Cost-Effectiveness of Androgen Suppression Therapies in Advanced Prostate Cancer

Ahmed M. Bayoumi, Adalsteinn D. Brown, Alan M. Garber

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).


    ABSTRACT
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Background: The costs and side effects of several antiandrogen therapies for advanced prostate cancer differ substantially. We estimated the cost-effectiveness of antiandrogen therapies for advanced prostate cancer. Methods: We performed a cost-effectiveness analysis using a Markov model based on a formal meta-analysis and literature review. The base case was assumed to be a 65-year-old man with a clinically evident, local recurrence of prostate cancer. The model used a societal perspective and a time horizon of 20 years. Six androgen suppression strategies were evaluated: diethylstilbestrol (DES), orchiectomy, a nonsteroidal antiandrogen (NSAA), a luteinizing hormone-releasing hormone (LHRH) agonist, and combinations of an NSAA with an LHRH agonist or orchiectomy. Outcome measures were survival, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios. Results: DES, the least expensive therapy, had a discounted lifetime cost of $3600 and the lowest quality-adjusted survival, 4.6 QALYs. At a cost of $7000, orchiectomy was associated with 5.1 QALYs, resulting in an incremental cost-effectiveness ratio of $7500/QALY relative to DES. All other strategies—LHRH agonists, NSAA, and both combined androgen blockade strategies—had higher costs and lower quality-adjusted survival than orchiectomy. These results were sensitive to the quality of life associated with orchiectomy and the efficacy of combined androgen blockade, and they changed little when prostate-specific antigen results were used to guide therapy. Under a wide range of other assumptions, the cost-effectiveness of orchiectomy relative to DES was consistently less than $20 000/QALY. Androgen suppression therapies were most cost-effective if initiated after patients became symptomatic from prostate metastases. Conclusions: For men who accept it, orchiectomy is likely to be the most cost-effective androgen suppression strategy. Combined androgen blockade is the least economically attractive option, yielding small health benefits at high relative costs.



    INTRODUCTION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Cancer of the prostate is expected to cause more than 31 000 deaths in the United States in 2000 (1). In previous years, annual Medicare expenditures for prostate cancer have exceeded $1.4 billion (2). Although metastatic prostate cancer is incurable (3), medical and surgical androgen suppression can palliate its symptoms and may prolong survival (4,5). Currently, there is little basis for determining which of the available androgen suppression treatments represents the best value. The efficacy of surgical androgen suppression (orchiectomy) is similar to that of any single medication, but the side effects and costs of each therapy differ substantially. Combination strategies may improve efficacy while increasing both toxicity and costs. Combinations of different classes of medications (a nonsteroidal antiandrogen [NSAA] with a luteinizing hormone-releasing hormone [LHRH] agonist) and of surgery plus medication (an NSAA) have been studied.

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.


    SUBJECTS AND METHODS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We used decision analysis to estimate the gains in quality of life, survival, and costs from treating recurrent prostate cancer. We constructed a Markov model to examine the effects of androgen suppression therapy. Markov models characterize a disease as distinct health states; the natural history is described by the possible transitions between states (6,7). Throughout the analysis, we followed the recommendations of the Panel on Cost-Effectiveness in Health and Medicine wherever possible (8). For example, we used a societal perspective and discounted costs and health effects at 3% per year. Complete model details and assumptions are available from the Journal's web site at: http://www.jnci.oupjournals.org.

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. 1Go). 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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Fig. 1. Markov cycle diagram of prostate cancer natural history model. Simplified model is shown. Patients are treated with one of six possible androgen suppression strategies. Circles represent Markov states in the model. Arrows represent transitions between states. Patients can also experience local bladder outlet obstruction, as well as side effects from androgen suppression therapy. DES = diethylstilbestrol; NSAA = nonsteroidal antiandrogen; LHRH = luteinizing hormone-releasing hormone.

 
At the end of each 1-month cycle, patients could experience progression of their disease (including death from prostate cancer), die of unrelated causes, or remain in the same health state. Health states were further defined according to the androgen suppression therapy used (first-line, second-line, or none), side effects from treatment (present or absent), and benefits from medication withdrawal where appropriate. At any time, patients could also experience local bladder outlet obstruction, leading to a transient decrease in quality of life and extra costs (13). The occurrence of local obstruction did not alter the risk of future events, such as recurrent obstruction. At the conclusion of the model's 20-year time horizon, nearly all patients will have died, and none will be cured of their prostate cancer.

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 rates—the proportion of individuals moving from one state to the next in a given period—based 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 1Go). 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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Table 1. Efficacy and toxicity of androgen suppression therapies: model assumptions*
 
We assumed that androgen suppression strategies decreased disease progression rates by two thirds when prostate cancer was hormone sensitive (19,20). We assumed that recurrent prostate cancer was initially responsive to androgen suppression but eventually developed hormone resistance and progressed clinically (24,25). We estimated the relative efficacy of androgen suppression strategies from a formal meta-analysis (12). The meta-analysis provided a point estimate of the efficacy of each therapy (relative to orchiectomy) and a 95% confidence interval. While the point estimates varied between strategies, all 95% confidence intervals overlapped. Thus, our base case assumption was that all strategies were of equal efficacy. In a sensitivity analysis, we examined how using the point estimates of efficacy might change the results.

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 2Go). 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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Table 2. Quality-of-life weights and costs*
 
Perhaps our most controversial base case assumption is that orchiectomy and medical therapies (without major side effects) were associated with equivalent quality of life. The literature suggests that men differ in how they view orchiectomy (35,36). Some men consider it to be disfiguring, and it may connote mutilation, castration, and emasculation. Other men are satisfied that subcapsular orchiectomy or testicular prostheses can make the disfigurement minimal or tolerable (30,3739). Some men prefer orchiectomy to medical androgen suppression, since they can thereby avoid drug-related side effects, repeated clinic visits, and, in some cases, injections. Thus, our base case assumption was that orchiectomy and medical therapies had similar effects on quality of life. We also explored the consequences of large, differential quality-of-life effects in a sensitivity analysis.

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 1Go). Finally, we modified the structure of our model to examine two management issues—1) 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. 2Go). 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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Fig. 2. State definitions and transitions used in the base case and sensitivity analyses. Circles represent state definitions. Arrows represent transitions between states. Numbers represent the 1-month transition probabilities between states. Dashed arrows indicate which transition probabilities are modified by androgen suppression therapy in each model.

 
The use of PSA testing after definitive radiation therapy may allow for the diagnosis of recurrent prostate cancer by biochemical markers before it is clinically apparent (14,44). Because some clinicians initiate therapy at the first rise in PSA levels after definitive treatment, patients may use androgen suppression for longer periods than assumed in the base case (11,45). To investigate how such clinical strategies might change our cost-effectiveness estimates, we redefined the health states and adjusted transition rates in the model to describe disease progression from the first rise in PSA levels after definitive treatment to the development of asymptomatic and then symptomatic distant metastases (14,46). Incorporating PSA monitoring increased the time spent after initiation of androgen suppression therapy to death by about 2.3 years over the base case and resulted in an average time of 8 years from PSA-level rise to first diagnosed distant metastasis, estimates consistent with the literature (14,47).

Calculating Cost-Effectiveness Ratios

The incremental cost-effectiveness of one strategy (A) relative to another (B) was calculated as


(1)

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).


    RESULTS
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We first estimated the health effects associated with androgen suppression strategies. Although each therapy was associated with an equal reduction in risk of disease progression among patients receiving treatment, overall survival differed because of differential rates of side effects, both nonfatal (but severe enough to require discontinuation of therapy) and fatal. DES treatment resulted in an average survival of 6.9 years for a 65-year-old man with advanced prostate cancer. NSAA treatment increased survival to 7.4 years, while orchiectomy increased survival to 7.6 years. Treatment with an LHRH agonist or either CAB strategy resulted in an average survival of 7.5 years. The effects on discounted quality-adjusted survival were similar: DES resulted in a survival of 4.6 QALYs; orchiectomy and LHRH agonists each resulted in a survival of 5.1 QALYs, and NSAA and both CAB strategies yielded survivals of 5.0 QALYs (Table 3Go).


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Table 3. Cost-effectiveness estimates*
 
In contrast to the similar effects on quality-of-life and survival estimates, the lifetime costs of the strategies differed markedly. The discounted lifetime costs associated with treatment were $3600 (DES), $7000 (orchiectomy), $16 100 (NSAA), and $27 000 (LHRH agonists). The costs associated with orchiectomy were least prone to discounting effects, since they were incurred early. The lifetime cost of CAB with NSAA plus orchiectomy was $20 700; with NSAA plus LHRH agonist, the lifetime cost was $40 300.

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 strategies—LHRH agonists, NSAA, and both CAB regimens—had 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. 3Go). 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. 4Go). 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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Fig. 3. Health benefits and costs associated with androgen suppression strategies using alternative efficacy assumptions. Efficacy assumptions are based on point estimates from the meta-analysis. Lines connecting points representing two treatments indicate the incremental cost-effectiveness of the therapies. DES = diethylstilbestrol; NSAA = nonsteroidal antiandrogen; LHRH = luteinizing hormone-releasing hormone; QALY = quality-adjusted life years.

 


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Fig. 4. Sensitivity analysis of the efficacy of combined androgen blockade. Open squares in top panel (A) represent the incremental cost-effectiveness of combined androgen blockade (CAB) with a nonsteroidal antiandrogen (NSAA) plus a luteinizing hormone-releasing hormone agonist (LHRH) relative to orchiectomy. Solid circles in bottom panel (B) represent the incremental cost-effectiveness of CAB with an NSAA plus orchiectomy relative to orchiectomy alone. Dashed vertical lines represent the point estimate of efficacy from the meta-analysis of CAB relative to orchiectomy, and shaded areas indicate the 95% confidence interval. The base case assumed that CAB regimens had the same effectiveness as orchiectomy. QALY = quality-adjusted life years.

 
We examined the assumption that quality of life with orchiectomy was similar to that of other strategies (quality weight of 0.92). If the quality-of-life weight assigned to the state of living with an orchiectomy and no distant metastases were 0.88 or greater, the incremental cost-effectiveness of other strategies compared with orchiectomy would exceed $100 000/QALY. If the quality-of-life weight assigned to orchiectomy were less than 0.83, the incremental cost-effectiveness of LHRH agonists relative to orchiectomy would be less than $50 000/QALY.

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 cancer—because 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.


    DISCUSSION
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
We evaluated the cost-effectiveness of androgen suppression strategies for men with advanced prostate cancer. Our principal finding is that the effectiveness of orchiectomy is comparable to that of medical management, even though orchiectomy is much less expensive. Our analysis indicates that, for men who decline orchiectomy, an NSAA such as nilutamide has a cost-effectiveness ratio relative to DES of less than $50 000/QALY.

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.


    NOTES
 
Editor's note: The authors of this article are responsible for its contents, including any clinical or treatment recommendations. No statement in this article should be construed as an official position of the Agency for Healthcare Research and Quality or the U.S. Department of Health and Human Services.

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.


    REFERENCES
 Top
 Notes
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

1 Greenlee RT, Murray T, Bolden S, Wingo PA. Cancer statistics, 2000. CA Cancer J Clin 2000;50:7–33.[Abstract/Free Full Text]

2 Haas GP, Sakr WA. Epidemiology of prostate cancer. CA Cancer J Clin 1997;47:273–87.[Abstract/Free Full Text]

3 Kuyu H, Lee WR, Bare R, Hall MC, Torti FM. Recent advances in the treatment of prostate cancer. Ann Oncol 1999;10:891–8.[Abstract]

4 Robson M, Dawson N. How is androgen-dependent metastatic prostate cancer best treated? Hematol Oncol Clin North Am 1996;10:727–47.[Medline]

5 The Medical Research Council Prostate Cancer Working Party Investigators Group. Immediate versus deferred treatment for advanced prostatic cancer: initial results of the Medical Research Council Trial. Br J Urol 1997;79:235–46.[Medline]

6 Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13:322–38.[Medline]

7 Beck JR, Pauker SG. The Markov process in medical prognosis. Med Decis Making 1983;3:419–58.[Medline]

8 Gold MR, Seigel JE, Russell LB, Weinstein MC, editors. Cost-effectiveness in health and medicine. New York (NY): Oxford University Press; 1996. p. 1–311.

9 Mahler C, Denis LJ. Hormone refractory disease. Semin Surg Oncol 1995;11:77–83.[Medline]

10 Small EJ, Vogelzang NJ. Second-line hormonal therapy for advanced prostate cancer: a shifting paradigm. J Clin Oncol 1997;15:382–8.[Abstract]

11 Scher HI. Management of prostate cancer after prostatectomy: treating the patient, not the PSA. JAMA 1999;281:1642–5.[Free Full Text]

12 Aronson N, Seidenfeld J, Samson DJ, Albertsen PC, Bayoumi AM, Bennett C, et al. Relative effectiveness and cost-effectiveness of methods of androgen suppression in the treatment of advanced prostatic cancer. Evidence Report/Technology Assessment No. 4. (Prepared by Blue Cross and Blue Shield Association Evidence-based Practice Center under Contract No. 290-97-0015). AHCPR Publication No. 99-E0012. Rockville (MD): Agency for Health Care Policy and Research; 1999.

13 Fleming C, Wasson JH, Albertsen PC, Barry MJ, Wennberg JE. A decision analysis of alternative treatment strategies for clinically localized prostate cancer. Prostate Patient Outcomes Research Team. JAMA 1993;269:2650–8.[Abstract]

14 Pound CR, Partin AW, Eisenberger MA, Chan DW, Pearson JD, Walsh PC. Natural history of progression after PSA elevation following radical prostatectomy. JAMA 1999;281:1591–7.[Abstract/Free Full Text]

15 Kuban DA, el-Mahdi AM, Schellhammer PF. Prognosis in patients with local recurrence after definitive irradiation for prostatic carcinoma. Cancer 1989;63:2421–5.[Medline]

16 Kuban DA, el-Mahdi AM, Schellhammer PF. Potential benefit of improved local tumor control in patients with prostate carcinoma. Cancer 1995;75:2373–82.[Medline]

17 Cowen ME, Chartrand M, Weitzel WF. A Markov model of the natural history of prostate cancer. J Clin Epidemiol 1994;47:3–21.[Medline]

18 Crawford ED, Eisenberger MA, McLeod DG, Spaulding JT, Benson R, Dorr FA, et al. A controlled trial of leuprolide with and without flutamide in prostatic carcinoma. N Engl J Med 1989;321:419–24.[Abstract]

19 Byar DP. Proceedings: The Veterans Administration Cooperative Urological Research Group's studies of cancer of the prostate. Cancer 1973;32:1126–30.[Medline]

20 Byar DP, Corie DK. Hormone therapy for prostate cancer: results of the Veterans Administration Cooperative Urological Research Group Studies. NCI Monogr 1988;7:165–70.[Medline]

21 Prostate Cancer Trialists' Collaborative Group. Maximum androgen blockade in advanced prostate cancer: an overview of 22 randomised trials with 3283 deaths in 5710 patients. Lancet 1995;346:265–9.[Medline]

22 Miller DK, Homan SM. Determining transition probabilities: confusion and suggestions. Med Decis Making 1994;14:52–8.[Medline]

23 Black WC, Nease RF Jr, Welch HG. Determining transition probabilities from mortality rates and autopsy findings. Med Decis Making 1997;17:87–93.[Medline]

24 Bubley GJ, Balk SP. Treatment of metastatic prostate cancer. Lessons from the androgen receptor. Hematol Oncol Clin North Am 1996;10:713–25.[Medline]

25 Garnick MB. Hormonal therapy in the management of prostate cancer: from Huggins to the present. Urology 1997;49(3A Suppl):5–15.[Medline]

26 Wysowski DK, Fourcroy JL. Flutamide hepatotoxicity. J Urol 1996;155:209–12.[Medline]

27 Krahn MD, Mahoney JE, Eckman MH, Trachtenberg J, Pauker SG, Detsky AS. Screening for prostate cancer. A decision analytic view. JAMA 1994;272:773–80.[Abstract]

28 Denis L. Commentary on maximal androgen blockade in prostate cancer: a theory to put into practice? Prostate 1995;27:233–40.[Medline]

29 Presant CA, Soloway MS, Klioze SS, Yakabow A, Presant SN, Mendez RG, et al. Buserelin treatment of advanced prostatic carcinoma. Long-term follow-up of antitumor responses and improved quality of life. Cancer 1987;59:1713–6.[Medline]

30 Lucas MD, Strijdom SC, Berk M, Hart GA. Quality of life, sexual functioning and sex role identity after surgical orchidectomy in patients with prostatic cancer. Scand J Urol Nephrol 1995;29:497–500.[Medline]

31 Albertsen PC, Aaronson NK, Muller MJ, Keller SD, Ware JE Jr. Health-related quality of life among patients with metastatic prostate cancer. Urology 1997;49:207–16; discussion 216–7.

32 Bennett CL, Matchar D, McCrory D, McLeod DG, Crawford ED, Hillner BE. Cost-effective models for flutamide for prostate carcinoma patients: are they helpful to policy makers? Cancer 1996;77:1854–61.[Medline]

33 Hillner BE, McLeod DG, Crawford ED, Bennett CL. Estimating the cost effectiveness of total androgen blockade with flutamide in M1 prostate cancer. Urology 1995;45:633–40.[Medline]

34 Patrick DL, Erickson P. Health status and health policy: quality of life in health care evaluations and resource allocation. New York (NY): Oxford University Press; 1993. p. 58–180.

35 Litwin MS, Shpall AI, Dorey F, Nguyen TH. Quality-of-life outcomes in long-term survivors of advanced prostate cancer. Am J Clin Oncol 1998;21:327–32.[Medline]

36 Cassileth BR, Soloway MS, Vogelzang NJ, Chou JM, Schellhammer PD, Seidmon EJ, et al. Quality of life and psychosocial status in stage D prostate cancer. Zoladex Prostate Cancer Study Group. Qual Life Res 1992;1:323–9.[Medline]

37 Merrill DC. Treatment of metastatic prostate cancer. Factors that influence treatment selection and methods to increase acceptance of orchiectomy. Urology 1988;32:408–12.[Medline]

38 Lynch MJ, Pryor JP. Testicular prostheses: the patient's perception. Br J Urol 1992;70:420–2.[Medline]

39 Montgomery P, Shanti G. The influence of bilateral orchiectomy on self-concept: a pilot study. J Adv Nurs 1996;24:1249–56.[Medline]

40 NASA. Parametric cost estimating reference manual: inflation calculator. 1998. Available from URL: http://www.jsc.nasa.gov/bu2/inflate.html. Accessed September 20, 1998.

41 Cardinale V, editor. Drug Topics Red Book. Montvale (NJ): Medical Economics; 1997. p. 205, 260, 292, 376–7, 420, 422, 468, 522.

42 Taplin SH, Barlow W, Urban N, Mandelson MT, Timlin DJ, Ichikawa L, et al. Stage, age, comorbidity, and direct costs of colon, prostate, and breast cancer care. J Natl Cancer Inst 1995;87:417–26.[Abstract]

43 Coley CM, Barry MJ, Fleming C, Fahs MC, Mulley AG. Early detection of prostate cancer. Part II: estimating the risks, benefits, and costs. American College of Physicians. Ann Intern Med 1997;126:468–79.[Abstract/Free Full Text]

44 Ferguson JK, Oesterling JE. Patient evaluation if prostate-specific antigen becomes elevated following radical prostatectomy or radiation therapy. Urol Clin North Am 1994;21:677–85.[Medline]

45 Montie JE. Follow-up after radical prostatectomy or radiation therapy for prostate cancer. Urol Clin North Am 1994;21:673–6.[Medline]

46 Zietman AL, Dallow KC, McManus PA, Heney NM, Shipley WU. Time to second prostate-specific antigen failure is a surrogate endpoint for prostate cancer death in a prospective trial of therapy for localized disease. Urology 1996;47:236–9.[Medline]

47 Lillis P, Thompson IM. Should asymptomatic progression following definitive local treatment for prostate cancer be treated? Hematol Oncol Clin North Am 1996;10:703–12.[Medline]

48 Tengs TO, Adams ME, Pliskin JS, Safran DG, Siegel JE, Weinstein MC, et al. Five-hundred life-saving interventions and their cost-effectiveness. Risk Anal 1995;15:369–90.[Medline]

49 Litwin MS, Pasta DJ, Stoddard ML, Henning JM, Carroll PR. Epidemiological trends and financial outcomes in radical prostatectomy among Medicare beneficiaries, 1991 to 1993 [published erratum appears in J Urol 1998;160:2164]. J Urol 1998;160:445–8.[Medline]

50 Herr HW, Kornblith AB, Ofman U. A comparison of the quality of life of patients with metastatic prostate cancer who received or did not receive hormonal therapy. Cancer 1993;71:1143–50.[Medline]

51 Holtgrewe HL, Bay-Nielsen H, Bouffioux C, Carlsson P, Lanson Y, Oesterling J, et al. The economics of prostate cancer. In: Murphy G, Griffiths K, Denis L, Khoury S, Chatelain C, Cockett AT, editors. First international consultation on prostate cancer. London: Scientific Communication International, Ltd; 1997. p. 399–414.

52 Smith DC, Pienta KJ. The use of prostate-specific antigen as a surrogate end point in the treatment of patients with hormone refractory prostate cancer. Urol Clin North Am 1997;24:433–7.[Medline]

Manuscript received January 3, 2000; revised August 16, 2000; accepted August 30, 2000.


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