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Irinotecan in second-line treatment of metastatic colorectal cancer: improved survival and cost-effect compared with infusional 5-FU |
Iveson T J, Hickish T, Schmitt C, Van Cutsem E |
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Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology The use of irinotecan (IRI) (350 mg/m2 as a 90-minute infusion once every 3 weeks) as a second-line treatment for patients with metastatic colorectal cancer who were resistant to infusional 5-fluorouracil (5-FU) therapy.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised patients aged 18 to 75 years with histologically-proven progressive metastatic adenocarcinoma of the colon or rectum;
a World Health Organisation (WHO) performance status of 2 or less, an absolute neutrophil count of at least 2.0x10^9/L, a platelet count of at least 100x10^9/L, and total serum bilirubin of 1.25 times the upper limit of normal (ULN) or less; and
transaminase below 3 times the ULN (in the case of lever metastases, transaminase concentrations of 5 times ULN or less and bilirubin 1.5 times the ULN or less were permitted), and creatinine of 135 micromol/L or less.
Patients were excluded if they had undergone prior treatment with topoisomerase I inhibitors, raltitrexed, or oxaliplatin. Also, if they had bulky disease (>50% hepatic involvement; >25% lung involvement, or abdominal mass >/= 10 cm), central nervous system metastases, or unresolved bowel obstruction or diarrhoea.
Setting The setting was a hospital. The economic study was carried out in the UK.
Dates to which data relate The effectiveness and resource use data were gathered from October 1995 to July 1997. A formal price year was not reported.
Source of effectiveness data The effectiveness evidence was derived from a single study, which was published in elsewhere (see Other Publications of Related Interest).
Link between effectiveness and cost data The costing was performed prospectively on the same sample of patients as that used in the effectiveness study.
Study sample Preliminary power calculations showed that a total of 258 patients was required to detect statistically significant differences in the main outcome measure, assuming an anticipated 5% loss to follow-up. The method of sample selection was not reported. Of the initial sample of 267 patients allocated to the two study groups, 6 patients in the IRI group and 5 patients in the 5-FU group did not receive any treatment cycle due to consent withdrawal, death or non-metastatic disease. Thus, the final sample comprised 125 patients in the IRI arm and 129 patients in the 5-FU arm. The median age in the IRI arm was 58 years (range: 30 - 75) and 43% of the patients were women. The median age in the 5-FU arm was 58 years (range: 25 - 75) and 35% were women.
Study design This was a multi-centred, randomised clinical trial, which was carried out in 46 centres in Belgium, France, Germany, Italy, The Netherlands, Spain and Switzerland. Randomisation was stratified by centre and performance status was performed with a minimisation procedure, which was not reported. The follow-up assessments were conducted every 3 to 5 weeks during treatment. The patients were regularly evaluated every 6 to 8 weeks after treatment, until death or for a maximum of one year. The median follow-up was 15 months. It appears that no loss to follow-up was observed. No blind assessment was conducted.
Analysis of effectiveness The basis for the analysis of the clinical study (intention to treat or treatment completers only) was not reported. Several outcome measures were evaluated in the primary trial, such as (progression-free) survival, quality of life and efficacy. However, survival was the outcome measure relevant in the present economic evaluation and will be reported. There was, however, no statistically significant difference in quality of life measures, although more adverse events were reported in the IRI group. The study groups were shown to be comparable at baseline in terms of their demographic and clinical characteristics. There was a significant difference with respect to the percentage of patients with hyperleukocytosis, but the two groups were similar in terms of the mean white-blood-cell counts.
Effectiveness results One-year survival was 44.8% In the IRI group and 32.4% in the 5-FU group. Median survival was 10.8 months (95% confidence interval, CI: 9.5 - 12.8) in the IRI group and 8.5 months (95% CI: 7.7 - 10.5) in the 5-FU group. Both differences were statistically significant. Thus, the survival gain with IRI over 5-FU was 0.19 months.
Clinical conclusions The effectiveness study showed that IRI, as second-line treatment for patients with metastatic colorectal cancer, was statistically more effective than 5-FU in increasing survival.
Measure of benefits used in the economic analysis Survival was the benefit measure used in the economic analysis. It was derived from the effectiveness study.
Direct costs Discounting was not relevant since the costs were incurred over a short time period, due to the short survival of patients with metastatic colorectal cancer. The unit costs were generally reported separately from the quantities of resources used. The economic evaluation included drug acquisition costs, administration costs (inpatient stay and disposable equipment), and expenses associated with complications of treatment and disease. These expenses were for visits to the oncologist, radiologist, gynaecologist, surgeon, dermatologist, urologist, general physician, emergency unit, other specialists, general practitioner or nurse visits, and laboratory tests, radiotherapy, X-rays and blood transfusions. The cost/resource boundary adopted was that of the UK NHS. Resource use was estimated prospectively alongside the clinical trial and some assumptions reflecting UK practice were also made. The drug costs were taken from the British National Formulary, while the hospital costs were obtained from extra-contractual referral tariffs. The Department of Health provided cost data relating to general medicine and ward tariffs. Other costs, such as laboratory costs and diagnostic tests, were obtained from the Qost database (involving data from 12 NHS Trusts). Personal Social Services Research Units provided cost data for professional expenses. Some costs were estimated for the period 1996 to 1997 and 1998, but a formal price year was not reported.
Statistical analysis of costs The costs were treated deterministically.
Indirect Costs The indirect costs were not included in the analysis.
Sensitivity analysis Sensitivity analyses were not conducted.
Estimated benefits used in the economic analysis See the 'Effectiveness Results' section.
Cost results The estimated total costs per patient were 8,253 with IRI, 6,791 with 5-FU (B1 regime), 5,983 with 5-FU (B2), 9,981 with 5-FU (B3a) and 8,958 with 5-FU (B3b).
The drug acquisition costs were higher with IRI, while administration costs were higher with the 5-FU therapy.
Synthesis of costs and benefits An incremental analysis was conducted to combine the costs and benefits of the two treatments. The incremental cost per life-year gained with IRI was 7,695 over 5-FU (B1) and 11,947 over 5-FU (B2). IRI dominated both the other 5-FU regimes (B3a and B3b) which were more expensive and less effective.
Authors' conclusions The use of irinotecan (IRI) as second-line therapy for metastatic colorectal cancer was cost-effective in comparison with standard 5-fluorouracil (5-FU).
CRD COMMENTARY - Selection of comparators The rationale for the choice of the comparator was clear. 5-FU was selected because it represented the standard approach for the treatment of patients with metastatic colorectal cancer. You should decide whether it represents a valid comparator in your own setting.
Validity of estimate of measure of effectiveness The analysis of the effectiveness used a randomised controlled trial, which was appropriate for the study question. The study sample appears to have been representative of the study population. Randomisation was stratified. The study groups were comparable at baseline and preliminary power calculations were performed. Statistical analyses were conducted to consider the impact of confounding factors. The length of follow-up was reported. These issues enhance the internal validity of the analysis. However, the basis for the analysis of the clinical study (intention to treat or treatment completers only) and the method of sample selection were not reported.
Validity of estimate of measure of benefit The benefit measure used in the economic analysis was survival, which was derived from the effectiveness study. Discounting was not applied due to the short time horizon of the study. The use of survival permits comparisons to be made with the benefits of other interventions implemented in the health care system.
Validity of estimate of costs The perspective adopted in the study was explicitly reported. It appears that all the relevant categories of costs have been included in the analysis. The unit costs and the quantities of resources used were reported separately. However, a price year was not mentioned, thus making reflation exercises in other settings difficult. The source of the cost data was given for all cost components. The costs were estimated alongside the effectiveness trial. The costs were treated deterministically and no sensitivity analyses were conducted. The cost estimates were specific to the UK setting and were generalised from a multi-centre, multi-national clinical trial.
Other issues The authors compared their findings with those from published studies and other interventions funded in the UK setting. The issue of the generalisability of the study results was addressed in that the authors used UK-specific cost data in conjunction with a multi-national clinical study. However, no sensitivity analyses were conducted, which tends to limit the external validity of the present study. The study enrolled patients with metastatic colorectal cancer and this was reflected in the conclusions of the analysis. The authors acknowledged that mean total costs and median survival were used to calculate the cost-effectiveness analysis, although the use of lifetime estimates would have been more appropriate. The choice was made to avoid making assumptions and to maintain consistency of the trial results. However, lifetime estimates were calculated and these did not vary substantially from those observed in the main analysis.
Implications of the study The main implication of the analysis is that IRI, as second-line treatment for metastatic colorectal cancer, is effective in improving survival and represents good value for money in the UK setting. If ongoing studies show a potential beneficial role for IRI as first-line therapy, then its cost-effectiveness could improve further.
Source of funding Supported by an unconditional educational grant from Rhone-Poulenc Rorer.
Bibliographic details Iveson T J, Hickish T, Schmitt C, Van Cutsem E. Irinotecan in second-line treatment of metastatic colorectal cancer: improved survival and cost-effect compared with infusional 5-FU. European Journal of Cancer 1999; 35(13): 1796-1804 Other publications of related interest Rougier P, Van Cutsem E, Bajetta E, et al. Randomised trial of irinotecan versus infusional fluorouracil by continuous infusion after fuorouracil failure in patients with metastatic colorectal cancer. Lancet 1998;352:1407-12.
Indexing Status Subject indexing assigned by NLM MeSH Adult; Aged; Antineoplastic Combined Chemotherapy Protocols /economics /therapeutic use; Camptothecin /administration & Colorectal Neoplasms /drug therapy /economics; Cost-Benefit Analysis; Drug Costs; Female; Fluorouracil /administration & Humans; Male; Middle Aged; Neoplasm Metastasis; Prospective Studies; Survival Analysis; Treatment Outcome; derivatives /economics; dosage /analogs & dosage /economics AccessionNumber 21999002096 Date bibliographic record published 30/09/2003 Date abstract record published 30/09/2003 |
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