Clinical trial NCT01837693: Cervical Cancer Prevention: From DNA to mRNA? - New Technologies for Cervical Cancer Screening 2
Official title: HPV as Primary Screening Test in Cervical Cancer Prevention: From DNA to mRNA? A Randomised Controlled Trial Nested in a Double Testing Study With Long Term Follow up
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Precancerous Conditions
Neoplasms
Keywords: cervical cancer screening
CIN
cervical cancer
biomarkers
sensitivity and specificity
Lead sponsor: Azienda USL Reggio Emilia - IRCCS
Sponsor class: OTHER_GOV
First posted: 2013-04-23
Enrollment: 60000
Sex: FEMALE
Minimum age (years): 25
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: SCREENING

Brief summary: In industrialized countries, cervical cancer is a well controlled disease thanks to the diffusion of Pap test and, in particular, to organized screening programs, which are able to detect and treat pre-invasive lesions (cervical intraepithelial neoplasia, CIN). The human papilloma virus (HPV) has been recognised as the necessary, but not sufficient, cause of cervical cancer, so a new screening test based on the identification of high risk (HR) HPV types has been developed(HPV DNA test). This test has demonstrated to be more effective than cytology in reducing the incidence and the mortality of cervical cancer, but it is less specific, so the use of a test triage is necessary to reduce the number of colposcopies and the risk of over-diagnosis (due to the potential regressivity of pre-invasive lesions). Until now, the triage test used is the cytology (Pap test).

Recently specific biomarkers (mRNA and p16 tests) have been introduced for high grade CIN, targeting the molecular alterations strictly associated to transformation rather than simply detecting HR-HPV infections. These tests are more specific than HPV DNA test with a modest reduction of sensitivity for high-grade lesions.

This is a multicenter randomised trial nested into some Italian screening programs based on the use of HPV DNA test as primary test.

All women with positive HPV DNA test will be tested for cytology and also for mRNA and p16. Women with positive cytology will be referred to colposcopy, while women with negative cytology will be randomized into two arms.

This study aims to evaluate if mRNA and p16 could be used as test of triage of HPV DNA or as a primary screening test with direct sending in colposcopy.

In particular the main objectives are:

* Measuring the cumulative detection rate of CIN2+ in the five years following a HPV DNA positive test and mRNA or p16 negative.
* Measuring the potential reduction of overdiagnosis of using mRNA or p16 test instead of DNA, with direct sending in colposcopy
* Measuring the reduction of overdiagnosis of cytological triage or triage with mRNA or p16 compared to the direct sending in colposcopy in women with HPV DNA test positive.

Secondary objectives are:

* to assess the feasibility of mRNA testing in primary screening
* to validate the sample techniques for the new tests
* to standardize quality controls for the the new tests

Detailed description: Individual data about the following study steps are collected according a fixed format:

1. recruited women
2. HPV DNA result
3. cytology and randomization results
4. p16 result
5. mRNA result
6. colposcopies (with relative cytology and histologies) results
7. Women excluded after informed consent
8. Interventions During the first year of recruitment, there will be two semi-annual sending of data, then each year.

To analyze the study progress in each center, summary tables will periodically send to the PI.

All CIN lesions and cancers found in the study will be be blindly reviewed. A set of quality assurance procedures will be implemented for both the molecular tests, including the use of controls provided by the manufacturers with known HPV DNA or mRNA content and the circulation of clinical samples prepared by the laboratories participating in the study.

Eligibility criteria: Inclusion Criteria:

* women invited for a new screening round based on HPV DNA test

Exclusion Criteria:

* women not resident in the screening area, or pregnant, or with treated CIN in the 5 previous years, or in post-colposcopy follow up, or in repetition for unsatisfactory cytology.

Primary outcomes:
measure: cumulative incidence of CIN2+ in women with positive DNA and negative mRNA or p16
timeFrame: 5 years
Secondary outcomes:
measure: comparison between CIN2+ detection rates in the two arms in women with p16 or mRNA negative
timeFrame: 1 year
measure: comparison between CIN2+ detection rates in the two arms in women with negative cytology
timeFrame: 1 year
measure: comparison between CIN2+ detection rate in the two arms in women with p16 or mRNA positive
timeFrame: 1 year
Other outcomes:
Locations:
city: Este
country: Italy
facility: Unità Locale Socio-Sanitaria 17 Este Monselice
city: Florence
country: Italy
facility: Istituto per lo Studio e la Prevenzione Oncologica
city: L'Aquila
country: Italy
facility: Azienda Sanitaria Locale 1-L'Aquila
city: Padua
country: Italy
facility: Istituto Oncologico Veneto
city: Perugia
country: Italy
facility: Azienda Sanitaria Locale 2- Regione Umbria
city: Reggio Emilia
country: Italy
facility: Azienda Sanitaria Locale Reggio Emilia
city: Rome
country: Italy
facility: Laziosanità - Agenzia di Sanità Pubblica della Regione Lazio
city: Rome
country: Italy
facility: Regina Elena Cancer Institute
city: Tivoli
country: Italy
facility: Azienda Sanitaria Locale Roma G
city: Trento
country: Italy
facility: Azienda Sanitaria della Provincia Autonoma di Trento
city: Turin
country: Italy
facility: Centro per la Prevenzione Oncologica del Piemonte
Study officials:
affiliation: Epidemiology Service, Local Health Authority of Reggio Emilia, Italy
name: Paolo Giorgi Rossi, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Benevolo M, Mancuso P, Allia E, Gustinucci D, Bulletti S, Cesarini E, Carozzi FM, Confortini M, Bisanzi S, Rubino T, Rollo F, Marchi N, Farruggio A, Pusiol T, Venturelli F, Giorgi Rossi P; New Technologies for Cervical Cancer 2 (NTCC2) Working Group. Determinants of p16/Ki-67 adequacy and positivity in HPV-positive women from a screening population. Cancer Cytopathol. 2021 May;129(5):383-393. doi: 10.1002/cncy.22385. Epub 2020 Nov 3.