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

Study Overview
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Brief Summary
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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.

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

Conditions
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Rectal Cancer

Intervention / Treatment
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* 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


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 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: Supportive Care
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Chemotherapy and Radiochemotherapy<br>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<br>* 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<br>Radiation: 50 Gy, 2 Gy/session; 25 fractions<br>* Radiochemotherapy 5 weeks<br>Procedure: Local excision in good responders<br>* 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.<br>Procedure: Rectal excision in bad responders<br> <br> Drug: Capecitabine<br>* 1600 mg/m2 daily 5 days/7<br>|
| Active Comparator: Radiochemotherapy<br>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<br>* Radiochemotherapy 5 weeks<br>Procedure: Local excision in good responders<br>* 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.<br>Procedure: Rectal excision in bad responders<br> <br> Drug: Capecitabine<br>* 1600 mg/m2 daily 5 days/7<br>|

What is the study measuring?
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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 |
| --- | --- | --- |
| 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 | 
| Tolerance to treatment | Number of patients with adverse events | From beginning of neoadjuvant treatment until 1 year after surgery | 
| 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Folfirinox, Organ preservation, Local excision, Radiochemotherapy, Neoadjuvant chemotherapy, Tumour response