Screening Triage and Risk Stratification

Cervix Cancer Clinical Trial

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Official title:

Improving Screening Triage in Older Postmenopausal HPV-screen-positive Women Aged 50-64 and Risk-stratification of Women Aged 23-64 After Excision

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT05727228
• Other study ID #: 2704
• Status: Recruiting
• Start date: February 27, 2023
• Est. completion date: February 2027

Study information

• Verified date: February 2023
• Source: University of Aarhus
• Contact: mette tranberg, post doc
• Phone: 40113676
• Email: mettrani[@]rm.dk
• Is FDA regulated: No
• Study type: Observational [Patient Registry]

Clinical Trial Summary

• To investigate the performance of cytology, extended genotyping, p16/Ki67 dual stain cytology, DNA methylation and viral load as triage markers in post-menopausal HPV-screen-positive women aged 50-64 years in the organized screening program to predict the risk of developing CIN2+. (work package 1)

• To investigate the performance of cytology, extended genotyping, p16/Ki67 dual stain cytology, DNA methylation and viral load six months after cervical excision to predict the long-term risk of residual/recurrent CIN2+ lesions among women aged 23-64 (work-package 2)

Description:

As HPV-positive women may have a transient infection which would be cleared with treatment, triage of HPV-positive women are needed to decrease the colposcopy referral. Liquid-based cytology (hereinafter cytology) are often used as triage for HPV-positive women. HPV 16/18 are the predominant HPV types in younger women and are for all aged referred directly for colposcopy. However as women age, hrHPV other types become more prevalent(10) and these types are triaged with cytology. However, as cytology undergo subjective interpretation and as it may have a decreased sensitivity in with increasing age(11, 12) cytology may not be the most optimal triage marker in postmenopausal women.

p16/Ki67 dual stain cytology (hereinafter DS) is another triage marker. p16 is a cell-cycle regulator protein and Ki67 is a proliferation-associated protein which under normal circumstances are mutual exclusive. Thus, in an HPV-transformed cell co-expression of p16 and Ki67 indicates cell deregulation and increased risk of cervical precancer.(13) In several studies DS have shown better sensitivity and negative predictive value (NPV) as compared to cytology in triaging HPV-positive women(14-17) and women with low-grade cytology (ASC-US and LSIL)(18-20).

Methylation of HPV-positive women benefits from a more objective evaluation than both cytology and DS and has in shown promising results in triaging HPV-positive women.(21) Most studies on DS and methylation have however, been conducted in younger women and studies evaluation the performance in postmenopausal women are needed.

Women diagnosed with CIN2+ undergo excisional treatment removing the lesions and thereby reducing the woman's risk of developing cervical cancer. The most frequently used method is loop electrosurgical excision procedure (LEEP). Despite treatment, women previously diagnosed with CIN3+ lesion are at greater risk of developing cervical cancer with the risk increasing with increasing age.(22) Surveillance after LEEP consist of test-of cure (i.e. cytology and HPV test) six months after LEEP in several countries.(23-27) Treatment of CIN2+ is however, not always successful and residual or recurrent high-grade disease (CIN2+) occurs on average in 8% (ranging from 4% to 18%) of treated women, with the majority of treatment failure occurring mainly the first two post-operative years.(28, 29) Persistent HPV infection and positive margins after LEEP are risk factors for residual or recurrent disease after LEEP(28). However, not all women are at the same risk of recurrent disease, but still managed the same way as women at higher risk and therefore a future risk-stratification are needed to individualize the follow-up pathways. Moreover, introduction of a risk-stratification in the follow-up pathway may also decrease the number of open-ended follow-up pathways. In a recent study in HPV-positive women 60-64 years only 26% had follow-up as recommended.(30)

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 5000
• Est. completion date: February 2027
• Est. primary completion date: February 2027
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Female
• Age group: 23 Years to 64 Years

Eligibility

Inclusion Criteria:

• HPV-screen-positive (aged 50-64)

• Women who undergo test-of-cure (i.e. HPV and cytology) six months after LEEP in Central Denmark Region (aged 23-64)

• Women who undergo follow-up test (i.e. HPV and cytology) 12 months after LEEP

• A valid cytology-triage result (aged 23-64)

Exclusion Criteria:

• Listed in the registry as a person who have rejected to participate in research

• Invalid cytology and HPV result six months after LEEP

• No residual material available

Related Conditions & MeSH terms

• Cervix Cancer
• HPV Testing
• Postmenopausal Women
• Uterine Cervical Neoplasms

Intervention

Other:
• cytology, p16/ki67 dual stain cytology (DS), extended genotyping, DNA methylation, viral load,
p16/Ki67 dual stain cytology, extended genotyping and DNA methylation will be performed from the residual cell-pellet from the HPV-positive screening samples. If no cytology-triage testing is performed as a part of the screening algorithm, a cytology will be performed at inclusion. If any residual material is left after DS, extended genotyping and DNA methylation, it will be stores at -80 degrees for future purposes.

Locations

Country	Name	City	State
Denmark	Department of Pathology	Randers	Central Denmark Region

Sponsors (2)

Lead Sponsor	Collaborator
University of Aarhus	Randers Regional Hospital

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The number of women with CIN2+ diagnosed in either cervical biopsies or cone biopsy	The detection of underlying CIN2 or worse	at baseline ( within 3 months after index sample)
Primary	The number of women with CIN2+ diagnosed in either cervical biopsies or cone biopsy	The detection of underlying CIN2 or worse	at follow-up ( 1.5 years after index sample)
Primary	The number of women with CIN3+ diagnosed in either cervical biopsies or cone biopsy	The detection of underlying CIN3 or worse	at baseline ( within 3 months after index sample)
Primary	The number of women with CIN3+ diagnosed in either cervical biopsies or cone biopsy	The detection of underlying CIN3 or worse	at follow-up (1.5 years after index sample)
Secondary	Clinical accuracy (sensitivity and specificity of each triage marker and in different combinations)	sensitivity to detect underlying CIN2+ and specificity to exclude underlying CIN2+	at baseline (within 3 months after index sample)
Secondary	Clinical accuracy (sensitivity and specificity of each triage marker and in different combinations)	sensitivity to detect underlying CIN2+ and specificity to exclude underlying CIN2+	at follow-up (1.5 years after index sample)
Secondary	HPV genotype distribution	We will measure the distribution of hrHPV types among these older women	at baseline (within 3 months after index sample)
Secondary	DS positivity rate	We will measure the DS positivity rate among these older women	at baseline (within 3 months after index sample)