title

Ro resection rate

Description

To confirm the feasibility of a tailored management with a 90% R0 resection rate achieved for all arms.

Time Frame

Within 15 days after surgery

Secondary Outcome Measure Information:

Title

Efficiency of MRI for prognosis

Description

To specify the efficiency of MRI for prognosis in terms of volumetry, downstaging, downsizing and CRM measurement after completion of the induction trichemotherapy.

Time Frame

Within 15 days after the surgery

Title

Compliance rate with neoadjuvant treatment schedule

Description

To measure the compliance rate to the whole neoadjuvant schedule (induction CT + radiochemotherapy)

Time Frame

Within 4 months after the start of treatment

Title

Acute and late toxicity of neoadjuvant treatments

Description

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).

Time Frame

For the duration of treatment, as expexcted to be up to 4 months and within the 5-year follow-up

Title

Pathological complete response rate

Description

To assess the pathological complete response rate (ypT0N0)

Time Frame

Within 15 days after surgery

Title

Tumor regression grade (TRG)

Description

To assess at pathologic examination the tumor regression grade (TRG) according to the Dworak classification.

Time Frame

Within 15 days after surgery

Title

Perioperative and postoperative morbidity

Description

To assess the impact of the therapeutic strategy on perioperative and postoperative morbidity.

Time Frame

Within 6 weeks after surgery and during the 5-year follow-up

Title

Sphincter-saving surgery rate

Description

To assess the impact of the therapeutic strategy on the rate of sphincter-saving surgery.

Time Frame

Up to 2 months after the end of the neoadjuvant treatment

Title

Functional outcome

Description

To assess the long-term digestive,urinary and sexual functional results of tailored strategy

Time Frame

For a 5-year follow-up

Title

Quality of life

Description

To assess the impact of treatments on quality of life according to the EORTC QLQ-C30.

Time Frame

For a 5-year follow-up

Title

Local recurrence rate

Description

To measure the local recurrence rate in each treatment arm.

Time Frame

For a 5-year follow-up

Title

Incidence of metastases

Description

To measure the incidence of distant metastases (liver, pulmonary, peritoneal, ganglionnary or any others) in each treatment arm.

Time Frame

For a 5-year follow-up

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Philippe ROUANET, MD, Ph D

Organizational Affiliation

CRLC Val d'Aurelle-Paul Lamarque

Official's Role

Principal Investigator

Facility Information:

Facility Name

CRLC Val d'Aurelle-Paul Lamarque

City

Montpellier

ZIP/Postal Code

34298

Country

France

12. IPD Sharing Statement

Citations:

PubMed Identifier

34759247

Citation

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.

Results Reference

derived

PubMed Identifier

28594714

Citation

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.

Results Reference

derived

Learn more about this trial

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

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