Download Economic Evaluation of Anastrozole Versus Tamoxifen for Early

VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
Available online at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/vhri
Economic Evaluation of Anastrozole Versus Tamoxifen for Early Stage
Breast Cancer in Singapore
Vivianne Shih, PharmD, BCOP, BCPS1, Alexandre Chan, PharmD, MPH, BCPS, BCOP1,2, Feng Xie, PhD3,4, Yu Ko, PhD2,*
1
Department of Pharmacy, National Cancer Centre Singapore, Singapore; 2Department of Pharmacy, Faculty of Science, National University of Singapore,
Singapore; 3Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada; 4Programs for Assessment of Technology in
Health Research Institute, Hamilton, ON, Canada
A B S T R A C T
Objectives: In Singapore, breast cancer is the leading female malignancy and its incidence has increased threefold over the past decades.
For treatment of postmenopausal, hormone receptor positive early
stage breast cancer, tamoxifen or aromatase inhibitors such as anastrozole are prescribed either as first-line therapy or sequentially. Currently, anastrozole is patented with a higher drug cost compared with
tamoxifen. Hence, the aim of this study was to conduct an economic
evaluation of anastrozole versus tamoxifen in early stage breast
cancer. Methods: A Markov model with a lifetime horizon was developed by using results from the Arimidex, Tamoxifen, Alone or in Combination trial. Direct medical costs were estimated by billing data obtained via financial electronic databases. Utility scores were elicited
from 20 experienced oncology nurses using the visual analogue scale.
Cost per quality-adjusted life-years was calculated by using the societal perspective. A discount rate of 3% for both charges (expressed in
2010 Singapore dollars) and benefits was used. Results: At an addi-
Introduction
In Singapore, there are more than 6000 newly diagnosed cancer
cases annually [1]. Breast cancer is the leading female malignancy
and constitutes approximately 30% of all female cancers [2]. Although there has been a threefold increase in breast cancer incidence between 1968 and 2002 [3], the mortality of breast cancer
patients has decreased over the years. The 5-year age standardized relative survival was 46.1% from 1973 to 1977 compared with
76.1% from 1998 to 2002 [4], which has translated to an increasingly high cost of illness for breast cancer that amounts to billions of dollars each year [5–7]. An estimated lifetime per-patient cost of breast cancer was reported to be between US
$20,000 and US $100,000 [8]. The treatment cost of cancer has
been escalating and will continue to increase, especially with
the discovery of new targeted drugs that would have a significant impact on health care resources [9,10]. Because health care
resources are often limited, it would be prudent to choose the
most cost-effective treatment for patients to ensure that resources are efficiently allocated [11].
tional cost of S $17,597, anastrozole treatment resulted in a gain of
0.085 life-year survival and 0.154 quality-adjusted life-year. The incremental cost-effectiveness ratio of anastrozole was S $207,402 per lifeyear gained and S $114,061 per quality-adjusted life-year gained compared with tamoxifen. Conclusion: This is the first economic
evaluation that used 10-year results from the Arimidex, Tamoxifen,
Alone or in Combination trial and utility elicited from the local population. If the World Health Organization’s recommendation of 1 to 3
gross domestic product range is an acceptable threshold, anastrozole is
deemed cost-effective compared with tamoxifen in the treatment of
early stage breast cancer.
Keywords: anastrozole, breast cancer, cost-effectiveness analysis, costutility analysis, tamoxifen.
Copyright © 2012, International Society for Pharmacoeconomics and
Outcomes Research (ISPOR). Published by Elsevier Inc.
Endocrine therapy is one of the main treatment modalities
for breast cancer and approximately two-third of all breast cancer patients are required to receive treatment with endocrine
therapy [12]. Tamoxifen has been advocated as the gold standard of endocrine treatment over the past few decades and has
been shown to improve both disease-free survival (DFS) and
overall survival [13,14]. One of the major drawbacks, however, is
its unfavorable side-effect profile such as vaginal bleeding
and/or discharge, endometrial cancer, and thromboembolic
events.
The third-generation aromatase inhibitors (AIs), such as anastrozole, are an attractive alternative treatment option among
postmenopausal patients. Currently, there is no consensus regarding the duration of therapy with AIs or the optimal sequence
for administration. Nevertheless, numerous clinical practice
guidelines from the American Society of Clinical Oncology, National Comprehensive Cancer Network, and St. Gallen International Expert Consensus on the primary treatment of breast cancer have advocated the use of AIs as part of adjuvant treatment for
postmenopausal hormone receptor (HR)-positive early stage
breast cancer patients [15–17]. AIs can be prescribed as front-line
Conflicts of interest: The authors have indicated that they have no conflicts of interest with regard to the content of this article.
* Address correspondence to: Yu Ko, Department of Pharmacy, Faculty of Science, National University of Singapore, Block S4, 18 Science
Drive 4, Singapore 117543.
E-mail: [email protected].
2212-1099/$36.00 – see front matter Copyright © 2012, International Society for Pharmacoeconomics and Outcomes Research (ISPOR).
Published by Elsevier Inc.
doi:10.1016/j.vhri.2012.03.013
VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
therapy, sequential with tamoxifen, or as extended therapy after 5
years of treatment with tamoxifen.
A large randomized controlled trial, the Arimidex, Tamoxifen,
Alone or in Combination (ATAC) [18 –21], has demonstrated both
the efficacy and tolerability of anastrozole as the first-line endocrine therapy for postmenopausal HR-positive breast cancer patients. Anastrozole has been shown to significantly prolong DFS
and reduce the rates of breast cancer recurrences. This trial led to
the approval of anastrozole by the US Food and Drug Administration for adjuvant treatment of HR-positive early stage breast cancer. Anastrozole has a different side-effect profile compared with
tamoxifen and can cause musculoskeletal side effects such as myalgia, arthralgia, and bone loss that can adversely affect the healthrelated quality of life (HRQOL) of patients [22]. Currently, anastrozole
is still patented, and its drug acquisition cost is estimated to be approximately 25 times higher than that of tamoxifen (National Cancer
Centre, personal communication, June 2010). The high drug cost
would greatly increase the cost of adjuvant therapy, because most
patients require 5 years of anastrozole treatment.
Although multiple studies have investigated the cost-effectiveness of various AIs compared with that of tamoxifen [23–29] in
Belgium, Brazil, Canada, Germany, the United Kingdom, and the
United States and reported that anastrozole is cost-effective compared with tamoxifen, none have been conducted in Singapore. It
is essential to perform an economic evaluation of endocrine therapy in breast cancer patients in Singapore because health care
systems and utility scores of patients could differ among countries, and therefore it may not be appropriate to extrapolate previous published study results to our local population. Hence, the
objective of this study was to conduct an economic evaluation of
anastrozole, the first AI approved for adjuvant treatment of postmenopausal women with HR-positive early stage breast cancer, in
comparison with tamoxifen by using the ATAC trial as the main
source of effectiveness data. Anastrozole was chosen because the
ATAC trial is the largest adjuvant trial with the longest follow-up
data to date. The results of this study are valuable because they
can assist in health care resource allocation and aid physicians’
decision making during prescribing.
Methods
In the ATAC trial, postmenopausal patients with invasive operable
breast cancer were randomized to anastrozole, tamoxifen, or a
combination of both for up to 5 years on completion of primary
therapy (surgery ⫾ radiotherapy ⫾ chemotherapy). The combination arm failed to show any benefit in terms of efficacy or sideeffects tolerability over tamoxifen alone. The primary end points
of the study were DFS and occurrence of adverse effects. After a
median of 10 years, anastrozole was demonstrated to improve
DFS, time to recurrence, and time to distant recurrence when compared with tamoxifen.
A Markov model was constructed by using TreeAge Pro 2009
(release 1.0.2) (TreeAge Software, Inc, MA) based on ATAC trial
data. A hypothetical cohort of 1000 postmenopausal women
(mean age of 64 years) with HR-positive early stage breast cancer
who had completed primary therapy and who were eligible for
adjuvant endocrine therapy was used in the model. The patients
were followed for a lifetime horizon.
A societal perspective was taken but only direct medical costs
were included in the analysis. Indirect costs were not included in
this study because the mean age of the patients was 64 years and
hence most were not likely to be working. Costs were expressed in
2010 Singapore dollars. Costs and benefits were both discounted at
3% per year.
47
Model structure
The structure of the Markov model is shown in Figure 1. A total of
five mutually exclusive health states were defined as no recurrence (NR), locoregional recurrence (LR), distant recurrence (DR),
death from breast cancer, and death from other causes [24]. Each
cycle represented 1 year. All patients were assumed to enter the
model under the “no recurrence” health state. At the end of each
cycle, a patient could either remain at the same health state or
move to a different health state on the basis of ATAC trial results.
However, patients at absorbing health states (i.e., death from
breast cancer or other causes) were not allowed to move to other
health states. In addition, patients could only be in one of the five
defined health states at a time and these patients were not allowed to switch between treatment arms.
Model inputs
Data inputs were obtained from the 10-year analysis of the ATAC
trial [18], interviews with oncology nurses, local financial electronic databases, and published literature.
Recurrence rates for breast cancer were obtained from the
ATAC trial and published literature [18,24]. Using these recurrence
rates, the respective probabilities of general, local, and distant recurrences were calculated (Table 1). Percentages of patients who
experienced adverse events (AEs) were obtained from the ATAC
trial [20]. The risk of AEs was assumed to be constant over the 5
years of treatment. Mortality rates due to breast cancer after recurrence were assumed to be similar and constant for both anastrozole and tamoxifen [25]. The age-dependent mortality rates for
all causes of the general female population were obtained from the
Department of Statistics, Singapore (Table 1) [30].
Resource utilization and costs
The National Cancer Centre (NCCS) is the largest ambulatory cancer center in Singapore that treats approximately 70% of all cancer
patients. A retrospective cohort of postmenopausal, HR-positive
early stage breast cancer patients treated at the NCCS with either
anastrozole or tamoxifen adjuvant therapy from January 2001
through December 2009 was reviewed. Patients’ medical records
(both electronic and hard copy) as well as medication dispensing
records from the pharmacy department were accessed. These patients were then allocated into the three respective different
health states (NR, LR, and DR).
Direct medical costs were estimated from billing data obtained
via financial electronic databases of the NCCS and the Singapore
General Hospital. These medical costs included physicians’ consultation fees, costs of scans, laboratory, and procedures, drug
costs, treatment costs for AEs, and hospitalization (Table 2). In this
study, costs for the NR state for both anastrozole and tamoxifen
included only major costly AEs such as endometrial cancer, spine
fracture, ischemic cardiovascular events, and venous thromoboembolism. The cost data were obtained via International Classification of Diseases, Ninth Revision, Clinical Modification, codes from the
Singapore General Hospital. All costs were inflated to 2010 costs by
the Singapore consumer price index (health care component)
based on first and second quarter values [31].
Utility measurement
There are various methods to obtain utility values, namely, direct
measurement, published literature, or expert opinion. Although
there is no preferred method, direct measurement can overcome
potential bias from the other two methods due to imprecise estimates and bias from the selection of literature to be used. A targeted literature review was conducted to identify the adverse-effect profiles of endocrine therapies and their impact on various
health-related quality-of-life aspects. A total of 20 hypothetical
health states and their descriptions were developed and under-
48
VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
Fig. 1 – Simplified structure of the Markov model.
went content validation by an expert panel, which consisted of
three breast cancer oncologists and four oncology nurses who had
at least 2 years of experience in oncology. The health state descriptions were reviewed and modified to ensure their accuracy with
regard to symptoms and patients’ feelings, and the level of detriment in each health-related quality-of-life aspect was included.
Health state utilities were elicited through an interview of 20
NCCS oncology nurses with a minimum 2 years of experience in
oncology and were conducted by a trained research assistant.
Health state utility scores were obtained by using the visual analogue scale (VAS). In the VAS, if “dead” was placed at the 0 of the
scale, the utility score for each of the other health states was the
scale value of its placement. However, if being dead was considered better than the worst health state and placed at some point
between 0 (the worst health state) and 1 (perfect health), scale
recalibration was then conducted. The adjusted score was equal to
VASadj ⫽ (raw score ⫺ score_dead) ⁄ (1 ⫺ score_dead)
where score_dead is the scale placement of the “dead” state.
Hence, after recalibration, the adjusted utility scores were on a
scale of 0 (dead) and 1 (perfect health). For each health state, the
mean adjusted VAS utility scores and percentages of patients are
presented in Table 3.
Data analyses
Cost-effectiveness analyses (CEAs) and cost-utility analyses
(CUAs) were conducted by using the Markov model built. Both the
incremental cost-effectiveness ratio and the incremental costutility ratio (ICUR) were calculated and expressed as cost per lifeyear survival and cost per quality-adjusted life-year (QALY)
gained, respectively. To examine the robustness of study results,
multiple one-way sensitivity analyses were performed.
Assumptions made in this study for the construction of the
Markov model are summarized in the Appendix in Supplemental
Materials found at http://dx.doi.org/10.1016/j.vhri.2012.03.013.
Multiple one-way deterministic sensitivity analyses were conducted on key parameters, including the recurrence rates between
anastrozole and tamoxifen, AE rates, treatment costs, utility
scores, and discount rates. For general recurrence rates, ⫾50%
variation in the difference between anastrozole and tamoxifen
was used, whereas ⫾15% and ⫾20% variation from base values for
LR and DR was used, respectively. Rates of AEs were varied ⫾15%
from base values. For NR costs, ⫾50% variation from the base values was used, whereas for LR and DR costs, 5th and 95th percentiles from the median were utilized. Utility scores were varied by
using ⫾10% variation from base values. Discount rates were varied
from 0% to 8%.
49
VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
Table 1 – Probabilities of recurrence rates and age-dependent mortality rates for all causes of the female population.
Recurrence rates
General recurrence [18]
Anastrozole
Tamoxifen
Local recurrence [24]
Anastrozole/tamoxifen
Distant recurrence [18]
Anastrozole
Tamoxifen
Year
Base value
Low value
High value
1–10
11–35
1–10
11–35
0.0195
0.0216
0.0237
0.0216
0.0174
0.0150
—
—
0.0216
0.0193
—
—
1–35
0.1758
—
—
1–10
11–35
1–35
0.660
0.600
0.600
0.460
0.400
0.400
0.860
0.800
0.800
Age-dependent mortality
All-cause mortality [30]
Age group (y)
60–64
65–69
70–74
75–79
80–84
85 and above
0.0050
0.0097
0.0157
0.0296
0.0473
0.1066
Results
Cost-effectiveness and cost-utility analyses
Both the CEA and CUA results are presented in Table 4. For the
base-case analysis, the mean cost per patient was higher for anastrozole (S $36,499) versus tamoxifen (S $19,402). Anastrozole, how-
ever, had a slightly longer overall mean survival compared with
that of tamoxifen (12.96 years vs. 12.87 years, respectively). As for
mean QALYs, it was reported to be 8.26 per patient for anastrozole
and 8.10 per patient for tamoxifen.
Hence, anastrozole resulted in a gain of 0.085 life-year survival
and 0.154 QALYs at an additional charge of S $17,597. The incre-
Table 2 – Estimated costs for medical management and adverse events used in the model*.
Median/mean costs
(S $ per year)
No recurrence
Drug cost
Anastrozole
Tamoxifen
Consultation
Anastrozole
Years 1–5
Years 6–10
Tamoxifen
Years 1–5
Years 6–10
Laboratory
Anastrozole
Years 1–5
Tamoxifen
Years 1–5
Scan
Anastrozole/tamoxifen
Bisphosphonates
Year 1–5
Calcium
Locoregional recurrence
Distant recurrence
Adverse events
Endometrial cancer
Ischemic cerebrovascular event
Spine fracture
Venous thromboembolic event
SD
Low values/5th
percentile
High values/95th
percentile
9.75 per 1 mg tablet
0.4 per 10 mg tablet
205.08
51.27
139.54
65.54
0
344.62
190.81
257.05
51.41
187.88
69.17
0
444.93
239.29
30.4
12.48
300.19
126.21
39.76
318.64
203.05
83.53
1,381.72
766.97
28.8
4,172.71
16,773.59
132.35
0
3,388.69
4,097.23
1,248.25
52.58
33,616.02
68,754.26
7,729.57
1,779.83
7,499.23
3,322.63
1,033.57
899.92
3,749.62
871.68
21,408.83
2,669.75
11,248.85
12,606.41
Reference: International Classification of Diseases, Ninth Revision, Clinical Modification, codes from Singapore General Hospital (adverse events) and
electronic databases from National Cancer Centre Singapore, Singapore (all other charges).
* Charges expressed as 2010 Singapore dollars.
50
VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
Table 3 – Percentages of patients and mean adjusted VAS utility scores for various health descriptions/states used in
the model.
Health states
Mean adjusted VAS
utility scores
SD
0.860
0.482
0.475
0.372
0.704
0.554
0.329
0.519
0.256
0.629
0.730
0.472
0.12
0.17
0.20
0.21
0.21
0.21
0.20
0.18
0.19
0.18
0.18
0.23
0.468
0.491
0.473
0.18
0.23
0.28
1.00
3.60
95.40
0.400
0.365
0.370
0.25
0.26
0.28
3.60
48.20
48.20
No recurrence
No side effect
Hip fracture
Wrist fracture
Spine fracture
Vaginal bleeding
Deep vein thrombosis
Pulmonary embolism
Cataract
Ischemic cerebrovascular events
Musculoskeletal disorder
Hot flushes
Endometrial cancer
Locoregional recurrence
New contralateral breast cancer
No side effects
General side effects
Distant recurrence
No side effects
Side effects from chemotherapy
Side effects from hormonal therapy
Percentages of patients (%) [20]
Anastrozole
Tamoxifen
6.60
1.20
2.30
1.50
5.40
1.6
1.20
5.90
2.00
35.60
35.70
0.20
0.60
1.00
2.00
0.90
10.20
2.40
2.10
6.90
2.80
29.40
40.90
0.80
VAS, visual analogue scale.
mental cost-effectiveness ratio of anastrozole was S $207,402 per
life-year gained and S $114,061 per QALY gained.
Sensitivity analyses
Results of multiple one-way sensitivity analyses were represented
by a tornado diagram (Fig. 2 ). There was a 4 times difference in the
ICUR for the general recurrence rates for anastrozole and costs of
NR anastrozole when one-way sensitivity analyses were conducted. Hence, ICURs were sensitive to these two parameters. The
most important inputs for the model were identified to be the
recurrence rates followed by the costs for the NR state (anastrozole) and the percentages of patients with spine fracture and endometrial cancer. A summary of multiple one-way analyses conducted is shown in Table 5. In contrast, there were hardly any
differences in the ICUR for percentages of LR or DR patients with
no AE, discount rates, or utilities values.
Discussion
Our study findings were similar to those of other published CEA
and CUA studies that compared anastrozole to tamoxifen as firstline therapy [23–29]. Majority of the studies utilized ATAC trial
efficacy data at 5 years and utility data obtained from published
literature. Regardless of the perspectives chosen and countries
where studies were conducted, all of them demonstrated that
anastrozole was more cost-effective than tamoxifen, with ICURs
ranging from approximately S $7118 to S $96,752.
One-way sensitivity analysis would allow a single variable to
vary over a range of possible values based on assumptions made
and to determine the robustness of study results. Based on the
multiple one-way sensitivity analyses conducted, results were consistent with other published studies in which ICURs were largely
dependent on recurrence rates whereas utilities and AE rates did not
impact study results [24,26,27,29]. As demonstrated by Lux et al. [29],
the single most important model input was the hazard ratio for time
Table 4 – Cost-effectiveness and cost-utility analyses*.
Tamoxifen
Anastrozole
Tamoxifen
Anastrozole
Cost (C)
(S $)
Incremental
cost
Effectiveness
(E) (LYG)
Incremental
effectiveness
19,402
36,999
17,597
12.873
12.958
0.085
Cost (C)
(S $)
Incremental
cost (S $)
Effectiveness
(E) (QALY)
Incremental
effectiveness
19,402
36,999
17,597
8.101
8.255
0.154
ICER, incremental cost-effectiveness ratio; LYG, life-years gained; QALY, quality-adjusted life-years.
* Charges expressed in 2010 Singapore dollars.
C/E
ICER
1507
2855
207,402
C/E
ICER
2395
4482
114,061
51
VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
Fig. 2 – Tornado diagram for incremental cost/QALY comparing anastrozole with tamoxifen.
to recurrence. Similarly, in this study, the top three crucial model
inputs were all related to recurrence rates such as general recurrence
rates, rate of DR for tamoxifen, and rate of LR to DR.
This study has a few strengths. First, most studies used the
5-year completed analysis data from the ATAC trial except for one
study [29] that used 100-month analysis data. However, our study
used the most updated 10-year analysis results from the ATAC
trial. With the availability of 10-year analysis results, previous
studies’ assumption of a carryover effect over the next 5 years
after adjuvant treatment was not necessary. In addition, compared with other studies, our study model was strengthened by
utilizing retrospective data from local patient population to estimate resource consumptions instead of relying on expert opinion
or using published literature as data inputs.
Another unique feature of our study model was its input for
utility values. A majority of studies used utility values obtained
Table 5 – Summary of multiple one-way sensitivity analyses results*.
Sensitivity analysis
Base case
Discount rate
0%
4%
8%
Costs for NR anastrozole
50% decrease
50% increase
Costs for NR tamoxifen
50% decrease
50% increase
General recurrence rates for anastrozole
50% decrease in difference
50% increase in difference
LR to DR rate
15% decrease
15% increase
DR rate for anastrozole
20% decrease
20% increase
DR rate for tamoxifen
20% decrease
20% increase
% DR patients, no AE
15% decrease
15% increase
% LR patients, no AE
15% decrease
15% increase
Incremental
costs (S $)
Incremental
QALYs
Incremental cost-utility ratio
(S $ per QALY)
18,000
0.154
114,061
18,841.22
17,208.72
15,779.37
0.22
0.14
0.1
86,242
123,954
165,332
20,774.30
81,386.27
0.15
0.15
134,653
527,522
19,654.70
6,097.58
0.15
0.15
127,396
39,523
16,389.86
17,747.42
0.32
0.08
51,552
216,652
17,556.67
17,639.60
0.12
0.17
145,824
106,635
17,806.06
17,388.61
0.24
0.07
75,491
239,210
17,361.23
17,833.45
0.07
0.24
258,038
73,912
17,597.34
17,597.34
0.15
0.15
113,800
115,160
17,597.34
17,597.34
0.16
0.15
113,178
117,893
AE, adverse event; DR, distant recurrence; LR, local recurrence; NR, no recurrence; QALY, quality-adjusted life-years.
* $ expressed in 2010 Singapore dollars.
52
VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
from the literature. In particular, a couple of studies [26,29,32]
cited the study by Sorensen et al. [33] that had been published only
in an abstract form. Because utility values differ among various
countries, it would be an added advantage to use utility values
elicited from the local population. In this study, preferences of
health care professionals were utilized. They can be viewed as an
“intermediate” population acting as proxy for patients. To date,
there is no agreement with regard to the population that should be
approached for the measurement of utility values [34,35]. Using
patients and the general population as the source of utility estimates both have their own set of limitations; for example, “ceiling
effect” and “floor effect” may occur, respectively [36]. Instead,
more importantly, preferences should be chosen on the basis of
the perspective of the study.
To the best of our knowledge, this is the first economic evaluation to address the role of anastrozole over tamoxifen in the
treatment of postmenopausal early stage breast cancer patients in
Asia. Currently, in Singapore, the Pharmacoeconomics and Drug
Utilization Unit, established in 2001, conducts ongoing reviews
and revisions to the standard drug list. The standard drug list
contains essential drugs that have to be available at affordable
prices at public health care institutions. Both CEA and CUA studies
are beneficial in assisting decision making with regard to reimbursement issues and the prescribing of medications.
Adjuvant endocrine therapy comprises tamoxifen and AIs. Although AIs have been shown to have better DFS and overall survival and possess a different side-effect profile compared with
tamoxifen, their drug acquisition costs are much higher. By conducting CEA or CUA studies, long-term effects such as AEs and the
effectiveness of drug therapy can be predicted and this would help
with physicians’ decision making and resource allocation.
To date, there is no fixed acceptable cost-effectiveness threshold that has been defined in Singapore and no consensus among
different countries. An acceptable reimbursement range in the
United States has been reported to be US $50,000 to US $100,000
per QALY gained [37,38]. In the United Kingdom, according to the
National Institute for Health and Clinical Excellence, a conventional threshold is €20,000 to €30,000 per QALY [39]. The World
Health Organization has proposed to use a country’s per-capita
gross domestic product (GDP) to establish thresholds. If the value
is worked out to be equal or less than 3 times the GDP, then the
drug therapy in question would be considered as cost-effective
[40]. Using this as a reference, Singapore’s 2010 per-capita GDP was
reported at S $59,813 from the Department of Statistics [41]; therefore, an acceptable threshold would be S $179,439. In this study,
the ICUR was reported to be S $114,061 per QALY gained. As such,
anastrozole may be considered cost-effective.
There are several limitations in this study. First, cost data were
obtained from a retrospective cohort of patients and estimation
had to be made on long-term cost data (e.g., 10 years) for patients
on anastrozole because data were not available. In addition, costs
for major AEs that often required hospitalization were taken from
only one institution, which may not be representative of other
hospitals. Another potential limitation was that utility values used
were obtained from the VAS method that has generally been considered to be less preferred compared with standard gamble and
time trade-off methods [42]. In several similar studies, standard
gamble was used [26,27,29] whereas the others did not indicate
explicitly. There seems to be evidence that utility obtained via VAS
may not necessarily be inferior compared with that obtained via
standard gamble [43] but further research is needed to ascertain
that. Moreover, because the utility scores were obtained from a
small group of nurses, great variation in the utility scores was
observed and the study results may be sensitive to utility scores
used. With pharmacoeconomic models, assumptions are necessary because it is not feasible to include all possible event occurrences and to have all data inputs available. Although multiple
one-way sensitivity analyses for key parameters of the models
were conducted, there could be an underestimation of uncertainty
because they are not able to capture potential interaction among
the various parameters. Besides, selection bias may occur because
of the lack of consensus regarding which variables and range of
values to be adjusted.
Pharmacoeconomic modeling would be useful in an era
whereby there are escalating costs coupled with limited resources.
Economic analyses have numerous potential applications in policy decision making [44] such as reimbursement issues, negotiation of drug prices [45], and development of clinical practice guidelines. It is also important to present all information available
clearly that would subsequently allow policymaking to be transparent. Future research may include comparison of sequential tamoxifen with anastrozole or with other AIs and comparison between two AI therapies such as letrozole and anastrozole in
adjuvant treatment of breast cancer. Economic evaluation of such
studies would definitely be an added piece of useful information
for drug prescribing because clinical data have not been able to
determine the optimal duration of AI and sequence.
Conclusion
If the World Health Organization’s recommendation of 1 to 3 GDP
range is an acceptable threshold, our study results suggest that
although anastrozole has a higher drug acquisition cost, its use
over tamoxifen in the treatment of postmenopausal early stage
breast cancer can be justified in Singapore based on both effectiveness and utility data.
Acknowledgments
We thank all the breast oncologists and oncology nurses from the
NCCS as well as staff from SGH Finance department who have
helped to make this project possible.
Source of financial support: This study was sponsored by Dr.
Ko’s start-up research grant provided by the National University of
Singapore.
Supplemental Materials
Supplemental material accompanying this article can be found in the
online version as a hyperlink at http://dx.doi.org/10.1016/j.vhri.
2012.03.013 or, if a hard copy of article, at www.valueinhealthjournal.
com/issues (select volume, issue, and article).
REFERENCES
[1] Wong CS, Chow KY, Lim GH, et al. Cancer Survival in Singapore 1968 –
2002. Singapore Cancer Registry, National Registry of Diseases Office,
2008.
[2] Singapore Cancer Registry Interim Report. Trends in Cancer Incidence
in Singapore 2003–2007. National Registry of Diseases Office, 2009.
[3] Sim X, Ali RA, Wedren S, et al. Ethnic differences in the time trend of
female breast cancer incidence: Singapore, 1968 –2002. BMC Cancer
2006;6:261.
[4] Lim GH, Wong CS, Chow KY, et al. Trends in long-term cancer survival
in Singapore: 1968 –2002. Ann Acad Med Singapore 2009;38:99 –105.
[5] Dahlberg L, Lundkvist J, Lindman H. Health care costs for treatment of
disseminated breast cancer. Eur J Cancer 2009;45:1987–91.
[6] Max W, Sung HY, Stark B. The economic burden of breast cancer in
California. Breast Cancer Res Treat 2009;116:201–7.
[7] Broekx S, Den Hond E, Torfs R, et al. The costs of breast cancer prior to
and following diagnosis. Eur J Health Econ 2011;12:311–7.
VALUE IN HEALTH REGIONAL ISSUES 1 (2012) 46 –53
[8] Campbell JD, Ramsey SD. The costs of treating breast cancer in the US:
a synthesis of published evidence. Pharmacoeconomics 2009;27:199 –
209.
[9] Savage P. Development and economic trends in cancer therapeutic drugs
in the the UK from 1955 to 2009. J Oncol Pharm Pract 2012;18:52– 6.
[10] Soria JC, Blay JY, Spano JP, et al. Added value of molecular targeted
agents in oncology. Ann Oncol 2011;22:1703–16.
[11] Meropol NJ, Schulman KA. Cost of cancer care: issues and
implications. J Clin Oncol 2007;25:180 – 6.
[12] Nadji M, Gomez-Fernandez C, Ganjei-Azar P, et al.
Immunohistochemistry of estrogen and progesterone receptors
reconsidered: experience with 5,993 breast cancers. Am J Clin Pathol
2005;123:21–7.
[13] Tamoxifen for early breast cancer: an overview of the randomised
trials. Early Breast Cancer Trialists’Collaborative Group. Lancet 1998;
351:1451– 67.
[14] Effects of chemotherapy and hormonal therapy for early breast cancer
on recurrence and 15-year survival: an overview of the randomised
trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 2005;
365:1687–717.
[15] Burstein HJ, Prestrud AA, Seidenfeld J, et al. American Society of
Clinical Oncology clinical practice guideline: update on adjuvant
endocrine therapy for women with hormone receptor-positive breast
cancer. J Clin Oncol 2010;28:3784 –96.
[16] National Comprehensive Cancer Network Clinical Practice Guidelines
in Oncology. Breast Cancer 2011;2. Available from: http://www.
nccn.org/professionals/physician_gls/pdf/breast.pdf. [Accessed May
13, 2010].
[17] Carlson RW, Hudis CA, Pritchard KI. Adjuvant endocrine therapy in
hormone receptor-positive postmenopausal breast cancer: evolution
of NCCN, ASCO, and St Gallen recommendations. J Natl Compr Canc
Netw 2006;4:971–9.
[18] Cuzick J, Sestak I, Baum M, et al. Effect of anastrozole and tamoxifen
as adjuvant treatment for early-stage breast cancer: 10-year analysis
of the ATAC trial. Lancet Oncol 2010;11:1135– 41.
[19] Forbes JF, Cuzick J, Buzdar A, et al. Effect of anastrozole and tamoxifen
as adjuvant treatment for early-stage breast cancer: 100-month
analysis of the ATAC trial. Lancet Oncol 2008;9:45–53.
[20] Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex,
Tamoxifen, Alone or in Combination) trial after completion of 5 years’
adjuvant treatment for breast cancer. Lancet 2005;365:60 –2.
[21] Baum M, Budazar AU, Cuzick J, et al. Anastrozole alone or in
combination with tamoxifen versus tamoxifen alone for adjuvant
treatment of postmenopausal women with early breast cancer: first
results of the ATAC randomised trial. Lancet 2002;359:2131–9.
[22] Khan QJ, O’Dea AP, Sharma P. Musculoskeletal adverse events
associated with adjuvant aromatase inhibitors. J Oncol August 24,
2010. Epub ahead of print.
[23] Hillner BE. Benefit and projected cost-effectiveness of anastrozole versus
tamoxifen as initial adjuvant therapy for patients with early-stage
estrogen receptor-positive breast cancer. Cancer 2004;101:1311–22.
[24] Rocchi A, Verma S. Anastrozole is cost-effective vs tamoxifen as initial
adjuvant therapy in early breast cancer: Canadian perspectives on the
ATAC completed-treatment analysis. Support Care Cancer 2006;14:
917–27.
[25] Moeremans K, Annemans L. Cost-effectiveness of anastrozole
compared to tamoxifen in hormone receptor-positive early breast
cancer: analysis based on the ATAC trial. Int J Gynecol Cancer 2006;
16(Suppl. 2):576 – 8.
[26] Locker GY, Mansel R, Cella D, et al. Cost-effectiveness analysis of
anastrozole versus tamoxifen as primary adjuvant therapy for
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35]
[36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44]
[45]
53
postmenopausal women with early breast cancer: a US healthcare
system perspective. The 5-year completed treatment analysis of the
ATAC (‘Arimidex’, Tamoxifen Alone or in Combination) trial. Breast
Cancer Res Treat 2007;106:229 –38.
Mansel R, Locker G, Fallowfield L, et al. Cost-effectiveness analysis of
anastrozole vs tamoxifen in adjuvant therapy for early stage breast
cancer in the United Kingdom: the 5-year completed treatment
analysis of the ATAC (‘Arimidex’, Tamoxifen alone or in combination)
trial. Br J Cancer 2007;97:152– 61.
Fonseca M, Araujo GT, Saad ED. Cost-effectiveness of anastrozole, in
comparison with tamoxifen, in the adjuvant treatment of early breast
cancer in Brazil. Rev Assoc Med Bras 2009;55:410 –5.
Lux MP, Wöckel A, Benedict A, et al. Cost-effectiveness analysis of
anastrozole versus tamoxifen in adjuvant therapy for early-stage
breast cancer—a health-economic analysis based on the 100-month
analysis of the ATAC trial and the German health system. Onkologie
2010;33:155– 66.
Yearbook of Statistics, Singapore. The Singapore Department of
Statistics. 2010.
Consumer Price Index. July 2010. Available from: http://www
.singstat.gov.sg/stats/themes/economy/hist/cpi.html. [Accessed March
6, 2012].
Lipsitz M, Delea TE, Guo A. Cost effectiveness of letrozole versus
anastrozole in postmenopausal women with HR⫹ early-stage breast
cancer. Curr Med Res Opin 2010;26:2315–28.
Sorensen SV, Brown R, Benedict A, et al. Patient-rated utilities in
postmenopausal early breast cancer (EBC): a cross-country
comparison. Value Health 2004;7:641–2.
Stamuli E. Health outcomes in economic evaluation: who should value
health? Br Med Bull 2011;97:197–210.
Drummond M, Brixner D, Gold M, et al. Toward a consensus on the
QALY. Value Health 2009;12(Suppl. 1):S31–5.
De Wit GA, Busschbach JJ, De Charro FT. Sensitivity and perspective in
the valuation of health status: whose values count? Health Econ 2000;
9:109 –26.
Meltzer D. Accounting for future costs in medical cost-effectiveness
analysis. J Health Econ 1997;16:33– 64.
Ubel PA, Hirth RA, Chernew ME, et al. What is the price of life and why
doesn’t it increase at the rate of inflation? Arch Intern Med 2003;163:
1637– 41.
National Institute for Health and Clinical Excellence. Guide to the
Methods of Technology Appraisal. London, UK: National Institute for
Health and Clinical Excellence, 2004.
Hillner BE, Smith TJ. Efficacy does not necessarily translate to cost
effectiveness: a case study in the challenges associated with 21stcentury cancer drug pricing. J Clin Oncol 2009;27:2111–3.
Economic Indicators. The Singapore Department of Statistics.
Available from: http://www.singstat.gov.sg/stats/keyind.html.
[Accessed March 6, 2012].
Whitehead SJ, Ali S. Health outcomes in economic evaluation: the
QALY and utilities. Br Med Bull 2010;96:5–21.
Parkin D, Devlin N. Is there a case for using visual analogue scale
valuations in cost-utility analysis? Health Econ 2006;15:653– 64.
Yothasamut J, Tantivess S, Teerawattananon Y. Using economic
evaluation in policy decision-making in Asian countries: mission
impossible or mission probable? Value Health 2009;12(Suppl. 3):
S26 –30.
Dranitsaris G, Truter I, Lubbe MS, et al. The application of
pharmacoeconomic modelling to estimate a value-based price for new
cancer drugs. J Eval Clin Pract 2012;18:343–51.