Abstract
BackgroundThe FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). Adding cetuximab to FOLFOX or FOLFIRI increased efficacy in patients with k-ras wild type mCRC. We explored the dose limiting toxicity and feasibility of the combination cetuximab, irinotecan, oxaliplatin, 5-FU and FA in mCRC patients.MethodsIn a dose-escalation study patients with previously untreated mCRC and a WHO performance status 0–1 received cetuximab (500 mg/m2, 2 h), followed by irinotecan (95, 125, and 165 mg/m2 in the dose levels [DL] 1, 2, and 3 respectively), followed by oxaliplatin (85 mg/m2, 2 h) which was given parallel to FA (400 mg/m2, 2 h) and followed by 5-FU (3200 mg/m2, 46 h) in an outpatient setting every two weeks. The primary endpoints were the maximum tolerable dose and the safety. The trial was approved by the local ethics committee.ResultsFrom 2007 to 2008, twenty patients were treated in this trial. In the first dose level (irinotecan 95 mg/m2) one patient developed neutropenia grade 4. One patient experienced diarrhoea grade 3 as DLT in dose level 2 (irinotecan 125 mg/m2). In dose level 3 (irinotecan 165 mg/m2), three patients experienced a DLT (diarrhoea grade 3 and two patients with neutropenia grade 4). Thus, the recommended dose for a phase II trial is 125 mg/m2 irinotecan in combination with oxaliplatin, 5-FU/FA and cetuximab. Most common grade ≥3 toxicities were neutropenia (40%), diarrhoea (25%) and acne-like rash (15%). No therapy associated death occurred.The confirmed overall response rate in all cohorts was 75% (95%-CI 51-91%). The best response was reached after a median of 3.0 (95%-CI 2.2 to 3.7) months. Median progression free survival (PFS) is 16 (95%-CI 12.6-19.4) months, overall survival (OS) 33 (95%-CI 26.2-39.8) months.ConclusionsThe combination of cetuximab and FOLFOXIRIis feasible and has an acceptable toxicity profile in patients with a good performance status. The observed clinical activity with a confirmed response rate of 75% is promising and further evaluated in the ongoing CELIM2.Trial registrationhttp://www.clinicaltrials.gov: NCT00422773.
Highlights
The FOLFOXIRI regimen increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer
Metastasectomies can provide curative treatment with a 5-year overall survival of 48% if metastases are resectable at the time of diagnosis of the metastases and 33%, if initially non-resectable liver metastases are resected after tumour shrinkage due to chemotherapy [1]
An Italian phase III trial demonstrated an increase of the response rates (RR) and a prolongation of the progression free and overall survival with significantly more liver resections in the FOLFOXIRI arm, and increased toxicity, especially diarrhoea and neutropenia compared to the FOLFIRI arm [6]
Summary
The FOLFOXIRI regimen (irinotecan, oxaliplatin, fluorouracil [5-FU] and folinic acid [FA]) increased the response rate and overall survival compared to FOLFIRI in patients with metastatic colorectal cancer (mCRC). As there is a correlation between response to chemotherapy and the resection rate [2] it might be interesting to develop chemotherapy schedules that are able to induce early and meaningful tumour shrinkage Both irinotecan and oxaliplatin, each in combination with infusional 5-fluorouracil (5-FU)/ folinic acid (FA) have been the standard chemotherapy regimens in mCRC inducing response rates (RR) of 40% to 50% [3,4]. One strategy to maximize tumour response is to combine all cytotoxic drugs into a “FOLFOXIRI” regimen Such an approach had promising results in earlier phase II trials [5]. An Italian phase III trial demonstrated an increase of the RR and a prolongation of the progression free and overall survival with significantly more liver resections in the FOLFOXIRI arm, and increased toxicity, especially diarrhoea and neutropenia compared to the FOLFIRI arm [6]
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