Pilot implementation REsearch for revision of screening policy in the NatiOnal cerVicAl cancer screening program ZORA (PRENOVA ZORA)

BASIC DATA OF THE RESEARCH PROJECT

• ARIS code: V3-2320
• TITLE: Pilot implementation REsearch for revision of screening policy in the NatiOnal cerVicAl

cancer screening program ZORA (PRENOVA ZORA)

• PRICE CLASS: F
• PROJECT LEADER: Assoc. Prof. Urška Ivanuš

• APPLICANT RESEARCH ORGANISATION: INSTITUTE OF ONCOLOGY LJUBLJANA
• PARTICIPATING RESEARCH ORGANISATIONS: Gynecological clinic of the UKC Ljubljana, Gynecological clinic of the UKC Maribor,  University of Ljubljana, Faculty of Mathematics and Physics
• DURATION: 1.10.2023 - 30.09.2026  
• FINANCING: Slovenian Research and Innovation Agency

Project Summary

The project was approved by the Slovenian Research and Innovation Agency, in the public tender for a selection of research projects under the Targeted Research Programmes 2023.

Funds: € 140,000

Funders:

• Ministry of Health of RS (MoH)
• Slovenian Research and Innovation Agency (ARIS)

Leading research organization:

• Institute of Oncology Ljubljana (IOL), with the ZORA Program as a leading coordinator (Urška Ivanuš)

Collaborating research organizations:

• Gynecologic Clinics at University Medical Centre Ljubljana (UMCL) (Špela Smrkolj)
• Gynecologic Clinics at University Medical Centre Maribor (UMCMB) (Maja Pakiž)
• Faculty of Mathematics and Physics (FMF) (Robert Jeraj)

Timeline: start at the end of 2023; duration of 3 years

Bases (starting points)

Although cervical cancer (CC) is the most preventable of all cancers, it remains the 4th most common cancer in women worldwide by incidence and the 3rd most common cancer by mortality. Slovenia was identified as one of the European countries with a high incidence of CC in the past years. Thanks to the effective early detection and treatment of precancerous changes through the National Cervical Cancer Screening Program ZORA (ZORA Program), it is now among the countries with the lowest incidence.

Identifying HPV infection as the primary cause of CC, new technologies for prevention and early detection of CC have been developed for both primary and secondary prevention, which include HPV vaccination and HPV testing, respectively. As of 2020, the World Health Organization (WHO) has actively advocated for the elimination of CC, and the European Commission included this goal in Europe's Beating Cancer Plan (EBCP) published in 2021. Furthermore, on December 9, 2022, the European Council's updated recommendations for CC screening programs were adopted, urging all countries to make significant changes in the CC screening policy. Switch from cytology-based to HPV screening was recommended - due to improved sensitivity, robustness and self-sampling.  In Slovenia, the EBCP is being implemented through the strategic goals of the National Cancer Control Program (NCCP) 2022–2026. NCCP includes also strategic goals of the ZORA programme: finishing the implementation study of HPV testing-based screening by the end of 2025, introducing liquid-based technology by the end of 2026, and limiting the opportunistic screening outside the organized program.

Project objectives and aims

The overall objective of the project is to update the screening policy of the ZORA Program in accordance with European recommendations and NCCP goals, thereby accelerating the elimination of CC in Slovenia and simultaneously improving the benefits and limiting harms of the screening.

In line with the project goals, our specific objectives are as follows:

1. To prepare clinical groundwork and an action plan for conducting the implementation (pilot) study under the ZORA Program.
2. To conduct the implementation (pilot) study.
3. To analyze data from the study together with the ZORA Registry data, including the quality of services, the expected impact of the revised screening policy on health services, and the disease burden.
4. To analyze the cost-effectiveness of the chosen screening strategies, encompassing both administrative and healthcare services, while identifying resource requirements, healthcare harms and benefits, and expenses of the new program compared to the current program.
5. To decide upon a new screening strategy and revise the existing ZORA Program Guidelines, in accordance with the instructions in the Rules on the Implementation of National Screening Programmes for Early Detection of Cancer and Premalignant Lesions (Official Gazette of the Republic of Slovenia, No. 57/18 and 68/19).
6. To prepare a draft of clinical guidelines and clinical pathway from the invitation, screening, triage, diagnostics, treatment and post-treatment follow-up.
7. Develop a protocol and action plan for the roll-out of the new screening policy at the national level.

Project description

1. Pilot study: Within ZORA program we will explore new screening and triage strategies for early detection of precancerous changes of the cervix. We will evaluate various screening and triage tests on liquid samples, such as (i) HPV tests without genotyping, with partial and complete genotyping, (ii) immunocytochemical staining of p16/Ki-67, and (iii) methylation assay.

2. Implementational study: Based on the results of the pilot study, we will conduct an implementation study to assess the harms and benefits of the novel screening methods and strategies. We will also prepare clinical, organizational, and legal frameworks for the modification of the ZORA Program screening policy. This will include resource assessment, cost-effectiveness analysis, and a plan for the integration of these innovations into the healthcare system at the national level.

3. Clinical Guidelines:

As part of the proposed project, we will update the existing ZORA Program's Clinical Guidelines for Gynaecology and Cytopathology:

• Clinical Guidelines of the ZORA Program for Gynaecologists: the clinical guidelines will include recommendations and algorithms for the management of women based on the results of screening and triage tests, as well as based on colposcopy and histopathological cervical reports. The current Guidelines for the comprehensive management of women with precancerous cervical changes were last updated in 2011 - when for the management of women with low-grade cervical changes, the triage test for HPV was implemented and we have completely switched using the Bethesda cytological classification for women. In this proposed project, we will comprehensively revise the guidelines, both in terms of screening and triage tests, and the management of women based on the results of these tests, as well as in terms of the management of women based on histopathology results. In the clinical guidelines, we will also introduce a new section for multidisciplinary consultations in line with the guidelines provided by the ZORA program.

• Clinical Guidelines of the ZORA Program for Cytopathology: they will contain clinical recommendations for processing and assessment of liquid-based cervical samples in cytopathology laboratories. The most recent revision of the Guidelines for Reporting of Cervical Cytology – Bethesda Classification, which was completed in 2022, did not incorporate clinical recommendations for liquid-based cytology. In the proposed project, we will revise the guidelines to make them suitable for diagnosing cytological specimens obtained from liquid samples, as well as for any other morphological assays.

4. ZORA Program Guidelines: The new screening strategy of the ZORA Program will be documented as Revised ZORA Program's Guidelines.

5. Protocol and action plan for the implementation of the new screening policy in Slovenia: we will finish the project with a detailed protocol and an action plan for the implementation of new screening policy at the national level.