Annals of Oncology Advance Access originally published online on May 2, 2006
Annals of Oncology 2006 17(7):1072-1082; doi:10.1093/annonc/mdl093
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© 2006 European Society for Medical Oncology
Cost effectiveness of bisphosphonates in the management of breast cancer patients with bone metastases
1 Pharmerit, Bethesda, MD; 2 Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA; 3 Clinique de Genolier, 1 route du Muids, 1245 Genolier, Switzerland
* Correspondence to: Mr M. Botteman, Pharmerit, 7272 Wisconsin Avenue, Suite 300, Bethesda, MD 20814, USA. Tel: +1-301-941-1942; E-mail: mbotteman{at}pharmerit.com
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Abstract |
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Background: Bisphosphonates are recommended to prevent skeletal related events (SREs) in patients with breast cancer and bone metastases (BCBM). However, their clinical and economic profiles vary from one agent to the other.
Materials and methods: Using modeling techniques, we simulated from the perspective of the UK's National Health Service (NHS) the cost and quality adjusted survival (QALY) associated with five commonly-used bisphosphonates or no therapy in this patient population. The simulation followed patients into several health states (i.e. alive or dead, experiencing an SRE or no SRE, and receiving first or second line therapy). Drugs costs, infusion costs, SREs costs, and utility values were estimated from published sources. Utilities were applied to time with and without SREs to capture the impact on quality of life.
Results: Compared to no therapy, all bisphosphonates are either cost saving or highly cost-effective (with a cost per QALY 
£6126). Within this evaluation, zoledronic acid was more effective and less expensive than all other options.
Conclusions: Based on our model, the use of bisphosphonates in breast cancer patients with bone metastases should lead to improved patient outcomes and cost savings to the NHS and possibly other similar entities.
Key words: bone metastases, breast cancer, cost and cost analysis, cost effectiveness
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introduction |
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Every year, an estimated 9000 breast cancer patients develop bone metastases in the UK [1
]. These metastases are associated with considerable skeletal morbidity, including severe bone pain, pathologic fractures, spinal cord compression, and hypercalcemia of malignancy [2]. These complications in turn are associated with a significant burden in terms of quality of life [3], resource utilization and costs [4–8].
Bisphosphonates have emerged as the standard therapeutic option for the prevention of skeletal complications secondary to bone metastases [2]. Although several have demonstrated significant benefits compared to placebo [2, 9], important differences in their individual profiles have been noted, including in terms of efficacy [2, 10], bioavailability and tolerability [11], administration time and burden, with implications in terms of patient satisfaction, costs, and clinic output [11–13]. Bisphophonates also vary in acquisition costs (from £165 to £195 per month in the UK for oral and intravenous therapy). Since these agents can be taken for months, if not years, they can have a significant financial impact on the National Health Service (NHS) [14].
Recent published analyses have assessed the health economic value of bisphosphonates in the UK. One study [15] focused on the role and value of bisphosphonates as a class in the management of skeletal related events (SREs) in breast cancer patients with bone metastases. Others [16, 17] evaluated the relative economic value of various bisphosphonates. However, these studies suffer from a number of important limitations. In particular, all studies excluded at least one bisphosphonate, usually i.v. ibandronate, and only one considered oral clodronate [15]. Some also did not include a ‘no therapy’ comparator [16, 17] and none considered important recently published clinical trial results [3, 18, 19].
The goal of this study was, therefore, to build upon previous economic analyses to update and more comprehensively assess, from the perspective of the NHS, the relative cost-effectiveness of commonly used bisphosphonates and ‘no therapy’ in the management of SREs in breast cancer patients with bone metastases and receiving chemotherapy or hormone therapy.
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design and general model structure
A literature-based decision analytic model was developed to compare the direct costs and quality adjusted life expectancy (QALE) of six cohorts of breast cancer patients with bone metastases receiving no therapy (i.e. placebo), oral ibandronate (OI), i.v. ibandronate (IBN), zoledronic acid (ZA), generic pamidronate (PA), or generic oral clodronate (OC). It uses life table analysis techniques to follow for 10 years (when approximately 99% of patients in the cohort are projected to be dead) the six cohorts of patients into various health states, each characterized by its associated costs and quality of life (measured using quality-adjusted life-year [QALY] weights).
In defining the health states, the following assumptions were made. Initial bisphosphonate therapy was stopped when: (a) the patient ceased to be compliant (presumably due to an adverse event); (b) the cancer progressed to a point where therapy was deemed unnecessary (patient no longer therapy candidate); or (c) the patient had died. Patients who became noncompliant with their initial therapy were assumed to either never resume any bisphosphonate therapy in 50% of cases or to start a 2nd line therapy (i.e. second bisphosphonate therapy) until cancer progression or death in the remainder 50% of cases. Patients previously on i.v. therapy who were initiating second line therapy were switched to OI and patients previously on oral therapy who were initiating second line therapy were switched to i.v. therapy (in equal proportion between IBN, ZA, and PA). This assumption is similar to that made by De Cock et al. [16].
Based on the above assumptions, a total of six health states (plus one for death) were defined according to whether the patient was receiving therapy (three categories: 1. on first line agent, 2. on second line agent, and 3. not on any agent) and whether the patient was experiencing a SRE or not (two categories). Patients were assumed to remain in each health state for one month at a time before being redistributed into another or the same health state according to a set of transition probabilities.
Economic and health effects occurring beyond the first year of analysis were discounted at 3.5% per annum, in accordance with NHS economic research guidelines.
epidemiological data
Consistent with long-term clinical and epidemiologic studies [20–22] and economic analyses [15, 23], patients were assumed to have a median survival of 18.8 months (regardless of therapy, consistent with the fact that bisphosphonates in this setting are not associated with statistically significant improved survival [24]).
Subjects not receiving bisphosphonate therapy were assumed to experience 3.05 SREs per year, equal to the pooled average rate of such events observed in the placebo group of large bisphosphonate trials [18, 21, 25, 26]. In the model, consistent with previous analyses, SREs were assumed to include pathologic fractures, radiation therapy for bone pain or to treat or prevent a fracture, surgery to stabilize bone fractures, spinal cord compression and hypercalcemia of malignancy.
efficacy of bisphosphonates in preventing SREs
The Anderson Gill multiple event hazard ratio [2] was selected as the primary efficacy measure for the analysis. The Anderson–Gill multiple event hazard ratio has been advocated as a preferred measure over the SMR (skeletal morbidity rate, measuring the number of skeletal related events divided by time on study), as it accounts for inter- and intra-patient variations in event rates and provides a statistically robust and comprehensive assessment of skeletal morbidity throughout the entire length of patient follow-up [2]. A hazard ratio <1 indicates a favorable treatment effect. However, since Anderson–Gill multiple event hazard ratio was not available for OC, we also conducted a secondary analysis relying on a secondary measure, the SMR which was available for all agents, except OI. This secondary analysis also served as a validation step of the results of the Anderson-Gill analysis.
Data on the Anderson–Gill statistic and the SMR ratio for each therapy are summarized in Table 1. In the model, the Anderson Gill statistic and the SMR ratio of each therapy were multiplied with the baseline pooled SRE of 3.05 per patient-year in the no therapy group to estimate the number of SRE per patient-year associated with each therapy. This allowed for indirect comparisons of each bisphosphonate with a common, standardized baseline rate. For instance, the Anderson-Gill hazard ratio for oral ibandronate was 0.62. If this ratio is applied to a baseline SMR of 3.05 in the no therapy group, the SMR for patients receiving oral ibandronate would be 1.89 (3.05 x 0.62). In comparison, the Anderson–Gill hazard ratio for intravenous ibandronate was 0.71 (based on a different trial), therefore the SMR in patients receiving this therapy would be 2.17 (3.05 x 0.71).
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pain and quality of life effects of bisphosphonates
Bisphosphonate agents have been demonstrated to significantly improve or reduce deterioration in pain and/or quality of life scores compared with placebo [2
, 18, 19, 24, 27–33]. However, these benefits appear to vary somewhat by agent and instrument used to measure pain and quality of life improvement, precluding a perfectly reliable comparative analysis of the pain reduction benefits of bisphosphonates [27]. Nevertheless, several studies have reported improvements in pain scores associated with the use of i.v. ZA 4 mg [18, 19, 28] and i.v. PA [27, 28]. Neither agent was found effective in improving pain score in one small study [34]. No differences in pain scores improvements have been found between ZA and PA [28, 34]. A single trial [29] has demonstrated the sustained and significant improvements in pain scores associated with IBN, which were broadly similar to those reported for ZA in a comparable placebo-controlled study [18]. Pooled results from two clinical trials summarized in one single publication indicate that OI significantly improved pain scores [35]. In studies published until now the pain score reductions in patients treated with OI did not reach statistical significance until week 12. OC has been demonstrated to improve pain scores in one [31] of two published studies [31, 32]. In at least one study, a trend in better pain reduction has been observed with intravenous bisphosphonates (60 mg PA) compared to high dose (2400 mg/day) OC [33]. With regard to quality of life, similar patterns have been observed regarding the impact of the various bisphosphonates on quality of life [27, 29, 30, 32], including in particular the most recent findings that ZA improves quality of life [3, 19].
Next, it was necessary to assign utility values to these pain and quality of life improvements. Dranitsaris and Hsu [36] have reported the only published empirically-based estimates of utilities for bisphosphonate therapy and SRE for patients with advanced breast cancer receiving PA. In this study, time spent without an SRE has a utility of 0.64 (95% CI 0.53 to 0.76) and 0.56 (95% CI 0.45 to 0.68), for patient receiving and not receiving PA, respectively. Time spent with an SRE was valued at 0.46 (95% CI 0.37 to 0.54) and 0.31 (95% CI 0.23 to 0.38), respectively. Accordingly, the benefits of PA therapy over no therapy were 0.08 (i.e. 0.64 minus 0.56) during time without SRE and 0.15 (i.e. 0.46 minus 0.31) during time with SRE.
Based on the above evidence, the quality of life benefits of all i.v. bisphosphonates were assumed to be similar and to commence after the first month of therapy. The utility values for i.v. bisphosphonates were as reported in the Dranitsaris and Hsu study [36]. The benefits of OI were assumed to be similar to those of i.v. bisphosphonate except that they would be delayed until the completion of the 12th week of therapy [30]. Finally, we assumed that the benefits of OC therapy would be half as large as the other therapies.
safety of bisphosphonates
In general, bisphosphonates are well tolerated [2, 11]. Oral administration is often associated with gastrointestinal (GI) adverse events (AEs), which in turn are associated with compliance and persistence problems (see below). Intravenous bisphosphonates are generally associated with mild to moderate flu-like symptoms following infusion [2, 11]. Intravenous bisphosphonates can also have adverse effects on renal function, but are generally mild to moderate in severity (i.e. mild elevation of serum creatinine) and manageable. The incidence of severe renal adverse events is generally low [2, 11]. Nevertheless, routine serum creatinine monitoring has been recommended for i.v. pamidronate and zoledronic acid [37] and, according to clinical assessment of the individual patient, it is recommended (per the Summary of Product Characteristics of IV Ibandonrate) that renal function, serum calcium, phosphate and magnesium should be monitored in patients treated with i.v. ibandronate.
Based on the above evidence, the quality of life and economic impact related to drug-induced severe adverse events were not included in the model given the rarity of such events. This assumption is consistent with the approaches used in several other economic models [15, 23, 36].
compliance and persistence with therapy
Because i.v. bisphosphonates are administered in a hospital or infusion center, compliance with therapy is less of a concern than with oral therapies [38]. The monthly probability of discontinuation of initial i.v. therapy due to an AE was therefore based on a pooled average estimate across trials of these agents [10, 21, 25] and was assumed to be identical across all i.v. formulations (0.79% [95% CI 0.68% to 0.92%]).
Discontinuation rates for oral bisphosphonates, as a class and across a wide range of indications, are notoriously high due in part to high rates of GI side effects [38] and complex daily regimens. In the clinical trial setting, the rate of study withdrawal for OC among breast cancer patients with bone metastases has been reported to be approximately 34–35% [26, 32]. Outside of this setting, the discontinuation rate for all oral bisphosphonates in patients with a variety of cancers and bone metastases has been reported to be 74% at 6 months [39], suggesting that the rates of discontinuation with oral bisphophonates are possibly twice as high in the non-experimental than experimental setting. This conclusion is consistent with the finding that clinical trials data are inadequate to ascertain actual compliance with long-term oral therapy [38]. In the model, the monthly rate of discontinuation was assumed to be 74% over 6 months for OC (20.11% per month [95% confidence interval 16.63% to 24.56%]).
The rate of withdrawal due to GI AEs at one month was 8% in a clinical trial of 110 patients with various cancers and metastatic bone disease receiving 5–50 mg OI [40]. A discontinuation rate due to adverse events (10%) was reported in a pooled analysis of two 96-week trials of OI in 564 breast cancer patients with bone metastases. No information exists regarding the rate of discontinuation with OI outside the somewhat artificial environment of the clinical trial setting mentioned above. For the purpose of the model, we assumed that in the non-experimental setting, OI's discontinuation rate would be twice the rate observed in the largest of the above two clinical trials (0.95% per month [95% confidence interval 0.61% to 1.30%]).
costs inputs
For the purpose of the model, only SRE-related costs were included because it was implicitly assumed that bisphosphonate therapy would not alter disease prognosis [24].
The average hospital cost associated with an SRE (£2016) (Table 2) was based on an updated estimate originally provided by Ross et al. [15].
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Community care costs were also included in the analysis. Specifically, the cost of treating bone pain was assumed to be avoided in one out of every seven patients while receiving bisphosphonate therapy [15
, 41]. The monthly cost of bone pain was based on the inflation-adjusted costing algorithm provided by Ross et al. [15] (£120/month in year 1, £557/month in year 2, £1514/month in year 3). The analysis also included the community care costs for patients with pathological long-bone fractures (assumed to account for 61% of all patients with non-vertebral fractures), again, adopting the Ross et al. [15] costing protocols. We conservatively adopted Ross et al.'s [15] least intensive protocol and assumed that the community care would last 3 months only (Ross et al. assumed that these costs could last anywhere from 0 to 12 months [15]). Using most recent cost data, the community care cost for long bone pathological fractures is estimated at £1620 per month (Table 3).
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The cost of bisphosphonate therapy includes drug, clinical staff time, and supply and laboratory testing costs (Table 4). Drug costs were obtained from the British National Formulary (BNF) [42
]. The amount of clinical staff time and resource use for the i.v. administration of PA and ZA was estimated based on the results of a US time and motion study [12]. In the absence of information on the time and resource use for IBN administration, we assumed that these costs would be the average of the cost of PA and ZA. Finally, the analysis also assumed that all patients initiating second line therapy would require a 1 h visit with a medical consultant (at £92).
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outcome measures
The cost effectiveness of each agent versus no therapy was summarized using the ratio of incremental cost and incremental QALY (the ‘cost-effectiveness ratio’) and the net monetary benefit (NMB). The NMB is a linear transformation of the cost-effectiveness ratio in which both the costs and the QALY of the interventions are expressed in monetary units. In the NMB approach, the maximum amount (‘
’) the NHS is willing to pay to gain a QALY is assigned to each QALY gained to express these QALYs in monetary terms. In the UK, this ‘’ has been implicitly set by the National Institute for Clinical Excellence (NICE) at £30 000 [43]. Both measures are complementary and provide information regarding the economic value of a given intervention [44]. The NMB is simple to interpret: a given bisphosphonate is considered cost effective versus no therapy if its NMB 
£0 and is considered the therapy of choice (among other bisphosphonates) if it has the greatest NMB [44].
sensitivity analyses
We performed a series of univariate sensitivity analyses on parameters affecting all or some therapies. We also performed a probabilistic sensitivity analysis via 1000 Monte Carlo simulations in which several parameters were varied simultaneously over specified probability distributions. The parameters included in the multivariate probabilistic sensitivity analyses and their probability distributions are listed in Table 5.
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main results
The baseline results for the primary and secondary analyses are provided in Table 6. In the primary analysis, which excluded OC, patients receiving bisphosphonate therapy are predicted to experience on average 1.65 to 2.40 fewer SREs over their lifetime than patients not receiving a bisphosphonate. Furthermore, bisphosphonates resulted in a 0.185 to 0.205 gained in quality-adjusted life expectancy (QALE). The largest of these gains were observed with ZA, followed by PA, IBN, and OI. The lifetime SRE-related cost in the no therapy group was £18 662. Bisphosphonates reduced the cost of SREs to £11 314 to £13 632, representing a 27% to 39% reduction in costs. Bisphosphonates also decreased the cost of pain care (Table 6). However, these savings were offset to various degrees by drug acquisition and administration costs. Overall, compared to no therapy, bisphosphonate therapy was cost saving with both ZA and OI, but not for PA and IBN. All bisphosphonates were cost effective versus no therapy, with cost per QALY gained £2400 or less. Finally, the most cost-effective bisphosphonates according to both the cost per QALY gained and NMB methods was ZA, followed by OI, PA, and IBN.
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The secondary analysis, which included OC but excluded OI, found similar patterns (Table 6) and suggests that bisphosphonate therapy is cost effective, with cost per QALY gained £6100 or less. ZA was also found to be more effective and less expensive than all other therapies or no therapy. Again, both in terms of the cost per QALY and NMB, ZA was most cost effective, followed by PA, IBN, and OC.
univariate sensitivity analyses
Univariate sensitivity analyses focusing on the NMB indicate that the main results are generally robust (Figures 1–2). Specifically, all therapies were considered cost effective versus no therapy, with all NMB values >£0, irrespective of the change in assumptions. Variables with the greatest impact were the SMR in no therapy, the cost of SRE, and the median survival. The ranking of therapy preference remained unchanged except in one scenario in each analysis. Specifically, in the primary analysis, when the administration time for IBN was assumed to be equal to that of ZA, IBN became slightly more attractive than PA. In the secondary analysis, OC became preferred to IBN when the proportion of patients switching to second line after discontinuing first line therapy due to an AE was assumed to be 100%.
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For ease of presentation, several model inputs were not included in Figures 1–2 above. In particular, changes in assumptions regarding utilities were not presented. However, the choice of utility inputs can have a profound impact on the results. For instance, when all utility weights were selected to bias the results against (in favor) bisphophonates, the cost effectiveness worsens (improved) dramatically.
multivariate sensitivity analyses
The multivariate sensitivity analyses focused directly on the ranking of various therapies and the decision at hand, that is, what is the course of action that is most likely to maximize the NMB given the willingness to pay for a QALY.
Specifically, Figure 3 plots out for various willingness to pay values (ranging from £0 to £100 000), the proportion of Monte Carlo simulations (n = 1000) each intervention (including no therapy) has the greatest NMB. For instance, assuming a willingness to pay for a QALY of £30 000, ZA would be the preferred intervention in 51% of the 1000 Monte Carlo simulations, followed by OI (33%), IBN (10%), PA (4%), and no therapy (3%, when none of the bisphosphonates are cost effective). If one assumes that the willingness to pay for a QALY is £0, that is, the decision makers seeks to select the least expensive intervention, regardless of gains in QALY, the preferred course of action is most likely to use ZA (which will yield a maximum NMB in 44% of model simulations), followed by OI (37%), IBN (7%), PA (4%), and no therapy (9%). As Figure 1 indicates, ZA is consistently the preferred therapy, and this preference increases as the willingness to pay for a QALY increases. Similar results were found in the secondary analysis (data not shown).
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discussion |
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The present analysis suggests that as a group, bisphosphonates for the prevention of skeletal related events in UK breast cancer patients with bone metastases are either cost saving or at least highly cost effective compared to no therapy. The analysis also reveals that not all bisphosphonates are equally cost effective. Specifically, across several analyses (primary, secondary, base case, and sensitivity analyses), ZA consistently appeared to be more cost effective than all other therapies, followed by OI, PA and IBN (in the primary analysis) and PA, IBN, and OC (in the secondary analysis). This ranking is basically reflective of the efficacy data in Table 1. As there have not been head-to-head comparisons among agents except for ZA versus PA, this ranking might not be reflective of a real difference among these agents.
Nevertheless, based on our results, the societal public health impact of treating breast cancer patients with ZA as opposed to not treating or treating them with other bisphosphonates could be significant. Every year 9000 breast cancer patients develop bone metastases in the UK [1]. Treating all 9000 patients with ZA as opposed to not treating them at all could lead to annual cost savings of £17.5–20.4 million. Likewise, treating all patients with ZA as opposed to treating them with another agent could lead to savings varying between £1.4 million and £27.3 million, depending on the comparator.
Taken as a whole, the results of our analysis are consistent with those of Ross et al. [15] in the UK, who found that bisphosphonates for the prevention of SRE in breast cancer patients with bone metastases would cost £1340 per QALY gained. The convergence of Ross et al.'s results and our findings is not a surprise, since we largely adopted and updated many but not all of their assumptions. These results are also consistent with (albeit better than) the results of Dranitsaris and Hsu [36] in Canada who found that the use of PA in this patient population would cost CAN$18 400 per QALY gained. On the other hand, Hillner et al.'s [23] US analysis, found that PA was cost-ineffective (cost per QALY ranging from $108,200 to $305 300). Two reasons largely explain the conclusions reached by Hillner et al. First, unlike our analysis, Hillner et al. assumed no QoL benefits associated with pain relief for patients taking bisphosphonates but not experiencing an SRE. This assumption was based on expert opinion. In contrast, our analysis was based on a preference survey of members of the general public who are potential candidates for the intervention [36], consistent with well known guidelines for economic evaluation. Accordingly, Hillner et al. report that the QALY gains associated with PA therapy versus placebo are only 0.025–0.037 versus 0.15 in Dranitsaris and Hsu [36] and 0.19 in the present analysis. In addition, Hillner et al. adopted a US perspective, where costs, in particular for bisphosphonates, were assumed to be significantly higher than in the UK.
In contrast, our analysis found some important differences with previous analyses comparing the relative cost effectiveness of various bisphosphonates. For instance, De Cock et al. [16] compared the cost effectiveness of OI versus ZA and PA in breast cancer patients with metastatic bone disease undergoing i.v. chemotherapy. This analysis concluded that OI was less expensive and more effective than the intravenous comparators. De Cock et al. [16] relied on the skeletal morbidity period rate (SMPR), which was available only for OI. In addition, because previous trials compared ZA to PA, no efficacy data of ZA versus placebo were available at the time of the analysis of De Cock et al. Thus, these authors assumed that both ZA and OI would be equally effective in preventing SRE compared to placebo. In addition, De Cock et al. assumed that neither ZA nor PA would be associated with reduction in bone pain, whereas only patients receiving OI would experience such benefits. Finally, De Cock et al. [16] further assumed that ‘after 6 months of bisphosphonates, 25% of patients would decline further i.v. treatment because of the inconvenience of monthly hospital visits’ whereas only 3.2% receiving OI would discontinue therapy over a 2-year period. (No references were provided, beside ‘expert opinion’, to support the 25% discontinuation rate associated with i.v. therapy.)
Our analysis found that ZA and PA were both more cost effective than OI, in part because we based our analysis on the recent placebo-controlled trial [18] that showed that ZA was highly effective compared with placebo in preventing SREs. In this trial, the hazard ratio of SRE using the Andersen-Gill multiple event analysis was 0.56, which is better than the hazard ratio reported for OI (0.62). This new trial, as well as other recently published studies have shown that ZA (and PA) are associated with significant improvements in both pain and quality-of-life scores [3, 18, 19]. With regards to the compliance issue, although an intense debate has recently emerged regarding the level of compliance with intravenous and oral bisphosphonates in this setting [38, 39, 45–48], it is difficult to imagine that 25% of patients receiving i.v. bisphosphonates would simply discontinue therapy due to the inconvenience of monthly hospital visits. Likewise, it is unlikely that the two-year rate of discontinuation of OI due to AE outside of the clinical trial environment would be 3.2% only, especially given the evidence related to the very low compliance rates reported with all other oral bisphophonates in the cancer setting [39]. In our analysis, we adopted the perspective that oral therapies, and in particular oral clodronate, are less likely to be equally adhered to than i.v. therapies, primarily based on the observation that compliance with oral bisphosphonates is poor, even among patients with metastatic disease. Specifically, we assumed that the monthly probability of discontinuation for i.v. therapy would be 0.008 versus 0.009 (thus almost identical) but significantly better than for OC (0.201). However, in univariate sensitivity analyses, we found that adopting significantly better compliance rates for oral therapies (including notably better compliance with OI compared to i.v. therapy) did not change the main conclusions, in part because half of the patients stopping therapy are assumed to embark on a second line therapy, thus blunting the effect of discontinuing a primary therapy.
A third analysis [17] reports a head-to-head comparison of PA and i.v. ZA adopting a cost minimization perspective to assess the one-year budgetary impact of the two agents. This analysis reports that PA is economically superior to ZA because of its lower acquisition price and comparable efficacy. However, this conclusion is based on the 1-year results [28] of a 2-year trial [10]. The selection of the 1-year results is debatable since at 1 year, no statistically significant differences between the agents were reported [28] whereas at 2 years a 20% significant difference in the risk of events favoring ZA has been reported [10]. Since the median survival for metastatic breast cancer is typically about 18–23 months, as assumed in our analysis, it is not clear why, even within the context of a budget impact analysis, one should limit the analysis to just 1 year. In addition, this analysis assumed that the acquisition costs for PA would be £80, which is about 50% lower than the BNF listed price (and the value used in other economic analyses, including ours). However, this lower price was not supported by a reference. Had Guest et al. [17] referred to the 2-year results and used the more commonly used BNF prices, the results would have been more favorable to ZA, consistent with our analysis.
Key drivers of the cost effectiveness included the frequency of SREs, the costs managing SREs, assumptions about the magnitude of the quality of life impacts of bisphosphonate therapies, and the effectiveness of therapy in preventing SREs. Our model assumed that the SMR in untreated patients was 3.05. This assumption is more conservative than in other analyses [15, 23] but is consistent with the rate observed in large clinical trials of bisphosphonates.
The cost of managing an SRE was assumed to be £3054 (which included £2016 for the cost of hospitalization and £1038 for outpatient care associated with the treatment of long-bone fractures). The cost of inpatient care is similar to the cost used in other studies, notably Ross et al. [15], on which we based our estimate, De Cock et al. [16] or Groot et al. [6, 7]. Although Ross et al. [15] estimated that the cost of outpatient care for long-bone fractures could range from £1300 per fracture (lower cost estimate for one month) to £47 300 per fracture (higher cost estimate for 12 months), they decided to include these costs only in their sensitivity analysis, due to the uncertainty associated with the actual estimate. Our own sensitivity analysis on the cost of SRE had an important impact on the cost effectiveness but did not change the ranking of therapies based on a comparison of their NMB (assuming a willingness to pay for a QALY of £30 000).
Other important somewhat uncertain variables are the utilities associated with the various health states. In the present model, empirically-driven estimates of utilities for bisphosphonate therapy and SRE for patients with advanced breast cancer were taken from Dranitsaris and Hsu [36]. However, sensitivity analyses also indicate that the results of the model are heavily dependent on assumptions regarding utilities. To the best of our knowledge, no other estimates of utilities have been reported for these health states. De Cock et al. [16] made a series of assumptions based on a mix of literature estimates and expert opinion. Specifically, these authors have assumed that time spent without SRE was associated with a utility of 0.42 (on OI therapy) and 0.40 (on ZA or PA). They also assumed that these utilities were reduced by 30% in presence of an SRE. Similarly, Hillner et al. [23] also used expert opinion in a cost utility analysis of PA versus no therapy. If the assumptions of Hillner et al. had been used in the present model, the cost effectiveness of bisphosphonate agents would have remained favorable and their relative ranking in terms of cost effectiveness would not have changed. Thus, although uncertainty exists with regards to the set of utilities assumptions one should rely upon, existing evidence and expert opinion in previous economic analyses both seem to lead to similar conclusions in our analysis.
Finally, the efficacy assumptions used in the model are probably the most critical element of this analysis. It is undeniably difficult to draw firm conclusions regarding the relative efficacy of various bisphosphonates given that little direct head-to-head comparative data are available, except for one large trial directly comparing PA and ZA [10]. Thus the various bisphosphonates can only be compared indirectly, with all the inherent and important limitations this approach carries. This being said, it is unlikely that no differences between these agents exist. In fact, in at least one study, the Rosen et al. [10] trial, ZA has been demonstrated via the Andersen–Gill method to be superior to PA. Additionally, PA and ZA are the only two bisphosphonates to have produced statistically significant clinical benefit across multiple end points, especially the more conservative first-event analyses [2]. For instance, ZA significantly reduced the rate, incidence and risk of SREs by approximately 40% compared with placebo. In contrast, pamidronate reduced the number of patients experiencing 1 SRE by approximately 22% compared with placebo, and oral or i.v. ibandronate reduced the percentage of patients with a new bone event by only 13% and 18% (neither significantly), respectively [2]. In addition, differences appear to exist between bisphosphonates in terms of their ability to decrease the risk of the individual components of the composite SRE measure, at least in terms of statistical significance in the studies reported until now. For instance, IBN does not appear to significantly reduce the risk of non-vertebral fractures or events requiring surgery [25]; OI does not significantly reduce vertebral and non vertebral fractures [35]; and OC does not significantly reduce non-vertebral fractures or the need for radiotherapy [26]. In contrast, in one study ZA has been shown to consistently reduce the incidence of all types of complications [18]. Finally, in contrast to other bisphosphonates, OI has not statistically delayed the median time to the first SRE [35].
Thus although there is uncertainty regarding the relative efficacy of bisphosphonates, it seems clear that differences must exist. Rather than ignoring them, they should be included as fully as possible to provide the most comprehensive assessment of the relative value of different bisphosphonates, until a direct comparison identifies the real importance of any of the discussed differences.
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Our economic analysis suggests that bisphosphonate therapies are highly cost effective for the prevention of SREs in breast cancer patients. Within the limits of this evaluation, ZA consistently appears to be most cost effective, being the least expensive and most effective intervention, when compared, mostly indirectly, to no therapy and the other bisphosphonates. Our model therefore suggests that treating breast cancer patients with bone metastases with ZA should lead to improved patient outcomes and cost savings.
Received for publication January 21, 2006. Revision received March 26, 2006. Accepted for publication March 27, 2006.
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