Use of irinotecan combined with 5-fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer

Question What is the role of irinotecan combined with 5-fluorouracil and leucovorin as first-line systemic therapy in the management of metastatic colorectal cancer? Perspectives Evidence was selected and reviewed by two members of the Gastrointestinal Cancer Disease Site Group (DSG) of the Cancer Care Ontario Practice Guidelines Initiative and by methodologists. The present practice guideline has been reviewed and approved by the Gastrointestinal Cancer DSG, which comprises medical and radiation oncologists, surgeons, a pathologist, and two community representatives. Outcomes The primary outcome of interest was survival. Secondary outcomes of response rate, time to disease progression, and quality of life were also considered. Methodology A systematic search of the MEDLINE (1976-2000), CANCERLIT (1983-2000), and Cochrane Library (Issue 4, 2000) databases and of relevant conference proceedings was undertaken. Reference lists were also scanned for additional citations. Randomised trials and meta-analyses of an active treatment arm using irinotecan as first-line therapy as compared with a control arm without irinotecan in patients with metastatic colorectal cancer were eligible for inclusion. Results: Quality of Evidence. One published meta-analysis of individual patient data and two randomised phase III trials comparing irinotecan combined with 5-fluorouracil and leucovorin (5-FU/LV) versus 5-FU/LV alone as first-line therapy in patients with metastatic or advanced colorectal cancer met the inclusion criteria. Two randomised phase II trials were also reviewed. Benefits. A published meta-analysis using individual patient data from the two phase III trials detected a significant survival benefit favouring irinotecan/5-FU/LV as compared with 5-FU/LV alone [hazard ratio (HR): 0.79; 95% confidence interval (CI): 0.66-0.94; p < 0.009]. Patients in the irinotecan arm experienced superior tumour response rates (pooled data: 37% vs. 21%; p < 0.0001) and median time-to-tumour-progression (pooled data: 6.9 months vs. 4.3 months; p < 0.0001). Although the trials showed a benefit for irinotecan/5-FU/LV, some uncertainty remains regarding the relative benefit of sequential as compared with combined therapy because the trials were not designed to compare these two approaches. Quality of life was formally measured in both phase III trials, and no difference between the arms was detected in either trial. Harms. Irinotecan/5-FU/LV is associated with more grade 3 or grade 4 diarrhoea, nausea, and vomiting, and with more grade 1 or grade 2 alopecia, but with less severe mucositis. Hospitalisations were also more frequent with irinotecan. If used in a first-line strategy, 100% of eligible patients will receive irinotecan (with a potential for increased toxicity) as compared with possibly only 30%-40% if irinotecan is used as second-line therapy. Recommendations: These recommendations apply to adult patients with metastatic colorectal cancer for whom chemotherapy is being considered as first-line treatment. It is reasonable to offer the patient a choice between irinotecan/5-FU/LV and 5-FU/LV. Survival and response improvements with irinotecan/5-FU/LV must be balanced against the increased toxicity (more hair loss, diarrhoea, and hospitalisation with irinotecan as compared with more mucositis without irinotecan). Excess thrombotic events are also seen with irinotecan. For patients offered irinotecan therapy, careful monitoring of adverse effects and early intervention for diarrhoea should be part of the treatment process. Qualifying Statement: Caution should be exercised in recommending irinotecan to patients with a performance status greater than 1 [Eastern Cooperative Oncology Group (ECOG) scale]. All patients who may be eligible for this treatment should be warned of the adverse effects of irinotecan/5-FU/LV.