Affiliations of authors: Department of Health Policy and Management, Harvard School of Public Health, Boston, MA (JJK, SJG); Department of Pathology, College of Physicians and Surgeons of Columbia University, New York, NY (TCW)
Correspondence to: Sue J. Goldie, MD, MPH, Department of Health Policy and Management, Harvard School of Public Health, Harvard Initiative for Global Health, 104 Mount Auburn St., 3rd Floor, Cambridge, MA 02138 (e-mail: sue_goldie{at}harvard.edu).
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ABSTRACT |
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INTRODUCTION |
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In many European countries, cervical cancer screening guidelines include the use of conventional cytology (13), although they vary widely with respect to the frequency of screening, age to start and stop screening, target coverage rates, and follow-up strategies for equivocal or mildly abnormal results (Table 1) (1418). These countries will soon face decisions about whether or not to incorporate HPV DNA testing and what types of strategies will be most cost-effective. Although previous studies have evaluated the costs and benefits of alternate strategies for cervical cancer screening in the United Kingdom and The Netherlands (1929), to our knowledge, there has not been a comparative analysis that has involved multiple European countries and has focused on integrating HPV DNA testing into cervical cancer screening programs. Our objective was to assess the costs and benefits associated with HPV DNA testing in four European countries (the United Kingdom, The Netherlands, France, and Italy) to assist decision makers faced with choices about the adoption of this new technology.
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METHODS |
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We adapted a previously described computer-based model (3034) to simulate the natural history of cervical carcinogenesis using a sequence of monthly transitions among health states (Fig. 1). For each analysis, a country-specific cohort of nonHIV infected women entered the model and faced age-dependent probabilities of acquiring HPV, developing cervical intraepithelial neoplasia (CIN), or developing cancer. Women with HPV infection or established cervical lesions can regress to normal or develop higher-grade lesions or cervical cancer. Women at any age may die of cervical cancer or other causes.
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HPV Screening Strategies
We explored two main ways to incorporate HPV DNA testing into screening (22,41): 1) cytology throughout a woman's lifetime, using HPV DNA testing as a triage strategy for equivocal cytology results (i.e., "HPV triage") and 2) cytology until age 30 years, followed by HPV DNA testing in combination with cytology in women more than 30 years of age (i.e., "combination testing"). We restricted HPV DNA testing as a primary screening test to women more than 30 years of age because the best available data on HPV DNA test performance are from women more than 30 years of age and because the proportion of women younger than 30 years of age who test positive for HPV DNA would be prohibitively high (31). Strategies were compared with the status quo screening policy in each country. We allowed for changes in screening frequency but made the conservative assumption that the screening interval would be no longer than every 5 years and no shorter than every 3 years for women in the general population.
For each country's status quo policy, we assumed the use of conventional cytology at the screening ages, interval, and coverage rate specified in Table 1 (1318). Cytology results were classified as atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesions (LSILs), or high-grade squamous intraepithelial lesions (HSILs), consistent with the Bethesda system (42). We assumed that a "borderline" result by the European reporting system was equivalent to a result of "ASCUS," a "mildly abnormal" result was equivalent to "LSIL," and a "moderate" or "severe" result was equivalent to "HSIL." Biopsy-confirmed cervical disease was defined as either cervical intraepithelial neoplasia grade 1 (CIN 1) or grade 2,3 (CIN 2,3). We defined coverage as the proportion of eligible women at each scheduled screening interval who were screened.
For the base case, we made the following assumptions: 1) each woman in the cohort, regardless of her underlying risk, is equally likely to miss a scheduled screening examination; 2) an equivocal cytology result is followed by repeat cytology screening every 6 months for 1 year in the United Kingdom and The Netherlands and by colposcopy referral in France and Italy; 3) in the combination testing strategy, cytologically normal women who are HPV DNA positive return at 6 and 12 months for repeat cytology and HPV DNA testing, and those who remain HPV DNA positive after 12 months and/or have subsequent abnormal cytology are referred to colposcopy; 4) for HPV triage, HPV DNA testing is a "reflex" test, in which a sample is co-collected at the time of the cytology screen for an additional cost of $2; 5) colposcopy is performed on all women with cytologic results of HSIL; women without visible lesions on colposcopy do not receive biopsy, and treatment is reserved for biopsy-confirmed CIN 2,3; and 6) women who are treated for CIN 2,3, or have biopsy-confirmed CIN 1 return for a repeat cytology test 12 months later, regardless of the general population screening frequency.
Base Case Data
Selected input parameters used for the base case are presented in Table 2 (7,1320,22,25,2931,4372). Input parameters for the natural history of HPV and cervical cancer were based on population studies primarily in the United States (62), although age-specific HPV incidence rates were derived for each country by calibrating the models to country-specific cancer data, as described above.
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Cost-effectiveness Analysis
We adopted a societal perspective for the cost-effectiveness analysis and followed the recommendations of the Panel on Cost-Effectiveness in Health and Medicine (39). Costs were expressed in 2004 USD to facilitate comparisons across countries. Because there are uncertainties with respect to quality of life associated with HPV positivity, cervical cancer precursors, and invasive cancer, we conducted the base case analysis using reduction in the risk of cancer and increase in life expectancy as the primary outcomes. Future costs and life-years were discounted at an annual rate of 3%.
The performances of the two alternative screening strategies were measured using the incremental cost-effectiveness ratio, which is defined as the additional cost of a specific screening strategy, divided by its additional clinical benefit compared with the next-most-expensive strategy. Strategies that were defined as dominated (those with higher costs and lower benefits than other options) or weakly dominated (those with higher incremental cost-effectiveness ratios than more effective options) were excluded from the incremental cost-effectiveness calculations.
Although multiple criteria exist for categorizing the cost effectiveness of interventions, most of these criteria have been proposed within the context of a single country (39). Because of the comparative nature of our four-country analysis, we chose to use guidelines that are specifically intended for international comparisons. According to these guidelines, which are from the Commission on Macroeconomics and Health, interventions with cost-effectiveness ratios that are less than the gross domestic product per capita are considered very cost-effective and those with ratios that are less than three times the gross domestic product per capita are considered cost-effective (40).
Sensitivity Analyses
We performed extensive sensitivity analyses because of the considerable amount of uncertainty and variation in country-specific estimates of screening test performance and costs. Additional analyses were conducted to assess how the results might differ if we: 1) allowed for more frequent screening intervals with cytology alone; 2) assumed different follow-up strategies for HPV DNApositive women with normal cytology; 3) replaced conventional cytology with liquid-based cytology, which is more costly ($7 additional) per test and has higher sensitivity (68%) and lower specificity (93%) than conventional cytology (20); or 4) included quality-adjusted life expectancy as an outcome. For this last analysis, we applied stage-specific quality weights for time spent with invasive cancer (ranging from 0.48 with distant cancer to 0.68 with local cancer), and age-specific quality weights (ranging from 0.79 to 0.90) for noncancer states to reflect average quality of life decrements in women who were over 40 years of age (76). Quality weights were varied ±50% in sensitivity analysis.
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RESULTS |
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To evaluate our model calibration, we used number of cases and population size of women in 5-year age intervals from the IARC data (3538) to calculate the standard error and 95% confidence intervals for the age-specific incidence rates. We found that our model predictions for age-specific cancer incidence fell within or very close to the 95% confidence interval of the IARC data for all age groups.
Model projections of intermediate outcomes were then compared with those from other published models of cervical cancer screening in European countries. Rates of colposcopy referral among women without CIN or cancer for combination testing were approximately 31% greater for 3-year screening compared with 5-year screening in the United Kingdom using our model, compared with 29% that was projected by an independent U.K. model (19). When we used this model to simulate a population of U.S. women, the projected reduction in the lifetime cancer risk was 74% with the 3-year combination strategy, similar to the 78% that was projected from an analysis exploring HPV DNA testing options in the U.S. (77).
Base Case
The total lifetime discounted costs, life expectancy (discounted and undiscounted), and reduction in lifetime risk of cancer associated with alternative cervical cancer screening strategies for all four countries are shown in Table 3. In all countries, strategies that incorporated HPV DNA testing were preferable to the status quo strategy. Incremental cost-effectiveness ratios for HPV triage were less than $13 000 per year of life saved, whereas those for combination testing ranged from $9800 to $75 000 per year of life saved, depending on screening interval. In the United Kingdom, both strategies of HPV triage or combination testing every 5 years cost less than $15 000 per year of life saved. At more frequent screening intervals, combination testing ranged from $33 200 (3-, 5-year) to $75 900 (3-year) per year of life saved. All other strategies, including the status quo, were more costly and either less effective (i.e., strongly dominated) or less cost-effective (i.e., weakly dominated). In The Netherlands, France, and Italy, the results were similar to those in the United Kingdom. In The Netherlands, all nondominated strategies cost less than $40 000 per year of life saved, and in France and Italy, all nondominated strategies cost less than $30 000 per year of life saved.
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Results were most sensitive to changes in the relative performance and costs of the different screening tests. Results were less sensitive to changes within the plausible range of natural history parameters and to changes in costs of diagnostic workup and treatment for CIN and cancer.
Screening with the combination strategy every 5 years was very cost-effective (i.e., less than the country-specific gross domestic product), provided that its sensitivity exceeded 85% in the United Kingdom and Italy, and 90% in The Netherlands and France; HPV triage strategies at these thresholds consistently cost less than $15 000 per year of life saved with either 3- or 5-year screening. If the sensitivity fell below 65%, combination testing cost more than three times the gross domestic product per capita in all four countries. Using the most optimistic estimates for combined cytology and HPV DNA testing in the literature (sensitivity 100%, specificity 94%) (65), the cost per year of life saved for 5-year combination testing was reduced by approximately 9% in all four countries, compared with the base case results.
Varying the cost of screening changed the cost-effectiveness outcome. When the cost of both HPV DNA testing and cytology in women more than 30 years of age was reduced by 25%, the combination strategy every 3 years cost less than the per capita gross domestic product per year of life saved in all countries. When these costs were doubled, ratios for every 3-year combination strategies exceeded the gross domestic product per capita, and HPV triage became the preferred strategy; however, when using the threshold of three times the gross domestic product per capita, the combination strategy was still preferred.
Because of the variation in colposcopy and biopsy costs and management protocols for CIN in European countries, we varied these costs in our model from 25% to 200% of their base case values; however, the rank ordering of strategies did not change and the cost-effectiveness ratios varied minimally. For example, in Italy and France, the cost of the HPV triage strategy every 5 years ranged from $1100 per year of life saved and $1700, respectively, when colposcopy costs decreased by 75%, to $2400 per year of life saved and $3800, respectively, when colposcopy costs were doubled.
We evaluated how more frequent screening with cytology alone (i.e., status quo strategies every 1 or 2 years for all four countries, as well as 3 years for the United Kingdom and The Netherlands) compared with strategies that incorporated HPV DNA testing. In most analyses, frequent screening with cytology alone was either strongly or weakly dominated; in Italy, annual screening with cytology alone was not dominated but cost more than $3 million per year of life saved. Moreover, unless the sensitivity of the cytology test was greater than 95% in the United Kingdom, The Netherlands, and France, the status quo strategies were always strongly dominated by HPV triage. In Italy, when sensitivity of cytology exceeded 90%, the status quo strategy every 3 years cost $67 200 per year of life saved.
We explored the impact of the following alternative protocols for the management of women who are cytologically normal and HPV DNA positive: 1) colposcopy and more frequent follow-up screening (yearly or biennially); 2) HPV DNA test at 6 and/or 12 months, followed by more frequent screening for 5 years; and 3) combination of cytology and HPV DNA testing at 6 and/or 12 months, followed by more frequent screening for 5 years. Under all of these assumptions, combination testing in women more than 30 years of age was the most cost-effective strategy compared with HPV triage testing.
When conventional cytology was replaced with liquid-based cytology in the model, the cost-effectiveness ratios associated with combined HPV DNA testing and cytology in women more than 30 years of age were reduced by approximately 20% compared with the base case. Analyses in which health states were adjusted for quality of life resulted in cost-effectiveness ratios that were approximately 15% lower than in the base case.
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DISCUSSION |
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In all four countries, the choice between using HPV DNA testing as triage or in combination with cytology was most sensitive to changes in the relative performance and costs of the different screening tests. In particular, using the threshold of gross domestic product per capita for defining cost-effectiveness, we found that, if the sensitivity of the combination test decreased by 5%10% or the cost of combination test doubled, HPV triage became the most attractive strategy. If we used both cost-effectiveness and the rate of colposcopy referrals as independent criteria that influence the choice between HPV triage and combination testing, HPV triage had a substantially lower referral rate. The enhanced sensitivity of combination testing was associated with decreased specificity compared with HPV triage, resulting in more than a twofold increase in colposcopy referral rate. If this increase in referral rate is associated with quality of life decrements and/or if the capacity to manage the increased referrals is lacking, these factors will need to be weighed against the added benefits of the more sensitive test.
No universal criterion exists that defines a threshold "cost-effectiveness" ratio (i.e., above which an intervention would not be cost-effective and below which it would be cost-effective). Because of the comparative nature of our four-country analysis, we chose to use guidelines specifically intended for international comparisons that were proposed by the Commission on Macroeconomics and Health (40). Individual countries may have a different willingness to pay for a year of life saved. For example, in the United States, a threshold of $50 000 per year of life saved is often cited. Interestingly, even using this more generous criterion would not change the results of our analysis. For a variety of reasons, European countries might elect to use stricter thresholds than those implied by the Commission definition; in such a situation, the choice between HPV triage and combination testing could change. We emphasize that our analysis is not intended to provide the correct choice for any particular country; rather, our objective is to provide transparent information about the relationship between the relative costs and effects for each screening strategy so that decision makers from specific countries might use this information in their deliberations about the adoption of HPV DNA technology.
Our analysis has several limitations. Country-specific data were not available for all of the input parameters required for the model, and unknown factors that contribute to population heterogeneity could not be modeled. Similarly, there are no empiric country-specific data suitable for inclusion in this model on the cost and quality of life decrements associated with women being informed that they have high-risk types of HPV. Therefore, we purposefully did not conduct a detailed analysis of every potential strategy that would be of interest within each countrysuch analyses require detailed country-specific data and careful consideration of regional practice patterns. With ongoing prospective studies in country-specific settings, we anticipate that better data will be available in the future, and it will be an important priority to assimilate these data and refine analyses.
The long-term outcomes associated with different strategies for managing HPV DNApositive women are not known. Consequently, we focused our analysis on relatively few strategies and also omitted strategies that are largely untested, such as screening at intervals double and triple the length of the status quo (e.g., every 1015 years). Strategies with lengthened screening intervals will be relevant to women with several consecutive negative cytology and HPV DNA testing results, but better data are needed on their long-term safety to merit serious consideration in countries with established cytology screening programs.
With respect to European countries in particular, a cost-effectiveness analysis in the United Kingdom (19) and exploratory work assessing the potential value of HPV testing (2123,25) have been published, as have an overview of cervical cancer screening policies and identification of influential parameters on cost-effectiveness (27), and cost-effectiveness analyses of different cervical cancer screening strategies using cytology throughout Europe (20,24,26,28,29). Our results, which suggest that improved outcomes and cost-effectiveness are associated with HPV DNA testing, are consistent with these other published analyses. By including the United Kingdom and The Netherlands, in which previous cervical cancer screening analyses have been conducted, we were able to ensure model corroboration prior to adapting them to France and Italy, which have rarely been the focus of published cost-effectiveness analyses. The unique contribution of this four-country analysis that extends the prior work of others is the provision of a broad comparative overview of the potential value of HPV DNA testing across countries with different epidemiologic profiles and budgets.
The development of sound clinical guidelines and public health policy requires careful consideration of the incremental benefits, harms, and costs that are associated with new technology and its adoption into existing screening strategies, compared with the status quo. As a result of the rapid infusion of new technologies for cervical cancer screening, there is an increased need for policy evaluation to guide such investments. Even before definitive long-term data are available for different HPV DNA testing strategies, cost-effectiveness analyses can be used to explore the implications of changes in broad national screening policies. We found that HPV DNA testing not only has the potential to improve the effectiveness of cervical cancer prevention programs but may also be more cost-effective than current status quo policies that rely solely on conventional cytology.
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NOTES |
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Manuscript received November 17, 2004; revised April 13, 2005; accepted April 28, 2005.
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