Several studies on cost-effectiveness in

ovarian cancer management have been

reported that inform optimal therapy.

J. L. Munro. Sheep Farm in Winter. Mixed media on canvas, 24 × 48.

A Review of Cost-Effectiveness Studies in Ovarian Cancer

Gregory P. Sfakianos, MD, and Laura J. Havrilesky, MD, MHSc

Background: Ovarian cancer is the fifth leading cause of all cancer-related deaths among women. While the
costs of diagnosis and treatment impact the affected individual and the health system, the most important costs
for the patient are often the pain and suffering associated with ovarian cancer. The quality of life associated
with any management decision should be closely examined. Cost-effectiveness models take into account costs,
effects, and quality of life and provide clinicians with useful tools to aid in making these difficult decisions.
Methods: A comprehensive review of cost-effectiveness analyses was undertaken concerning screening for and
treatment of ovarian cancer.
Results: Screening methods to detect ovarian cancer are unproven, and the majority of women present with
advanced-stage disease. Multimodal screening strategies with high specificities targeted at the highest-risk
individuals are the most likely strategies to be cost-effective. Primary treatment with intravenous paclitaxel
and platinum regimens has proven to be cost-effective in multiple studies. Studies evaluating intraperitoneal
chemotherapy show that this strategy is potentially cost-effective over a long-term time horizon. A cost-effectiveness
analysis of the management of recurrent platinum-sensitive ovarian cancer showed that treatment with
carboplatin and paclitaxel is cost-effective compared to single-agent therapy. However, the preferred option for
patients with recurrent platinum-resistant ovarian cancer appears to be supportive care (no chemotherapy) or
single-agent therapy.
Conclusions: Many therapeutic choices are cost-effective in the treatment of ovarian cancer. Cost-effectiveness
models offer one way to examine options in the management of a disease. The quality of life of the patient should
be the most important factor in any management decision and is incorporated into well-designed studies on
cost-effectiveness.

Introduction related deaths among women. The American Cancer

Ovarian cancer is the leading cause of death among gyne-
cologic cancers and the fifth leading cause of all cancer-
From the Division of Gynecologic Oncology at Duke University
Medical Center, Durham, North Carolina.
Submitted January 19, 2010; accepted October 12, 2010.
Address correspondence to Gregory P. Sfakianos, MD, Duke University
Medical Center, Division of Gynecologic Oncology, DUMC 3079,
Durham, NC 27710. E-mail: Gregory.sfakianos@duke.edu
No significant relationship exists between the authors and the
companies/organizations whose products or services may be ref-
erenced in this article.
Society estimates that 21,880 new cases of ovarian cancer
were diagnosed and 13,850 women died of the disease in
the United States in 2010.1 The lifetime risk of invasive
ovarian cancer in the United States is approximately
1.4% (1 in 71), and the lifetime risk of dying of invasive
ovarian cancer is 1.1% (1 in 95).
Unfortunately, screening methods to detect ovarian
cancer are currently unproven, and the majority of
women present with advanced disease. Overall 5-year
survival rates are approximately 49%. The majority of
women present with stage III or IV disease, with survival

January 2011, Vol 18, No.1 Cancer Control 59

rates of only 19% to 47%. In contrast, stage I ovarian
cancer has a favorable 5-year survival rate of 90%.2,3 The
standard approach to primary management is surgery
followed by platinum-based chemotherapy. Despite ad-
vances in chemotherapy, treatment for recurrent ovarian
cancer is almost never curative, and most women will
eventually die of this disease.
The costs associated with cancer impact both the
affected individual and the health system. Health care
costs have risen dramatically and now exceed 17% of the
United States gross domestic product (GDP).4 Ovarian
cancer treatment in particular is susceptible to rising
costs due to the constant influx of novel chemotherapeu-
tics and biologics, most of which are more costly than the
established front-line therapies but have limited proven
benefit. The costs associated with care of ovarian cancer
patients are considerable and are highest during the first
year of diagnosis and the last year of life.5
This article reviews the relevant cost-effectiveness
analyses that have informed decisions about screening
for and treatment of ovarian cancer.
Cost-Effectiveness Analyses
Cost-effectiveness analyses compare the relative value of
various clinical strategies. These analyses offer a unique
way to examine options in the management of disease. A
cost-effectiveness analysis is defined by the United King-
dom’s National Institute for Health and Clinical Excel-
lence (NICE) as an economic study design in which the
consequences of different interventions are measured
using a single outcome, usually in “natural” units (eg,
life-years gained, deaths avoided, heart attacks avoided,
or cases detected). Alternative interventions are then
compared in terms of cost per unit of effectiveness.6
Such an analysis should compare the health interven-
tion of interest to the existing standard of care. If the
standard practice does not appear to be a cost-effective
option relative to other available options, the analyst
should incorporate other relevant alternatives into the
analysis. For example, a “do nothing” alternative or a
viable lower-cost alternative might be used.
Costs that are generally accounted for in a cost-ef-
fectiveness model include medical costs (eg, hospitaliza-
tion, physician, drugs, copayments) and nonmedical costs
(eg, transportation, time costs of giving or receiving care,
and out-of-pocket expenses). Costs of lost productivity
include the cost of lost leisure time or work time. Intan-
gibles include pain, suffering, and adverse events. Effec-
tiveness data for each management strategy are preferably
derived from randomized controlled trials (RCTs), but
this is not always possible. The most commonly reported
result of a cost-effectiveness analysis is the incremental
cost-effectiveness ratio (ICER), which expresses a com-
parison of an intervention or strategy to an alternative
strategy. The ICER for comparison of novel intervention
A compared to standard intervention B is defined as:
60 Cancer Control
Cost A – Cost B
ICER =
Effect A – Effect B
Strategies are usually compared using either the cost
per year of life saved, which quantifies improvements in
survival, or the cost per quality-adjusted life year (QALY),
which quantifies improvements in survival while also
accounting for differences in quality of life associated
with different strategies. Of the two, QALYs are the rec-
ommended outcome for cost-effectiveness analyses.7 In
order to report results in QALYs, a utility must be as-
signed to the health state of interest. A utility is a number
between 0 and 1, where 1 represents perfect health and
0 represents death. Accepted methods for calculating
a utility include the time trade-off and standard gamble
methods, which are usually performed via an extensive
interview designed to determine an individual’s prefer-
ences for one health state (eg, progressive metastatic
ovarian cancer) compared with another (eg, perfect
health).8 QALYs capture both the quantity (length) of
life and its quality; the ideal treatment should maximize
both.9 The ICER represents the additional cost of one
unit of outcome gained (life-years saved or QALY) by a
health care intervention or strategy when compared to
the next best alternative, mutually exclusive intervention
or strategy.9
The term “cost-effective” does not mean that the
strategy saves money, but rather that the additional cost
of the intervention is worthwhile. The concept of cost-
effectiveness requires a value judgment — what one
person believes is a good price for an additional outcome,
someone else may not. Cost-effectiveness analyses in
ovarian cancer typically focus on the costs of treatments,
the survival outcomes, and the toxicities related to each
treatment.10 An intervention is generally considered cost-
effective relative to an alternative strategy if it costs less
than US $50,000 per QALY.11 However, social norms may
raise this value such that interventions costing $100,000
or more per QALY have sometimes been considered cost-
effective.6 The sensitivity analysis, in which the impact
of varying key assumptions or estimates on the model’s
results is assessed, is as important as the absolute value of
the ICER in a cost-effectiveness analysis. In combination,
the base case (or main) outcome and the relevant sensi-
tivity analyses allow us to draw appropriate conclusions
from a decision model.
Ovarian Cancer Screening
The ability to accurately detect early-stage disease may
have the potential to dramatically improve survival
from ovarian cancer. However, the low prevalence of
ovarian cancer may limit the achievable effectiveness
and cost-effectiveness of general population screening.
The combination of a specificity of a screening test and
the disease prevalence determines the positive predic-
January 2011, Vol 18, No.1
tive value (PPV) of a screening test, which is a measure
of the number of diagnostic procedures necessary to
diagnose one case of cancer. A PPV of at least 10% is
generally considered clinically acceptable for a screening
test.12 The tests that have been most extensively evalu-
ated as screening methods include pelvic examination,
the measurement of serum levels of CA-125, and ultra-
sound scanning.
Prospective evaluation of CA-125 in the general popu-
lation reveals that its specificity for early-stage disease is
fairly high (96% to 100%), but the sensitivity was as low
as 57% in one study.13-16 In a prospective study of women
over 50 years of age, a PPV of 4.6% was achieved using
CA-125 alone.14 Transvaginal ultrasound has also been
evaluated; in the largest study of women at average risk,
mostly early-stage carcinomas were detected. However,
most of these carcinomas were of nonserous epithelial
origin.17 Menon et al18 evaluated patients with an elevat-
ed CA-125 and an abnormal transvaginal ultrasound and
determined that the risk of developing a cancer in the
subsequent year was increased approximately 300-fold.
This supports use of these screening tests in combination.
However, a pilot RCT of multimodality screening in which
women were randomized to a control group or screen-
ing that involved measurement of serum CA-125, pelvic
ultrasonography if CA-125 was greater than or equal to
30 U/mL, and referral if ovarian volume was greater than
8.8 mL on ultrasound failed to demonstrate a significant
difference in the number of deaths from ovarian cancer
between the control and screened groups.19
Several groups have developed models to predict the
success of population-based screening strategies. Skates
and Singer20 developed the first mathematical model of
the natural history of ovarian cancer, using stochastic
progression across the four clinical stages to estimate
the effectiveness of annual screening of postmenopausal
women using CA-125. Their model predicted that screen-
ing could save at least 3 years of life per case detected.
Urban et al21 modified the Skates and Singer model in
examining single modality and multimodality strategies
that involved both CA-125 and ultrasound. A multimodal
strategy involving CA-125 with a threshold for positivity
of either elevation above 35 U/mL or doubling since the
previous screen, followed by transvaginal ultrasound
only if CA-125 is positive, was found to be efficient in
that no other strategies saved as many years of life at
lower cost per year of life saved. They estimated the
cost-effectiveness of different screening strategies for a
population of 1 million women over age 50 years over a
period of 30 years using a stochastic simulation model.
All costs were measured in 1990 dollars, and all costs and
benefits were discounted by 5% to 1990. Used annually,
they predicted that a multimodal strategy would cost US
$51,000 per year of life saved and would be potentially
cost-effective. Both of these models assumed a fixed
duration for each disease stage based on expert opinion
January 2011, Vol 18, No.1
(stage I: 9 months; stage II: 4.5 months; stage III: 12
months; and stage IV: 3 months).
A third ovarian cancer natural history model22 used
a Markov transition state design that allowed direct pro-
gression from stage I to either stage II or stage III disease,
which is consistent with the common clinical presenta-
tion and stage distribution of the disease. We utilized a hy-
pothetical screening test whose characteristics and cost
could be adjusted to reflect different potential screening
modalities, and we assigned costs to false-positive results.
The model was calibrated against data from the Surveil-
lance, Epidemiology and End Results (SEER) program for
ovarian cancer incidence, stage distribution, and mortal-
ity. The model predicted that an annual screening test
with a sensitivity of 85% and a specificity of 95% would
have a PPV of 0.55%. At screening test specificities of up
to 99%, the model-predicted PPV of annual testing did
not exceed 4%. However, at a specificity of 99.9%, the
PPV for annual screening was 22%. Annual screening of a
population of women aged 50 to 85 years at average risk
of ovarian cancer was predicted to improve life expec-
tancy by 2.92 days on average, with an ICER of $73,469
(2007 US dollars) per year of life saved compared with
no screening. However, simulated screening of a “high-
risk” population of women aged 50 to 85 years with a
relative risk of developing ovarian cancer of 2 resulted in
an improvement in the ICER to $36,025 per year of life
saved compared with no screening. Costs and outcomes
were discounted at an annual rate of 3%. Based on this
model, annual screening for ovarian cancer might be
cost-effective in high-risk populations, and the specificity
of a screening test would need to exceed 99% to achieve
clinically acceptable PPVs of greater than 10%.22
Two RCTs in progress are the United Kingdom Col-
laborative Trial of Ovarian Cancer Screening (UKCTOCS)
and the Prostate, Lung, Colorectal and Ovarian (PLCO)
Cancer Screening Trial in the United States. The PLCO
study is an RCT that randomized women aged 55 to 74
years to either screening with annual ultrasound and
CA-125 (intervention group) or a control group who
received usual care (no screening). Recently, an analysis
on the first four rounds of screening revealed that the
highest PPV achieved with screening was 1.3%, and 72%
of the screen-detected cases were late-stage disease (III
or IV). The effect of screening on mortality is not yet
known, but initial results are not encouraging.23 Between
2001 and 2005, the UKCTOCS randomized 202,638 post-
menopausal women aged 50 to 74 years to three arms:
(1) no treatment (n = 101,359), (2) a multimodal screen-
ing consisting of annual CA-125 screening (interpreted
by a risk of ovarian cancer algorithm) and transvaginal
ultrasound scan as a second-line test (n = 50,640), or
(3) annual screening with transvaginal ultrasound (n
= 50,639). The initial round of “prevalence” screening
resulted in a sensitivity, specificity, and PPV of 89.5%,
99.8%, and 35.1%, respectively, for multimodal screening
Cancer Control 61
and 75.0%, 98.2%, and 2.8% for ultrasound for primary
invasive epithelial ovarian and tubal cancers. The trial
is ongoing, with the final screening tests taking place
in 2011, and all women will be followed until the end
of 2014. The initial screen has established that these
screening strategies are feasible.24 While the improved
specificity, PPV, and stage distribution of cancers reported
in this trial are encouraging, both mortality data and final
analysis of the costs of the multimodality screening algo-
rithm are critical to any assessment of the costs, benefits,
and potential cost-effectiveness of screening. Moreover,
quality of life has not been taken into account in any of
these economic models.
Chemotherapy for Newly Diagnosed
Ovarian Cancer
The recommended treatment for ovarian cancer entails
primary surgery for diagnosis, staging, and cytoreduction
followed by chemotherapy. Intravenous chemotherapy
usually consists of a taxane and a platinum agent for 3
to 6 cycles; patients with advanced intraperitoneal (IP)
disease are often candidates for IP chemotherapy. Based
on the National Comprehensive Cancer Network (NCCN)
2009 guidelines, patients who are eligible for chemo-
therapy should be informed about the options of either
intravenous (IV) chemotherapy or a combination of IV
and IP chemotherapy.25 IV chemotherapy should consist
of a taxane and a platinum agent for 3 to 6 cycles, while
IP chemotherapy should be given in combination with
IV chemotherapy utilizing taxane and platinum agents.
The first cost-effectiveness studies in ovarian cancer
chemotherapy were performed in response to the in-
troduction of taxanes into the front-line chemotherapy
regimen for this disease. Two independent RCTs, one
by the Gynecological Oncology Group (GOG 111) and
another by the European-Canadian Intergroup (OV-10),
demonstrated that cisplatin plus paclitaxel as primary
chemotherapy is superior to previous therapy of cisplatin
plus cyclophosphamide in clinical response rate, progres-
sion-free survival, and overall survival.26-28 Three phase III
RCTs subsequently showed similar efficacy of paclitaxel
in combination with either carboplatin or cisplatin for the
adjuvant treatment of ovarian cancer.29-31 The carboplatin
combination was better tolerated and has subsequently
become a standard first-line treatment.32
When first introduced, paclitaxel plus cisplatin was
a more expensive therapy than the old standard of cyclo-
phosphamide plus cisplatin. A number of cost-effective-
ness investigations using GOG 111 data based on cispla-
tin plus paclitaxel vs cisplatin plus cyclophosphamide
were performed. From the perspective of a US oncology
practice, the total drug costs for cisplatin plus paclitaxel
were four times higher than those for cisplatin plus cy-
clophosphamide (US $9,918 vs $2,527; 1996 costs).33
Compared with cisplatin plus cyclophospha-mide, the
incremental costs per year of life gained for cisplatin
62 Cancer Control
plus paclitaxel therapy were US $19,820 for inpatient
treatment and $21,222 for outpatient treatment. These
incremental costs fall well within the generally accepted
cost-effective range for new therapies.
From a Canadian health system perspective, cisplatin
plus paclitaxel had an ICER of $32,213 (1993 costs for
drug and hospital costs in Canadian currency [CaD]) per
life-year gained compared to cyclophosphamide plus
cisplatin.34 The investigators originally concluded that
it may not be possible to adopt this as first-line therapy
for all advanced-stage ovarian cancer patients because
it would cost the province of Ontario an additional
CaD $9 million annually. Ontario has a fixed budget
for cancer care, and this new therapy would mean that
fewer resources would be available for treating patients
with recurring disease. However, initial adjuvant chemo-
therapy in Canada now often includes a platinum agent
in addition to paclitaxel. Berger et al35 investigated the
cost-effectiveness of cisplatin plus pac-litaxel from the
perspective of the national health services of various
European countries. The incremental costs of cisplatin
plus paclitaxel per life-year saved were evaluated for
Germany (US $9,362), Spain (US $6,395), France (US
$6,642), Italy (US $11,420), the Netherlands (US $7,796),
and the United Kingdom (US $6,403).35 Of note, carbo-
platin and paclitaxel are now both marketed as generic
agents, and therefore these prior studies are less appli-
cable than when first published.
The NCCN 2009 guidelines for ovarian cancer rec-
ommend IP chemotherapy as primary/adjuvant therapy
for optimally debulked ( 1 cm) stage II or greater
ovarian cancer treatment.25 Three phase III clinical trials
identified advantages to the use of IP chemotherapy for
adjuvant treatment of stage III ovarian cancer.36-38 The
most recent of these studies demonstrated an overall
survival advantage of 16 months in the IP arm at the
expense of increased adverse events and a significant
reduction in quality of life.
Two analyses have evaluated the cost-effectiveness
of IP chemotherapy for the primary treatment of stage III
ovarian cancer. When comparing IP to IV chemotherapy,
Bristow et al39 reported that IP chemotherapy was po-
tentially cost-effective compared with IV, with an ICER
of $37,454 per QALY (2006 US dollars). Havrilesky et
al40 reported an estimate of $180,022 per QALY (2006
US dollars) when using a 7-year time horizon, which was
consistent with the current duration of survival results
from GOG 172. However, when the time horizon was ex-
tended to a lifetime under the assumption that any survival
advantage realized with IP chemotherapy would persist
over that period, the ICER of IP chemotherapy dropped to
US $32,053 per QALY. Also of note, under the assumption
that IP chemotherapy is equally effective as an outpatient
regimen, the ICER of IP vs IV chemotherapy becomes even
more attractive. While both studies informally incorpo-
rated quality of life based on the surveys administered to
January 2011, Vol 18, No.1
patients enrolled on GOG trials of chemotherapy, neither
performed a validated utility assessment. Our conclu-
sions are that IP chemotherapy is potentially cost-effective
for women with stage III disease, but that more formal
incorporation of quality of life, longer-term follow-up of
the results of the last phase III study, and investigation of
outpatient IP regimens would strengthen this conclusion.
Finally, the recent addition of biologic agents such
as bevacizumab to first-line chemotherapy regimens for
ovarian cancer has shown promise, as reported at the 2010
meeting of the American Society of Clinical Oncology
(ASCO).41 No formal cost-effectiveness studies incorpo-
rating this therapy have yet been published, but concerns
have been raised over the high cost of new therapies com-
pared with their potential level of benefit.42
Chemotherapy for Recurrent
Ovarian Cancer
Most women with ovarian cancer will achieve clinical
remission following surgery and primary adjuvant che-
motherapy. Unfortunately, the majority of patients even-
tually develop recurrent disease that is rarely curable.43
Patients who experience recurrence more than 6 months
after completing a first-line chemotherapy regimen are
considered to have “platinum-sensitive” ovarian cancer
and have an excellent response rate when re-treated with
platinum agents.44,45
The optimal treatment of recurrent ovarian cancer
is subject to ongoing debate and is affected by consid-
erations of survival, toxicity, and quality of life. Prior
studies indicate that patients with platinum-sensitive
disease have a good response rate to re-treatment with
platinum-based regimens.46-49 Two large RCTs compared
the use of single-agent therapy with combination regi-
mens for platinum-sensitive ovarian cancer.50,51 These
studies identified a progression-free survival advantage
for the combination regimens of gemcitabine plus car-
boplatin and paclitaxel plus platinum chemotherapy
(as well as an overall survival advantage for paclitaxel
plus platinum) compared with platinum alone, and the
authors suggested that the combination regimens should
be considered standard of care.
Based on these two studies, Havrilesky et al52 recently
published a Markov state transition model that evaluated
the optimal treatment strategy for patients with recurrent
platinum-sensitive ovarian cancer. We determined that
paclitaxel plus carboplatin has an ICER of $15,564 per
additional progression-free year compared with single-
agent carboplatin, while gemcitabine plus carboplatin
has a less attractive ICER of $278,388 per additional
progression-free year compared with paclitaxel plus
carboplatin. Given that both carboplatin and paclitaxel
are now available as generic drugs in the United States,
their cost advantage is not surprising. We also evaluated
neurologic and hematologic toxicities by incorporating
these into a sensitivity analysis and varying the severity
January 2011, Vol 18, No.1
and costs associated with treatment. Over a reasonable
range of utility (quality of life) scores, the paclitaxel/
carboplatin regimen was still cost-effective compared
with carboplatin alone, and gemcitabine plus carboplatin
remained non–cost-effective.52 These results must be
interpreted on an individual basis with the patient’s prior
adverse event profile in mind. For example, it is unlikely
that a patient with severe neurotoxicity due to prior
taxane treatment would be re-treated with the same drug.
Recurrent ovarian cancer that occurs within 6
months of completing a first-line chemotherapy regimen
has a poor prognosis, with cure being unlikely. Rocconi
et al53 performed a cost-effectiveness analysis of treat-
ment options for recurrent platinum-resistant ovarian
cancer and concluded that only best supportive care
(ie, no chemotherapy) was clearly cost-effective, while
second-line monotherapy was possibly marginally cost-
effective (ICER US $64,104 per year of life saved). Even
without incorporation of toxicity rates and costs, the
authors found that combination chemotherapy regimens
were never cost-effective for platinum-resistant disease
due to unfavorable ICERs.
Conclusions
While decisions surrounding the diagnosis and treat-
ment of cancer are difficult and cost is not usually the
most pressing concern of decision makers, the increasing
burden of the rising cost of health care demands atten-
tion. As newer, higher-cost therapies become available,
formal evaluation of the costs and benefits of these new
treatments in comparison to existing and established
strategies should be a high priority. Screening for ovarian
cancer has yet to be proven effective in any population,
and as such it has not been proven to be cost-effective.
Women with ovarian cancer are at a high risk of recur-
rence and often receive multiple chemotherapy regi-
mens. Cost-effectiveness studies to date support the use
of IP chemotherapy under certain assumptions. Likewise,
the use of multiagent chemotherapy regimens appears
to be cost-effective for women with platinum-sensitive
recurrence. For those with platinum-resistant disease,
single-agent chemotherapy or even supportive care are
the strategies of choice. Cost-effectiveness models offer
a way to objectively examine management options and
give perspective to difficult therapeutic decisions.
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