Economic evaluation of adjuvant trastuzumab therapy for HER2-positive early-stage breast cancer: systematic review and quality assessment

Figures & data

Table 1. General Study Information and Methodology of EEs on Adjuvant Trastuzumab regimen for HER2-positive EBC patients

Study	Setting	Type of EE	Intervention	Comparator	Perspective	Time horizon
Neyt et al. [28]	Belgium	CEA	12 months of adjuvant trastuzumab plus CT	CT: Doxorubicin-cyclophosphamide-paclitaxel	Hospital	Not detailed
Dedes et al. [29]	Switzerland	CEA	12 months of adjuvant trastuzumab plus CT	CT: Anthracycline-based or Anthracycline-Taxane or Non- Anthracycline	Health care provider	15 years
Garrison et, al. [30]	US	CUA	12 months of adjuvant trastuzumab after CT	CT: Doxorubicin-cyclophosphamide-paclitaxel	Health care payer; Societal	20 years; Lifetime
Kurian et al. [31]	US	CUA	12 months of adjuvant trastuzumab after CT	CT 1: Doxorubicin-cyclophosphamide-paclitaxel CT 2: Carboplatin and docetaxel	Societal	Not detailed
Liberato et al. [32]	Italy	CUA	12 months of adjuvant trastuzumab after CT	CT: Doxorubicin-cyclophosphamide-paclitaxel	Health care system	15 years
Norum et al. [33]	Norway	CEA	FEC100 (fluorouracil, epirubicin, cyclophosphamide) regimen for six cycles on a 3-weekly basis followed by trastuzumab 3-weekly administration for 17 cycles	FEC100 regimen for six cycles on a 3-weekly basis	Not detailed	20 years
Neyt et al. [34]	Belgium	CEA	12 months of adjuvant trastuzumab plus CT	CT: Anthracycline-based or Anthracycline-Taxane or Non- Anthracycline	Health care payer	Lifetime
Shiroiwa et al. [35]	Japan	CEA	12 months of adjuvant trastuzumab plus CT	CT: Anthracycline-based or Anthracycline-Taxane or Non- Anthracycline	Health care payer	50 years
Chen et al. [44]	China	CUA	12 months of adjuvant trastuzumab after CT	CT: Anthracycline-Taxane	Health insurance system	Lifetime
Skedgel et al. [36]	Canada	CUA	12 months of adjuvant trastuzumab after CT	Regimen not detailed	Direct payer	25 years
Van Vlaenderen et al [37]	Belgium	CUA	Adjuvant trastuzumab plus CT	Regimen not detailed	Health care payer	Lifetime
Macedo et al. [38]	Portugal	CUA	12 months of adjuvant trastuzumab after CT	CT: Doxorubicin-cyclophosphamide-paclitaxel	Societal	45 years
Hall et al. [39]	UK	CUA	Trastuzumab administered every 3 weeks, sequentially after CT	CT: Anthracycline-based or Anthracycline-Taxane or Non- Anthracycline	Health care system	Lifetime
Hedden et al. [40]	Canada	CUA	12-month adjuvant trastuzumab plus CT	Regimen not detailed	Health care system	28 years
Buendia et al. [45]	Colombia	CUA	12 months of adjuvant trastuzumab after CT	CT: Doxorubicin-cyclophosphamide-paclitaxel	Health care payer	Lifetime
Aboutorabi et al. [46]	Iran	CUA	12 months of adjuvant trastuzumab after CT	CT: Doxorubicin-cyclophosphamide-docetaxel	Health care system	20 years
Pichon-Riviere et al. [47]	Argentina, Bolivia, Brazil, Colombia, Chile, Peru, Uruguay	CUA	12 months adjuvant trastuzumab plus CT	Regimen not detailed	Health care	Lifetime
Lang et al. [41]	Taiwan	CUA	12 months adjuvant trastuzumab plus CT	CT: combination of docetaxel or paclitaxel, doxorubicin and cyclophosphamide	National health insurance system	20 years
Leung et al. [42]	New Zealand	CUA	4-month CT regimen plus concurrent trastuzumab for a period of 12 months	CT: Taxane	Health care system	Lifetime
Seferina et al. [43]	Netherlands	CUA	12 months adjuvant trastuzumab plus CT	Regimen not detailed	Health care	Lifetime
Ansaripour et al. [48]	Iran	CUA	12 months adjuvant trastuzumab plus CT	Regimen not detailed	Healthcare system	Lifetime
Kongsakon et al. [49]	Thailand	CEA	12 months of adjuvant trastuzumab plus CT	CT: Taxane-only	Societal	Lifetime

Figure 1. Study selection flow diagram of economic evaluations of adjuvant trastuzumab therapy for HER2-positive EBC patients

Table 2. Summary of general study characteristics and different methodologies used in the included EEs (n = 22)

Study’s Characteristics	Number of studies	%
Study setting
High-Income Countries	16	72.7
Upper-Middle-Income Countries	6	27.3
First Author Affiliation
Academe	17	77.3
Research agency/group	4	18.2
Hospital	1	4.5
Funding Source
Research agencies/grants	5	22.7
Pharmaceutical industry	5	22.7
Academe	3	13.6
Declared no funding	3	13.6
Government	1	4.5
not reported	5	22.7
Type of Economic Evaluation
Cost-utility analysis	17	77.3
Cost-effectiveness analysis	5	22.7
Type of Model
Markov Model	20	90.9
Non-Markov Model	2	9.1
Intervention
Trastuzumab + anthracycline-taxane chemotherapy	9	40.9
Trastuzumab + taxane chemotherapy	3	13.6
Trastuzumab + any chemotherapy	3	13.6
Regimen not detailed	7	31.8
Incorporation of cardiotoxicity in the modeling
Yes	14	63.6
No	8	36.4
Study perspective
Healthcare payer/insurance	9	40.9
Healthcare system	6	27.3
Societal and Healthcare payer	2	9.1
Societal	2	9.1
Health Care provider	1	4.5
Hospital	1	4.5
not reported	1	4.5
Time horizon
10 years	1	4.5
15 years	2	9.1
20 years	2	9.1
25 years	1	4.5
28 years	1	4.5
45 years	1	4.5
50 years	1	4.5
Lifetime	11	50.0
Not reported	2	9.1
Cycle Length
3 weeks	1	4.5
1 month	3	13.6
3 months	3	13.6
1 year	10	45.5
Not applicable	2	9.1
Not reported	3	13.6
Discounting for costs
3%	15	68.2
3.5%	2	9.1
4%	1	4.5
5%	4	18.2
Discounting for outcomes
0%	1	4.5
1.5%	3	13.6
3%	11	50.0
3.5%	2	9.1
5%	4	18.2
Not reported	1	4.5
Types of uncertainty analysis
Univariate analysis alone	4	18.2
Probabilistic sensitivity analysis alone	2	9.1
Bivariate and Probabilistic sensitivity analysis	2	9.1
Univariate and Probabilistic sensitivity analysis	14	63.6

Table 3. Summary results of CHEERS scoring per reporting domain (n = 22)

Reporting Domain	Number of studies	%
Introduction
Title	20	90.9
Abstract	22	100.0
Methods
Background and Objectives	22	100.0
Target population and subgroups	22	100.0
Setting and location	22	100.0
Study perspective	21	95.5
Intervention	20	90.9
Comparator	20	90.9
Time Horizon	20	90.9
Discount Rate	22	100.0
Choice of Health Outcomes	21	95.5
Measurement of Effectiveness	18	81.8
Measurement and valuation of preference-based outcomes (n = 19)	4	21.1
Estimating costs and resources	22	100.0
Currency, price date and conversion	13	59.1
Choice of model	20	90.9
Assumptions	14	63.6
Analytical methods	22	100.0
Results
Study parameters	18	81.8
Incremental costs and outcomes	22	100.0
Characterizing uncertainty	22	100.0
Characterizing heterogeneity	5	22.7
Discussion
Study findings, limitations, generalizability, and current knowledge	22	100.0
Others
Source of Funding	17	77.3
Conflicts of Interest	15	68.2

Figure 2. Quality assessment of evidence used in economic evaluations of trastuzumab. Y-axis represents percentage of economic evaluations having a rank based on the Quality Assessment of Sources of Input Data using tool from Cooper et al. X-axis accounts for the high-income countries (HICs) and upper-middle-income countries (UMICs) assessed based on different input parameters

Table 4. Summary of cost-effectiveness analysis results of EEs of adjuvant trastuzumab therapy for HER2-positive EBC

Study	Country	Reported ICER at base year	Base year	ICER (USD 2017)	ICER I$ (PPP) 2017	CE Threshold (USD 2017)
HICs
ICER and Threshold = Cost per QALY gained
Garrison et, al. [30]	US	34,201 USD	2007	40,420	40,420	81,949
		27,637 USD		32,663	44,743
Kurian et al. [31]	US	39,982 USD	2007	47,253	47,253	42,547–354,555
Liberato et al. [32]	Italy	18,970 USD	2007	21,790	29,849	Not reported
Skedgel et al. [36]	Canada	72,292 Canadian Dollars	2007	78,929	65,230	54,590–109,180
Van Vlaenderen et al [37]	Belgium	10,315 Euros	2005	15,956	19,458	61,874
Macedo et al. [38]	Portugal	7,790 Euros	2010	11,334	18,580	Not reported
Hall et al. [39]	UK	25,803 Pounds	2008	57,803	82,575	67,204
Hedden et al. [40]	Canada	13,095 USD	2012	15,355	12,690	58,630
Lang et al. [41]	Taiwan	51,863 USD	2016	51,863	3,492	67,355
Leung et al. [42]	New Zealand	56,050 New Zealand Dollars	2011	47,231	31,073	37,920–75,840
Seferina et al. [43]	The Netherlands	4,304 Euros	2012	6,018	7,523	111,859
UMICs ICER and Threshold = Cost per QALY gained
Chen et al. [44]	China	8,046 USD	2009	9,976	3,218	Not reported
Buendia et al. [45]	Colombia	71,491 USD	2010	93,371	72	19,591
Aboutorabi et al. [46]	Iran	51,302 USD	2010	174,901	17	34,092
Pichon-Riviere et al. [47]	Argentina, Bolivia, Brazil, Colombia, Chile, Peru, Uruguay	42,104– 110,283 USD	2012	63,036–153,554	80–74,905*	11,648–14,971
Ansaripour et al. [48]	Iran	16,695 Euros	2017	18,088	1.76	22,572
Kongsakon et al. [49]	Thailand	3,387 USD	2012	3,526	286	5,148

Figure 3. Incremental cost-effectiveness ratios (I$, 2017) of trastuzumab and corresponding thresholds reported from health economic evaluation. Y-axis represents the incremental cost-effectiveness ratios (ICERs) reported from different economic evaluations. X-axis accounts for EEs assessed from high-income countries (HICs) and upper-middle-income countries (UMICs)

Neyt M, Albrecht, J, Cocquyt V. An economic evaluation of herceptin in adjuvant setting: the breast cancer international research group 006 trial. Ann Oncol. 2006;17(3):381–390.

 PubMed Web of Science ®Google Scholar

Dedes K, Szucs TD, Imesch P, et al. Cost-effectiveness of trastuzumab in the adjuvant treatment of early breast cancer: a model-based analysis of the HERA and FinHer trial. Ann Oncol. 2007;18(9):1493–1499.

 PubMed Web of Science ®Google Scholar

Garrison LP Jr, Lubeck D, Lalla D, et al. Cost-effectiveness analysis of trastuzumab in the adjuvant setting for treatment of HER2-positive breast cancer. Cancer. 2007 Aug 1;110(3):489–498.

 PubMed Web of Science ®Google Scholar

Kurian AW, Thompson R, Gaw AF, et al. A cost-effectiveness analysis of adjuvant trastuzumab regimens in early HER2/neu-positive breast cancer. J Clin Oncol. 2007 Feb 20;25(6):634–641.

 PubMed Web of Science ®Google Scholar

Liberato NL, Marchetti M, Barosi G. Cost effectiveness of adjuvant trastuzumab in human epidermal growth factor receptor 2–positive breast cancer. J Clin Oncol. 2007;25(6):625–633.

 PubMed Web of Science ®Google Scholar

Norum J, Olsen J, Wist EA, et al. Trastuzumab in adjuvant breast cancer therapy. A model based cost-effectiveness analysis. Acta Oncol. 2007;46(2):153–164.

 PubMed Web of Science ®Google Scholar

Neyt M, Huybrechts M, Hulstaert F, et al. Trastuzumab in early stage breast cancer: a cost-effectiveness analysis for Belgium. Health Policy. 2008;87(2):146–159.

 PubMed Web of Science ®Google Scholar

Shiroiwa T, Fukuda T, Shimozuma K, et al. The model-based cost-effectiveness analysis of 1-year adjuvant trastuzumab treatment: based on 2-year follow-up HERA trial data. Breast Cancer Res Treat. 2008 Jun;109(3):559–566.

 PubMed Web of Science ®Google Scholar

Chen W, Jiang Z, Shao Z, et al. An economic evaluation of adjuvant trastuzumab therapy in HER2-positive early breast cancer. Value Health. 2009 Nov-Dec;12(Suppl 3):S82–4.

 PubMed Web of Science ®Google Scholar

Skedgel C, Rayson D, Younis T. The cost-utility of sequential adjuvant trastuzumab in women with Her2/neu-positive breast cancer: an analysis based on updated results from the HERA trial. Value Health. 2009 Jul-Aug;12(5):641–648. .

 PubMed Web of Science ®Google Scholar

Van Vlaenderen I, Canon J, Cocquyt V, et al. Trastuzumab treatment of early stage breast cancer is cost-effective from the perspective of the Belgian health care authorities. Acta Clin Belg. 2009 Mar-Apr;64(2):100–112.

 PubMed Web of Science ®Google Scholar

Macedo A, Monteiro I, Andrade S, et al. [Cost-effectiveness of trastuzumab in the treatment of early stages breast cancer patients, in Portugal]. Acta Med Port. 2010 May-Jun;23(3):475–482.

 PubMed Web of Science ®Google Scholar

Hall PS, Hulme C, McCabe C, et al. Updated cost-effectiveness analysis of trastuzumab for early breast cancer: a UK perspective considering duration of benefit, long-term toxicity and pattern of recurrence. Pharmacoeconomics. 2011 May;29(5):415–432.

 PubMed Web of Science ®Google Scholar

Hedden L, O’Reilly RS, Lohrisch C, et al. Assessing the real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu positive breast cancer. Oncologist. 2012;17(2):164–171.

 PubMed Web of Science ®Google Scholar

Buendía JA, Vallejos C, Pichón-Rivière A. An economic evaluation of trastuzumab as adjuvant treatment of early HER2-positive breast cancer patients in Colombia. Biomedica. 2013 Jul-Sep;33(3):411–417.

 PubMed Web of Science ®Google Scholar

Aboutorabi AHM, Ghaderi H, Salehi M, et al. Cost-effectiveness analysis of trastuzumab in the adjuvant treatment for early breast cancer. Glob J Health Sci. 2014 Aug 14;;7(1):98–106.

 PubMedGoogle Scholar

Pichon-Riviere A, Garay O, Augustovski F, et al. Implications of global pricing policies on access to innovative drugs: the case of trastuzumab in seven Latin American countries. Int J Technol Assess Health Care. 2015 Jan;31(1–2):2–11.

 PubMed Web of Science ®Google Scholar

Lang HC, Chen H, Chiou TJ, et al. The real-world cost-effectiveness of adjuvant trastuzumab in HER-2/neu-positive early breast cancer in Taiwan. J Med Econ. 2016 Oct;19(10):923–927.

 PubMed Web of Science ®Google Scholar

Leung W, Kvizhinadze G, Nair N, et al. Adjuvant Trastuzumab in HER2-positive early breast cancer by age and hormone receptor status: a cost-utility analysis. PLoS Med. 2016 Aug 9;;13(8):e1002067.

 PubMed Web of Science ®Google Scholar

Seferina SC, Ramaekers B, de Boer M, et al. Cost and cost-effectiveness of adjuvant trastuzumab in the real world setting: A study of the Southeast Netherlands breast cancer consortium. Oncotarget. 2017;8(45):79223–79233.

 PubMedGoogle Scholar

Ansaripour A, Uyl-de Groot CA, Redekop WK. Adjuvant trastuzumab therapy for early HER2-positive breast cancer in Iran: a cost-effectiveness and scenario analysis for an optimal treatment strategy. Pharmacoeconomics. 2018;36(1):91–103.

 PubMed Web of Science ®Google Scholar

Kongsakon R, Lochid-Amnuay S, Kapol N, et al. From research to policy implementation: trastuzumab in early-stage breast cancer treatment in Thailand. Value Health Reg Issues. 2018;18:47–53.

 PubMedGoogle Scholar