Matejka Rebolj

The Danish National Patient Register

Introduction: The Danish National Patient Register (NPR) was established in 1977, and it is considered to be the finest of its kind internationally. Content: At the onset the register included information on inpatient in somatic wards. The content of the register has gradually been expanded, and since 2007 the register has included information on all patients in Danish hospitals. Validity and coverage: Although the NPR is overall a sound data source, both the content and the definitions of single variables have changed over time. Changes in the organisation and provision of health services may affect both the type and the completeness of registrations. Conclusion: The NPR is a unique data source. Researchers using the data should carefully consider potential fallacies in the data before drawing conclusions.

Long term predictive values of cytology and human papillomavirus testing in cervical cancer screening: joint European cohort study.

Objective To obtain large scale and generalisable data on the long term predictive value of cytology and human papillomavirus (HPV) testing for development of cervical intraepithelial neoplasia grade 3 or cancer (CIN3+). Design Multinational cohort study with joint database analysis. Setting Seven primary HPV screening studies in six European countries. Participants 24 295 women attending cervical screening enrolled into HPV screening trials who had at least one cervical cytology or histopathology examination during follow-up. Main outcome measure Long term cumulative incidence of CIN3+. Results The cumulative incidence rate of CIN3+ after six years was considerably lower among women negative for HPV at baseline (0.27%, 95% confidence interval 0.12% to 0.45%) than among women with negative results on cytology (0.97%, 0.53% to 1.34%)). By comparison, the cumulative incidence rate for women with negative cytology results at the most commonly recommended screening interval in Europe (three years) was 0.51% (0.23% to 0.77%). The cumulative incidence rate among women with negative cytology results who were positive for HPV increased continuously over time, reaching 10% at six years, whereas the rate among women with positive cytology results who were negative for HPV remained below 3%. Conclusions A consistently low six year cumulative incidence rate of CIN3+ among women negative for HPV suggests that cervical screening strategies in which women are screened for HPV every six years are safe and effective.

Cervical cancer screening policies and coverage in Europe.

The aim of the study was to compare current policy, organisation and coverage of cervical cancer screening programmes in the European Union (EU) member states with European and other international recommendations. According to the questionnaire-based survey, there are large variations in cervical cancer screening policies and inadequacies in the key organisational elements of the programme such as registration and monitoring required for quality-assurance and fail-safe mechanisms. Based on data from available screening registers, coverage of the screening test taken within the population-based programme was below 80% in all programmes, ranging from 10% to 79%. The screening capacity is satisfactory in most EU member states, however, and there is even over-capacity in several countries. There are also countries which do not have an acceptable capacity yet. Control of proper capacity along with education, training and communication among women, medical professionals and authorities are required, accordingly. The study indicates that, despite substantial efforts, the recommendations of the Council of the EU on organised population-based screening for cervical cancer are not yet fulfilled. Decision-makers and health service providers should consider stronger measures or incentives in order to improve cervical cancer control in Europe.

The challenges of organising cervical screening programmes in the 15 old member states of the European Union

Cervical cancer incidence and mortality can be reduced substantially by organised cytological screening at 3 to 5 year intervals, as was demonstrated in the Nordic countries, the United Kingdom, the Netherlands and parts of Italy. Opportunistic screening, often proposed at yearly schedules, has also reduced the burden of cervical cancer in some, but not all, of the other old member states (belonging to the European Union since 1995) but at a cost that is several times greater. Well organised screening programmes have the potential to achieve greater participation of the target population at regular intervals, equity of access and high quality. Despite the consistent evidence that organised screening is more efficient than non-organised screening, and in spite of the Cancer Screening Recommendations of the European Council, health authorities of eight old member states (Austria, Belgium, France, Germany, Greece, Luxembourg, Portugal and Spain) have not yet started national organised implementation of screening for cervical cancer. A decision was made by the Irish government to extend their pilot programme nationally while new regional programmes commenced in Portugal and Spain. Introduction of new methods of prevention, such as HPV screening and prophylactic HPV vaccination, can reduce the burden further, but this will require a high level of organisation with particular attention needed for the maximisation of population coverage, compliance with evidence-based guidelines, monitoring of data enabling continued evaluation and improvement of the preventive programmes.

Monitoring a national cancer prevention program: Successful changes in cervical cancer screening in the netherlands

The success of screening, an important cancer prevention tool, depends on the quality and efficiency of protocols and guidelines for screening and follow‐up. However, even centrally organized screening programs such as the Dutch cervical screening program occasionally show problems in performance. To improve this program, the screening scheme, follow‐up, administration and financing protocols and guidelines were thoroughly changed in 1996. This study evaluates the consequences for the performance of the national program. Five‐year coverage rate, the proportion of screened women sent to follow‐up, follow‐up compliance and duration, and the yearly number of Pap smears before and after the changes in 1996 were compared. Five‐year coverage increased substantially in the added target age groups (30–34, and 54–60 years); in the old target age group (35–53 years) it remained around 80%. The percentage of screened women sent to follow‐up decreased from almost 19–3% per screening round, due to a more restrictive use of the Pap 2 classification, and an evidence‐based cessation of follow‐up of negative smears without endocervical cells. Follow‐up compliance has improved, and the average time until a woman is either referred or rejoins the regular screening schedule, has become shorter. The total number of smears, a strong determinant of screening costs, has decreased by 20% primarily due to the changed follow‐up recommendations. In conclusion, the 1996 changes in protocols and guidelines, and their implementation have increased coverage and efficiency, and decreased the screening‐induced negative side effects.

Nonattendance is still the main limitation for the effectiveness of screening for cervical cancer in the Netherlands

Although mass screening for cervical cancer has been operational for more than 2 decades in the Netherlands, 700 women are still diagnosed with this cancer each year (9 per 100,000). We investigated these cases, in order to evaluate opportunities to further increase the effectiveness of the programme. We analyzed the screening history of women diagnosed with cervical cancer between 1994–1997 using the Dutch national pathology file that includes cervical cytology and histological results. More than half of the cases did not have previous preventive cervical smears, and another 30% had never been invited to the programme because of their age. In the future, we estimate that two thirds of all Dutch women with invasive cervical cancer will be unscreened or under‐screened, based on current screening participation of more than 70%. We conclude that increasing screening participation has much more potential for further reducing cervical cancer incidence than reducing the screening interval, increasing the age range or having a screening test with higher sensitivity.

Process performance of cervical screening programmes in Europe

Standardised tables of aggregated data were collected from 15 European national or regional cervical screening programmes and key performance indicators computed as reported in European Union (EU) Guidelines, 2nd edition. Cytological results varied widely between countries both for the total proportion of abnormal tests (from 1.2% in Germany (Mecklenburg-Vorpommern) to 11.7% in Ireland-Midwest Region) and for their distribution by grade. Referral rates for repeat cytology (ranging from 2.9% of screened women in the Netherlands to 16.6% in Slovenia) or for colposcopy (ranging from 0.8% in Finland to 4.4% in Romania-Cluj) and the Positive Predictive Value (PPV) of colposcopic attendance (ranging from 8% in Romania-Cluj to 52% in Lithuania) were strongly influenced by management protocols, in particular for atypical squamous cells of undetermined significance (ASCUS) and low-grade squamous intraepithelial lesion (LSIL) cytology. However, cytology-specific PPV also showed remarkable variability. The detection rate of CIN2+ histology ranged from <0.1% of screened women in Poland to >1% in England and Denmark. Low attendance for colposcopy after referral was observed in some east-European countries. These comparisons may be useful for improving the performance of cervical screening in general and more so if new screening technologies and vaccination for Human Papillomavirus are introduced. Overall, quality was better in countries that have operated organised programmes for a longer time, plausibly as a result of long-lasting monitoring and quality assurance activities. Therefore, the availability of these data, the first comparing European countries, and the increased number of countries that can provide such data (only five in 2004) represent progress. Nevertheless, there is a clear need to standardise the cytological and histological classifications used in screening, as well as data registration systems across Europe.

Disagreement between human papillomavirus assays: an unexpected challenge for the choice of an assay in primary cervical screening.

We aimed to determine the disagreement in primary cervical screening between four human papillomavirus assays: Hybrid Capture 2, cobas, CLART, and APTIMA. Material from 5,064 SurePath samples of women participating in routine cervical screening in Copenhagen, Denmark, was tested with the four assays. Positive agreement between the assays was measured as the conditional probability that the results of all compared assays were positive given that at least one assay returned a positive result. Of all 5,064 samples, 1,679 (33.2%) tested positive on at least one of the assays. Among these, 41% tested positive on all four. Agreement was lower in women aged ≥30 years (30%, vs. 49% at <30 years), in primary screening samples (29%, vs. 38% in follow-up samples), and in women with concurrent normal cytology (22%, vs. 68% with abnormal cytology). Among primary screening samples from women aged 30–65 years (n = 2,881), 23% tested positive on at least one assay, and 42 to 58% of these showed positive agreement on any compared pair of the assays. While 4% of primary screening samples showed abnormal cytology, 6 to 10% were discordant on any pair of assays. A literature review corroborated our findings of considerable disagreement between human papillomavirus assays. This suggested that the extent of disagreement in primary screening is neither population- nor storage media-specific, leaving assay design differences as the most probable cause. The substantially different selection of women testing positive on the various human papillomavirus assays represents an unexpected challenge for the choice of an assay in primary cervical screening, and for follow up of in particular HPV positive/cytology normal women.

Human papillomavirus testing in primary cervical screening and the cut-off level for hybrid capture 2 tests: systematic review

Objective To determine the trade-off between the sensitivity and the specificity for high grade cervical intraepithelial neoplasia at hybrid capture 2 cut-off values above the standard ≥1 relative light units/cut-off level (rlu/co). Design Systematic review. Data sources PubMed. Study selection Randomised controlled trials in primary cervical screening using hybrid capture 2 testing in the intervention arms. Articles published until August 2010 were included if the numbers of women with positive test results and with cervical intraepithelial neoplasia were stratified by hybrid capture 2 cut-off levels. Participants Women in the baseline screening rounds of the trials. Interventions Hybrid capture 2 screening in the baseline round including the diagnostic follow-up as practised in the randomised controlled trials and as reported by hybrid capture 2 cut-off values. Results Owing to heterogeneity in the trials, meta-analysis was not possible. Including cut-off values up to ≥10 rlu/co, 25 observation points were available for analysis. The relative sensitivity for cervical intraepithelial neoplasia grade III or higher at cut-off levels of ≥2, ≥4 or ≥5, and ≥10 rlu/co compared with a cut-off level of ≥1 rlu/co varied by trial, but at their lowest they were 0.97, 0.92, and 0.91, respectively. A similar pattern was observed for cervical intraepithelial neoplasia grade II or higher. The specificity would increase by at least 1%, 2%, and 3%, respectively, so that up to 24%, 39%, and 53%, of positive hybrid capture 2 test results not associated with high grade neoplasia could be avoided. Only two outliers existed to this general pattern. Conclusions Although the data were derived from the baseline screening rounds only, the decrease in the sensitivity for high grade cervical intraepithelial neoplasia using a hybrid capture 2 cut-off level between ≥2 rlu/co and ≥10 rlu/co seemed acceptable given the international recommendations for testing for human papillomavirus DNA in cervical screening, which require 90% or more sensitivity for cervical intraepithelial neoplasia grade II or higher compared with hybrid capture 2 at ≥1 rlu/co. The data suggest that the hybrid capture 2 cut-off level could be increased in primary screening; this seems reasonably safe and is significantly less burdensome for women.

Introduction of human papillomavirus vaccination in Nordic countries

INTRODUCTION Cervical screening has helped decrease the incidence of cervical cancer, but the disease remains a burden for women. Human Papillomavirus (HPV) vaccination is now a promising tool for control of cervical cancer. Nordic countries (Denmark, Finland, Greenland, Iceland, Norway and Sweden) are relatively wealthy with predominantly publicly paid health care systems. The aim of this paper was to provide an update of the current status of introduction of HPV vaccine into the childhood vaccination programs in this region. METHODS Data on cervical cancer, cervical screening programs, childhood immunization and HPV vaccination programs for Nordic countries were searched via PubMed and various organizations. We furthermore contacted selected experts for information. RESULTS The incidence of cervical cancer is highest in Greenland (25 per 100,000, age standardized, World Standard Population, ASW) and lowest in Finland (4 per 100,000 ASW) and rates in the other Nordic countries vary between 7 and 11 per 100,000 ASW. Greenland and Denmark were first to introduce HPV vaccination, followed by Norway. Vaccination programs are underway in Sweden and Iceland, while Finland has just recently recommended introduction of vaccination. HPV vaccination has been intensively debated, in particular in Denmark and Norway. DISCUSSION In Nordic countries with a moderate risk of cervical cancer and a publicly paid health care system, the introduction of HPV vaccination was a priority issue. Many players became active, from the general public to health professionals, special interest groups, and the vaccine manufacturers. These seemed to prioritize different health care needs and weighed differently the uncertainty about the long-term effects of the vaccine. CONCLUSION HPV vaccination posed a pressure on public health authorities to consider the evidence for and against it, and on politicians to weigh the wish for cervical cancer protection against other pertinent health issues.