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Breast Cancer Res Treat. Author manuscript; available in PMC 2015 August 10.
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Published in final edited form as:

Breast Cancer Res Treat. 2015 May ; 151(1): 27–40. doi:10.1007/s10549-015-3383-6.

A review of systematic reviews of the cost-effectiveness of

hormone therapy, chemotherapy, and targeted therapy for
breast cancer
Vakaramoko Diaby1, Rima Tawk#2, Vassiki Sanogo#3,4, Hong Xiao5, and Alberto J.
Montero6
1Division
of Economic, Social and Administrative Pharmacy College of Pharmacy and
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Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL, USA

2Instituteof Public Health, College of Pharmacy and Pharmaceutical Sciences, Florida A&M
University, Tallahassee, FL, USA
3Unitéde Formation et de Recherche (UFR) Sciences Economiques et Développement,
Université Alassane Ouattara, Bouaké, Côte d'Ivoire
4Center for Economic Forecasting and Analysis (CEFA), Florida State University (FSU),
Tallahassee, FL, USA
5College of Pharmacy, University of Florida, Gainesville, FL, USA
6Taussig Cancer Center Department of Solid Tumor Oncology, Cleveland, OH, USA
#
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These authors contributed equally to this work.

Abstract
Breast cancer is a global health concern. In fact, breast cancer is the primary cause of death among
women worldwide and constitutes the most expensive malignancy to treat. As health care
resources are finite, decisions regarding the adoption and coverage of breast cancer treatments are
increasingly being based on “value for money,” i.e., cost-effectiveness. As the evidence about the
cost-effectiveness of breast cancer treatments is abundant, therefore difficult to navigate,
systematic reviews of published systematic reviews offer the advantage of bringing together the
results of separate systematic reviews in a single report. As a consequence, this paper presents an
overview of systematic reviews of the cost-effectiveness of hormone therapy, chemotherapy, and
targeted therapy for breast cancer to inform policy and reimbursement decision-making. A
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systematic review was conducted of published systematic reviews documenting cost-effectiveness

analyses of breast cancer treatments from 2000 to 2014. Systematic reviews identified through a
literature search of health and economic databases were independently assessed against inclusion
and exclusion criteria. Systematic reviews of original evaluations were included only if they
targeted breast cancer patients and specific breast cancer treatments (hormone therapy,
chemotherapy, and targeted therapy only), documented incremental cost-effectiveness ratios, and
were reported in the English language. The search strategy used a combination of these key words:

Vakaramoko Diaby diaby_v@yahoo.fr; vakaramoko.diaby@famu.edu.

Conflict of interest The authors have no conflicts of interest to declare.
 Diaby et al. Page 2

“breast cancer,” “systematic review/meta-analysis,” and “cost-effectiveness/economics.” Data

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were extracted using predefined extraction forms and qualitatively appraised using the assessment
of multiple systematic reviews (AMSTAR) tool. The literature search resulted in 511
bibliographic records, of which ten met our inclusion criteria. Five reviews were conducted in the
early-stage breast cancer setting and five reviews in the metastatic setting. In early-stage breast
cancer, evidence about trastuzumab value differed by age. Trastuzumab was cost-effective only in
women with HER2-positive breast cancer younger than 65 years and over a life-time horizon. The
cost-effectiveness of trastuzumab in HER2-positive metastatic breast cancer yielded conflicting
results. The same conclusions were reached in comparisons between vinorelbine and taxanes. In
both early stage and advanced/metastatic breast cancer, newer aromatase inhibitors (AIs) have
proved cost-effective compared to older treatments. This overview of systematic reviews shows
that there is heterogeneity in the evidence concerning the cost-effectiveness of hormone therapy,
chemotherapy, and targeted therapy for breast cancer. The cost-effectiveness of these treatments
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depends not only on the comparators but the context, i.e., adjuvant or metastatic setting, subtype
of patient population, and perspective adopted. Decisions involving the cost-effectiveness of
breast cancer treatments could be made easier and more transparent by better harmonizing the
reporting of economic evaluations assessing the value of these treatments.

Keywords
Breast cancer; Hormone therapy; Chemotherapy; Targeted therapy; Economic evaluation; Cost-
effectiveness; Systematic review

Background
Breast cancer, a type of cancer that develops from breast tissue, [1] is a global health
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concern. In fact, breast cancer is the primary cause of death among women worldwide [2]
and constitutes one of the most expensive malignancies to treat. [3] As such, breast cancer
puts a heavy burden on patients and their families, as well as healthcare systems across the
world. [4].

Strategies to combat the breast cancer pandemic are geared toward prevention, early
detection, and treatment. [5] Over the past decades, medical breakthroughs have shown that
breast cancer is a multifaceted disease with different subtypes and stages. This medical
progress has shaped the development of strategies to treat breast cancer more efficiently.

Since health care systems worldwide have finite resources, the adoption (clinical decision)
and coverage of new breast cancer treatments are increasingly being made based on the
concept of “value for money” (cost-effectiveness), which takes into consideration the costs
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associated with the selection of a particular treatment over its comparators. [6–8].

There is a plethora of published studies (individual studies and systematic reviews) of the
cost-effectiveness of breast cancer treatments that decision-makers can access. However, for
most decision-makers, it is difficult to navigate through and utilize this large body of
evidence when making decisions routinely. Systematic reviews of published systematic
reviews are designed to help solve this issue by bringing together the results of separate

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systematic reviews in a single report. Systematic reviews themselves vary in terms of quality
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and scope and may duplicate studies. [9, 10] Using evidence from reviews of systematic
reviews allows quick and easy comparison of existing findings of a large volume of studies,
and identification of the direction (unidirectional or conflicting evidence) and magnitude of
the evidence.

The objective of this study was to systematically identify and review published systematic
reviews on the cost-effectiveness of hormone therapy, chemotherapy, and targeted therapy
for breast cancer, building on the methods proposed by Smith et al. [10] Based on the
findings of the review, the authors make recommendations for future research aimed at
documenting the cost-effectiveness of breast cancer treatments in order to enlighten policy
and reimbursement decision-making.

Methods
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Sources and search strategy

A systematic review was conducted of published systematic reviews documenting the cost-
effectiveness of breast cancer treatments. As such, the unit of analysis in the current study is
a systematic review of studies of the topic under evaluation, unlike traditional systematic
reviews. The systematic reviews were identified through a literature search of the following
databases for the period January 1, 2000–December 31, 2014: Ovid Medline and Embase,
the US National Library of Medicine's PubMed, and ISI's Web of Knowledge, Cochrane
Database of Systematic Reviews, Center for Reviews and Dissemination (CRD) database
(including the National Health Service Economic Evaluation Database, the Database of
Abstracts of Reviews of Effects, and Health Technology Assessments), and Econlit.
Keywords used to develop the search strategy comprised “breast cancer” terms coupled with
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“systematic review/meta-analysis” and “cost-effectiveness/economics” terms using Boolean

operators as well as truncation and wildcard operators (see Appendix). In addition, a manual
search of the reference lists of previously captured articles was carried out to increase the
likelihood of locating relevant systematic reviews. The grey literature was also searched
using “Grey Matters,” [11] a tool developed by the Canadian Agency for Drugs and
Technologies in Health (CADTH) to help find evidence that is not commercially published.
Finally, one expert AJM in the field of breast cancer provided the authors with feedback on
potential sources of evidence on the topic.

Review selection process

The records obtained from the literature search, containing titles and abstracts of the
reviews, were exported into Refworks. Figure 1 depicts the selection process of articles
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included in our systematic review. First, duplicates were identified and removed from the
pool of bibliographic records. Then, three independent reviewers (VD, RT, and VS)
screened the abstracts of the unique records, and those considered out of scope [no
systematic review conducted, review targeting interventions other than treatments and a
different disease than breast cancer] were discarded. Afterward, available full-text copies of
the remaining papers were retrieved, perused, and assessed against the inclusion and
exclusion criteria by VD, RT, and VS. Disagreements were resolved by consulting with two

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additional reviewers (HX and AJM). Systematic reviews were included only if they targeted
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breast cancer patients, specific breast cancer treatments (hormone therapy, chemotherapy,
and targeted therapy), documented incremental cost-effectiveness ratios and were reported
in English language. The review was not restricted to a specific sub-type or stage of breast
cancer. However, articles were excluded if they presented costs or benefits information only,
described a methodological approach only, or were non-journal papers except reports.

Study characteristics, findings, and quality assessment of reviews

Data from the included papers were extracted and synthesized (numerically) using
predefined extraction forms documenting the characteristics of the systematic reviews
(Tables 1, 2). The characteristics of the studies included in the assessed systematic reviews
(Tables 3, 4, 5) were interventions, objectives, main conclusions, (Table 6) and the quality
assessment of systematic reviews (Table 7). As suggested by Smith et al. [10] the quality
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and strength of evidence of each systematic review were assessed against a validated tool
named assessment of multiple systematic reviews (AMSTAR). [12] The tool covers 11
domains from the establishment of the research question to the assessment of publication
bias. AMSTAR is purported to be an enhanced and refined version of previous tools. [12]
Since the tool does not allow for quantifying the performance of the systematic reviews
against its domain, we developed a scoring scale matching the fourth-point response choices
of the AMSTAR, based on previously published approaches. [5, 13] The four-point response
choices, Yes, No, Can't answer, assign the scores 1, 0, 0. For dimensions that were not
applicable, the maximum score was reduced by 1 for comparability purposes across studies.
The new scoring scale was used to adapt the existing AMSTAR tool to fit our needs (Table
1). The scores were expressed in percentages to facilitate the comparison of the
performances of the systematic review with regard to quality.
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Results
Literature search
The literature search yielded 511 bibliographic records (including records obtained from
manual and grey literature searches) (Fig. 1). From this initial pool of records, 56 duplicates
were identified and excluded. Following the titles and abstracts review, 455 (including one
reference retrieved by hand search) studies were rejected for being out of scope. Of the
remaining records subject to the full-text review, seven were removed using the exclusion
criteria. The final set of bibliographic records reviewed was composed of ten systematic
reviews.

Characteristics of the reviews and their included studies

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Ten systematic reviews that both assessed studies on the cost-effectiveness of breast cancer
treatment strategies and met our inclusion criteria were published between 2001 and 2014.
The reviews were similar in regard to their purpose, but different in the stated objectives and
interventions compared. Table 2 highlights the main characteristics of each systematic
review. Regarding the time horizon covered for review searches, only one study was from
inception of the database to 2011. [14] For the remainder, three review searches covered 15
years of publications, [15–17] two review searches were conducted over a 10-year period,

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[18, 19] two review studies had a time horizon of 6 years, [20, 21] and the last two review
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searches covered, respectively, 9 [22] and 3 years. [23] The sample sizes of the systematic
reviews ranged between four [16, 23] and 23. [20] Tables 3, 4, 5 highlight the main
characteristics of studies that were included in each of the systematic reviews. All of the
reviews covered a wide spectrum of geographical areas [Euro zone; North America; Asia
Latin America; and Australasian eco zone (Table 3)] in which the individual economic
evaluations were conducted. In terms of breast cancer stage, 54 % of economic evaluations
assessed treatment strategies for advanced stage cancer, while 45 % of them evaluated
treatment options for early stage. 59 % of these economic evaluations were cost-
effectiveness analyses, while 41 % were cost-utility analyses. The majority (76 %) of these
evaluations were model-based and the remaining evaluations were trial-based. With regard
to the temporal framework of the economic evaluations included in the reviews, 18 and 82
% of these studies were conducted over a short-term (between 0 and 5 years) and long-term
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(beyond 5 years) periods, respectively. The most commonly adopted perspective in reviewed
economic evaluations was the payer perspective (71 %). The societal perspective was
adopted in 10 % of the cases, while other perspectives (different than payer or societal—
e.g., US hospital) represented 19 % of the cases. Data sources were relatively well-
documented in the majority of individual studies. These studies generally applied
discounting, conducted sensitivity analyses, and presented incremental analyses.

Study findings and quality assessment of the reviews

The study findings can be categorized into two groups, results for early breast cancer and
advanced/metastatic breast cancer. These results are summarized in Table 6.

Early breast cancer—Five reviews examined the cost-effectiveness of treatments for

early breast cancer.
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John-Baptiste et al. [17] reviewed economic evaluations that compared AIs (anastrozole and
letrozole) versus tamoxifen. Studies included in this review suggest that choosing AIs for
first-line therapy for early breast cancer represents good value for money compared to
tamoxifen. However, John-Baptiste et al. [17] recommended that caution be used when
drawing conclusions about the value of AIs versus tamoxifen, as these studies tend to
overestimate the cost-effectiveness of AIs. Their results may, therefore, be suboptimal to
inform policy decisions. This review was of relative good scientific quality (score = 70 %)
as per the standards of the modified AMSTAR tool.

In the same vein, Frederix et al. [19] appraised economic evaluations comparing AIs
(anastrozole, letrozole, exemestane, combinations) versus tamoxifen. Unfortunately, the
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included studies did not come to a consensus as to whether AIs represent better value for
money compared to tamoxifen. In fact, some economic evaluations presented a very low
incremental cost-effectiveness ratio (ICER) while others presented very high ICER,
although they used very similar data sources. The review by Frederix et al. was judged of
relatively good scientific quality (score = 70 %), according to the modified AMSTAR tool
standards.

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Ferrusi et al. [14] reviewed economic evaluations of adjuvant trastuzumab targeted therapy
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to assess the extent to which decision support recommendations were adopted by economic
evaluations producers. The adjuvant use of trastuzumab was the base-case scenario in these
economic evaluations, while the long-term use of trastuzumab in MBC was considered in
sensitivity analyses. Trastuzumab appeared to be generally cost-effective when its use was
limited to a year. The short-term use (base-case scenario) of trastuzumab was more cost-
effective than longer term use (sensitivity analysis) from a health economic point of view.
The cost-effectiveness of trastuzumab was heavily influenced by the choice of testing
strategy (details not reported). The scientific quality of this review was judged fair (score =
60 %), according to the modified AMSTAR standards.

Chan et al. [18] assessed economic evaluations comparing trastuzumab versus standard
treatment/chemotherapy without trastuzumab. The authors stated that the ICERs reported in
their systematic review supported the conclusion that trastuzumab was cost-effective as
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adjuvant therapy in women with HER2-positive breast cancer younger than 65 years, over a
life-time horizon. However, adjuvant trastuzumab was not found to be cost-effective when
used in HER2-positive breast cancer patients older than 75 years, or with a time horizon of
less than 10 years. Using the modified AMSTAR tool, this review was judged fair (score =
60 %) in terms of its scientific quality.

Norum 2006 [23] assessed the cost-effectiveness of adjuvant trastuzumab in early breast
cancer and made recommendations for future economic evaluations. Even though the
number of individual studies (4) included in the review was limited, the adjuvant
trastuzumab in early breast cancer was found cost-effective, except for subgroups of stage
III breast cancer and seniors (65 years and beyond). The scientific quality of this review was
deemed relatively good (score = 70 %), based on the modified AMSTAR tool.
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Advanced/metastatic breast cancer—In the metastatic setting, five reviews examined

the cost-effectiveness of treatments for breast cancer.

Benedict et al. [21] evaluated the cost-effectiveness of aromatase inhibitors (AIs)—

letrozole, exemestane, anastrozole, and fulvestrant in metastatic hormone receptor-positive
breast cancer relative to either tamoxifen or megestrol as first- and second-line therapy,
respectively. These analyses suggested, that AIs were highly cost-effective in the metastatic
setting irrespective of country and the line of therapy. This review was judged of relative
good scientific quality as suggested by the score (70 %) obtained using the modified
AMSTAR tool.

Foster et al. [20] assessed the economic impact of various metastatic breast cancer (MBC)
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treatments including hormonal and targeted therapies. The results of the economic
evaluations included in the review suggest that endocrine therapies were very cost-effective.
Specifically, newer AIs (anastrozole and letrozole) were found to be cost-effective in the
first-line therapy when compared to tamoxifen, in patients with hormone receptor-positive
breast cancer. In addition, various studies included in the systematic review by Foster al.
[20] looked at the cost-effectiveness of fulvestrant (second or third line option) in hormone
receptor-positive postmenopausal women with MBC. The cost-effectiveness of adding

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fulvestrant to existing treatment sequences, including adding fulvestrant to a chemotherapy

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sequence, was either cost-saving or highly cost-effective compared to a non-fulvestrant

sequence. In regard to the cost-effectiveness of targeted therapies, the ICERs were
influenced by the chemotherapy that these targeted therapies were paired with. Trastuzumab
was found cost-effective when administered alone as first-line therapy in HER2-positive
breast cancer patients compared to standard chemotherapy. The same conclusion was
reached when trastuzumab was combined with paclitaxel compared with chemotherapy
alone or when trastuzumab was compared to Vinorelbine. However, the combination of
trastuzumab plus capecitabine versus capecitabine alone was not found cost-effective. Other
targeted therapies were also assessed as part of the systematic review by Foster et al. [20].
The combination of lapatinib and capecitabine, for the treatment of HER2-positive advanced
and MBC patients (not naïve to trastuzumab), was cost-saving compared with trastuzumab-
containing regimens. The combination was not cost-effective compared to capecitabine
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alone or vinorelbine alone. The same conclusion was reached when bevacizumab was
combined with chemotherapy regimens in the treatment of HER2-positive MBC patients.
Using the modified AMSTAR tool, this review was judged fair (score = 60 %) in terms of
its scientific quality.

Blank et al. [22] reviewed the data on the cost-effectiveness of cytotoxic chemotherapy and
targeted therapy (trastuzumab and bevacizumab) for MBC. The pharmacoeconomic studies
included in this review yielded varying conclusions. Evaluations on cytotoxic agents showed
mainly favorable ICERs, while those on targeted therapies indicated both favorable and non-
favorable ratios. Indeed, Bevacizumab used in combination with paclitaxel as first-line
option was not cost-effective compared with paclitaxel alone. As for trastuzumab, its cost-
effectiveness differed according to the perspective of the studies (payer, hospital, societal)
and the regimen it was part of. The scientific quality of this review was considered relatively
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good (modified AMSTAR score = 70 %).

Parkinson et al. [15] appraised the quality of economic evaluations of trastuzumab in the
metastatic setting, and identified potential determinants of conflicting results. Trastuzumab
was paired with a taxane (docetaxel or paclitaxel), an AI (anastrozole), or a cytotoxic agent
(capecitabine). The assessed economic evaluations were not in agreement regarding the
cost-effectiveness of trastuzumab in the treatment of HER2-positive MBC. The authors
suggested potential explanations for these results. The differences may be attributed to the
judgments made by the authors selecting the comparators, extrapolating randomized
controlled trial data, and making assumptions in modeling costs and outcomes. In terms of
scientific quality, the review was judged fair with a modified AMSTAR score of 60 %.
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Lewis et al. [16] aimed at evaluating the clinical effectiveness and cost-effectiveness of
vinorelbine compared to taxane therapy (docetaxel or paclitaxel, both administered every 3
weeks) in the metastatic setting. The review yielded conflicting results. In fact, one
economic evaluation reported that vinorelbine was a preferred strategy over taxane therapy,
while another concluded that vinorelbine was less effective and less expensive than taxane
therapy, and a third evaluation found vinorelbine to be inferior to taxanes. The authors
concluded that additional studies were needed to shed light on the true cost-effectiveness of

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vinorelbine in treating metastatic breast cancer. This review had the highest score in terms of
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scientific quality (modified AMSTAR score = 100 %) among the systematic reviews.

Discussion
This review has focused on published systematic reviews of the cost-effectiveness of
hormone therapy, chemotherapy, and targeted therapy for breast cancer, conducted from
2000 to 2014. A total of 511 bibliographic records were found, with 10 included and fully
reviewed. The time horizon for literature review searches ranged from three [23] to 15 years
[15–17]. In addition, the sample size of the systematic reviews varied between four [16, 23]
and 23 studies [20]. Most economic evaluations covered a long-term temporal framework
while adopting a model-based cost-effectiveness analysis (CEA) design, and a payer
perspective. The studies included in the review included patients from most of the world
except for Africa. The study findings can be summarized as follows. First, in early stage
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postmenopausal hormone receptor-positive breast cancer, there was heterogeneity in the

evidence regarding the cost-effectiveness of AIs versus tamoxifen, i.e., studies investigating
these treatments both low and high ICERs. As such, additional studies are needed to shed
light on the cost-effectiveness of AIs versus tamoxifen at this stage. [17, 19] That being said,
we can reasonably anticipate that future economic studies will likely find AIs highly cost-
effective compared to tamoxifen because of longer follow-up in adjuvant AI studies and
lower cost of AIs since they have become all generic. In the advanced/metastatic breast
cancer setting, newer AIs have proved cost-effective compared to older treatments. [20, 21]
Second, the cost-effectiveness of trastuzumab was influenced by age and time horizon.
Trastuzumab was cost-effective as adjuvant therapy in women with HER2 + breast cancer
younger than 65 years and over a life-time horizon. However, trastuzumab was not found to
be cost-effective as adjuvant therapy in HER2 + breast cancer patients older than 75 years or
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with a time horizon of less than 10 years. [18] The cost-effectiveness of trastuzumab was
also evaluated in the metastatic setting. The systematic reviews appraising the cost-
effectiveness of trastuzumab for metastatic breast cancer were inconclusive, meaning that
individual evaluations yielded conflicting results. [15, 20] Similarly, Lewis et al. [16]
assessed the clinical effectiveness and cost-effectiveness of vinorelbine compared to taxane
therapy in the management of MBC. The review also yielded conflicting results. We did not
find a connection between the discrepancies in cost-effectiveness results of studies and their
geographical area of origin, although most studies were carried out in middle- to high-
income countries. All the reviews were assessed for scientific quality against the modified
AMSTAR tool. Their quality ranged from fair [14, 15, 18, 20] to excellent [16].

Like all systematic reviews, ours is prone to a number of limitations. In fact, our searches
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were limited to English articles and restricted to a time frame between 2000 and 2014. The
review focused on specific treatments only, although breast control treatment strategies have
a broader scope, including additionally early detection and diagnosis. The limitations
inherent in this review may have resulted in some studies being missed in the literature
searches. We also acknowledge the possibility that errors may have been made in the
interpretation of the results of the systematic reviews that were reviewed. That being said, it
is the authors' understanding that the guidelines for overview of systematic reviews were
adhered to [10].

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Concluding remarks
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Evidence produced by economic evaluations in general, and in the breast cancer field in
particular, have the potential of informing clinical and reimbursement decision-making. The
literature contains a plethora of economic evaluations dealing with different aspects of
breast cancer treatments. It is therefore, important to ensure that all relevant economic
evidence is appropriately synthesized to enable and facilitate reimbursement of potentially
valuable treatments by decision-makers. Based on the review of the studies included in the
current paper, some recommendations previously published by many authors apply and are
recapped here.

The ability for decision-makers to arrive at an appropriate conclusion about the cost-
effectiveness of breast cancer treatment strategies could be made easier and more
transparent by better harmonizing the reporting of economic evaluations assessing the value
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of these treatment strategies. Even though some efforts have been made to tackle this issue
(e.g., task forces on best practices in reporting the results of economic evaluations from
different professional societies, such as the International Society for Pharmacoeconomics
and Outcomes Research), room still exists to improve and strengthen recommendations for
standardization in modeling treatment strategies in breast cancer. Doing so will facilitate
comparability and consistency of economic evaluations of breast cancer treatments across
healthcare jurisdictions worldwide. The stakes are high since providing coverage for a
treatment that, in reality, is not cost-effective will result in huge opportunity costs and
prevent other patients from accessing alternatives that are potentially valuable. In turn, a
policy decision that denies coverage of a treatment that, in reality, is cost-effective will
certainly prevent patients from getting access to effective treatments, which itself may result
in productivity losses. Future research investigating ways to improve and ensure adherence
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to guidelines for the reporting of economic evaluations is therefore warranted.

Acknowledgments
The authors are grateful to Julian Renaine, data research librarian at Florida State University, for his help in
accessing some databases as part of our literature search. Janet P. Barber, Ph.D., helped edit the final version of the
paper.

Appendix

Search strategies for databases included in the review

See Tables 8, 9, 10, 11, 12, 13, 14.
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Table 8

Search in Ovid Medline (Searched on January 17th, 2015)

Search query Records

1 Exp breast neoplasms/ 220,788
2 Breast$ adj3 neoplasm$.tw. 1359
3 ((Breast$ adj3 cancer$) OR (breast$ adj3 carcino$)).tw. 195,725

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Search query Records

4 OR/1–3 257,657
5 Cost:.mp. 415,611
6 Cost-benefit analys:.mp. 61,927
7 Health care costs.mp. 33,335
8 OR/5–7 415,620
9 (Systematic$adj2 review$).mp. 0
10 (Systematic$adj2 overview$).mp. 0
11 (Meta analy* OR metaanaly*).ti,ab,pt. 74,616
12 Review.pt. 1,904,235
13 Search:.tw. 223,617
14 OR/9–13 2,069,965
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15 4 AND 8 AND 14 1343

16 Limit 15 to (English and year = “2000–2014”) 37

Table 9

Search in OVID Embase

Search query Records

1 Breast tumor.mp. or (breast and cancer).ti,ab. 94,033
2 (Cost or costs).tw. 107,6024
3 (Research synthesi OR pooled OR systematic review.de OR meta-analysis.de OR (evidence base OR 243,398
evidence based OR methodol* OR systematic OR quantitative* OR studies OR search* AND
(review.de OR review.it)))
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4 1 AND 2 AND 3 725

5 Limit 4 to english 725
6 Limit 5 to year = “2014” 55
7 Limit 6 to humans 55

Table 10

Search in Pubmed (Searched on January 17th, 2015)

Search query Records

1 “Breast Neoplasms”[mesh:exp] 220,426
2 “Carcinoma, Ductal, Breast”[mesh:exp] 12,090
3 “Inflammatory Breast Neoplasms”[mesh:exp] 205
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4 “Triple Negative Breast Neoplasms”[mesh:exp] 484

5 ((“breast”[mesh] OR “breast diseases”[mesh:exp]) AND (“Neoplasms”[mesh:exp] OR 224,201
“Adenocarcinoma”[mesh:exp] OR “Carcinoma”[mesh:exp]))
6 Brca[tiab] 2403
7 (Breast[tiab] AND (adenocarcinoma*[tiab] OR cancer*[tiab] OR carcinoma*[tiab] OR metasta*[tiab] 244,490
OR neoplasm*[tiab] OR tumor[tiab] OR tumors[tiab] OR tumour[tiab] OR tumours[tiab]))
8 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 296,390
9 (Meta-Analysis[ptyp] OR systematic[sb]) 233,666

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Search query Records

10 Cost*[tiab] 384,322
11 “Costs and cost analysis”[mesh:noexp] 41,888
12 Cost-benefit analys*[tiab] 3261
13 Cost-benefit analysis[mesh] 60,696
14 Health care costs[mesh:noexp] 27,761
15 #10 OR #11 OR #12 OR #13 OR #14 431,794
16 #8 AND #9 AND #15 378
17 #16 AND (“2000/01/01”[PDAT]: “2014/12/31”[PDAT]) AND English[Language] AND “humans” 268
[MeSH Terms]

Table 11
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Search in ISI's Web of Knowledge

Search query Records

1 TS = (Systematic review* or Meta-analysis*) 123,684
2 TS = Economics* 62,123
3 TS = (Breast cancer* or Breast Neoplasm*) 284,995
5 #1 AND #2 AND #3 18

Limiters – English language and Publication year (2000–2014); Limiters apply to all searches
Indexes = SCI-EXPANDED, SSCI, A&HCI, CPCI-S, CPCI-SSH, BKCI-S, BKCI-SSH, CCR-EXPANDED
Table 12

Search in Cochrane Database of Systematic Reviews (Searched on January 17th, 2015)

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Search query Records

1 ((Breast$ or mammary) adj3 (neoplas$ or tumor$ or cancer$ or carcinom$)).mp. 108
2 ((Beast$ or mammary) adj3 (neoplas$ or tumor$ or cancer$ or carcinom$)).kw. 34
3 OR/1–2 119
4 (Econom* or cost* or pric* or pharmacoecon* or cost NEXT (effectiveness or utili* or benefit or 83,659
minimi*) or (expenditure) or (value NEAR/2 money) or budget* or preference or qaly or (quality
NEXT adjusted) or utility or utilities or financ* NEXT (management or support or organized))
5 AND/3–4 108
6 #5 and Publication year from 2000 to 2014 33

Table 13

Search in Center for Reviews and Dissemination (CRD) database (Searched on January
Author Manuscript

19th, 2015)

Search query Records

1 ((Systematic* adj review*) OR (Meta-analysis*)) IN DARE, NHSEED, HTA 48,534
2 (Economics*) OR (Cost*) OR (Costs*) IN DARE, NHSEED, HTA 23,784
3 (Drug*$therapy*) OR (Chemotherapy*) OR (Adjuvant*) IN DARE, NHSEED, HTA 3689
4 (Breast cancer:ti) IN DARE, NHSEED, HTA 1322

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Search query Records

5 (English:lp) IN DARE, NHSEED, HTA from 2000 to 2014 27,686
6 #1 AND #2 AND #3 AND #4 AND #5 94

Table 14

Search in EconLit—(Searched on January 19th, 2015)

Search query Records

1 Systematic review* or meta-analysis* 1091
2 Economics* 565,958
3 Breast cancer* or breast neoplasm* 245
Author Manuscript

4 LA english 1,299,261
5 S1 AND S2 AND S3 AND S4 3

Limiters—published date: 20000101-20141231; limiters apply to all searches

References
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5. Zelle SG, Baltussen RM. Economic analyses of breast cancer control in low- and middle-income
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countries: a cost-effectiveness analysis for India. J Natl Cancer Inst. 2008; 100:1290–1300.
[PubMed: 18780864]
8. Younis T, Skedgel C. Is trastuzumab a cost-effective treatment for breast cancer? Expert Rev
Pharmacoecon Outcomes Res. 2008; 8(5):433–442. [PubMed: 20528328]
9. Becker, LA.; Oxman, AD. Overviews of reviews. In: Higgins, JP., editor. Cochrane handbook for
systematic reviews of interventions. Chichester; Wiley: 2008. p. 607-631.
10. Smith V, Devane D, Begley CM, et al. Methodology in conducting a systematic review of
systematic reviews of health-care interventions. BMC Med Res Methodol. 2011; 11:15. [PubMed:
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21291558]
11. Canadian Agency for Drugs and Technologies in Health. Information Services, Canadian Agency
for Drugs and Technologies in Health. Ottawa: 2011. Grey matters: a practical search tool for
evidence-based medicine.
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the methodological quality of systematic reviews. J Clin Epidemiol. 2009; 62:1013–1020.
[PubMed: 19230606]
13. Gerard K, Seymour J, Smoker I. A tool to improve quality of reporting published economic
analyses. Int J Technol Assess Health Care. 2000; 16:100–110. [PubMed: 10815357]

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14. Ferrusi IL, Leighl NB, Kulin NA, et al. Do economic evaluations of targeted therapy provide
support for decision makers? Am J Manag Care. 2011; 17(Suppl 5 Developing):SP61–SP70.
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[PubMed: 21711079]
15. Parkinson B, Pearson SA, Viney R. Economic evaluations of trastuzumab in HER2-positive
metastatic breast cancer: a systematic review and critique. Eur J Health Econ. 2014; 15:93–112.
[PubMed: 23436142]
16. Lewis R, Bagnall AM, King S, et al. The clinical effectiveness and cost-effectiveness of
vinorelbine for breast cancer: a systematic review and economic evaluation. Health Technol
Assess. 2002; 6:1–269.
17. John-Baptiste AA, Wu W, Rochon P, et al. A systematic review and methodological evaluation of
published cost-effectiveness analyses of aromatase inhibitors versus tamoxifen in early stage
breast cancer. PLoS One. 2013; 8:e62614. [PubMed: 23671612]
18. Chan AL, Leung HW, Lu CL, et al. Cost-effectiveness of trastuzumab as adjuvant therapy for early
breast cancer: a systematic review. Ann Pharmacother. 2009; 43:296–303. [PubMed: 19193576]
19. Frederix GW, Severens JL, Hovels AM, et al. Reviewing the cost-effectiveness of endocrine early
breast cancer therapies: influence of differences in modeling methods on outcomes. Value Health.
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2012; 15:94–105. [PubMed: 22264977]

20. Foster TS, Miller JD, Boye ME, et al. The economic burden of metastatic breast cancer: a
systematic review of literature from developed countries. Cancer Treat Rev. 2011; 37:405–415.
[PubMed: 21477928]
21. Benedict A, Brown RE. Review of cost-effectiveness analyses in hormonal therapies in advanced
breast cancer. Expert Opin Pharmacother. 2005; 6:1789–1801. [PubMed: 16144501]
22. Blank PR, Dedes KJ, Szucs TD. Cost effectiveness of cytotoxic and targeted therapy for metastatic
breast cancer: a critical and systematic review. Pharmacoeconomics. 2010; 28:629–647. [PubMed:
20524722]
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Fig. 1.
Flow diagram depicting the articles selection process
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 Diaby et al. Page 15

Table 1

Modified AMSTAR tool

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Domains Response choice Scoring scale

1. Was an “a priori” design provided? Yes 1
The research question and inclusion criteria should be established before the conduct of the review No 0
Can't answer 0
Not applicable −1*
2. Was there duplicate study selection and data extraction? Yes 1
There should be at least two independent data extractors and a consensus procedure for disagreements No 0
should be in place
Can't answer 0
Not applicable −1*
3. Was a comprehensive literature search performed? Yes 1
At least two electronic sources should be searched. The report must include years and databases used No 0
(e.g., Central, EMBASE, and MEDLINE). Key words and/or MESH terms must be stated, and where
Author Manuscript

feasible, the search strategy should be provided. All searches should be supplemented by consulting Can't answer 0
current contents, reviews, textbooks, specialized registers, or experts in the particular field of study, and
Not applicable −1*
by reviewing the references in the studies found
4. Was the status of publication (i.e., grey literature) used as an inclusion criterion? Yes 1
The authors should state that they searched for reports regardless of their publication type. The authors No 0
should state whether or not they excluded any reports (from the systematic review), based on their
publication status, language etc Can't answer 0
Not applicable −1*
5. Was a list of studies (included and excluded) provided? Yes 1
A list of included and excluded studies should be provided No 0
Can't answer 0
Not applicable −1*
6. Were the characteristics of the included studies provided? Yes 1
In an aggregated form, such as a table, data from the original studies should be provided on the No 0
participants, interventions, and outcomes. The ranges of characteristics in all the studies analyzed, e.g.,
Author Manuscript

age, race, sex, relevant socioeconomic data, disease status, duration, severity, or other diseases should be Can't answer 0
reported
Not applicable −1*
7. Was the scientific quality of the included studies assessed and documented? Yes 1
“A priori” methods of assessment should be provided (e.g., for effectiveness studies if the author(s) chose No 0
to include only randomized, double-blind, placebo-controlled studies, or allocation concealment as
inclusion criteria); for other types of studies, alternative items will be relevant Can't answer 0
Not applicable −1*
8. Was the scientific quality of the included studies used appropriately in formulating conclusions? Yes 1
The results of the methodological rigor and scientific quality should be considered in the analysis and the No 0
conclusions of the review, and explicitly stated in formulating recommendations
Can't answer 0
Not applicable −1*
9. Were the methods used to combine the findings of studies appropriate? Yes 1
For the pooled results, a test should be done to ensure the studies were combinable, to assess their No 0
homogeneity (i.e., Chi-squared test for homogeneity, 12). If heterogeneity exists, a random effects model
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should be used and/or the clinical appropriateness of combining should be taken into consideration (i.e., is Can't answer 0
it sensible to combine?)
Not applicable −1*
10. Was the likelihood of publication bias assessed? Yes 1
An assessment of publication bias should include a combination of graphical aids (e.g., funnel plot, other No 0
available tests) and/or statistical tests (e.g., Egger regression test)
Can't answer 0

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 Diaby et al. Page 16

Domains Response choice Scoring scale

Not applicable −1*
Author Manuscript

11. Was the conflict of interest included? Yes 1

Potential sources of support should be clearly acknowledged in both the systematic review and the No 0
included studies
Can't answer 0
Not applicable −1*
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Table 2

Characteristics of the systematic reviews

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Authors, year Study objectives Interventions compared Time Horizon covered Sample size
Benedict and To review the cost-effectiveness of Aromatase inhibitors versus 1998–2004 17
Brown [21] hormonal treatment options for Tamoxifen for first-line therapy.
advanced breast cancer Newer aromatase inhibitors
(letrozole, anastrozole,
exemestane, fluvestrant) versus
older treatments (megestrol,
tamoxifen) for second-line therapy
for advanced breast cancer
John-Baptiste et To evaluate published cost-effectiveness Aromatase inhibitors (anastrazole 1996–2011 18
al. [17] analyses of aromatase inhibitors and and letrozole) versus tamoxifen
tamoxifen in early-stage breast cancer
Frederix et al. [19] To primarily identify published cost- Aromatase inhibitors compared to 2000–2010 20
effectiveness analyses and cost-utility tamoxifen
analyses of endocrine therapies for the
treatment of early breast cancer.
Secondly, to identify whether
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differences in seven modeling

characteristics are related to differences
in outcome of these cost-effectiveness
and cost-utility analyses
Chan et al. [18] To identify published, original, cost- Standard treatment/chemotherapy 1998–2008 13
effectiveness analyses presenting cost/ without trastuzumab.
quality-adjusted life year (QALY) ratios
for trastuzumab used as an adjuvant
treatment for HER2 + early breast
cancer and to evaluate the quality of
reporting the favorable cost-
effectiveness ratios
Blank et al. [22] To review the evidence on the cost Conventional cytotoxic 2000–2009 13
effectiveness of conventional chemotherapy versus targeted
chemotherapy and targeted therapy for therapy (trastuzumab).
metastatic breast cancer
Lewis et al. [16] To evaluate the clinical effectiveness Vinorelbine, docetaxel, paclitaxel, 1986–2001 14
and cost-effectiveness of vinorelbine in 5-fluorouracil, and gemcitabine
the management of breast cancer
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Foster et al. [20] To understand the economic impact of Treatments for metastatic breast 2004–2010 23
metastatic breast cancer (MBC) and its cancer including trastuzumab,
treatment, and to evaluate the designs of capecitabine, and nab-paclitaxel
these studies
Ferrusi et al. [14] To facilitate the decision-making Trastuzumab targeted therapy and Inception-2011 15
process of economic evaluations based other treatment modalities
on recommendations
Parkinson et al. To assess the quality of economic trastuzumab versus any 1996–2011 12
[15] evaluations of trastuzumab, and identify comparator
potential drivers of conflicting
conclusions
Norum J. [23] To assess the cost-effectiveness of Adjuvant trastuzumab versus any 2003–2006 4
adjuvant of trastuzumab in early breast comparator
cancer and make recommendations for
future economic evaluations
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Table 3

Characteristics of the studies included in the assessed systematic reviews

Authors, year Country/region Target population Breast cancer stage Type of economic evaluation Study design
Diaby et al.

I II III IV CMA CEA CUA CBA Trial-based Model-based Unknown/Other

Benedict and Brown Australia, Belgium, Canada, Women with advanced breast 0 0 0 17 0 11 6 0 0 17 0
[21] France, Germany, Italy, cancer
Netherlands, Spain, UK, US
John-Baptiste et al. Euro zone, US, UK, Canada, Postmenopausal women with 18 0 0 0 0 18 16 0 0 18 0
[17] Brazil, Colombia, Korea early-stage breast cancer
Frederix et al. [19] US, UK, Canada, Brazil, All patients recommended for 20 0 0 0 NS 14 19 NS 20 0 0
Belgium, Germany, Sweden the adjuvant treatment of
and Spain breast cancer
Chan et al. [18] US, Canada, Brazil, Italy, Women with HER2 + early- 13 0 0 0 0 13 0 0 0 13 0
Belgium, Sweden, Norway, stage breast cancer
Poland, Switzerland,
Australia, Taiwan
Blank et al. [22] UK, Greece, France, Women with metastatic breast 0 0 0 13 0 13 0 0 6 4 (3 Other)
Norway, Switzerland, US, cancer
Canada
Lewis et al. [16] US, Canada, UK, France Women with metastatic breast 0 0 0 4 0 1 4 0 0 4 0
cancer
Foster et al. [20] Australia, Canada, France, Women with metastatic breast 0 0 0 35 0 7 14 0 NS 13 9
Germany, Italy, Spain, cancer
Sweden, Switzerland, UK,
US.
Ferrusi et al. [14] US, UK, Canada Women with early-stage breast 15 0 0 0 NS NS NS NS NS 12 2
cancer
Parkinson et al. [15] US, Australia, Sweden, UK, Women with HER2 + 0 0 0 12 0 9 6 0 3 8 4
Italy Norway, France, metastatic breast cancer
Switzerland, Belgium
Norum J. [23] Belgium, US, Canada, Women eligible for adjuvant 3 0 1 0 0 4 0 0 0 4 0
Denmark treatment of HER2 + breast

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cancer.

NS not specified clearly, CMA cost minimization analysis, CEA cost-effectiveness analysis, CUA cost-utility analysis, CBA cost-benefit analysis HER2+: Human epidermal growth factor receptor 2 positive
Page 18
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Table 4

Characteristics of the studies included in the assessed systematic reviews

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Authors, year Time frame Perspective Measure of effectiveness Data sources

clearly
documented

0–5 years 6 Payer Societal Other/NS Yes No

years
and +
Benedict and 8 9 16 0 US hospital (1) Life years gained (17) and 17 0
Brown [21] both Life years and QALYs
(6)
John-Baptiste et 0 18 16 1 Multiple perspective (1) QALYs and Life years (10); 18 0
al. [17] QALYs only (6) and Life
years only (2)
Frederix et al. 0 20 20 0 0 Life years (14); QALYs (19) 16 4
2012 [19]
Chan et al. [18] 0 11 5 4 4 Life years (5) QALYs (11) 13 0
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Blank et al. [22] 2 11 5 2 7 Progression-free (1); Life 13 0

years (6); QALYs (7)
Lewis et al. [16] 4 0 0 1 3 QALYs; HRQoL; QALMs; 4 0
QAPFS
Foster et al. [20] Not clearly specified. The majority of studies used third-party payer QALYs (16); PFLYs (4); 23 0
Few studies had life- perspective. No further information provided Life years gained (3)
time and 10-year
time horizon
Ferrusi et al. 1 14 12 2 2 QALYs; Life years gained 15 0
[14]
Parkinson et al. 6 8 9 2 4 Life years (12); QALYs (9); Reported for
[15] PFLYs (1) the majority of
studies.
Norum J. [23] 0 4 3 0 1 Life years (3) 2 2

NS not specified clearly, N/A not applicable, QALYs quality-adjusted life years, HRQoL, health-related quality of life, QALMs quality-adjusted life
months, QAPFS quality-adjusted progression-free survival, PFLYs progression-free life years
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Table 5

Characteristics of the studies included in the assessed systematic reviews

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Authors, year Discounting Sensitivity analysis Incremental analysis

Yes No N/A Deterministic Probabilistic Yes No

Benedict and Brown 2005 17 0 0 Often used (no 2 15 2
[21] quantification)
John-Baptiste et al. [17] 17 1 0 12 11 18 0
Frederix et al. [19] 20 0 0 19 13 20 0
Chan et al. [18] 13 0 0 Sensitivity analysis conducted for 11 out of the 13, but 13 0
type not specified
Blank et al. [22] 5 The remained 6 5 13 0
studies did not
state discount
rates.
Lewis et al. [16] 3 1 0 Sensitivity analysis conducted for 3 out of the 4, but type 3 1
not specified
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Foster et al. [20] NS NS NS NS NS 22 NR

Ferrusi et al. [14] NS NS NS 12 10 Yes NS
Parkinson et al.[15] 10 5 0 Sensitivity analysis was conducted in all evaluations. 12 0
Deterministic in most studies and few probabilistic.
Norum J. [23] 3 1 0 Sensitivity analysis was done for 1 study, but type not 3 1
specified.

NS not specified clearly, NR not reported

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Table 6

Interventions, objectives, and main conclusions of systematic reviews

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Authors, year Interventions compared Study objectives Main conclusions

Benedict and Aromatase inhibitors versus To review the cost-effectiveness of These analyses suggest, that new AIs are
Brown [21] tamoxifen for first-line therapy. hormonal treatment options for good value for money compared with older
Newer aromatase inhibitors advanced breast cancer treatments (megestrol, tamoxifen)
(letrozole, anastrozole, irrespective of country and the line of therapy
exemestane, fluvestrant) versus
older treatments (megestrol,
amoxifen) for second-line
therapy for advanced breast
cancer
John-Baptiste et Aromatase inhibitors To evaluate published cost- Studies that compared aromatase inhibitors
al. [17] (anastrazole and letrozole) effectiveness analyses of aromatase versus tamoxifen tend to overestimate the
versus tamoxifen inhibitors and tamoxifen in early- cost-effectiveness of AIs, making the results
stage breast cancer suboptimal to inform policy
Frederix et al. Aromatase inhibitors compared To primarily identify published cost- Harmonization of modeling techniques for
[19] to tamoxifen effectiveness analyses and cost- different therapeutic groups/diseases and
utility analyses of endocrine transparent modeling practices need to be
Author Manuscript

therapies for the treatment of early adhered to in order to increase comparability

breast cancer. Secondly, to identify across pharmacoeconomic evaluations
whether differences in seven
modeling characteristics are related
to differences in outcome of these
cost-effectiveness and cost-utility
analyses
Chan et al. [18] Standard treatment/ To identify published, original, cost- Most studies suggest that trastuzumab may
chemotherapy without effectiveness analyses presenting be cost-effective for treatment of early breast
trastuzumab. cost/quality-adjusted life year cancer in a 1-year treatment regimen
(QALY) ratios for trastuzumab used
as an adjuvant treatment for HER2 +
early breast cancer and to evaluate
the quality of reporting the favorable
cost-effectiveness ratios
Blank et al. [22] Conventional cytotoxic To review the evidence on the cost- The pharmacoeconomic studies yielded
chemotherapy versus targeted effectiveness of conventional varying conclusions. Studies on cytotoxic
therapy (trastuzumab). chemotherapy and targeted therapy agents showed mainly attractive cost-
for metastatic breast cancer effectiveness ratios while targeted therapies
presented both attractive and less attractive
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ratios
Lewis et al. [16] Vinorelbine, docetaxel, To evaluate the clinical effectiveness One economic evaluation reported that
paclitaxel, 5-fluorouracil, and and cost-effectiveness of vinorelbine vinorelbine was more effective and less
gemcitabine in the management of breast cancer costly than taxane therapy, one found
vinorelbine to be less effective and less
expensive than either of the taxanes and a
third evaluation found vinorelbine to be less
effective and more expensive than taxane
therapy. Conflicting results
Foster et al. [20] Treatments for metastatic breast To understand the economic impact Hormonal therapies seem to be very cost-
cancer including trastuzumab, of metastatic breast cancer (MBC) effective. Specifically, newer aromatase
capecitabine, and nab-paclitaxel and its treatment, and to evaluate the inhibitors (anastrozole and letrozole) have
designs of these studies shown to be cost-effective in the first-line
therapy when compared to tamoxifen in
estrogen-receptorpositive patients.
trastuzumab is generally cost-effective. Other
targeted therapies (HER2 receptor) have not
been considered cost-effective
Ferrusi et al. [14] Trastuzumab targeted therapy To facilitate the decision-making Trastuzumab appeared to be generally cost-
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and other treatment modalities process of economic evaluations effective when its use was limited to a year.
based on recommendations The short-term use of trastuzumab was more
attractive than its longer term use, from a
health economic point of view

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 Diaby et al. Page 22

Authors, year Interventions compared Study objectives Main conclusions

Parkinson et al. Trastuzumab versus any To assess the quality of economic The economic evaluations did not arrive at a
[15] comparator evaluations of trastuzumab, and consensus regarding the cost-effectiveness of
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identify potential drivers of trastuzumab for metastatic breast cancer

conflicting conclusions
Norum J. [23] Adjuvant trastuzumab versus any To assess the cost-effectiveness of The adjuvant trastuzumab in early breast
comparator adjuvant of trastuzumab in early cancer is cost-effective, except for subgroups
breast cancer and make of stage III breast cancer and seniors
recommendations for future
economic evaluations
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Table 7

Quality assessment of systematic reviews

Authors, year Domains of the modified AMSTAR tool

Diaby et al.

Final scores (%)

1 2 3 4 5 6 7 8 9 10 11
Benedict and Brown [21] 1 1 1 0 0 1 1 1 −1* 0 1 7 (70)
John-Baptiste et al. [17] 1 1 1 1 0 0 1 1 −1* 0 1 7 (70)
Frederix et al. [19] 1 0 1 0 0 1 1 1 −1* 0 1 7 (70)
Chan et al. [18] 1 1 1 0 0 1 1 1 −1* 0 0 6 (60)
Blank et al. [22] 1 0 1 0 1 1 1 1 −1* 1 1 7 (70)
Lewis et al. [16] 1 1 1 1 1 1 1 1 −1* −1* 1 9 (100)
Foster et al. 2011 [20] 1 1 0 1 0 1 1 1 −1* 0 0 6 (60)
Ferrusi et al. [14] 1 1 1 0 0 1 1 1 −1* 0 0 6 (60)
Parkinson et al. [15] 1 0 1 1 0 1 1 1 −1* 0 0 6 (60)
Norum J. 2006 [23] 1 0 1 1 0 1 1 1 −1* 0 1 7 (70)

% percentage

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