Optimisation of Response for Organ Preservation in Rectal Cancer : Neoadjuvant Chemotherapy and Radiochemotherapy vs. Radiochemotherapy (GRECCAR12)

Standard treatment of rectal cancer is rectal excision with neoadjuvant radiochemotherapy. A new concept suggests organ preservation as an alternative to rectal excision in good responders after neoadjuvant radiochemotherapy to decrease surgical morbidity and increase quality of life. The rational is the fact that 15% of patients have sterilized tumours after radiochemotherapy for T3T4 rectal cancer. The French GRECCAR 2 trial is the first phase III trial investigating this strategy: patients with T2T3 low rectal carcinomas (size ≤4 cm) received 50 Gy with capecitabine and good clinical responders (≤2 cm) were randomized between local and rectal excision. The main findings were: the rate of complete pathologic response was higher after radiochemotherapy for small T2T3 than for T3T4 tumours (40% vs 15% ypT0) and good pathologic responders (ypT0-1) were associated with zero positive mesorectal nodes.

The objective of the new trial is to increase the proportion of patients treated with organ preservation by optimizing tumour response. As compared to Folfiri, tritherapy Folfirinox has been shown to enhance the response rate. In patients with colorectal metastases, response rate and R0 resection were twice higher, resulting in improved survival. Folfirinox also increases response and chance of R0 resection rates in initially unresectable colorectal metastases, compared to standard or intensified bi-chemotherapy regimens. Adding two months of neoadjuvant chemotherapy (Folfirinox) before radiochemotherapy, the investigators expect to increase chance of organ preservation rate, as compared to radiochemotherapy alone.

Study Overview

• Status: Active, not recruiting
• Conditions: Rectal Cancer
• Intervention / Treatment: Drug: Neoadjuvant chemotherapy Folfirinox, 4 cycles; Radiation: 50 Gy, 2 Gy/session; 25 fractions; Procedure: Local excision in good responders; Procedure: Rectal excision in bad responders; Drug: Capecitabine

• Study Type: Interventional
• Enrollment (Actual): 218
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Amiens, France
    • Service de Chirurgie Digestive, CHU Amiens Picardie
  • Besançon, France
    • Service de Chirurgie Digestive, CHU de Besançon
  • Bordeaux, France
    • Service de Chirurgie Digestive, Institut Bergonié
  • Bordeaux, France
    • Service de Chirurgie Digestive, Hôpital Haut-Lévêque - CHU de Bordeaux
  • Clermont-Ferrand, France
    • Service de Chirurgie Digestive, CHU Estaing - CHRU Clermont Ferrand
  • Clichy, France
    • Service de Chirurgie Digestive, Hôpital Beaujon - APHP
  • Dijon, France
    • Service de Chirurgie Digestive, Centre Georges François Leclerc - Dijon
  • La Tronche, France
    • Service de Chirurgie Digestive, Hôpital Albert Michallon - CHU de Grenoble
  • Lille, France
    • Service de Chirurgie Digestive, Centre Oscar Lambret - Lille
  • Lyon, France
    • Service de Chirurgie Digestive, Centre Léon Bérard - Lyon
  • Lyon, France
    • Service de Chirurgie Digestive, Hôpital Lyon Sud - CHU Lyon
  • Marseille, France
    • Service de Chirurgie Digestive, CHU de la Timone - Marseille
  • Marseille, France
    • Service de Chirurgie Digestive, Institut Paoli Calmette - Marseille
  • Marseille, France
    • Service de Chirurgie Digestives, Hôpital Européen de Marseille
  • Montpellier, France
    • Service de Chirurgie Digestive, Institut du Cancer de Montpellier
  • Mougins, France
    • Service d'Oncologie et Radiothérapie, Centre Azuréen de Cancérologie
  • Nancy, France
    • Service de Chirurgie Digestive,Institut de Cancérologie de Lorraine
  • Nantes, France
    • Service de Chirurgie Digestive, Hôtel Dieu - CHU de Nantes
  • Nîmes, France
    • Service de Chirurgie Digestive, CHU Carémeau - Nîmes
  • Paris, France
    • GH Paris saint Joseph
  • Paris, France
    • Service de Chirurgie Digestive et Oncologique, Hôpital Bicêtre - APHP
  • Paris, France
    • Service de Chirurgie Digestive, Hôpital les Diaconnesses
  • Paris, France
    • Service de Chirurgie Digestive, Hôpital Saint-Antoine - APHP
  • Paris, France
    • Service de Chirurgie Digestive, Hôpital Saint-Louis - APHP Paris
  • Rennes, France
    • Service de Chirurgie Digestive, Hôpital Pontchaillou - CHU Rennes
  • Rouen, France
    • Service de Chirurgie Digestive, Hôpital Charles Nicolle - CHU de Rouen
  • Toulouse, France
    • Service de Chirurgie Digestive, Hôpital Purpan - CHU de Toulouse
  • Vandœuvre-lès-Nancy, France
    • Service de chirurgie digestive, CHRU de Nancy -Hôpital de Brabois
  • Villejuif, France
    • Département de chirurgie digestive, Institut Gustave Roussy

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Rectal adenocarcinoma
• cT2T3
• cN0-1 (≤ 3 positive lymph nodes or size ≤8mm)
• Tumour size ≤4 cm
• Location ≤10 cm from the anal verge
• No distant metastasis
• Patient ≥18 years
• ECOG ≤2
• Effective contraception during the study
• Patient and doctor have signed informed consent

Exclusion Criteria:

• T1 or T4
• Tumour size >4cm
• N2 (>3 positive lymph nodes or size >8mm)
• Tumour > 10 cm from the anal verge
• Distant metastasis
• Chronic intestinal inflammation and/or bowel obstruction
• Contra indication for chemotherapy and/or radiotherapy
• Previous pelvic radiotherapy or chemotherapy
• Severe renal, hepatic insufficiency (serum creatinine<30ml/min)
• Peripheral neuropathy > grade 1
• Complete or partial Dihydropyrimidine deshydrogenase (DPD) deficiency (uracilemia ≥ 16 ng/mL)
• Concomitant treatment with millepertuis, yellow fever vaccine, phenytoin or sorivudine (or chemically equivalent)
• Pregnant or breast-feeding woman.
• Persons deprived of liberty or under guardianship
• Impossibility for compliance to follow-up

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Chemotherapy and Radiochemotherapy; Neoadjuvant chemotherapy Folfirinox, 4 cycles: oxaliplatin: 85 mg/m2; irinotecan: 180 mg/m²; folinic acid: 400 mg/m2 (DL form) or 200 mg/m2 (L form); 5FU: 2400 mg/m2 Radiochemotherapy : 2 to 4 weeks after chemotherapy, 5 weeks (50 Gy, 2 Gy/session; 25 fractions) + capecitabine (1600 mg/m2 daily 5 days/7)	Drug: Neoadjuvant chemotherapy Folfirinox, 4 cycles; oxaliplatin: 85 mg/m2; irinotecan: 180 mg/m²; folinic acid: 400 mg/m2 (DL form) or 200 mg/m2 (L form); 5FU: 2400 mg/m2; Radiation: 50 Gy, 2 Gy/session; 25 fractions; Radiochemotherapy 5 weeks; Procedure: Local excision in good responders; If local excision: Surveillance if ypT0-1 or ypT2Nx/cN0 (no lymph node at baseline imaging); Complementary rectal excision if ypT2Nx/cN1, ypT3 or R1.; Procedure: Rectal excision in bad responders; Drug: Capecitabine; 1600 mg/m2 daily 5 days/7
Active Comparator: Radiochemotherapy; Radiochemotherapy: 5 weeks (50 Gy, 2 Gy/session ; 25 fractions) + capecitabine (1600 mg/m2 daily 5 days/7, excluding weekends)	Radiation: 50 Gy, 2 Gy/session; 25 fractions; Radiochemotherapy 5 weeks; Procedure: Local excision in good responders; If local excision: Surveillance if ypT0-1 or ypT2Nx/cN0 (no lymph node at baseline imaging); Complementary rectal excision if ypT2Nx/cN1, ypT3 or R1.; Procedure: Rectal excision in bad responders; Drug: Capecitabine; 1600 mg/m2 daily 5 days/7

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of organ preservation and absence of stoma	Number of patients with organ preservation and absence of stoma at 1 year after surgery	1 year after surgery

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Tolerance to treatment	Number of patients with adverse events	From beginning of neoadjuvant treatment until 1 year after surgery
Compliance to treatment	Number of patients receiving full neoadjuvent treatment and the allocated surgery	From beginning of neoadjuvant treatment until surgery, expected average 20 weeks after neoadjuvant treatment
Rate of clinical complete response	To determine the rate of grade 1 : no tumor at digital examination	At 8 weeks after neoadjuvant treatment
Rate of radiological response	To determine the rate of tumor ≤ 2 cm with TRG1-3 at MRI	At 8 weeks after neoadjuvant treatment
Rate of complete pathologic response	To determine the rate of ypT0	At surgery, expected average 10 weeks after neoadjuvant treatment
Correlation between radiological and clinical response	To analyse the correlation between radiological response ( tumor ≤ 2 cm with TRG1-3 at MRI) and clinical response (grade 1)	Between 8 to 10 weeks after neoadjuvant treatment
Correlation between radiological (radiomic analysis) and pathologic response	To analyse the correlation between radiological response ( tumor ≤ 2 cm with TRG1-3 at MRI) and pathological response (ypT0)	Between 8 to 10 weeks after neoadjuvant treatment
Rate of curative surgery	To determine the rate of R0 resection	At surgery, expected average 10 weeks after neoadjuvant treatment
Surgical morbidity	To analyse the cumulative Clavien-Dindo at 1 year	From surgery until 1 year of follow-up
Quality of life	To examine score of questionnaires : QLQ CR-30, QLQ CR-29	From randomization until 1 year after surgery
Local recurrence	To determine the rate of local recurrence at 3 years	From surgery until 3 years of follow-up
Overall survival	To determine the rate of overall survival at 3 years	From surgery until 3 years of follow-up
Disease-free survival	To determine the rate of disease-free survival at 3 years	From surgery until 3 years of follow-up

Collaborators and Investigators

• Sponsor: University Hospital, Bordeaux
• Investigators: Principal Investigator: Christophe LAURENT, Prof., University Hospital Bordeaux, France

Study record dates

Study Major Dates

• Study Start (Actual): January 28, 2016
• Primary Completion (Actual): June 9, 2022
• Study Completion (Estimated): June 1, 2024

Study Registration Dates

• First Submitted: July 6, 2015
• First Submitted That Met QC Criteria: July 31, 2015
• First Posted (Estimated): August 3, 2015

Study Record Updates

• Last Update Posted (Actual): March 7, 2024
• Last Update Submitted That Met QC Criteria: March 6, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Neoadjuvant chemotherapy; Local excision; Organ preservation; Radiochemotherapy; Tumour response; Folfirinox
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Capecitabine; Folfirinox
• Other Study ID Numbers: CHUBX 2014/33

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO