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Surveillance After Treatment for Cervical Intraepithelial Neoplasia Outcomes, Costs, and Cost-Effectiveness Joy Melnikow, MD, MPH, Shalini Kulasingam, PhD, Christina Slee, MPH, L. Jay Helms, Miriam Kuppermann, PhD, MPH, Stephen Birch, DPhil, Colleen E. McGahan, MSc, Andrew Coldman, PhD, Benjamin K. S. Chan, MS, and George F. Sawaya, MD OBJECTIVE: To estimate outcomes and costs of surveillance strategies after treatment for high-grade cervical intraepithelial neoplasia (CIN). METHODS: A hypothetical cohort of women was evaluated after treatment for CIN 2 or 3 using a Markov model incorporating data from a large study of women treated for CIN, systematic reviews of test accuracy, and individual preferences. Surveillance strategies included initial conventional or liquid-based cytology, human papillomavirus testing, or colposcopy 6 months after treatment, followed by annual or triennial cytology. Estimated outcomes included CIN, cervical cancer, cervical cancer deaths, life expectancy, costs, cost per life-year, and cost per quality-adjusted life-year.

From the Center for Healthcare Policy and Research and the Department of Economics, University of California, Davis, California; the Division of Epidemiology and Community Health, School of Public Health, University of Minnesota, Minneapolis, Minnesota; the Departments of Obstetrics, Gynecology & Reproductive Sciences and Epidemiology & Biostatistics, University of California, San Francisco, San Francisco, California; the Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada; the Surveillance and Outcomes Unit and Population Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada; and the Oregon Evidence-based Practice Center, Oregon Health and Science University, Portland, Oregon. Supported by National Cancer Institute grant R01 CA109142. Presented at the 25th International Papillomavirus Conference, May 8 –14, 2009, Malmo¨, Sweden. Corresponding author: Joy Melnikow, MD, MPH, Department of Family and Community Medicine, Center for Healthcare Policy and Research, University of California, Davis, 4860 Y St, Suite 2300, Sacramento, CA 95817; e-mail: jamelnikow@ucdavis.edu. Financial Disclosure Dr. Kulasingam has previously received research support from Merck and CSL-Australia. She has also served as a consultant for CSL-New Zealand and Sanofi-Pasteur MSD and is currently a consultant for Medtronic. The other authors did not report any potential conflicts of interest. © 2010 by The American College of Obstetricians and Gynecologists. Published by Lippincott Williams & Wilkins. ISSN: 0029-7844/10

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PhD,

RESULTS: Conventional cytology at 6 and 12 months, followed by triennial cytology, was least costly. Compared with triennial cytology, annual cytology follow-up reduced expected cervical cancer deaths by 73% to 77% and had an average incremental cost per life-year gained of $69,000 to $81,000. For colposcopy followed by annual cytology, the incremental cost per life-year gained ranged from $70,000 to more than $1 million, depending on risk. Between-strategy differences in mean additional life expectancy per woman were less than 4 days; differences in mean incremental costs per woman were as high as $822. In the cost-utility analysis, colposcopy at 6 months followed by annual cytology had an incremental cost per quality-adjusted life-year of less than $5,500. Human papillomavirus testing or liquid-based cytology added little to no improvement to life-expectancy with higher costs. CONCLUSION: Annual conventional cytology surveillance reduced cervical cancers and cancer deaths compared with triennial cytology. For high risk of recurrence, a strategy of colposcopy at 6 months increased life expectancy and quality-adjusted life expectancy. Human papillomavirus testing and liquid-based cytology increased costs, but not effectiveness, compared with traditional approaches. (Obstet Gynecol 2010;116:1158–70)

E

ach year in the United States an estimated 500,000 women have cervical intraepithelial neoplasia (CIN) grade 2 and 3 diagnosed.1 Detection and treatment of these high-grade precancerous lesions have been accompanied by large reductions in cervical cancer incidence and mortality in many countries with widespread cytology-based screening programs.2 After treatment of CIN, follow-up surveillance strategies must strike a balance between the detection and treatment of persistent or incident lesions and the overuse of costly and invasive diagnostic procedures

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and tests. Evidence on the patterns of recurrence of CIN after treatment indicates an elevated risk for approximately 6 years after treatment, with the level of risk depending on initial CIN grade and treatment type.3 The risk of invasive cervical cancer, although still low, remains elevated for many years after treatment for CIN.3,4 Current recommendations by the American College of Obstetricians and Gynecologists and by the American Society of Colposcopy and Cervical Pathology suggest that after treatment women may be followed-up with a combination of cytology, colposcopy, and human papillomavirus (HPV) testing.5,6 Specifically, both guidelines suggest that surveillance can consist of either a single test for oncogenic HPV at 12 months or cytology testing at 6 and 12 months; American Society of Colposcopy and Cervical Pathology additionally endorses a combination of cytology and colposcopy at 6-month intervals. If all test results are normal, then routine screening for at least 20 years is advised. If any test result is abnormal, then colposcopy is recommended. The meaning of “routine” screening had been unspecified; recently released American College of Obstetricians and Gynecologists recommendations suggest follow-up with annual cytology.7 Although many options for posttreatment surveillance are proposed, the precise ordering of tests and periodicity of testing that maximize benefits and make the most productive use of resources has not been determined. Given the large number of women diagnosed with CIN 2 or 3, recommendations for posttreatment follow-up will affect hundreds of thousands of women each year in the United States. We conducted a cost-effectiveness analysis of strategies for follow-up of women after treatment for CIN, taking into consideration recurrence risk based on initial CIN grade and treatment type as well as the effect of these strategies on health-related quality-of-life.

MATERIALS AND METHODS This study was reviewed and approved by the University of California Davis Institutional Review Board. A state-transition Markov model was developed to predict outcomes after treatment of CIN. We evaluated 12 different surveillance strategies to detect subsequent disease in women who had previously been treated for CIN 2 or 3 (Box 1). Four strategies involving liquid-based cytology were subsequently excluded from the analysis, leaving eight remaining strategies. Model outcomes included recurrent (residual or incident) CIN 1, 2, and 3, invasive cervical cancer, incidental hysterectomy, death from cervical cancer, and death from all other causes. Rates of

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Box 1. Surveillance Strategies Evaluated in the Markov Model Conventional cytology at 6 and 12 months, then annually Conventional cytology at 6 and 12 months, then triennially Liquid-based cytology at 6 and 12 months, then annually* Liquid-based cytology at 6 and 12 months, then triennially* HPV testing† at 6 months, cytology at 12 months, then annual cytology HPV testing† at 6 months, cytology at 12 months, then triennial cytology HPV testing† and cytology at 6 months, cytology at 12 months, then annual cytology HPV testing† and cytology at 6 months, cytology at 12 months, then triennial cytology HPV testing† with liquid-based cytology at 6 months, cytology at 12 months, then annual cytology* HPV testing† with liquid-based cytology at 6 months, cytology at 12 months, then triennial cytology* Colposcopy at 6 months, then annual cytology Colposcopy at 6 months, then triennial cytology * Strategies involving liquid-based cytology subsequently were eliminated from the base-case model. † HPV testing performed with Hybrid Capture 2.

false-positive test results were estimated for each strategy, based on test specificity. Costs were assessed from the payer perspective, and estimates of outcomes and program costs were projected for a cohort of 500,000 women. Projected life expectancy, qualityadjusted life expectancy, total lifetime health care costs for surveillance and treatment of CIN, and incremental costs and effects associated with each strategy were tabulated. Incremental cost-effectiveness ratios that measure the average cost per life-year or quality adjusted life-year were calculated, in which the lowest cost program was used as the baseline, and each alternative strategy was compared with the next lower cost strategy. Strategies found to be more costly with no increase in effectiveness or less costly but less cost-effective than an alternative strategy were considered dominated by other strategies and excluded from further analysis. Health outcomes and costs occurring in the future were discounted at 3% annually for the base case.8 The model simulated a cohort of women at age 30 just after treatment for CIN 2 or 3 and followed them in 6-month cycles until age 85 years. Initial surveillance testing and follow-up of recurrent CIN occurred in 6-month cycles. Women progressed through the different health states of the model (eg, no disease, CIN 1, CIN 2 or 3, cancer [stages I–IV])

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Initial diagnosis and treatment

Surveillance model Outcomes

Normal

Initial surveillance test at 6 months (Box 1) Pretreatment diagnosis

False positive

Treatment Cytology

Lifetime follow-up

Cryotherapy CIN 2

CIN 1 HPV testing

Annual cytology

Laser CIN 3 Loop excision or cone biopsy

CIN 2 or CIN 3 HPV testing and cytology

Triennial cytology

Colposcopy

Cervical cancer Stages I窶的V Death from cervical cancer Death from other causes

Fig. 1. Overview of the Markov model structure. Melnikow. Surveillance After Treatment for CIN. Obstet Gynecol 2010.

based on estimates of residual disease after treatment and incident CIN. Residual disease probabilities were stratified by type of treatment (loop excision or cone biopsy of the cervix, laser ablation or excision, or cryotherapy) and initial CIN grade (CIN 2 or 3). An overview of the model structure is shown in Figure 1. Women with residual or incident CIN could have their disease regress, progress, or persist. Women with cancer (stages I, II, III, IV) could have their cancer detected during screening or if they presented to a health care provider because of symptoms. Women who did not have their disease detected could progress to the next stage, remain in the same stage, or die of cervical cancer. Each year, women also faced an age-specific risk of dying from other causes or undergoing hysterectomy for reasons other than cervical cancer. We assumed that women with a history of treatment for CIN 2 or 3 would undergo total and not supracervical hysterectomy.9 We assessed outcomes with and without quality adjustment using utilities obtained from a diverse group of women with differing levels of experience, with the outcomes included in the model.10 Selected model parameters including probabilities, estimates of test sensitivity and specificity, costs, and utilities are presented in Table 1. Movement between states over time was based on 6-month transition probabilities derived from the

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literature and a population-based retrospective cohort study of more than 37,000 women followed-up for up to 18 years in British Columbia (British Columbia cohort).3,11 The British Columbia cohort study was a large, population-based, longitudinal follow-up study of CIN recurrence in women after treatment for CIN. The mean age of women in the cohort who were treated for CIN 2 or 3 was 30 years, so we applied this as the age of women in the hypothetical model cohort. Rates of residual and incident disease were based on analysis of this cohort data. Residual disease estimates were based on disease detection within 3 years of initial treatment among individuals who had undergone at least one cytology test during each year. Incident disease estimates were based on disease detection outside this period in individuals who had negative cytology tests within the first 3 years after treatment. For base-case estimates, we used the highest estimate of residual disease after treatment of women for CIN 2 or 3 derived from this British Columbia cohort. We assumed that disease detected within the first 3 years after treatment was residual and present at the onset of the model, and that after 3 years CIN 2 or 3 was new (incident) disease. Women who had been successfully treated were assumed to be at risk for incident CIN. Residual and incident CIN were detected based on the sensitivity of the surveillance testing strategy. Undetected disease was as-

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sumed to progress or regress according to the model parameters for the natural history of CIN. Noncervical cancer deaths were estimated using data from the National Center for Health Statistics.12 Incidental hysterectomy rates were estimated using published age-specific estimates.13 Estimates of cancer symptoms and progression rates between International Federation of Gynecology and Obstetrics stages I through IV were based on published estimates.14 Five-year stage-specific survival was based on data from Surveillance Epidemiology and End Results.15 Sensitivity and specificity of conventional cytology, Hybrid Capture 2 HPV DNA testing, and the combination of the two were obtained from a metaanalysis of studies of Hybrid Capture 2 testing for high-risk HPV compared with cytology as follow-up after treatment of CIN16 and an analysis of Hybrid Capture 2 and conventional cytology test performance of pooled data from primary screening studies.17 Estimates for the performance of liquid-based cytology were obtained from a large randomized trial that compared the relative sensitivity and positive predictive value of liquid-based compared with conventional cytology.18 Because the trial found that liquid-based cytology had similar sensitivity and lower specificity than that of conventional cytology, with higher costs, liquid-based cytology strategies were consistently more costly and less effective (dominated) and were subsequently excluded from the base-case analysis. Strategies using liquid-based cytology were included in sensitivity analyses of test sensitivity and specificity, however. The sensitivity and specificity of colposcopy were derived from a study comparing visual colposcopy physician impression to four-quadrant cervical biopsy in women undergoing colposcopy and biopsy for diagnostic reasons.19 Costs were estimated from the payer’s perspective. Costs for cervical cancer treatment (local, regional, and distant) were derived from estimates for a group model health maintenance organization.20 Local cancer was assumed to be stage I, regional stages II–III, and distant stage IV. Age-specific net costs for the last year of life were based on Medicare reimbursements.21 Costs of cervical cancer screening with conventional and liquid-based cytology (Pap tests) and Hybrid Capture 2 HPV testing, as well as colposcopy, cryotherapy, laser, loop excision, cold-knife cone biopsy, and hysterectomy, were based on average Medicare reimbursements for clinical pathways developed by experienced physicians on the research team (J.M. and G.S.) using published algorithms as a guide.5,22 Each pathway was specified for a typical patient as a comprehensive series of diagnosis-related

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group codes for hospital charges reimbursed under the prospective payment system and Current Procedural Terminology codes for laboratory tests, anesthesiology, and all other professional services that were not covered by the diagnosis-related group reimbursement. The Medicare average reimbursement for hospital care was calculated by dividing the total Medicare reimbursements for that diagnosis-related group by the associated number of discharges using data from the Medicare Provider Analysis and Review.23 Costs were assigned to laboratory procedures on the basis of the midpoint for the Clinical Diagnostic Laboratory Fee Schedules used for Medicare claims payment.24 Costs for anesthesiology were based on the sum of national average time units and base units multiplied by the average anesthesia conversion factor.25 For all other professional services, costs were based on total transitioned facility relative value units multiplied by a conversion factor.26 All costs were adjusted to constant year 2007 dollars using the Medical Care Component of the Consumer Price Index. Only direct costs were included in the analyses. Time trade-off utilities27 (health state preferences) for the various surveillance strategies and their associated potential outcomes were obtained from interviews with a diverse group of 76 English-speaking or Spanish-speaking women who had at least one abnormal cytology test result within the past 2 years.10 Utilities for 11 different treatment or outcome combinations were directly assessed. We assumed the utility for a negative HPV test result was equivalent to the utility for a negative HPV test result with a normal cytology result. We interpolated two additional utility scores not available from the data: an initial normal colposcopy was assumed to be halfway between a normal cytology result and an abnormal cytology test followed by normal colposcopy, and a period of no testing after a normal surveillance test was assumed to be halfway between a normal cytology result and a period of no testing after treatment for CIN 2 or 3 for the first 15 years after treatment because of greater anxiety (Table 1). All interpolated values were explored with wide ranges in sensitivity analyses. Key assumptions of the model included: Women who had excisional treatments had clear margins (ie, no evidence of residual disease). Women adhered to surveillance, follow-up, and treatment protocols. Human papillomavirus DNA testing was conducted using the Hybrid Capture 2 test.

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Table 1. Selected Parameters and Base Estimates Used in the Model Parameter

Base Estimate

RESIDUAL CIN Index disease CIN 2; treatment with cone biopsy or loop excision CIN 1 CIN 2 CIN 3 Index disease CIN 2; treatment with laser CIN 1 CIN 2 CIN 3 Index disease CIN 2; treatment with cryotherapy CIN 1 CIN 2 CIN 3 Index disease CIN 3; treatment with cone biopsy or loop excision CIN 1 CIN 2 CIN 3 Index disease CIN 3; treatment with laser CIN 1 CIN 2 CIN 3 Index disease CIN 3; treatment with cryotherapy CIN 1 CIN 2 CIN 3 INCIDENT CIN Index disease CIN 2 CIN 1 CIN 2 CIN 3 Index disease CIN 3 CIN 1 CIN 2 CIN 3 CIN PROGRESSION OVER 6 MO CIN 1 to CIN 2 (younger than 35 years) CIN 1 to CIN 2 (35 years or older) CIN 1 to CIN 3 CIN 2 to CIN 3 (younger than 35 years) (35–44 years) (45 years or older) CIN 3 to stage I cancer CIN REGRESSION OVER 6 MO CIN 1 to normal (younger than 35 y) CIN 1 to normal (35 y or older) CIN 2 to CIN 1 CIN 2 to normal CIN 3 to CIN 2 CIN 3 to CIN 1 or normal (younger than 45 y) CIN 3 to CIN 1 or normal (45 y or older)

Range

Source (References) British Columbia Database

.039 .021 .018

.022–.039 .012–.021 .010–.018

.124 .065 .053

.071–.124 .037–.065 .030–.053

.18 .096 .081

.103–.180 .055–.096 .046–.081

.047 .023 .056

.027–.047 .013–.023 .032–.056

.145 .068 .178

.083–.145 .039–.068 .099–.178

.207 .098 .245

.118–.207 .056–.098 .140–.245 British Columbia Database

.0019 .0015 .0015

.0011–.0032 .0008–.0028 .0005–.0043

.0019 .0015 .003

.0011–.0032 .0008–.0028 .0017–.0055

.015 .072 .015 .019 .039 .05 .019

.0075–.03 .036–.144 .0075–.03 .019–.038 .019–0.78 .025–.1 .0095–.038

.051 .031 .11 .1 .007 .007 .005

.026–.102 .016–.062 .055–.22 .05–.2 .0035–.014 .0035–.014 .0025–.01

14

14

(continued)

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Table 1. Selected Parameters and Base Estimates Used in the Model (continued) Parameter SURVEILLANCE TEST SENSITIVITY AND SPECIFICITY HPV Sensitivity (CIN 2⫹) Sensitivity (CIN 1) Specificity (less than CIN) Conventional cytology Sensitivity (CIN 2⫹) Sensitivity (CIN 1) Specificity (less than CIN) Liquid-based cytology Sensitivity (CIN 2⫹) Sensitivity (CIN 1) Specificity (less than CIN) HPV and cytology Sensitivity (CIN 2⫹) Sensitivity (CIN 1) Specificity (less than CIN) Colposcopy visual impression Sensitivity (CIN 1⫹) Specificity (less than CIN) COSTS (United States 2007 $) Tests and procedures Loop excision Cone biopsy Hysterectomy: vaginal Hysterectomy: abdominal Office visit HPV test* Conventional cytology Liquid-based cytology Cryotherapy Colposcopy with biopsy Colposcopy without biopsy Cervical cancer treatment Local Regional Distant Cost in last year of life TIME TRADE–OFF UTILITIES (mean scores) No surveillance† Normal cytology (Pap) test result Normal HPV test result (alone or in combination with cytology) Abnormal cytology (Pap) test result, normal colposcopy Normal cytology (Pap) test result, abnormal (positive) HPV test Normal colposcopy surveillance result† CIN 1 CIN 1 surveillance CIN 2–3 CIN 2–3 post-treatment surveillance Early (microinvasive) cervical cancer Early cervical cancer: follow-up, survivor Invasive cervical cancer Invasive cervical cancer: follow-up, survivor

Base Estimate

Range

Base

Alternate estimates

Source (References) 16,17,28

.91 .76 .75

0.944, 0.961 0.792, 0.806 0.750, 0.916

.77 .68 .90

0.642, 0.530 0.573, 0.473 0.963, 0.969

.77 .68 .90

0.904 0.807 0.645

.92 .68 .90

0.992 0.807 0.645

17,29

16

19,30 .88 .57

.879–1 .566–1 ⫾25%

$484 $6,034 $7,810 $13,102 $72 $50 $15 $30 $202 $271 $143

Clinical pathway

$0–$50

20,31 $30,252 $53,526 $142,371 $46,483 .912⫻15 y then .989 .989 .953 .927

21 Interviews10 .989–1 .989–1 .953–1 .927–1

.909 .960 .897 .897 .806 .835 .724 .816 .666 .754

.927–1 .897–.998 .897–.998 .806–.996 .897–.996 .724–.950 .816–.972 .666–.940 .754–.943

CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. * HPV testing performed with Hybrid Capture 2. † Value is interpolated.

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Women with normal initial surveillance test results were screened again with cytology in 6 months (1 year after treatment). If the cytology result was normal, women were followed-up with cytology either annually or triennially. Abnormal cytology results of atypical squamous cells of undetermined significance or worse or a positive HPV test result led to diagnostic colposcopy with biopsy of any abnormal areas. Women with a normal colposcopic visual impression returned to the first step of the surveillance strategy. Women who had residual or recurrent CIN 1 were followed-up with repeat colposcopy. If repeat colposcopy result was negative, then they returned to surveillance and follow-up. Persistent CIN 1 was assumed to be treated with loop excision. Residual CIN 2 or 3 detected at the first visit after treatment was assumed to be treated a second time with cone biopsy (75%), loop excision (20%), or hysterectomy (5%); those not treated with hysterectomy returned to the first step of the surveillance strategy. Women with recurrent CIN 2 or 3 on biopsy found after the first 12 months were treated a second time with cone biopsy (75%), loop excision (20%), or hysterectomy (5%), and were not at risk for additional recurrence. Women with cancer received stage-specific treatment. The utility for HPV testing only with receipt negative results would be similar to the utility for undergoing both HPV and Pap testing and receiving negative or normal results from these two tests. We examined the effect on projected model outcomes from varying test sensitivity, specificity, probability of residual CIN, costs, and utilities using one-way sensitivity analyses. We selected alternate estimates from recently published meta-analyses of primary screening for the sensitivity and specificity of cytology,17 HPV testing,17,28 and liquid-based cytology.29 A recently published cohort study comparing colposcopy with cytology provided alternate estimates of sensitivity and specificity for colposcopy and cytology.30 Alternate estimates of residual CIN were calculated by applying a different approach to the data from the British Columbia Cytology Database. We used an alternate estimate of cervical cancer costs from the literature adjusted to 2007 dollars.31 Costs of cytology, HPV testing, and colposcopy were varied individu-

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ally by 25%. The discount rate for costs and outcomes was varied from 1% to 5%. We assessed the effect of substituting median utility scores in place of means, and in separate analyses we varied the two interpolated utility scores to the extremes of their ranges. Multi-way sensitivity analysis of test characteristics simultaneously varied sensitivity and specificity of cytology and HPV testing. Multi-way scenario analyses examined the effect of simultaneous changes to estimates of sensitivity, specificity, costs, and utilities in analyses that favored liquid-based cytology or HPV testing.

RESULTS Consistent with findings in the British Columbia cohort study, women with an initial diagnosis of CIN 2 treated by loop excision or cone biopsy had the lowest estimated risk of subsequent disease, whereas women with an initial diagnosis of CIN 3 treated by cryotherapy had the highest risk.3 Women treated with laser consistently had estimated outcomes intermediate between women treated with excision and women treated with cryotherapy (data not shown). We calibrated the model by comparing the observed cervical cancer rate in the British Columbia cohort study to the expected cervical cancer rates predicted by the model for conventional cytology screening strategies, assuming a distribution of CIN grade and treatment type comparable to the British Columbia cohort. The expected cervical cancer rates for annual (21.3/100,000 woman-years) and triennial screening (51.2/100,000 woman-years) bracketed the observed rate (46.6/100,000 woman-years). Projected program costs, rates of CIN 1, CIN 2, and CIN 3, invasive cervical cancers, cervical cancer deaths, and false-positive tests with follow-up through age 85 for the two posttreatment states with the highest and lowest rates of subsequent disease are shown for a hypothetical cohort of 500,000 women in Table 2. Nondominated strategies are shown in bold. Whether the initial diagnosis was CIN 2 or CIN 3, the lowest cost strategy was surveillance with conventional cytology at 6 and 12 months, followed by triennial screening if initial results were normal. This strategy, however, also resulted in the largest number of subsequent cancers and cancer deaths. Reductions in cancer deaths noted are compared with this baseline. For women with an initial diagnosis of CIN 2 treated with loop excision (lowest risk of residual disease), follow-up with annual cytology reduced the number of cervical cancers and reduced cancer deaths by approximately 74% compared with triennial cytology, but with greater program costs (an

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Table 2. Projected Outcomes and Program Costs for a Hypothetical Cohort of 500,000 Women Evaluated From Age 30 to 85 Years Showing Expected False-Positive Results, Cervical Intraepithelial Neoplasia 1 Cases, Cervical Intraepithelial Neoplasia 2 or 3 Cases, Cancers (All Stages), and Cancer Deaths

Strategy INITIAL DIAGNOSIS OF CIN 2 TREATED WITH EITHER CONE BIOPSY OR LOOP EXCISION Conventional cytology (q3) HPV testing (q3) HPV and conventional cytology (q3) Colposcopy (q3) Conventional cytology (q1) HPV testing (q1) HPV and conventional cytology (q1) Colposcopy (q1) INITIAL DIAGNOSIS OF CIN 3 TREATED WITH CRYOTHERAPY Conventional cytology (q3) Colposcopy (q3) HPV testing (q3) HPV and conventional cytology (q3) Conventional cytology (q1) HPV testing (q1) Colposcopy (q1) HPV and conventional cytology (q1)

False Positives

Cancer

Cancer Deaths

Program Costs (Millions)

121,478 122,524 122,638 123,041 117,754 118,646 118,742 119,137

6,582 6,549 6,546 6,546 1,958 1,940 1,938 1,937

673 670 669 669 153 151 151 151

$2,212 $2,256 $2,272 $2,279 $2,623 $2,670 $2,687 $2,699

252,072 266,838 260,429 261,455 250,527 257,628 263,807 258,517

7,858 7,032 7,285 7,220 2,680 2,367 2,211 2,331

796 717 741 734 211 186 173 183

$3,043 $3,053 $3,081 $3,094 $3,373 $3,439 $3,445 $3,456

CIN 1

CIN 2 or 3

901,958 976,705 999,663 1,067,333 1,357,754 1,436,328 1,459,838 1,533,583

62,330 62,528 62,562 63,241 62,846 62,915 62,924 63,114

787,136 926,524 864,998 881,701 1,163,267 1,268,554 1,365,853 1,289,051

136,740 144,000 138,730 139,067 140,860 142,237 144,915 142,445

CIN, cervical intraepithelial neoplasia; HPV, human papillomavirus. q1 indicates screening with conventional cytology every year after initial surveillance test and subsequent cytology test 6 months apart with normal results. q3 indicates screening with conventional cytology every 3 years after initial surveillance test and subsequent cytology test 6 months apart with normal results. Strategies are ordered by ascending program cost. Strategies found to be more costly with no increase in effectiveness or less costly but less cost-effective than an alternative strategy were considered dominated by other strategies. Nondominated strategies are shown in bold. Dominance is calculated based on average additional discounted costs and average additional discounted life-years (not shown in Table). Small differences in cancer deaths are obscured by rounding.

additional $411 million). For women with an initial diagnosis of CIN 3 treated with cryotherapy (highest risk of residual disease), colposcopy followed by triennial cytology surveillance reduced cancers and reduced cancer deaths by approximately 10% compared with triennial cytology with a relatively small program cost increase ($10 million). Greater reductions were found for follow-up with annual cytology (cancer deaths reduced by 73%), but at substantially greater program costs (an additional $330 million). Table 3 shows projected total costs and effectiveness, incremental costs and effectiveness, and incremental cost-effectiveness ratios for nondominated strategies for initial diagnoses of CIN 2 or CIN 3 treated with cryotherapy or excisional procedures, with life expectancy as the outcome. More intensive strategies had higher average costs per additional life-year for women at greater risk for subsequent disease, but differences in average effectiveness were generally less than .01 year (less than 4 additional

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days of life expectancy per woman). Annual follow-up with cytology had greater effectiveness and higher costs than triennial cytology follow-up for all initial diagnosis or treatment combinations. The average cost per additional life-year for annual cytology follow-up was less than $100,000 for all combinations of initial diagnosis and treatment. For initial diagnosis or treatment combinations with higher risks of residual disease (CIN 3 treated with cryotherapy), initial colposcopy followed by annual cytology was more effective but more costly than cytology as an initial test followed by annual cytology. Strategies involving HPV testing were dominated except for women with CIN 2 treated by excision for which the average cost per additional life-year was more than $1 million. Including women’s utilities in the analysis resulted in much greater projected differences by follow-up strategy for quality-adjusted life-years than the differences projected for unadjusted life-years (Table 4). The strategy of initial cytology followed by annual

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Table 3. Life Expectancy Analysis Strategy INITIAL DIAGNOSIS OF CIN 2 Cone or loop excision Conventional cytology (q3) Conventional cytology (q1) HPV testing (q1) Colposcopy (q1) Cryotherapy Conventional cytology (q3) Colposcopy (q3) Conventional cytology (q1) Colposcopy (q1) INITIAL DIAGNOSIS OF CIN 3 Cone or loop excision Conventional cytology (q3) Conventional cytology (q1) Colposcopy (q1) Cryotherapy Conventional cytology (q3) Colposcopy (q3) Conventional cytology (q1) Colposcopy (q1)

Average Cost

Incremental Cost

Average Life Expectancy (y)

Incremental Effectiveness (y)

Average Cost per Life-Year Gained

$4,423 $5,245 $5,340 $5,398

$822 $94 $58

25.2271 25.2372 25.2373 25.2374

.0102 .0001 .0001

$80,882 $1,068,182 $1,160,000

$5,175 $5,253 $5,915 $6,066

$78 $662 $151

25.2254 25.2268 25.2365 25.2371

.0014 .0097 .0006

$55,437 $68,318 $255,499

$4,642 $5,445 $5,596

$803 $151

25.2257 25.2367 25.2372

.0108 .0005

$74,214 $319,239

$6,086 $6,105 $6,747 $6,890

$19 $641 $143

25.2202 25.2249 25.2342 25.2362

.0047 .0093 .002

$4,083 $69,036 $69,961

CIN, cervical intraepithelial neoplasia. q1 indicates screening with conventional cytology every year after initial surveillance test and subsequent cytology test 6 months apart with normal results. q3 indicates screening with conventional cytology every 3 years after initial surveillance test and subsequent cytology test 6 months apart with normal results. Average lifetime health care costs, incremental costs, average life expectancy, incremental effectiveness, and average costs per additional life-year saved for surveillance strategies not dominated in the analysis, by initial diagnosis, and treatment type.

cytology surveillance was dominated. Initial colposcopy followed by annual cytology surveillance resulted in substantially higher quality-adjusted effectiveness than in the analysis that used life-expectancy as an outcome. It added little average cost per qualityadjusted life year gained and showed little variation related to risk of disease recurrence. Strategies involving HPV testing were dominated for all combinations of initial diagnosis and initial treatment in the costutility analysis. The pattern of findings in the range of sensitivity analyses was remarkably robust to variations in test sensitivity, specificity, costs, and utilities. In the life expectancy analysis, both HPV testing and liquidbased cytology projected average costs per life-year gained of more than $350,000 when their respective sensitivities or specificities were changed to the values reported in the systematic reviews of primary screening by Arbyn29 or Cuzick.17 After adjusting the sensitivity and specificity of conventional cytology by applying primary screening values from the Cuzick systematic review16 or values from the Soutter study,30 colposcopy remained the only nondominated strategy in the life expectancy analysis for initial surveillance

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of women who had CIN 3 previously treated with cryotherapy. When sensitivity and specificity of both HPV testing with Hybrid Capture 2 and cytology were changed in a multi-way analysis to primary screening values, HPV testing for women with CIN 2 treated with excision was associated with an average cost per life-year gained of $40,595 compared with more than $1 million in the base case. Human papillomavirus testing continued to be dominated for women treated with cryotherapy for CIN 3. In the quality-adjusted analysis, no adjustment of surveillance test sensitivity and specificity altered the pattern of findings of the base-case analysis. In sensitivity analyses of the costs, we varied the costs of HPV testing, cytology, colposcopy, and cancer individually. For HPV testing, we lowered the cost to less than that of conventional cytology. Even at a hypothetical zero cost per HPV test, the conventional cytology strategies remained less costly because of higher specificity. Raising the cost of cytology by $10 eliminated all but the colposcopy strategy with triennial follow-up for surveillance of women at high risk (those with CIN 3 treated with cryotherapy). Raising or lowering the cost of colposcopy by 25% had minimal

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Table 4. Cost Utility Analysis Strategy INITIAL DIAGNOSIS CIN 2 Cone biopsy or loop excision Conventional cytology (q3) Colposcopy (q3) Colposcopy (q1) Cryotherapy Conventional cytology (q3) Colposcopy (q3) Colposcopy (q1) INITIAL DIAGNOSIS CIN 3 Cone biopsy or loop excision Conventional cytology (q3) Colposcopy (q3) Colposcopy (q1) Cryotherapy Conventional cytology (q3) Colposcopy (q3) Colposcopy (q1)

Average Cost

Incremental Cost

Average QALY

Incremental QALY

Average Cost per QALY Gained

$4,423 $4,558 $5,398

$134 $840

23.907 24.270 24.431

.363 .161

$369 $5,217

$5,175 $5,253 $6,066

$78 $813

23.825 24.178 24.333

.353 .155

$221 $5,246

$4,642 $4,763 $5,596

$120 $833

23.891 24.254 24.414

.362 .160

$331 $5,193

$6,086 $6,105 $6,890

$19 $784

23.762 24.113 24.266

.351 .153

$54 $5,133

CIN, cervical intraepithelial neoplasia; QALY, quality-adjusted life-year. q1 indicates screening with conventional cytology every year after initial surveillance test and subsequent cytology test 6 months apart with normal results. q3 indicates screening with conventional cytology every 3 years after initial surveillance test and subsequent cytology test 6 months apart with normal results. Average lifetime quality-adjusted costs, incremental costs, average QALY, incremental QALY, and average cost per additional QALY for all strategies not dominated in the analysis by initial diagnosis and treatment type.

effects on the results of the analysis. Substitution of alternate cervical cancer costs from the literature31 had essentially no effect on model outcomes. Sensitivity analysis of the utility scores had little effect on the pattern of findings in the cost-utility analysis. When median utilities were substituted for means throughout the model, the average cost per quality-adjusted life-year gained for colposcopy followed by annual cytology remained less than $50,000 for all combinations of initial diagnosis or treatment, but was higher than values in the base-case analysis. Varying the interpolated utilities had even less effect on the model results, except when the value assigned to intervals of no testing was raised to that of having just had a normal cytology test. In that case, the only nondominated strategies were initial cytology or colposcopy with triennial cytology follow-up. In multi-way scenario analyses favoring HPV testing, we simultaneously lowered the cost of HPV testing by 20%, increased the cost of colposcopy by 20%, and substituted the values for sensitivity and specificity for HPV testing and for cytology from the Cuzick systematic review of primary screening.17 Using this set of highly favorable assumptions, HPV testing with triennial cytology (after CIN 2 treated with loop excision) or annual cytology (after CIN 3 treated with cryotherapy) produced an average cost

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per life-year gained that ranged from $28,422 to $38,066 in the life expectancy analysis but remained dominated in the cost-utility analysis. The multi-way scenario analysis of liquid-based cytology was approached similarly and included lowering the cost of liquid-based cytology by 20% and raising the cost of colposcopy by 20%. Test sensitivity and specificity values for liquid-based cytology were applied from Arbyn.29 Despite these favorable assumptions, the average cost per life-year gained for liquid-based cytology exceeded $1 million, and liquid-based cytology was dominated in the cost-utility analysis.

DISCUSSION Published recommendations for surveillance after treatment for CIN were based on expert review of current medical literature at the time that the recommendations were formulated.5,6,7,22 These recommendations do not distinguish between women at higher and lower risk for recurrence. No randomized, controlled trials have compared different follow-up strategies after treatment for CIN. Our model was based on recently published data, including a large observational study3 that indicated that initial treatment type and CIN grade are associated with marked differences in recurrence risks and a rigorous systematic review that defined the test sensitivity and speci-

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ficity of HPV testing with Hybrid Capture 2 and cytology for follow-up after treatment.16 These data were not available when the most recent guidelines were formulated. Our study is subject to the limitations of modeling, which can never fully represent the realities of clinical care and the health care system. We modeled clinical practice strategies and applied costs for surveillance of women being cared for in the United States. Although some model parameters were based on limited data and therefore their precise values were uncertain, the stability of the model projections over a range of sensitivity analyses suggests that our estimates of costs and outcomes are reasonable for women in surveillance after treatment of CIN. Our findings do not apply to women undergoing primary screening, nor do they apply to women with positive margins after excisional treatment, because we had no data on outcomes of surveillance for women with positive margins. Our assumption of 100% adherence to follow-up was not realistic, but to affect the relative cost-effectiveness of the follow-up strategies the rates or distribution of adherence would have to differ between strategies. Identified factors influencing adherence to follow-up with abnormal cytology include health beliefs, social support, patient education, counseling and reminder systems, and lesion severity,32 but type of recommended follow-up has not been shown to influence adherence.33 We interpolated two utility values and assumed that the utility for normal cytology with a negative HPV test result was equivalent to the utility for a negative HPV test result alone. Although these values were not directly obtained from interviews, varying them in sensitivity analysis had little effect on the model results. Our findings suggest that surveillance strategies may be tailored to recurrence risk defined by initial CIN grade and treatment type. Traditional methods of surveillance using conventional cytology or initial colposcopy, depending on recurrence risk, provide the greatest effectiveness relative to resources invested in surveillance. Initial conventional cytology at 6 and 12 months followed by surveillance with annual cytology, consistent with recent American College of Obstetricians and Gynecologists recommendations,7 appears to represent the most productive use of health care resources for this patient group to reduce subsequent cancers and cancer deaths. Initial screening with colposcopy adds some additional life expectancy for women at higher risk for recurrence and was highly valued, as indicated by findings from the cost-utility analysis.

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Liquid-based cytology was consistently more expensive and less effective than alternative strategies. Human papillomavirus testing using Hybrid Capture 2, when it was not dominated in the analysis, added little life expectancy at high cost compared with older approaches to surveillance based on conventional cytology. Human papillomavirus testing became a more reasonable alternative when we altered the sensitivity and specificity to values derived from studies of primary screening. These values are likely not applicable to the posttreatment surveillance setting, in which the prevalence of HPV is much higher than in screening settings.16 New tests and technologies often diffuse into practice before a full evaluation of their potential benefits, harms, and costs. Alexander and Stafford,34 arguing for the importance of timely comparative effectiveness data, have pointed out that innovations in medical practice are often adopted with great enthusiasm and only later are found to be wanting. Human papillomavirus testing using Hybrid Capture 2 and liquid-based cytology have diffused widely in the United States and elsewhere, with limited evaluation of which circumstances may justify the additional resources required by these tests.35,36 Although American Cancer Society guidelines recommend that negative results from highly sensitive HPV testing could enable longer intervals for primary screening,37 practicing physicians in the United States have generally continued to perform annual screening,38 a practice that appears to be preferred by many women.39,40 Our base-case assumptions related to the performance of these technologies were supported by recently published large studies of their use in primary screening. A recent randomized trial of liquid-based cytology compared with conventional cytology in more than 85,000 women found no difference in relative sensitivity and positive predictive value.40 A randomized trial of the addition of HPV testing to cytology among nearly 25,000 women followed-up over the course of two rounds of triennial screening found no difference in the detection of CIN 3 or higher.41 This result indicates that our estimate of the sensitivity of HPV testing may have been overly favorable, based on studies comparing only a first round of screening. Our findings, however, relate only to posttreatment surveillance. They suggest that newer technologies have increased the cost of surveillance after treatment without providing any meaningful increase in life expectancy or reductions in cancer, compared with traditional approaches to surveillance. Increasing use of conventional cytology and initial colpos-

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copy for surveillance of women at high risk would reduce the costs of posttreatment surveillance and provide health care resources that could be used more productively to broaden access to cervical cancer screening, treatment, and surveillance.

17. Cuzick J, Clavel C, Petry KU, Meijer CJ, Hoyer H, Ratnam S, et al. Overview of the European and North American studies on HPV testing in primary cervical cancer screening. Int J Cancer 2006;119:1095–101.

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2. Woolf T. Screening for cervical cancer. Preventing disease: Beyond the rhetoric. New York (NY): Springer Verlag; 1990. p. 319 –23.

20. Helms LJ, Melnikow J. Determining costs of health care services for cost-effectiveness analyses: the case of cervical cancer prevention and treatment. Med Care 1999;37:652– 61.

3. Melnikow J, McGahan C, Sawaya GF, Ehlen T, Coldman A. Cervical intraepithelial neoplasia outcomes after treatment: long-term follow-up from the British Columbia Cohort Study. J Natl Cancer Inst 2009;101:721– 8.

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23. Centers for Medicare and Medicaid Services. 100% Medicare Provider Analysis and Review (MEDPAR). Available at: http:// www.cms.hhs.gov/MedicareFeeforSvcPartsAB/03_MEDPAR. asp. Retrieved October 19, 2009.

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18. Ronco G, Cuzick J, Pierotti P, Cariaggi MP, Dalla Palma P, Naldoni C, et al. Accuracy of liquid based versus conventional cytology: overall results of new technologies for cervical cancer screening: randomised controlled trial. BMJ 2007;335:28.

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