Beruflich Dokumente
Kultur Dokumente
Lung Cancer
journal homepage: www.elsevier.com/locate/lungcan
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
522
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-
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 (%)
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
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
2nd-Line pemetrexed
524
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
525
Table 5
Estimated non-small cell lung cancer treatment costs per unit and total times per cycle (Refs. [25,26], specialists opinion).
Unit
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$/cycle)b
a
b
2 Weeks
Time
3320.5
6.1
Cycle
Day
3 Cycle
Cycle
Day
Cycle
Cycle
Time
Cycle
Cycle
Time
4084.6
0.1
0.9
55.8
89.9
4.1
43.5
4.3
16.4
20.8
34.6
1
29
1
1
24.3
19.1
182.6
1
4
1
7946
Time
Time
Time
Erlotinib
Subsequent cycle
1st Cycle
1
21
0.33
1
21
1
1
Before 2nd-line
therapy
1
3
21
1
1
1
1
1
3
1
0.5
4453
5
1
4
1
5682
1
1.5
1
0.25
2049
0.25
111
Including pharmacy fee, prescription fee, and technical base fee for dispensing pharmacist.
Due to rounding, the total costs are not equal to the sum of the gures in each column.
3. Results
3.1. Cost-effective analysis
Results of our analyses are shown in Table 6. For all histologies, the expected OS and QALYs were 451.8 days and 0.6770
QALYs for consolidation therapy and 366.2 days and 0.5511 QALYs
for non-consolidation therapy. ICER was US$ 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.
526
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$/QALY)
451.8
366.2
0.6770
0.5511
64,409
38,843
109,024
203,022
489.4
359.5
0.7321
0.5411
68,536
39,872
80,563
150,115
509.0
406.7
0.7608
0.6241
70,595
42,070
101,787
208,778
355.9
374.5
0.5267
0.5640
49,285
35,452
Dominated
Dominated
OS, overall survival; QALY, quality-adjusted life years; ICER, incremental cost-effectiveness ratio; LYG, life years gained.
solidation therapy were 4.0 months and 11.5 months, and those
for non-consolidation therapy were 2.0 months and 10.2 months,
respectively. These results are similar to those of Ciuleanu et al.
[9], and our model was considered appropriate based on their
ndings.
Based on our model, the ICERs for consolidation therapy for all
histologies were about US$ 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
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$/LYG)
Fig. 2. Results of one-way sensitivity analysis. ICER, incremental cost-effectiveness ratio; LYG, life years gained; OS, overall survival; PFS, progression-free survival; AE,
adverse events. Consolidation PEM: PFS, PFS for consolidation therapy with pemetrexed; Control BSC: PFS, PFS for BSC; 2nd Line PEM: PFS, PFS for 2nd line therapy with
pemetrexed; Consolidation PEM: OS, OS for consolidation therapy with pemetrexed; Control BSC: OS, OS for BSC; Consolidation PEM: rate, % of patients for consolidation
therapy with pemetrexed who received post therapy; Control BSC: rate, % of patients for BSC who received post therapy; 2nd Line Pem: rate, % of patients for 2nd line
treatment with pemetrexed who received post therapy; AE Rate Con Pem: % of adverse event (neutropenia, febrile neutropenia, leukopenia) for patient with consolidation
therapy with pemetrexed; Consolidation PEM: LOS, length of stay in hospital of patient for consolidation therapy with pemetrexed.
50,000
50,000
40,000
40,000
30,000
30,000
20,000
20,000
10,000
10,000
0
-50
-150
0
50
150
250
-150
-10,000
-50
50
250
150
250
50,000
50,000
40,000
40,000
30,000
30,000
20,000
20,000
10,000
10,000
0
-50
150
-10,000
(c) Adenocarcinoma
-150
527
0
50
150
250
-10,000
-150
-50
50
-10,000
Fig. 3. Results of probabilistic sensitivity analysis by histological type. LYG, life years gained. Solid line: threshold of JPY 5 million/LYG (US$ 43,478/LYG). Dotted line: threshold
of JPY 10 million/LYG (US$ 86,957/LYG).
All Histology
Non-Squamous
Adenocarcinoma
30%
20%
10%
0%
0
50,000
100,000
150,000
200,000
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
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.
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