Beruflich Dokumente
Kultur Dokumente
Abstract
In the last two decades, computer-based models of cervical cancer screening have been used to evaluate the cost-effectiveness of different
secondary prevention policies. Analyses in countries with existing screening programs have focused on identifying the optimal screening
interval, ages for starting and stopping screening, and consideration of enhancements to conventional cytology, such as human papillomavirus
(HPV)-DNA testing as a triage for equivocal results or as a primary screening test for women over the age of 30. Analyses in resource-poor
settings with infrequent or no screening have focused on strategies that enhance the linkage between screening and treatment, consider
noncytologic alternatives such as HPV-DNA testing, and target women between the ages of 35 and 45 for screening one, two, or three times
per lifetime. Despite differences in methods and assumptions, this paper identifies the qualitative themes that are consistent among studies,
and highlights important methodological challenges and high-priority areas for further work.
© 2006 Elsevier Ltd. All rights reserved.
0264-410X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.vaccine.2006.05.114
S.J. Goldie et al. / Vaccine 24S3 (2006) S3/164–S3/170 S3/165
This chapter will synthesize the findings from cost- be expanding coverage in the population by using new
effectiveness analyses (CEAs) that have focused on cytology- technology such as HPV-DNA testing in a cost-effective
based cervical cancer screening and identify several qualita- manner and deciding how a vaccine could be utilized given
tive themes [2–5]. Second, consistent findings from analy- existing screening practices. In the US, screening strategies
ses that have considered HPV-DNA testing as a triage for implemented in clinical practice are often incongruent with
equivocal cytologic abnormalities [6–11] and HPV-DNA those recommended by clinical guidelines, which in turn,
testing as a primary screening test with or without cytol- at least until recently, are not always the most cost-effective
ogy [7–9,11–13] will be described for countries with exist- strategies. However, in recent years, consistent with find-
ing screening programs. Key themes from studies that have ings from cost-effectiveness analyses, recommendations
assessed noncytology-based strategies that enhance the link- have shifted to screening less frequently, delaying the ini-
age between screening and treatment and may be more feasi- tiation of screening until 3 years after sexual debut, and
ble in developing countries [14–17] will be identified. Finally, considering cessation of screening for women over age 65
a summary of the most important methodological challenges who have been regularly screened and are negative.
and high-priority areas deserving of analytic attention will be • There appears to be little benefit from beginning screening
provided. at a very young age, and there could be harmful conse-
quences due to unnecessary colposcopy and other proce-
dures. In most countries with existing screening programs,
2. Prior CEAs in developed countries the recommended age of beginning cytology screening
ranges from 21 to 25 [4]. In the US prior to 1992, most
The vast majority of published CEAs of population-based national guidelines recommended initiating cervical can-
cervical cancer screening performed in the last two decades cer screening with the onset of sexual activity or at age 18
have focused on high-income countries. Consequently, they [19]. An analysis that compared this recommendation to
have addressed issues such as the choice of screening inter- policies that delayed screening until 3 years after sexual
val, ages for starting and stopping screening, enhancements debut showed delayed screening to be more cost-effective.
to conventional cytology, and integrating HPV-DNA testing • For women who have undergone cervical cancer screen-
into cytology-based screening programs as a triage for equiv- ing at regular intervals throughout their lifetime and have
ocal cytology results or as a primary screening test for women consecutive negative results, a policy that discontinues
over the age of 30. Several general themes emerge from mul- screening around age 65 is reasonable [20]. Benefits of
tiple studies despite differences in modeling structure and screening (in terms of life-expectancy gains) in a well-
assumptions. These can be summarized as follows: screened cohort decline rapidly after age 65 because the
risk of dying from cervical cancer is substantially reduced
• The cost-effectiveness of screening in the general popu- because of the natural history of the disease, a reduc-
lation becomes increasingly less favorable as programs tion in prevalence resulting from screening and treatment
are intensified by screening more frequently than every at younger ages, and increasing risk of death from other
2–3 years and/or aggressively following equivocal or low- causes. The relative cost-effectiveness of continued regular
grade cytological abnormalities that are likely to regress. screening in low-risk older woman will somewhat depend
This occurs because for any given level of test sensitivity on the screening frequency. For example, when screening
and specificity, costs increase almost linearly with shorter intervals are three to five years, termination of screening
intervals while the incremental gains in benefits rapidly at age 65 does not save many resources [21]. It should
diminish. In most analyses in developed countries, screen- be noted, however, that where women have not previously
ing intervals of 3–5 years usually fall within acceptable been screened, screening at older ages is very cost-effective
limits of cost-effectiveness ratios. Biennial and annual because there is a large risk of disease in older unscreened
screening strategies have very high cost-effectiveness women.
ratios, and are generally considered not cost-effective from • Strategies that employ screening tests with higher sen-
a policy perspective. The high costs of frequent screen- sitivity than conventional Pap smears (e.g., liquid-based
ing are due not only to the increased number of tests, but cytology with HPV-DNA testing to triage equivocal cytol-
also the detection and treatment of more low-grade lesions ogy results, enhanced cytology with computer-assisted
which, in the absence of screening, would regress on their imaging, primary screening with HPV-DNA testing in
own without intervention. older women) without modifying the routine screening
The majority of European countries recommend screen- interval offer little incremental benefit but increase costs,
ing beginning between the ages of 20 and 25 years, and and thus are associated with very high incremental cost-
continuing every 3–5 years until age 60–65 [18]. These effectiveness ratios. For example, in an analysis of screen-
general policies have cost-effectiveness ratios that would ing in the US, the magnitude of the life-expectancy gains
be considered very cost-effective according to multiple for annual screening with HPV-DNA testing and cytol-
suggested criteria for cost-effectiveness ratio thresholds ogy compared with biennial screening with those same
(see Chapter 18; [4]). For these countries, priorities should tests was 4 hours. Accordingly, the incremental cost-
S3/166 S.J. Goldie et al. / Vaccine 24S3 (2006) S3/164–S3/170
ing sensitivity has a greater impact when coverage is lower. influential on population impact and cost-effectiveness in
For example, at 25% coverage, reduction in lifetime risk of settings with infrequent screening, while changes in speci-
cancer is 13% when increasing sensitivity from 60 to 100%, ficity are much less influential.
whereas at 100% coverage, reduction in cancer risk is only • In developing countries, within-country and between-
4%. country differences affect screening cost components to a
Several general themes have been identified by studies greater degree than in resource-rich settings (see Chapter
focusing on resource-poor settings that have been unable to 18). The absolute level of cervical cancer mortality reduc-
implement and support ongoing screening programs. These tion is most sensitive (by far) to coverage rates, minimizing
can be summarized as follows: loss to follow-up of women with positive results, and long-
term effectiveness of cryosurgery in screen/treat strategies,
• For countries with limited resources, screening efforts whereas the cost-effectiveness ratios are most sensitive to
should target women age 35 or older, and strategies should nonmedical costs (time and transportation) and the avail-
focus on screening all women at least once in their life- ability and cost of cancer treatment (see Chapter 18).
time before increasing the frequency of screening. If high
coverage can be achieved, screening two to three times
per lifetime could reduce lifetime cancer risk by 25–40%. 4. Overview of CEA results in all world regions
Targeting the appropriate age groups is crucial, generally
around age 35 and then at 40 in the case of two lifetime The need for a global perspective in a discussion of poli-
screening tests; screening three times in a lifetime should cies for cervical cancer prevention is made apparent by a
occur between 30 and 50 years of age with spacing between comparison of the strategies used in very different settings.
tests of about 5 years. Fig. 3 shows the discounted lifetime costs and clinical bene-
• Results of published analyses show that the choice between fits (expressed as reduction in the lifetime risk of cancer) of
cytology, HPV-DNA testing (most-effective), and visual different screening strategies performed at different screen-
methods (least costly), is most sensitive to the ability to ing intervals. The cost-effectiveness of moving from one
link screening and treatment in fewer visits, the resources screening strategy to a more costly alternative is represented
required with each test, and test sensitivity. by the difference in cost divided by the difference in can-
• When screening is only one to three times per lifetime, and cer incidence reduction associated with the two strategies.
if coverage rates are below 25%, enhancements to screen- Strategies lying on the efficiency curve dominate those lying
ing test sensitivity have minimal impact at the population to the right of the curve (not shown) because they are more
level (e.g., increasing sensitivity from 60 to 100% provides effective, and either cost less or have a more attractive cost-
an incremental reduction in the lifetime risk of cancer of effectiveness ratio, than the next best strategy. For each strat-
less than 5%). However, provided widespread coverage egy on the curve, a range of cost-effectiveness ratios and
can be achieved, small changes in sensitivity are more examples of countries in which cost-effectiveness analyses
Fig. 3. Efficiency frontier depicting costs and benefits of screening strategies in different regions of the world [6–10,12,17,26]. Strategies differ by screening
test (i.e., visual inspection using acetic acid (VIA), HPV-DNA testing, conventional cytology, and * liquid-based cytology with HPV-DNA testing to triage
equivocal results) and screening frequency.
S.J. Goldie et al. / Vaccine 24S3 (2006) S3/164–S3/170 S3/169
were conducted are shown based on a review of the pub- stantial cohort effects that will affect cancer incidence and
lished literature. The slope between two strategies is steepest mortality, including exposure to HPV (age at sexual debut,
when the net gain in cancer incidence reduction is greatest average number of partners), exposure to factors which may
(see Chapter 18). In this figure, strategies differ by screening contribute to increased cancer risk once infected with HPV
test and screening frequency, ranging from once per lifetime (pregnancy, smoking, HIV), changes in competing risks (age-
to annual screening. specific mortality from other causes, rates of hysterectomy for
Strategies at the lower left of the curve are those which benign disease), changes in factors which affect diagnosis of
involve less technically intensive tests (VIA and HPV-DNA cervical cancer (access to medical care, changes in endemic
testing) and infrequent screening intervals (e.g., one to conditions, which lead to symptoms that mimic early cer-
three times per lifetime). Such strategies, which have cost- vical cancer), and changes in stage-specific survival from
effectiveness ratios ranging from $110 to $2500 per YLS, cervical cancer (improvements in treatments, reductions in
are considered to be attractive strategies for countries in poor morbidity and mortality associated with treatment). Ideally,
regions of the world, such as India and Thailand [17]. age–period–cohort models could help address some of these
Screening at 3- and 5-year intervals using conventional issues, but the data necessary for construction of these mod-
cytology produces cost-effectiveness ratios that range from els are not commonly available, especially in the developing
$6800 to $25,600 per YLS based on analyses in European countries where some of these secular trends may be most
countries such as the UK, The Netherlands, France, and Italy dramatic.
[7,8,10], and 2-year screening with cytology ranges from The choice of model structure will continue to be challeng-
$34,500 to $56,400 per YLS based on analyses in Australia ing. Cervical cancer natural history and screening models
and the US [6,9,12,26]. More aggressive strategies, such as have evolved considerably in parallel with a better under-
screening every 2 years or annually using liquid-based cytol- standing of the role of HPV in cervical carcinogenesis, and
ogy (with HPV-DNA testing for triage of equivocal cytology as the policy questions become more complex, this pro-
results), fall on the “flat of the curve” because they have cess will need to continue. For example, analyses focusing
much higher costs yet add very little benefit; these strategies, on HPV-DNA testing as a primary screening test require
assessed mainly in analyses conducted to address clinical additional sophistication in model structure to represent the
guideline questions in the US, range from $174,200 to over detailed age-specific patterns of HPV positivity in women
$1 million per YLS [6,9]. without cytologic abnormalities, with equivocal and low-
It is compelling to examine this figure in the context of grade abnormalities, and with high-grade disease. To assess
the most pressing policy issues in developing versus devel- newer screening strategies that diverge based on an indi-
oped countries. From a broad public health perspective we are vidual woman’s history, we require first order Monte Carlo
reminded of the differences in the potential “value” of a sin- methods (see Chapter 18), which more easily allow the ana-
gle dollar invested where it is needed most (i.e., in developing lyst to incorporate many dimensions of heterogeneity (e.g.,
countries) versus the “value” of a dollar invested in wealthy type-specific HPV, individual-based risk factors such as HIV,
countries with existing screening. It is interesting to invert the parity, smoking, etc.), to reflect both variability and uncer-
incremental cost-effectiveness ratio to gain an insight into the tainty in a more sophisticated manner and to permit the
differences between the most aggressive screening strategy risk of a single event to depend on a series of past events.
shown on the graph (far upper right) and the least aggressive Models used for evaluating cervical cancer control strate-
(far lower left). Expressing the incremental benefits relative gies in developing countries must be able to accommodate
to the incremental costs using a “benefit-cost ratio” would more details regarding the operational delivery of screen-
translate to 2.2 weeks of average life expectancy gain per ing and treatment services. Models that include vaccination
$50,000 in the US. In contrast, in India, this would translate strategies will need to either link with, or utilize parame-
to a gain of 5000 years of life expectancy per $50,000. ters from, dynamic transmission models (see Chapter 21).
Finally, for analyses that address the critical questions about
how screening test performance might change in the presence
5. Ongoing challenges of a type-specific vaccination (see Chapter 20), the mod-
els need to fully represent HPV type-specific heterogeneity.
There will always be parameter and model uncertainty in The price of representing increasing complexity and hetero-
each of the model-based analyses summarized here. Param- geneity of HPV types in a model of cervical carcinogenesis
eter uncertainty concerns the true values of the input param- is that the number of “unobserved” natural history param-
eters, whereas model uncertainty involves the way these eters quickly multiplies. Fortunately, epidemiologic data on
parameters are modeled (or synthesized or manipulated to age-related prevalence of type-specific HPV, age-related inci-
be appropriate for the model structure). Typically, models dence of CIN and invasive cancer, and the distribution of HPV
are calibrated to match data on age-specific cancer incidence types within CIN and cancer are increasingly available. These
and mortality, and, if available, prevalence of HPV and CIN. data, together with formal calibration methods, can theoret-
A limitation of this approach is that modelers are matching a ically permit the development of a model that both respects
cohort simulation to cross-sectional data. There may be sub- our uncertainty regarding natural history but forces the model
S3/170 S.J. Goldie et al. / Vaccine 24S3 (2006) S3/164–S3/170
to be consistent with multiple sources of epidemiologic data [11] Holmes J, Hemmett L, Garfield S. The cost-effectiveness of human
[27]. papillomavirus screening for cervical cancer. A review of recent
modelling studies. Eur J Health Econ 2005;6(1):30–7.
[12] Mandelblatt JS, Lawrence WF, Womack SM, Jacobson D, Yi B,
Hwang YT, et al. Benefits and costs of using HPV testing to screen
Disclosed potential conflicts of interest for cervical cancer. JAMA 2002;287(18):2372–81.
[13] Sherlaw-Johnson C, Gallivan S. The planning of cervical can-
ERM: Consultant (Merck and Co., Inc., Medical Trans- cer screening programmes in Eastern Europe: is viral testing a
suitable alternative to smear testing? Health Care Manage Sci
portation Management, Inc.); Research Grants (Merck and
2000;3(4):323–9.
Co., Inc.) [14] Sherlaw-Johnson C, Gallivan S, Jenkins D. Evaluating cervical can-
cer screening programmes for developing countries. Int J Cancer
1997;72(2):210–6.
Acknowledgments [15] Goldie SJ, Kuhn L, Denny L, Pollack A, Wright TC. Policy analysis
of cervical cancer screening strategies in low-resource settings: clin-
ical benefits and cost-effectiveness. JAMA 2001;285(24):3107–15.
SJG and JJK gratefully acknowledge grant support from
[16] Mandelblatt JS, Lawrence WF, Gaffikin L, Limpahayom KK,
the US National Cancer Institute (grant #R01 CA093435) Lumbiganon P, Warakamin S, et al. Costs and benefits of different
and The Bill and Melinda Gates Foundation (grant #30505), strategies to screen for cervical cancer in less-developed countries.
and the valuable contributions of Steven Sweet and Meredith J Natl Cancer Inst 2002;94(19):1469–83.
Holtan of the Harvard School of Public Health, Boston, MA, [17] Goldie SJ, Gaffikin L, Goldhaber-Fiebert JD, Gordillo-Tobar
A, Levin C, Mahe C, et al. Cost-effectiveness of cervical-
for their outstanding technical assistance.
cancer screening in five developing countries. N Engl J Med
2005;353(20):2158–68.
[18] van Ballegooijen M, van den Akker-van Marle E, Patnick J, Lynge
References E, Arbyn M, Anttila A, et al. Overview of important cervical cancer
screening process values in European Union (EU) countries, and
[1] Goldie SJ. Chapter 15: public health policy and cost-effectiveness tentative predictions of the corresponding effectiveness and cost-
analysis. J Natl Cancer Inst Monogr 2003;31:102–10. effectiveness. Eur J Cancer 2000;36(17):2177–88.
[2] Brown AD, Garber AM. Cost-effectiveness of three meth- [19] American College of Obstetricians and Gynecologists. ACOG prac-
ods to enhance the sensitivity of Papanicolaou testing. JAMA tice bulletin. Cervical Cytology Screening. Number 45, August 2003.
1999;281:347–53. Int J Gynaecol Obstet 2003;83(2):237–47.
[3] Maxwell GL, Carlson JW, Ochoa M, Krivak T, Rose GS, Myers [20] Mandelblatt J, Lawrence W, Yi B, King J. The balance of harms, ben-
ER. Costs and effectiveness of alternative strategies for cervi- efits, and costs of screening for cervical cancer in older women: the
cal cancer screening in military beneficiaries. Obstet Gynecol case for continued screening. Arch Intern Med 2004;164(3):245–7
2002;100(4):740–8. [discussion 47–48].
[4] van den Akker-van Marle ME, van Ballegooijen M, van Oort- [21] Philips Z, Whynes DK. Early withdrawal from cervical can-
marssen GJ, Boer R, Habbema JD. Cost-effectiveness of cervical cer screening: the question of cost-effectiveness. Eur J Cancer
cancer screening: comparison of screening policies. J Natl Cancer 2001;37(14):1775–80.
Inst 2002;94(3):193–204. [22] Legood R, Gray A, Wolstenholme J, Moss S. Lifetime effects, costs,
[5] Kulasingam SL, Myers ER, Lawson HW, McConnell KJ, Ker- and cost effectiveness of testing for human papillomavirus to manage
likowske K, Melnikow J, et al. Cost-effectiveness of extending low grade cytological abnormalities: results of the NHS pilot studies.
cervical cancer screening intervals among women with prior nor- Br Med J 2006;332(7533):79–85.
mal pap tests. Obstet Gynecol 2006;107(2 Pt 1):321–8. [23] Myers ER, McCrory DC, Subramanian S, McCall N, Nanda K, Datta
[6] Kim JJ, Wright TC, Goldie SJ. Cost-effectiveness of alternative S, et al. Setting the target for a better cervical screening test: char-
triage strategies for atypical squamous cells of undetermined sig- acteristics of a cost-effective test for cervical neoplasia screening.
nificance. JAMA 2002;287(18):2382–90. Obstet Gynecol 2000;96(5 Pt 1):645–52.
[7] Sherlaw-Johnson C, Philips Z. An evaluation of liquid-based cytol- [24] Suba EJ, Nguyen CH, Nguyen BD, Raab SS. De novo establishment
ogy and human papillomavirus testing within the UK cervical cancer and cost-effectiveness of Papanicolaou cytology screening services
screening programme. Br J Cancer 2004;91(1):84–91. in the Socialist Republic of Vietnam. Cancer 2001;91(5):928–39.
[8] Kim JJ, Wright TC, Goldie SJ. Cost-effectiveness of human papil- [25] Montz FJ, Farber FL, Bristow RE, Cornelison T. Impact of increasing
lomavirus DNA testing in the United Kingdom, The Netherlands, Papanicolaou test sensitivity and compliance: a modeled cost and
France, and Italy. J Natl Cancer Inst 2005;97:888–95. outcomes analysis. Obstet Gynecol 2001;97(5 Pt 1):781–8.
[9] Goldie SJ, Kim JJ, Wright TC. Cost-effectiveness of human papillo- [26] Neville AM, Quinn MA. An alternative cost effectiveness analysis
mavirus DNA testing for cervical cancer screening in women aged of ThinPrep in the Australian setting. Aust NZ J Obstet Gynaecol
30 years or more. Obstet Gynecol 2004;103(4):619–31. 2005;45(4):289–94.
[10] Berkhof J, de Bruijne MC, Zielinski GD, Bulkmans NW, Rozen- [27] Kim JJ, Kuntz KM, Goldhaber-Fiebert J, Mahmud S, Villa LL,
daal L, Snijders PJ, et al. Evaluation of cervical screening strategies Franco EL, et al. Calibration of a natural history model of cer-
with adjunct high-risk human papillomavirus testing for women vical cancer using longitudinal primary data. In: Proceedings of the
with borderline or mild dyskaryosis. Int J Cancer 2006;118(7):1759– 22nd international papillomavirus conference and clinical workshop.
68. 2005 [Abstract].