Combined incentive actions, focusing on primary care professionals, to improve cervical cancer screening in women living in socioeconomically disadvantaged geographical areas: a study protocol of a hybrid cluster randomised effectiveness and implementation trial- RESISTE.

INTRODUCTION: Cervical cancer (CC) causes thousands of deaths each year. Nearly 100% of cases are caused by oncogenic strains of human papillomavirus (HPV). In most industrialised countries, CC screening (CCS) is based on the detection of HPV infections. For many reasons including lower adherence to CCS, underserved women are more likely to develop CC, and die from it. We aim to demonstrate that the use of incentives could improve screening rates among this population. METHODS AND ANALYSIS: Our cluster randomised, controlled trial will include 10 000 women aged 30-65 years eligible for CCS, living in deprived areas in four French departments, two mainlands and two overseas, and who did not perform physician-based HPV testing within the framework of the nationally organised screening programme. HPV self-sampling kit (HPVss) will be mailed to them. Two interventions are combined in a factorial analysis design ending in four arms: the possibility to receive or not a financial incentive of €20 and to send back the self-sampling by mail or to give it to a health professional, family doctor, gynaecologist, midwife or pharmacist. The main outcome is the proportion of women returning the HPVss, or doing a physician-based HPV or pap-smear test the year after receiving the HPVss. 12-month follow-up data will be collected through the French National Health Insurance database. We expect to increase the return rate of HPV self-samples by at least 10% (from 20% to 30%) compared with the postal return without economic incentive. ETHICS AND DISSEMINATION: Ethics approval was first obtained on 2 April 2020, then on July 29 2022. The ethics committee classified the study as interventional with low risk, thus no formal consent is required for inclusion. The use of health insurance data was approved by the Commission Nationale Informatique et Libertés on 14 September 2021 (ref No 920276). An independent data security and monitoring committee was established. The main trial results will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: NCT04312178.

Successful retrieval of human papillomavirus DNA after a 4.5 year storage on FTA elute cards.

Efficient primary (vaccination) and secondary (screening) prevention strategies have the potential to eliminate cervical cancer worldwide. In this context, surveillance of HPV infections remains mandatory to assess the efficacy and the impact of screening and vaccination policies. Therefore there is a need to safely store cervical samples to conduct long-term studies in vaccinated and non-vaccinated subjects. Up-dated data on cervical specimen preservation on FTA® cards indicate that HPV DNA can be safely retrieved after 54 months of storage. A concordance of 97 % was achieved between HPV genotypes detected in initial cervical samples and on FTA® cards 4.5 years later. Even if a drop in HPV viral loads was observed in some cases at 4.5 years, using FTA® cards for safe and long-term storage of cervical samples represents an interesting option.

[Screening and early diagnosis of cervical cancer]. / Dépistage et diagnostic précoce du cancer du col de l'utérus.

Because of the natural history of precancerous cervical lesions, cancer of the cervix uteri is easily preventable by screening. Pap smear is an effective and simple test, not very expensive and harmless. In France, 3000 to 3500 new cases still occur every year especially due to insufficient participation of the target population but also because of low sensibility of the test and problems in the management of cytological abnormalities. Organisation of screening, following the Alsatian model, which has been operational for 15 years, would be a cost-effective strategy. Changing Pap smear for HPV testing needs careful assessment by national population based randomized studies before any routine use.

Cervical morbidity in Alsace, France: results from a regional organized cervical cancer screening program.

In 1994, a pilot program of cervical cancer screening was introduced in the Alsace region, France. Women aged 25-65 years were proposed to have one Pap smear every 3 years. The objective was to assess cervical morbidity in Alsace before the human papillomavirus vaccinated population reaches the age of screening. Data on cervical lesions and cancers were collected by EVE for the period September 2008 to August 2011 from existing medical services and cytopathology laboratories in Alsace. Cytological and histological data were completed with data from the two cancer registries covering the region (Bas-Rhin and Haut-Rhin). Cancer incidence rates were computed for the target population (truncated to 25-64 years) and were age standardized according to the world reference population. World standardized incidence rates for the whole female population were obtained from the two cancer registries. During 2008-2011, 565 153 smears were performed in 498 913 women aged 25-64 years, representing an average of 1.13 smears/woman and 1.62 smears/screened woman. The overall screening coverage was 70.1% over the 3-year period. Histologically confirmed high-grade lesions were found in 2303 women (0.5%). Moreover, 215 cervical cancers were reported among women aged 25-64 years (crude and standardized truncated incidence rate of 10.6 and 10.0/100 000 women-years, respectively). The overall screening coverage of 70% at 3 years is higher than the national rate (57%), and the overall cancer incidence of 5.5/100 000 is below the national French level. The EVE database will be useful to assess trends in cervical morbidity over time and to further assess the effect of screening as well as of human papillomavirus vaccination.

Excess cervical cancer screening smears: Any benefit? A retrospective cohort in Alsace, France.

Objectives Although cervical cancer screening guidelines in France recommend a smear test every three years, many physicians order more regular screening. We aimed to assess the benefits or harms of shorter intervals between screenings, both for women and public health. Methods For a retrospective cohort of women aged 25-65 who had two normal smears and at least one additional smear, data were sourced from a regionally organized cervical cancer screening programme in France, with follow-up for nine years. Based on the interval between the second and third smear, two groups were formed; the first comprised overscreened women (interval <24 months), and the second of 'correctly' screened women (interval between 24 and 42 months). The primary outcome was cervical intraepithelial neoplasia 2 or worse (CIN2+); secondary outcomes were cervical cancers and CIN1 lesions. Results Among 63,821 women, CIN2+ incidence rate per 10,000 women per year was 14.5 for 40,350 overscreened women, and 11.5 for 23,471 correctly screened women. Age-adjusted relative risk was 1.22[1.02; 1.46]. We found no significant difference for cancer (RR = 1.39; 95%CI = [0.60; 3.61]), but did find additional CIN1 in the overscreened group (RR = 2.09; 95%CI = [1.76; 2.51]). Conclusions A shorter interval between smears has a low benefit for CIN2+ lesion detection, which may not help avoid cancer. The excess number of CIN1 detected by overscreening may cause needless risk and excess costs due to overtreatment.

Reporting reactive cellular changes on smears among women who undergo cervical cancer screening: results of a cohort study after seven years of follow-up.

OBJECTIVE: To identify whether women presenting with reactive cellular changes (RCC) on their cervical smear face an increased risk for developing high grade cervical intraepithelial neoplasia (CIN2-3) or cancer as compared with women with an entirely normal smear. STUDY DESIGN: French data from the association in charge of organized cervical cancer screening in Bas-Rhin administrative region were used to establish a cohort of 96,215 women presenting with a smear classified as entirely normal or with RCC during the year 2001. The Kaplan-Meyer method was used to calculate the probabilities of CIN2-3 and cancer at seven years of follow-up. Univariate and multivariate survival analyses were performed using Cox proportional hazard models. RESULTS: Among the 95,559 women included in the final analysis, 32.2% presented a smear with RCC. After seven years of follow-up, 441 women developed a CIN2-3 and 35 a cancer. Probability of CIN2-3 was increased in the RCC group as compared with the group of women with a normal smear (0.7% versus 0.5%, p=0.002). Multivariate analyses showed that, compared with a normal cervical smear, RCC were associated with a significant 37% increased risk of CIN2-3 (HR=1.37 CI95 [1.13-1.66]). However, the risk of cancer was not significantly increased (HR=1.11 CI95 [0.55-2.23]). CONCLUSION: This study showed that, at seven years, women with RCC on their cervical smear face an increased risk of CIN2-3 but no significant increased risk of cancer. The distinction between entirely normal and RCC cervical smears should therefore not lead to specific clinical management.

Long-term storage and safe retrieval of human papillomavirus DNA using FTA elute cards.

Biobanking or collection and storage of specimens for future research purposes have become an essential tool in many fields of biomedical research and aims to provide a better understanding of disease mechanisms as well as the identification of disease-specific biomarkers that can navigate in complex diseases. In this study, we assessed the use of Flinders Technology Associates (FTA) cards as a long-term storage device for cervical specimens with suspected human papillomavirus (HPV) infections. HPV detection and genotyping results in liquid-based transport media were compared to HPV results from FTA cards. The overall agreement for the presence of any HPV infection between liquid-based medium and FTA cards stored for 1 year at ambient temperature was 100%. Reproducibility analysis of HPV detection and genotyping from FTA cards demonstrated that FTA cards are a reliable medium to store and preserve viral nucleic acids. Biobanking of cervical cells on FTA cards may provide a key resource for epidemiological and retrospective HPV studies.

Reliability of Endocervical Curettage in the Diagnosis of High-grade Cervical Neoplasia and Cervical Cancer in Selected Patients.

AIM: To analyze the reliability of endocervical curettage (ECC) in the diagnosis of high-grade cervical intraepithelial neoplasia and cervical cancer, and to identify risk factors associated with diagnostic underestimation. MATERIALS AND METHODS: A retrospective study was carried-out involving 445 patients who underwent ECC for: endocervical lesion incompletely visible on colposcopy or inaccessible to biopsy; atypical glandular cells on smear, or discrepancy between colposcopic impression and cytological abnormalities. RESULTS: Comparison between ECC and final diagnosis showed a perfect match in 362 patients (81.3%). For 189 patients with pre-cancerous or cancerous endocervical lesions, the sensitivity, specificity, and positive and negative predictive values were 87.3%, 96.9%, 95.4% and 91.9%, respectively. No clinical, cytological or colposcopic characteristics were associated with significantly increased risk of diagnostic underestimation with ECC. CONCLUSION: ECC is a very reliable tool for reducing the number of unnecessary treatments, without increasing the risk of allowing some lesions to evolve into cancer.

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.

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.