Projects / Programmes source: ARIS

Pilot project on acceptability and quality of HPV self sampling in non-responders to National Cervical Cancer Screening Programme NP ZORA

Research activity

Code Science Field Subfield
3.08.00  Medical sciences  Public health (occupational safety)   

Code Science Field
B680  Biomedical sciences  Public health, epidemiology 

Code Science Field
3.03  Medical and Health Sciences  Health sciences 
cervical cancer, organised population based screening programme, non-responders, self-sampling, HPV test
Evaluation (rules)
source: COBISS
Researchers (24)
no. Code Name and surname Research area Role Period No. of publicationsNo. of publications
1.  14114  PhD Darja Arko  Oncology  Researcher  2015 - 2016  319 
2.  17170  Sonja Bebar  Oncology  Researcher  2013 - 2016  123 
3.  20050  PhD Barbara Gazič  Oncology  Researcher  2014 - 2016  171 
4.  32509  Kristina Gornik Kramberger  Oncology  Researcher  2015 - 2016  42 
5.  37822  Simona Hutter Čelik  Oncology  Researcher  2015 - 2016  20 
6.  32519  PhD Urška Ivanuš  Oncology  Researcher  2013 - 2016  285 
7.  36525  PhD Katja Jarm  Oncology  Researcher  2013 - 2016  118 
8.  10772  PhD Rajko Kavalar  Oncology  Researcher  2015 - 2016  248 
9.  15076  PhD Veronika Kloboves-Prevodnik  Oncology  Researcher  2014 - 2016  273 
10.  32529  MSc Jakob Koren  Oncology  Researcher  2013 - 2016  31 
11.  15712  Martina Kos  Public health (occupational safety)  Technical associate  2013 - 2016  39 
12.  27594  PhD Mateja Krajc  Medical sciences  Researcher  2013 - 2016  352 
13.  15394  MSc Slavica Lahajnar  Oncology  Researcher  2013 - 2016  131 
14.  23193  MSc Mateja Marčec  Human reproduction  Researcher  2013 - 2014  29 
15.  21548  PhD Nataša Nolde  Medical sciences  Researcher  2013 - 2016  57 
16.  08007  PhD Srdjan Novaković  Oncology  Researcher  2013 - 2016  475 
17.  29647  PhD Maja Pakiž  Human reproduction  Researcher  2013 - 2016  202 
18.  12199  PhD Živa Pohar Marinšek  Oncology  Researcher  2013 - 2016  143 
19.  04399  PhD Maja Primic-Žakelj  Oncology  Head  2013 - 2016  834 
20.  23551  PhD Alenka Repše Fokter  Metabolic and hormonal disorders  Researcher  2013 - 2016  229 
21.  32527  Uršula Salobir Gajšek  Oncology  Researcher  2013 - 2016  45 
22.  01324  PhD Iztok Takač  Human reproduction  Researcher  2013 - 2016  900 
23.  23050  PhD Vesna Zadnik  Public health (occupational safety)  Researcher  2013 - 2016  481 
24.  25531  PhD Tina Žagar  Oncology  Researcher  2013 - 2016  226 
Organisations (3)
no. Code Research organisation City Registration number No. of publicationsNo. of publications
1.  0302  Institute of Oncology Ljubljana  Ljubljana  5055733000  15,118 
2.  0334  University Medical Centre Maribor  Maribor  5054150000  23,031 
3.  1187  General hospital Celje  Celje  5064716  2,839 
Cervical cancer is one of few cancers that can be prevented by early detection and treatment of precancerous lesions. In 2003, the Council of the European Union issued recommendations for the introduction of population-based organized cancer screening programs and defined the conditions that have to be fulfilled for their implementation. Slovenian national cervical cancer screening programme ZORA (NP ZORA) is running in accordance with these recommendations since 2003. In the first five years we have already achieved the targeted three-year coverage (70 %), while the incidence of cervical cancer decreased by more than a third. Despite the recall system, over a quarter of women do not attend for screening (non-responders). More than half of the new cervical cancer cases occur in this group of women, most in advanced stages and difficult to cure, so the exploration of innovative methods to increase the coverage is becoming the leading challenge within the organized screening programmes in Europe. According to the results of studies from abroad, the most effective method is self-sampling for the detection of infection with high-risk Human papillomavirus (HPV test) at home.   The main goal of the proposed project is to improve the quality of the NP ZORA so that the incidence of cervical cancer continues to decline, mainly due to increase in coverage of women who previously did not attend the screening programme. It is reasonably to expect the reduction of cervical cancer treatment costs as well as costs of premature death.   Specific objectives of the project are: To test the new screening method (self-sampling HPV test at home) in the representative sample of Slovenian non-responders with a randomised intervention trial. This study, performed for the first time in Slovenia, will assess whether the method is acceptable and effective enough for alternative screening of Slovenian non-responders. To assess the added value of selected biomarkers (P16INK4a in Ki-67, DNA methylation) in the triage of woman with a positive HPV test result in screening. To compare two self-sampling devices to assess, which one is more acceptable for Slovenian women and yields more cervical precancerous lesions and cancer (CIN2+). One of the key outcomes of the project will be »Recommendations for the upgrade of NP ZORA«, with assessment of the impact that the implementation of the new method would have on the coverage of the target population and the incidence of cervical cancer in Slovenia. We will propose the update of the existing clinical pathway of NP ZORA and gather data for cost-effectiveness analysis. The new method is interesting also because it enables screening at home, which (despite increased coverage of the target population) will not increase the burden of screening visits at already overcrowded gynaecology clinics, where regular screening examinations are preformed. Second key outcome of the project will be »Guidelines for triage of screen detected HPV-positive women«, which will represent key guidelines for triage in case NP ZORA will be upgraded with the new method. Today, no recommendations exists regarding the alternative screening of non-responders, mainly due to the lack of comparable data from well-organized, population based screening programs (also Slovenian). Key Slovenian and foreign experts who are participating in the preparation of Slovenian and European guidelines are involved in the project. Our research methodology is comparable to international studies, so that Slovenian data might be included in meta-analyses (a) to assess the effectiveness of new methods for screening of non-responders, (b) to assess the optimal triage of HPV-positive women and the added value of new methods (immunostaining and DNA methylation) and (c) for comparison between different self-sampling devices.
Significance for science
The results of our study have demonstrated, that the response rate to HPV self-sampling at home was high in both intervention arms and significantly higher than in the comparison arm. We have also found that the response rate may be associated with the type of tester and that the new test p16/Ki-67 is quite easy to implement in cytology laboratories participating in NP ZORA with excellent results. The main scientific findings are the following: • According to our knowledge we have conducted the first randomised controlled trial where different testers for self-sampling were compared. Our results show that the type of the tester might be significantly associated with the response rate, which until now was not known. One tester had significantly lower response rate (33%) than others (39% and 40%). This finding has scientific as well as applicative value. When upgrading the screening programme with HPV self-sampling at home one aims to achieve as high response rate as possible to improve coverage with a screening test in the target population in order to achieve additional reduction of cervical cancer incidence. • Our study is one of the few randomised controlled trials in which opt-in (woman receives tester if she orders it) and opt-out (women receives tester without ordering it, but she can inform us if she doesn't want to receive it) approach was compared. In first opt-in studies the response rate was much lower than in opt-out approach and comparable to comparison arm. However, our results were different, since we have managed to achieve good response rate in opt-in and opt-out approach (34% and 38%), significantly higher than in comparison arm (18 %). We assume that a comparable response in both approaches is due to the choice offered to women weather to order a tester for HPV test at home or to attend a gynaecologist for a PAP test. About half of women who responded had performed HPV test at home and half attended a gynaecologist. This is an important finding, because 4-times less testers are sent with opt-in compared to opt-out approach- also the response rate after the tester is already sent is 2,5-times higher with opt-in approach. This significantly reduces the number of tester loss and costs if opt-in approach is implemented in the organised screening programme compared to opt-out approach. • There are just a few published reports about the process of the implementation of test p16/Ki-67 within the experienced cytology laboratories that participate in the national cervical cancer screening. We have evaluated different steps in the process of learning with the aim to identify the optimal learning approach that yields best results in shortest time. Test p16/Ki-67 had higher inter-laboratoriy agreement than test PAP and higher sesnitivity for HSIL+ at same specificity. • New scientific findings will be published also as three PhD articles of three researchers participating in the project: Urska Ivanuš from OIL, Urska Salobir Gajšek from Hospital General Celje and Mateja Marcec from Hospital General Ptuj (formerly UCC Maribor).
Significance for the country
The project is important for Slovenia in several aspects: • During the project protocols for HPV self-sampling were prepared, tested and optimised for the first time in Slovenia. The management and coordination centre of National cervical cancer screening programme ZORA at the Institute of Oncology Ljubljana got valuable experience with this new approach of screening. The information system for the support of self-sampling protocols was set and we also gain the first information about how Slovenian non-responders to regular screening programme respond, if they have an option for self-sampling at home. These experiences and results are very important for further development of national screening programme in Slovenia. Upgrading the screening policy with HPV test at home for non-responders could contribute to higher coverage of the target population with a screening test, which would lead to further decrease in the incidence of cervical cancer. • During the project the new technology for dual immunostaining of cervical smears with p16/Ki-67 was implemented and tested for the first time in Slovenia. We also managed to train all cytologists and cytotechnicians form 3 out of 9 cytology laboratories that participate in NP ZORA to evaluate smears stained with the new method. With this process we have not only gained valuable experience and knowledge about the new method but also the first results regarding its effectiveness in a population of Slovenian women; both effects are important for further development of NP ZORA. • Blinded revision of PAP smears and cervical histology was performed for the first time in Slovenia and results were compared between the three cytology and three pathology laboratories that participate in NP ZORA. We gained important insight in the quality of work of the laboratories that participate in NP ZORA that will be used in further educational training for the professionals. • High number of non-responders that were included in the randomised controlled trial and high response rate led to detection of 82 high-grade precancerous lesions (HSIL) in prior non-responders. With early detection and treatment of precancerous lesion cervical cancer was prevented. Due to the good results of this project we have decided to include test HPV at home for non-responders as well as new method for the triage of HPV-positive women with p16/Ki-67 test in the Project of NP ZORA screening policy renewal, which is recommended by new European guidelines for quality assurance in cervical cancer screening from 2015. Renewal of the screening policy was one of NP ZORA's key objectives in the National cancer control program for the period 2017-2021. We intend to submit a proposal for screening policy change to Health Council at Ministry of Health by 2021. We expect that implementation of these new methods into NP ZORA will increase the coverage of the target population with a screening test and will lead to further reduction of the incidence of cervical cancer in Slovenia.
Most important scientific results Annual report 2014, 2015, final report
Most important socioeconomically and culturally relevant results Annual report 2014, 2015, final report
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