Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial
- Study type
- Clinical trial
- Design
- Multicentre, open-label (unblinded) randomised trial
- Sample size
- 387 patients
- Source
- The Lancet · 2000
In plain words
This study looked at adding the drug irinotecan to standard chemotherapy (fluorouracil and folinate) for people with cancer of the colon and rectum (bowel cancer) that had spread to other parts of the body. Adding this drug made tumours shrink more often, slowed the disease's progression and helped patients live longer. Some side effects were more common with irinotecan, but they could be managed.
Key results
Treatment arms and regimens
Irinotecan with fluorouracil (5-FU) and calcium folinate (leucovorin), on a weekly or every-2-weeks infusion schedule chosen by each centre (199 patients).
Every-2-weeks schedule (per "Combination regimen 2" of the Camptosar FDA label; the days 1 and 2 every-2-weeks infusional regimen supported in the label by data from this trial, Study 2; 6-week cycle with the next cycle starting on day 43): irinotecan 180 mg/m² IV infusion over 90 minutes on days 1, 15 and 29; leucovorin 200 mg/m² IV infusion over 2 hours on days 1, 2, 15, 16, 29 and 30; followed by fluorouracil 400 mg/m² IV bolus and 600 mg/m² IV infusion over 22 hours on the same days.
The weekly schedule dose is not given in the abstract or the FDA label, and the full text was not openly accessible to us. Antiemetics, atropine and loperamide were given for prevention or control of symptoms; for diarrhoea persisting more than 24 hours despite loperamide, diarrhoea with fever, or ANC below 500/mm³, a 7-day course of an oral fluoroquinolone was given (FDA label, Study 2).
Fluorouracil and calcium folinate alone on a weekly or every-2-weeks schedule chosen by the centre (in the FDA label for the every-2-weeks subgroup: "infusional 5-FU/leucovorin days 1 and 2 every 2 weeks"). Doses for this group are not given in the abstract or the label (188 patients).
Source of the regimen details: FDA label for Camptosar (DailyMed; section 2.1 "Combination regimen 2" and sections 6 and 14, Study 2); the weekly schedule dose and control group doses are not given in the abstract or label, and the full text was not openly accessible
Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.
Study population
Patients with advanced colorectal cancer who had received no prior chemotherapy (except adjuvant treatment). According to the FDA label (Study 2): median age 62 years (27 to 75) in the irinotecan group and 59 years (24 to 75) in the control group; performance status 0 in 51%, 1 in 42% and 41%, and 2 in 7% and 8%; rectal primary tumour in 45% and 35%; prior adjuvant 5-FU in 26% and 24%.
Endpoints
Response rate and time to disease progression; also duration of response, survival and quality of life. Analyses were done in the intention-to-treat population and in evaluable patients.
Safety and side effects
Some grade 3 and 4 adverse events were significantly more common in the irinotecan group, but these were described as predictable, reversible, non-cumulative and manageable.
According to the FDA label (Study 2, every-2-weeks schedule subgroup only: 145 versus 143 patients): grade 3 and 4 adverse events overall 72.4% versus 39.2%; grade 3 and 4 neutropenia 46.2% versus 13.4%; grade 3 and 4 late diarrhoea 14.4% versus 6.3%; febrile neutropenia 3.4% versus 0.7%; grade 3 and 4 asthenia 9.0% versus 4.2%; cholinergic syndrome (any grade) 28.3% versus 0.7%. In the whole of Study 2, death within 30 days of last treatment was 4.1% versus 2.8%, and one possibly treatment-related death (neutropenic sepsis, 0.7%) occurred in the irinotecan group; discontinuation due to adverse events 6.2% versus 0.7%.
Clinical significance and place in guidelines
Based on the authors' conclusion, irinotecan combined with fluorouracil and calcium folinate should be considered a reference first-line treatment for metastatic colorectal cancer. The current status of this regimen in treatment guidelines should be checked separately.
Limitations
The study was open-label, and the infusion schedule (weekly or every 2 weeks) was chosen by each centre. Some grade 3 and 4 adverse events were more common in the irinotecan group. Other limitations are not reported in the abstract.
This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.