Cost-effectiveness of androgen suppression therapies in advanced prostate cancer Bayoumi A M, Brown A D, Garber A M 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 Six androgen suppression therapies for advanced prostate cancer were examined. These were diethylstilbestrol (DES), bilateral orchiectomy, a nonsteroidal antiandrogen (NSAA; nilutamide), a luteinising hormone-releasing hormone (LHRH) agonist (goserelin), and two combined androgen blockade strategies (NSAA with a LHRH agonist, and NSAA with orchiectomy). Type of intervention Palliative care. Economic study type Cost-effectiveness and cost-utility analyses. Study population The study population comprised patients with a prior history of prostate cancer with no distant metastases. All of the patients had received definitive treatment with either radiotherapy or radical prostatectomy after initial diagnosis. Those patients who opted for watchful waiting at initial presentation were excluded. Setting The setting of the study was unclear. The economic study was carried out in the USA. Dates to which data relate The effectiveness and resource utilisation data were derived from studies published between 1973 and 1999. The price year was 1998. Source of effectiveness data The effectiveness evidence was derived from a review of published studies, supported by the authors' assumptions. Modelling A Markov model was used to simulate the natural history of prostate cancer in a hypothetical 65-year-old patient in a time horizon of 20 years. The health states assessed in the model were local recurrence of prostate cancer, asymptomatic distant metastases, symptomatic distant metastases, and death. Patients experiencing severe side effects or disease progression were switched to a second-line therapy. Each cycle lasted one month and transition probability data were derived from the literature. Outcomes assessed in the review The outcomes assessed in the review were used as inputs in the model. These were the efficacy (base-case and meta- Page: 1 / 6
analysis estimates) and toxicity of antiandrogen therapies and the quality of life weights, as follows: the alternative efficacy (relative hazard ratio for disease progression) for the six therapies; the probabilities of minor, major, and severe side effects; the proportion responding, mean and maximum duration of response, and relative hazard for disease progression with androgen withdrawal; the proportion responding, the mean duration of response, and the relative hazard for disease progression for secondline therapy (based on ketoconazole); the quality of life weights for local recurrent disease, distant asymptomatic disease (either hormone responsive or resistant), and adjustment for living with minor side effects; and several outcomes incurred during transitions between states, such as the annual probability of a local bladder outlet obstruction and quality of life loss with either local bladder outlet obstruction or with severe side effects. Study designs and other criteria for inclusion in the review The authors reported that some of the primary studies used to derive the effectiveness evidence were randomised controlled trials. Sources searched to identify primary studies Not reported. 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 The effectiveness evidence was derived from twelve primary studies. Methods of combining primary studies Investigation of differences between primary studies Results of the review In the base-case, it was assumed that all strategies were equally effective. The mean alternative (meta-analysis) efficacy was 1 for orchiectomy (referent), 0.97 (range: 0.76-1.25) for DES, 1.22 (range: 0.97-1.54) for NSAA, 0.98 (range: 0.78-1.23) for NSAA plus orchiectomy, 1.11 (range: 0.89-1.39) for LHRH antagonist, and 0.94 (range: 0.78-1.14) for LHRH antagonist plus NSAA. The probability of minor side effects with all treatments was 55% (range: 20-80). Page: 2 / 6
The probability of major side effects was 14.3% (range: 0-50) for DES, 6.8% (range: 0-50) for NSAA, 9.4% (range: 0-50) for NSAA plus orchiectomy, 1.3% (range: 0-50) for LHRH antagonist, and 11% (range: 0-50) for LHRH antagonist plus NSAA. Severe side-effects (excess mortality rate per 10,000 patient-years) were 100 (range: 0-500) for DES and 3 (range: 0-100) for NSAA. For androgen withdrawal, the proportion responding was 35% (range: 0-100), the mean duration of response was 3.5 months (range: 0-12), the maximum duration of response was 12 months (range: 0-48), and the relative hazard for disease progression was 0.33 (range: 0.1-1). For second-line therapy, the proportion responding was 20% (range: 0-50), the duration of response was 3 months (range: 0-12), and the relative hazard for disease progression was 0.33 (range: 0.1-1). The quality of life weights were 0.92 (range: 0.8-1) for local recurrent disease, 0.9 (range: 0.8-1) for distant asymptomatic disease, 0.8 (range: 0.4-0.9) for distant asymptomatic disease (hormone responsive), 0.4 (range: 0.1-0.7) for distant asymptomatic disease (hormone resistant), and 0.85 (range: 0.5-1) for adjustment for living with minor side effects. The annual probability of a local bladder outlet obstruction was 2.20% (range: 0-4.4). The quality of life loss with local bladder outlet obstruction was 0.1 months (range: 0-0.2). The quality of life loss with severe side effects was 0.1 months (range: 0-0.2). Methods used to derive estimates of effectiveness The authors made some assumptions concerning the effectiveness evidence, in order to support the data derived from published studies and to construct the decision model. Estimates of effectiveness and key assumptions Some of the assumptions made by the authors were as follows: neither the type of definitive therapy, nor any use of adjuvant hormonal therapy, influenced disease course after recurrence; antiandrogen therapies reduced the disease progression rates by two thirds when prostate care was hormone sensitive; recurrent prostate cancer was initially responsive to androgen suppression but eventually developed hormone resistance and progression clinically; the patients did not experience a reduction in quality of life until the development of hormone-resistant symptomatic distant metastases; and the same utility score was attributed to orchiectomy and the medical therapies. In addition, the model was intentionally biased in favour of combined androgen blockade strategies, on the basis of two assumptions. First, a patient intolerant of one NSAA would start another, and second, that some patients would benefit from NSAA withdrawals with a transiently decreased risk of disease progression. Measure of benefits used in the economic analysis The benefit measures used in the economic analysis were survival (discounted and undiscounted) and the qualityadjusted life-years (QALYs). Both were derived from the decision model and a 3% discount rate was used. The utility scores reflected the preferences of both the patients and physicians. Page: 3 / 6
Direct costs A 3% discount rate was used since the time horizon of the study was 20 years. The unit costs and the quantities of resources were not reported. The cost/resource boundary was unclear. The cost items included in the analysis were androgen suppression therapies, other prostate cancer treatments, and side effects. It was assumed that the costs of treating other health conditions were similar among the antiandrogen therapies. The costs were estimated using both actual data derived from Medicare charges and published data obtained from the literature. The quantities were estimated from a review of studies published between 1973 and 1999. The Gross Domestic Product deflator was used to update all the costs to 1998, which represented the selected price year. Statistical analysis of costs No statistical analyses of the costs were conducted. Indirect Costs The indirect costs were not included. Currency US dollars ($). Sensitivity analysis Sensitivity analyses were conducted to assess the robustness of the estimated cost-utility ratios to variations in all the parameters used in the decision model, within the ranges reported in the effectiveness analysis. In addition, the assumption of equal efficacy of all treatments was replaced with the meta-analysis estimates. A modified decision tree was also constructed to take into account both a different start of the therapy and the inclusion of information derived from the prostate-specific antigen test. The assumption that orchiectomy was not a feasible option was also examined. The analyses conducted were mainly one-way analyses. Estimated benefits used in the economic analysis The undiscounted life-years were 6.86 for DES, 7.58 for orchiectomy, 7.39 for NSAA, 7.54 for NSAA plus orchiectomy, 7.54 for LHRH antagonist, and 7.52 for LHRH antagonist plus NSAA. The discounted life-years were 5.96 for DES, 6.52 for orchiectomy, 6.38 for NSAA, 6.49 for NSAA plus orchiectomy, 6.50 for LHRH antagonist, and 6.48 for LHRH antagonist plus NSAA. The discounted QALYs were 4.64 for DES, 5.10 for orchiectomy, 4.98 for NSAA, 5.05 for NSAA plus orchiectomy, 5.08 for LHRH antagonist, and 5.03 for LHRH antagonist plus NSAA. Cost results The undiscounted costs were $4,100 for DES, $7,500 for orchiectomy, $18,400 for NSAA, $23,200 for NSAA plus orchiectomy, $30,900 for LHRH antagonist, and $46,200 for LHRH antagonist plus NSAA. The discounted costs were $3,600 for DES, $7,000 for orchiectomy, $16,100 for NSAA, $20,700 for NSAA plus orchiectomy, $27,000 for LHRH antagonist, and $40,300 for LHRH antagonist plus NSAA. Synthesis of costs and benefits The costs and benefits were combined by an incremental cost-utility analysis. No comparison with no treatment was made. Page: 4 / 6
Orchiectomy dominated all strategies (more effective and less costly) except DES, with an incremental cost per extra life-year of $6,100 and an incremental cost per extra QALY of $7,500 over DES, both discounted. The results of the study were relatively robust to variations tested in the sensitivity analyses. Orchiectomy generally remained the dominant strategy, except in relation to DES, and its incremental cost-utility ratio over DES remained relatively low. When orchiectomy was not considered a feasible alternative, the incremental cost per extra QALY of NSAA over DES was $43,200. The sensitivity analyses also showed that, if the utility weight of orchiectomy was less than 0.83, the incremental cost per QALY of LHRH agonist over orchiectomy would fall below $50,000. Authors' conclusions Orchiectomy was the most cost-effective treatment for patients with advanced prostate cancer. For men who declined orchiectomy, nonsteroidal antiandrogen (NSAA) therapy represented the most feasible option, with an incremental cost per quality-adjusted life-year (QALY) below the threshold of $50,000 over diethylstilbestrol (DES). CRD COMMENTARY - Selection of comparators The rationale for the choice of the strategies was clear. The six therapies were selected as they represented feasible interventions for patients with advance prostate cancer. However, it was unclear what the incremental cost-effective ratio of DES over no treatment was, although presumably the costs of treating disease not remedied by DES outweigh the cost of the DES itself. You should assess whether they represent widely used therapies in you own setting. Validity of estimate of measure of effectiveness The effectiveness analysis used a review of the literature. However, details of the review process were not reported. For example, the sources searched, and the methods used to ensure the validity, comparability, and combination of the primary studies. Several assumptions were also made to support the effectiveness evidence. The authors acknowledged that the use of different sources could have increased the uncertainty around the results of the analysis. Extensive sensitivity analyses were therefore conducted, using the range of values derived from the literature. Validity of estimate of measure of benefit The benefit measures used in the economic analysis (QALYs and life-years) appear to have been appropriate for assessing the impact of the treatments on the patients' health, in the case of prostate cancer. Both were obtained through the use of a Markov model, which simulated the natural history and treatment of the disease. The utility scores were obtained from a meta-analysis of the patients' and physicians' preferences. Validity of estimate of costs Although the authors stated that a societal perspective was adopted in the study, the indirect costs were not included. Consequently, it was unclear whether some of the cost items had been omitted from the analysis. Most of the estimated costs represented charges (from Medicare rates) and, therefore, did not reflect true opportunity costs. The unit costs and the quantities of resources were not reported separately, thus reducing transparency and the opportunity for generalisability. No statistical analyses were conducted on the costs. Other issues The authors made few comparisons of their findings with those from other studies. The issue of the generalisability of the study results to other settings was not explicitly addressed. However, several sensitivity analyses were conducted, thus enhancing the external validity of the study. The effectiveness results were reported in full, although the costing was lacking. Page: 5 / 6
Powered by TCPDF (www.tcpdf.org) Implications of the study The authors highlight the fact that orchiectomy represents the most cost-effective intervention, but the acceptability of orchiectomy varies among patients. They recommend assessing quality-of-life effects of different antiandrogen therapies in future research. Source of funding Supported by the Blue Cross and Blue Shield Association Technology Evaluation Center, and the Evidence-based Practice Center of the Agency for Healthcare Research and Quality. Bibliographic details Bayoumi A M, Brown A D, Garber A M. Cost-effectiveness of androgen suppression therapies in advanced prostate cancer. Journal of the National Cancer Institute 2000; 92(21): 1731-1739 PubMedID 11058616 Other publications of related interest Comment: Journal of the National Cancer Institute 2000;92:1704-6. Indexing Status Subject indexing assigned by NLM MeSH Aged; Androgen Antagonists /economics /therapeutic use; Antineoplastic Agents, Hormonal /economics /therapeutic use; Antineoplastic Combined Chemotherapy Protocols /economics /therapeutic use; Cost-Benefit Analysis; Diethylstilbestrol /economics /therapeutic use; Disease Progression; Gonadotropin-Releasing Hormone /agonists; Humans; Male; Markov Chains; Neoplasm Recurrence, Local /therapy; Orchiectomy /economics; Prostate-Specific Antigen /blood; Prostatic Neoplasms /drug therapy /economics /immunology /surgery /therapy; Quality of Life; Quality- Adjusted Life Years; Survival Analysis; Time Factors; Treatment Outcome; United States AccessionNumber 22000001752 Date bibliographic record published 31/01/2003 Date abstract record published 31/01/2003 Page: 6 / 6