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Journal of Oncology Practice, Vol 2, No 2 (March), 2006: pp. 57-66 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JOP.2.2.57
Individualized Strategy for Dosing Luteinizing Hormone–Releasing Hormone Agonists for Androgen-Independent Prostate Cancer: Identification of Outcomes and CostsCommunity and Preventive Medicine; The James P. Wilmot Cancer Center; and the Department of Medicine, University of Rochester, Rochester, NY Corresponding author: Deepak M. Sahasrabudhe, MD, The James P. Wilmot Cancer Center, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 704, Rochester, NY 14642, Deepak_Sahasrabudhe{at}URMC.Rochester.edu
PURPOSE: Continuing androgen suppression is the current standard in men with androgen-independent prostate cancer (AIPC). An individualized strategy, wherein luteinizing hormone–releasing hormone agonists (LH-RHas) are redosed when serum testosterone approaches a non-castrate level, may decrease costs without worsening outcomes. To understand possible outcomes, we performed a cost-utility analysis comparing individualized and fixed LH-RHa dosing strategies in men with AIPC. METHODS: The model used a societal perspective, a 5-year time horizon, and 3% annual cost discounting. The model accounted for direct costs of androgen suppression. Utilities were varied in accordance with published preference data. RESULTS: Under base-case assumptions, individualized LH-RHa dosing yielded 1.089 expected quality-adjusted life years (QALYs), compared with 1.094 expected QALYs for fixed LH-RHa dosing. In cost analysis, lifetime per-patient costs for androgen suppression were estimated to be $5,694 for individualized LH-RHa dosing and $9,157 for fixed LH-RHa dosing. Applied to the total population, a strategy of individualized LH-RHa dosing would cost $170 million for androgen suppression, compared with $274 million for fixed LH-RHa dosing. Under these assumptions, adopting the individualized strategy resulted in $692,600 gained from a societal perspective for each QALY lost (the decremental cost utility). CONCLUSION: The results suggest that an individualized LH-RHa dosing strategy would be associated with moderate savings on an individual basis but substantial savings on a population basis, and would not adversely affect quality of life or life expectancy. Further research is needed to establish the effects of this strategy on symptoms and survival, as well as patient satisfaction and true costs.
Prostate cancer is a common cancer in American men, with 230,110 new cases and 29,900 deaths estimated for 2004.1 Costs for the last year of life are estimated at $24,660.2 Early in its natural cycle, prostate cancer is androgen dependent. Late in the clinical course, it is androgen independent, and is refractory to hormonal therapy. However, even in the androgen-independent state, prostate cancer is likely to contain subpopulations of cells that are androgen dependent. This hypothesis is supported by a retrospective analysis demonstrating a 2- to 6-month prolongation in median survival for men who continued androgen suppression.3 On the basis of these limited data, continued androgen suppression in men with androgen-independent prostate cancer (AIPC) is the current standard of care. In the past, testosterone suppression was achieved by bilateral orchiectomy (surgical castration). For the last two decades, injection of long-acting luteinizing hormone-releasing hormone agonists (LH-RHas) has been used to achieve androgen ablation. Although LH-RHas have the advantages of reversibility and patient acceptance,4 they are expensive. Approximately 75% of men treated with androgen suppression for prostate cancer elect for LH-RHa.5 The two commonly used formulations, goserelin and leuprolide, are typically administered in doses that have a recommended redosing interval of 3 months and have average wholesale prices of $1,409.98 and $1,796.51, respectively.6 LH-RHas are typically administered at a fixed dose and schedule without adjustment for patient or response characteristics, which distinguishes these agents from other hormonal agents such as insulin or levothyroxine. Testosterone suppression by LH-RHa can last longer than the standard dosing interval,7 particularly in men with a long history of LH-RHa use.8 Individualized dosing regimens for LH-RHa, in which serum testosterone is monitored serially and LH-RHa redosed only after testosterone begins to approach the noncastrate range, offer a potential strategy for minimizing costs without worsening outcomes. Two feasibility trials, enrolling 22 and 32 men each, have already found this to be possible in diverse patient populations.7,9 If there is equal survival and symptom control with individualized dosing of LH-RHa, there could be savings in health care costs without compromising outcome. Individualized androgen suppression appears to be a safe alternative on the basis of general observations in prostate cancer clinical trials. In a randomized trial in stage D2 disease, orchiectomy was not found to be inferior to goserelin,10 suggesting that the direct antitumor effects of LH-RHa were minimal, if any. A meta-analysis of androgen suppression in advanced prostate cancer found no significant difference in the odds of surviving to 2 years for LH-RHa as compared with orchiectomy.11 Our research aims were to determine which factors could nullify our hypothesis that outcomes were equivalent, and to what degree costs could be reduced by individualized treatment. We chose to evaluate life expectancy (LE) with adjustment for quality of life. Quality-adjusted life years (QALYs) were determined by weighting LE for the preference patients have for the health state, primarily based on possible symptoms. We modeled the effects of individualized and fixed LH-RHa dosing strategies on QALYs for a base case using the best estimates of relevant variables and performed sensitivity analysis over a wide range of values. We determined the cost of an individualized LH-RHa dosing strategy for men with AIPC and compared these costs to other strategies.
Study Design This analysis uses a Markov process decision analytic model to estimate the costs and outcomes of four strategies for androgen suppression in men with AIPC. The four strategies shown in Figure 1 include individualized LH-RHa dosing, fixed LH-RHa dosing, discontinuing androgen suppression, and orchiectomy.
We considered parameters required for the actual administration of each strategy (drug costs, laboratory testing, health care provider costs, surgical costs), characteristics of the patients (LE, preferences for treatment), and parameters necessary for evaluation of a palliative therapy (adverse effects of medication, quality of life). Values for these parameters were obtained from the published literature and the Centers for Medicare & Medicaid Services database, and are described in Tables 1 and 2. Where values were not well described in the literature, estimates were used.
We performed a base analysis that measured costs and utilities using the estimate thought to be the most accurate for each parameter in the model. We performed one-way sensitivity analyses, which evaluated the impact of using more extreme estimates of each parameter on outcomes and costs. Through sensitivity analyses, model parameters that are influential in determining the outcomes and cost of each strategy were identified. Finally, we performed multiway sensitivity analyses, which vary estimates across more than one parameter. These analyses depict consequences across a range of favorable and unfavorable circumstances.
Perspective, Time Horizon, and Discounting
Study Population
Model and Transition Probabilities
Mortality and castrate duration probabilities. We used mortality rates from a combined analysis of 760 men with AIPC in six Cancer and Leukemia Group B (CALGB) trials to estimate the monthly mortality, which includes death from prostate cancer as well as other causes.12 The median age at enrollment for these CALGB studies was 71 years. The monthly mortality rate was approximately 0.053, and remained fairly constant over 60 months. We assumed that this would be the monthly mortality rate with any form of complete castration (  20 ng/dL), such as orchiectomy or LH-RHa administration with resultant serum testosterone of less than 20 ng/dL.13 Based on findings of a 2- to 6-month survival benefit in a retrospective analysis of men with AIPC who continued castration,3 we increased the monthly mortality rate in the base analysis for men who stopped androgen suppression such that their median survival in the base case was 2 months shorter than for those patients with complete castration. Six studies were identified with data addressing duration of castrate testosterone after withdrawal of LH-RHa, with a total of 115 patients with heterogeneous characteristics (Table 3). Taken together, these studies suggest that in many men treated with LH-RHa, testosterone remains in the castrate range beyond the expected effective period of the drug (e.g., 3 months in a 3-month depot formulation). This range is quite variable, from less than the expected duration to beyond 36 months.
Patient and treatment factors associated with longer duration of androgen suppression are shown in Table 3. Older age was positively associated with the duration of castrate testosterone in one study,9 but not in another.14 Longer duration of prior androgen suppression was identified in two studies to be associated with delays to noncastrate9 and healthy14 levels. Although there is an association of the effect of age on duration of use and vice versa, the assumption that these factors are independent is physiologically plausible, given the well-known decline in serum testosterone with normal aging and studies demonstrating damage to the testes and impaired testosterone production after LH-RHa.15-17 It appears that the duration of LH-RHa therapy is correlated with the duration for which testosterone remains in castrate range after discontinuation of therapy.18 In the study by Hall et al,18 wherein the median duration of treatment with LH-RHa was 38.6 months, four of the 14 men had castrate-level testosterone at 12 months after discontinuing therapy. In the study by Pedraza and Kwart,8 the median duration of LH-RHa treatment was 108 months, and all four patients' testosterone levels remained in the castrate range for more than 36 months. In our base case, we assumed that 95% of men would become castrate with administration of LH-RHa, given findings in a single study estimating that 5% to 13% of men do not achieve castrate testosterone levels with LH-RHa.19 For the men who do become castrate, we assumed that the median duration of castrate level testosterone after stopping administration of LH-RHa would be 6 months, with a distribution between 3 and 8 months. This was based on durations reported for 32 men who had been receiving LH-RHa therapy for a median of 7.5 months (range 3 to 49 months) before stopping LH-RHa treatment.9 The monthly monitoring reported in this article made it possible to model month-to-month changes and accurately account for costs over time. The actual duration of castrate level testosterone in the population is likely to be longer because of prolonged previous use of LH-RHa.
Strategy Descriptions and Transition Probabilities Strategy 2: Fixed-schedule LH-RHa dosing. Men who continue fixed-schedule LH-RHa dosing will receive it every 3 months, without serial testosterone determination or antiandrogen. However, some men will not be castrate and thus may potentially be undertreated. Strategy 3: Stopping androgen suppression. Men who are found to be noncastrate and elect to stop androgen suppression can only transition to continue suffering from AIPC without castration or to death. They may choose this to avoid surgery itself or the adverse effects of castration. Strategy 4: Orchiectomy cohort. Men who are found to be noncastrate may elect to have orchiectomy. They will have the procedure in month 1 and subsequently will not require serial testosterone determinations, LH-RHa dosing, or antiandrogen.
Costs Direct medical costs. The direct medical costs we have accounted for are listed in Table 1. We assigned all of the costs by 1-month intervals. All of the costs of the LH-RHa were assigned to the month in which it was administered. For base case, we chose goserelin because of its lower average wholesale price and bicalutamide because it is a once-a-day drug, which we assume would be preferable for most patients even though it does not represent the lowest possible cost for the individualized strategy. Flutamide, which is administered three times a day, is less expensive, but it is unlikely to be favored by patients. For administration costs, we used 2003 values for injection of a therapeutic agent (HCPC 90782) from the Centers for Medicare & Medicaid Services Web site (www.cms.hhs.gov/). For the base case, we used the median value for the nationwide estimates of cost. Other costs. We have chosen not to include indirect medical costs or direct nonmedical costs. Because these patients have advanced cancer and may receive chemotherapy, they are likely to be in contact with the medical system at least as frequently as would be needed by any of our androgen-suppression strategies. We have chosen not to include productivity costs. We do not expect significant variation in cost or lost time from work lost among strategies.
Quality of Life On the basis of these findings, we rated health states for our base case in which men are noncastrate highest (0.8), followed by health states in which men are castrate (completely or incompletely) on medical management (0.75), and finally orchiectomy (0.70). Disutility for temporary health states was applied on a monthly basis (Table 2).
Outcome Measures
Sensitivity Analyses
Our base-case assumptions are conservative. The values described in the favorable estimates scenario are more likely to be obtained in practice (Table 4).
Effects on Unadjusted Survival We started by modeling LE without adjustment for quality of life. In this scenario, the individualized androgen-suppression strategy yielded an estimated LE of 1.463 years, whereas the standard androgen-suppression strategy yielded an estimated LE of 1.459 years. This effect is a result of identifying and offering orchiectomy to men who are not castrate after LH-RHa administration.
Effects on QALYs Under the base-case scenario, individualized LH-RHa dosing resulted in 1.089 expected QALYs, compared with 1.094 expected QALYs from fixed-schedule LH-RHa dosing (Table 4). We found that a strategy of stopping androgen suppression resulted in 1.004 QALYs, and immediate orchiectomy resulted in 1.008 QALYs (data not shown). In sensitivity analysis, the maximum difference between individualized androgen suppression and standard androgen suppression was 0.078 QALYs (Table 4). This occurred when the LE for men on continued androgen suppression was 13 months and individualized LH-RHa dosing results in a survival decrement of 1 month compared with fixed-schedule dosing. We found no evidence in the literature to suggest this decrement would occur, but used this scenario to model effects should there be unanticipated problems.
Effects of Intervention on Costs In multiway sensitivity analysis, combined unfavorable estimates regarding the castrate interval, LH-RHa cost, antiandrogen cost, and the cost of testosterone testing resulted in individual cost savings of only $272. With combined favorable estimates regarding the castrate interval, LH-RHa cost, and cost of LH-RHa administration, the cost savings were $6,701 per individual over his lifetime (Table 3). Population costs. When the base-case scenario findings are applied to the estimated population of men with AIPC, the cost savings for individualized LH-RHa dosing strategy compared with the fixed-schedule dosing would be $104 million (Table 5). These savings would be less or more depending on the size of the actual population. With sensitivity analysis, we identified no situation in which the societal savings were less than $34 million when an individualized strategy was used, except if a combination of four unfavorable variables were modeled simultaneously (Table 4); in this case the savings was only $8 million.
Decremental Cost Utility The relatively new conceptual framework, called decremental cost utility,25 can be used to compare the individualized dosing strategy with the fixed-schedule in terms of the dollars gained for each QALY lost under the base-case assumptions (Table 6). Under these assumptions, adopting the individualized strategy resulted in a gain of $692,600 from a societal perspective for each QALY lost.
A review of published cost-utility analyses that adhered to methodological recommendations of the U.S. Public Health Service identified four studies of oncologic interventions.26 These studies had variable interventions (chemotherapeutic, surgical, and stem-cell transplantation), and the incremental cost-utilities ranged from $5,400/QALY to $21,000/QALY.
A relatively simple practice modification to individualized dosing of LH-RHa in men with AIPC has the potential to offer considerable cost savings on a societal basis with very little, if any, decrement in quality-adjusted survival. Even under the conservative assumptions of our model, the decrement in QALYs with individualized LH-RHa dosing appears to be minimal. Our findings of a 0.005-QALY loss with individualized dosing represents a loss of 1.83 quality-adjusted days. We chose to limit our analysis to men with AIPC because, as a group, they are more likely to have been receiving LH-RHa longer and to be older. These two factors are associated with longer castrate duration after LH-RHa treatment withdrawal.9 These savings should be obtained even with new LH-RHa formulations with dosing intervals of 6 months27 or 1 year28 because the duration of androgen suppression is likely to be prolonged after discontinuation of these formulations. The population to which individualized dosing may be applied is likely larger, both on the basis of our conservative estimate of the number of men with AIPC and the other populations who may be treated in this manner, such as men undergoing intermittent androgen ablation. Additionally, recent phase III trials of taxanes have reported median survivals of approximately 18 months in men with AIPC.29,30 A recent retrospective analysis of men with AIPC from a single institution revealed a median survival of 40 months in men with skeletal metastasis at initial staging and 68 months in men without metastases at initial staging.31 These reported data suggest that our assumptions about survival in the base model are conservative; thus, the cost savings in this population may be larger than we estimated. Our analysis is limited in that some of the measures used are not available in the literature. In our base case, we assumed that LE would be equal because we assumed that suppression of testosterone would be equal. However, in vitro studies suggest that LH-RHa may have direct inhibitory effects on androgen-independent DU 145 prostate cancer cell lines by preventing epidermal growth factor receptor–mediated tumor growth through a protein kinase C pathway32 or insulin-like growth factor system.33 Additionally, there is a case report of an apparent response to LH-RHa in an orchiectomized AIPC patient.34 Another possible area of concern is the small period of time in which serum testosterone may have begun to rise and may stimulate tumor cells. Evidence from two small clinical trials of 22 and 32 patients suggests that symptoms and prostate-specific antigen do not rise during these intervals.7,9 Additionally, the utility analysis we have chosen, although able to model multiple influencing variables, is not able to provide an estimate of variability in outcomes. The population to which individualized dosing may be applied is likely larger, both on the basis of our conservative estimate of the number of men with AIPC and the other populations who may be treated in this manner, such as men undergoing intermittent androgen ablation. On the basis of available data, the strategy of individualized dosing of LH-RHa is feasible and should be safe. To some men it may even be preferable for reasons such as limitation of seemingly unnecessary medications and associated injections. The results presented in this article suggest that a strategy of individualized LH-RHa dosing would not adversely affect QALYs and would be associated with moderate savings on an individual basis and substantial savings on a societal basis. Our findings persisted over the wide range of assumptions tested in sensitivity analysis. A randomized clinical trial will be required to determine the clinical outcomes and cost of individualized LH-RHa dosing strategy as compared with standard fixed-dose therapy. The ethical and methodologic questions for research are still being developed,25 but we believe this work illustrates the value in pursuing them.
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict existed for drugs or devices used in a study if they are not being evaluated as part of the investigation.
We thank Murray Krahn, MD, and Karen Bremner for sharing their preferences data with us. This article was supported in part by Agency for Healthcare Research and Quality National Research Service Award Institutional Research Training Grant No. 2 T32 HS000044-13 (J.A.W.).
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1935-469X. Print ISSN: 1554-7477
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Abstract
Introduction
