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A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer |
Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M |
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Authors' objectives To evaluate the marginal clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed, as both monotherapy and combination therapy, in the first- and second-line treatment of patients with advanced colorectal cancer, as compared with established treatments. The specific objectives were: to evaluate the relative clinical effectiveness of irinotecan, oxaliplatin and raltitrexed on disease progression rates; to estimate their relative effect on overall survival and quality-of-life adjusted survival; to evaluate their side-effect profiles; to estimate the incremental cost-effectiveness of the three drugs in comparison with conventional therapy; and to estimate the overall cost associated with the use of these drugs in England and Wales.
Searching MEDLINE, EMBASE, the Science Citation Index (SCI), the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the NHS Centre for Reviews and Dissemination databases (DARE, NHS EED and HTA) and the Office of Health Economics' Health Economics database (HEED). Date and language restrictions were not applied. PubMed was also searched over the last 6 months to identify recent studies not yet indexed on MEDLINE. Abstracts of the American Society for Clinical Oncology (ASCO) for 1997 to 2000 were searched using the ASCO website.
Current research and 'grey' literature was identified by searching sources including the National Research Register, the Medical Research Council Clinical Trials Register, the US National Institutes of Health Clinical Trials Register and Current Research in Britain (CRIB) databases. The publication lists and current research registers of health technology assessment and guideline-producing agencies, as well as funding and regulatory bodies, were also consulted. Industry submissions and the reference lists of included studies were handsearched, and citation searches were undertaken using the SCI search facility. A further search was conducted for economic studies relating to the main comparators to the three drugs and to the different drug regimens, to inform the economic analysis. Keyword strategies were developed using key references retrieved through initial scoping searches.
Study selection Study designs of evaluations included in the reviewSystematic reviews, randomised controlled trials or economic evaluations were eligible for inclusion in the review.
Specific interventions included in the reviewIrinotecan, oxaliplatin or raltitrexed, used alone or in combination with other agents versus conventional 5-fluorouracil (FU)-based treatment, irinotecan, oxaliplatin or raltitrexed, alone or in combination with other agents, or best standard care (BSC). BSC was non-chemotherapy-based palliative care.
Details of the different drug dosages and specific regimens were provided in the review.
Participants included in the reviewParticipants with colorectal cancer were eligible for inclusion in the review if they were initially diagnosed with metastatic disease, or had developed metastatic disease after having received adjuvant 5FU-based (first-line) therapy, or had proved resistant to previous 5FU treatment for metastatic disease. Further details of the participants' characteristics were provided in the review.
Outcomes assessed in the reviewThe outcomes assessed in the qualifying studies had to include at least one of the following: survival rates, disease progression rates, health-related quality of life, adverse events, and/or costs.
How were decisions on the relevance of primary studies made?Two reviewers assessed the relevance of the primary studies identified in relation to the objectives and inclusion criteria specified. The authors did not state if the reviewers were blinded to the results and/or source or whether the assessments were made independently.
Assessment of study quality Randomised controlled trials were assessed according to the scale of Jadad et al. (see Other Publications of Related Interest), which addresses randomisation, blinding and the handling of withdrawals and drop-outs. A formal validity assessment was not possible in some cases as the trials had been published in abstract format only. The authors do not state how the validity assessment was performed.
The authors did not state that they assesed the validity of systematic reviews and economic evaluations.
Data extraction The data were extracted by one researcher and checked by a second, using customised data extraction forms. Any disagreements were resolved by discussion.
Data, where available, were extracted on: the duration of treatment; progression-free survival; overall survival; 1-year survival; survival from diagnosis to death; pain-free survival; symptom-free survival; time to deterioration of performance status; time to weight loss of more than 5%; response rates; response duration; treatment-related deaths; grade 3 to 4 toxicities; hospital admissions for severe adverse events; cumulative number of hospital days for severe adverse events; and quality of life, according to each of the three interventions (irinotecan, oxaliplatin or raltitrexed) as first or second-line therapy. Data were also extracted on: country, recruitment dates, interventions, study type, source of funding, participants and sample size.
Methods of synthesis How were the studies combined?The authors reported that a meta-analysis of the trial results was considered to be inappropriate owing to the variety of irinotecan and oxaliplatin regimens used, and the variety of comparator regimens used with all the drugs. Additionally, it would not have been possible to undertake a meta-analysis of the survival data because typically these data were presented as median survival times only. Studies were therefore combined narratively by drug intervention as first- or second-line therapy, and no statistical pooling was undertaken.
How were differences between studies investigated?No formal test of heterogeneity was undertaken as the studies were considered too heterogeneous to pool.
Results of the review A total of 23 studies were eligible for inclusion in the review. There were 6 randomised controlled trials relating to the use of irinotecan as first-line treatment and 7 studies for second-line treatment. There were 7 studies relating to the use of oxaliplatin as first-line treatment, and 3 for second-line treatment. There were 4 studies relating to the use of raltitrexed as first-line treatment of advanced colorectal cancer.
Only preliminary data were available for some of the eligible studies, therefore, information on the numbers of participants was not always available; for further details see the tables in the review.
There was good evidence to suggest that the use of a combination of irinotecan with FU and folinic acid (FA) in the first-line treatment of advanced colorectal cancer can extend survival by 2 to 3 months, compared with either FU-FA alone or irinotecan alone. However, this was at the cost of increased toxicity in comparison with FU-FA alone. Monotherapy with irinotecan as second-line treatment appeared to extend median progression-free survival and overall survival by approximately 1 month and approximately 2 months, respectively, compared with FU-FA alone; again, this was at the cost of increased toxicity. There was some preliminary evidence to suggest that, compared with FU-FA alone, the combination of irinotecan-FU-FA after FU-FA failure may extend median progression-free survival by approximately 2 months, and overall survival by nearly 3 months.
For oxaliplatin as first-line therapy, there was good evidence to suggest that a combination with an infusional FU-FA regimen extends median progression-free survival by 2 to 3 months, compared with FU-FA alone; again, this was associated with increased toxicity. This combination may also prolong overall survival. The improved response rate achieved by the addition of oxaliplatin to FU-FA may also enable larger numbers of patients to undergo potentially curative surgical resection of liver metastases. Preliminary data suggested that oxaliplatin together with 5FU may extend median progression-free survival as second-line treatment, compared with either 5FU or irinotecan monotherapy.
Raltitrexed as first-line therapy appeared to reduce both progression-free and overall survival in comparison with FU-FA, and is therefore associated with a higher mortality rate. There is, therefore, no advantage is using raltitrexed in the treatment of advanced colorectal cancer when patients are able to tolerate FU-FA treatment.
Based upon the analyses made in this review, oxaliplatin showed greater improvement than irinotecan in progression-free survival curves, although no survival benefit has been shown in clinical trials with oxaliplatin, whereas it has with irinotecan.
Cost information Yes. The cost of treatment with 5FU and FA by the de Gramont infusional regimen has been estimated at £2,500 per month when given on an in-patient basis, or £1,500 on an out-patient basis. The addition of oxaliplatin or irinotecan adds £800 and £1,000 per month, respectively, to this regimen. The Mayo 5FU regimen is £1,100 a month; the cost of therapy with raltitrexed has been shown to be similar to that for the Mayo regimen. The estimated cost of second-line treatment with irinotecan alone is £1,780. The total treatment costs for oxaliplatin are £5,330 greater than in-patient treatment costs with the de Gramont FU-FA regimen. With irinotecan, the additional cost is £11,400. The total cost of single-agent irinotecan for second-line treatment is less than that of 5FU by the de Gramont regimen. In comparison with BSC, the additional cost of giving irinotecan is £7,600.
Calculations of cost-effectiveness were based on progression-free survival, not survival. The marginal cost per progression-free year for oxaliplatin, compared with the de Gramont 5FU regimen, was £23,000. The equivalent cost for irinotecan was £58,400. If all treatments are given on an out-patient basis, the marginal cost per progression-free year is unchanged for oxaliplatin, £49,000 for irinotecan and £26,400 for second-line irinotecan. For second-line treatment, the marginal cost per life-year gained, based on survival benefit, is zero when irinotecan is compared with the de Gramont regimen given as in-patient therapy, £11,200 for out-patient therapy, and between £17,700 and £28,200 when compared with BSC. Authors' conclusions For first-line treatment, the combination of either irinotecan or oxaliplatin with infusional FU-FA appeared to extend median progression-free survival by 2 to 3 months when compared with FU-FA alone, although with increased toxicity. Irinotecan has also been demonstrated to extend overall survival. Raltitrexed appeared to reduce both progression-free and overall survival in comparison with FU-FA. Irinotecan monotherapy as a second-line treatment appeared to extend median progression-free survival and overall survival by approximately one month and approximately two months, respectively, compared with FU-FA alone, although this was also at the cost of increased toxicity. As a second-line therapy, preliminary data suggested that oxaliplatin together with 5FU may extend median progression-free survival, compared with either 5FU or irinotecan monotherapy.
CRD commentary The review question and the study selection criteria were stated clearly. The literature search was explained well and was extremely thorough. The validity of the randomised controlled trials was assessed, but not that of the systematic reviews and economic evaluations. The authors did not provide information on how the validity assessment was performed. Given the heterogeneity of the data in terms of the different drug regimens used, the decision not to pool the data and undertake a meta-analysis seemed appropriate.
The authors' conclusions seem appropriate in the light of the evidence they present.
Implications of the review for practice and research Practice: The authors state that in the sub-section 'Factors relevant to the NHS', currently about 30% of patients who die of colorectal cancer receive chemotherapy for advanced disease, while another 15% have the capacity to benefit from such chemotherapy. The majority of those who receive chemotherapy presumably receive a 5FU-based regimen, and probably most of these are the de Gramont infusional regimen. If chemotherapy is extended to all those patients who have a capacity to benefit from it, expenditure thus has the potential to increase by 50%, even before the introduction of new agents. The introduction of the new therapies would increase the treatment options for the current pool of patients and would potentially increase the number of lines of therapy they may receive, as well as having further resource implications. Further implications for practice in terms of the new therapies are discussed.
Research: The authors state that more evidence of the relative benefits of oxaliplatin and irinotecan for the treatment of advanced colorectal cancer is required, including the optimal time to introduce these drugs (as first or second-line therapy). In addition, more evidence is needed on whether both drugs should be offered routinely, and if so, in which order.
The authors also state that randomised controlled trials are required to explore the following: the relative efficacy of second-line 5FU plus mitomycin C versus irinotecan or oxaliplatin; whether raltitrexed is beneficial in comparison with either BSC alone or irinotecan alone in patients with specific metabolic intolerance of 5FU; the relative efficacy of different sequences of therapies; the optimum duration of therapy, i.e. whether therapy should be continued to disease progression, death or unacceptable toxicity, or only until response, with or without consolidation; and the relative efficacy of oxaliplatin and 5FU in patients with a family history of colorectal cancer caused by hereditary non-polyposis colorectal cancer gene mutation.
The authors also state that given the palliative objectives of therapy, research is required to address the issue of measuring quality of life in patients with terminal cancer.
Funding NHS R&D Health Technology Assessment (HTA) Programme, project number 00/13/01.
Bibliographic details Lloyd Jones M, Hummel S, Bansback N, Orr B, Seymour M. A rapid and systematic review of the evidence for the clinical effectiveness and cost-effectiveness of irinotecan, oxaliplatin and raltitrexed for the treatment of advanced colorectal cancer. Health Technology Assessment 2002; 5(25): 1-128 Other publications of related interest Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 1996;17:1-12.
Indexing Status Subject indexing assigned by NLM MeSH Antimetabolites, Antineoplastic /adverse effects /therapeutic use; Antineoplastic Agents /adverse effects /therapeutic use; Antineoplastic Agents, Phytogenic /adverse effects /therapeutic use; Antineoplastic Combined Chemotherapy Protocols /therapeutic use; Camptothecin /adverse effects /analogs & Colorectal Neoplasms /drug therapy /economics /epidemiology /mortality; Cost-Benefit Analysis; Drug Costs; England /epidemiology; Organoplatinum Compounds /adverse effects /therapeutic use; Quality of Life; Quinazolines /adverse effects /therapeutic use; Randomized Controlled Trials as Topic; Survival Analysis; Thiophenes /adverse effects /therapeutic use; Treatment Outcome; Wales /epidemiology; derivatives /therapeutic use AccessionNumber 12002008371 Date bibliographic record published 28/02/2003 Date abstract record published 28/02/2003 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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