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

Phase 3

Completed

• Conditions: Rectal Cancer
• Interventions: Radiation: 50 Gy, 2 Gy/session; 25 fractions; Drug: Neoadjuvant chemotherapy Folfirinox, 4 cycles; Procedure: Local excision in good responders; Procedure: Rectal excision in bad responders; Drug: Capecitabine

• Registration Number: NCT02514278
• Lead Sponsor: University Hospital, Bordeaux

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-07-06
• Study First Submitted QC: 2015-07-31
• Study First Posted: 2015-08-03
• Study Start: 2016-01-28
• Primary Completion: 2022-06-09
• Study Completion: 2024-06-30
• Status Verified: 2024-08
• Last Update Submitted: 2024-08-13
• Last Update Posted: 2024-08-14

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 218

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

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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

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Chemotherapy and Radiochemotherapy	Capecitabine	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)
Radiochemotherapy	Rectal excision in bad responders	Radiochemotherapy: 5 weeks (50 Gy, 2 Gy/session ; 25 fractions) + capecitabine (1600 mg/m2 daily 5 days/7, excluding weekends)
Radiochemotherapy	50 Gy, 2 Gy/session; 25 fractions	Radiochemotherapy: 5 weeks (50 Gy, 2 Gy/session ; 25 fractions) + capecitabine (1600 mg/m2 daily 5 days/7, excluding weekends)
Radiochemotherapy	Local excision in good responders	Radiochemotherapy: 5 weeks (50 Gy, 2 Gy/session ; 25 fractions) + capecitabine (1600 mg/m2 daily 5 days/7, excluding weekends)
Radiochemotherapy	Capecitabine	Radiochemotherapy: 5 weeks (50 Gy, 2 Gy/session ; 25 fractions) + capecitabine (1600 mg/m2 daily 5 days/7, excluding weekends)
Chemotherapy and Radiochemotherapy	50 Gy, 2 Gy/session; 25 fractions	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)
Chemotherapy and Radiochemotherapy	Local excision in good responders	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)
Chemotherapy and Radiochemotherapy	Neoadjuvant chemotherapy Folfirinox, 4 cycles	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)
Chemotherapy and Radiochemotherapy	Rectal excision in bad responders	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)

Primary Outcome Measures

Name	Time	Method
Rate of organ preservation and absence of stoma	1 year after surgery	Number of patients with organ preservation and absence of stoma at 1 year after surgery

Secondary Outcome Measures

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

Trial Locations

Locations (29)

Service de Chirurgie Digestive, Hôpital Albert Michallon - CHU de Grenoble; 🇫🇷 La Tronche, France

Service de Chirurgie Digestive, CHU de Besançon; 🇫🇷 Besançon, France

Service de Chirurgie Digestives, Hôpital Européen de Marseille; 🇫🇷 Marseille, France

Service de Chirurgie Digestive, Hôpital Lyon Sud - CHU Lyon; 🇫🇷 Lyon, France

Service de Chirurgie Digestive, Institut Bergonié; 🇫🇷 Bordeaux, France

Service d'Oncologie et Radiothérapie, Centre Azuréen de Cancérologie; 🇫🇷 Mougins, France

Service de Chirurgie Digestive, Hôtel Dieu - CHU de Nantes; 🇫🇷 Nantes, France

Service de Chirurgie Digestive, Hôpital Beaujon - APHP; 🇫🇷 Clichy, France

Service de Chirurgie Digestive, Centre Oscar Lambret - Lille; 🇫🇷 Lille, France

Service de Chirurgie Digestive, CHU Estaing - CHRU Clermont Ferrand; 🇫🇷 Clermont-Ferrand, France

Service de Chirurgie Digestive,Institut de Cancérologie de Lorraine; 🇫🇷 Nancy, France

Service de Chirurgie Digestive, Centre Georges François Leclerc - Dijon; 🇫🇷 Dijon, France

Service de Chirurgie Digestive, CHU Amiens Picardie; 🇫🇷 Amiens, France

Service de Chirurgie Digestive, CHU de la Timone - Marseille; 🇫🇷 Marseille, France

Service de Chirurgie Digestive, Institut du Cancer de Montpellier; 🇫🇷 Montpellier, France

Service de Chirurgie Digestive, Hôpital les Diaconnesses; 🇫🇷 Paris, France

GH Paris Saint Joseph; 🇫🇷 Paris, France

Service de Chirurgie Digestive, Hôpital Pontchaillou - CHU Rennes; 🇫🇷 Rennes, France

Service de Chirurgie Digestive, CHU Carémeau - Nîmes; 🇫🇷 Nîmes, France

Service de Chirurgie Digestive et Oncologique, Hôpital Bicêtre - APHP; 🇫🇷 Paris, France

Département de chirurgie digestive, Institut Gustave Roussy; 🇫🇷 Villejuif, France

Service de Chirurgie Digestive, Hôpital Saint-Antoine - APHP; 🇫🇷 Paris, France

Service de Chirurgie Digestive, Hôpital Saint-Louis - APHP Paris; 🇫🇷 Paris, France

Service de Chirurgie Digestive, Hôpital Charles Nicolle - CHU de Rouen; 🇫🇷 Rouen, France

Service de Chirurgie Digestive, Hôpital Purpan - CHU de Toulouse; 🇫🇷 Toulouse, France

Service de chirurgie digestive, CHRU de Nancy -Hôpital de Brabois; 🇫🇷 Vandœuvre-lès-Nancy, France

Service de Chirurgie Digestive, Hôpital Haut-Lévêque - CHU de Bordeaux; 🇫🇷 Bordeaux, France

Service de Chirurgie Digestive, Centre Léon Bérard - Lyon; 🇫🇷 Lyon, France

Service de Chirurgie Digestive, Institut Paoli Calmette - Marseille; 🇫🇷 Marseille, France