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Economic evaluation of antiaromatase agents in the second-line treatment of metastatic breast cancer |
Verma S, Rocchi A |
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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 anastrozole, exemestane, letrozole and megesterol for the second-line treatment of metastatic breast cancer.
Economic study type Cost-effectiveness analysis.
Study population The study population comprised a hypothetical cohort of 1,000 65-year-old women with metastatic breast cancer who had failed tamoxifen.
Setting The setting was secondary care. The economic study was carried out in Canada.
Dates to which data relate The effectiveness data were derived using studies dating from 1996 to 2000. The price year was 2000.
Source of effectiveness data The evidence for the final outcomes was derived from a review of published studies, supplemented by unpublished clinical trial data from one of the studies.
Modelling The first two years of survival estimation used observed data from the studies exclusively. Subsequent years were extrapolated based on the method of maximum likelihood, with the assumption that the time to death followed a Weibull distribution. The LIFEREG procedure of the SAS statistical software package (version 6.12) was used to calculate survival estimates.
A Markov model was used whereby the hypothetical cohort were assigned to either megesterol or an AA, and followed until their death or the end of the 3-year time horizon. The time horizon was then varied to 4 and 5 years in the sensitivity analysis. The Markov model consisted of three phases of care:
hormonal care, from initiation of second-line hormonal treatment with megesterol or an AA, to discontinuation of second-line hormonal treatment;
ongoing care, from discontinuation of second-line hormonal treatment, to 13 weeks prior to death from breast cancer, or to 1 week prior to death from other causes; and
terminal care, the 13 weeks prior to and including death from breast cancer, or the final week prior to death from other causes.
Patients discontinuing hormonal care switched to ongoing care. Patients who discontinued hormonal care due to disease progression incurred additional costs, owing to the diagnosis of progression and the potential need for chemotherapy. Patients who died ceased incurring costs for ongoing care and, instead, incurred the cost of terminal care.
Outcomes assessed in the review The outcome assessed in the review was survival benefit.
Study designs and other criteria for inclusion in the review The review consisted of published megesterol-controlled phase III clinical trials. These compared megesterol with the AAs (anastrozole, exemestane and letrozole) in women with metastatic breast cancer who had failed first-line tamoxifen.
Sources searched to identify primary studies Criteria used to ensure the validity of primary studies Methods used to judge relevance and validity, and for extracting data Number of primary studies included Four primary studies were included in the review. Two studies compared megesterol with anastrozole, one compared megesterol with exemestane, and the other compared megesterol with letrozole.
Methods of combining primary studies Patient-level survival data were only available from one study, which compared megesterol with exemestane. Therefore, in the presence of a survival benefit statistically equivalent to exemestane, survival with other AAs was assumed to be identical to survival with exemestane.
Investigation of differences between primary studies The authors reported that the inclusion criteria and study populations were similar for all of the trials.
Results of the review In the exemestane trial, the objective response rate was not significantly different between the comparators, 15% for exemestane and 12.4% for megesterol. However, the secondary time dependent outcomes, including time to progression (TTP), time to treatment failure (TTF) and survival, were consistently improved. The median survival was 123.4 weeks for megesterol, but had not yet been reached for exemestane.
In the anastrozole trials, there was no significant difference in objective response rate, TTP or TTF. However, a post-hoc pooled analysis of the two pivotal trials detected a significant survival difference for the 1-mg dose, (p<0.025), but not the 10-mg dose, (p=0.09), compared with megesterol.
In the letrozole trial, the objective response rate was significantly different, 24% for letrozole 2.5 mg versus 16% for megesterol, (p=0.04). Of the secondary outcomes, TTF and duration of response, but not TTP or overall survival, were significantly superior for letrozole.
Megesterol survival, as predicted by the statistical model, was 17% at 5 years. This corresponded well with the literature estimates of 5-year survival.
For anastrozole 1 mg, a hazard ratio of 0.78 for survival was reported (1 trial), using a Cox proportional hazard model. Using the same methodology, a hazard ratio of 0.76 was calculated for survival with exemestane. As the two results were not statistically significant, (p=0.88), the survival extrapolations for exemestane were applied to anastrozole.
No survival advantage was seen when letrozole was compared with megesterol. Therefore, the survival predicted for megesterol patients was applied to letrozole patients in the base-case.
Measure of benefits used in the economic analysis The measure of benefits used in the economic analysis was the years of life saved.
Direct costs The resource use and the costs were not reported separately. The direct costs of the health service were included in the analysis. These were for hormonal care with megesterol and the three AAs, disease progression, chemotherapy following disease progression, ongoing care and terminal care. The costs of disease progression included hospitalisation, specialist visits and diagnostic tests. Medications, physician services, laboratory tests and procedures were priced using current fee schedules in Canada. The hospital costs were determined from the Ontario Case Costing Project (www.occp.com). The costs of home care were determined from Ontario Community Care Access Centres. The resource use data were obtained from published clinical trials, Statistic Canada's Population Health Model for breast cancer (POHEM), and the opinions of an expert panel of Canadian oncologists. Discounting was necessary since the costs were incurred during more than two years, and was performed using a 5% discount rate for both the costs and benefits. The study reported the average costs per patient. The price year was 2000.
Statistical analysis of costs The costs were treated as point estimates (i.e. the data were deterministic).
Indirect Costs The indirect costs were not included in the analysis.
Sensitivity analysis Sensitivity analyses were conducted to determine the robustness of the model. The parameters varied were the duration of survival benefit with the AAs (extended from 3 years to 4 and 5 years), the discount rate (0%), the costs of ongoing and terminal care (+/- 25%), and the cost of death from other causes (substituted with the cost of a breast cancer death). A worst-case scenario combined the analyses that decreased the cost-effectiveness of exemestane.
Estimated benefits used in the economic analysis The estimated benefits used in the economic analysis were a survival benefit of 123.39 weeks for megesterol and letrozole, and 130.46 weeks for anastrozole and exemestane.
Cost results The total cost per patient was Can$39,800 when treated with megesterol, Can$41,000 when treated with anastrozole and exemestane, and Can$39,500 when treated with letrozole.
Synthesis of costs and benefits Where there was a difference in survival between the AAs and megesterol, the costs and benefits were combined as the incremental cost per life-year gained (LYG). A cost-minimisation analysis was adopted where there was no difference in survival between the AAs and megesterol. Hence, the cost-effectiveness ratio of anastrozole or exemestane versus megesterol was Can$9,000 per LYG. When letrozole was compared with megesterol there was a saving of Can$300 but no difference in LYG. When anastrozole or exemestane were compared with letrozole, the cost-effectiveness ratio was Can$11,000 per LYG.
The results from the sensitivity analysis suggested that, overall, the model was robust, as the results fell within a narrow range (Can$7,400 to Can$12,800 per LYG) when exemestane was compared with megesterol.
Authors' conclusions Some antiaromatase agents (AAs), such as exemestane and anastrozole, offered excellent value compared with megesterol.
CRD COMMENTARY - Selection of comparators A justification was given for using megesterol as the comparator. Megesterol was the least-expensive alternative to AAs, and it provided a common reference point for the indirect comparison of all AAs with each other.
Validity of estimate of measure of effectiveness The authors did not state that a systematic review of the literature had been undertaken to identify relevant research and minimise biases. However, the review only included 'gold' standard randomised clinical trials to provide the primary inputs for the consequences. Further, the four studies included in the review had similar inclusion criteria and similar study populations.
Validity of estimate of measure of benefit The measure of health benefit, the LYG, was obtained through modelling parameters and extrapolation from primary studies. The authors assumed that, in the absence of a survival benefit, survival with AAs would be identical to survival, thus biasing against the new interventions.
Validity of estimate of costs All the categories of cost relevant to the perspective adopted (the health care system) were included in the analysis. For each category of cost, all the relevant costs seem to have been included. The costs and the quantities were not reported separately, which will limit the generalisability to other settings. Resource use was obtained from published sources and expert opinion. Despite the fact that some of the resource use data were derived from assumptions and expert opinion, the authors failed to undertake a sensitivity analysis of the quantities. This may limit the interpretation of the study findings. The unit costs were obtained from published sources and fee schedules. A sensitivity analysis of the prices was satisfactorily performed, using ranges that appear to have been appropriate. Discounting was necessary since all the costs were incurred during more than two years, and was performed at a rate of 5%. The price year was reported, which will aid any possible reflation exercises.
Other issues The authors made appropriate comparisons of their findings with those from other studies. Prior economic evaluations of letrozole versus megesterol, conducted in the UK and Canada, found the cost-effectiveness of letrozole to be $5,000 per LYG. However, such studies were sensitive to assumptions of efficacy and, in the sensitivity analysis, megesterol became the dominant strategy. Two other economic evaluations of exemestane versus megesterol found acceptable cost-effectiveness results, albeit higher than in the present study, due to higher health care costs. The issue of generalisability to other settings was partly addressed through the sensitivity analysis, although the authors cautioned that small differences in prices could impact on the results. Hence, the results presented may not be generalisable outside Canada. The authors do not appear to have presented their results selectively and their conclusions appear to reflect the scope of the analysis.
The authors reported a number of further limitations to their study. For example, the heterogeneity in patients with metastatic breast cancer may mean that the estimated resource use from other patient populations is not generalisable. Hence, this could lead to some inaccuracies in the costing. The authors also pointed out that the anastrozole survival data have been questioned due to the inconsistency of the benefit between trials, across outcomes and across dosages.
Implications of the study Based on the available data, the authors recommended the use of exemestane and anastrozole as appropriate choices for second-line hormonal treatment of metastatic breast cancer.
Bibliographic details Verma S, Rocchi A. Economic evaluation of antiaromatase agents in the second-line treatment of metastatic breast cancer. Supportive Care in Cancer 2003; 11(11): 728-734 Other publications of related interest Nuijten M, Meester L, Waibel F, et al. Cost effectiveness of letrozole in the treatment of advanced breast cancer in postmenopausal women in the UK. Pharmacoeconomics 1999;16:379-97.
Nuijten M, McCormick J, Waibel F, et al. Economic evaluation of letrozole in the treatment of advanced breast cancer in postmenopausal women in Canada. Value in Health 2000;3:31-9.
Will PB, Berthelot J-M, Houle C, et al. A model for estimating the costs and burdens of breast cancer diagnosis and treatment in Canada. Health Reports 1993;5:399-408.
Will PB, Berthelot J-M, Le Petit C, et al. Estimates of the lifetime costs of breast cancer treatment in Canada. European Journal of Cancer 2000;36:724-35.
Indexing Status Subject indexing assigned by NLM MeSH Aged; Androstadienes /economics /therapeutic use; Antineoplastic Agents /economics /therapeutic use; Aromatase Inhibitors; Breast Neoplasms /drug therapy /economics /pathology; Canada; Clinical Trials, Phase III as Topic; Cost-Benefit Analysis; Enzyme Inhibitors /economics /therapeutic use; Female; Humans; Megestrol /economics /therapeutic use; Middle Aged; Nitriles /economics /therapeutic use; Quality-Adjusted Life Years; Randomized Controlled Trials as Topic; Survival Analysis; Triazoles /economics /therapeutic use AccessionNumber 22003001436 Date bibliographic record published 31/07/2004 Date abstract record published 31/07/2004 |
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