Elsevier

The Lancet

Volume 355, Issue 9209, 25 March 2000, Pages 1041-1047
The Lancet

Articles
Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial

https://doi.org/10.1016/S0140-6736(00)02034-1Get rights and content

Summary

Background

Irinotecan is active against colorectal cancer in patients whose disease is refractory to fluorouracil. We investigated the efficacy of these two agents combined for first-line treatment of metastatic colorectal cancer.

Methods

387 patients previously untreated with chemotherapy (other than adjuvant) for advanced colorectal cancer were randomly assigned open-label irinotecan plus fluorouracil and calcium folinate (irinotecan group, n=199) or fluorouracil and calcium folinate alone (no-irinotecan group, n=188). Infusion schedules were once weekly or every 2 weeks, and were chosen by each centre. We assessed response rates and time to progression, and also response duration, survival, and quality of life. Analyses were done on the intention-to-treat population and on evaluable patients.

Findings

The response rate was significantly higher in patients in the irinotecan group than in those in the no-irinotecan group (49 vs 31%, p<0·001 for evaluable patients, 35 vs 22%, p<0·005 by intention to treat). Time to progression was significantly longer in the irinotecan group than in the no-irinotecan group (median 6·7 vs 4·4 months, p<0·001), and overall survival was higher (median 17·4 vs 14·1 months, p=0·031). Some grade 3 and 4 toxic effects were significantly more frequent in the irinotecan group than in the no-irinotecan group, but effects were predictible, reversible, non-cumulative, and manageable.

Interpretation

Irinotecan combined with fluorouracil and calcium folinate was well-tolerated and increased response rate, time to progression, and survival, with a later deterioration in quality of life. This combination should be considered as a reference first-line treatment for metastatic colorectal cancer.

Introduction

Standard therapy for metastatic colorectal cancer is fluorouracil, commonly modulated by calcium folinate, which typically yields a median survival time of 10–14 months.1, 2 Fluorouracil can be used as first-line or secondline therapy and a different regimen of fluorouracil can be administered as second-line treatment if first-line treatment fails. Survival time in these patients is typically short. Quality of life in patients receiving this treatment is generally poor.3, 4, 5, 6, 7, 8, 9, 10

Irinotecan inactivates topoisomerase I and thereby inhibits cell division.11, 12, 13 The drug has no cross-resistance with fluorouracil and functions via a novel molecular mechanism.14 Phase III studies of patients whose disease had not responded to first-line fluorouracil, or patients whose disease had progressed after first-line fluorouracil treatment, showed increased survival times in patients given irinotecan compared with those receiving best supportive care15 or high-dose fluorouracil and calcium folinate alone by continuous infusion.16 Data suggest that the development of well-tolerated regimens that combine irinotecan and high-dose fluorouracil and calcium folinate may be beneficial in the first-line treatment of colorectal cancer.

Phase I dose-escalation studies were done to test combined irinotecan with fluorouracil and calcium folinate weekly or every 2 weeks.17, 18 These regimens were selected for first-line treatment of advanced colorectal cancer, based on promising antitumour efficacy and an acceptable safety profile. The choice of regimen was left to investigators, according to local clinical practice, since the two regimens are widely used in Europe. The irinotecan combination and fluorouracil and calcium folinate alone were expected to differ by similar magnitudes in each regimen. Analysis of pooled data for efficacy showed that irinotecan gave a significant survival advantage.

We did a phase III multicentre randomised trial that was designed to assess whether the addition of irinotecan to fluorouracil and calcium folinate would benefit patients previously untreated with chemotherapy (other than adjuvant) for metastatic colorectal cancer.

Section snippets

Patients

From May, 1997, to February, 1998, we enrolled patients who met the following eligibility criteria: histologically proven adenocarcinoma of the colon or rectum; age 18–75 years; WHO performance status of 2 or less and life expectancy of more than 3 months; haemoglobin 100 g/L or more; absolute neutrophil count 2·0×10°/L; platelets 150×109/L or more; creatinine 1·25 or less times the upper limit of normal; total bilirubin 1·25 or less times the upper limit of normal; aspartate aminotransferase

Patients and treatment

387 patients were randomly assigned treatment. 385 patients received at least one infusion. Two patients received no study treatment because consent was withdrawn. Of the 385 patients treated in the study, only 97 (25%) received treatment by the weekly regimen (54 in the irinotecan group and 43 in the no-irinotecan group). The other 288 patients received treatment every 2 weeks (145 in the irinotecan group and 143 in the no-irinotecan group).

Baseline demographic and pretreatment characteristics

Discussion

Combination of irinotecan with fluorouracil and calcium folinate significantly increased response rates, time to progression, and survival. The survival advantage was reached, despite a higher proportion of patients receiving further chemotherapy in the no-irinotecan group (58·3 vs 39·4%).

This study population was large (385 patients treated), and the patients were representative of candidates for first-line chemotherapy in clinical practice, except that an unexpectedly high proportion of them

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