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oxaliplatin +leucovorinL+5-Fluorouracile +cetuximab+'Metastases Resection ( multiple steep surgery possible)

Irinotecan+ + leucovorinL +5-Fluorouracile + cetuximab +'Metastases Resection ( multiple steep surgery possible)

Metastases resection will be process by surgery, after a randomized chemotherapy (FOLFOX or FOLFIRI) + Target therapy (Cetuximab). The surgery will allow to compare the pathological response on the resected metastases by the chemotherapy + target therapy type.

Metastases Resection ( multiple steep surgery possible)

5-FU bolus 400 mg/m2, IV bolus every 2 weeks 5-FU continuous infusion 2400 mg/m2, 46-hour cont. IV infusion every 2 weeks

5-Fluorouracile

Leucovorin L (levoleucovorin) 200 mg/m2 (or folinic acid 400 mg/m²) in 250 ml glucose 5%, 2-hour IV infusion

leucovorin L

Oxaliplatin 85 mg/m² in 150 ml NaCl 0.9%, 2-hour IV infusion every 2 weeks

Irinotecan 180 mg/m² in 150 ml NaCl 0.9%, 1.30-hour IV infusion every 2 weeks

Cetuximab 400 mg/m² in 100 ml NaCl 0.9% 2-hour IV infusion for 1rst cycle and after the 1rst cycle 250 mg/m² in 100 ml NaCl 0.9% 1-hour IV infusion

Marc Van den Eynde, MD

Javier Carrasco, MD PhD

To analyze the pathological tumor response on resected colorectal cancer metastases after preoperative treatment with cetuximab combined with FOLFOX or FOLFIRI regimen in a prospective cohort (RAS and B-RAF WT tumors) and to correlate this response with patient's outcome.

This is a phase II , openlabel, randomized study in patients with confirmed diagnosis of potentially or borderline resectable metastatic colorectal adenocarcinoma (RAS and B-RAF WT tumors ), who have not received prior chemotherapy for their metastatic disease.

The study is designed to compare pathological responses observed after pre-operative chemotherapy cetuximab with FOLFOX or FOLFIRI.

Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

Randomised Phase 2 Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

Major pathological response rate (MPRR) is defined as the proportion of patients presenting a major pathological response. Pathologic response will be evaluated according the Rubbia-Brandt Tumor Regression Grade classification .For patients with multiple colorectal metastases the global pathological response will be categorized based on the mean TRG of all metastases.: a major response is defined as a mean TRG \< 3, a partial response is defined for patient presenting a mean TRG ≥3 and \<4, and a no response for patient with a mean TRG ≥4.

-Progression Free Survival (PFS) is defined as the time from randomization to the time of first event (relapse of the original mCRC, development of a new colorectal cancer or death due to any cause). Patients without any such event at the time of data analysis will be censored at the last date they were known to be event-free. PFS analysis will be based on tumour assessments and survival follow-up assessments.

The overall survival will be analyzed at the end of study (3 year of recruitment and one year of follow-up).

Clinical response rate at time of surgery: Clinical tumour response will be measured according to the RECIST 1.1 criteria

Metabolic response rate at time of surgery (in selected centres only, optional): Metabolic tumour response will be measured according to the EORTC criteria . PET-Scan evaluation remains optional to selected centres only.

. Severe pre- or postoperative complications within 30 days of surgery:

* surgery-associated bleeding requiring replacement with \> 4 units of erythrocyte concentrates,
* wound infection,
* intra-abdominal infection,
* severe sepsis (American College of Chest physicians/Society of Critical Care Medicine, 1992),
* impaired wound healing,
* subphrenic or perihepatic abscess requiring drainage during hospital stay or within 30 days after the operation,
* re-laparotomy connected with the resection,
* a biliary fistula for more than 10 days with a discharge of \> 100 mL/day,
* transient liver failure (bilirubin \> 10 mg/dL lasting \> 3 days),
* renal failure requiring dialysis,
* respiratory failure with renewed necessary mechanical ventilation, venous thromboembolism,
* cardiac failure,
* death of the patient as a result of the operation.

Curative resection rate (R0 resection) is defined by the surgical clearance (+/- radiofrequency ablation) of all detectable hepatic lesions with tumor-free margins at histo-pathological evaluation.

Systemic neo-adjuvant chemotherapy in mCRC frequently causes morphological lesions involving hepatic microvasculature . Sinusoidal obstruction, complicated by perisinusoidal fibrosis and veno-occlusive lesion of the non tumoral liver, should be included in the list of the adverse side-effects of colorectal systemic chemotherapy, in particular related to the use of oxaliplatin.

Spots Global Cancer Trial Database for Study Comparing Pathological Responses Observed on Colorectal Cancer Metastases Resected After Preoperative Treatment Combining Cetuximab With FOLFOX or FOLFIRI in RAS and B-RAF WT Tumors

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