Adjuvant FOLFIRI Based-chemotherapy After Resection of CLM Responding to Preoperative FOLFIRI

This study is a National, multicenter, open-label randomized, 2-arm, phase III superiority trial comparing postoperative reintroduction of FOLFIRI based-chemotherapy (experimental arm) vs no treatment (control arm) in patients undergoing resection of colorectal liver metastases after good response to FOLFIRI-based chemotherapy with or without targeted agent.

Inclusion criteria

are:

• Histologically proven resected metachronous CLM with curative intent that could not be treated with perioperative oxaliplatin-based chemotherapy for oncologic or tolerability reasons. For this study, metachronous CLM is defined as liver recurrence occurring more than 12 months after treatment of the primary colorectal cancer.
• No more than 10 treated CLM at surgery
• At least 2 cycles and no more than 8 cycles of preoperative FOLFIRI based chemotherapy ± targeted therapy.
• Preoperative FOLFIRI based chemotherapy ± targeted therapy administered no more than 12 weeks before surgery
• R0/R1resection ± radiofrequency ablation with curative intent of all liver deposits with no macroscopic residual liver disease
• Objective response to preoperative therapy defined as complete or partial radiological response and/or major or complete pathologic response
• No extrahepatic or residual liver disease on baseline work-up including thoraco-abdominal CT scan within 6 weeks after surgery. 1 non-specific lung nodule of less than 10 mm in maximum diameter is not considered as extra-hepatic metastases
• Primary tumor (or liver metastasis) of CRC must be characterized for RAS and BRAF status
• No contraindication to FOLFIRI based chemotherapy
• Patients must be 18 years old or older
• A WHO performance status of 0 or 1
• Participants must be affiliated to a social security scheme The primary objective is demonstrate an improvement of disease-free survival rate at 3 years.

In the experimental arm, patients will be treated with irinotecan 180 mg/m2 + leucovorin 400 mg/m2 at day 1 then 5-FU 400 mg/m2 bolus followed by 2400 mg/m2 continuous infusion over 46 h biweekly. For a total of 12 cycles of perioperative chemotherapy including the preoperative chemotherapy.

In the control arm, patients do not receive any adjuvant treatment. This is an intention-to-treat trial. Based on published data, 3-year DFS in the control arm is 25%. Expected 3-year DFS in the experimental group is 40%. The sample size in each group is 127, with a total number of 185 events required, an exponential maximum likelihood test of equality of survival curves with a 0,050 two-sided significance level will have 80% power to detect the difference between groups (constant hazard-ratio of 0,662); assuming a 36 month length of accrual period, a 72 maximum length of follow up and 5% annual attrition (following exponential model) over study period (following exponential model) over study period.

Inclusion criteria

• Histologically proven resected metachronous CLM with curative intent that could not be treated with perioperative oxaliplatin-based chemotherapy for oncologic or tolerability reasons. For this study, metachronous CLM is defined as liver recurrence occurring more than 12 months after treatment of the primary colorectal cancer.
• No more than 10 treated CLM at surgery
• At least 2 cycles and no more than 8 cycles of preoperative FOLFIRI based chemotherapy ± targeted therapy.
• Preoperative FOLFIRI based chemotherapy ± targeted therapy administered no more than 12 weeks before surgery
• R0/R1resection ± radiofrequency ablation with curative intent of all liver deposits with no macroscopic residual liver disease
• Objective response to preoperative therapy defined as complete or partial radiological response and/or major or complete pathologic response
• No extrahepatic or residual liver disease on baseline work-up including thoraco-abdominal CT scan within 6 weeks after surgery. 1 non-specific lung nodule of less than 10 mm in maximum diameter is not considered as extra-hepatic metastases
• Primary tumor (or liver metastasis) of CRC must be characterized for RAS and BRAF status
• No contraindication to FOLFIRI based chemotherapy
• Patients must be 18 years old or older
• A WHO performance status of 0 or 1
• Participants must be affiliated to a social security scheme

Exclusion criteria

• Palliative/R2 resection of CLM
• 10 lesions or more treated at the time of surgery
• Patients undergoing only radiofrequency ablation of all liver deposit (this situation precludes the assessment of pathologic response to preoperative chemotherapy)
• Extra-hepatic or residual metastasis of CRC
• Absence of objective response to therapy (radiological or pathological response )
• Inflammatory bowel disease
• Known UGT1A1*28 allele homozygosity
• complete absence of dihydropyrimidine dehydrogenase (DPD) activity (blood uracil level ≥ 150 ng/ml
• Contraindications to investigational medicinal products (irinotecan, 5-FU, folinic acid) and to auxiliary medicinal products (ondansetron, methylprednisolone)
• Persistent toxicity ≥ grade 1 related to preoperative FOLFIRI based chemotherapy
• Known pregnancy (pregnancy test for women of childbearing) or breastfeeding women