Affiliations of authors: A. M. Bayoumi, Department of Medicine, University of Toronto, and Inner City Health Research Unit, St. Michael's Hospital, Toronto, Canada; A. D. Brown, Department of Public Health and Primary Care, University of Oxford, U.K.; A. M. Garber, Department of Veterans Affairs, Palo Alto Health Care System, CA, and Center for Primary Care and Outcomes Research, Stanford University School of Medicine, San Francisco, CA.
Correspondence to: Ahmed M. Bayoumi, M.D., M.Sc., 2-024 Shuter Wing, St. Michael's Hospital, 30 Bond St., Toronto, ON, Canada M5B 1W8 (e-mail: ahmed.bayoumi{at}utoronto.ca).
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ABSTRACT |
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INTRODUCTION |
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We evaluated the cost-effectiveness of androgen suppression in the form of orchiectomy, medication monotherapy, and combined androgen blockade. We also explored how cost-effectiveness varies with the time of initiation of therapy, whether prompted by symptoms or biochemical evidence of disease progression using prostate-specific antigen monitoring.
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SUBJECTS AND METHODS |
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The Base Case
The base case patient was assumed to be a 65-year-old man with a previous history of prostate cancer. We assumed that the patient at entry into the model, had clinically evident, localized cancer recurrence (e.g., involvement of seminal vesicles) but no distant metastases. He had received definitive treatment at his initial diagnosis with either radiotherapy or radical prostatectomy; thus, our model did not include patients who opted for watchful waiting at initial presentation. We assumed that neither the type of definitive therapy nor any use of adjuvant hormonal therapy influenced disease course after recurrence.
We designated the first androgen suppression therapy used as "first-line therapy." Patients were switched from first-line therapy to an alternative androgen suppression regimen, designated as "second-line therapy," following a severe side effect or disease progression. We assumed that patients used ketoconazole chemotherapy as the second-line agent but that only some patients experienced a transient decrease in disease progression rates (9,10). Patients who did not respond to ketoconazole stopped all androgen suppression. All patients received chemotherapy and end-of-life medical care before dying.
Disease Progression
Disease progression was assumed to occur in a fixed sequence of four health states: 1) local recurrence of prostate cancer, 2) asymptomatic distant metastases, 3) symptomatic distant metastases, and 4) death (Fig. 1). In our base case, we assumed that biochemical monitoring (with prostate-specific antigen) was not used to guide treatment decisions. Local recurrence (meaning recurrent prostate cancer confined to the organ or capsule, invading the seminal vesicles, or involving pelvic lymph nodes) required a treatment approach based on clinical, rather than biochemical, markers. Such an approach is consistent with the best evidence available to date and is the approach used in almost all clinical trials; therefore, we modeled this approach in our base case and addressed the use of biochemical markers in a sensitivity analysis (11,12).
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Transitions between health states depended on the biologic behavior of the cancer and the response to treatment. We calculated the probability of moving from one health state to the next from natural history data and randomized controlled trials (4,1421). We estimated transition ratesthe proportion of individuals moving from one state to the next in a given periodbased on the mean time spent in each state. We next calculated monthly transition probabilities, assuming constant rates, using the formula (22) probability = 1 exp ( annual rate/12).
We refined our estimates to account for both treatment effects and the substantial competing risk of death from other causes (23). With these model assumptions, men with hormone-sensitive disease would have an average cancer-free survival of about 4.5 years, following the first diagnosis of a distant metastasis, in close agreement with a recent observational study's estimate of just under 5 years (14).
Androgen Suppression Strategies
We evaluated six androgen suppression strategies: a surgical strategy, three single drug medication strategies, and two combined androgen blockade (CAB) strategies (Table 1). The surgical strategy was bilateral orchiectomy. The single drug medication strategies were diethylstilbestrol (DES), a luteinizing hormone-releasing hormone (LHRH) agonist, and a nonsteroidal antiandrogen (NSAA). Although most clinicians would no longer consider DES for androgen suppression, we have included it as an historical comparison. The CAB strategies were an NSAA plus an LHRH agonist or an NSAA plus orchiectomy. In each medication class, we examined only the least expensive agent, assuming that the toxic effects and effectiveness of medications within a class were comparable (12). Thus, the LHRH agonist that we evaluated was goserelin, and the NSAA that we evaluated was nilutamide. Our base case model did not include a strategy in which patients were left untreated.
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The models incorporated two additional advantages when an NSAA was used as part of a CAB regimen. First, we assumed that patients intolerant of one NSAA would start another. Second, we assumed that some patients would benefit from NSAA withdrawal with a transiently decreased risk of disease progression. The net effect of these assumptions was to bias the model in favor of CAB strategies.
Side Effects
We distinguished between fatal side effects, severe side effects that required discontinuation of treatment, and bothersome but tolerable minor side effects. Fatal side effects, including hepatic failure from an NSAA and excess cardiac death from DES, could occur at any time during treatment (19,20,26). Severe side effects, such as copious diarrhea, occurred only in the first month of treatment and were assigned a one-time incremental cost and decrease in quality of life (13,27). Minor side effects, such as hot flashes, were assigned a continuous incremental cost and loss of quality of life for the duration of medication use. We assumed that minor side effects occur with equal frequency in all strategies. Rates for severe and minor side effects were pooled estimates of toxic effects reported in trials included in the meta-analysis (12).
Quality of Life
We assigned a quality-of-life weight to each health state, reflecting the symptoms associated with advanced prostate cancer and its treatment (25,2832) (Table 2). We based these estimates on a review of the literature assessing prostate cancer-related quality of life from the perspectives of patients and physicians (27,33,34). We assumed that men did not experience a substantial decrease in quality of life until hormone-resistant symptomatic distant metastases developed.
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Costs
Our model included the costs of androgen suppression strategies, other prostate cancer treatments, and side effects. We assumed that costs not in the model, such as the costs of treating other health conditions, were equivalent with each androgen suppression therapy. This assumption is reasonable, since no therapies conferred large survival advantages; thus, we anticipate the rates of other diseases among the various strategies to be similar. All costs were updated to 1998 U.S. dollars with the use of the Gross Domestic Product deflator (40). We based medication costs on the manufacturer's wholesale drug price (41). We assumed that an NSAA was included in the first 2 weeks of LHRH agonist therapy to avoid worsening the androgen-dependent symptoms of prostate cancer. The cost of orchiectomy was derived from an estimate based on Medicare physician and outpatient facility charges (33). Other costs were based on comprehensive costing studies (27,42,43). We assumed that minor side effects were associated with the cost of one additional office visit per year (43). We assumed that severe side effects were associated with a cost greater than the annual cost associated with minor side effects but less than that of treating the first recurrence of prostate cancer. We estimated the cost of treating bladder outlet obstruction from a previous estimate of the cost of transurethral prostatectomy for local obstruction (43).
Sensitivity Analysis
We investigated the effect of modifying several base case assumptions in sensitivity analyses. First, we relaxed the assumption that all treatments were equally effective. Instead, we based our alternative efficacy assumptions on the point estimates from the meta-analysis that suggested that CAB regimens might be somewhat more effective than monotherapies (12), although the differences were not statistically significant. Next, we varied each input variable over a wide range (Table 1). Finally, we modified the structure of our model to examine two management issues1) when to initiate treatment and, 2) how to incorporate information from the prostate-specific antigen (PSA) test into treatment decisions.
Determining when to initiate androgen suppression therapy is relevant for patients who have asymptomatic regional metastatic prostate cancer at diagnosis. Androgen suppression could be started at the time of diagnosis, delayed until distant metastases are first diagnosed, or delayed until distant metastases are first symptomatic. We analyzed these strategies for each androgen suppression therapy by modifying the state definitions and transition rates in our model (Fig. 2). We assumed that the timing of androgen suppression therapy conferred no survival benefit, consistent with the meta-analysis results (12). We do not address here the optimal timing of androgen suppression therapy for patients with locally advanced cancer undergoing radiation treatment.
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Calculating Cost-Effectiveness Ratios
The incremental cost-effectiveness of one strategy (A) relative to another (B) was calculated as
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Health effects were expressed as life years or quality-adjusted life years (QALY) saved. The analysis was conducted with DATA software version 3.0.16 (TreeAge, Williamstown, MA).
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RESULTS |
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These cost and effectiveness estimates implied that the incremental cost-effectiveness of orchiectomy relative to DES was $6100 per life year gained. When quality-of-life effects were incorporated, the incremental cost-effectiveness of orchiectomy relative to DES was $7500 per QALY gained. All other strategiesLHRH agonists, NSAA, and both CAB regimenshad higher costs and lower quality-adjusted survival than orchiectomy at the base case estimates of quality of life.
Results of Sensitivity Analysis
We repeated the analysis assuming that the therapies differed in efficacy and basing our new efficacy values on the point estimates from the meta-analysis (12). Under these assumptions, the lowest quality-adjusted discounted survival was 4.6 QALYs with NSAA, and the highest was 5.1 QALYs with the combination of NSAA plus LHRH agonist. The lowest lifetime cost was $3600 with DES, and the highest was $41 400 with the combination of NSAA plus LHRH agonist. The incremental cost-effectiveness of orchiectomy relative to DES was $8100/QALY (Fig. 3). Monotherapy with NSAA, NSAA plus orchiectomy, and LHRH agonists had higher costs, lower survival, and lower quality-adjusted survival than orchiectomy. The cost-effectiveness of CAB with NSAA plus LHRH compared with orchiectomy was $1 110 000/QALY. CAB with NSAA plus orchiectomy had higher costs and lower quality-adjusted survival. We evaluated various estimates of the efficacy of CAB relative to orchiectomy, using a range for sensitivity analysis based on the 95% confidence intervals from the meta-analysis (Fig. 4
). Compared with orchiectomy, the cost-effectiveness of CAB with NSAA plus LHRH agonists in this range was always greater than $100 000/QALY. In contrast, the cost-effectiveness of CAB with NSAA plus orchiectomy in this range was as low as $43 400/QALY.
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If strategies involving orchiectomy are not viable options, the incremental cost-effectiveness of NSAA relative to DES becomes relevant; it was $43 200/QALY. The incremental cost-effectiveness of LHRH agonists relative to NSAA was $73 900/QALY. The combination of LHRH agonist plus NSAA resulted in higher costs and less quality-adjusted survival than LHRH agonists alone.
The model was insensitive to other input assumptions. For example, the cost-effectiveness ratio of orchiectomy relative to DES did not vary greatly when we changed the following parameters over the prespecified ranges: the quality-of-life weight for minor side effects ($6500$15 200/QALY); the cost of orchiectomy ($3400$15 400/QALY), the discount rate ($6000 $11 700/QALY), and the age of the patient ($5800$11 000/QALY when the age was 50 or 75 years, respectively).
Timing also affects cost-effectiveness. For patients presenting with regional metastases at diagnosis, the greatest benefits and least cost were obtained by performing orchiectomy when patients developed symptomatic distant metastases. Quality-adjusted survival was 7.0 discounted QALYs if orchiectomy was delayed until symptomatic distant metastases developed and quality of life was low. Slightly less benefit (6.8 discounted QALYs) resulted when orchiectomy was performed as soon as asymptomatic distant metastases were detected, and the least benefit (6.2 QALYs) when orchiectomy was performed when stage C prostate cancer was initially diagnosed. Costs were lower when orchiectomy was performed late rather than early$5200 with symptomatic distant disease, $5600 with asymptomatic distant disease, and $7400 at diagnosis with stage C prostate cancerbecause fewer patients underwent the procedure. These results were only mildly sensitive to changes in the discount rate.
After the states and transition rates were modified to simulate the consequences of incorporating PSA testing, the relative rankings of the strategies remained unchanged. Under these assumptions, the incremental cost-effectiveness ratio of orchiectomy relative to DES was $6500/QALY. All other therapies were more expensive and less beneficial.
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DISCUSSION |
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While DES is less expensive than orchiectomy, it is also less effective. Under a wide range of assumptions, the incremental cost-effectiveness of orchiectomy relative to DES is less than $20 000/QALY, an estimate that is usually considered to represent a very good value. This cost-effectiveness ratio is comparable to many commonly accepted health interventions (48).
The acceptability of orchiectomy undoubtedly varies greatly from patient to patient. For many, it will be a highly cost-effective treatment option. For others, the very concept of orchiectomy may be objectionable. Epidemiologic studies (49) indicate that for every two Medicare beneficiaries treated with orchiectomy, five are treated with LHRH agonists. However, it is unclear whether treatment decisions are guided by patient preference or if orchiectomy diminishes quality of life more than medical therapies for most men. How patients value the quality-of-life effects of different androgen suppression strategies and how they use these values in making treatment decisions are topics for future research.
Combined androgen blockade is popular but expensive and, according to the results of a meta-analysis, differences between its efficacy and that of orchiectomy are not statistically significant (12). For the incremental cost-effectiveness of combined androgen blockade with an NSAA and an LHRH agonist compared with orchiectomy to be less than $100 000/QALY, this combination must decrease the rate of disease progression by at least 20%. Less expensive combined androgen blockade can be achieved with orchiectomy plus an NSAA. This combination must reduce the rate of disease progression by 10% to reach an incremental cost-effectiveness ratio of less than $100 000/QALY relative to orchiectomy alone. For perspective, the lower bound of the 95% confidence interval of the rate of progression relative to orchiectomy was 22% for each CAB strategy.
The greatest quality-of-life gains and least cost may be obtained by initiating therapy in later stages of disease. Consistent with our results, a small study (50) found that the quality of life of asymptomatic patients with prostate cancer who did not receive hormonal therapy was similar to or better than that of patients who received hormonal therapy. Furthermore, we modeled the effects of late therapy as delaying the time until severe ill health occurs, although androgen suppression therapies likely also improve the health of patients with symptomatic metastases. Thus, our estimate of the benefit of delaying therapy may still be too low. Our study further indicates that initiating a palliative treatment based on a biochemical rather than on a clinical marker of disease progression has little clinical support and is unlikely to be cost-effective.
Our results are consistent with a previous analysis that examined the incremental cost-effectiveness of CAB with orchiectomy plus flutamide compared with orchiectomy alone (32,33). The principal difference with the earlier study is that our assumptions about the efficacy of CAB, based on a rigorous meta-analysis, were less optimistic. In addition, our analysis incorporates more clinical events, including local bladder outlet obstruction, the influence of biochemical monitoring, and issues related to the optimal timing of androgen suppression therapy. Our results do not apply to other clinical uses of androgen suppression, such as adjuvant chemotherapy of early prostate cancer. Furthermore, we did not evaluate therapies that are not approved for use in the United States, such as cyproterone acetate.
Our analysis calls into question the cost-effectiveness of widespread use of expensive androgen suppression strategies for men with advanced prostate cancer and the initiation of such therapy solely because of biochemical evidence of disease progression. Since Medicare spent more than $477 million on LHRH agonists in 1994, the potential for cost savings are considerable (51), yet our analyses also indicate the difficulties associated with determining the most efficient option while incorporating individual preferences. For example, orchiectomy is most economically attractive for many patients, but medical therapies are likely to be the most cost-effective choice for others. Quality of life is a paramount concern when evaluating therapies for advanced prostate cancer; careful assessment of how individuals value orchiectomy will help clinicians, patients, and policy makers determine which of the available surgical and medical therapies yields the best value for the money.
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NOTES |
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Supported by the Blue Cross and Blue Shield Association Technology Evaluation Center, an Evidence-based Practice Center of the Agency for Healthcare Research and Quality. This work was developed under contract with the Agency for Healthcare Research and Quality (AHRQ contract No. 290-97-0015).
We are grateful for many helpful comments on earlier versions of this work from Naomi Aronson, Peter Albertsen, Charles Bennett, Victor Hasselblad, David Samson, Jerome Seidenfeld, Timothy Wilt, and Kathleen Ziegler.
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