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European Guidelines for Quality Assurance in Cervical Cancer Screening have been initiated in the Europe Against Cancer Programme. The first edition established the principles of organised population-based screening and stimulated numerous pilot projects. The second multidisciplinary edition was published in 2008 and comprises ~250 pages divided into seven chapters prepared by 48 authors and contributors. Considerable attention has been devoted to organised, population-based programme policies which minimise adverse effects and maximise benefits of screening. It is hoped that this expanded guidelines edition will have a greater impact on countries in which screening programmes are still lacking and in which opportunistic screening has been preferred in the past. Other methodological aspects such as future prospects of human papillomavirus testing and vaccination in cervical cancer control have also been examined in the second edition; recommendations for integration of the latter technologies into European guidelines are currently under development in a related project supported by the European Union Health Programme. An overview of the fundamental points and principles that should support any quality-assured screening programme and key performance indicators are presented here in a summary document of the second guidelines edition in order to make these principles and standards known to a wider scientific community.
Cancer is common in older people but cancer of the uterine cervix primarily affects younger women, with the majority of cases appearing between the ages of 35 and 50, when many women are actively involved in their careers or caring for their families. In the European Union (EU) 34 000 new cases and >16 000 deaths due to cervical cancer are reported annually [1, 2].
The burden of cervical cancer is particularly high in the new member states. The highest annual world-standardised mortality rates are currently reported in Romania and Lithuania (13.7/100 000 and 10.0/100 000, respectively) and the lowest rates in Finland (1.1/100 000). Governmental authorities, parliamentary representatives and advocates should be aware that the substantially higher dimension of this public health problem in the east of the EU requires special attention.
Among all malignant tumours, cervical cancer is the one that can be most effectively controlled by screening. Detection of cytological abnormalities by microscopic examination of Pap smears and subsequent treatment of women with high-grade cytological abnormalities avoids development of cancer .
Cytological screening at the population level every 3–5 years can reduce cervical cancer incidence up to 80% . Such benefits can only be achieved if quality is optimal at every step in the screening process, from information and invitation of the eligible target population to performance of the screening test and follow-up, and, if necessary, treatment of women with screen-detected abnormalities.
Quality assurance of the screening process requires a robust system of programme management and coordination, assuring that all aspects of the service are performing adequately. Attention must be paid not only to communication and technical aspects but also to qualification of personnel, performance monitoring and audit, as well as evaluation of the impact of screening on the burden of the disease.
Population-based screening policy and organisation conforming to evidence-based standards and procedures provide the overall programmatic framework essential to implementation of quality assurance and are therefore crucial to the success of any cervical cancer screening programme.
Establishment of screening registries and linkage of individual screening data with cancer registry data, taking into account appropriate data protection standards and methods, are essential tools of monitoring and evaluation.
The first edition of the European Guidelines for Quality Assurance in Cervical Cancer Screening  established the principles of organised population-based screening and was pivotal in initiating pilot projects in Europe. A number of countries have in the meantime developed organised population-based screening approaches, which are illustrated in Section 2.4.2 of the second edition . It is hoped that this new guideline edition will have a greater impact on those countries in which opportunistic, rather than organised, population-based screening has been the preferred model in the past.
Transformation of these programmes to the population-based approach with quality assurance at all appropriate levels has the potential to substantially improve the accessibility, the effectiveness and the cost-effectiveness of the respective services. At the same time, substantial numbers of unnecessary screening examinations could be avoided by adhering to the interval for cervical cancer screening recommended in the European guidelines (3–5 years) [7, 8]. Towards this end, considerable attention has been given to the essential aspects of developing an organised population-based programme policy that minimises the adverse effects and maximises the benefits of screening.
The current recommendations are also particularly relevant to planning new cervical cancer screening programmes in Europe. Different solutions fulfilling the recommended methodological standards need to be implemented in different countries and regions with diverse levels of resources and general health care infrastructure.
More than a decade has passed since the publication of the first guideline edition. The current expanded edition therefore also includes extensive updates on technical details and documentation, as well as assessment of new technologies, e.g. liquid-based cytology (LBC), automated interpretation of Pap smears and testing for human papillomaviruses (HPVs). The scope of the current guideline has also been extended to include comprehensive instructions prepared by a multidisciplinary team of experts for general practitioners, gynaecologists and cytopathologists. Much more extensive recommendations on follow-up, diagnosis and management of women with positive cervical cytology have been added. This necessitated the incorporation in the second edition of a separate chapter on techniques and quality assurance in histopathology and, for the first time, detailed guidance for clinicians in dealing with abnormal cytology, including management according to the severity of cytological abnormalities and management of histologically confirmed cervical epithelial neoplasia.
A major further addition has been the inclusion of uniform indicators for monitoring programme performance and for identifying and reacting to potential problems at an early time. The indicators deal with screening intensity, test performance and diagnostic assessment and treatment and address aspects of the screening process that influence the impact as well as the human and financial costs of screening. Standard tables have been provided for documenting screening policies and for tabulating the person-based data used to generate the uniform performance indicators. The availability of these standardised tools will substantially improve data comparability and the exchange of experience and results between screening programmes in Europe. Such exchange, in turn, is essential to effective Pan-European collaboration in implementing and continuously improving the quality and effectiveness of cervical cancer screening programmes.
Cervical cytology still is the cornerstone of cervical cancer prevention programmes in Europe, although new perspectives for other screening technologies are developing rapidly. The principles of quality assurance, performance monitoring and evaluation and many of the procedures and methodological standards laid down in the current guideline edition are of equal relevance to cervical cancer screening on the basis of other conceivable methods. It is therefore expected that the publication of the updated and revised second edition will also promote rigorous standards in the evaluation and application of new screening technologies, thereby improving the effectiveness of cervical cancer prevention in Europe.
Over the short and medium term, screening for cervical cancer precursors and management of screen-detected lesions will remain the most effective tool for cervical cancer prevention in Europe. However, the field of cervical cancer prevention is rapidly developing due to better understanding of the natural history of the disease. Persistent infection with one of 13–16 oncogenic HPV types is now known to be a key prerequisite for development of cervical cancer [9, 10]. The overwhelming evidence linking HPV infection to cervical cancer has prompted the development of test systems to detect its nucleic acids as well as prophylactic and therapeutic vaccines.
Primary prevention by prophylactic vaccination against the HPV types that are causally linked with most cervical cancers in Europe is likely to become a feasible option for cervical cancer control, provided the current cost of inoculation regimens is substantially reduced.
While prophylactic vaccination, primarily in young girls, may provide important future health gains, cervical screening will need to be continued . Neglecting cervical cancer screening due to the current availability of a vaccine could paradoxically lead to an increase in cancer cases and deaths.
Development of comprehensive European guidelines on prevention of cervical cancer that appropriately integrate screening and vaccination strategies is a key aim of the next phase of guideline development activities supported by the EU Health Programme.
The current updated and expanded second guideline edition has been prepared by a multidisciplinary team of experts appointed by the European Commission from the former European Cervical Cancer Screening Network (ECCSN) established under the Europe Against Cancer Programme. In addition to the cytopathologists, epidemiologists, general practitioners, gynaecologists, histopathologists, virologists and specialists in social science serving as editors and authors, experts from outside ECCSN were also invited to write, review and contribute to the development of the second edition. Besides the input of the 48 experts from 17 member states directly involved in the production of the guidelines, numerous comments and suggestions were provided by experts attending meetings held in Denmark, Finland, Greece, Hungary and Luxembourg from 2003 to 2006 by ECCSN and the European Cancer Network (ECN) in which the former cancer screening networks have been consolidated.
A draft-revised guideline was made available for public consultation on the internet in December 2003. The results of this consultation were incorporated into a new draft, which was reviewed by experts invited by the International Agency for Research on Cancer (IARC) to Lyon, France, in June 2005. Two or three reviewers were invited for each chapter, in order to comment on the contents and to ensure that all relevant references available had been considered. The further revised guideline content was subsequently discussed with screening experts from 23 member states and 1 applicant country of the EU at the ECN meeting in February 2006. Since then, IARC has provided technical and scientific support to the editorial board and the authors for the final preparation of the guideline document.
The final recommendations and standards of best practice in the revised and updated second guideline edition are on the basis of the expert consensus in the editorial board after the above-mentioned consultations and discussions. They take into account the available evidence of screening and diagnostic procedures and programmes. For assessing evidence of effectiveness, two criteria were used: study type and study outcomes. Study types were ranked from high- to low-level evidence as follows: (i) randomised clinical trials, (ii) observational studies: case–control studies and cohort studies and (iii) correlational studies (time trends, geographical comparisons). Outcomes of studies were ordered as follows: (i) reduction of mortality from cervical cancer, (ii) reduction of incidence of invasive cervical cancer, (iii) reduction of incidence of cervical intraepithelial neoplasia (CIN) 3 or cancer (CIN3+), (iv) increased detection of high-grade histologically confirmed CIN (CIN3+ or CIN2+), (v) increased test positivity rate without or with small loss in positive predictive value for CIN2+. Throughout this guideline, scientific evidence on which the recommendations are based is indicated by references in the text. Where no observed data were available, outcomes simulated by mathematical models and expert opinion were accepted as lowest level of evidence.
The authors conducted systematic literature searches and used available systematic reviews and published meta-analyses. Publication of the handbook for cervical cancer prevention by the IARC Working Group on the Evaluation of Cancer Preventive Strategies in 2005, which included several ECN experts, was also helpful. Several pioneering population-based randomized trials have been conducted in recent years, or are currently being conducted, in various member states: LBC (Italy, The Netherlands), automated cytological screening (Finland); HPV-based versus cytology and combined (cytology+HPV) screening (Finland, Italy, The Netherlands, Sweden, UK). The results available from these trials were taken into account during the preparation of the second guideline edition up to July 2007. In addition, several meta-analyses were carried out to assess the level of evidence of new screening or management methods: LBC versus conventional cytology; HPV testing in triage of minor cytological lesions to identify women needing further follow-up, in follow-up after treatment of CIN to predict success or possible failure of treatment and in primary screening. In the meta-analyses carried out for the current guideline edition, it was only possible to assess cross-sectional outcomes (outcome types 4–5); an insufficient number of trials had reached longitudinal outcomes before final closure of chapter revisions in mid-2007. One additional meta-analysis concerned obstetrical adverse effects of treatment of precancerous lesions.
Due to the rapid accumulation of evidence on new technologies and prevention strategies, review and updating of the current guidelines has already been initiated under the current EU Health Programme [European Cooperation on Development and Implementation of Cancer Screening and Prevention Guidelines (ECCG-ECN)].
EU: ECCSN (SPC.2002475), ECN (2004309), and ECCG-ECN (2006322).
The travel grants received by MA from producers of HPV vaccines (GlaxoSmithKline and Sanofi-Pasteur MSD) ceased in 2008.
The views expressed in the publication are those of the authors; the European Commission is not responsible for any use which may be made of the information contained therein.
A list of key performance indicators is provided for monitoring the screening process and for identifying and reacting to potential problems at an early time . The indicators address aspects of the screening process which influence the impact as well as the human and financial costs of screening. The present parameters assume that cytology is used as the primary screening test, which is currently recommended. However, most of the present parameters may also be applied, with only small changes, if a different screening method (e.g. HPV DNA testing) is used. Depending on the respective screening test and the screening policy, the values of some parameters (e.g. detection rates of CIN, positive predictive values or specificity) will change. Before calculation of the recommended performance parameters, it is essential to verify key programme conditions which may influence the applicability and the further interpretation of respective parameters. As a minimum, the conditions indicated in Table 1 should be reported. For more information, see Annex 1 of Chapter 2 of the full guideline document .
|1. Programme structure|
|1.1 Catchment area|
|1.2 Start date of the programme (month, year)|
|1.3 Youngest age targeted for screening|
|1.4 Oldest age targeted for screening|
|1.5 Recommended interval between negative tests (in years)|
|1.6 Groups (if any) not eligible to participate in screening (e.g. hysterectomised)a|
|1.7 Screening test|
|2. Does the programme invite|
|2.1 All women in the eligible target population, regardless of Pap test history?|
|2.2 All women in the eligible target population, except those who had a recent Pap test (within the past 6 months or 1 year)?|
|2.3 Only the women in the eligible target population who did not receive a Pap test within the recommended screening interval (3 or 5 years)?|
|2.4 Other, specify:|
|2.5 No invitations are issued?|
|3. Does the invitation include?|
|3.1 A pre-fixed, modifiable appointment|
|3.2 An invitation to get in touch to arrange an appointment|
|3.3 Other, specify:|
|4. Are noncompliers reminded?|
|4.1 All women|
|4.2 Some womenb|
|5. Diagnostic protocols|
|5.1 Cytology results for which repeat cytology is recommended|
|5.2 Cytology results for which referral for colposcopy is recommended|
HPV, human papillomavirus.
Three groups of indicators can be distinguished:
Widespread application of the following uniform parameters to report programme performance should facilitate collaborative studies and comparison between countries and regions and should thereby help to develop an evidence base for setting future Pan-European quality standards.
The rationale and approach for calculation of the following parameters are provided in Sections 7.2–7.4 of Chapter 7 of the full guideline document . Specific instructions are indicated in Section 7.5 of Chapter 7 and are reproduced below.
Most of the key performance indicators can be directly computed from the tables presented in the annex of Chapter 2 in the full guideline document (Full pdf guideline version : http://bookshop.europa.eu/eubookshop/publicationDetails.action?pubuid=547021) . However, a number of indicators are on the basis of the incidence of invasive cervical cancers in women with different screening history. These indicators provide a more direct evaluation of the impact of screening, but they need to be computed over longer periods of time and linkage of screening registry data with cancer registry data is required for some indicators; see also Section 5 in Chapter 2 in the full guideline document.
For short-term monitoring purposes, the calculations in the annex to Chapter 2 in ref. 31 are on the basis of annually aggregated data. Additional aggregation over different periods of time is recommended, particularly over the full screening interval of a given screening programme (3 or 5 years), and is required for some of the performance parameters. Wherever possible, longer and shorter evaluation periods should also be considered.
For calculations for a given period of time, such as the recommended screening interval (3 or 5 years), the dates on which the period starts and ends and the procedure for determining the target population should be recorded. For calculations on the basis of the size of the target population, use the average over the given time period.
Note that parameters 6 (Incidence of invasive cancer in unscreened women), 14 (Cancer incidence after normal cytology) and 19 (Incidence of invasive cancer after abnormal cytology) require linkage with cancer registry data. The follow-up periods recommended for calculation of cervical cancer incidence are 6 months longer than the recommended screening interval of the respective programme (3.5 or 5.5 years). The purpose of adding one-half year to the screening interval is to include screen-detected cancer at the next screening episode. Calculations on the basis of longer follow-up periods are also recommended.