Anda di halaman 1dari 8

Lung Cancer 74 (2011) 521528

Contents lists available at ScienceDirect

Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan

Pharmacoeconomic analysis of consolidation therapy with pemetrexed after


rst-line chemotherapy for non-small cell lung cancer
Takanori Tsuchiya a, , Takashi Fukuda b , Masashi Furuiye c,d , Koichi Kawabuchi a
a
Health Care Economics, Department of Health Science Policies, Division of Public Health, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University,
1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan
b
Department of Health Economics and Epidemiology Research, School of Public Health, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
c
Integrated Pulmonology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan
d
Furuiye Clinic, 2-34-8 Maruyama-dai, Konan-ku, Yokohama, Kanagawa 233-0013, Japan

a r t i c l e

i n f o

Article history:
Received 23 January 2011
Received in revised form 14 March 2011
Accepted 3 April 2011
Keywords:
Pharmacoeconomics
Cost-effectiveness analysis
Non-small cell lung cancer
Pemetrexed
Erlotinib
Consolidation therapy

a b s t r a c t
Prolongation of progression-free survival and overall survival have been reported with consolidation
therapy after rst-line chemotherapy in non-small cell lung cancer, but only a few pharmacoeconomic analyses have been performed. We performed a pharmacoeconomic analysis to assess the
cost-effectiveness of consolidation therapy with pemetrexed compared with non-consolidation therapy.
We developed a Markov model to evaluate the incremental cost-effectiveness ratio (ICER) of consolidation therapy with pemetrexed compared with non-consolidation therapy based on previous reports. We
analyzed all histology groups together, and individually analyzed non-squamous cell carcinoma, in which
pemetrexed has been shown to be more effective, and squamous cell carcinoma, in which pemetrexed
has been shown to be less effective. We conducted a Monte-Carlo simulation to assess the uncertainty
for our analysis model and the willingness to pay using thresholds. The ICER for consolidation therapy with pemetrexed was about US$ 109,024/life years gained (LYG) (JPY 12.5 million/LYG) and US$
203,022/quality-adjusted life years (QALY) (JPY 23.3 million/QALY) for all histology. For non-squamous
cell carcinoma, respective values were US$ 80,563/LYG (JPY 9.3 million/LYG) and US$ 150,115/QALY (JPY
17.3 million/QALY). Both % of probability at a threshold of JPY 5.0 million (US$ 43,478) for all histology
and non-squamous cell carcinoma were less than 0.1%. This result indicates that it is difcult to use consolidation therapy as the standard of care in Japan while being covered by general medical insurance.
2011 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
In 2006, more than 60,000 people died from lung cancer,
the leading cause of death in Japan; both the incidence and the
mortality rate from lung cancer have been continuously increasing since 1960s [1]. Initial therapy for advanced non-small cell
lung cancer (NSCLC) is systemic chemotherapy with a two-drug
combination regimen including platinum [2,3]. After initial therapy and disease progression, docetaxel is used for second-line
chemotherapy.
Recently, several new anti-cancer drugs such as pemetrexed
and erlotinib were approved in Japan as second-line chemotherapy for NSCLC. Pemetrexed is a novel, multitargeted antifolate
chemotherapy agent. A randomized phase III study in previously treated patients with NSCLC demonstrated non-inferiority

Corresponding author. Tel.: +81 3 5803 5931; fax: +81 3 5803 5933.
E-mail address: sph53c29@ivy.ocn.ne.jp (T. Tsuchiya).
0169-5002/$ see front matter 2011 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.lungcan.2011.04.002

of pemetrexed compared with docetaxel, one of the standards of


care for second-line chemotherapy [4]. Based on a sub-population
analysis, however, pemetrexed was shown to be more effective for
non-squamous cell carcinoma, including adenocarcinoma and large
cell carcinoma, than for squamous cell carcinoma [5]. Pemetrexed
is widely used as not only second-line therapy, but also as rst-line
therapy with platinum, including cisplatin and carboplatin, because
the rate and severity of adverse events are lower and milder than
for other anti-cancer drugs [4].
Generally, second-line therapy starts after conrmation of
radiographic disease progression. However, there are some study
reports and reviews that discuss maintenance therapy during
which some rst-line drugs are administered continuously, and
consolidation therapy, during which a different drug treatment
starts before disease progression [610]. In particular, consolidation therapy with pemetrexed and erlotinib has been shown to
increase progression free survival (PFS) (pemetrexed, 2.0 months;
erlotinib, 1.2 weeks) and overall survival (OS) (pemetrexed, 2.8
months; erlotinib, 1.0 month).

522

T. Tsuchiya et al. / Lung Cancer 74 (2011) 521528

Although new anti-cancer drugs have been approved, and new


treatment patterns, including maintenance/consolidation therapy,
have been developed, medical costs for cancer therapy are increasing [11,12]. In Japan, medical costs for cancer in 2007 were about
US$ 26.7 billion (JPY 3,071.6 billion), representing 12% of all medical costs [13]. The number of patients with cancer is increasing,
and as a result, medical costs will continue to increase. Koinuma
reported that the economic burden of a cancer patient treated
with chemotherapy and imatinib are about 130% and 150% more,
respectively, compared with costs for a patient treated without
chemotherapy [14]. In addition, some physicians have been forced
to change and/or withdraw treatment based on the patients economic situation. Therefore, it is not enough to assess the efcacy of
an anti-cancer drug costs must be assessed as well.
Several pharmacoeconomic analyses of pemetrexed for rstline and second-line treatment have been reported [1517].
However, economic assessments for maintenance/consolidation
therapy are limited, with only a single analysis having been performed in a US population [18]. The purpose of this study was
to conduct a pharmacoeconomic analysis of consolidation therapy compared with non-consolidation therapy in Japan. We also
assessed if there were any differences between histological subtypes, because previous reports have shown that it is more effective
to treat patients with non-squamous cell carcinoma than squamous
cell carcinoma with pemetrexed [5,9].

2. Materials and methods


2.1. Economic evaluation
We built a Markov model to evaluate the cost-effectiveness of
consolidation therapy compared with non-consolidation therapy
[19]. Our economic analysis was conducted from the perspective of
the healthcare payer, and we calculated only direct medical costs
(i.e., indirect costs, such as work loss, and direct non-medical costs,
such as transportation costs, were not included in our analysis).
The primary result of this analysis is described as the incremental
cost-effectiveness ratio (ICER).
Data were primarily expressed as ICER based on life years gained
(LYG), because survival prolongation is a popular index to assess
anti-cancer drug efcacy. In addition, we assessed quality-adjusted
life years (QALY), because a patients quality of life during treatment
is an important factor [20]. We adopted a 3% discount rate per year
for both outcomes and costs [21].

2.2. Patients and treatment


Data for patients in this study were obtained from previous studies [4,9,22]. Based on these studies, for this analysis, the patient
population in the model was assumed to include Japanese men with
stage IIIB and IV NSCLC who were in their 60s. This population was
chosen because more than 70% of patients in a previous report by
Ciuleanu et al. [9] were male and their median age was 60 years.
To calculate the dose of pemetrexed, we assumed the body surface
area of all patients was 1.70, calculated by a height and weight of
164.6 cm and 64.5 kg, respectively, based on a report by Ciuleanu
et al. [9] and the National Health and Nutrition Survey, respectively
[23].
We considered the following two chemotherapy schedules: (1)
consolidation therapy in which pemetrexed treatment was started
after rst-line therapy with no disease progression, and (2) nonconsolidation therapy, in which pemetrexed treatment was started
after disease progression for rst-line therapy. For both groups, we
assumed erlotinib treatment was used post-therapy.

The dose of pemetrexed was the same as used in a previous


reports (500 mg/m2 every 3 weeks until disease progression) [4,9],
and vitamin B12 and folic acid were provided to all patients prophylactically for side effects during the study period. Erlotinib
150 mg/day for post therapy of pemetrexed was provided until
disease progression.
2.3. Model of economic analysis
The cost-effectiveness of consolidation therapy for pemetrexed
was assessed based on data from reports by Ciuleanu et al. [9],
Hanna et al. [4], and Shepherd et al. [22]; the Markov model is
shown in Fig. 1. Modeling began with the rst cycle of therapy after
completing rst line chemotherapy without progression disease
and followed each patients 3-week cycle for 3 years or until their
death, taking into account their treatment schedule for pemetrexed
and the rate of mortality [23].
For consolidation therapy, ve discrete health states were
considered: consolidation therapy with pemetrexed (cPEM); disease progression after consolidation therapy with no second-line
therapy (cPD-1), erlotinib treatment as second-line therapy after
consolidation therapy with pemetrexed (cErl); disease progression after second-line therapy of erlotinib (cPD-2), and cDeath.
At rst, the patient received pemetrexed as consolidation therapy (cPem, health state). After disease progression, the patient
moved to cErl, cPD-1, or cDeath. From the cErl health state,
the patient moved to cPD-2 or cDeath after disease progression
with erlotinib. For the cPD-1 and cPD-2 health states, the patient
received only palliative care and moved to the cDeath health state
only. For non-consolidation therapy, seven discrete health states
were considered: non-consolidation therapy with best supportive
care (BSC; no chemotherapy after rst-line therapy); progression
after rst-line therapy with no second- and third-line therapy
(nPD-1); pemetrexed treatment as second-line therapy after disease progression (nPem); disease progression after second-line
therapy with no third-line therapy (nPD-2); erlotinib treatment as
third-line therapy after disease progression of second-line therapy (nErl); disease progression after third-line therapy (nPD-3);
and nDeath. For the BSC, nPem, and nErl health states, the
patient moved to nPem, nPD-1, or Death health states; nErl,
nPD-2 or nDeath health states; and nPD-3 or nDeath health
states, respectively. For nPD-1, nPD-2, and nPD-3, the patient
received palliative care only and moved to the nDeath health
state.
In this study, we analyzed data using a Markov model. One
Markov cycle corresponds to 3 weeks, based on the treatment
schedule of pemetrexed. The probability of moving to the next
health state was based on PFS and OS data, which were reported
in previous reports [4,5,9,22], and calculated using the following
equation:
p=1


t

1 S(t)

where p = moving probability, t = time, and S(t) = % of population that is progression free or still surviving. For probability
of erlotinib as second line treatment for consolidation therapy
group, and those of pemetrexed as second line treatment and
erlotinib as third line treatment for non-consolidation therapy
group, we multiplied the above moving probabilities by the rates
of patients with receiving additional anti-cancer drug therapy
after going Ciuleanus and Hannas study [4,9]. The calculated
OS and PFS are expressed as the time from completing rst line
chemotherapy.
Based on results of clinical trials, it is more effective to used
pemetrexed for patients with non-squamous cell carcinoma than
those with squamous cell carcinoma [5]. In this study, we ana-

T. Tsuchiya et al. / Lung Cancer 74 (2011) 521528

523

Fig. 1. Markov model for pharmacoeconomic analysis. cPem, consolidation therapy with pemetrexed; cPD-1, disease progression after consolidation therapy with no secondline therapy; cErl, erlotinib treatment as second-line therapy after consolidation therapy with pemetrexed; cPD-2, disease progression after second-line therapy of erlotinib;
BSC, non-consolidation therapy with best supportive care; nPD-1, progression after rst-line therapy with no second- and third-line therapy; nPem, pemetrexed treatment
as post BSC therapy after disease progression; nPD-2, disease progression after pemetrexed treatment with no third-line therapy; nErl, erlotinib treatment as third-line
therapy after disease progression of pemetrexed; nPD-3, disease progression after third-line therapy.
Table 1
Characteristics of patients with non-small cell lung cancer in randomized clinical trials.
Ciuleanu et al. [9]

Number of patients
Median age
Sex (male %/female %)
ECOG PS (%)

0
1
2
3
Histology (%)
Adenocarcinoma
Squamous
Febrile neutropenia
Grades 34 adverse event (%)
Neutropenia/leukopenia
Nausea/vomiting
Fatigue
Diarrhea
Rash
Rate of receiving post systemic anticancer therapy (%)

Hanna et al. [4]

Shepherd et al. [22]

Consolidation pemetrexed

BSC

2nd-Line pemetrexed

Erlotinib

BSC

441
60.6
73/27
40
60
0
0
50
26

5
2
5
1
1
51

222
60.4
73/27
38
62
0
0
48
30

1
1
1
0
0
67

283
59
68.6/31.4

488
62
64.5/35.5
13.1
52.5
25.8
8.6
50.4
29.5

243
59
65.8/34.2
14.0
54.3
23.0
8.6
49.0
32.1

88.6
11.4
0
54.4
27.6
1.9
5.3
4.1
5.3
0.4
0.8
46.6

6
19
6
9

3
23
1
0

ECOG PS, Eastern Cooperative Oncology Group Performance Status; BSC, best supportive care.

lyzed not only all histology, but also non-squamous cell carcinoma,
including adenocarcinoma and large cell carcinoma, and squamous
cell carcinoma. The probabilities of moving from an earlier health
state to a later health state based on previous reports are shown in
Tables 13.

2.4. Utility
Utility scores in our model were derived from a recent study
performed in the United Kingdom [20]. The base utility score
was 0.6532, and it was decreased due to disease progression and

Table 2
Median progression-free survival (mPFS) and median overall survival (mOS) by histological type from previous studies.
Ciuleanu et al. [9]

All histology
Non-squamous
Adenocarcinoma
Squamous

Hanna et al. [4]

Scagliotti et al. [5]

Consolidation pemetrexed

BSC

mPFS (month)

mOS (month)

mPFS (month)

mOS (month)

mPFS (month)

mOS (month)

4.0 (3.14.4)
4.4 (4.05.6)
4.6 (4.06.0)
2.4 (1.62.8)

13.4 (11.915.9)
15.5 (13.218.1)
16.8 (14.019.7)
9.9 (7.511.5)

2.0 (1.52.8)
1.8 (1.52.8)
2.7 (1.62.8)
2.5 (1.53.2)

10.6 (8.712.0)
10.3 (8.112.0)
11.5 (9.115.3)
10.8 (8.513.2)

2.9
3.1
3.5
2.3

8.3
9.3
9.0
6.2

95% Condence intervals are shown in parentheses.

2nd-Line pemetrexed

524

T. Tsuchiya et al. / Lung Cancer 74 (2011) 521528

Table 3
Moving probabilities between each health stage in the Markov model.
Description

cPem to cPem
cPem to cErl
cPem to cPD-1
cPem to cDeath
cPD-1 to cPD-1
cPD-1 to cDeath
cErl to cErl
cErl to cPD-2
cErl to cDeath
cPD-2 to cPD-2
cPD-2 to cDeath
nBSC to nBSC
nBSC to nPem
nBSC to nPD-1
nBSC to nDeath
nPD-1 to nPD-1
nPD-1 to nDeath
nPem to nPem
nPem to nPD-2
nPem to nErl
nPem to nDeath
nPD-2 to nPD-2
nPD-2 to nDeath
nErl to nErl
nErl to nPD-3
nErl to nDeath
nPD-3 to nPD-3
nPD-3 to nDeath

Probability

Reference

All

Non-squamous

Adeno-carcinoma

Squamous

0.8867
0.0575
0.0552
0.0006
0.8479
0.1521
0.8038
0.1953
0.0009
0.9351
0.0649
0.7868
0.1425
0.0702
0.0006
0.8473
0.1527
0.8471
0.0810
0.0710
0.0009
0.8473
0.1527
0.8038
0.1953
0.0009
0.8716
0.1284

0.8964
0.0525
0.0505
0.0006
0.8479
0.1521
0.8038
0.1953
0.0009
0.9471
0.0529
0.7661
0.1563
0.0770
0.0006
0.8473
0.1527
0.8562
0.0763
0.0666
0.0009
0.8473
0.1527
0.8038
0.1953
0.0009
0.8605
0.1395

0.9007
0.0504
0.0484
0.0006
0.8479
0.1521
0.8038
0.1953
0.0009
0.9527
0.0473
0.8371
0.1088
0.0536
0.0006
0.8473
0.1527
0.8714
0.0682
0.0595
0.0009
0.8473
0.1527
0.8038
0.1953
0.0009
0.8564
0.1436

0.8188
0.0921
0.0885
0.0006
0.8479
0.1521
0.8038
0.1953
0.0009
0.9131
0.0869
0.8253
0.0888
0.0853
0.0006
0.8473
0.1527
0.8114
0.1002
0.0875
0.0009
0.8473
0.1527
0.8038
0.1953
0.0009
0.8811
0.1189

[9]
[9]
[9]
[23]
[22]
[22,23]
[22]
[22]
[22,23]
[9,22]
[9,22]
[9]
[9]
[9]
[23]
[22]
[22,23]
[4,5]
[4,5]
[4,5]
[4,23]
[22]
[22,23]
[22]
[22]
[22,23]
[4,5,22]
[4,5,22]

cPem, consolidation therapy with pemetrexed; cErl, erlotinib treatment as second-line therapy after consolidation therapy with pemetrexed; cPD-1, disease progression
after consolidation therapy with no second-line therapy; cDeath, death; cPD-2, disease progression after second-line therapy of erlotinib; nBSC, non-consolidation therapy
with best supportive care; nPem, pemetrexed treatment as second-line therapy after disease progression; nPD-1, progression after rst-line therapy with no second- and
third-line therapy; nDeath, death; nPD-2, disease progression after second-line therapy of pemetrexed with no third-line therapy; nErl, erlotinib treatment as third-line
therapy after disease progression of second-line therapy; nPD-3, disease progression after third-line therapy.

adverse events. In this study, for each health state, the values were
calculated considering the types of adverse events and disease progression (Table 4).

Table 4
Utility score (Ref. [20]).
Utility score

2.5. Costs
The perspective adopted in the analysis was that of Japanese
healthcare payer, and we conducted a cost-effectiveness analysis
for consolidation and non-consolidation therapy using direct medical costs only. These direct medical costs were developed using a
standard treatment model based on expert opinions. For the rst
cycle of treatment, we assumed that patients stayed in the hospital
for 2 weeks with underwent ve sets of blood tests and ve sets
of X-rays. After the rst cycle of treatment, patients had an examination every week, a blood test and X-ray test every cycle, and a
computed tomography scan every three cycles. We converted $1 to
JPY 115 based on the purchasing power parties for gross domestic
products in 2009 [24].
Medical costs were calculated for the year 2009 according to
the Japanese drug tariff and medical treatment fee per treatment/procedure (Table 5) [25,26]. For after progression disease
and no further treatment stages (cPD-1, cPD-2, nPD-1, nPD-2, and
nPD-3), we assumed that the patient used home medical services including bi-weekly medical examination, nursing care 2
times/week, home medical service fee, which cost US$ 884/cycle
[25]. In addition, for the last cycle before the patients death, we
calculated the cost for patients receiving care in a palliative care
unit, which was US$ 6903/cycle (at payment system: US$ 329/day)
[25]. Our analyses included costs for treatment of grade 3/4 adverse
events. The frequency of adverse events was derived from previous trials [4,9,22], and we assumed that (1) these events are
occurred every cycles with the same possibilities, (2) the same

Consolidation therapy
cPem
cErl
cPD-1
cPD-2
Death
Non-consolidation therapy
nBSC
nPem
nErl
nPD-1
nPD-2
nPD-3
Death

0.6532
0.6532
0.4734
0.4734
0
0.6532
0.6532
0.4734
0.4734
0.4734
0.4734
0

Adverse event

Utility decrements

Neutropenia/leukopenia
Febrile neutropenia
Fatigue
Nausea/vomiting
Diarrhea
Rash

0.08973
0.09002
0.07346
0.04802
0.0468
0.03248

cPem, consolidation therapy with pemetrexed; cErl, erlotinib treatment as


second-line therapy after consolidation therapy with pemetrexed; cPD-1, disease progression after consolidation therapy with no second-line therapy; cDeath,
death; cPD-2, disease progression after second-line therapy of erlotinib; nBSC, nonconsolidation therapy with best supportive care; nPem, pemetrexed treatment as
second-line therapy after disease progression; nPD-1, progression after rst-line
therapy with no second- and third-line therapy; nDeath, death; nPD-2, disease progression after second-line therapy of pemetrexed with no third-line therapy; nErl,
erlotinib treatment as third-line therapy after disease progression of second-line
therapy; nPD-3, disease progression after third-line therapy.

T. Tsuchiya et al. / Lung Cancer 74 (2011) 521528

525

Table 5
Estimated non-small cell lung cancer treatment costs per unit and total times per cycle (Refs. [25,26], specialists opinion).
Unit

Unit cost (US$)

Pemetrexed
1st Cycle

Hospitalization fee
Outpatient service fee
Drug acquisition costs
Pemetrexed
Folic acid
Vitamin B12
Ramosetron
Erlotinib
Injection fee
Outpatient chemotherapy fee
Preparation in sterile environment
Pharmacy feea (inpatient)
Pharmacy feea (outpatient)
Peripheral blood tests fee
Chest X-rays
1 Time
2 Times
CT scan
Total (US$/cycle)b
a
b

2 Weeks
Time

3320.5
6.1

Cycle
Day
3 Cycle
Cycle
Day
Cycle
Cycle
Time
Cycle
Cycle
Time

4084.6
0.1
0.9
55.8
89.9
4.1
43.5
4.3
16.4
20.8
34.6

1
29
1
1

24.3
19.1
182.6

1
4
1
7946

Time
Time
Time

Erlotinib
Subsequent cycle

1st Cycle

1
21
0.33
1
21

1
1

Before 2nd-line
therapy

1
3

Best supportive care


Subsequent cycle

21

1
1
1
1
1
3
1
0.5
4453

5
1
4
1
5682

1
1.5

1
0.25
2049

0.25
111

Including pharmacy fee, prescription fee, and technical base fee for dispensing pharmacist.
Due to rounding, the total costs are not equal to the sum of the gures in each column.

adverse event with grade 3/4 could be occurred during treatment


period, repeatedly, and (3) the same adverse event is not occurred
within a same cycle. The cost of leukopenia, neutropenia, and
febrile neutropenia included the cost of three outpatient visits.
We assumed that patients received granulocyte colony stimulating factor three times and antibiotics for prophylaxis of infection
for 7 days. In addition, patients underwent blood tests to determine neutrophil counts (total for grade 3/4 adverse events: US$
481/event).
Based on a specialists opinion, treatment costs for nausea/vomiting, diarrhea, and skin disorders included the cost of
ramosetron hydrochloride, a 5-HT3 receptor antagonist, for 2 days
(US$ 28/event); loperamide hydrochloride for 3 days (US$ 4/event);
and clobetasone butyrate, a steroid (US$ 9/event). We assumed
that no treatment was needed for fatigue, thrombocytopenia, and
anemia.

3. Results
3.1. Cost-effective analysis
Results of our analyses are shown in Table 6. For all histologies, the expected OS and QALYs were 451.8 days and 0.6770
QALYs for consolidation therapy and 366.2 days and 0.5511 QALYs
for non-consolidation therapy. ICER was US$ 109,024/LYG (JPY
12,537,811/LYG) and US$ 203,022/QALY (JPY 23,347,549/QALY),
respectively.
For non-squamous cell carcinoma and adenocarcinoma, ICER
was US$ 80,563/LYG (JPY 9,264,791/LYG) and US$ 101,787/LYG
(JPY 11,705,548/LYG), respectively, and those based on QALY were
US$ 150,115/QALY (JPY 17,263,183/QALY) and US$ 208,778/QALY
(JPY 24,009,522/QALY), respectively. For squamous cell carcinoma,
both results of consolidation therapy were dominated by nonconsolidation therapy.

2.6. Sensitivity analyses


3.2. Sensitivity analysis
To evaluate the uncertainty and robustness of the model, we
performed one-way and probabilistic sensitivity analyses [19].
One-way sensitivity analyses were performed by varying each
model parameter, while not varying the other parameters, over
a range of values derived from 95% condence intervals or the
25% value. We varied discount rate between 0% and 7% [27],
and palliative care cost between US$ 0 and US$ 6903 which was
palliative care unit for 21 days. In addition, for length of stay
in hospital of consolidation therapy with pemetrexed, we varied
length of stay in hospital between 0 day and 14 days, because
the patients who can receive consolidation therapy with pemetrexed might be better condition than those with pemetrexed
treatment as second line therapy. A probabilistic analysis was performed using a Monte-Carlo simulation [19]. In this method, all
parameters were randomly drawn for 10,000 times from distributions of their probabilities (triangular distribution for moving
health states in the model). Results of these simulations were
provided to generate not only the model outcome probabilities, but also cost-effectiveness acceptability curves (CEAC). The
CEAC provides the probability that one intervention is more costeffective than a single alternative at differing willingness-to-pay
thresholds.

To conrm the robustness of this analysis, we performed


one-way sensitivity analysis while changing several parameters,
including PFS, OS, transition rate, and discount (Fig. 2). The primary and secondary driver was palliative cost and % of patients
who received next therapy after consolidation therapy, but the
ICERs were more than US$ 67,785/LYG (JPY 7,795,273/LYG), and
the assessment of superiority/inferiority did not change from the
point of economic evaluation. For analysis with QALY, the ICERs
for all histological types were more than US$ 150,000/QALY even
though utility scores changed to favor consolidation therapy over
non-consolidation therapy (data not shown).
The results of probabilistic sensitivity analysis with a MonteCarlo simulation are shown in Fig. 3. The triangular distribution
was applied as the probability distribution of parameters. For
all histology, non-squamous cell carcinoma, and adenocarcinoma,
more than 90% cases of consolidation therapy were more effective than non-consolidation therapy, but the cost of consolidation
therapy was about US$ 29,000/LYG additional compared with nonconsolidation therapy.
The probabilities of cost-effectiveness at JPY 10 million/LYG
(US$ 86,957/LYG) threshold were 17.7%, 54.7%, and 28.0% for all

526

T. Tsuchiya et al. / Lung Cancer 74 (2011) 521528

Table 6
Results of Markov model analysis by histological type.

All histology
Consolidation therapy
Non-consolidation therapy
Non-squamous cell carcinoma
Consolidation therapy
Non-consolidation therapy
Adenocarcinoma
Consolidation therapy
Non-consolidation therapy
Squamous cell carcinoma
Consolidation therapy
Non-consolidation therapy

OS (day)

QALY

Cost (US$)

ICER (US$/LYG)

ICER (US$/QALY)

451.8
366.2

0.6770
0.5511

64,409
38,843

109,024

203,022

489.4
359.5

0.7321
0.5411

68,536
39,872

80,563

150,115

509.0
406.7

0.7608
0.6241

70,595
42,070

101,787

208,778

355.9
374.5

0.5267
0.5640

49,285
35,452

Dominated

Dominated

OS, overall survival; QALY, quality-adjusted life years; ICER, incremental cost-effectiveness ratio; LYG, life years gained.

histology, non-squamous cell carcinoma, and adenocarcinoma,


respectively. The probability of cost-effectiveness at JPY 5 million/LYG (US$ 43,478/LYG) threshold was 0.0% for all histology
groups (Fig. 4).
4. Discussion
In this study, we performed a pharmacoeconomic analysis using
a Markov model for consolidation therapy with pemetrexed after
initial chemotherapy compared with non-consolidation therapy for
patients with NSCLC. The calculated median PFS and the OS for con-

solidation therapy were 4.0 months and 11.5 months, and those
for non-consolidation therapy were 2.0 months and 10.2 months,
respectively. These results are similar to those of Ciuleanu et al.
[9], and our model was considered appropriate based on their
ndings.
Based on our model, the ICERs for consolidation therapy for all
histologies were about US$ 109,024/LYG (JPY 12.5 million/LYG)
and about US$ 203,022/QALY (JPY 23.3 million/QALY). We also
assessed differences between the sub-populations (histological
differences). For squamous cell carcinoma, consolidation therapy
was dominated by non-consolidation therapy. Recently, results

(b) Non-Squamous Cell Carcinoma

(a) All Histology


Consolidation_PEM: PFS
Control_BSC: PFS
2nd Line_PEM: PFS
Consolidation_PEM: OS
Control_BSC: OS
Consolidation_PEM: Rate
Control_BSC: Rate
2nd Line_PEM: Rate
Discount Rate
AE Rate_Con_PEM
Consolidation_PEM: LOS
Paliiative Care Cost
0

50,000

100,000

150,000

200,000

250,000

50,000

100,000

150,000

200,000

250,000

ICER (US$/LYG)

ICER (US$/LYG)

(c) Adenocarcinoma
Consolidation_PEM: PFS
Control_BSC: PFS
2nd Line_PEM: PFS
Consolidation_PEM: OS
Control_BSC: OS
Consolidation_PEM: Rate
Control_BSC: Rate
2nd Line_PEM: Rate
Discount Rate
AE Rate_Con_PEM
Consolidation_PEM: LOS
Paliiative Care Cost
0

50,000

100,000

150,000

200,000

250,000

ICER (US$/LYG)
Fig. 2. Results of one-way sensitivity analysis. ICER, incremental cost-effectiveness ratio; LYG, life years gained; OS, overall survival; PFS, progression-free survival; AE,
adverse events. Consolidation PEM: PFS, PFS for consolidation therapy with pemetrexed; Control BSC: PFS, PFS for BSC; 2nd Line PEM: PFS, PFS for 2nd line therapy with
pemetrexed; Consolidation PEM: OS, OS for consolidation therapy with pemetrexed; Control BSC: OS, OS for BSC; Consolidation PEM: rate, % of patients for consolidation
therapy with pemetrexed who received post therapy; Control BSC: rate, % of patients for BSC who received post therapy; 2nd Line Pem: rate, % of patients for 2nd line
treatment with pemetrexed who received post therapy; AE Rate Con Pem: % of adverse event (neutropenia, febrile neutropenia, leukopenia) for patient with consolidation
therapy with pemetrexed; Consolidation PEM: LOS, length of stay in hospital of patient for consolidation therapy with pemetrexed.

T. Tsuchiya et al. / Lung Cancer 74 (2011) 521528

Incremental Cost (US$)

(a) All Histology

(b) Non-Squamous Cell Carcinoma

50,000

50,000

40,000

40,000

30,000

30,000

20,000

20,000

10,000

10,000

0
-50

-150

0
50

150

250

-150

-10,000

-50

50

250

150

250

(d) Squamous Cell Carcinoma

50,000

50,000

40,000

40,000

30,000

30,000

20,000

20,000

10,000

10,000

0
-50

150

-10,000

(c) Adenocarcinoma

-150

527

0
50

150

250

-10,000

-150

-50

50

-10,000

Fig. 3. Results of probabilistic sensitivity analysis by histological type. LYG, life years gained. Solid line: threshold of JPY 5 million/LYG (US$ 43,478/LYG). Dotted line: threshold
of JPY 10 million/LYG (US$ 86,957/LYG).

Probability cost effectiveness

of consolidation therapy on PFS and OS were reported with no


signicant differences between therapies in terms of safety proles
[9,10]. Furthermore, for consolidation therapy, authors said that
more patients can take further treatment as one of merit to prolong their survival time [9,10]. In addition, a pharmacoeconomic
analysis for consolidation therapy in NSCLC patients after initial
chemotherapy has been reported [18]. This latter study was based
on Medicare, and showed the cost effectiveness of maintenance
chemotherapy with pemetrexed for non-squamous cell carcinoma.
In our study, for non-squamous cell carcinoma, ICER based on LYG
was US$ 80,563/LYG (JPY 9,264,791/LYG), which was the most
cost-effective nding and similar to the previous study [18]. However, according to Ciuleanu et al. [9], only 11% of patients receiving
100%
90%
80%
70%
60%
50%
40%

All Histology
Non-Squamous
Adenocarcinoma

30%
20%
10%
0%
0

50,000

100,000

150,000

200,000

Willing to pay threshold (US$/LYG)


Fig. 4. Cost-effectiveness acceptability curve. LYG, life years gained.

placebo plus BSC group received second-line treatment with pemetrexed. Therefore, if more patients in the placebo plus BSC group
were treated with pemetrexed after progression, the ICER might
have been higher compared with the value based on our model.
Because PFS and OS for second-line patient with non-squamous
cell carcinoma were shown to be longer than those for all histology,
when pemetrexed was treated as their second-line treatment [5].
In the United States and the United Kingdom, US$
50,000100,000 per QALY and 20,00030,000 per QALY are
considered acceptable thresholds for cost-effectiveness. In Japan,
there is no consensus regarding the threshold of cost-effectiveness,
but JPY 56 million (US$ 43,47852,174) is sometimes used based
on previous reports [21]. In this study, all ICERs based on LYG
were more than US$ 80,563/LYG (JPY 9.2 million/LYG), and those
based on QALY were more than US$ 150,115/QALY (JPY 17.3
million/QALY), whose changes did not affect the cost-effectiveness
when conducting one-way sensitivity analysis by varying values
of PFS, OS, hospitalization period and palliative cost per cycle. In
addition, the probabilities of cost-effectiveness for non-squamous
cell carcinoma for JPY 5 and 10 million/LYG (US$ 43,478 and
86,956/LYG) were 0.0% and 54.7%, respectively. New approved
anti-cancer drugs have been noted to be associated with high
costs [11,12]. Last year, the American Society of Clinical Oncology
published guidelines that can be used to assess the costs of high
quality cancer treatment [28]. Although consolidation therapy was
determined to be cost-effective in a US study [18], results of this
study of a Japanese population covered by general medical insurance indicate that it will be difcult to get consolidation therapy
accepted as the standard of care in Japan. However, further study
and discussion are warranted, as recently, some drugs have been

528

T. Tsuchiya et al. / Lung Cancer 74 (2011) 521528

recommended for the end of life period even though their ICERs
are more than the threshold of cost-effectiveness [29,30].
Limitations of this study must be considered. This pharmacoeconomic analysis was not conducted using head-to-head clinical
study data, but was based on data from several previous clinical
studies. We performed our pharmacoeconomic analysis not only
for all histologies, but also for non-squamous cell carcinoma and
squamous cell carcinoma. However, the adverse event rates for
non-squamous cell carcinoma and squamous cell carcinoma were
considered to be the same as those for all histologies. Differences
in adverse event rates among different histologies could affect our
results.
The utility score at each Markov stage was estimated based on
a previous report [20]. However, the utility score was not matched
exactly to the stage of consolidation therapy. In this study, we found
favorable utility scores for consolidation therapy and unfavorable
utility scores for non-consolidation therapy, but the ICER based on
QALY was more than US$ 150,000/QALY.
Some limitation were considered, but we demonstrated a pharmacoeconomic analysis for consolidation therapy with pemetrexed
that considered the next therapy (i.e., second-line therapy for
consolidation therapy, third-line therapy for non-consolidation
therapy), and our Markov model could be applied to other drugs.
5. Conclusion
In conclusion, we conducted a pharmacoeconomic analysis
regarding consolidation therapy with pemetrexed after rst-line
chemotherapy from the point of view of the Japan health care payer.
The ICERs were more than US$ 80,563/LYG (JPY 9.2 million/LYG) for
all histology groups, which did not meet the threshold index of JPY
5 million/LYG (US$ 43,478/LYG). In Japan, this treatment method
is covered by medical insurance, but further assessment is needed
for this approach to become the standard of care for treatment of
NSCLC.
Conict of interest
Takanori Tsuchiya is an employee of Pzer Japan Inc.; however,
Tsuchiyas role in that company was not related to this analysis. No
other author has any conicts of interest associated with this study.
Acknowledgements
The authors thank Takeru Shiroiwa (College of Life Sciences,
Ritsumeikan University) who provided feedback and valuable comments. This pharmacoeconomic analysis was not supported by any
external funding.
References
[1] Cancer mortality (19582008) [Internet]. Tokyo: Center for Cancer Control and Information Services; 2008 [cited 2010 June 1]. Available from:
http://ganjoho.ncc.go.jp/professional/statistics/statistics.html [in Japanese].
[2] Pster DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, Baker Jr S, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung
cancer guideline: update 2003. J Clin Oncol 2004;22:33053.
[3] DAddario G, Felip E. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2009;20:
iv6870.
[4] Hanna N, Shepherd FA, Fossella FV, Pereira JR, De Marinis F, von Pawel J, et al.
Randomized phase III trial of pemetrexed versus docetaxel in patients with
non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol
2004;22:158997.

[5] Scagliotti G, Hanna N, Fossella F, Sugarman K, Blatter J, Peterson P, et al. The


differential efcacy of pemetrexed according to NSCLC histology: a review of
two phase III studies. Oncologist 2009;14:25363.
[6] Gridelli C, Maione P, Rossi A, Ferrara ML, Bareschino MA, Schetino C, et al. Potential treatment opinions after rst-line chemotherapy for advanced NSCLC:
maintenance treatment or early second-line? Oncologist 2009;14:13747.
[7] Jalal SI, Ademuyiwa FO, Hanna NH. The role of maintenance chemotherapy in
advanced nonsmall cell lung cancer. Curr Opin Oncol 2009;21:1105.
[8] Fedias PM, Dakhil SR, Lyss AP, Loesh DM, Waterhouse DM, Bromund JL, et al.
Phase III study of immediate compared with delayed docetaxel after front-line
therapy with gemcitabine plus carboplatin in advanced non-small-cell lung
cancer. J Clin Oncol 2009;27:5918.
[9] Ciuleanu T, Brodowicz T, Zielinski C, Kim JH, Krzakowski M, Laack E, et al.
Maintenance pemetrexed plus best supportive care versus placebo plus best
supportive care for non-small-cell lung cancer: a randomized, double-blind,
phase 3 study. Lancet 2009;374:143240.
[10] Cappuzzo F, Ciuleanu T, Stelmakh L, Cicenas S, Szczsna A, Juhsz E, et al.
Erlotinib as maintenance treatment in advanced non-small-cell lung cancer:
a multicentre, randomized, placebo-controlled phase 3 study. Lancet Oncol
2010;11:5219.
[11] Bach PB. Limits on Medicares ability to control rising spending on cancer drugs.
New Engl J Med 2009;360:62633.
[12] Fojo TGC. How much is life worth: Cetuximab, non-small cell lung cancer, and
the $440 billion question. J Natl Cancer Inst 2009;101:10448.
[13] Summary of medical care expenditure in 2007 [Internet]. Tokyo: Ministry
of Health, Labour and Welfare; 2009 [cited 2010 August 25]. Available from: http://www.mhlw.go.jp/toukei/saikin/hw/k-iryohi/07/index.html
[in Japanese].
[14] Koinuma N. Economic burden of cancer patients undergoing oral chemotherapy. Jpn J Cancer Chemother 2010;37:12303 [in Japanese].
[15] Asukai Y, Valladares A, Camps C, Wood E, Taipale K, Arellano J, et al. CostEffectiveness analysis of pemetrexed versus docetaxel in second-line treatment
of non-small cell lung cancer in Spain: results for the non-squamous histology population. BMC Cancer [Internet] 2010;10 [cited 2010 June 01]. Available
from: http://www.biomedcentral.com/1471-2407/10/26.
[16] Carlson JJ, Reyes C, Oestreicher N, Lubeck D, Ramsey SD, Veenstra DL. Comparative clinical and economic outcomes of treatments for refractory non-small
cell lung cancer (NSCLC). Lung Cancer 2008;61:40515.
[17] Klein R, Muehlenbein C, Liepa AM, Babineaux S, Wielage R, Schwartzberg
L. Cost-effectiveness of pemetrexed plus cisplatin as rst-line therapy
for advanced nonsquamous non-small cell lung cancer. J Thorac Oncol
2009;4:140414.
[18] Klein R, Wielage R, Muehlenbein C, Liepa AM, Babineaux S, Lawson A, et al. CostEffectiveness of pemetrexed as rst-line maintenance therapy for advanced
nonsquamous non-small cell lung cancer. J Thorac Oncol 2010;5:126372.
[19] Drummond MF, Sculpher MJ, Torrance GW, OBrien BJ, Stoddart GL. Methods
for the economic evaluation of health care programs. 3rd ed. New York: Oxford
University Press; 2005.
[20] Nafees B, Stafford M, Gavriel S, Bhalla S, Watkins J. Health state utilities for non small cell lung cancer. Health Qual Life Outcomes [Internet]
2008:6 [cited 2010 Jul 14]. Available from: http://www.ncbi.nlm.nih.gov/pmc/
articles/PMC2579282/pdf/1477-7525-6-84.pdf.
[21] Shiroiwa T, Sung YK, Fukuda T, Lang HC, Bae SC, Tsutani K. International survey on willingness-to-pay (WTP) for one additional QALY gained: what is the
threshold of cost effectiveness? Health Econ 2010;19:42237.
[22] Shepherd FA, Pereira JR, Ciuleanu T, Tan EH, Hirsh V, Thongprasert S, et al.
Erlotinib in previous treated non-small-cell lung cancer. New Engl J Med
2005;353:12332.
[23] National Health and Nutrition Survey [Internet]. Tokyo: Ministry of
Health, Labour and Welfare; 2010 [cited 2010 July 14]. Available from:
http://www.mhlw.go.jp/bunya/kenkou/eiyou09/01.html [in Japanese].
[24] Purchasing power parties comparative price level [Internet].
Paris:
Organization
for
Economic
Co-Operation
and
Development (OECD); 2010 [cited 2010 July 23]. Available from:
http://stats.oecd.org/Index.aspx?DataSetCode=PPPGDP.
[25] Quick reference of medical service fee. Tokyo: Igakutsushinsha; 2008 (2009
enlarged edition) [in Japanese].
[26] National health insurance drug price standard. Tokyo: Jiho; 2008 [in Japanese].
[27] Gold MR, Siegel JE, Russell LB, Weinstein MC. Cost-effectiveness in health and
medicine. New York: Oxford University Press; 1996.
[28] Meropol NJ, Schrag D, Smith TJ, Mulvey TM, Langdon Jr RM, Blum D, et al. American Society of Clinical Oncology guidance statement: the cost of cancer care. J
Clin Oncol 2009;27:386874.
[29] National institute for health and clinical excellence appraising life-extending,
end of life treatments [Internet]. London: National Institute for Health
and Clinical Excellence (NICE); 2009 [cited 2010 Dec 01]. Available from:
http://www.nice.org.uk/media/E4A/79/SupplementaryAdviceTACEoL.pdf.
[30] Mayor S. NICE recommends kidney cancer drug it previous rejected on cost
grounds. Br Med J 2009;338:b499.

Anda mungkin juga menyukai