folfoxiri compared to folfox in first line treatment of metastatic colorectal cancer

Conditions: Metastatic Colorectal Cancer

Summary: the purpose of the study is to evaluate if the exposure to all the three active cytotoxic agents (folfoxiri regimen) is superior in terms of progression-free survival to conventional chemotherapy with the folfox regimen as first-line treatment of chemo-naive metastatic colorectal cancer patients. a second primary aim is to evaluate the response rate, safety and tolerability of the chemotherapy of folfoxiri regimen in this patient population. patients will be randomized to two therapy groups: experimental arm a: chemotherapy with folfoxiri standard arm b: chemotherapy with folfox

survival of patients with metastatic colorectal cancer is correlated with the proportion of patients who receive all the three active drugs , but not with the proportion of patients who receive any second-line therapy. a superior efficacy in pfs,orr and os of folfoxiri has been reported with acceptable toxicity. moreover,evidence suggests that continuous dosing metronomic chemotherapy may be more efficacious than interval-chemotherapy. therefore, a way to improve the outcome of metastatic colorectal cancer patients could be to administer a maintenance first-line regimen containing the three active agents.

Eligibility criteria:
inclusion criteria: * signed informed consent obtained before any study specific procedures. -subjects must be able to understand and willing to sign a written informed consent. * male or female subjects ≥ 18 years ≤ 75 years of age * patients must have an eastern cooperative oncology group (ecog) performance status of 0 or 2.(ecog ps 0-2 for≥18 years ≤ 65 years of age ，ecog ps 0-1 for \>65 years of age) * histological or cytological documentation of adenocarcinoma of the colon or rectum. all other histological types are excluded. * there must be documentation by pet/ct scan, ct scan, mri, or intraoperative palpation (at the time of resection of the primary colorectal tumor, if applicable) that the patient has evidence of metastases (histologic confirmation of metastasis is not required.). * at least one measurable lesion according to response evaluation criteria in solid tumors (recist) criteria measured within 4 weeks prior to registration. * no previous chemotherapy or target therapy for metastatic disease (adjuvant chemotherapy for non-metastatic disease is allowed if terminated more than 6 months ago). * in case of previous radiotherapy, at least one measurable lesion should be located outside the irradiated field. * adequate bone marrow, hepatic and renal function as assessed by the following laboratory requirements conducted within 7 days of starting study treatment: * leukocytes ≥ 3.0 x109/ l, absolute neutrophil count (anc) ≥ 1.5 x109/ l, platelet count ≥ 100 x109/ l, hemoglobin (hb) ≥9g/ dl. * total bilirubin ≤ 1.5 x the upper limit of normal (uln). * alanine aminotransferase (alt) and aspartate aminotransferase (ast) ≤ 5 x uln. * alkaline phosphatase limit ≤ 5x uln. * amylase and lipase ≤ 1.5 x the uln. * serum creatinine ≤ 1.5 x the uln. * calculated creatinine clearance or 24 hour creatinine clearance ≥ 50 ml/ min. exclusion criteria: * previous palliative chemotherapy for metastatic disease，previous adjuvant chemotherapy including irinotecan or oxaliplatin within 6 months before random assignment. * previous or concurrent cancer that is distinct in primary site or histology from colorectal cancer within 5 years prior to randomization. * life expectancy \> 12 weeks; * extended field radiotherapy within 4 weeks or limited field radiotherapy within 2 weeks prior to randomization. subjects must have recovered from all therapy-related toxicities. * major surgical procedure, open biopsy, or significant traumatic injury within 4 weeks before start of study medication. * congestive heart failure ≤ new york heart association (nyha) class 2. * significant cardiovascular disease including unstable angina or myocardial infarction within 6 months before initiating study treatment or a history of ventricular arrhythmia * arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within the 6 months before start of study medication. * any evidence of active infection. * history of interstitial pneumonitis or pulmonary fibrosis * pregnancy or lactation at the time of study entry. * known dihydropyrimidine dehydrogenase (dpd) deficiency * any illness or medical conditions that are unstable or could jeopardize the safety of the subjects and his/her compliance in the study. * active inflammatory bowel disease or other bowel disease causing chronic diarrhoea * subjects with known allergy to the study drugs or to any of its excipients. * current or recent (within 4 weeks prior to starting study treatment) treatment of another investigational drug or participation in another investigational study. * continuous use of immunosuppressive agents (except the use of corticosteroids as anti-emetic prophylaxis/treatment).

Keywords: colorectal cancer metastatic colorectal cancer folfoxiri folfox oxaliplatin irinotecan leucovorin 5-fu