An evaluation of liquid-based cytology and human papillomavirus testing within the UK cervical cancer screening programme Sherlaw-Johnson C, Philips Z

An evaluation of liquid-based cytology and human papillomavirus testing within the UK cervical cancer screening programme Sherlaw-Johnson C, Philips Z Record Status This is a critical abstract of an economic evaluation that meets the criteria for inclusion on NHS EED. Each abstract contains a brief summary of the methods, the results and conclusions followed by a detailed critical assessment on the reliability of the study and the conclusions drawn. Health technology Several screening strategies for the detection of cervical cancer, based on liquid-based cytology (LBC) and human papillomavirus (HPV) testing, were examined. Strategy 1 was repeat cytology. All women from the age of 21 to 64 years were screened. Mildly abnormal and borderline results during routine screening were followed up according to UK recommendations for repeat cytology. Strategy 2 was HPV triage. Routine screening was carried out as in strategy 1, with HPV testing as a triage for mild and borderline smear results during routine screening. If HPV testing was positive for high-risk types, the women were referred for colposcopy, otherwise they had repeat cytology as in strategy 1. Strategy 3 was primary HPV testing. Screening was carried out as in strategy 1 until the age of 30 years, after which routine smear testing was replaced by primary HPV testing with cytology as a triage for women found to be positive for high-risk HPV types. If the cytological result was abnormal, the women were referred for colposcopy, otherwise they had a follow-up HPV test in 6 months. If this repeat HPV test was negative, the women reverted to routine screening. Strategy 4 was combined cytology and HPV testing. Screening was carried out as in strategy 1 until the age of 30 years, after which primary smear testing was combined with HPV testing. Women with moderate or severe smear abnormalities were referred for colposcopy. Women with mild or borderline smear results, or a negative smear and a positive HPV test, underwent repeat combined testing at 6-month intervals. Women reverted to routine screening after a combination of a clear smear test and a negative HPV result. All the strategies were evaluated with 3- and 5-year routine intervals. Strategies 1 to 3 were evaluated both with and without LBC. Therefore, a total of 14 screening strategies was considered. Type of intervention Screening. Economic study type Cost-effectiveness analysis. Study population The study population comprised a hypothetical cohort of women aged from 15 years. Setting The setting was not stated. The economic study was carried out in the UK. Dates to which data relate The effectiveness data were derived from studies published between 1988 and 2003. No specific dates for the resource Page: 1 / 9

use data were reported. The price year was 2001. Source of effectiveness data The effectiveness evidence was derived from a synthesis of completed studies. Modelling A mathematical model, based on a Markov process, was used to simulate the natural history of disease and to determine the impact of the alternative screening strategies on costs and survival in women aged from 21 to 64 years. The impact on survival was evaluated in a hypothetical woman of 15 years of age who was free from disease. Women moved from a disease-free state to a high-risk HPV infection condition (most commonly, types 16, 18, 31, and 33), then could progress to three pre-cancer states, corresponding to the three grades of cervical intraepithelial neoplasia (CIN 1, 2 or 3). Woman could then develop invasive cancer, followed by death (due to cancer or other causes) or cure. The time horizon of the model was lifetime. The cycle length was one year. Outcomes assessed in the review The outcomes estimated from published and observed data were: the percentage of women contracting high-risk HPV infections over a given year; the persistence of HPV infections; the percentage of women contracting HPV infections over a given year in the absence of high-risk HPV; the percentage of HPV infections progressing to CIN over a year; the percentage of CIN lesions progressing over a year; the annual regression of CIN lesions; the duration of pre-clinical invasive cancer stages; the stage distribution of new clinical cancers; the proportion of cancers cured; age-related mortality from other causes; the probability of a borderline or mild smear result given the underlying histology; the probability of a moderate or severe smear result given the underlying histology; the sensitivity of the HPV test to detect high-grade CIN; the proportion of inadequate smear results; the impact of LBC on smear test sensitivity; and the proportion of inadequate smear test results with LBC. These data were used to populate the natural history model. Study designs and other criteria for inclusion in the review It was unclear whether a systematic review of the literature was undertaken. No information on the primary studies that Page: 2 / 9

provided the evidence was given. Age-related mortality from other causes was based on life tables for England and Wales. Sources searched to identify primary studies Not stated. Criteria used to ensure the validity of primary studies Not stated. Methods used to judge relevance and validity, and for extracting data Not stated. Number of primary studies included The evidence came from 18 primary studies. Methods of combining primary studies The primary estimates derived from published studies appear to have been combined using narrative methods. Investigation of differences between primary studies Not stated. Results of the review The percentage of women contracting high-risk HPV infections over a given year was 30%, declining to 0% with age. The mean persistence of HPV infections was one year, increasing to 17 years with age. The percentage of women contracting HPV infections over a given year in the absence of high-risk HPV was 0% for all ages. The percentage of HPV infections progressing to CIN over a year was 19%, increasing to 24% with age. The percentage of CIN 1 lesions progressing over a year was 13%, increasing to 17% with age. The percentage of CIN 2 lesions progressing over a year was 17%. The percentage of CIN 3 lesions progressing over a year was 0.7%. The annual regression of CIN 1 lesions was 70%, declining to 20% with age. The annual regression of CIN 2 or 3 lesions was 7%, declining to 2% with age. The mean duration of pre-clinical invasive cancer stages was 5 months for stage 1, 1.5 months for stage 2, 1 month for stage 3, and 20 days for stage 4. The stage distribution of new clinical cancers was 40% in stage 1, 31% in stage 2, 21% in stage 3, and 8% in stage 4. The proportion of cancers cured was: 95%, decreasing to 70% with age for stage 1 cancer; Page: 3 / 9

65%, decreasing to 30% for stage 2 cancer; 45%, decreasing to 30% for stage 3 cancer; and 20%, decreasing to 10% for stage 4 cancer. Age-related mortality from other causes was not reported. The probability of a borderline or mild smear result given the underlying histology was 2.8% for a normal test, 53% for CIN 1, 23% for CIN 2, 24% for CIN 3, and 40% for invasive cancer. The probability of a moderate or severe smear result given the underlying histology was 0.6% for a normal test, 14% for CIN 1, 18% for CIN 2, 41% for CIN 3, and 60% for invasive cancer. The HPV test had a sensitivity of 88% (range: 65-95) for detecting high-grade CIN. The proportion of inadequate smear results was 10%. It was assumed that LBC did not increase the sensitivity of the smear test. The proportion of inadequate smear test results with LBC was 5% (range: 2-10). Measure of benefits used in the economic analysis The summary benefit measure was life expectancy from age 15 years, which was obtained from the decision model. Other outcome measures considered were the total deaths averted, the CIN (stage 2 or 3) detected per lifetime, and the inappropriate referrals for coloscopy per lifetime. An annual discount rate of 3.5% was applied because of the long timeframe of the model. Direct costs An annual discount rate of 3.5% was applied since lifetime costs were considered. The unit costs were presented separately from the quantities of resources used for some cost items only. The health services included in the economic evaluation were screening tests, colposcopy, biopsy, and the treatment of CIN and invasive cancer. Laboratory costs included staff, equipment, transport, and consumables. The administration costs for conventional and LBC methods were considered comparable. The perspective of the health care provider was adopted in the study. Resource use was estimated from authors' assumptions and primary resource use data derived from a survey of general practices in the UK. The costs were derived from NHS sources and published studies. The price year was 2001. Statistical analysis of costs The costs were treated deterministically. Indirect Costs The indirect costs were not considered. Currency UK pounds sterling (). Sensitivity analysis Univariate and multivariate sensitivity analyses were carried out to address the issue of variability in the data. The impact on the estimated cost-effectiveness ratios of changes in discount rates for both costs and benefits, and in all other model inputs, was examined. The impact of LBC was also investigated. The ranges used in the analysis were Page: 4 / 9

mainly derived from the literature. Estimated benefits used in the economic analysis The average discounted life expectancy from age 15 years was: 25.292 with no screening; 25.316 with repeat cytology with LBC every 5 years; 25.317 with HPV triage with LBC every 5 years; 25.316 with repeat cytology without LBC every 5 years; 25.319 with primary HPV with LBC every 5 years; 25.317 with HPV triage without LBC every 5 years; 25.318 with primary HPV without LBC every 5 years; 25.320 with repeat cytology with LBC every 3 years; 25.321 with both HPV triage with LBC every 3 years, and combined cytology and HPV with LBC every 5 years; 25.320 with repeat cytology without LBC every 3 years; 25.321 with both primary HPV with LBC every 3 years, and HPV triage without LBC every 3 years; 25.320 with primary HPV without LBC every 3 years; and 25.323 with combined cytology and HPV with LBC every 3 years. The percentage of death averted compared with no screening was: 64.89% with repeat cytology with LBC every 5 years; 67.63% with HPV triage with LBC every 5 years; 64.89% with repeat cytology without LBC every 5 years; 71.29% with primary HPV with LBC every 5 years; 66.72% with HPV triage without LBC every 5 years; 68.55% with primary HPV without LBC every 5 years; 73.12% with repeat cytology with LBC every 3 years; 74.95% with HPV triage with LBC every 3 years; 77.69% with combined cytology and HPV with LBC every 5 years; 72.20% with repeat cytology without LBC every 3 years; 74.03% with primary HPV with LBC every 3 years; 74.03% with HPV triage without LBC every 3 years; Page: 5 / 9

70.38% with primary HPV without LBC every 3 years; and 80.43% with combined cytology and HPV with LBC every 3 years. The cases of CIN (stage 2 or 3) detected per lifetime were similar among strategies. The lifetime risk of inappropriate referrals for colposcopy was: 0.084 with repeat cytology with LBC every 5 years; 0.099 with HPV triage with LBC every 5 years; 0.083 with repeat cytology without LBC every 5 years; 0.390 with primary HPV with LBC every 5 years; 0.099 with HPV triage without LBC every 5 years; 0.367 with primary HPV without LBC every 5 years; 0.132 with repeat cytology with LBC every 3 years; 0.158 with HPV triage with LBC every 3 years; 0.515 with combined cytology and HPV with LBC every 5 years; 0.131 with repeat cytology without LBC every 3 years; 0.613 with primary HPV with LBC every 3 years; 0.157 with HPV triage without LBC every 3 years; 0.574 with primary HPV without LBC every 3 years; and 0.810 with combined cytology and HPV with LBC every 3 years. Cost results The average discounted costs were: 86.14 with no screening; 159.79 with repeat cytology with LBC every 5 years; 162.54 with HPV triage with LBC every 5 years 166.06 with repeat cytology without LBC every 5 years; 169.50 with primary HPV with LBC every 5 years; 170.38 with HPV triage without LBC every 5 years; 187.72 with primary HPV without LBC every 5 years; 214.59 with repeat cytology with LBC every 3 years; 219.23 with HPV triage with LBC every 3 years; Page: 6 / 9

219.50 with combined cytology and HPV with LBC every 5 years; 224.13 with repeat cytology without LBC every 3 years; 227.87 with primary HPV with LBC every 3 years; 231.17 with HPV triage without LBC every 3 years; 256.01 with primary HPV without LBC every 3 years; and 309.58 with combined cytology and HPV with LBC every 3 years. Synthesis of costs and benefits Incremental cost-effectiveness ratios were calculated to combine the costs and benefits (life expectancy) of the alternative screening strategies in comparison with the next less costly strategy. Dominated alternatives were excluded. The incremental cost per life-year gained was: 3,067 with HPV triage with LBC every years; 3,720 with primary HPV with LBC every 5 years; 22,628 with combined cytology and HPV with LBC every 5 years; and 37,846 with combined cytology and HPV with LBC every 5 years. All options that did not involve LBC were dominated. Those including it were either on, or very close to the efficiency frontier, with the exception of the 3-year repeat cytology strategy. The results of the sensitivity analyses did not produce substantial changes in the results of the base-case analysis. If a higher marginal cost of LBC over conventional smears was assumed, options involving conventional methods were cheaper for primary smear testing, but not for primary HPV testing. Authors' conclusions The options for introducing liquid-based cytology (LBC) in cervical cancer screening were cost-effective from the perspective of the health care payer. Similar conclusions were reached when HPV testing as a triage for mild or borderline smear abnormalities was further added to current screening. CRD COMMENTARY - Selection of comparators The selection of the comparators was appropriate, as it covered both current practice in the UK and alternative screening strategies for the detection of cervical cancer. The authors described each of the screening options. You should decide whether they are valid comparators in your own setting. Validity of estimate of measure of effectiveness The effectiveness evidence came from published and observed studies. The authors did not state explicitly whether a systematic review of the literature had been undertaken. The methods used to extract and then combine the primary estimates were not reported. The designs of the primary studies were not described, thus it was difficult to assess the validity of the sources used. Some data were derived from statistics from the Department of Health and life tables. Most of the model inputs were examined in the sensitivity analysis. Validity of estimate of measure of benefit Page: 7 / 9

The summary benefit measure was appropriate because it captured the impact of the interventions on patient survival, which is the most relevant dimension of health affected by cervical cancer. However, the impact of screening on quality of life was not investigated. The benefits were discounted. Different discount rates were applied and the option of no discounting was also examined. The use of survival permits comparisons with the benefits of other health care interventions. Validity of estimate of costs The authors stated explicitly the perspective adopted in the study. As such, all the relevant categories of costs were included in the analysis. Some costs were presented as macro-categories, which could limit the possibility of replicating the cost analysis. Discounting was performed and different discount rates were investigated in the sensitivity analysis. The price year was reported, which aids reflation exercises in other settings. Resource use was estimated from a survey of UK general practices. The costs were derived from typical National Health Service sources and some assumptions were made. The cost estimates were varied in the multivariate sensitivity analysis. The authors stated that the costs used in the model were the best estimators available. Other issues The authors compared their findings with other studies that had reached similar conclusions to those observed in the current study. However, it was noted that the cost-effectiveness of the screening strategies depended on the assumed marginal cost for the new technology. The authors stated that their study was the first to evaluate the whole range of alternative screening options. The issue of the generalisability of the study results to other settings was addressed. The authors stated that the study was carried out within the context of the UK, thus caution is required when extrapolating the study results to other countries. The external validity of the study was enhanced in the sensitivity analyses, where alternative assumptions were tested. Implications of the study The study results suggested that LBC and primary HPV testing could be efficiently introduced into routine cervical cancer screening programmes in the UK. The marginal cost of LBC in comparison with conventional methods represented a key factor. Source of funding None stated. Bibliographic details Sherlaw-Johnson C, Philips Z. An evaluation of liquid-based cytology and human papillomavirus testing within the UK cervical cancer screening programme. British Journal of Cancer 2004; 91(1): 84-91 PubMedID 15162150 DOI 10.1038/sj.bjc.6601884 Other publications of related interest Kim JJ, Wright TC, Goldie SJ, et al. Cost-effectiveness of alternative triage strategies for atypical squamous cells of undetermined significance. JAMA 2002;287:2382-90. Payne N, Chilcott J, McGoogan E. Liquid-based cytology in cervical screening: a rapid and systematic review. Health Technology Assessment 2000;4:1-73. Page: 8 / 9

Powered by TCPDF (www.tcpdf.org) Indexing Status Subject indexing assigned by NLM MeSH Adult; Colposcopy; Cost-Benefit Analysis; Female; Great Britain; Health Care Costs /statistics & numerical data; Humans; Mass Screening /economics /standards; Middle Aged; Models, Theoretical; Papillomaviridae /pathogenicity; Papillomavirus Infections /diagnosis /economics; Practice Guidelines as Topic; Risk Factors; Specimen Handling; Triage; Uterine Cervical Neoplasms /prevention & control /virology; Vaginal Smears AccessionNumber 22004000961 Date bibliographic record published 30/04/2005 Date abstract record published 30/04/2005 Page: 9 / 9