Stefan Lönnberg

Detection rates of precancerous and cancerous cervical lesions within one screening round of primary human papillomavirus DNA testing: prospective randomised trial in Finland

Objective To compare the detection rates of precancerous and cancerous cervical lesions by human papillomavirus (HPV) DNA testing and by conventional cytology screening. Design Prospective randomised trial. Two cohorts were followed over one screening round of five years, screened initially by primary HPV DNA testing or by primary Pap test. Setting Population based programme for cervical cancer screening in Finland. Participants Women aged 25-65 years invited for screening in 2003-07 (101 678 in HPV arm; 101 747 in conventional cytology arm). Intervention Women were randomly allocated (1:1) to primary HPV DNA screening followed by cytology triage if they had positive results, or to primary cytology screening. Screening method was disclosed at the screening visit. Trial personnel involved were aware of all test results. Main outcome measures Cumulative detection rates of cervical intraepithelial neoplasia (CIN), adenocarcinoma in situ (AIS), and invasive cervical cancer before the second screening (after five years) or before 31 December 2008. Lesions detected at screening and during the five year interval were included. Results 1010 and 701 precancerous or cancerous lesions were detected during an average follow-up of 3.6 years in the HPV and cytology arms, respectively. Among invited women, the hazard ratio was 1.53 (95% confidence interval l.28 to 1.84) for CIN grade 1, 1.54 (1.33 to 1.78) for CIN 2, 1.32 (1.09 to 1.59) for CIN 3 or AIS, and 0.81 (0.48 to 1.37) for cervical cancer. In 25-34 year old participants, the cumulative hazard (or cumulative detection rate) was 0.0057 (0.0045 to 0.0072) for HPV screening versus 0.0046 (0.0035 to 0.0059) for conventional screening; corresponding data for women aged 35 years and older were 0.0022 (0.0019 to 0.0026) and 0.0017 (0.0014 to 0.0021), respectively. Conclusions Primary HPV DNA screening detects more cervical lesions than primary cytology within one screening round of five years. Even if the detection rate of CIN 3 or AIS increased in the HPV arm in both age groups, the absolute difference in cumulative rates in women aged 35 years or older was small. By carefully selecting age groups and screening intervals, HPV screening could increase the overall detection rate of cervical precancerous lesions only slightly. However, these findings should be interpreted in the context of the high level of opportunistic screening that occurs in Finland. Trial registration International Standard Randomised Controlled Trial ISRCTN23885553.

Age-Specific Effectiveness of the Finnish Cervical Cancer Screening Programme

Background: There is currently some uncertainty about the effectiveness of screening outside the established core ages of 30 to 60. We audited the screening histories of cervical cancers and conducted a case–control evaluation of the effectiveness of organized screening in different ages. Methods: Screening histories for 1,546 cervical cancer cases and 9,276 age-matched controls were derived by linkage to the screening register. ORs and 95% confidence intervals (CI) for the association of participation in a program screen and cervical cancer diagnosis in the following screening interval were estimated using conditional logistic regression and corrected for self-selection bias. Results: Participation in a single screen was associated with a 47% decrease in cervical cancers, but this effect was age-dependent. Screening at 25 showed little or no impact on the risk of cervical cancer in the next interval, whereas screens at 40 to 65 showed protective effects of 51% to 66%. Conclusions: Program screening at the age of 25 is not associated with a reduced risk of cervical cancer in the following screening interval. Additional analyses are needed that also take opportunistic screening of women during the first rounds of organized screening into consideration. In contrast, screening yields substantial risk reductions in older ages at least up to the age of 60. This study also provides moderate indication of a long-lasting risk reduction associated with screening at the age of 65. Impact: Cervical cancer screening effectiveness is for the first time evaluated at different ages up to 65 with correction for self-selection bias of participation in organized screening. Cancer Epidemiol Biomarkers Prev; 21(8); 1354–61. ©2012 AACR.

Mortality audit of the Finnish cervical cancer screening program

Incidence‐based evaluations of cervical cancer screening programs have suggested age‐specific impacts and there is uncertainty regarding the effectiveness of screening outside the ages of 30–60 years. We audited the screening histories of cervical cancer deaths and conducted a case‐control evaluation of the effectiveness of organized screening in different ages with mortality as outcome. We included all 506 cervical cancer deaths in Finland in 2000–2009 due to cancers diagnosed in 1990 or later, and 3,036 controls matched by age at diagnosis to the cases. Squamous cell carcinoma constituted 59% of the cases, adenocarcinomas 29%, and the remaining 12% were other specified and unspecified cervical malignancies. Most deaths (54%) were due to cancers diagnosed more than 5 years after last screening invitation, 24% were diagnosed among nonattenders and only 14% of deaths occurred among women who had attended invitational screening. The risk reduction associated with attending a single program screen at an age below 40 was nonsignificant (OR 0.70; 95% CI 0.33–1.48), while clear risk reductions were observed after screening at the age of 40–54 (OR 0.33; CI 0.20–0.56) and 55–69 (OR 0.29; CI 0.16–0.54). This study also provides some indication of a long‐lasting additional effect of screening at the age of 65. Possible avenues for improving the effectiveness of the Finnish screening program include efforts to increase attendance and an extension of the target ages to include 65‐to 69‐year‐old women. The potential benefit of increasing the sensitivity of the screening test or shortening the screening interval is smaller.

Towards better implementation of cancer screening in Europe through improved monitoring and evaluation and greater engagement of cancer registries

Proposals to improve implementation, monitoring and evaluation of breast, cervical and colorectal cancer screening programmes have been developed in a European project involving scientists and professionals experienced in cancer registration (EUROCOURSE). They call for a clear and more active role for cancer registries through better interfaces with cancer screening programmes and adapting data contents of cancer registries for evaluation purposes. Cancer registries are recognised as essential for adequate evaluation of cancer screening programmes, but they are not involved in screening evaluation in several European countries. This is a key barrier to improving the effectiveness of programmes across Europe. The variation in Europe in the implementation of cancer screening offers a unique opportunity to learn from best practices in collaboration between cancer registries and screening programmes. Population-based cancer registries have experience and tools in collecting and analysing relevant data, e.g. for diagnostic and therapeutic determinants of mortality. In order to accelerate improvements in cancer control we argue that cancer registries should take co-responsibility in promoting effective screening evaluation in Europe. Additional investments are vital to further development of infrastructures and activities for screening evaluation and monitoring in the national settings and also at the pan-European level. The EUROCOURSE project also aimed to harmonise implementation of the European quality assurance guidelines for cancer screening programmes across Europe through standardising routine data collection and analysis, and definitions for key performance indicators for screening registers. Data linkage between cancer and screening registers and other repositories of demographic data and cause of death and where available clinical registers is key to implementing the European screening standards and thereby reducing the burden of disease through early detection. Greater engagement of cancer registries in this collaborative effort is also essential to develop adequate evaluation of innovations in cancer prevention and care.

Status of implementation and organization of cancer screening in The European Union Member States—Summary results from the second European screening report

The second report on the implementation status of cancer screening in European Union (EU) was published in 2017. The report described the implementation status, protocols and organization (updated till 2016) and invitation coverage (for index year 2013) of breast, cervical and colorectal cancer screening in the EU. Experts in screening programme monitoring (N = 80) from the EU Member States having access to requisite information in their respective countries provided data on breast, cervical and colorectal cancer screening through online questionnaires. Data was collected for screening performed in the framework of publicly mandated programmes only. Filled in questionnaires were received from 26 Member States for all three sites and from one Member State for breast cancer only. Substantial improvement in screening implementation using population‐based approach was documented. Among the age‐eligible women, 94.7% were residents of Member States implementing or planning population‐based breast cancer screening in 2016, compared to 91.6% in 2007. The corresponding figures for cervical cancer screening were 72.3 and 51.3% in 2016 and 2007, respectively. Most significant improvement was documented for colorectal cancer screening with roll‐out ongoing or completed in 17 Member States in 2016, compared to only five in 2007. So the access to population‐based screening increased to 72.4% of the age‐eligible populations in 2016 as opposed to only 42.6% in 2007. The invitation coverage was highly variable, ranging from 0.2–111% for breast cancer, 7.6–105% for cervical cancer and 1.8–127% for colorectal cancer in the target populations. In spite of the considerable progress, much work remains to be done to achieve optimal effectiveness. Continued monitoring, regular feedbacks and periodic reporting are needed to ensure the desired impacts of the programmes.

Cervical cancer prevented by screening: Long-term incidence trends by morphology in Norway.

Both major morphologic types of cervical cancer, squamous cell carcinoma (SCC) and adenocarcinoma (AC), are causally related to persistent infection with high‐risk human papillomavirus (hrHPV), but screening has primarily been effective at preventing SCC. We analysed incidence trends of cervical cancer in Norway stratified by morphologies over 55 years, and projected SCC incidence in the absence of screening by assessing the changes in the incidence rate of AC. The Cancer Registry of Norway was used to identify all 19,530 malignancies in the cervix diagnosed in the period 1956–2010. The majority of these (82.9%) were classified as SCCs, 10.5% as ACs and the remaining 6.6% were of other or undefined morphology. By joint‐point analyses of a period of more than five decades, the average annual percentage change in the age‐standardised incidence was −1.0 (95%CI: −2.1–0.1) for cervical SCC, 1.5 (95%CI:1.1–1.9) for cervical AC and −0.9 (95%CI: −1.4 to −0.3) for cervical cancers of other or undefined morphology. The projected age‐standardised incidence rate of cervical SCC in Norway, assuming no screening, was 28.6 per 100,000 woman‐years in 2010, which compared with the observed SCC rate of 7.3 corresponds to an estimated 74% reduction in SCC or a 68% reduction due to screening in the total cervical cancer burden. Cytology screening has impacted cervical cancer burden more than suggested by the overall observed cervical cancer incidence reduction since its peak in the mid‐1970s. The simultaneous substantial increase in cervical adenocarcinoma in Norway is presumably indicative of an increase in exposure to HPV over time.

Validation of histological diagnoses in a national cervical screening register

Abstract Background. Monitoring and evaluation of cancer screening programmes require accurate data on invitations, visits, test results, diagnoses and management. The purpose of this study was to evaluate the completeness and accuracy of histological diagnoses (cervical precancerous lesions and cancer) in the Finnish cervical cancer screening register by comparing data with the cancer register and the administrative hospital discharge register. Material and methods. Screening data covering all 16 353 screening episodes that resulted in a referral for colposcopy over the period of 1998–2007 were individually linked with hospital discharge and cancer register data using the unique personal identifier. Agreement between registers, as well as sensitivity, coverage and positive predictive values (PPV) for the screening register and the hospital discharge register diagnosis, were estimated. Invasive cases in the cancer register and pooled cases of precancerous lesions were used as reference case populations. Results. The sensitivity of the screening register for cervical cancer was 69%, the coverage 100% and the PPV 77%. Corresponding values for the hospital discharge register were 81%, 100% and 83%, respectively. Sensitivity of the screening register for cervical intraepithelial neoplasia grade 2 or worse (CIN2+) against the pooled case population was 89% and coverage 99%. Corresponding values for the hospital discharge register were 78% and 93%. Kappa-values for pair-wise agreement between the three registers ranged between 0.73 and 0.79, often the lesion grade was lower in the screening register than in the other two registers. Conclusions. The data in the screening register has high coverage and is thus useful for statistical and evaluation purposes. However, in order to improve the accuracy of diagnostic information, there are grounds to consider data retrieval through systematic linkage to other health care registers.

Cervical cancer prevented by screening

Both major morphologic types of cervical cancer, squamous cell carcinoma (SCC) and adenocarcinoma (AC), are causally related to persistent infection with high‐risk human papillomavirus (hrHPV), but screening has primarily been effective at preventing SCC. We analysed incidence trends of cervical cancer in Norway stratified by morphologies over 55 years, and projected SCC incidence in the absence of screening by assessing the changes in the incidence rate of AC. The Cancer Registry of Norway was used to identify all 19,530 malignancies in the cervix diagnosed in the period 1956–2010. The majority of these (82.9%) were classified as SCCs, 10.5% as ACs and the remaining 6.6% were of other or undefined morphology. By joint‐point analyses of a period of more than five decades, the average annual percentage change in the age‐standardised incidence was −1.0 (95%CI: −2.1–0.1) for cervical SCC, 1.5 (95%CI:1.1–1.9) for cervical AC and −0.9 (95%CI: −1.4 to −0.3) for cervical cancers of other or undefined morphology. The projected age‐standardised incidence rate of cervical SCC in Norway, assuming no screening, was 28.6 per 100,000 woman‐years in 2010, which compared with the observed SCC rate of 7.3 corresponds to an estimated 74% reduction in SCC or a 68% reduction due to screening in the total cervical cancer burden. Cytology screening has impacted cervical cancer burden more than suggested by the overall observed cervical cancer incidence reduction since its peak in the mid‐1970s. The simultaneous substantial increase in cervical adenocarcinoma in Norway is presumably indicative of an increase in exposure to HPV over time.

Low Proportion of False-Negative Smears in the Finnish Program for Cervical Cancer Screening

Background: We assessed the performance and validity of cytology in the Finnish screening program by considering high-grade neoplasia and cervical cancer (CIN3+) rates as detected in the program and by reevaluating cases observed after a negative screening test. Methods: This retrospective study included 915 screen-detected CIN3+ cases and 421 cases observed after a negative screen. Randomized and blinded reevaluation of potential false-negative screening tests covered 345 archival case smears from women without a referral to colposcopy, as well as 689 control smears for estimating performance and validity measures. Results: The false-negative rate at the cutoff of low-grade squamous intraepithelial lesion or worse was 35% (95% confidence interval, 30-40%). In the subpopulation with original screening result of Pap I, the false-negative rate was 23% (18-28%). Sensitivity of screening laboratory rereading for detecting low-grade lesions or worse as atypical was 75% (67-82%) and specificity 93% (91-94%). Reproducibility of specific cytologic diagnoses was only fair. False negatives constituted 11% of all CIN3+ diagnoses in the screened population; those false negatives with an original Pap I screening result constituted 5%. Conclusions: Although screen failures in the form of diagnostic false negatives occur within the Finnish screening program, their effect on cancer incidence is fairly small and cannot be readily decreased without sacrificing the high specificity of screening or without high incremental costs. Feedback for the screening laboratories is needed, however, to improve the reproducibility of cytologic diagnoses to optimize the burden of intensified follow-up and treatment of precancerous lesions. Cancer Epidemiol Biomarkers Prev; 19(2); 381–7

Personal and provider level factors influence participation to cervical cancer screening: A retrospective register-based study of 1.3 million women in Norway

High coverage is essential for an effective screening programme. Here we present screening barriers and facilitators among 1.3 million women aged 25-69years eligible for screening within the Norwegian Cervical Cancer Screening Program (NCCSP). We defined non-adherence as no screening test in 2008-2012. We divided adherent women into those screened spontaneously, and those who had a smear after receiving a reminder from the NCCSP. Explanatory variables were extracted from several nationwide registers, and modelled by modified Poisson regression. In total, 34% of women were non-adherent. 31% of native Norwegians were non-adherent, compared to 50% of immigrants. Immigrant status was a strong predictor of non-adherence, but the vast majority of non-adherent women were still native Norwegians. Higher non-adherence rates were associated with having a male general practitioner (GP), a foreign GP, a young GP, and distance to the screening site. Being unmarried, having no children, having lower socioeconomic position and region of residence predicted non-adherence and, to a smaller extent, reminded adherence to screening. In contrast, previous experience with cervical abnormalities substantially increased adherence to screening. The population-based screening programme promotes equity by recruiting women who are less likely to participate spontaneously. However, socioeconomic disparities were evident in a country with a nationwide programme and a policy of equal access to health care. Initiatives aimed at removing practical and financial barriers to equitable screening delivery and at reducing the effect of sociodemographic attributes on screening participation are needed.