Algorithm for Cervix Carcinoma Screening in CZ Using the Detection of HPV DNA and CINtec Plus

Study Overview
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Brief Summary
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Cervix carcinoma has been a serious, long-term issue in the Czech Republic. The cause of nearly all cervix carcinomas is human papilomavirus (HPV). Hence the detection of the HPV genome is a more prospective screening tool with higher sensitivity than a cytological swab. As shown by comparative studies, the sensitivity of the HPV DNA test in the detection of severe pre-cancer is 35% higher on average when compared to the cytological test. The study repeatedly determined the presence of the HPV genome, including the prevalence of selected HPV genotypes (16, 18 and other hrHPV) and conventional cytology. The relative sensitivity of the two methods was specified. In the course of the prospective follow-up, the incidence of pre-cancers and invasive tumours in the study population were specified.

Detailed Description
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Cervix carcinoma has been a serious, long-term issue in the Czech Republic. About 1,000 new cases are diagnosed every year and about 400 female patients die as a result of the disease. More than 20,000 women in the Czech Republic live with a history of cervix carcinoma therapy and the potential risk of its recurrence. Although the past years have been marked with effective organisational changes in cervix carcinoma screening thanks to which a decreasing trend of its incidence can be observed, there is a lack of substantial impact on the occurrence of advanced stages of the disease and mortality. Similar data have also been reported internationally: foreign authors analysed cases of patients with a malignant cervix tumour. They reported that 24 - 32% of females with a diagnosed malignant tumour had periodically undergone cytological screening. The reason is that the sensitivity of an individual cytological examination for detecting severe pre-cancer is limited, ranging between 40 - 75% and only increasing with repeated examinations. The negative predictive value of the cytological swab is additionally limited and reaches 0.78% in recent studies over a three-year screening interval. The cause of nearly all cervix carcinomas is human papilomavirus (HPV). Hence the detection of the HPV genome is a more prospective screening tool with higher sensitivity than a cytological swab. The sensitivity of the validated HPV DNA test using PCR method reaches 94.5% for detecting severe pre-cancer (confidence interval 94.2 - 96.9%). As shown by comparative studies, the sensitivity of the HPV DNA test for the detection of severe pre-cancer is 35% higher on average when compared to the cytological test. The HPV DNA test in addition shows a significantly better negative three-year predictive value (0.34%) and the low value continues for at least another five years. The lower specificity of the HPV DNA test can be compensated by selective genotype specification with proof of the most frequent oncogenic genotypes HPV 16 and HPV 18. This promising procedure, validated by large multicentric randomised studies and introduced to clinical practice in several European countries, primarily uses the detection of HPV DNA. The study repeatedly determined the presence of the HPV genome, including the prevalence of selected HPV genotypes (16, 18 and other hrHPV) and conventional cytology. The relative sensitivity of the two methods was specified. In the course of the prospective follow-up, the incidence of pre-cancers and invasive tumours in the study population were specified.

Official Title
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Algorithm for Cervix Carcinoma Screening in the Czech Republic Using the Detection of HPV DNA With Selective HPV 16/18 Genotype and Special CINtec Plus Cytological Colouring

Conditions
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Algorithm for Cervix Carcinoma Screening

Intervention / Treatment
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* Diagnostic Test: HPV DNA test with selective HPV 16/18 genotyping (cobas® 4800 HPV Test, Roche)
* Diagnostic Test: p16 and Ki-67 biomarker detection in the form of dual cytological staining (CINtec Plus, Roche)
* Diagnostic Test: standard conventional cytology PAP test


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Informed consent signature Age 30 - 60 Screening (not reviewing after previous abnormal cytological finding) Sampling of gravid women possible Exclusion Criteria: Refusal to take part

Ages Eligible for Study
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Minimum Age: 30 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Study Plan
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How is the study designed?
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Arms and Interventions

| Intervention/Treatment |
| --- |
|Diagnostic Test: HPV DNA test with selective HPV 16/18 genotyping (cobas® 4800 HPV Test, Roche)|The enrolled patients underwent standard conventional cytology plus a test for the detection of high-risk human papilomavirus (hrHPV) with selective genotype specification (HPV 16, 18 and other hrHPV) - combined screening. In defined cases of positive hrHPV, the patient underwent reflexive examination by CINtec plus technology. After the initial combined screening the patients continued in the standard Czech screening practice (annual conventional cytology) or be treated according to the particular finding of the initial episode. For three years, the incidence of pre-cancers and invasive cervix carcinomas were monitored and data were entered into an electronic register. The second combined screening episode followed in year 3. An evaluation of its results immediately followed.|
|Diagnostic Test: p16 and Ki-67 biomarker detection in the form of dual cytological staining (CINtec Plus, Roche)|The enrolled patients underwent standard conventional cytology plus a test for the detection of high-risk human papilomavirus (hrHPV) with selective genotype specification (HPV 16, 18 and other hrHPV) - combined screening. In defined cases of positive hrHPV, the patient underwent reflexive examination by CINtec plus technology. After the initial combined screening the patients continued in the standard Czech screening practice (annual conventional cytology) or be treated according to the particular finding of the initial episode. For three years, the incidence of pre-cancers and invasive cervix carcinomas were monitored and data were entered into an electronic register. The second combined screening episode followed in year 3. An evaluation of its results immediately followed.|
|Diagnostic Test: standard conventional cytology PAP test|The enrolled patients underwent standard conventional cytology plus a test for the detection of high-risk human papilomavirus (hrHPV) with selective genotype specification (HPV 16, 18 and other hrHPV) - combined screening. In defined cases of positive hrHPV, the patient underwent reflexive examination by CINtec plus technology. After the initial combined screening the patients continued in the standard Czech screening practice (annual conventional cytology) or be treated according to the particular finding of the initial episode. For three years, the incidence of pre-cancers and invasive cervix carcinomas were monitored and data were entered into an electronic register. The second combined screening episode followed in year 3. An evaluation of its results immediately followed.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prevalence of hrHPV positivity in the Czech population | The ratio of patients with a positive HPV test in the first combined screening episode and the number of examined women. | 49 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Specification of prevalence of selected hrHPV genotypes | Representation of individual hrHPV genotypes in the first and the second screening episode in all examined women and in all HPV positive women. | 49 months | 
| Detection level of pre-cancers and invasive carcinomas in the first combined screening episode (indicator of relative sensitivity of the two methods) | The ratio of detected diseases and the number of examined women in the first screening episode, a secondary endpoint. | 49 months | 
| Incidence of pre-cancers and invasive carcinomas in the course of the follow-up | The cumulative incidence of diseases considering the censored patients, a secondary endpoint. | 49 months | 
| Incidence of pre-cancers and invasive carcinomas after the second screening episode | The cumulative incidence of the disease in patients based on the initial HPV test results and initial cytology results. | 49 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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HPV DNA, LIBUSE, CINtec plus, cytology, cervix carcinoma, human papilomavirus