Virus Research 89 (2002) 301 /309

Review

www.elsevier.com/locate/virusres

Health economics and cervical cancer prevention: a global

perspective
Sue J. Goldie *
Department of Health Policy and Management, Harvard School of Public Health, 718 Huntington Avenue, 2nd floor Boston, MA 021155924, USA

Abstract
Recent scientific advances are providing an opportunity to revisit strategies for cervical cancer prevention. How to
invest health resources wisely, such that clinical benefits are maximized */and opportunity costs are minimized */is a
critical question in the setting of new technology. In addition to an interventions effectiveness, public health decisionmaking requires consideration of its feasibility, sustainability and affordability. No clinical trial or single cohort study
will be able to simultaneously consider all of these components. A mathematical simulation model can be a useful tool
with which to evaluate alternative cervical cancer control strategies by extending the knowledge from empirical studies
to real-world situations. Models combine information about the natural history of disease with other relevant
demographic, epidemiological, and economic characteristics. We describe a comprehensive Cervical Cancer Policy
Model with a flexible structure that may be modified as new data on the biology of disease become available. This
model provides an analytic framework to synthesize data on costs and benefits, to help design clinical guidelines, and to
inform development of sound health policy. Examples of cost-effectiveness analyses conducted in the US and South
Africa illustrate inevitable tradeoffs when choosing among a variety of interventions to decrease cervical cancer
mortality, and demonstrate how these methods can facilitate a bridge between research and health policy.
# 2002 Elsevier Science B.V. All rights reserved.
Keywords: Cervical cancer; Public health policy; Mathematical models; Cost-effectiveness analysis

1. Introduction
In the past several years there have been
substantial advances in our understanding of the
epidemiology of cervical carcinogenesis and the
causal role of oncogenic human papillomavirus
(HPV) (IARC, 1995; Bosch et al., 2002; Franco et
al., 1999). Despite this scientific progress cervical

* Tel.: /1-617-432-2010; fax: /1-617-432-0190

E-mail address: sgoldie@hsph.harvard.edu (S.J. Goldie).

cancer continues to have a devastating impact on

women worldwide, with an estimated 400 000
women developing cervical cancer each year.
(Pisani et al., 1997, 1999; Sankaranarayanan et
al., 1998; Parkin et al., 1999). The disproportionate impact of cervical cancer morbidity and
mortality in developing countries is extreme */
less than 5% of women are screened in the very
settings where more than 80% of cases occur
(Ponten et al., 1995).
The most critical policy questions related to
cervical cancer control differ drastically between

0168-1702/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 1 6 8 - 1 7 0 2 ( 0 2 ) 0 0 1 9 9 - 5

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S.J. Goldie / Virus Research 89 (2002) 301 /309

developed and developing countries. In countries

with organized screening programs, there has been
a marked reduction in the incidence of invasive
cancer. (Bosch et al., 2002; Ponten et al., 1995).
However, screening and access to treatment have
not been equally accessible to all groups of
women*/in fact, many of the incident cases of
cancer occur in women who have not had regular
cervical Pap smears. In the United States, for
example, there are well-documented differences in
cervical cancer mortality among women who are
older, poor, or from select cultural minorities,
compared with the general population (Miller et
al., 1998). There is an urgent need to identify costeffective public health strategies for increasing
screening coverage. From a broad health policy
perspective, the most pressing issue relates to the
enormous economic burden attributable to organized screening programs*/more than 50 million
Pap smears are performed annually in the US and
costs are estimated to exceed several billion dollars
(Bosch et al., 2002). How to invest public health
resources wisely, such that clinical benefits to
women are maximized*/and opportunity costs
are minimized */is a critical question in the setting
of enhanced cytologic methods, new technology,
and HPV DNA testing.
The most relevant health policy issue in developing countries is how to implement an effective
and feasible cervical cancer screening program in
the setting of competing health problems and
limited resources. Recent clinical studies have
shown promising results for simple visual screening methods and HPV DNA testing followed by
treatment, with and without colposcopic triage.
Although the long-term effectiveness of these noncytological screening strategies is still uncertain,
they represent hopeful alternatives in settings
where cervical cytology has not been possible. In
middle-income countries where cytology screening
has been available but a reduction in cancer has
not been achieved, the most pressing public health
questions are how to effectively target screening
programs to those women at highest risk for
cervical cancer, and how to improve the quality
of cytological interpretation. Finally, from a
global public health perspective, and particularly
relevant in resource-poor countries where interval

cervical cytology screening has not been available,

a challenge of highest priority is how to ensure
investment of adequate resources to develop a
type-specific HPV vaccine.
Rather than a singular focus on efficacy, public
health decision-making requires consideration of
an interventions real world effectiveness */including its feasibility, likelihood of sustainability
and affordability. However, evaluating the effectiveness of any large-scale public health intervention is difficult because of the multiple components
inherent in the process. For example, regardless of
the target population, the optimal cervical cancer
screening policy mandates consideration of different screening tests, alternative reactions to abnormal results, and alternative treatment options for
pre-cancerous lesions. In addition, evaluating
program effectiveness requires specification of
the underlying natural history of disease, an
understanding of the heterogeneity of risk in the
population, information with respect to the performance and effectiveness of screening and treatment, and finally, accessibility, compliance and
feasibility in the targeted setting. No clinical trial
or single longitudinal cohort study will be able to
consider all of these components and assess all
possible strategies for all possible populations.
These facts, together with the need for decisionmaking in the setting of incomplete information,
make the discipline of decision science a potentially useful tool for public health.
Decision analysis as a discipline offers an
explicit, quantitative, and systematic approach to
decision making under uncertainty. The field
contains elements of economics, statistics, and
psychology, and encompasses a collection of
quantitative methods that have been developed
to guide the management of complex problems
that require simultaneous consideration of multiple competing choices, different perspectives, and
inevitable tradeoffs. Inherent in a decision analytic
approach is an explicit focus on identifying,
measuring, and valuing the outcomes or consequences of decisions, as well as using probabilistic
methods to describe the uncertainty about these
outcomes that exists at the time when decisions are
made.

S.J. Goldie / Virus Research 89 (2002) 301 /309

When a decision analysis formally compares the

relationship between the health and economic
consequences associated with different public
health care interventions, it is considered a costeffectiveness analysis. The application of economics to public health policy does not mean necessarily that less money should be spent, but rather
that the use of resources might be more efficient.
Different types of economic evaluations are commonly confused. It is important to distinguish
between cost-effectiveness analyses and cost-minimization and cost-benefit analyses-each have a
very different role (Drummond et al., 1997; Gold
et al., 1996). A cost-effectiveness analysis evaluates
an intervention (e.g. cervical cancer screening
strategy) through the use of an incremental costeffectiveness ratio. In this ratio, all health outcomes (compared to an alternative) are included in
the denominator, and all costs or changes in
resource use (compared to an alternative) are
included in the numerator. This type of analysis
defines the opportunity cost of choosing one
strategy over another, and provides useful data to
a wide range of policy makers in different settings
(e.g. health delivery organizations, government
agencies, professional guidelines committees, nongovernmental organizations, and ministries of
health).
The elements of a decision analysis or a costeffectiveness analysis (e.g. objectives, alternative
choices, all potential consequences, and values) are
incorporated into a model in order to structure the
decision problem over time. While different types
of models may be chosen to accommodate the
complexity of the decision, all rely on the use of
quantitative mathematical analysis to compare the
expected value of different options. A decision
analytic approach using a mathematical model
simulation model can be a useful tool with which
to evaluate alternative cervical cancer strategies by
extending the knowledge from empirical studies to
real-world situations (Gold et al., 1996; Halpern et
al., 1998). Models combine information about the
natural history of disease and performance of
screening and treatment with other relevant demographic and epidemiological characteristics of the
population under study. Costs and health effects
can be extrapolated beyond the time horizon of a

303

single clinical study and multiple potential strategies can be evaluated. In addition to relating
clinical and biological information, they provide
insight into the relative importance of different
components of the screening process and investigate how cost-effectiveness ratios will change if
values of key parameters are changed. By identifying the parameters that are most influential they
can help to prioritize and guide data collection
efforts.
In the last two decades several cervical cancer
models have been used to address specific health
policy questions (Habbema et al., 1984; Eddy,
1990; Fahs et al., 1992; Gustafsson and Adami,
1992; Sherlaw-Johnson et al., 1994, 1997; Jenkins
et al., 1996; van Ballegooijen et al., 1997; Cuzick et
al., 1999; Goldie et al., 1999, 2001a,b; Myers et al.,
2000; McCrory et al., 1999; Brown and Garber,
1999; van den Akker-van Marle et al., 2002; Kim
et al., 2002; Mandelblatt et al., 2002). These
models have provided important groundwork for
thinking about the data requirements necessary to
evaluate new strategies for cervical cancer screening, such as HPV testing, and the potential benefits
of HPV vaccination. In general, prior analyses
have shown the cost-effectiveness of screening is
sensitive to the age groups at which screening is
targeted, generally indicating it is more costeffective to focus screening efforts on women older
than 25 years of age. The majority of analyses
report diminishing marginal gains at screening
intervals of more than 3 years. Those that have
evaluated newer technologies have generally found
small improvements in life expectancy with technologies that enhance the sensitivity of the conventional Pap smear, unless screening is
infrequent. Recently, models have begun to incorporate state-of-the-art epidemiologic information on the natural history of HPV. (Jenkins et al.,
1996; van Ballegooijen et al., 1997; Myers et al.,
2000; Goldie et al., 2001a,b; Kim et al., 2002;
Mandelblatt et al., 2002) As these models evolve in
sophistication, the focus of future cost-effectiveness analyses should be driven by the most
pressing policy questions facing different regions
of the world.
To illustrate the potential value of such a model,
we briefly describe the development of a compre-

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S.J. Goldie / Virus Research 89 (2002) 301 /309

hensive Cervical Cancer Policy Model. This model

provides a comprehensive analytic framework to
inform the optimal design of clinical guidelines
and health policy for the prevention of cervical
cancer and has a flexible structure that may be
modified and updated as new data on the biology
and epidemiology of disease become available.
Examples of cost-effectiveness analyses conducted
in the US and South Africa will demonstrate how
a model such as this one can facilitate a bridge
between research and health policy (Goldie et al.,
2001b; Kim et al., 2002).

2. Description of a global cervical cancer policy

model
State transition models are analytical tools
designed to simulate the natural history of disease
and assess the impact of various preventive or
therapeutic interventions. The natural history of
disease is modeled as a sequence of transitions
among mutually exclusive health states, defined to
describe each individuals clinical condition, quality of life, prognosis, and resource utilization. Data
on costs, clinical effects, and health-related quality
of life associated with alternative clinical strategies
are synthesized to estimate intermediate (e.g. cases
of cancer) and long-term clinical outcomes (e.g.
life expectancy).
Health states in the model incorporate cervical
disease status (normal, CIN 1, CIN 2, CIN 3 and
CIS, and local, regional and distant invasive
cancer) and HPV DNA status (high-risk versus
low-risk types of HPV DNA). Biopsy-confirmed
cervical disease is defined as either CIN 1 or CIN
2, 3, whereas cytology results are classified as
atypical squamous cells (ASC), low-grade squamous intraepithelial lesions (LSIL), or high-grade
squamous intraepithelial lesions (HSIL). HPV
infection is defined as either detectable or undetectable to accurately represent the proportion in
CIN 1 and CIN 2,3 that would be detectable in a
clinical practice setting. This structure allows
calibration to cross-sectional data on the distribution of detectable HPV DNA within low and highgrade SIL. Invasive cervical cancer is stratified
according to the cancer staging system of the

National Cancer Institutes Surveillance, Epidemiology, and End-Results (SEER) Program (local,
regional and distant cancer). Details of the model
have been published elsewhere (Goldie et al.,
2001a,b; Kim et al., 2002).
A cohort of sexually-naive women, free of
disease, enter the model at age 13 and each month
face an age-dependent risk of acquiring HPV.
Women with detectable high-risk types of HPV
have a greater risk of CIN 2,3 and invasive cancer
than those with undetectable HPV. The undetectable dimension of the HPV health states contains
women with high-risk HPV types not detected
using a single test and women with low-risk HPV
types. The detectable dimension of the HPV health
states contains women truly infected with high-risk
HPV types, as well as some women with false
positive test results (e.g. low-risk types of HPV).
Transition probabilities, extrapolated from published literature, are used to move women through
different health states over time. The time horizon
of the analysis incorporates a womans entire
lifetime and is divided into equal monthly increments, referred to as Markov cycles, during which
women transition from one health state to
another. In each month, women may acquire
HPV, develop incident SIL, progress to a higher
grade SIL or cancer, and regress from a higher to
lower grade SIL or normal. The model distinguishes women with previously abnormal screening tests, prior treatment for CIN, and detected
cervical disease (through symptoms or screening).
In each cycle of the model, women can die from
stage-specific cervical cancer mortality, and age-,
sex- and race-adjusted all-cause mortality.
The model permits the evaluation of screening
strategies involving one or more tests, allows the
sensitivity and specificity of each screening test to
be conditional on individual factors, such as age or
underlying disease status. A unique diagnostic and
treatment strategy may be specified for each
screening test result. Risk of recurrence following
treatment depends on the efficacy and effectiveness
of the treatment choice, and may also be conditional on characteristics of the target population.
To model the development of symptoms from
invasive cervical cancer and the identification of
asymptomatic abnormalities through screening,

S.J. Goldie / Virus Research 89 (2002) 301 /309

the model distinguishes between detected and

undetected health states. Women with false-positive screening test results accrue the costs and
morbidity of a diagnostic work-up before resuming a regular screening schedule. Women who
develop invasive cervical cancer have a monthly
probability of developing symptoms that can then
lead to diagnostic work-up and medical care.
Several key features enhance this models face
validity and flexibility. Health states for cervical
neoplasia may be defined using the new Bethesda
classification system or using CIN terminology
(Solomon et al., 2002). Health states for cervical
cancer states may be defined using the staging
system of the SEER Program of the National
Cancer Institute (e.g. Local, Regional and Distant)
or the staging system of the Federation Internationale de Gynecologie et dObstetrique (FIGO)
system (Stage I, Stage II, Stage III, and Stage IV)
(Pecorelli et al., 1999; Surveillance, Epidemiology,
End Results (SEER) Cancer Statistics Review,
1973 /1994, 1997).
The predictive validity of this model has been
assessed by generating projections of age-specific
prevalence curves of HPV, LSIL and HSIL, agespecific cervical cancer incidence, and lifetime
cancer incidence and mortality, and comparing
these to published data not used for parameter
estimation. Details of these exercises have been
described elsewhere (Goldie et al., 1999, 2001a,b;
Kim et al., 2002).

3. Selected results from a policy analysis in South

Africa
We conducted a policy analysis comparing the
clinical benefits, costs, and cost-effectiveness of
different cervical cancer screening strategies in
black South African women (Goldie et al.,
2001b). Screening strategies incorporated visual
inspection with acetic acid (VIA) of the cervix,
conventional cytology, and HPV DNA testing of
either self-collected or clinician-collected samples.
Strategies also differed in the number of required
clinical visits, the frequency of screening and the
response to a positive test result. Clinical data were
obtained from a South African screening study,

305

international databases, and published literature.

Cost data were obtained from South African fee
schedules, local cost accounting systems, and two
South African national surveys.
In general, we found that a single lifetime
screen, using either a one-visit strategy (i.e. screen
and treat) with VIA, or a two-visit strategy with
VIA or HPV, would reduce the lifetime risk of
cancer from 22 to 32% for less than $50 per year of
life saved. In agreement with others, we found that
targeting this single lifetime screening to
unscreened women 35 /40 years of age provided
the best balance between clinical benefits and
costs. Performing screening two times per lifetime
(at ages 35 and 40 or 40 and 45) could be done for
less than $250 per YLS and would reduce the
lifetime risk of cancer up to 38%. Performing
screening three times in a lifetime (at ages 35, 40,
and 45), rather than twice, reduced cancer incidence up to 43% but cost substantially more (/
$500 per YLS). All screening strategies relying on
two or three screening tests per lifetime were more
effective if conducted every 5, rather than every 10,
years.
One-visit strategies in which screening and
treatment were performed at the same visit were
more effective and less costly than two and threevisit strategies in which women were screened at
one visit and underwent treatment at a later date.
Single visit strategies eliminated the costs involved
with the second visit, but more importantly,
eliminated the loss to follow-up that occurred
with each additional visit.
There are inevitable tradeoffs with all preventive
health interventions that are targeted at the
population level, including cervical cancer screening. Introducing one and two-visit strategies that
eliminate colposcopic evaluation and treat all
screen-positive women has important implications.
Both VIA and HPV testing have a relatively low
specificity and therefore a substantial number of
women without cervical disease undergo treatment
(e.g. cryotherapy). Our analysis incorporated the
known clinical and economic consequences resulting from immediate treatment and, even when the
false-positive rate of these non-cytological strategies increases to 20%, our results were robust. A
key question, however, that could change the

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S.J. Goldie / Virus Research 89 (2002) 301 /309

attractiveness of single visit see and treat options,

relates to the long-term effectiveness of this
strategy. We therefore emphasized in our original
manuscript (Goldie et al., 2001b), and reiterate
here, that additional studies are needed to establish the efficacy and complications of cryotherapy
when performed without colposcopy in low resource settings.
All screening tests may not be equally available
in low resource settings and certain screening tests
may be selected for programmatic reasons. For
example, in some regions it may not be feasible to
provide the ongoing training necessary for VIA. In
others, the cost of HPV testing may not be
affordable. In some countries, treating screen
positive women lacking cervical disease may be
inconsistent with womens preferences, despite the
fact that, at least in the case of HPV testing, screen
positive women are at significant risk for developing cervical disease. In other settings, a low
cultural acceptance of pelvic examinations may
make HPV testing of self-collected vaginal specimens the most attractive strategy. Finally, implementing screening programs based on VIA, HPV
testing, or cytology requires different types of
resources, and the relative availability of these in
different settings will impact the choice of strategy.

4. Selected results from a policy analysis in the US

This year a national consensus conference was
held to develop evidence-based guidelines for the
management of women with cervical cytologic
abnormalities (Wright et al., 2002) An important
topic addressed was how to manage the approximately 2.5 million US women with equivocal
cervical cytology results (e.g. ASC) each year. To
inform the guideline process we assessed the
clinical benefits and costs associated with the
following strategies for a cytologic result of
ASC-US: (1) immediate colposcopy; (2) HPV
DNA testing and triage (colposcopy if high-risk
HPV types are detected); (3) repeat cytology at 6
and 12 months, (colposcopy if a repeat abnormal
result occurs); and (4) ignoring all cytologic results
of ASC-US. Several HPV DNA testing scenarios
were evaluated */reflex HPV testing using residual

liquid-based cytology specimens, reflex HPV testing using samples co-collected at the time of
conventional cytology, and having a woman with
an ASC-US result return for HPV testing. Data
were from clinical trials, prospective studies, and
other published literature. Details of the study are
published elsewhere (Kim et al., 2002).
In the context of every 2- or 3-year screening
program the least costly strategy was to ignore a
cytologic result of ASC-US (79 /84% total cancer
incidence reduction), followed sequentially by
HPV DNA testing (86 /90% total cancer incidence
reduction), and then immediate colposcopy (87 /
91% total cancer incidence reduction) depending
on whether liquid-based or conventional cytology
was used. Compared to reflex HPV DNA testing,
repeat cytology was always less effective but more
costly.
When all potential screening options were
compared by simultaneously varying alternative
strategies to manage ASC-US, screening frequencies, and type of cytology test (liquid-based versus
conventional cytology), every 1-year liquid-based
cytology with reflex HPV testing costs $750 000
per YLS when compared to every 2-year liquidbased cytology; every 2-year liquid-based cytology
with reflex HPV testing costs $174 200 per YLS
when compared to every 3-year liquid-based
cytology. Every 3-year liquid-based cytology incorporating reflex HPV testing costs $59 600 per
YLS compared to every 5-year liquid-based cytology.
Our conclusions from this study were threefold:
First, in the context of current cervical cancer
screening practice in the US, follow-up for an
equivocal cytologic result of ASC-US provides a
7/11% incremental reduction in lifetime cancer
risk compared to ignoring the result (i.e. reclassifying ASC-US as normal). Second, reflex HPV
DNA testing provides clinical benefits of a similar
magnitude as immediate colposcopy for women
with ASC-US, but is much less costly. Finally, an
every 3-year cervical cancer screening program
incorporating liquid-based cytology and reflex
HPV DNA testing is more effective and less costly
than annual screening with conventional cytology.
The aggregate health economic costs saved by
adopting such a policy would exceed $15 billion

S.J. Goldie / Virus Research 89 (2002) 301 /309

dollars per a typical cohort of US women ages 18/

24.

5. Global inequity in cervical cancer control

worldwide
Fig. 1 shows the discounted lifetime costs and
clinical benefits (expressed as reduction in the
lifetime risk of cancer) of different screening
strategies performed at different screening intervals. The cost-effectiveness of moving from one
screening strategy to a more costly alternative is
represented by the difference in cost divided by the
difference in cancer incidence reduction associated
with the two strategies. Strategies lying on the
efficiency curve dominate those lying to the right
of the curve because they are more effective, and
either cost less or have a more attractive costeffectiveness ratio, than the next best strategy. (A
cost-effectiveness ratio is shown for each strategy.)
The slope between two strategies is steeper when

307

the net gain in cancer incidence reduction is

greater.
The once, twice and three times in a lifetime
screening strategies described in the South African
analysis are shown clustered in the left lower
corner of the efficiency curve in Fig. 1*/ in this
region of the curve the slope is steep demonstrating rapid escalating clinical benefits (relative to
doing nothing) for minimal costs. The three
representative strategies from the US analysis are
shown in the upper right corner of the efficiency
curve*/in this region of the curve the slope is quite
flat, demonstrating the very small incremental
clinical benefits gained by more frequent screening
in relationship to the accompanying incremental
costs. The cost-effectiveness ratios associated with
the most aggressive screening strategies reflect this
relationship*/for example, liquid cytology with
reflex HPV testing every 1 year, compared to every
2 years, costs more than $500 000 per year of life
saved.
It is compelling to examine this figure in the
context of the most pressing policy issues in

Fig. 1. Costs and benefits of cervical cancer screening.

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S.J. Goldie / Virus Research 89 (2002) 301 /309

developing versus developed countries. In the US,

we are faced with the challenge of how to ensure
that the price we pay for achieving incremental
hours of life-expectancy gain does not represent
the opportunity cost of reducing disparities in
screening and treatment which would provide far
greater public health benefits. In other words, the
challenge for public health policy makers is to
ensure that we do not keep indiscriminately
moving to the right on the flat of the curve (i.e.
expending more and more resources with rapidly
diminishing clinical gains). In developing countries, the relevant challenge for public health is
how to get on the curve at all */i.e. move from
doing nothing or indefinitely waiting for more
information to screening women at least once,
twice, or three times during their lifetime.
From a global public health perspective Fig. 1
illustrates the global inequity in our approach to
cervical cancer control worldwide, and reflects the
enormous difference in the value of a dollar
invested in developing country cervical cancer
screening programs versus the value of a dollar
in wealthy countries with organized screening. It is
interesting to flip the cost-effectiveness ratio (i.e.
employ a benefit/cost ratio) to gain insight into
the profound inequity displayed in this figurerather than $750 000 per year of life gained in the
US (associated with annual liquid-based cytology
and reflex HPV testing, compared to every 2 year
screening), lets express the relationship between
costs and benefits as the incremental benefits
provided for some fixed dollar amount, for
example $50 000. In the US, this would translate
to a benefit /cost ratio of 15 weeks of average life
expectancy gain per $50 000. In contrast, in South
Africa, this would translate to a benefit /cost
ratio of 1000 years of life expectancy gain per
$50 000.

6. Conclusion
Advances in our understanding of the epidemiology of HPV and cervical cancer will undoubtedly influence clinical medicine, public health, and
health policy. How to utilize new technology most
effectively will require careful consideration of the

net clinical benefits, as well as the potential harms,

at both an individual and a population level.
Although cost-effectiveness analysis is only one
input to decision-making, such analyses when
conducted rigorously and explained clearly, can
help illustrate the tradeoffs with different policy
alternatives. The use of decision analytic models in
the assessment of cervical cancer prevention policy
is a good example of how the strengths and
limitations of the experimental and modeling
approaches may be complementary */and how
these methods can be used together to provide
insight that one could not provide alone.

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