Introduction
Prostate cancer is one of the most commonly diagnosed
cancers according to the GLOBOCAN data.[] In Turkey, prostate cancer is the second most frequently
diagnosed cancer in males, with an age-standardized
incidence rate of 32.9 per 100.000 population,
according to the Turkey Ministry of Health Cancer Statistics.[] According to the National Cancer Institute,
approximately 77% of the cases were reported to
have localized and 13% regional disease at a diagnosis
the estimated 5-year survival rate in those patients was
100%, while it was 98% for all disease stages.3 Prostate
cancer is most frequently diagnosed in older males
(aged 65-74 years).[] As the proportion of older age
groups increase in population demographics, the burden
of prostate cancer on public health and healthcare
systems also grows in parallel. Projections about the
cost of treatment for prostate cancer in 2020 in the
United States have indicated that it will be >$16 billion,
compared to approximately $12 billion in 2010.[]
Currently, the treatment of locally advanced prostate
cancer is based on androgen deprivation therapy
(ADT) and radiotherapy, as testosterone induces
the growth of prostate cancer tissue. ADT focuses on
reducing serum testosterone levels to the point that
would be reached with surgical castration.[] Current
guidelines on prostate cancer define the castration
levels of testosterone as <20 ng/dL after more precise
laboratory tests were developed to measure the testosterone
levels [] and studies have shown that higher
levels of serum testosterone in patients with advanced
prostate cancer are associated with increased mortality.[,] However, the castrate level considered by the
regulatory authorities and in clinical trials addressing
castration in prostate cancer is still <50 ng/dL.[] Testosterone
levels <20 ng/dL are associated with a significantly
lower risk of death compared with testosterone
levels of ≥20 ng/dL.[-] The most common method
of ADT is the use of synthetic peptides that mimic natural
luteinizing hormone-releasing hormone (LHRH),
namely LHRH agonists.
LHRH agonists have a high affinity for the gonadotropic-
releasing hormone receptor and benefit from
longer half-lives than natural LHRH agonists.[] LHRH
agonists have become a standard treatment for locally
advanced and advanced prostate cancer as effectiveness
is higher than antiandrogen monotherapy.[]
Leuprorelin or leuprolide acetate is one of the most
widely prescribed LHRH agonists, due to its favorable
tolerability, and has been used for several years in
the treatment of prostate cancer. Leuprorelin acetate
Atrigel, a second-generation LHRH agonist, has been
developed to reach lower castrate testosterone levels
than conventional LHRH agonists.[] In Turkey, the
3-month subcutaneous formulation of leuprorelin acetate
Atrigel (Eligard®) contains 22.5 mg of leuprorelin
acetate (Eligard® 22.5 mg), whereas the 3-month subcutaneous/
intramuscular formulation of leuprolide acetate microsphere (Lucrin®) contains 11.25 mg of
leuprolide acetate (Lucrin® 11.25 mg). A comparison
between leuprorelin acetate Atrigel (Eligard®) 7.5 mg
1-month formulation and leuprolide acetate microsphere
(Lupron®) 7.5 mg 1-month formulation that
is registered elsewhere has shown that the area under
the curve is 1.9 times higher with leuprorelin acetate
Atrigel for leuprolide acetate release; which means that
leuprorelin acetate Atrigel has provided an additional
14 days of testosterone suppression.[] Conventional
LHRH agonists are known to fail to reach testosterone
levels of <50 ng/dL by 2% to 17% and <20 ng/dL by
13% to 37% of patients5; however, analyses with leuproreline
acetate Atrigel have shown that testosterone
levels were suppressed to <20 ng/dL in 88.3% to 97.5%
of the patients with 1-, 3-, 4-, and 6-month formulations,
respectively.[]
The present study aims to evaluate the clinical effectiveness
and cost of leuprorelin acetate Atrigel
(Eligard®, Astellas Pharmaceuticals, Turkey) in the
treatment of prostate cancer and to calculate its cost-effectiveness
compared with other LHRH agonists, including
leuprolide acetate microsphere (Lucrin®, Abbvie
Pharmaceuticals, Turkey), goserelin (Zoladex LA®,
Astra Zeneca, Turkey), and triptorelin (Decapeptyl®,
Ferring, Turkey).
Methods
This study was conducted at the Hacettepe University,
in the Faculty of Medicine in the Ankara province of
Turkey and included 173 patients with prostate cancer
treated with definitive conformal radiotherapy (3-dimensional
conformal radiotherapy or intensity-modulated
radiation therapy) with a total dose of 74 Gy to76
Gy in conventional fractionation and maximal androgen
blockade. All patients uniformly received three
months of neo-adjuvant and six months of adjuvant
maximal androgen blockade. Patients were grouped as
intermediate or high risk, according to the American
Joint Committee on Cancer 2010 guidelines or Gleason
score.[,] As almost all patients were covered by the
social security system, direct cost-based cost-effectiveness
analyses were performed from the government
(Turkish Social Security Institution) perspective.
The primary outcome for health-related outcomes
was life-years gained (LYG), which was calculated as
the difference between the follow-up duration and calculated
life expectancy for each patient (presented as
life-years lost). Effectiveness of the treatment was measured
through the difference in life-years lost among postrethe
treatment options. Target serum testosterone levels
were also considered during the assessments and two
separate analyses were performed for castration levels
of testosterone of <20 ng/dL and <50 ng/dL.
Cost-effectiveness analyses were based on the estimated
costs at three disease periods (relapse-free,
postrelapse, and postdistant metastasis) and overall
survival estimates. Both the costs and survival estimates
were based on individual patient data. For estimating
the direct costs of the treatment, a prostate
biopsy was assumed to be performed at the beginning
of the disease, 37-38 sessions of radiotherapy were assumed
to be received by each patient (expert opinion),
and LHRH treatments were assumed for six months for
the intermediate-risk patients and 24 months for the
high-risk patients.[] Intermediate risk was defined as
stage T2b, according to the American Joint Committee
on Cancer guidelines, the Gleason score of 7, or prostate-
specific antigen levels of >10 ng/mL and ≤20 ng/
mL. High risk was defined as stage T2c, prostate-specific
antigen levels of >20 ng/mL, or the Gleason score
of ≥8.[,]
The prices and monthly costs of hormone therapy,
chemotherapy, radiotherapy, and follow-up for each
of three disease periods (relapse-free, postrelapse, and
postdistant metastasis) were included in the model.
Only direct costs were considered. Resource utilization
was estimated in accordance with the National
Comprehensive Cancer Network guidelines and expert
opinion. The prices of medications and services were
drawn from the list released by the Turkish Ministry of
Health and the Social Security Institution.
The currency reported in this study was Turkish
lira (TL) and the prices of the relevant medications and
procedures were as of 12 November 2018. The willingness-
to-pay threshold per LYG was set equal to the
gross domestic product per capita, which was declared
as 10.597 US dollars (49.806 TL; 1 US dollar=4.7 TL in
mid-2018) for the year 2017 by the Turkish Statistical
Institute. The study model is summarized in Figure 1.
Fig. 1. Structure of the study model.
Statistical Analysis
Data were analyzed using PASW Statistics for Windows,
version 18.0 (SPSS Inc., Chicago, IL, USA). Descriptive
statistics were expressed as numbers and percentages
for categorical variables and as median and
minimum-maximum for numerical variables. Chisquare
test and, when the condition for chi-square was
not met, Fisher's exact test was used for the comparison
of independent categorical variables. In multiple
independent group comparisons, the Kruskal-Wallis test was used for non-normally distributed numerical
variables. A P-value of <0.05 was considered statistically
significant.
Results
This study included 173 patients with prostate cancer.
The median follow-up duration was 125.37 (range
10.84-214.37) months for the entire cohort. No clinically
significant difference was obtained among the
groups classified according to LHRH analogue type
(Table 1). Distribution of the patients according to
LHRH analogues, risk group, and serum testosterone
levels are summarized in Table 2. In the intermediaterisk
group, the proportion of patients whose serum
testosterone levels were <20 ng/dL and <50 ng/dL
with leuprorelin acetate Atrigel were 80% and 100%,
respectively. The corresponding data were 33.3% and
77.8% for leuprolide acetate microsphere, respectively;
64% and 84% for goserelin, respectively; and 37.5%
and 62.5% for triptorelin, respectively. In the high-
-risk group, the proportions of patients whose serum
testosterone levels were <20 ng/dL and <50 ng/dL with
leuprorelin acetate Atrigel were 90% and 100%, respectively.
The corresponding data were 52.4% and 71.4%
for leuprolide acetate microsphere, respectively; 53.3%
and 81.3% for goserelin, respectively; and 40% and
66.7% for triptorelin, respectively.
Table 1 Patient characteristics classified by luteinizing hormone-releasing hormone agonists
Table 2 Distribution of the patients according to luteinizing hormone-releasing hormone analogues by risk groups and
serum testosterone levels
When the costs of the treatments according to the
risk groups and serum testosterone levels were evaluated
for three disease periods (relapse-free, postrelapse, and postdistant metastasis), the treatment costs
for leuprorelin acetate Atrigel were found to be slightly
lower than leuprolide acetate microsphere, but slightly
higher than goserelin and triptorelin. The total costs, survival estimates, incremental cost-effectiveness ratios
(ICERs), and net monetary benefit values according to
the risk groups and serum testosterone levels are presented
in Table 3. LYG with leuprorelin acetate Atrigel popuversus
no LHRH agonists was superior to other medications
versus no LHRH agonists. Similarly, total treatment
costs for leuprorelin acetate Atrigel were all lower
than other LHRH agonists, which yielded significant
net monetary benefits and ICER values in both risk
groups for all testosterone levels. Cost-effectiveness
analyses showed that leuprorelin acetate Atrigel provided
savings of 9861.89 TL, 1882.98 TL, and 7959.64
TL against leuprolide acetate microsphere, goserelin,
and triptorelin, respectively, in the intermediate-risk
patients whose testosterone suppression target was
<20 ng/dL. For the patients in the intermediate-risk
group whose testosterone suppression target was <50
ng/dL, these savings were 4430.01 TL, 1486.22 TL, and
6162.20 TL, respectively.
Table 3 Treatment costs at an individual patient leve
In high-risk patients, the cost savings with leuprorelin
acetate Atrigel against leuprolide acetate microsphere,
goserelin, and triptorelin were 8243.54 TL,
4861.84 TL, and 9098.58 TL, respectively, for patients
with a testosterone suppression target of <20 ng/dL and
5840.38 TL, 913.63 TL and 5056.03 TL, respectively, for
patients with a testosterone suppression target of <50
ng/dL. For all study patients, leuprorelin acetate Atrigel provided cost savings of 8386.04 TL, 3710.79 TL,
and 8446.64 TL against leuprolide acetate microsphere,
goserelin, and triptorelin, respectively, in patients with
a testosterone suppression target of <20 ng/dL and
479.41 TL, 1142.13 TL, and 5490.79 TL, respectively, in
patients with a testosterone suppression target of <50
ng/dL.
A deterministic sensitivity analysis was performed
using 75% and 125% as low and high values, respectively,
of all relevant input parameters. If the parameter
uncertainty was unknown, a standard 25% variation
was used. Sensitivity analyses also showed that
leuprorelin acetate Atrigel was superior to its comparators
by means of ICER values at low- and high-sensitivity
margins.
Discussion
Prostate cancer is second-leading cancer among males
in Turkey, which has a significant economic burden
on the healthcare systems. The Republic of Turkey
Ministry of Health reported that the incidence rate of
prostate cancer in males was 32.9 per 100.000 population in 2014.2 which means that more than 26.000
individuals are diagnosed with prostate cancer each
year. When the excellent survival rate in this disease
is considered, together with the high incidence rate,
there is a growing share of costs related to the treatment
of prostate cancer among all healthcare expenditures.
From this point of view, determining the cost-effectiveness
of currently available therapeutic methods
is crucial for guiding both regulatory authorities and
physicians. Based on this necessity, we conducted a
comprehensive cost-effectiveness analysis to evaluate
the leuprorelin acetate Atrigel, in comparison with
other available LHRH agonists in the market. Overall,
we found that leuprorelin acetate Atrigel was both clinically
and economically superior to other comparators,
such as leuprolide acetate microsphere, goserelin, and
triptorelin, which yielded the conclusion that leuprorelin
acetate Atrigel was the most cost-effective LHRH
agonist in the market.
The analyses of our study were conducted for patients
with intermediate and high risk, as well as for
target testosterone levels of <20 ng/dL and <50 ng/dL.
The risk stratification directly affects duration, and target
testosterone levels are directly associated with the
achievement of pharmacological castration and patient
outcomes, which all eventually affect the cost of treatment.
Target testosterone levels that should be achieved
for castration is reported to be <20 ng/dL11; however,
regulatory authorities and clinical trials still use a testosterone
target of <50 ng/dL for castration. Overall,
we found that leuprorelin acetate Atrigel provided significantly
greater clinical effectiveness in terms of LYGs
and superior economic efficiency concerning ICER
values compared to other LHRH analogues.
When all patients with prostate cancer were considered
without risk stratification, in patients who
achieved a target testosterone level of <20 ng/dL with
leuprorelin acetate Atrigel compared with leuprolide
acetate microsphere, goserelin, and triptorelin, LYGs
were 0.46 years, 0.35 years, and 0.55 years, respectively,
and cost savings were 8386.04 TL, 3710.79 TL, and
8446.64 TL, respectively. In patients who achieved a
target testosterone level of <50 ng/dL, LYGs were 0.53
years, 0.36 years, and 0.70 years, respectively, and cost
savings were 5479.41 TL, 1142.13 TL, and 5490.79 TL,
respectively. Based on these calculations, leuprorelin
acetate Atrigel can be accepted as the treatment of
choice among currently available LHRH analogues.
Currently, ADT with LHRH agonists is the recommended
first-line treatment for symptomatic and asymptomatic
patients with advanced disease, as well as for symptomatic patients with locally advanced disease.
Among LHRH agonists and leuprorelin or leuprolide
acetate preparations, leuprorelin acetate Atrigel has a
unique polymeric delivery system that provides a continuous
administration of leuprolide acetate during
biodegradation of the leuprorelin depot. In Europe,
there are three commercially available forms of leuprorelin
acetate Atrigel, which contain 7.5 mg, 22.5 mg,
and 45 mg doses for 1-, 3- and 6-months of administration
interval, respectively. A previous study that evaluated
the economic impact of different preparations
of leuprolide acetate in the management of advanced
prostate cancer reported that the 6-month depot formulation
of leuprorelin acetate Atrigel was found to
be the most cost-effective treatment option, despite its
higher unit price.[] Another study that evaluated the
efficacy, safety, and costs of treatment with 1-, 3- and
6-monthly depot formulations of leuprolide acetate in
ADT for prostate cancer in nine European countries
(Austria, Belgium, Czech Republic, Hungary, Italy, Latvia,
Netherlands, Poland, and Portugal) reported that
these leuprorelin acetate Atrigel formulations provided
similar efficacy and safety; however, the 6-month formulation
offered the greatest cost savings and could be
considered the treatment of choice in eligible patients.
[] In the present study, different formulations of leuprorelin
acetate Atrigel were not evaluated. However,
considering our findings in conjunction with the
currently available literature, long-depot formulation
of leuprorelin acetate Atrigel can be suggested as the
treatment of choice in prostate cancer compared with
other leuprolide acetate preparations in the market.
The present study has some limitations. First, the
number of patients using leuprorelin acetate Atrigel
is relatively low in comparison with other LHRH analogues.
This may be considered as a lack of power of
the study. However, individual, patient-based cost calculations
and standardization of the initial assumptions
for treatment, like a biopsy, or duration of treatment in
separate risk groups and target testosterone levels, can
waive the concerns about the study power. Second, only
direct medical costs were estimated in our cost-effectiveness
model. Nevertheless, the cost of cancer treatment
includes direct costs and nonmedical costs like
out-of-pocket expenditures, indirect costs (such as productivity
loss), and psychosocial costs (such as quality-
of-life loss).[] However, as literature data support
that leuprorelin acetate Atrigel is associated with patient
satisfaction in the treatment of locally advanced and
metastatic prostate cancer,[] we prioritized the estimations
and cost-effectiveness of direct medical costs Longrelated
with leuprorelin acetate Atrigel and other LHRH
analogues from the perspective of buyers in Turkey. The
literature also supports this assumption, as the 6-month
depot formulation of leuprorelin acetate Atrigel has
been reported to be associated with reduced anxiety,
decreased emotional burden, improved flexibility with
scheduling, less frequent injections, improved comfort,
fewer doctor visits, decreased site reactions, decreased
cost, fewer missed visits, and in theory, decreased risk of
a breakthrough.[] Moreover, as the indirect costs may
vary from country to country, the direct costs may provide
more robust figures for further comparisons among
various healthcare systems. Another limitation of this
study is the standardization of treatment-associated factors
for each patient. However, as mentioned previously,
this standardization provides more robust estimations
of direct costs of each treatment option, as well as more
robust comparisons of both clinical and economical effectiveness
measures.
Conclusion
According to the results of this cost-effectiveness analysis,
leuprorelin acetate Atrigel was clinically more
effective compared with other LHRH analogues in
intermediate- and high-risk patients, as well as in all
patients in any risk group, when the testosterone suppression
target was <20 ng/dL or <50 ng/dL. For intermediate-
risk patients, high-risk patient, and all patients
in any risk group, leuprorelin acetate Atrigel was
cost-saving compared with other LHRH analogues,
whether the testosterone suppression target was <20
ng/dL or <50 ng/dL. These clinical and economic findings
show that leuprorelin acetate Atrigel can be considered
the treatment of choice in prostate cancer.
Peer-review: Externally peer-reviewed.
Conflict of Interest: Gokhan Ozyigit received honoraria
and grant support from Astellas Pharma Inc. Fadil Akyol declared
no conflict of interest.
Ethics Committee Approval: The study was reviewed and
approved by the Hacettepe University Faculty of Medicine
ethics Committee.
Financial Support: Medical writing support was provided
by Safak Dulger of Omega CRO, Ankara, Turkey, funded by
Astellas Pharma, Turkey. Editorial assistance was provided by
Beatrice Vetter-Ceriotti, PhD, Lauren Smith and Jane Beck
of Complete HealthVizion, funded by Astellas Pharma Inc.
Authorship contributions: Concept - G.O; Design - G.O.;
Supervision - F.A.; Funding - Astellas Pharma Turkey; Materials - G.O.; Data collection and/or processing - G.O; Data
analysis and/or interpretation - G.O., F.A.; Literature search
- G.O.; Writing - G.O., Ş.D.; Critical review - G.O.
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