The Value of HPV DNA Testing Using Self-collected Sampling in Non Attendees Cervical Cancer Screening and Molecular Triage Strategies on Self-sampled Material for HPV Positive Women.

The study will be performed in the Tuscany Region including three organised screening programmes : Florence, Viareggio, and Carrara. In these areas, cervical screening programmes actively invite all the resident female population aged 34-64 years for HPV (Human Papilloma Virus) test as primary screening test (Florence and Viareggio), according to the new protocol for cervical cancer screening in Tuscany Region, or Pap-test every 3 years (Carrara). Women aged 34-64 years who had been invited by the screening programme in the previous round of screening and had failed to respond for at least 3 years will be eligible for mail recall.

In the 3 involved screening programs , every year about 63.000 in the age class 34-64 years are invited to participate at the screening program and about 40% of women do not responded to the invitation of the program. Out of them, 8000 eligible women consecutively selected from the lists will be randomised in two groups. The aim is to evaluate the response rate to invitation to a self obtained vaginal-cervical sample for hr-HPV infection testing in comparison to the standard written reminder letter. Randomisation will be performed centrally by the coordinating centre (ISPO) using computer generated random numbers. In the first year a random sample of 4000 eligible women from the 4 screening programs will be invited to participate in the study sending self sampling at home. In the control arm , the women will receive the usual recall with a new invitation letter with a prefixed appointment (it can be moved with a phone call) to perform HPV screening test in the local districts or clinic. In the intervention arm selected to receive self sampling at home, the investigators will allocate randomly the women to 2 different self sampling devices differing in having or not a preservative buffer.

So the group of women allocated in the intervention arm (4000) will be further randomized 1:1 for receiving S-wet or S-dry device .

Assuming that the compliance for the traditional method with an invitation letter is equal to 15% (Giorgi Rossi 2010), the present study is designed to be able to detect an absolute difference of 1.5% or greater in the attendance rate with a conventional levels of power (80%) and significance (95%, one side test) with a planned sample size of 8000 women. Assuming a sample size equal to 2000 women for each sampling devices, a significant difference equal to or greater than 4.0 percentage points more or less , considering a HPV positive rate of about 21% (Giorgi Rossi 2010) with same power and significance.

The study will be submitted , before starting, for approval to the Coordinating Center and Area Vasta Local Ethical Committees. Each women in the study groups will receive an alerting letter explaining that the local Public Screening Program would provide her with a box containing a self-sampler device completely free of charge to perform self- HPV screening test directly at home. After 1 week, each screening program involved in the study will ship by regular mail at home of the randomised women a letter of invitation to participate in the HPV screening program and a box with: self-sample sampling device, a HPV screening leaflet in use in Tuscany Region Program. Information related to the study, instructions to perform self-sampling, pre-printed labels to put on the tube, the informed consent form to sign , the questionnaire and a pre-stamped envelope to return the self-sampling kit. Questionnaires will be send with self-sampling device including items related to: date of women's latest Pap-test, questions about the self-sampling performance (pain, embarrassment, feasibility), what was mostly appreciated in the self-sampling (doing it by themselves, privacy, absence of a doctor, absence of speculum) and what they did not like regarding self-sampling (pain, the device, the instruction ). All information will be collected using 5-point ordinal scales on the general acceptability. Women that decide to participate in the study can send directly by regular mail to the local screening program the pre-stamped envelope with the self-sampling, the questionnaire and the signed informed consent (which will also include the authorization for telephone contact). In second year of study in the city of Florence the investigators will also evaluate the possibility to involve Drugstores in the distribution of self-sampling. In this case 500 randomised women will be invited by letter to perform self sampling for HPV screening test collecting the device in the drugstore. A list of drugstores which agreed to be included in the study will be available in the invitation letter. The impact on compliance and satisfaction of women will be evaluated. All HPV analysis and molecular tests will be performed in Molecular Laboratory of ISPO , the central lab for HPV screening test in Tuscany Region