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Use of irinotecan (Camptosar, CPT-11) combined with 5-fluorouracil and leucovorin (5FU/LV) as first-line therapy for metastatic colorectal cancer |
Gastrointestinal Cancer Disease Site Group |
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CRD summary This well-conducted review appropriately concluded that the addition of irinotecan to 5-fluorouracil and leucovorin (5FU-LV) is at least as effective as 5FU-LV alone. Survival and response improvements from adding irinotecan to 5FU-LV must be balanced against increased hair loss, diarrhoea, thrombotic events and hospitalisation. Patients should be offered therapy with or without irinotecan. Those receiving it should be monitored for adverse effects. Authors' objectives To assess whether adding irinotecan to first-line therapy with 5-fluorouracil plus leucovorin (5FU-LV) improves survival, time to disease progression, or quality of life in people with metastatic colorectal cancer.
Searching MEDLINE (1976 to January 2003), Cancerlit (1983 to October 2002), the Cochrane Library (Issue 4, 2002), PDQ, the proceedings of the American Society of Clinical Oncology (to 2002), the U.S. Food and Drug Administration website, and reference lists from retrieved papers were searched; the search terms were reported. No language restrictions were applied.
Study selection Study designs of evaluations included in the reviewAbstracts or full reports of meta-analyses or randomised phase II or phase III trials were eligible for inclusion.
Specific interventions included in the reviewStudies were eligible for inclusion in the review if they compared active treatment with a regimen containing irinotecan versus a control arm without irinotecan as first-line therapy for people with metastatic colorectal cancer. All of the studies included in the review compared irinotecan plus 5FU-LV with a 5FU-LV containing regimen, either alone or combined with another agent. The doses and treatment regimens varied between the included studies. Full details of the drug doses and schedules were provided.
Participants included in the reviewStudies were eligible if they included adults with metastatic colorectal cancer undergoing chemotherapy as first-line treatment.
Outcomes assessed in the reviewThe primary end point in the review was survival. The secondary end points were response rate, time to disease progression, and quality of life.
How were decisions on the relevance of primary studies made?Two members of the Gastrointestinal Cancer Disease Site Group and methodologists selected and reviewed the studies. The authors did not provide further details about how the studies were selected for the review.
Assessment of study quality The authors did not state that they assessed validity. This review was developed using the Practice Guidelines Development Cycle, which was reported elsewhere (see Other Publications of Related Interest).
Data extraction The authors did not state how the data were extracted for the review, or how many reviewers performed the data extraction. Data were extracted on publication details, sample size, study years, chemotherapy regimen, and outcomes.
Methods of synthesis How were the studies combined?The authors reported pooled survival and response rate data from a published meta-analysis of IPD. They pooled toxicity data from the irinotecan arms of 2 phase III trials by summing the number of adverse events across the trials and dividing by the total number of participants receiving irinotecan. The authors felt that it was inappropriate to pool toxicity data for the non-irinotecan arms because of the different toxicity profiles in the treatment regimens used.
How were differences between studies investigated?The authors described differences in the results, treatment strategies, and methodologies of the included studies. They did not report a heterogeneity analysis for the pooled data.
Results of the review The review included 9 studies: one individual patient data (IPD) meta-analysis of 2 trials (n=1,070) and 8 randomised controlled trials (6 phase III and 2 phase II). Two of the phase III randomised trials were included in the published meta-analysis.
Adding irinotecan to 5FU-LV appears at least as effective as 5FU-LV alone. A meta-analysis of IPD found a significant survival advantage in favour of adding irinotecan: median survival was 15.9 months with irinotecan versus 13.3 months without (hazard ratio 0.79, 95% confidence interval: 0.66, 0.94, P<0.009). Two randomised trials found improved response rates and median time to tumour progression: the pooled response rate was 37% with irinotecan versus 21% without (P<0.0001), while the pooled median time to tumour progression was 6.9 and 4.3 months with and without irinotecan, respectively (P<0.0001). These 2 trials found no difference between groups in quality of life. However, the addition of irinotecan to 5FU-LV was associated with more grade 3 or 4 diarrhoea, nausea and vomiting, more grade 1 or 2 alopecia, and more hospitalisations. Severe mucositis was less likely with added irinotecan.
Authors' conclusions The addition of irinotecan to 5FU-LV is at least as effective as 5FU-LV alone. Survival and response improvements from adding irinotecan to 5FU-LV must be balanced against increased hair loss, diarrhoea, thrombotic events and hospitalisation. Patients should be offered the choice of therapy with or without irinotecan. Those who choose irinotecan should be carefully monitored for adverse effects. CRD commentary This review included a specified research question and inclusion criteria. The search strategy appears appropriate. The authors did not report how they assessed the studies for relevance or validity. This makes it difficult to consider the overall quality of the review and the studies on which it was based. Some study details were presented in tabular format, but not descriptions of methodological features.
The authors pooled adverse effects data only for the irinotecan arms of 2 phase III trials that used 5FU-LV as control arms. When the literature search was updated, the authors did not include the findings of 4 newly identified phase III trials in the pooled analysis. These used different 5FU-LV regimens as control arms. A heterogeneity analysis, to assess the merit of pooling the data quantitatively, was not presented. Nor did the authors pool adverse effects data for the non-irinotecan arms of the trials. However, this appears appropriate given that these arms used different regimens, with varying toxicity profiles. The authors described their rationale clearly.
The data presented in the review appear to support the authors' conclusions, although the conclusions would have been strengthened if studies identified in the updated literature search had been more fully integrated into the qualitative and quantitative analyses.
Implications of the review for practice and research Practice: The authors stated that patients should be offered the choice of adding irinotecan to 5FU-LV. Survival and response improvements from the addition of irinotecan must be balanced against increased toxicity. Caution is advised when recommending irinotecan to people with an ECOG performance status of greater than 1. It remains uncertain whether combined (first-line) or sequential (second-line) use of irinotecan and 5FU-LV is most effective.
Research: The authors did not state any implications for future research. They identified 6 ongoing trials (as at January 2003).
Funding Cancer Care Ontario; Ontario Ministry of Health and Long-term Care.
Bibliographic details Gastrointestinal Cancer Disease Site Group. Use of irinotecan (Camptosar, CPT-11) combined with 5-fluorouracil and leucovorin (5FU/LV) as first-line therapy for metastatic colorectal cancer. Cancer Care Ontario Practice Guidelines Initiative 2001. Available at: https://www.cancercare.on.ca/common/pages/UserFile.aspx?fileId=88906 Accessed April, 2014 This paper is produced by Cancer Care Ontario Practice Guidelines Initiative. The series is published on the Internet and regularly updated. To ensure that you are viewing the most up to date version, go to the Cancer Care Ontario website at: http://www.cancercare.on.ca/english/toolbox/qualityguidelines/pebc/
This abstract is based on the web version accessed on 18/10/2004 Other publications of related interest 1. Browman GP, Levine MN, Mohide A, Hayward RS, Pritchard KU, Gafni A, et al. The practice guidelines development cycle: a conceptual tool for practice guidelines development and implementation. J Clin Oncol 1995;13:502-12. 2. Jonker D, Earle C, Kocha W, Moore M, Maroun J, Zuraw L, Gastrointestinal Cancer Disease Site Group. Use of irinotecan combined with 5-fluorouracil and leucovorin as first-line therapy for metastatic colorectal cancer. Curr Oncol 2001;8:60-8. Indexing Status Subject indexing assigned by CRD MeSH Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Camptothecin /administration & Colorectal Neoplasms /drug therapy; Fluorouracil /administration & Leucovorin /administration & Neoplasm Metastasis; dosage; dosage; dosage AccessionNumber 12003008195 Date bibliographic record published 28/02/2005 Date abstract record published 28/02/2005 Record Status This is a critical abstract of a systematic review that meets the criteria for inclusion on DARE. Each critical abstract contains a brief summary of the review methods, results and conclusions followed by a detailed critical assessment on the reliability of the review and the conclusions drawn. |
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