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A cost-benefit analysis of bevacizumab in

combination with paclitaxel in the first-line
treatment of patients with metastatic breast
cancer
ARTICLE in BREAST CANCER RESEARCH AND TREATMENT DECEMBER 2011
Impact Factor: 3.94 DOI: 10.1007/s10549-011-1919-y Source: PubMed

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Cleveland Clinic

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Breast Cancer Res Treat

DOI 10.1007/s10549-011-1919-y

BRIEF REPORT

A cost-benefit analysis of bevacizumab in combination

with paclitaxel in the first-line treatment of patients
with metastatic breast cancer
Alberto J. Montero Kiran Avancha
Stefan Gluck Gilberto Lopes

Received: 7 December 2011 / Accepted: 9 December 2011

Springer Science+Business Media, LLC. 2011

Abstract Bevacizumab in combination with chemotherapy increases progression-free survival (PFS), but not
overall survival when compared to chemotherapy alone in
the treatment of metastatic breast cancer (MBC). Recently
in November, 2011 the Food and drug administration
revoked approval of bevacizumab in combination with
paclitaxel for the treatment of MBC. The European Medicines Agency, in contrast, maintained its approval of
bevacizumab in MBC. While neither agency considers
health economics in their decision-making process, one of
the greatest challenges in oncology practice today is to
reconcile hard-won small incremental clinical benefits with
exponentially rising costs. To inform policy-makers in the
US, this study aimed to assess the cost-effectiveness of
bevacizumab/paclitaxel in MBC, from a payer perspective.
We created a decision analytical model using efficacy and
adverse events data from the ECOG 2100 trial. Health
utilities were derived from available literature. Costs were
obtained from the Center for Medicare Services Drug
Payment Table and Physician Fee Schedule and are represented in 2010 US dollars. Quality-adjusted life-years
(QALY) and incremental cost-effectiveness ratio (ICER)
were calculated. Sensitivity analyses were performed.
A. J. Montero
S. Gluck
Division of Hematology/Oncology, University of Miami
Sylvester Comprehensive Cancer Center, Miami, FL, USA
K. Avancha
University of Miami Miller School of Medicine Office
of Research, Miami, FL, USA
G. Lopes (&)
Johns Hopkins Singapore International Medical Centre
and Johns Hopkins University School of Medicine,
11 Jalan Tan Tock Seng, level 1, Singapore 308433, Singapore
e-mail: glopes@imc.jhmi.edu

Bevacizumab added 0.49 years of PFS and 0.135 QALY

with an incremental cost of $100,300, and therefore a cost
of $204,000 per year of PFS gained and an ICER of
$745,000 per QALY. The main drivers of the model were
drug acquisition cost, PFS, and health utility values. Using
a threshold of $150,000/QALY, drug price would have to
be reduced by nearly 80% or alternatively PFS increased
by 10 months to make bevacizumab cost-effective. The
results of the model were robust in sensitivity analyses.
Bevacizumab plus paclitaxel is not cost-effective in treating MBC. Value-based pricing and the development of
biomarkers to improve patient selection are needed to
better define the role of the drug in this population.
Keywords Breast cancer
Cost-benefit analysis

Pharmacoeconomics
Bevacizumab
Economics

Metastatic breast cancer
QALY

Introduction
The advent of molecularly targeted agents has directly
contributed to improving clinical outcomes in metastatic
breast cancer. Over the last two decades 5-year overall
survival rates in patients with stage 4 breast cancer in the
US have improved to approximately 23% [1]. However,
these improvements come at a cost particularly when we
consider the cost of monoclonal antibodies such as trastuzumab and bevacizumab which are at present among the
most expensive class of molecularly targeted drugs. Consequently, breast cancer is estimated to be the most
expensive cancer to treat in the U.S., costing an estimated
$16.5 billion in 2010, with an unsustainable rate of increase
[2]. While the cost of breast cancer care is increasing in
virtually all high-income countries, off-label use of

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Breast Cancer Res Treat

expensive medications that provide either only a very

marginal or no benefit is debatable [2].
An excellent example is bevacizumab, a monoclonal
antibody that targets circulating vascular endothelial growth
factor-A (VEGF), thereby interfering with the process of
tumor angiogenesis by preventing this ligand from interacting with its receptor [3]. Bevacizumab was the first antiangiogenic drug approved for the treatment of cancer with
initial approval in the setting of advanced colorectal cancer
and later in lung cancer in combination with chemotherapy
[4, 5]. The combination of bevacizumab and weekly paclitaxel, after the results of the E2100 randomized phase 3
trial demonstrated a near doubling in progression-free survival (PFS) with the combination over paclitaxel alone
[11.4 months vs. 5.9 months; hazard ratio 0.6; P \ 0.001],
was initially granted accelerated approval by the US
Food and Drug Administration (FDA) in 2008 as first-line
treatment of HER2-negative metastatic breast cancer
(MBC). The FDA then recently revoked the MBC indication from bevacizumab, on November 2011, citing safety
concerns and the failure of subsequent phase 3 studies to
show a similar magnitude of PFS benefit as E2100, and no
significant improvement in OS [6]. The European Medicines Agency (EMA), however, interpreted the bevacizumab data differently than the FDA, and bevacizumab
continues to be an approved option for MBC. In fact, the
EMAs Committee for medicinal products for human use
(CHMP) has approved extending the indication of bevacizumab in MBC, and also permitting it to be combined
with capecitabine in the first-line setting when a taxane/
anthracycline combination cannot be used [3].
While neither the FDA nor the EMA considers health
economics in their decision-making process, one of the
greatest challenges in the practice of oncology today is to
reconcile hard-won small incremental clinical benefits with
exponentially rising costs. This study aimed to assess the
cost-effectiveness of bevacizumab plus solvent-based paclitaxel in MBC, from a payer perspective and to better inform
US policymakers. We created a decision analytical model
using efficacy and adverse events data from the ECOG 2100
trial, because, thus far has the longest reported prolongation
of PFS, in absolute terms, with the combination of bevacizumab with cytotoxic chemotherapy in the MBC setting.

Methods
Overall model
To inform policy-makers, we aimed to assess the costeffectiveness of bevacizumab in combination with paclitaxel to paclitaxel alone in the treatment of patients with
metastatic breast cancer from a payer perspective in the

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Fig. 1 Tree-diagram shows the model assessing the costeffectiveness

of bevacizumab in combination with paclitaxel in the treatment of
patients with advanced breast cancer

United States. Using Excel 2007 software (Microsoft corp.,

Redmond, WA, USA), we developed the decision-analytic
model depicted in Fig. 1. Patients with advanced breast
cancer may receive paclitaxel alone or with bevacizumab
in the first-line setting. Upon progression there is no crossover to bevacizumab for patients who received paclitaxel
alone. The model assumes that second-line therapy and
beyond, as well as best supportive care (BSC) would be
similar in both arms and therefore costs would be evenly
distributed and would not bear importance in the incremental costs and benefits incurred to the bevacizumab arm.
Model inputs
Costs were obtained from the Center for Medicare Services
Drug Payment Table and Physician Fee Schedule and are
represented in 2010 US dollars. Base case patient had a
height of 65 inches and a weight of 70 kg and therefore a
BSA of 1.79 m2 (using Mosteller). We included costs for
drug acquisition, laboratory tests, physician, and administration fees. We decided not to include the cost of treating
adverse events as these were considered minor compared to
medication acquisition costs. No discounting was used due
to the short-time horizon.
Time in each treatment state was based on data from
ECOG 2100. Length of time on first-line treatment was
derived from median progression-free survival time. Health
utilities were derived from the work by Lloyd et al. [7].
Baseline and incremental and decrement values were as
follows: baseline 0.715, response (?0.075), progression
(-0.272), febrile neutropenia (-0.15), diarrhea or vomit
(-0.103), fatigue (-0.115), hair loss (-0.114), neuropathy
(-0.155). Utility value for second-line therapy and beyond
(before terminal state) was 0.45. Terminal state was considered to be the last 6 months and carried a utility value of
0.19. Incidence of adverse events were as follows; paclitaxel alone: alopecia, 79%; febrile neutropenia, 0.6%;
diarrhea ? vomiting, 2.7%; fatigue, 9.1%; neuropathy,
21.6%; for bevacizumab in combination with paclitaxel
they were: alopecia, 80%; febrile neutropenia, 0.8%;

Breast Cancer Res Treat

diarrhea ? vomiting, 2.7%; fatigue, 9.1%; neuropathy,

23%. Response rates were 36.9 and 21.2% for the combination and paclitaxel alone, respectively. The average
health utility for first-line treatment was 0.59 with paclitaxel and 0.6 with the combination.
Cost-effectiveness evaluation, sensitivity analysis,
and scenarios
Quality-adjusted life-years (QALY) and incremental costeffectiveness ratio (ICER) were calculated. The primary
endpoint was the ICER for bevacizumab in combination
with paclitaxel versus paclitaxel alone. We also calculated
the cost per progression-free survival year added as the
main endpoint in E2100 was progression-free survival.
We performed one-way sensitivity analysis to test the
robustness of the model. We also performed several other
analysis including different scenarios and assumptions,
such as using clinical outcomes from other trials and with
bevacizumab in combination with other chemotherapeutic
drugs, as well as a comparison of gemcitabine in addition
to paclitaxel versus paclitaxel alone [8, 9]. We also aimed
to evaluate at what cost and/or benefits the ICER would be
within acceptable thresholds.

Results
Table 1 summarizes the value and data source for each of
the model inputs. Bevacizumab was not cost-effective
using commonly accepted thresholds for willingness-topay. The addition of bevacizumab to weekly paclitaxel,
added 0.49 years of PFS and 0.135 QALY, and was

Table 1 Values of input

variables

associated with an incremental cost of $100,300. The

overall cost of paclitaxel plus bevacizumab was therefore
$204,000 per year of PFS gained, with an incremental costeffectiveness ratio (ICER) of $745,000 per QALY
(Table 2). The main cost element was the cost of bevacizumab. One-way sensitivity analyses were performed to
evaluate the potential impact of changes in model inputs.
The primary drivers of this cost-effectiveness model were:
cost of treatment with bevacizumab, PFS, and health utility
values.
Overall survival in the bevacizumab plus paclitaxel arm
would have to improve by an added 13.3 months, i.e., it
would have to reach 40 months, to generate an ICER below
$160,000 (Doubling median OS to 53.4 months would lead
to an ICER of $88,425). Progression-free-survival would
have to improve by an added 10 months (i.e., to
21.8 months) to generate an ICER below $160,000. Doubling PFS to 23.6 months would generate an ICER of
$138,700. The cost of treatment with bevacizumab would
have to be reduced by nearly 80% to generate an ICER
below $160,000.
In other scenario analyses assessing bevacizumab in
combination with docetaxel or capecitabine versus the
respective single agent alone (utilizing data from AVADO
and RIBBOn1) the anti-angiogenic agent was not found to
be cost effective either. Bevacizumab and docetaxel generated 0.0375 QALY with an ICER of $1,937,000 over
docetaxel alone (Based on AVADO). Bevacizumab in
addition to capecitabine led to an increase of 0.168 QALY
and an ICER of 425,000/QALY over capecitabine alone. In
other words, bevacizumab was found to be even less costeffective with docetaxel and did not reach accepted
thresholds with capecitabine.

Input

Cost (2010 USD)

Source

Monthly paclitaxel cost

$404.10

CMS

Monthly paclitaxel/bevacizumab
cost

$8,707.50

Time in each treatment state (months)

Paclitaxel

Paclitaxel/Bevacizumab

Source

Total survival time

25.2

26.7

ECOG 2100

Time in treatment state under

first-line treatment

5.9

11.8

Health Utilities by treatment state

Source

First-line treatment: Paclitaxel

0.59

First-line treatment: Paclitaxel/

Bevacizumab

0.60

Second-line treatment and

beyond

0.45

Terminal State

0.19

Derived from Lloyd et al. [7], adjusted for specific

adverse events and response rate with each
treatment

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Breast Cancer Res Treat

Table 2 Results of the
bevacizumab cost-effectiveness
model

Systemic therapy

Cost (2010
USD)

Paclitaxel

$2,384.28

Paclitxel/Bevacizumab

$102,748.10

Discussion
Our results confirm that even assuming the most optimistic
clinical data from E2100, the combination of bevacizumab
with weekly paclitaxel is not cost effective as first-line
therapy in MBC. Using a threshold of $150,000/QALY, as
a definition of what constitutes a cost-effective therapy, the
ICER of $745,000/QALY found in our model with paclitaxel/bevacizumab, means that the overall costs associated with bevacizumab would have to be reduced by nearly
80%. Alternatively PFS would have to be increased by an
additional 10 months, i.e., a median PFS of 21.4 months, in
order to make bevacizumab plus chemotherapy costeffective in the setting of MBC.
One other evaluation has been published to date with an
assessment of the cost-effectiveness of bevacizumab added
to paclitaxel from a Swiss health care system perspective
[10]. The authors utilized a Markov model, and also utilizing clinical trial results from ECOG 2100. In this study,
it was shown that use of bevacizumab in the treatment of
MBC was associated with an additional cost of EUR
40,369 and generated an increment of 0.22 QALY and an
ICER of EUR 189,427/QALY. In their probabilistic sensitivity analysis, the willingness-to-pay threshold of EUR
60,000 was never reached. These results, like ours, provide
additional evidence that the combination of bevacizumab
with chemotherapy is not cost-effective at currently
accepted thresholds in the treatment of metastatic breast
cancer [11].
The current growth of health care expenditures in the
United States remains on an unsustainable trajectory [2].
MBC will remain a significant economic burden in the US
based on major demographic shifts, i.e., an aging population and fact that incidence of breast cancer increases with
age. Even under the most optimistic assumptions, using
only the E2100 dataset which showed the greatest magnitude of benefit in terms of delaying median PFS, and
combination with weekly paclitaxel an inexpensive chemotherapeutic agent, the use of bevacizumab as first-line
therapy in MBC is not cost effective. This dilemma is not
unique to bevacizumab of course, but is a fact of cancer
care in the twenty-first century [2]. In fact, other recently
FDA approved therapies for the treatment of metastatic
solid tumors such as sipuleucel-T (metastatic prostate
cancer) and ipilimumab (metastatic melanoma) are even

123

Incremental
cost

QALYs

$100,363.82

1.02

Incremental
QALYs

ICER

0.135

$745,000/QALY

0.855

more expensive than bevacizumab providing what many

would argue are similar marginal benefits from cost-benefit
perspective.
However, bevacizumab could be utilized in a more costeffective manner in the setting of MBC. On the efficacy
side of the cost equation, identification of robust predictive
biomarkers would increase the overall efficacy of bevacizumab in MBC by treating only those patients most
likely to respond. Similarly, development of other drugs
that are more effective in inhibition of tumor angiogenesis
would also have the potential of increasing the overall antitumor effect of this therapeutic approach. On the cost side
of the equation, technical advances that reduce the production cost of monoclonal antibodies would have a
favorable impact on the cost-effectiveness of bevacizumab.
For example, development of less expensive generic and
biosimilar antibodies is already under way [12]. Development of other less expensive alternatives to antibodies may
represent a technological innovation that may bring the
cost down of targeted anti-angiogenic therapy in treating
MBC.
There are several limitations of this study. First, our
model likely underestimates the overall cost of bevacizumab in MBC because we did not take into account the
cost of treating bevacizumab related grade 34 severe
adverse toxicities, such as hypertension, proteinuria, bowel
perforation, bleeding, and thromboembolic events. While
they are uncommon, these complications known to be
attributed to bevacizumab would clearly increase the costs
associated with this drug above what is quantified in our
model.
In conclusion, bevacizumab plus weekly paclitaxel is
not cost-effective in the treatment of metastatic breast
cancer at an overall cost of $204,000 per year of PFS
gained, with an incremental cost-effectiveness ratio (ICER)
of $745,000 per QALY. In order to meet currently accepted
definitions of cost-effectiveness, the overall costs of bevacizumab would have to be decreased by approximately
80% or the overall median PFS observed in E2100 would
have to be increased twofold. From an economic perspective, the removal of the FDA indication for MBC is
entirely rational. Until predictive biomarkers are developed
that can accurately identify the subset of patients that
derive benefit from bevacizumab therapy, from a health
economics perspective, it should not be considered as part

Breast Cancer Res Treat

of standard of care for management of MBC, and should

not be used on an off-label basis in the U.S.
Conflicts of interest Gilberto Lopes has received honorarium and
grant funding from Roche. Stefan Gluck has received research
funding from Genentech. The other authors have no conflict of
interest to declare.

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