Clinical Trial Details
— Status: Not yet recruiting
Administrative data
NCT number |
NCT05283421 |
Other study ID # |
1-23-456 |
Secondary ID |
|
Status |
Not yet recruiting |
Phase |
N/A
|
First received |
|
Last updated |
|
Start date |
December 1, 2022 |
Est. completion date |
March 1, 2025 |
Study information
Verified date |
February 2022 |
Source |
University of Aarhus |
Contact |
Vibe M Bertelsen, MD, PhD student |
Phone |
+4578421069 |
Email |
vibebert[@]rm.dk |
Is FDA regulated |
No |
Health authority |
|
Study type |
Interventional
|
Clinical Trial Summary
Cervical cancer is the fourth most common cancer in women worldwide. It is caused by an
infection with human papillomavirus (HPV). A persistent infection with HPV is associated with
increased risk of precancerous lesions, which may further develop into cervical cancer. To
reduce the disease burden, accurate and timely diagnosis of cervical precancerous lesions are
crucial.
To identify cervical precancerous lesions, women are referred to colposcopy, which is the
most important diagnostic tools to detect cervical precancerous lesions. It allows close
visualization of the cervix in order to collect biopsies in the area called transformation
zone (TZ), which is where precancerous lesions develop. It is essential for the physician to
identify the TZ during colposcopy in order to obtain correct diagnosis. For women aged ≥50
this is often a challenge as TZ naturally with age, will retract further into the cervical
canal, making the area for sampling invisible, and thereby the colposcopy inadequate.
Consequently, this increases the risk of developing cancer due to diagnostic delay, and the
risk of several colposcopy examinations or overtreatment (cone biopsy), before a final
diagnosis is achieved.
Few studies suggest that pretreatment with local vaginal estrogen prior to colposcopy may
improve visualization of the TZ. Thereby, obtaining more accurate biopsies from the cervix,
and thus making a more accurate and timely diagnosis in the first outpatient visit.
The primary purpose of this study is to evaluate pre-diagnostic treatment with estrogen to
improve the diagnosis of women with cervical precancerous lesions, in order to prevent
cervical cancer.
The study ia s randomized controlled double-blinded multicenter study. The investigators will
use information from Danish National Patient registry, and data from the Danish Pathology
Data Bank. Enrollment will take place at the Departments of Gynecology in Denmark. Eligible
women aged ≥ 50 years will be randomized 1:1 to receive local vaginal estrogen or placebo
prior to the colposcopic examination.
The investigators believe the results will provide the prerequisite for obtaining correct
diagnosis, and thereby provide basis for choosing the right individualized examination- and
treatment plan. The results will also contribute with important knowledge, that may help
reduce the incidence and mortality rate of cervical cancer.
Description:
Cervical cancer is the fourth most common cancer in women worldwide, and comprises
approximately 7% of all new cancers in women. To reduce the disease burden, accurate and
timely diagnosis of cervical precancerous lesions are crucial.
Aim:
The aim of this study is to evaluate whether optimizing present procedures can improve
diagnosis of precancerous cervical lesions.
The study aims to:
1. Initiate a double-blinded study to investigate, if the diagnosis of cervical precancerous
lesions can be improved among elderly women aged ≥ 50 years, by providing pretreatment with
vaginal estrogen prior to the colposcopic examination.
Background:
In Denmark, about 400 women are diagnosed with cervical cancer annually, and around 15.000
women are diagnosed and treated with cervical precancerous lesions. Cervical cancer is
preventable through HPV vaccination and screening, yet the incidence rates have stagnated.
Cervical cancer is caused by an infection with a high-risk human papillomavirus (HPV), which
is a common sexually transmitted disease, with a life-time risk of >80%. In 10-15% of the
infected women, the infection becomes persistent, and may cause precancerous lesions
(Cervical Intraepithelial Neoplasia, CIN). CIN is graded according to severity (CIN1, CIN2,
and CIN3), and can progress and develop into cancer if left untreated. The classification of
CIN dictates the treatment course, and surgical treatment (cone biopsy) is recommended in
most cases of CIN2 or worse (CIN2+). To identify precancerous lesions, all 23-64-year-old
women in Denmark are invited for screening with a cervical cytology sample or an HPV test
every third or five years. The cervical cytology sample is classified as mild (low-grade
squamous intraepithelial lesion, LSIL) or moderate to severe (high-grade squamous
intraepithelial lesion, HSIL). ASCUS is a term used to describe atypical cervical squamous
cells of undetermined significance. An abnormal screening sample results in a referral for
further examination by colposcopy. It allows close visualization of the cervix in order to
detect suspicious lesions, and collection of cervical biopsies.
Diagnostic of cervical precancerous lesions:
Colposcopy is the most important diagnostic tools to detect cervical precancerous lesions and
thereby prevention of cervical cancer. The area on the cervix where precancerous lesions and
cancer develops is called the transformation zone (TZ), and the squamocolumnar junction (SCJ)
refers to the internal margin of the TZ. The TZ is classified as type 1, 2 or 3 according to
the visibility of all or part of the upper limit of the SCJ, that is either found completely
visible (TZ1), partly visible (TZ2) or not visible (TZ3). To perform optimal examination and
obtain a correct diagnosis, it is essential for the physician to identify the TZ. However,
the colposcopy procedure may be challenging and performs poorly, especially among elderly
women due to natural age-related changes of the cervix. After menopause, the TZ will retract
into the cervical canal, which makes visualization of the SCJ and TZ difficult, rendering the
colposcopy examination inadequate. Previous studies revealed inadequate colposcopy in up to
30-97%, increasing with age. Consequently, this increases the risk of developing cancer due
to diagnostic delay, but also the risk of undergoing several colposcopy examinations or
overtreatment by a cone biopsy (thereby also the risks related to surgery), causing adverse
psychological outcomes, before a final diagnosis is achieved. Evidence-based practice is
lacking on how, especially elderly women should be examined and followed-up in case of
inadequate colposcopic examinations. This is a noteworthy public health concern, as elderly
women are more likely to be diagnosed with advanced cervical cancer with higher mortality,
due to late prognosis and faster disease progression. Furthermore, this group of elderly
women is expected to increase in the future, due to the increasing female life expectancy,
and due to the extensions of the cervical cancer screening programs in some countries,
including Denmark.
Optimizing the colposcopic performance:
A few studies with limited sample sizes (ranging between 35 to 50 participants) suggested
that pretreatment with estrogen prior to colposcopy may improve visualization of TZ and
consequently improve diagnostics in elderly women. However, the quality of the previous
studies is far from adequate and comparable. Furthermore, apart from age, there is also no
risk factors described (e.g. previous dysplasia) with respect to the type of TZ as 1, 2 or 3.
Hypotheses for this study:
• Treatment with vaginal estrogen prior to colposcopy will improve the colposcopy performance
in women aged ≥ 50 years as compared to standard procedure which is no treatment.
Material and methods:
The study will be designed as a randomized controlled double-blinded multicenter study.
Enrollment will be performed at the Departments of Gynecology in Denmark (cities: Randers,
Herning, Horsens and Odense). Eligible women will be booked for colposcopy as usual. By using
the Danish National Patient registry, the investigators will be able to identify women
referred for colposcopy, and collect relevant patient data. This will be combined with data
from the nationwide Danish Pathology Data Bank, which will provide the histopathological
results of the biopsies. The colposcopic examination will be performed by nurses and
physicians who routinely perform colposcopies. Stata version 16 will be used for data
analysis, and data will be stored in the RedCap database. A study protocol will be prepared
in details. The report of the trial will conform to the CONSORT guidelines, and be reported
according to the STARD 2015 guidelines.
Eligible women will be randomized 1:1 prior to examination with either:
A) Pretreatment with vaginal application of estrogen 30 microgram once a day every night for
14 days.
B) Placebo with vaginal application without estrogen once a day every night for 14 days.
Study medication will be mailed to the women after receiving written and telephone informed
consent. The colposcopy examination will be performed according to current procedures and the
Danish national guidelines (DSOG). All biopsies will be collected in one tube for
histopathological evaluation. Patients will after examination be asked to score possible
discomfort experienced during the examination and possible side-effects of the pretreatment.
Statistical consideration:
Assuming that the TZ will be visible in 54% of women aged ≥ 50 years in the group receiving
placebo, and 81% in the estrogen pre-treatment group, the investigators will be able to
detect an improvement in visibility of TZ of 50% or above. This improvement estimate was
based on previous research, and also with reference to a clinically relevant threshold. Thus,
with a power of 90% and an alpha value of 5%, a sample size of 62 women in each group will be
required. To allow for a protocol violation of 20%, 75 women will be included in each group.
After enrollment of approximately 30 women in each group, an inter-rim analysis will be
performed.
Feasibility and ethics:
The chosen gynecological departments receive a large number of referrals for this patient
group, which will ensure a large enrollment. The study will be reported to the Danish Data
Protection Agency, the Central Denmark Region Committee on Biomedical Research Ethics and The
Danish Health Authority (Danish Medicine Agency), and also registered as a clinical trial
(www.clinicaltrials.gov). The GCP unit will supervise the project. Project information will
be given to the women orally and written, and they must understand Danish to accept given
information before participation. All information will be anonymized prior to analysis.
Participation in the study will not have any consequence for the treatment of the women. The
dose of estrogen is within the well-known standard recommendation, with a minimum of side
effect. It is widely used and recommended by gynecologists to women aged ≥50 years.