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Clinical and economic benefits of irinotecan in combination with 5-fluorouracil and folinic acid as first line treatment of metastatic colorectal cancer |
Cunningham D, Falk S, Jackson D |
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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 plus 5-fluorouracil and folinic acid (5-FU/FA) as first-line treatment for patients with metastatic colorectal cancer.
The regimen considered was irinotecan, 180 mg/m2 as a 90-minute intravenous (i.v.) infusion plus 5-FU/FA in accordance with the de Gramont regimen. The de Gramont regimen was 200 mg/m2 FA i.v. over 2 hours, followed by 400 mg/m2 5-FU as an i.v. bolus, then 600 mg/m2 5-FU as a continuous i.v. infusion over 22 hours/day on the first 2 days of every 2-week period. One treatment cycle corresponded to 3 infusions (6 weeks).
Economic study type Cost-effectiveness analysis.
Study population The population comprised patients with metastatic colorectal cancer.
Setting The setting was a hospital. The economic study was carried out in French and UK centres.
Dates to which data relate The dates to which the effectiveness and resource utilisation data related were not reported. The cost data related to different dates (1993/94, 1997/98, 1999, 2000, and 2001). The price year was not reported.
Source of effectiveness data The effectiveness data were derived from a single study composed of two stages. The results from the first stage have been published by Douillard et al. (see Other Publications of Related Interest).
Link between effectiveness and cost data The costing was undertaken on the same patient sample as that used in the single study. The single study was conducted over 2 stages. The costs related to the first stage of the study were collected prospectively, while those related to the second stage were collected retrospectively, on the basis of a case-note review.
Study sample The sample size was not reported to have been determined in the planning phase of the study to assure a certain power. The study sample was composed of 385 patients with metastatic colorectal cancer that received at least one cycle of treatment. Of these, 199 received a combination of irinotecan and 5-FU/FA therapy, and 186 received 5-FU/FA alone. Only those patients that received the de Gramont regimen were considered in the effectiveness analysis. The authors reported that 145 patients in the intervention group and 143 in the control group received the de Gramont regimen, and were therefore followed up in the first stage of the study.
Among the patients randomised to treatment with irinotecan plus 5-FU/FA, 39.4% failed first-line therapy, compared with 58.3% of those randomised to receive 5-FU/FA alone. Of these, 62 patients were followed in the second stage of the single study, in order to assess the resource utilisation associated with further chemotherapy in patients who had progressed during the first stage of the single study. The number of patients in each treatment arm during the second stage of the study was not reported. The authors did not provide evidence that the study sample was representative of the study population.
Study design This was a multi-centred randomised controlled study, which was conducted in France and the UK. The duration of follow-up in the first stage of the study was until disease progression, unacceptable toxicity or withdrawal. The duration of follow-up in the second stage was 3 years, until death or trial cut-off date (median: 14.7 months; range: 11.5 - 21.1 months). It was not reported how the 62 patients included in the second stage of the study were chosen from those that failed first-line treatment in the alternative treatment arms.
Analysis of effectiveness The authors reported that the basis for the analysis was intention to treat. The outcomes assessed for the first stage of the study and for both treatment arms (irinotecan plus 5-FU/FA and 5-FU/FA alone) were the response rate, the median time to disease progression, and the median overall survival. Also reported was the percentage of patients treated with 5-FU/FA alone that received further chemotherapy, and the percentage of them that received a regimen containing irinotecan. The median treatment duration and the cumulative number of infusions per patient over the study period were also assessed for both treatment arms. Most of the data were related to second-line therapy, although the authors reported that a small proportion of third-line treatment may have been included. The authors did not show that the groups were comparable at analysis, nor report how many patients were allocated in each one of the treatment arms in the second stage of the study.
Effectiveness results The response rate with irinotecan plus 5-FU/FA (41%) was significantly higher than that with 5-FU/FA alone (23%), (p<0.001). The median time for disease progression was also significantly higher with irinotecan plus 5-FU/FA (6.7 months) than with 5-FU/FA alone (4.4 months), (p<0.001). The median overall survival was again significantly higher with irinotecan plus 5-FU/FA (16.8 months) than with 5-FU/FA alone (14.0 months), (p<0.028).
The authors reported that among the patients who received 5-FU/FA alone, 58.3% received further chemotherapy and 31% were subsequently treated with a regimen containing irinotecan.
The median treatment duration was shorter for patients treated with 5-FU/FA alone (18.0 weeks) than for patients treated with irinotecan plus 5-FU/FA (24.6 weeks).
The cumulative number of infusions per patient over the study period was lower with 5-FU/FA (9.66 infusions) than with irinotecan plus 5-FU/FA (12.08 infusions).
Clinical conclusions The results of the single study showed that irinotecan plus 5-FU/FA was associated with better results in terms of the response rates, median time for disease progression, and median overall survival. There were also a smaller percentage of these patients receiving second-line therapy in comparison with those given 5-FU/FA alone.
Measure of benefits used in the economic analysis The health benefit measure used was the life-years gained.
Direct costs The resource quantities and the costs were reported separately. The costs included in the analysis were those of the health service. Only data relating to patients who received the de Gramont regimen were included in the cost analysis. Data relating to patients who received the AIO regimen were excluded, because this regimen is not used in the UK.
The costs included in the first stage of the study were the cumulative costs associated with drug acquisition (6,753.20 for irinotecan plus 5-FU/FA and 1,352.79 for 5-FU/FA), hospitalisation for administration of treatment, and disease complications. The hospitalisation costs included the unit costs of inpatient stay per infusion, day hospital attendance, insertion of tunnelled central line catheter, and disposable pump. The costs related to complications included hospitalisation, outpatient consultations, oncologist consultations, physiotherapist consultations, other specialist consultations, GP consultations, nursing time, and equipment.
The costs considered in the second stage of the study were those associated with further chemotherapy and those related to disease progression during the follow-up (i.e. hospitalisations, radiotherapy and second-line therapy).
The authors also reported the overall cumulative costs per 100 patients. The inpatient cumulative drug costs per patient were obtained from the British National Formulary (September 2001). The hospitalisation costs were obtained from 12 NHS Trusts in the UK (Qost database, 1997/98). Specialist consultation and diagnostic costs were obtained from the Qost database (1997/98). The official average length of stay published by the Department of Health (Department of Health Government Statistical Service, 1993/94) was used to calculate the costs per day. The costs related to health professional, nurse and GP consultations were obtained from a published study by Netten and Dennett (see Other Publications of Related Interest). The unit costs were estimated from actual data. Discounting was not carried out.
Statistical analysis of costs No statistical analyses of the resource utilisation or costs were reported.
Indirect Costs The indirect costs were not reported.
Sensitivity analysis The authors stated that a sensitivity analysis using UK data alone was performed to reflect the situation in the UK.
Estimated benefits used in the economic analysis The median survival gain of the combination of irinotecan plus 5-FU/FA over 5-FU/FA alone was 2.8 months, on other words 0.23 life-years gained.
Cost results The authors reported the following overall cumulative costs per 100 patients.
During the first stage of the study, the drug acquisition costs for irinotecan plus 5-FU/FA were 6,753.20, the drug administration costs were 1,825, and the complication costs were 1,480. For 5-FU/FA alone, the drug acquisition costs were 1,352.79, the drug administration costs were 1,537, and the complication costs were 1,146.90.
During the second stage of the study, for the treatment arm of irinotecan plus 5-FU/FA, the chemotherapy costs were 2,006.76, while the corresponding disease progression costs were 1,484.34. For the treatment arm of 5-FU/FA alone, the chemotherapy costs were 3,600.73, and the disease progression costs were 2,460.23.
The total costs (including the costs associated with both the first and second stages of the study) were 13,550 for irinotecan plus 5-FU/FA and 10,098 for 5-FU/FA alone.
Synthesis of costs and benefits The cost-effectiveness ratio per life-year gained was 14,794. This was calculated as the difference in the overall costs between irinotecan plus 5-FU/FA and 5-FU/FA alone, divided by the difference in median survival between them. The sensitivity analysis showed that the cost-effectiveness ratio increased to 16,015 when the analysis used UK data to reflect local practice.
Authors' conclusions Irinotecan plus 5-fluorouracil and folinic acid (5-FU/FA) may be viewed as a cost-effective treatment of metastatic colorectal cancer, compared with 5-FU/FA alone (the currently accepted best practice), because it produces a significant survival gain with a modest increase in the cost. Therefore, the authors support the use of irinotecan plus 5-FU/FA as first-line treatment for patients with metastatic colorectal cancer.
CRD COMMENTARY - Selection of comparators The choice of the comparator used, 5-FU/FA, was justified on the grounds that it is the most common regimen used in the UK.
Validity of estimate of measure of effectiveness The analysis used a randomised controlled trial, which seems to have been appropriate for the study question. The study sample is likely to have been representative of the study population. In terms of limitations in reporting, it was unclear from the paper how the patients followed up in the second stage of the study were selected from among those who presented disease progression after the first stage of the study. Also, the patient groups were not shown to be comparable at the baseline analysis. Appropriate statistical analyses were undertaken in the principal analyses. Although this study was a randomised controlled trial, the fact that some patients receiving 5-FU/FA alone were also given irinotecan may affect the interpretation of the results.
Validity of estimate of measure of benefit The estimation of benefits was presented in life-years saved, which was obtained directly from the effectiveness analysis. The authors justified this choice on the grounds that life-years saved was a major efficacy parameter used in most of the effectiveness analysis.
Validity of estimate of costs All the categories of costs relevant to the perspective adopted appear to have been included in the analysis. The resource quantities and the costs were reported separately, which will enhance the generalisability of the results to other settings. However, the costing was based on data collected from patients who received the de Gramont regimen during the first stage of the study, whilst overall survival was based on data from all patients. This makes the interpretation of the results problematic. The authors mentioned the importance of indirect costs in this kind of study, but justified their exclusion (in this case) due to the perspective adopted. Indirect costs (lost productivity, care by relatives, and so on) may be relevant for this patient domain if a societal perspective were to be adopted. No statistical analysis of the quantities was performed, thus introducing uncertainty in the reliability of the conclusions and limiting the interpretation of the study findings. There was also no statistical analysis of the costs. Discounting was not carried out. However, this was largely irrelevant for the purposes of the study, as the patients had a survival less than two years and the costs per patient were, therefore, incurred over less than two years.
Other issues A sensitivity analysis was performed to reflect the situation in the UK, but it was not stated how the analysis was carried out or what parameters were varied. The authors compared their findings with those obtained from other studies in terms of the use of irinotecan plus 5-FU/FA as second-line therapy for metastatic colorectal cancer. The issue of the generalisability to other settings was addressed in that the appropriateness to the UK context was examined.
Implications of the study The results of this study appear to favour the use of irinotecan plus 5-FU/FA as first-line therapy in the treatment of patients with metastatic colorectal cancer because, as the authors state, it increases the survival of patients at an acceptable cost. However, caution should be exercised when interpreting these results due to the caveats discussed.
Source of funding Supported by an unconditional educational grant from Aventis Pharma.
Bibliographic details Cunningham D, Falk S, Jackson D. Clinical and economic benefits of irinotecan in combination with 5-fluorouracil and folinic acid as first line treatment of metastatic colorectal cancer. British Journal of Cancer 2002; 86(11): 1677-1683 Other publications of related interest Cunningham D, Pyrhonen S, James RD, et al. Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer. Lancet 1998;352:1413-8.
de Gramont A, Bosset J-F, Milan C, et al. Randomised trial comparing monthly low-dose leucovorin and fluorouracil bolus with bimonthly high-dose leucovorin and fluorouracil bolus plus continuous infusion for advanced colorectal cancer: a French Intergroup Study. Journal of Clinical Oncology 1997;15:808-15.
Department of Health, Economic and Operational Research Division, Department of Health, 1994.
Doudillard JY, Cunningham D, Roth AD, et al. Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial. Lancet 2000;355:1041-7.
Netten A, Dennett J. Unit costs of health and social care. Kent: University of Kent, Personal Social Services Research Unit; 1998.
Indexing Status Subject indexing assigned by NLM MeSH Antineoplastic Agents, Phytogenic /administration & Antineoplastic Combined Chemotherapy Protocols /economics /therapeutic use; Camptothecin /administration & Colorectal Neoplasms /drug therapy; Costs and Cost Analysis; England; Fluorouracil /administration & Humans; Leucovorin /administration & derivatives /economics /therapeutic use; dosage; dosage; dosage /adverse effects /economics; dosage /analogs & AccessionNumber 22002001172 Date bibliographic record published 31/03/2003 Date abstract record published 31/03/2003 |
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