Title:
[Health technology assessment report. Use of liquid-based cytology for cervical cancer precursors screening].

Abstract:
OBJECTIVE OF THE PROJECT: Purpose of this Report is to evaluate the impact of the introduction of liquid-based cytology (LBC) in cervical cancer screening in terms of efficacy, undesired effects, costs and implications for organisation. EFFICACY AND UNDESIRED EFFECTS: LBC WITH MANUAL INTERPRETATION: The estimates of cross-sectional accuracy for high-grade intraepithelial neoplasia (CIN2 or more severe and CIN3 or more severe) obtained by a systematic review and meta-analysis published in 2008 were used. This review considered only studies in which all women underwent colposcopy or randomised controlled trials (RCTs) with complete verification of test positives. A systematic search of RCTs published thereafter was performed. Three RCTs were identified. One of these studies was conducted in 6 Italian regions and was of large size (45,174 women randomised); a second one was conducted in another Italian region (Abruzzo) and was of smaller size (8,654 women randomised); a third RCT was conducted in the Netherlands and was of large size (89,784 women randomised). No longitudinal study was available. There is currently no clear evidence that LBC increases the sensitivity of cytology and even less that its introduction increases the efficacy of cervical screening in preventing invasive cancers. The Italian randomised study NTCC showed a decrease in specificity, which was not observed in the other two RCTs available. In addition, the 2008 meta-analysis observed a reduction - even if minimal - in specificity just at the ASC-US cytological cut-off, but also a remarkable heterogeneity between studies. These results suggest that the effect of LBC on specificity is variable and plausibly related to the local style of cytology interpretation. There is evidence that LBC reduces the proportion of unsatisfactory slides, although the size of this effect varies remarkably. LBC WITH COMPUTER-ASSISTED INTERPRETATION: An Australian study, based on double testing, showed a statistically significant increase of the sensitivity for CIN2 or more of LBC with computer-assisted interpretation vs. conventional cytology with manual interpretation. However, an English RCT estimated that LBC with computer-assisted interpretation has a lower sensitivity than LBC with manual interpretation. COST AND ECONOMIC EVALUATION: In the current Italian situation the use of liquid-based cytology for primary screening is estimated to increase the costs of cytological screening. Liquid-based cytology needs shorter time for interpretation than conventional cytology. However, in the Italian situation, savings obtained from this time reduction and from the decreased number of repeats due to unsatisfactory slides are not currently sufficient to compensate the cost increase due to the prices currently applied by producers and to a possible greater number of colposcopies caused by LBC. In any case, at current prices, cost is estimated to increase even when assuming a referral rate to colposcopy with LBC similar or slightly lower than that with conventional cytology. For the costs of computer-assisted interpretation of liquid-based cytology, readers are referred to the relative HTA report (Epidemiol Prev 2012;36(5) Suppl 3:e1-43). ORGANISATIONAL AND ETHICAL ASPECTS: Ethical, legal and communication problems are judged to remain unchanged when compared to screening with conventional cytology. After having used the test for some time, interpreters prefer liquid-based to conventional cytology. Reduced time for interpretation makes the adoption of LBC a possible approach to deal with shortenings of cytology interpreters which is happening in Italy. However, alternative solutions, such as computer-assisted interpretation of cytology and the use of HPV as primary screening test, should be considered. Liquid-based cytology allows performing molecular tests, in particular the HPV test. This property allows triaging women with borderline or mild cytology by "reflex" molecular or immunocytochemical tests with no need to recall them. LBC sampling can be used also if HPV is applied as the primary screening test, allowing "reflex" triaging of HPV positive women by cytology with no need to recall them nor to take two samples, one for HPV testing and one for conventional cytology. This represents a remarkable advantage in terms of organization. However, costs are high because only 5-7% of women screened with this approach need interpretation of cytology. In addition, HPV testing with the Hybrid Capture assay on material preserved in LBC transport media needs a preliminary conversion phase, which limits the use of LBC for triaging HPV positive women. It is advisable that in the near future industry develops sampling/transport systems that allow performing both the HPV test and cytology or other validated triage tests without additional manipulations and at sustainable costs.