The Department of Health and the Welsh Assembly Government have asked the National Institute for Clinical Excellence (NICE or the Institute) to advise on the use of liquid-based cytology and update guidance issued to the NHS in England and Wales in June 2000 (Guidance No 5). The Appraisal Committee has had its first meeting to consider both the evidence submitted and the views put forward by the representatives nominated for this appraisal by professional organisations and patient/carer and service user organisations. The Committee has developed preliminary recommendations on the use of liquid-based cytology.

This document has been prepared for consultation with the formal consultees. It summarises the evidence and views that have been considered and sets out the preliminary recommendations developed by the Committee. The Institute is now inviting comments from the formal consultees in the appraisal process (the consultees for this appraisal are listed on the NICE website).

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.

The process the Institute will follow after the consultation period is summarised below. (For further details, see the Guide to the Technology Appraisal Process on the Institute's website).

• The Appraisal Committee will meet again to consider the original evidence and this Appraisal Consultation Document in the light of the views of the formal consultees.
• At that meeting, the Committee will also consider comments made on the document by people who are not formal consultees in the appraisal process.
• After considering feedback from the consultation process, the Committee will prepare the Final Appraisal Determination (FAD) and submit it to the Institute.
• Subject to any appeal by consultees, the FAD may be used as the basis for the Institute's guidance on the use of the appraised technology in the NHS in England and Wales.

The key dates for this appraisal are:

Closing date for comments: Tuesday 6 May 2003
Second Appraisal Committee meeting: Thursday 15 May 2003

Details of membership of the Appraisal Committee are given in Appendix A and a list of the sources of evidence used in the preparation of this document is given in Appendix B.

Note that this document does not constitute the Institute's formal guidance on this technology. The recommendations made in Section 1 are preliminary and may change after consultation.

It is recommended that liquid-based cytology (LBC) is used as the primary means of collecting samples in the cervical screening programme in England and Wales.

There is currently insufficient evidence to recommend one LBC product over another. The NHS Cervical Screening Programme (NHSCSP) may wish to consider evaluating further the different products as the method is introduced.

The annual incidence of cervical cancer in the UK is 9.7 per 100,000 population, with a mortality rate of 3.7 per 100,000 population. Pre-cancerous cervical cells cause no symptoms and may only be detected by population-screening methods. The NHSCSP, introduced in 1987, screens women with the aim of detecting pre-cancerous cervical cells before they progress to invasive cervical cancer.

The NHSCSP uses the Papanicolaou (Pap) smear test for cytological screening. Women aged 20-64 years are screened at 3-5-year intervals (depending on regional policy) for the early detection and treatment of pre-cancerous cells, with the aim of reducing the incidence and associated mortality of cervical cancer. Approximately 3.9 million women are tested in England each year, which equated to a coverage of 71.2% for 3-yearly and 81.6% for 5-yearly screening in 2001-2.

The Pap smear is usually carried out by a GP or nurse at a primary care or community clinic. Cervical cells are collected using a disposable spatula device, spread on to a glass slide and fixed. The slide is then sent to a hospital laboratory where it is stained and examined by a cytologist.

Smear tests are evaluated according to morphological features of the cervical cells, which indicate the degree of cellular abnormality (dyskaryosis). In the UK, smears are categorised using the British Society of Clinical Cytologists (BSCC) guidelines as negative, borderline, mild, moderate, severe or inadequate, depending on the degree of dyskaryosis. In the USA, the Bethesda system is used to classify cervical smears as atypical squamous cells of uncertain significance, atypical glandular cells of uncertain significance, low-grade squamous intraepithelial lesions and high-grade squamous intraepithelial lesions. The BSCC and Bethesda classification systems are similar but are not directly comparable.

Patient management depends on the classification of the smear test. Women with negative tests are invited for re-screening at the standard 3-5-year interval, while those with borderline or mildly dyskaryotic smears are monitored at a reduced screening interval. Women with moderately or severely dyskaryotic smear tests (or persistent inadequate or borderline tests) are referred for additional diagnostic testing, such as visual examination of the cervix with a binocular microscope (colposcopy), or histological examination of a tissue biopsy.

The principal criteria used to assess the effectiveness of the LBC method compared with the Pap smear are the sensitivity and specificity of each method, and the rate of 'inadequate' specimens. Sensitivity is the extent to which a test identifies true positive samples (sensitivity decreases as the number of 'false negatives' rises), and specificity is the extent to which the test excludes true negatives (specificity decreases as the number of 'false positives' increases).

Approximately 10% of Pap smear tests are inadequate - that is they cannot be interpreted because of problems with sample collection or preparation, such as insufficient cervical cells, or the presence of inflammatory cells, blood or mucus obscuring the sample. Women with inadequate test results are required to attend a repeat test, which is inconvenient and may cause anxiety.

LBC is a new method of cervical cell sample preparation. Samples are collected in the usual way using a spatula or brush-like device. The head of the device is rinsed or broken off into a vial of preservative fluid so that the majority of cervical cells are retained. Samples are transported to the laboratory where they are mixed to disperse the cells. Cellular debris, such as blood or mucus, is removed and a thin layer of cervical cells is deposited on a microscope slide, which is subsequently stained.

The LBC method aims to offer an improved means of slide preparation, with the intention of producing a more homogeneous sample than the Pap smear, which may make slides easier to read. LBC techniques are designed to reduce the rate of inadequate smear tests, achieve increased sensitivity and specificity, and improved efficiency of handling laboratory samples, resulting in increased laboratory productivity.

Current methods that use LBC technology are as follows.

• SurePath (formerly AutoCytePREP or CytoRich LBC)

  The SurePath method requires that the collection device be retained in the proprietary SurePath collection vial, which contains transport fluid, so that all cervical cells collected are sent to the laboratory. Vials are vortexed and centrifuged by laboratory personnel, then all subsequent preparation of the sample and slide is automated using the Prepstain machine, which processes 48 samples at a time.

• Cytoscreen

  Cytoscreen is a manual method of sample preparation using a proprietary sample collection device (CYTOPREP) and transport fluid (CYTeasy). Samples are vortexed and a photometric reading taken to estimate the cellularity of the sample. An aliquot of the sample is centrifuged onto a glass slide that is subsequently stained using normal laboratory procedures.

• Labonard Easy Prep

  Labonard Easy Prep is a manual method of sample preparation that uses a proprietary sample collection device (CYTOPREP brush) and fixative (CYTO-screen). An aliquot of sample fluid is placed in a separation chamber attached to a glass slide, which contains absorbent paper. Cervical cells sediment onto the slide in a thin layer and slides are stained using normal laboratory procedures.

• ThinPrep

  ThinPrep provides a semi-automated (T2000) or fully automated (T3000) method of sample preparation. Cervical samples are rinsed with proprietary PreservCyt transport medium into a vial, which is then processed by the ThinPrep method using the T2000 or T3000 machine. The T2000 machine processes slides individually, while the T3000 machine is a fully automated device that can batch-process up to 80 specimens per cycle. Subsequent staining and microscopic evaluation of the slides is conducted in a similar manner to a conventional smear test.
  

The Appraisal Committee considered evidence from a number of sources (see Appendix B).

All evidence relates to the ThinPrep and SurePath methods of LBC. No information relating to the Labonard Easy Prep or Cytoscreen methods was submitted by the manufacturers or identified during the course of the appraisal.

New evidence was provided by a UK pilot study that evaluated LBC and Pap smears at three sites (Norfolk & Norwich Hospital; Southmead Hospital North, Bristol NHS Trust; and Royal Victoria Infirmary, Newcastle). In addition, since the publication of the previous Assessment Report, evidence has become available from the following new studies: six studies comparing LBC and Pap smears with a reference method (histology/pathologist diagnosis), eight split-sample studies, six two-cohort studies, a Scottish implementation study and a New Zealand Health Technology Assessment of LBC.

A meta-analysis of 14 studies compared the sensitivity of LBC and the Pap smear in the detection of low-grade abnormalities (low-grade squamous intraepithelial lesions) in ordinary (n = 5) and high-risk (n = 10) populations (one trial was excluded from the meta-analysis because of insufficient biopsy data). The relative risk (RR) of a false-negative diagnosis with LBC compared with the Pap smear was calculated. LBC was associated with a non-statistically significant reduction in false negatives in the high-risk population (RR 0.88, 95% CI 0.67 to 1.15), a statistically significant reduction in false negatives in the ordinary population (RR 0.55, 95% CI 0.46 to 0.66), and a statistically significant combined reduction overall (RR 0.75, 95% CI 0.59 to 0.96). Overall sensitivity with LBC was improved by 12% compared with the Pap smear. Split-sample studies and two-cohort studies supported the increase in sensitivity found with LBC.

Meta-analysis of six studies found no difference between the specificity of LBC and Pap smears.

UK pilot studies showed a statistically significant decrease in the number of inadequate samples from 9.1% with Pap slides to 1.6% with LBC (87% reduction, p < 0.0001). The majority of 34 studies reporting the rate of inadequate samples noted that the rate was reduced with LBC.

A literature review identified four new economic evaluations of LBC compared with the Pap smear in the US population. These are of limited application to the UK because of differences in US incidence rates and costs, and differences in the Bethesda (US) and BSCC (UK) classification systems for cervical smears.

PathLore Ltd provided a cost analysis of the SurePath test. Increased capital costs of £50,000 and consumables costs of £2.50 per test may be offset by savings from the reduction in the number of inadequate samples and a quicker diagnosis, to give a gross saving of £0.89 per LBC test compared with the Pap smear. This is consistent with the costs reported in the pilot studies.

The Assessment Group updated the model in the previous Assessment Report with the data from the UK pilot study and literature. A cohort of 100,000 18-year-old women enrolled in the NHSCSP (screened between the ages of 21 and 64 years) were followed throughout their lifetime using a state transition model.

Key outcomes of the UK pilot study used to update the economic model were the rate of inadequate specimens and the amount of staff time required for smear taking, slide preparation and smear diagnosis. There was a 5-minute reduction in the time required for smear taking and consultation with LBC (average of 8 minutes and 35 seconds compared with 13 minutes and 20 seconds for the Pap smear). The extent of the increase in slide preparation time with LBC depended on the labour requirements of different LBC methods. Slide preparation with LBC took 4 minutes and 15 seconds (ThinPrep 2000), 38 seconds (ThinPrep T3000), or 1 minute and 52 seconds (SurePath system) compared with an average of 15 seconds for the conventional Pap smear. The aggregate cost of LBC was an average of £22.30 (range of £22.99 - T3000 £23.15 - T2000, and £20.76 - PrepStain) compared with £21.68 for the conventional Pap smear.

The UK pilot study estimated that a one-off transition cost of £10.27 million would be required for the national implementation of LBC.

The Assessment Group used data on the unit costs and 'inadequate' rate from the UK pilot study to update the economic model in the previous Assessment Report and estimate the incidence of and mortality from cervical cancer among women who had had cervical screening using LBC and Pap smear technologies. The one-off transition cost of implementing LBC was incorporated into the economic model as a cost of £0.13 per smear test (discounted over a 20-year lifetime of LBC).

The results of the economic analysis demonstrated the following.

• LBC dominated Pap smears because it was found to be less costly and more effective at 3- and 5-year screening intervals. LBC screening at 3- and 5-year intervals was found to be a cost-effective alternative to 5-yearly Pap screening, with an incremental cost below £10,000 per life-year gained.
• The cost effectiveness of LBC screening at different intervals was compared. The incremental cost of moving from 5-yearly to 3-yearly screening with LBC was £9621 per life-year gained.
• Conventional screening at 5 years is extremely cost effective compared with no screening, at a cost of £372 per life-year gained.

Sensitivity analysis demonstrated that, under all conditions, LBC dominates conventional screening methods at each screening interval. In the base case, the cost of LBC is based on LBC equipment working at a processing capacity of 60,000 tests per annum. In a sensitivity analysis where LBC equipment processed 30,000 tests per annum, capital costs were increased by 20% and consumables by 50%, and a conservative time saving of 1 minute per test was documented, which resulted in an increase in the marginal cost of LBC of £6.50 per test. Increases in the marginal cost of LBC had little effect on the cost effectiveness of LBC.

No studies were identified that compared the difference in the quality of life between women who had LBC smears and those who had Pap smears, and thus a cost per quality-adjusted life-year for different screening scenarios could not be reliably determined. The Assessment Group's model incorporated the assumption that the decrease in utility associated with living with invasive cancer, undergoing a colposcopy and receiving a borderline test would have an adverse effect on a woman's quality of life because of anxiety. When quality of life is taken into consideration, LBC still dominates conventional screening.

The UK pilot study report also contained an economic evaluation, which was consistent with the results of the model generated by the Assessment Group.

In summary, the increased capital, consumable and implementation costs of LBC may be offset by savings in the reduction of inadequate samples and time savings in sample collection through to diagnosis. LBC is a cost-effective alternative to the Pap smear on the assumption that the sensitivity and specificity of both methods are at least equal. However, it was not possible to distinguish between specific LBC technologies on the basis of cost effectiveness.

The Committee reviewed the data available on the clinical and cost effectiveness of LBC. It carefully considered results from the pilot site studies undertaken since the original guidance was issued, and the opinions of clinical experts, and took into account the likely effect LBC would have on women taking part in the NHSCSP. It was also mindful of the need to take account of the effective use of NHS resources.

The Committee considered evidence from screeners and cytopathologists that LBC produced a more homogeneous cellular preparation that was free from exudates, and that this would be likely to decrease the number of smears that were classified as inadequate (that is, considered unreadable and in need of repeat smear). However, there were concerns that, with the LBC method, there is no way of verifying that a sufficient number of cervical cells have been harvested by the smear taker. Poor sampling technique, resulting in the collection of too few cells, could mean that a sample might not adequately represent cells on the surface of the cervix. Consequently abnormalities may be missed, resulting in some false-negative results. However, the Committee concluded that this potential problem should be balanced against the screening frequency of the NHSCSP and the reported increased detection of high-grade lesions (severe dyskaryosis) with the LBC technique. Overall, the Committee was persuaded that LBC was likely to be an improvement over the currently used technique, and in particular the reduction of inadequate smears would be an important benefit to women in the NHSCSP because it would reduce the requirement for repeat smears.

Experts agreed that the evidence that has become available since the last guidance was issued and the results from the pilot sites suggested that the overall sensitivity of LBC was at least as good as, and may be better than, the Pap smear. However, the Committee was made aware of various confounding factors that may have contributed to the perceived increase in sensitivity of LBC, such as increased training and experience of the smear screeners and the type of sampling device used by the smear takers.

The Committee understood that an important factor in the assessment of the increased sensitivity of LBC was its enhanced ability to detect high-grade lesions (severe dyskaryosis), which was confirmed by the results from the pilot study. However, the Committee heard that this factor was offset by the fact that LBC might not confer increased sensitivity in the detection of low-grade lesions.

The Committee reviewed the draft report from the pilot study and noted a lack of consistency between the results of the pilot site using the SurePath device and two sites using the ThinPrep device. However, the Committee considered that, taking into account the advice from experts and the possible confounding factors of indirect comparisons, there was currently insufficient evidence to suggest that one technique should be recommended over another.

The Committee heard from the experts that LBC was likely to result in increased productivity in cytology laboratories because of a rise in the number of slides that can be read per hour and a reduced workload as a result of a lower incidence of inadequate samples and a reduced number of repeat smears. Although the screening of LBC thin layers is quicker because of the ease of reading a 'cleaner' slide preparation and screening a smaller area of the slide, it was mentioned that screening LBC slides is more tiring for staff, who consequently may require more breaks. The experts involved with the pilot sites said that smear takers and readers favoured the LBC method above the Pap smear.

The Committee considered that, taking into account a number of factors - including the potential for increased sensitivity, reduction of inadequate smears and probable improvements in laboratory efficiency - the LBC method was likely to be cost effective compared with the Pap smear, despite its higher associated cost. The Committee discussed whether the use of LBC would affect the cost effectiveness of population screening at different frequencies. However, this was considered to be beyond the remit of this review and to be the responsibility of the NHSCSP.

The Committee was aware that a number of manufacturers have LBC-related products. Evidence received during the appraisal related only to the SurePath and ThinPrep devices - no evidence was provided by the other manufacturers.

It is recommended that high-quality trials be undertaken to compare differences in performance between the ThinPrep and SurePath LBC methods.

Validation of cell numbers may be required to establish the adequacy of smears that will subsequently be prepared using the LBC method.

Clinical data relating to the sensitivity, specificity and rate of inadequate smears should be provided for the EasyPrep and Cytoscreen devices for future reviews of LBC.

Preliminary views on the resource impact for the NHS

This section outlines the Appraisal Committee's preliminary assessment concerning the likely impact on NHS resources if the recommendations in Section 1 were to be implemented. When guidance is issued, this section is intended to assist NHS planners and managers in its implementation. Therefore the Institute particularly welcomes comments and information from those who would be involved in the implementation of the guidance so that this section can be made as helpful and robust as possible.

The pilot studies estimated a one-off cost of between £10.1 million and £10.3 million for the conversion from Pap smears to LBC in England, which equates to a cost of approximately £73,000 for a local laboratory processing 30,000 tests per annum. These figures include the cost of training smear takers and laboratory staff, producing training material, sending off a backlog of samples, and structural changes to the laboratory. However, these costs may be overestimated because they are based on the assumption that all GPs and nurses will be trained in the use of LBC. In addition, the capacity of laboratories has been overestimated, because 75% of laboratories in England currently process fewer than 30,000 samples per annum. The centralisation of sample processing may be the most effective organisation of services. If sample preparation using LBC were to be centralised in regional laboratories, consideration would need to be given to the logistics and costs associated with sample transport and communication of the central processing laboratories with the local reporting laboratories.

The Assessment Report indicates that the costs of Pap smears and LBC are comparable, and time savings in the diagnosis of smears may contribute to increased laboratory productivity. The use of LBC in accordance with this guidance is likely to release resources within NHS organizations, although the nature and amounts involved will vary between local NHS communities.

Existing smear takers and laboratory staff will need additional training in the LBC method before the implementation of the recommendation in Section 1.1. Training of new smear takers and laboratory staff in the LBC method is likely to require similar resources to those for the training of staff in Pap smears.

Thin-layer preparations are the preferred sample preparation method for use with automated screening of LBC, should this be introduced into the NHSCSP at a later date.

The rate at which LBC is taken up throughout the NHS in England and Wales will depend on a number of logistical factors, which should be determined by the NHSCSP. During this period, the standard cervical screening method will need to run in parallel.

This section presents proposals for implementation and audit based on the preliminary recommendations for guidance in Section 1.

The NHS Cervical Screening Programme should use Liquid Based Cytology (LBC) as the primary means of collecting samples. Primary care trusts and NHS hospital laboratories processing cervical smears should support the implementation of this change in practice.

National and local guidelines, protocols or care pathways relating to the collection and processing of a cervical specimen should be changed to reflect the change in practice following adoption of this guidance.

The NHSCSP should include measurement of the correct use of LBC as part of an ongoing quality-assurance programme.

Local clinical audits on cervical screening could include measures of the correct use of LBC and inadequate specimens.

National Institute for Clinical Excellence (2000) Guidance on the use of liquid-based cytology for cervical screening. NICE Technology Appraisal Guidance No. 5. London: National Institute for Clinical Excellence. Available from: www.nice.org.uk/cat.asp?c=1121

The review date for a technology appraisal refers to the month and year in which the Guidance Executive will consider any new evidence on the technology, in the form of an updated Assessment Report, and decide whether the technology should be referred to the Appraisal Committee for review.

It is proposed that the guidance on this technology is reviewed in June 2006.

Professor David Barnett

Chairman, Appraisal Committee

April 2003

The Appraisal Committee is a standing advisory committee of the Institute. Its members are appointed for a 3-year term. A list of the Committee members who took part in the discussions for this appraisal appears below. The Appraisal Committee meets twice a month other than in December, when there are no meetings. The Committee membership is split into two branches, with the chair, vice-chair and a number of other members attending meetings of both branches. Each branch considers its own list of technologies and topics are not moved between the branches.

Committee members are asked to declare any interests in the technology to be appraised. If it is considered there is a conflict of interest, the member is excluded from participating further in that appraisal.

The minutes of each Appraisal Committee meeting, which include the names of the members who attended and their declarations of interests, are posted on the NICE website.

Dr Jane Adam

Radiologist, St George's Hospital, London

Dr Sunil Angris

General Practitioner, Waterhouses Medical Practice, Staffordshire

Professor David Barnett (Chair)

Professor of Clinical Pharmacology, University of Leicester

Professor John Brazier

Professor of Health Economics, Health Economics Research Unit, Institute of Applied Health Sciences, University of Aberdeen

Statistician, Institute of General Practice & Primary Care, Sheffield

The following documentation and opinion was made available to the Committee:

A.

The assessment report for this appraisal was prepared by the School of Health and Related Research (ScHARR), University of Sheffield.

Karnon J, Peters J, Chilcott J, McGoogan E Liquid-based Cytology in Cervical Screening: An Updated Rapid and Systematic Review January 2003.

The following organisations accepted the invitation to participate in this appraisal. They were invited to make submissions and comment on the draft scope and assessment report. They are also invited to comment on the ACD and consultee organisations are provided with the opportunity to appeal against the FAD.

I Manufacturer/sponsors/trade organisations:

• Association of British Health-Care Industries
• British In Vitro Diagnostics Association
• Cellpath Ltd
• Cytyc UK
• Pathlore Ltd
• Surgipath Europe Limited
• Tripath Imaging Europe

II Professional/specialist and patient/carer groups:

• British Gynaecological Cancer Society
• British Society for Clinical Cytology
• British Society of Colposcopy and Cervical Pathology
• Cancer Research UK
• Department of Health
• Institute of Biomedical Science
• Macmillan Cancer Relief
• Marie Curie Cancer Care
• Medical Women's Federation
• National Association of Cytologists
• Pathological Society of Great Britain and Ireland
• Royal College of Nursing
• Royal College of Obstetricians & Gynaecologists
• Royal College of Pathologists
• Wales Cancer Network
• Welsh Assembly Government
  

III Commentator organisations (without the right of appeal):

• National Collaborating Centre for Women & Children's Health
• Newcastle upon Tyne Hospitals NHS Trust
• NHS Cancer Screening Programmes
• NHS Confederation
• NHS Purchasing & Supplies Agency
• NHS Quality Improvement Scotland
• Norfolk & Norwich University Hospital NHS Trust
• North Bristol NHS Trust
  

The following individuals were selected from clinical expert and patient advocate nominations from the professional/specialist and patient/carer groups. They participated in the Appraisal Committee discussions and provided evidence to inform the Appraisal Committee's deliberations. They gave their expert personal view on liquid-based cytology by attending the initial Committee discussion and/or providing written evidence to the Committee. They are invited to comment on the ACD.

• Mrs Maggie Cooper, Cervical Screening Developments Coordinator, Marie Curie Cancer Care
• Mr Nick Dudding, Cytology Department, Royal Hallamshire Hospital
• Dr Amanda Herbert, Chair, British Society for Clinical Cytology
• Ms Eileen Hewer, Assistant Director of QA, Northern General Hospital, Sheffield
• Professor Henry Kitchener, Professor of Gynaecological Oncology, St Mary's Hospital, Manchester
• Dr Ray Lonsdale, Consultant Histopathologist & Clinical Director, Norfolk & Norwich University Hospital
• Dr Phillip Wilson, Consultant Pathologist, St George's Hospital, Tooting.