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The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review |
Garside R, Round A, Dalziel K, Stein K, Royle P |
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Authors' objectives To assess the efficacy and cost-effectiveness of imatinib, compared with existing drug treatments, for the treatment of chronic myeloid leukaemia (CML).
Searching The authors searched the following electronic sources from inception to August 2001: the Cochrane Library, Cancerlit, MEDLINE, EMBASE, the Science Citation Index, Web of Science Proceedings, BIOSIS Previews, the National Research Register, an Early Warning System database, NLM Gateway, Current Controlled Trials, ClinicalTrials.gov, CancerNet, the CancerNET website, Conference Proceedings Index, AIDS and Cancer Research Abstracts, the most recent version of PDQ, and the most recent version of conference abstracts reports on the 'Action on Smoking and Health' (http://www.ash.org) and 'American Society of Clinical Oncology' (http://www.asco.org) websites; the search terms were reported. The websites of the Food and Drug Administration (Center for Drug Evaluation and Research), Novartis (the manufacturers of imatinib), EMEA and ONS were also searched. Bibliographies of reviewed articles were checked for additional studies and the manufacturers of imatinib were contacted for unpublished studies.
Study selection Study designs of evaluations included in the reviewRandomised controlled trials (RCTs), cohort studies and case series with at least 20 participants were eligible for inclusion, as were economic analyses and quality of life studies. Phase I and phase II studies of imatinib were also eligible for inclusion in the review.
Specific interventions included in the reviewStudies of imatinib given orally were eligible for inclusion. Studies of other chemotherapies investigated in CML were also included: interferon alpha, hydroxyurea and busulphan.
Participants included in the reviewStudies of adult CML patients were eligible for inclusion. The included studies were of patients with chronic phase, accelerated phase and blast phase CML.
Outcomes assessed in the reviewThe outcomes of interest were overall survival, progression-free survival, haematological response, cytogenetic response, adverse events, quality of life and cost.
How were decisions on the relevance of primary studies made?Two reviewers independently assessed articles for inclusion and resolved any disagreements through discussion.
Assessment of study quality The validity of the RCTs was assessed on the basis of: sample size; the possibility of selection bias, performance bias, detection bias and attrition bias; the representativeness of the study sample; usual care setting; standard treatment regimen; standard treatment outcomes measured; and length of follow-up. The validity of non-randomised studies was also assessed. This was based on selection criteria, use of explicit inclusion or exclusion criteria, stage of disease at entry, concurrent treatments, extent of blinding, intention-to-treat analysis, patient characteristics and the treatment regimen followed. Two reviewers independently assessed the quality of the studies using a structured form.
Data extraction The data were extracted by one reviewer and checked by another. Where possible, response rates and survival were calculated from the original data presented in the reports, rather than the percentages reported. One-year survival had to be estimated from survival curves in some cases. When not reported in imatinib trials, 95% confidence intervals (CIs) were calculated.
Methods of synthesis How were the studies combined?The three phase II studies were compared with the results of studies of other chemotherapy drugs in a narrative synthesis. Findings from the included trials were listed to enable comparisons to be made. The authors acknowledged that such comparisons are difficult because of differences in the characteristics of patients enrolled in the studies and the large numbers of withdrawals in many studies; they advised caution when interpreting their results.
How were differences between studies investigated?Heterogeneity was not formally assessed. Differences between the studies of imatinib and other chemotherapy drugs were discussed.
Results of the review Sixty-one studies were included in the review. There were two phase I imatinib trials and three unpublished phase II imatinib trials, provided by Novartis, who manufacture imatinib. Of the three phase II imatinib trials, one included patients with chronic phase CML, one included patients with accelerated phase CML and one included patients with blast phase CML. Eleven RCTs and 40 case series of other chemotherapy drugs were included. Ten RCTs and 27 case series were of chronic phase CML, while one RCT and 13 case series were of accelerated and blast phase CML. The review also identified two quality of life studies and three cost-effectiveness studies.
No studies that directly compared imatinib with other chemotherapy drugs were identified. The authors reported that the phase I studies were small and were designed primarily to consider safety and dosage, and there was insufficient detail to draw any conclusions about efficacy.
Efficacy of imatinib for chronic phase CML.
Imatinib had a similar one-year survival rate to other chemotherapy drugs. The median survival at one year was 97% (n=532) in the imatinib trial, 96% (range: 93 to 98) in the 10 RCTs of other chemotherapy drugs, and 97% (range: 87 to 100) in the 27 case series of other chemotherapy drugs. No information on survival beyond one year was available. The complete haematological response rate was higher in the imatinib trial (median 89%) than in the RCTs (median 55%, range: 23 to 79) and case series (median 63%, range: 22 to 93) of other chemotherapy drugs. The complete cytogenetic response rate was also higher in the imatinib trial (median 36%) than in the RCTs (median 4%, range: 0 to 15) and case series (median 12%, range: 0 to 46) of other chemotherapy drugs.
Efficacy of imatinib for accelerated phase CML.
Imatinib had a higher one-year survival rate than other chemotherapy treatments, as reported in four case series. The median survival at one year was 74% in the imatinib trial and 32.5% (range: 28 to 37) in the case series of other chemotherapy drugs. The complete haematological response rate was similar in the imatinib trial (median 35%) to the case series (median 35%, range: 25 to 50) of other chemotherapy drugs. The complete cytogenetic response rate was also similar in the imatinib trial (median 17%) and case series (median 13%, range: 0 to 23) of other chemotherapy drugs.
Efficacy of imatinib for blast phase CML.
Imatinib had a higher one-year survival rate than other chemotherapy treatments, as reported in 12 case series. The median survival at one year was 28% in the imatinib trial and 13% (range: 6 to 17) in the case series of other chemotherapy drugs. The complete haematological response rate was lower in the imatinib trial (median 7%) than in the RCT (median 12%, range: 11 to 13) of other chemotherapy drugs, and was within the range of the 12 case series (median 20%, range: 0 to 33) of other chemotherapy drugs. The complete cytogenetic response rate was similar in the imatinib trial (median 7%) to the case series (median 8%, range: 0 to 21) of other chemotherapy drugs.
Severe or life-threatening adverse events.
A higher proportion of patients in the imatinib trials suffered from severe or life-threatening anaemia (median 37%), thrombocytopenia (median 43%), and leukopenia or neutropenia (median 58%) than those in trials of interferon alpha (median 4%, 13% and 5%, respectively). However, a high proportion of patients in other chemotherapy trials also suffered from severe or life-threatening leukopenia or neutropenia (median 61.5%) and severe or life-threatening liver effects (median 21%).
Cost information The authors identified one unpublished economic analysis of imatinib. The industry submission concluded that imatinib was a cost-effective treatment for CML in the chronic phase after interferon alpha failure, in the accelerated phase and in blast crisis. The cost per quality-adjusted life-year was high in all phases, but with a larger potential range in the chronic phase, and was sensitive to assumptions about long-term survival.
Authors' conclusions Imatinib appeared to offer an alternative treatment for CML in the accelerated and blast phases, but there was insufficient information about its use in the chronic phase to draw firm conclusions.
CRD commentary The review question was clearly defined in terms of the study design, patients, interventions and outcomes of interest. The search was extensive and efforts were made to identify unpublished research. However, electronic search strategies were restricted to English language publications, therefore language bias might have been present. Two reviewers independently assessed articles for inclusion and assessed the quality of the studies, while the data were extracted by one reviewer and checked by another; this reduces the possibility of reviewer error or bias.
The results of the studies were tabulated and some studies were further discussed in the text. However, there was no clear presentation of the study details for all studies. All of the data on the efficacy of imatinib and its adverse events were taken from three unpublished case series undertaken by Novartis. Details of these studies were not always clearly presented.
Whilst this appears to have been a well-conducted review, the authors' conclusions should be interpreted with caution given the lack of studies directly comparing imatinib with other chemotherapy drugs and the potential clinical heterogeneity between the studies that were compared. The authors' suggestion that further research into imatinib for CML is required appears appropriate.
Implications of the review for practice and research Practice: The authors stated that, until further research is undertaken, it is difficult to make secure recommendations for the use of imatinib for CML.
Research: The authors stated that more research into the use of imatinib for CML is needed. Such research should evaluate the efficacy of imatinib in chronic phase CML in the long term; use RCTs to compare the effectiveness of imatinib with interferon alpha, hydroxyurea and other chemotherapy drugs; elucidate the relationship between response rates and long-term survival with different treatments; and investigate adverse effects and long-term imatinib use.
Funding NHS R&D Health Technology Assessment (HTA) Programme, project number 01/26/01.
Bibliographic details Garside R, Round A, Dalziel K, Stein K, Royle P. The effectiveness and cost-effectiveness of imatinib in chronic myeloid leukaemia: a systematic review. Health Technology Assessment 2002; 6(33): 1-162 Indexing Status Subject indexing assigned by NLM MeSH Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents /economics /therapeutic use; Benzamides; Clinical Trials as Topic; Cost-Benefit Analysis; Female; Great Britain; Humans; Hydroxyurea /economics /therapeutic use; Imatinib Mesylate; Interferon-alpha /economics /therapeutic use; Leukemia, Myelogenous, Chronic, BCR-ABL Positive /drug therapy /economics; Male; Middle Aged; Piperazines /economics /therapeutic use; Pyrimidines /economics /therapeutic use; Treatment Outcome AccessionNumber 12003008165 Date bibliographic record published 31/03/2005 Date abstract record published 31/03/2005 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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