Annals of Oncology Advance Access originally published online on November 2, 2005
Annals of Oncology 2006 17(2):217-225; doi:10.1093/annonc/mdj048
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© 2005 European Society for Medical Oncology
Comparing cost/utility of giving an aromatase inhibitor as monotherapy for 5 years versus sequential administration following 2–3 or 5 years of tamoxifen as adjuvant treatment for postmenopausal breast cancer
Section of Oncology, Institute of Medicine, University of Bergen, Haukeland University Hospital, Bergen, Norway
* Correspondence to: Dr P. E. Lønning, Section of Oncology, Institute of Medicine, University of Bergen, Haukeland University Hospital, N-5021, Bergen, Norway. Tel: +47-55-972027; Fax: +47-55-973599; E-mail: per.lonning{at}helse-bergen.no
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Abstract |
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Background: Several studies have shown aromatase inhibitors administered as monotherapy or sequentially to tamoxifen to improve relapse-free survival in postmenopausal women with early breast cancer. Any difference in cost/utility between the strategies may be of importance to therapy selection.
Methods: Cost/utility was compared between the different regimens based on the theoretical assumption that costs, benefits and side-effects were similar for each drug and independent of whether it was administered as monotherapy or sequentially.
Results: Tamoxifen for 2–3 years followed by an aromatase inhibitor for 3 or 2 years provided the lowest cost/quality-adjusted life years (QALY) estimates, while administration of an aromatase inhibitor subsequent to 5 years on tamoxifen provided the highest values. The difference between strategies increased with patient age. Cost/QALY estimates were sensitive to an increase in hip fracture risk and to cost reductions due to relapse prevention. Adding oral bisphosphonates increased costs moderately.
Conclusions: While tamoxifen for 2–3 years followed by an aromatase inhibitor provided the lowest cost/QALY estimates, a further improvement of relapse-free survival of 1% if the aromatase inhibitor is given upfront provides an acceptable cost/QALY. In contrast, additional benefits achieved by administering an aromatase inhibitor subsequent to 5 years of tamoxifen provided unacceptable costs.
Key words: adjuvant therapy, aromatase inhibition, breast cancer, costs, utility
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introduction |
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Novel, third-generation aromatase inhibitors have revealed clinical superiority compared with conventional agents for endocrine treatment of postmenopausal breast cancer in the metastatic setting [1
]. Early results from three large adjuvant trials have shown all the three third-generation agents, anastrozole [2], letrozole [3] and exemestane [4], given either as monotherapy or following tamoxifen treatment for 2–5 years (Figure 1) to improve relapse-free survival compared with tamoxifen monotherapy. While the results have led to clinicians changing practice, implementing these compounds in the adjuvant setting [5], there is a need for long-term follow-up of these trials to fully assess the benefits as well as side-effects of treatment, and it will take several years to learn the results of head to head comparisons between different compounds and strategies.
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Based on current knowledge, we lack information on whether there could be any difference with respect to efficacy and toxicity between the different drugs or related to regimen of administration (monotherapy versus sequential treatment following tamoxifen). In this setting, any difference regarding cost/utility may be an important issue when selecting a regimen. Even if the retail price for the different aromatase inhibitors and their antitumor effects may be similar, the different regimens reported [2
–4] (Figure 1) may differ with respect to cost/utility. The aim of this paper is to compare cost/utility between the regimens reported based on three theoretical assumptions: (i) each drug is of similar efficacy preventing breast cancer relapse; (ii) each treatment strategy (monotherapy or sequential administration) reduces the absolute risk of relapse to a similar extent; and (iii) there is no difference regarding side-effects between the compounds. |
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Because cost/utilities in general are given in US dollars (USD) in the literature, costs were converted to this currency using the average exchange rate for the week 25–29 October 2004: 1 USD = 6.42 NOK = 0.7835 Euro. As the costs of all cancer drugs are covered by the Norwegian National Health System, for each drug retail price was used, subtracted for governmental tax (Table 1). Because the price of each drug may vary according to the marked situation and the aim of this paper is to compare the different strategies on a ‘conceptual’ basis, the price of the cheapest aromatase inhibitor on 1 October 2004 (exemestane) was used for each compound. In the text, the three regimens (Figure 1) are referred to as the anastrozole, letrozole and exemestane regimens based on the large published studies, while ongoing studies and preliminary reports are evaluating anastrozole administered sequentially and exemestane and letrozole monotherapy.
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For all evaluations reported, the terms costs and cost per additional life year or quality-adjusted life year gained (QALY) are in comparison with use of tamoxifen 20 mg daily monotherapy for 5 years, the previous ‘gold standard’ of adjuvant endocrine therapy.
Different scenarios are depicted in Figure 2. Cost/utility of the different strategies was calculated based on a ‘fixed’ value, assuming an absolute reduction in the number of relapses of 2% on an intention-to-treat basis (two out of 100 allocated to the regimen after primary surgery) compared with tamoxifen monotherapy for 5 years, exploring different models for each strategy (Table 2). As the intention was to compare the different strategies, the figure of 2% was used in the calculations for the group of lymph node-negative (N–) as well as lymph node-positive (N+) patients. Utilities were estimated on a lifetime basis. The number of patients on treatment in the tamoxifen monotherapy arm at different time intervals was calculated separately for N– and N+ patients using data from the Early Breast Cancer Trialist Group (EBCTG) 1998 overview [6]. As the annual relapse rate during the first years of follow-up is a non-linearly process with a peak around 2–3 years after primary surgery [7], the percentage of patients remaining relapse-free (RFS) was extrapolated from the curves in the EBCTG analysis [6] for 2.5 years. The exponential function was calculated from this figure, and used to compute the estimated RFS at 2 and 3 years in different models to test for sensitivity. For the 5–10 year interval, the intervals were calculated based on an exponential function.
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The number of patients on treatment with an aromatase inhibitor was calculated as an exponential function by adding the additional number of patients remaining relapse-free to the tamoxifen figures at the end of the different time intervals (interval 1 or 2, Table 2, left column). Different models used to estimate the benefits are given in Table 2.
The benefits with respect to RFS as well as overall survival and costs per year gained were calculated separately for N– and N+ patients assuming an age of 55, 65 or 75 years when commencing adjuvant therapy. A discount rate of 3% [8] was used for benefits as well as costs unless otherwise specified. The effects of including a potential reduction in contra-lateral breast cancer as well as an increased risk of hip fracture was calculated over a range based on current data in the literature [2–4, 6], while potential costs of adding an oral bisphosphonate as prophylactic therapy was calculated based on the theoretical assumptions that 100%, 50% or 20% of the patients may need such treatment in concert during the time interval they were exposed to the aromatase inhibitor. Considering costs per QALY gained, this was computed separately for N–/N+ patients within the three age groups rating life quality as 0.9, 0.8 or 0.7 [9, 10]. For these calculations, the average costs for each drug and the arithmetic mean of the time of relapse prevention was used to calculate the benefits of each model (Table 2), including the costs of treating 50% of the patients with the bisphosphonate during the time they were on treatment with an aromatase inhibitor. Regarding anastrozole and letrozole, the two additional relapses were considered prevented 1.875 years after commencing therapy with the aromatase inhibitor, with additional analysis assuming relapse prevention to occur after 2.5 or 3 years to test for sensitivity. For exemestane, the additional relapses prevented were assumed to occur 1 and 1.5 years after commencing therapy with exemestane following tamoxifen for 3 or 2 years, respectively.
Relapses include locoregional failures as well as distant metastases. Thus, for patients relapsing, 75% were assumed to die from their disease. For these patients, the mean life expectancy following relapse was assumed to be slightly above 2 years [11]. Assuming a life quality of 0.5 [12] and a discount rate of 3%, this provided a QALY of 1. The effect of including direct and indirect costs of relapse treatment was explored covering a range of 50 000 to 200 000 USD per relapse. The influence of including non-breast cancer deaths in the model was examined. Finally, the cost/utility of substituting the cheapest aromatase inhibitor regimen for the more expensive ones were calculated assuming an increased benefit of 1 per 100 for the more expensive regimen. All calculations were done manually using a Canon F-720 Scientific Calculator.
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costs
Computing the costs per year gained with no relapse, the ratio between the highest and lowest cost estimate in the four models (Table 2) was less than 1.2 within each group (age, node status and discount rate). Thus, the mean value was used for further calculations.
Table 3 provides costs depending on no discount or use of a discount ratio of 3% or 5%. As expected, lower costs were observed with the short-term exemestane regimens (2 or 3 years on therapy with the aromatase inhibitor) compared with the other two regimens. Interestingly, little difference was observed between the anastrozole regimen (aromatase inhibitor 5 years of monotherapy from the beginning) compared with the letrozole regimen (adding letrozole for 5 years following 5 years of exposure to tamoxifen), except in the oldest group of patients. The somewhat higher costs observed for N– compared with N+ patients with each regimen is due to the lower number of patients relapsing before and during treatment among N– patients, causing a higher number of N– patients to be exposed to the aromatase inhibitor.
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Effects of preventing contralateral breast cancer and including the costs of treatment with an oral bisphosphonate
Assuming tamoxifen to reduce the risk of a contralateral breast cancer to 0.0025/year [6
], based on the results from the adjuvant studies [2–4] a reduction in the contralateral breast cancer risk hazard ratio by 50% to 0.00125 during each year of exposure to the aromatase inhibitor was included in the model (Table 4). Table 4 further shows the effects of administering an oral bisphosphonate (aledronate 70 mg per week) to 100%, 50% or 20% of the patients (these figures does not include the potential benefits of preventing contralateral breast cancer).
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costs per QALY gained
The costs per QALY gained results are given in Table 5. Similar to what was recorded for RFS, there was a significant difference in the cost/QALY estimates between the short-term exemestane regimens compared with the anastrozole and letrozole regimen. Considering the latter two regimens, little difference was recorded between patients aged 55 or 65 years. However, for 75-year-old patients, the costs were higher for patients treated with the letrozole regimen, owing to a shorter life expectancy from commencing treatment with the aromatase inhibitor (relapse prevented at age 81.875 years) compared with the anastrozole regimen (relapse prevented at age 76.875 years).
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model sensitivity with respect to time of relapse prevention
Cost/QALY were estimated, assuming each relapse to be prevented 2.5 or 3 years (instead of 1.875 years) after implementing anastrozole or letrozole. This reduction in benefit increased the cost/QALY estimates for anastrozole and letrozole among 55-year-old women by only 3.3% and 6% for anastrozole and 3.4% and 6.5% for letrozole, 4.1% and 7.3% versus 4.8% and 8.5% among 65-year-old women, and 5.5%, 9.7%, 6.5% and 12.4%, respectively, among patients 75 years of age (data not shown).
effects of calculating benefit as a 2% reduction in relapse rate among patients remaining relapse-free
The calculations so far (Table 5) were based on the assumption that each strategy should prevent two relapses out of 100 patients initially allocated to the therapy, causing a larger reduction in relapse hazard ratio following implementation of the aromatase inhibitor after tamoxifen compared with upfront therapy. Assuming the risk of dying from breast cancer prior to treatment with the aromatase inhibitor to occur independently of whether the patient might eventually respond to treatment with the aromatase inhibitor, assuming a 2% reduction among patients still relapse-free would mean to reduce the number of relapses prevented by anastrozole by about 4% and 11% (meaning absolute values of 1.92% and 1.78%, respectively) for N– and N+ patients compared with the figure of 2% based on an intention-to-treat basis. For exemestane the benefit would be reduced by 8% and 20%, while for letrozole it would be about 16% and 31% for N– and N+ patients, respectively. A reduction in the benefit of 20%, 16% or 31% should lead to a corresponding increase in the cost/utility ratios of 25%, 19% and 45%, respectively (data not shown).
effects on the model of including non-breast cancer deaths
The annual death rate for Norwegian women in general is between 0.4% and 0.8% during the age interval of 55–65 years, 0.8% to 2.2% during 65 to 75 years, but increases from about 2.4% to 8.6% between 75 and 85 years of age.
Assuming the annual hazard for a non-breast cancer death to be constant (3.15%) during the age period of 75–80 years, this would reduce the costs of treatment with anastrozole by between 5% and 6% in N+ and N– patients. Assuming relapse prevention to occur 1.875 years or 3 years after commencing therapy, this will reduce the benefit by 5.9% and 9.1%, respectively. For the tamoxifen 2 years + exemestane 3 years regimen, cost reduction for N+ and N– patients were between 8% and 8.5%, while the benefit was reduced by 10.6%.
For the letrozole regimen, including non-breast cancer deaths reduced the costs for N– and N+ by about 21.7% and 27.6%, and the benefits by 22.2%.
In conclusion, including non-breast cancer deaths in the model has little impact on the cost/QALY estimates for any of these regimens, as the costs and benefits were reduced by about the same percentage.
effects of an increased rate of hip joint fractures
The average risk for a postmenopausal women of having a hip joint fracture is about 20% [13], but varies between different countries, with a high incidence in Scandinavian countries [14, 15]. While the average costs of acute treatment for an uncomplicated hip fracture is about 11 000 USD in Norway, additional costs over the next 12 months are about twice that amount [16]. Around 10% of the patients may need a secondary joint replacement (cost about 16 600 USD), increasing the average cost per hip joint fracture to about 40 000 USD. In the ATAC study, the increase in total fracture rate was about 60% in the first report [2], but reduced to an increase in total fracture rate and fractures of the hip of 43% and 20%, respectively, after a median follow-up of 68 months [17]. While an increase in hip fracture rate of 50% will add 4000 USD to the costs per patient only, excess post-traumatic mortality (depending on age) of 10–20% in postmenopausal women, with a similar number suffering chronic disability [16, 18, 19], may reduce benefits substantially.
Figure 3A–F reveals the effects on cost/QALY of an increased risk of hip fractures in N+ patients for the three age groups, assuming a life quality of 0.9 and 50% of the patients to receive oral bisphosphonates. In accordance with data in the literature [16], the effect of an increased incidence of hip joint fractures on utility was computed assuming two potential scenarios: the first assuming risk of death as well as the risk of permanent disability to be 10% each (Figure 3A, C and E), and the second assuming both risks to be 20% (Figure 3B, D and F). Excess fractures due to treatment were assumed to occur at the middle of the expected survival time from the day of implementing the aromatase inhibitor. As may be seen, even a moderate increase in fracture rate significantly increased cost/utility among the old patients.
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effects of including cost savings of relapse prevention
While there are reports in the literature estimating total costs of handling metastatic breast cancer [20
], data on cost-utility of using aromatase inhibitors as well as defined chemotherapy regimens in the metastatic setting [8, 21–23], taking into account recent changes in practice such as including not only the taxanes (retail price about 2000 USD/3 weeks for direct drug costs during therapy) but also trastuzumab for HER-2-positive patients as well as other forms of expensive therapies, we lack estimates regarding total costs of treatment and care for metastatic breast cancer. Owing to these uncertainties, the effects of including cost savings was calculated for the range of total costs per relapse varying from 50 000 to 200 000 USD using the same assumptions as for calculating cost/QALY outlined above (50% of patients to receive oral bisphosphonate on adjuvant treatment, 3% discount rate). The effect of including these costs for 65-year-old women with N+ cancer is illustrated in Figure 4. Interestingly, if the cost of a relapse extended to 250 000 USD, the cost/QALY for using exemestane 3 years became negative, meaning this strategy will be cost saving.
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cost/QALY of using the anastrozole (monotherapy) or letrozole (5 years of tamoxifen followed by 5 years of letrozole) versus tamoxifen for 2 years followed by exemestane 3 years assuming an additional benefit of reducing relapse rate by 1%
For these calculations, the number of relapses to be prevented was reduced by the relapse ratio up to the time of achieving the benefits. The costs per additional QALY achieved by substituting tamoxifen 2 years followed by exemestane for 3 years with anastrozole for 5 years or tamoxifen for 5 years followed by letrozole for 5 years was computed assuming one potential additional relapse (multiplied by the chance of being relapse-free) to be prevented per 100 patients with use of the most expensive regimen. The difference was calculated separately for N– and N+ patients within the three defined age groups, rating quality of life to 0.9 for non-relapsing patients and including the costs of administering oral bisphosphonates to 50% of the patients for the time interval they received the aromatase inhibitor. While exemestane was assumed to prevent both relapses 1.5 year after implementing therapy, for anastrozole and letrozole the difference was computed separately assuming all three relapses to be prevented either 1.5, 1.875 or 2.5 years after implementation the aromatase inhibitor.
For patients 55 years of age the cost per additional QALY by using the anastrozole regimen varied between 22 500 and 30 000 USD, at age 65 years between 29 000 and 40 000 USD, and at age 75 between 43 500 and 62 000 USD. For letrozole, the additional costs per QALY varied between 62 000 and >500 000 USD for patients at age 55 years. For patients at age 65 years, all estimates exceeded 120 000 USD, while at age 75 years, cost/QALY was >500 000 USD, and often became negative owing to the fact that there was no utility gained due to the limited life expectancy (data not shown).
Including non-breast cancer death rates in the models had minor effects on the final cost/QALY estimates for substituting anastrozole as well as letrozole for exemestane (reduced costs and benefits to about the same extent).
The inclusion of costs of relapse had a significant effect on these estimates, as illustrated in Figure 5 for N+ patients. While the figures are given for all the three age groups for anastrozole, for letrozole only the findings with respect to a 55-year-old woman are included. For women at the age of 65 or 75 years at the time they had their diagnosis, the cost per additional QALY exceed 100 000 USD for the whole cost range of 50 000–200 000 USD.
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discussion |
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Based on the results from the three large adjuvant studies reported so far [2
–4], aromatase inhibitors are now being implemented as routine adjuvant endocrine therapy in postmenopausal women [5]. However, we do not know which drug or which regimen (sequential treatment versus monotherapy) may be optimal with respect to efficacy as well as toxicity.
In this scenario, the issue of cost/utility of implementing one strategy compared with another becomes important. While endocrine therapy in general has been found to be associated with low cost/utility estimates in early therapy as well as in the advanced setting [21, 24–27], changing general practice of adjuvant hormonal therapy for postmenopausal women will affect hundreds of thousands of patients all over the world. Thus, there is a need to assess the cost/utility as well as potential differences between these novel strategies. The aim of this paper was to evaluate the cost/utility ratio of the different strategies (monotherapy versus different regimens of sequential treatment), as this should be of significant interest to decision-makers.
While we lack knowledge about the long-term effects of aromatase inhibitors versus tamoxifen monotherapy, based on the results reported so far, an absolute reduction in relapse rate of 2% with a concomitant reduction in breast cancer death of 1.5% is a conservative estimate for N+ patients and probably a more realistic value with respect to N–, low-risk patients. It may also be argued that a more realistic model should be to assume a given percentage of patients to benefit from treatment with the aromatase inhibitor following its implementation, including the fraction of patients relapsing or dying from other reasons before receiving treatment with the aromatase inhibitor, instead of an absolute reduction. On the contrary, early results from the adjuvant studies suggest a larger reduction in the hazard ratio for a relapse following implementation of the aromatase inhibitor in patients switching from tamoxifen [3, 4] compared with those receiving anastrozole from day 1 [2] Importantly, to calculate benefits based on percentage reduction among patients at risk instead of absolute benefits on an intention-to-treat basis should increase the cost/QALY of using the anastrozole regimen marginally, to have an in-between effect on the cost/QALY of the tamoxifen–exemestane approach, but to increase the cost/utility of the letrozole regimen significantly, enhancing the differences in the cost/utility estimates between the regimens and further substantiating the conclusions presented.
Preference score, or rating of life quality, is a complicated issue, involving technical as well as ethical aspects [28]. From the literature, a preference score in the range of 0.8 to 0.9 has been recorded among physicians as well as patients and general community members for patients undergoing uncomplicated treatment for primary breast cancer [9, 10]. A second issue relates to general heath problems in an aging population, with a gradual drop in preference score from about 0.85 to 0.7 in community populations over the age range from 35 to 75 years [29, 30]. Importantly, even though reducing utility estimates may increase the QALY estimates presented here by up to 30–35% in the oldest patient group, it should have marginal impact on the comparison between the treatment strategies and conclusions of this paper.
Certain findings, like the results that shorter duration of treatment (2 or 3 years) was less costly than 5 years of therapy with the aromatase inhibitor, are self-evident. More surprising, perhaps, was the influence of patient age on the cost/utility estimates, with a factor varying between 2 and 3 between the oldest and the youngest age group.
The differences between the age groups were aggravated by the potential loss of benefit associated with an increased risk of getting a hip fracture. While the three major trials have reported an increased risk of all bone fractures of between 22% and 43%, the increase in hip fracture rate was smaller. Notably, in the ATAC as well as the IES study fracture rates were compared between patients receiving the aromatase inhibitor and patients on tamoxifen. Tamoxifen is known to have a beneficial effect on bone metabolism, in particular with respect to trabecular bone [31]; thus, it is likely at least some of this difference was due to the effect of tamoxifen on bone metabolism. While hip fractures are the type of fractures most extensively studied with respect to long-term disability as well as enhanced mortality, recent studies [32, 33] have notably revealed an increased mortality following clinical vertebral fractures on an osteoporotic basis, while other fractures seems not to enhance risk. In a recent placebo-controlled trial, we found a moderate increase in bone loss in the hip but no significant effect on bone density in the lumbar spine during 2 years of therapy with exemestane [34]. In that study, none of the patients found to have a normal bone density at baseline became osteoporotic during 2 years on therapy. Most importantly, during a recent follow-up of the same study [35] we found the changes to be partly reversible 1 year after terminating treatment, suggesting long-term risk to be modest or even non-existant. Most importantly, the risk seems to be fully preventable. Notably, bisphosphonates have been found effective in preventing bone loss associated with artificial menopause as well as treatment with a LH–RH analog and an aromatase inhibitor in concert [36, 37]. Thus, by including administration of bisphosphonates to 50% of the patients as done for the estimates in this paper, it is unlikely we may see a significant risk of hip fractures over time in patients having aromatase inhibitors.
As expected, including the cost reduction due to relapse prevention significantly reduced cost/QALY estimate for each regimen. However, it had little effect on the ratio between the costs of the different approaches.
Of most interest were the results obtained by comparing the more expensive (5 years on treatment) with the less costly regimens (tamoxifen 2 years followed by exemestane for 3 years). For anastrozole monotherapy, assuming an additional relapse to be avoided per 100 patients was associated with a moderate cost/QALY in all age groups. As expected, including the costs of treating a relapse further reduced the cost/QALY estimates. Thus, if implementing an aromatase inhibitor from day 1 causes an even moderate improved survival compared with sequential treatment (the exemestane approach), the cost per QALY of the additional lives saved will be moderate. In contrast, any improvement was associated with high costs using the tamoxifen 5 years followed by letrozole 5 years regimen, with the potential exception of the youngest patients.
In contrast to the recent paper by Hillner [26] assessing the cost/utility of administering anastrozole as adjuvant treatment, this paper is not based on the exact data reported in each publication but estimates cost/utilities based on the general assumption by most clinicians that there is little (if any) difference between the compounds as well as the regimens of administration with respect to efficacy and side-effects. While there are ongoing studies evaluating sequential treatment versus monotherapy as well as direct comparison of anastrozole and exemestane on a head to head basis, it will take years to learn the results. In this scenario, any difference in cost/utility with respect to the individual treatment regimens may be of importance to decision-makers. The data presented here reveal 3 years of treatment with an aromatase inhibitor subsequent to 2 years with tamoxifen (the exemestane approach) to be associated with the lowest cost/QALY for each age group of patients independent of whether costs of side-effects such as an increased risk of hip joint fractures or reduced costs due to prevention of relapses were included in the calculations. Regarding the letrozole approach (5 years of an aromatase inhibitor following 5 years on tamoxifen), this was the regimen associated with the highest cost/QALY figures, in particular among the oldest patients. Notably, even a moderate increase in relapse prevention would advocate 5 years of monotherapy for sequential treatment. However, any long-term difference with respect to improved relapse-free survival for one of these strategies versus the other may strongly influence the difference between these strategies. Considering the letrozole approach, even an increase in relapse prevention from 2–3% should not advocate this approach.
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The author has over the years received speakers honoraria, participated in advisory boards, and received research funding from all the three major companies involved in development of aromatase inhibitors: Astra-Zeneca, Novartis and Pfizer. This work was performed without any financial support from industry, and the findings were not discussed with representatives from drug companies.
Received for publication June 14, 2005. Revision received August 10, 2005. Accepted for publication September 19, 2005.
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