Elsevier

The Lancet

Volume 370, Issue 9582, 14–20 July 2007, Pages 135-142
The Lancet

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Sequential versus combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (CAIRO): a phase III randomised controlled trial

https://doi.org/10.1016/S0140-6736(07)61086-1Get rights and content

Summary

Background

The optimum use of cytotoxic drugs for advanced colorectal cancer has not been defined. Our aim was to investigate whether combination treatment is better than sequential administration of the same drugs in patients with advanced colorectal cancer.

Methods

We randomly assigned 820 patients with advanced colorectal cancer to receive either first-line treatment with capecitabine, second-line irinotecan, and third-line capecitabine plus oxaliplatin (sequential treatment; n=410) or first-line treatment capecitabine plus irinotecan and second-line capecitabine plus oxaliplatin (combination treatment; n=410). The primary endpoint was overall survival. Analyses were done by intention to treat. This trial is registered with ClinicalTrials.gov with the number NCT00312000.

Findings

17 patients (nine in the sequential treatment group, eight in the combination group) were found to be ineligible and were excluded from the analysis. 675 (84%) patients died during the study: 336 in the sequential group and 339 in the combination group. Median overall survival was 16·3 (95% CI 14·3–18·1) months for sequential treatment and 17·4 (15·2–19·2) months for combination treatment (p=0·3281). The hazard ratio for combination versus sequential treatment was 0·92 (95% CI 0·79–1·08; p=0·3281). The frequency of grade 3–4 toxicity over all lines of treatment did not differ significantly between the two groups, except for grade 3 hand-foot syndrome, which occurred more often with sequential treatment than with combination treatment (13% vs 7%; p=0·004).

Interpretation

Combination treatment does not significantly improve overall survival compared with the sequential use of cytotoxic drugs in advanced colorectal cancer. Thus sequential treatment remains a valid option for patients with advanced colorectal cancer.

Introduction

Fluorouracil has been the standard of care for patients with advanced colorectal cancer for decades. The availability of irinotecan and oxaliplatin has increased the median overall survival for these patients.1 Several studies have shown a clinical benefit of adding irinotecan or oxaliplatin to fluorouracil in first-line treatment.2, 3, 4 Each drug can also confer a benefit in patients refractory to first-line fluorouracil-based chemotherapy.5, 6 In terms of survival, there does not seem to be an optimum sequence of administration of irinotecan and oxaliplatin,7 and the optimum timing of delivery of these agents has not been clearly defined. The survival results of randomised studies in which combination treatments were investigated should be interpreted with caution, since salvage treatments were not a prospective part of the study designs, which might have affected the results. Furthermore, the availability of irinotecan and especially oxaliplatin was variable during the period these studies were under way.8

Capecitabine, an oral fluoropyrimidine, has at least equivalent efficacy and a clinically meaningful safety advantage compared with fluorouracil treatment.9, 10 Phase II studies of the combination of capecitabine with either irinotecan or oxaliplatin show efficacy but also toxicity comparable with combination schedules with fluorouracil.11, 12 As a result, capecitabine is now often used as an alternative to fluorouracil in the treatment of advanced colorectal cancer, either as monotherapy or in combination therapy.

In the CApecitabine, IRinotecan, Oxaliplatin (CAIRO) trial, our aim was to determine whether first-line combination treatment is better than sequential administration of the same drugs in terms of overall survival in patients with advanced colorectal cancer.

Section snippets

Patients

Patients aged over 18 years were eligible if they had histologically proven colorectal cancer that was in an advanced stage not amenable to curative surgery, together with measurable or assessable disease parameters (serum carcino embryonic antigen as the only parameter for disease activity was not allowed), and no previous systemic treatment for advanced disease. Previous adjuvant chemotherapy was allowed provided that the last administration was given at least 6 months before randomisation.

Results

820 patients were randomised, 410 in each arm of the study (figure 1). 17 patients were found to be ineligible and were excluded from the analysis. Reasons for ineligibility were: histological diagnosis of colorectal cancer not confirmed (n=4); abnormal liver or renal function at baseline (4); previous chemotherapy for advanced colorectal cancer or adjuvant chemotherapy completed less than 6 months before randomisation (3); serious concomitant disease (2); recent history of second malignancy

Discussion

Our results show that, for patients with advanced colorectal cancer, combination treatment with all effective cytotoxic drugs was no better than their sequential use. Progression-free survival over all subsequent treatment lines was not significantly different between the study groups. Additionally, sequential treatment was associated with less toxicity during first-line treatment than was combination therapy.

The high median overall survival seen in patients receiving sequential therapy in

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