Management of low-grade cervical cytology in young women. Cohort study from Denmark.

OBJECTIVE: Cytology findings of atypical squamous cells of unknown significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) are common among women under 30, but evidence on best management strategy is insufficient. We therefore investigated how different management strategies used in Denmark influenced biopsy rates and detection of cervical intraepithelial neoplasia (CIN). METHODS: Register-based cohort study including Danish women aged less than 30 years and born 1980-95, with ASCUS/LSIL as their first abnormal cervical cytology in 2008-16. Rates and relative risks (RR) of biopsy and detection of CIN3+, CIN2 and < CIN2 during two years follow-up were compared between women referred directly to colposcopy after ASCUS/LSIL or undergoing additional testing, including mRNA or DNA test for high risk HPV or repeat cytology. RESULTS: 19,946 women with ASCUS and 19,825 with LSIL were included in the study of whom 92% had adequate information about follow-up. Among women referred directly to biopsy, CIN3+ was detected among 21%, CIN2 in 17%, while 62% had < CIN2. Repeating cytology after 6 months reduced the biopsy rate to 44% of which 53% had < CIN2. Biopsy rates with HPV test were 67% for DNA test, 77% with 14-type mRNA test and 58% with 5-type mRNA test. The detection of CIN3+ was somewhat higher, between 13% and 14% for the three HPV tests vs. 11% with repeat cytology. However, the detection of < CIN2 (not indicating treatment) also increased with RR 2.11 (95% CI 2.01-2.21) for 14-type mRNA test, 1.35 (95% CI 1.29-1.41) for 5-type mRNA test, and 1.86 (95% CI 1.76-1.97) with HPV DNA test. CONCLUSIONS: The choice of management strategy influences both the detection rate for severe lesions (CIN3+) and the proportion of women followed up for potentially insignificant findings.

High-grade cervical lesions after vaccination against human papillomavirus: A Danish cohort study.

INTRODUCTION: It is pertinent to evaluate the impact of vaccination against human papillomavirus (HPV) in real life. The aim of the study was to evaluate the real-life impact of HPV vaccination in the first birth cohort of Danish women offered free HPV vaccination as girls and invited to screening at the age of 23 years. MATERIAL AND METHODS: Women born in 1993 were offered free HPV vaccination at the age of 15 years but women born in 1983 have never been offered free HPV vaccination. We followed these two birth cohorts for 10 years from the age of 15 to after their first invitation to screening, and compared the risk of high-grade cervical intraepithelial neoplasia (CIN). Data were obtained from Danish national health registers. RESULTS: Vaccination coverage was 91% in the 1993 birth cohort and <0.1% in the 1983 cohort. Screening coverage was close to 80% in both cohorts. CIN2+ was detected in 4% of the 15 748 screened women born in 1983 and in 3% of the 19 951 screened women born in 1993. The risk of high-grade CIN was reduced by about 30% in the 1993 cohort compared with the 1983 cohort; for CIN2+ relative risk 0.74 (95% CI 0.66-0.82) and for CIN3+ relative risk 0.68 (95% CI 0.58-0.79). CONCLUSIONS: This study investigated the real-life impact of quadrivalent HPV vaccination by comparing a cohort of women offered HPV vaccination with a cohort of women not offered HPV vaccination. The observed decrease in the detection of high-grade cervical lesions following HPV vaccination is in line with results from the randomized trials and has important implications for future cervical screening of HPV vaccinated cohorts.

Prevalence of high-risk human papillomavirus after HPV-vaccination in Denmark.

Vaccination against human papillomavirus (HPV) has been introduced as a public health initiative in many countries, including Denmark since October 2008. It is important to monitor postimplementation effectiveness of HPV-vaccination at the population-level. We studied HPV-prevalence after first invitation to screening at age 23 years in women offered the quadrivalent HPV-vaccine at the age of 14 years. Randomly selected screening samples from women born in 1994 in four out of five Danish regions were subjected to analysis for HPV in addition to routine cytology. Cobas4800 was used in all participating pathology departments. Data from a Danish prevaccination cross-sectional study using Hybrid Capture 2, and a Danish split-sample study using Cobas4800 were used for comparison. In the period from February 2017 to April 2019, 6233 screening samples from women born in 1994 were selected for HPV-analysis; 27 samples had no HPV-test and 3 samples had no HPV-diagnosis, leaving 6203 samples with an HPV-diagnosis. Prevalence of any high-risk (HR) HPV was 35%; only 0.9% were positive for vaccine HPV types 16/18 while the remaining 34% were positive for other HR HPV. When comparing with prevaccination prevalence data, HPV-16/18 decreased by 95%; RR = 0.05 (95% CI 0.04-0.06), while other HR HPV remained fairly constant; RR = 0.88 (95% CI 0.82-0.94) and RR = 0.95 (95% CI 0.88-1.03), respectively. One-third of women vaccinated as girls with the quadrivalent HPV-vaccine were HR HPV-positive at time of first invitation to screening. Vaccine HPV-types 16 and 18 were almost eliminated, while the prevalence of nonvaccine HR HPV-types remained constant.

The EORTC CAT Core-The computer adaptive version of the EORTC QLQ-C30 questionnaire.

BACKGROUND: To optimise measurement precision, relevance to patients and flexibility, patient-reported outcome measures (PROMs) should ideally be adapted to the individual patient/study while retaining direct comparability of scores across patients/studies. This is achievable using item banks and computerised adaptive tests (CATs). The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) is one of the most widely used PROMs in cancer research and clinical practice. Here we provide an overview of the research program to develop CAT versions of the QLQ-C30's 14 functional and symptom domains. METHODS: The EORTC Quality of Life Group's strategy for developing CAT item banks consists of: literature search to identify potential candidate items; formulation of new items compatible with the QLQ-C30 item style; expert evaluations and patient interviews; field-testing and psychometric analyses, including factor analysis, item response theory calibration and simulation of measurement properties. In addition, software for setting up, running and scoring CAT has been developed. RESULTS: Across eight rounds of data collections, 9782 patients were recruited from 12 countries for the field-testing. The four phases of development resulted in a total of 260 unique items across the 14 domains. Each item bank consists of 7-34 items. Psychometric evaluations indicated higher measurement precision and increased statistical power of the CAT measures compared to the QLQ-C30 scales. Using CAT, sample size requirements may be reduced by approximately 20-35% on average without loss of power. CONCLUSIONS: The EORTC CAT Core represents a more precise, powerful and flexible measurement system than the QLQ-C30. It is currently being validated in a large independent, international sample of cancer patients.

Impact of HPV vaccination on outcome of cervical cytology screening in Denmark-A register-based cohort study.

4vHPV vaccination has been tested in randomized controlled trials under almost ideal conditions, and studies of real-life use have compared outcome between vaccinated and unvaccinated women from the same birth cohort and mostly before screening age. Here we present the first-to our knowledge-evaluation of the impact of the 4vHPV vaccination in real life without selection bias in the reported data. The study has been carried out by comparing the results after first cervical screening between an HPV-vaccinated and an unvaccinated birth cohort, consisting of women born in Denmark in 1993 and 1983, respectively. Cytology data covering an 8-year period, from the age of 15 (age of HPV-vaccination) to age 23 (age of invitation to first cervical screening), were retrieved from the Danish National Pathology Register. Abnormal cytology, defined as atypical squamous cell of undetermined significance and worse (ASCUS+) was detected in 9.4% of women born in 1993 as compared with 9.0% of women born in 1983; RR = 1.04 (95% CI 0.96-1.12), p = .29. Detection of high-grade squamous intraepithelial lesion (HSIL) was statistically significantly lower in the 1993 than in the 1983 cohort, RR = 0.6 (95% CI 0.5-0.7), p < .0001, while the opposite pattern was seen for ASCUS RR = 1.4 (95% CI 1.2-1.6), p < .0001. The decrease in HSIL means that more women can be spared referral for colposcopy and biopsy. The increase of ASCUS could be explained by transition from conventional to liquid-based cytology, but this observation requires further monitoring.

Danish method study on cervical screening in women offered HPV vaccination as girls (Trial23): a study protocol.

INTRODUCTION: The first birth cohorts of women offered human papillomavirus (HPV) vaccination as girls are now entering cervical screening. However, there is no international consensus on how to screen HPV vaccinated women. These women are better protected against cervical cancer and could therefore be offered less intensive screening. Primary HPV testing is more sensitive than cytology, allowing for a longer screening interval. The aim of Trial23 is to investigate if primary HPV testing with cytology triage of HPV positive samples is a reasonable screening scheme for women offered HPV vaccination as girls. METHODS: Trial23 is a method study embedded in the existing cervical screening programme in four out of five Danish regions. Without affecting the screening programme, women born in 1994 are randomised to present screening with liquid-based cytology every third year (present programme arm) or present screening plus an HPV test (HPV arm). The study started 1 February 2017 and will run over three screening rounds corresponding to 7-8 years. ANALYSES: The primary endpoint is cervical intraepithelial neoplasia grade 3 or above. The trial is undertaken as a non-inferiority study including intention-to-treat and per-protocol analyses. The potential effect of primary HPV screening with a 6-year interval will be calculated from the observed data. ETHICS AND DISSEMINATION: The study protocol has been submitted to the ethical committee and deemed a method study. All women are screened according to routine guidelines. The study will contribute new evidence on the future screening of HPV vaccinated birth cohorts of women. All results will be published in open-access journal. TRIAL REGISTRATION: NCT03049553; Pre-results.

An overview of cervical cancer epidemiology and prevention in Scandinavia.

New technologies such as human papillomavirus (HPV) testing and vaccination necessitate comprehensive policy analyses to optimize cervical cancer prevention. To inform future Scandinavian-specific policy analyses, we aimed to provide an overview of cervical cancer epidemiology and existing prevention efforts in Denmark, Norway and Sweden. We compiled and summarized data on current prevention strategies, population demography and epidemiology (for example, age-specific HPV prevalence and cervical cancer incidence over time) for each Scandinavian country by reviewing published literature and official guidelines, performing registry-based analyses using primary data and having discussions with experts in each country. In Scandinavia, opportunistic screening occurred as early as the 1950s and by 1996, all countries had implemented nationwide organized cytology-based screening. Prior to implementation of widespread screening and during 1960-66, cervical cancer incidence was considerably higher in Denmark than in Norway and Sweden. Decades of cytology-based screening later (i.e. 2010-2014), cervical cancer incidence has been considerably reduced and has converged across the countries since the 1960s, although it still remains lowest in Sweden. Generally, Scandinavian countries face similar cervical cancer burdens and utilize similar prevention approaches; however, important differences remain. Future policy analyses will need to evaluate whether these differences warrant differential prevention policies or whether efforts can be streamlined across Scandinavia.

Burden of HPV-caused cancers in Denmark and the potential effect of HPV-vaccination.

BACKGROUND: Denmark is one of the countries where Human papillomavirus (HPV)-vaccination at present includes only girls. However, the burden of HPV-related cancer in men is increasing, which would argue for gender-neutral vaccination. The aim of this study was to examine the burden of HPV-caused cancers in women and men, and to evaluate the potential of HPV-vaccination in cancer control. METHODS: Data were retrieved from the literature on population prevalence of high risk (HR) HPV, on HR HPV-prevalence and genotypes in HPV-related cancers, and on number of cytology samples in cervical screening. Data on annual biopsies and conisations were retrieved from the Danish National Health Service Register and the Danish National Patient Register. Incidences of HPV-related cancers in Denmark were extracted from NORDCAN. Number of HPV-caused cancers was calculated from number of HPV-related cancers and the proportion known to be caused by high-risk (HR) HPV. RESULTS: In cross-sectional surveys in Denmark, one fifth of women and almost one third of men were found to be positive for HR HPV. Per year, 548 HPV-caused cancer cases were diagnosed in women and 234 in men, and twice as many cancers in women as in men were preventable with HPV vaccination. However, including screening prevented cervical cancers, the burden of cancers caused by HPV-infection would be 1300-2000 in women as compared to 234 in men. CONCLUSION: Taking screening prevented cervical cancers into account, the cancer control potential of HPV-vaccination is considerably higher in women than in men. HPV-vaccination could reduce the burden of screening on women and on health care resources.

Development of a lack of appetite item bank for computer-adaptive testing (CAT).

PURPOSE: A significant proportion of oncological patients experiences lack of appetite. Precise measurement is relevant to improve the management of lack of appetite. The so-called computer-adaptive test (CAT) allows for adaptation of the questionnaire to the individual patient, thereby optimizing measurement precision. The EORTC Quality of Life Group is developing a CAT version of the widely used EORTC QLQ-C30 questionnaire. Here, we report on the development of the lack of appetite CAT. METHODS: The EORTC approach to CAT development comprises four phases: literature search, operationalization, pre-testing, and field testing. Phases 1-3 are described in this paper. First, a list of items was retrieved from the literature. This was refined, deleting redundant and irrelevant items. Next, new items fitting the "QLQ-C30 item style" were created. These were evaluated by international samples of experts and cancer patients. RESULTS: The literature search generated a list of 146 items. After a comprehensive item selection procedure, the list was reduced to 24 items. These formed the basis for 21 new items fitting the QLQ-C30 item style. Expert evaluations (n = 10) and patient interviews (n = 49) reduced the list to 12 lack of appetite items. CONCLUSIONS: Phases 1-3 resulted in 12 lack of appetite candidate items. Based on a field testing (phase 4), the psychometric characteristics of the items will be assessed and the final item bank will be generated. This CAT item bank is expected to provide precise and efficient measurement of lack of appetite while still being backward compatible to the original QLQ-C30 scale.