RATIONALE: A persistent high risk Human Papilloma Virus (hrHPV) infection can cause
(pre)malignant anogenital lesions of the cervix, vulva or vagina. Cervical high grade
squamous intraepithelial lesions (cHSIL) have a malignant potential and require adequate
therapy. The natural history of cHSIL is unpredictable: ~25% of cHSIL will regress, while 18%
will progress to invasive cervical cancer. The standard treatment of histologically confirmed
cHSIL is surgical excision by large loop excision of the transformation zone (LLETZ), with
potential complications, such as hemorrhage, infection and an increased risk of preterm birth
in subsequent pregnancies. Imiquimod cream has been studied as a non-invasive treatment
alternative and the recent TOPIC-3 trial for cHSIL a complete response rate of 55% upon
imiquimod therapy was reported. Imiquimod is now considered as a standard non-surgical
therapy for patients with cHSIL in the Netherlands, especially in those patients with a
future pregnancy wish. Side-effects of imiquimod therapy however are common and can be
extensive, consisting mostly of local inflammation and burning, but also systemic adverse
events such as headache and flu-like symptoms. Therapy adherence is challenging with up to
20% discontinuation of treatment due to the side effects and the 16 week treatment duration.
As such, biomarkers which can predict response to imiquimod therapy are warranted, to
increase therapy efficacy and to avoid side effects in patients who will not respond. Our
previous work shows that clinical response to imiquimod in cHSIL is associated with a
coordinated pre-existing type 1 T cell- and inflammatory myeloid cell infiltration and
provided the first set of parameters that potentially can function together as a predictive
biomarker CIBI (CHSIL Immune Biomarker for Imiquimod).
OBJECTIVE: This study aims to validate the potential of immune related biomarkers to predict
the clinical response of patients with primary cHSIL to imiquimod and aims to explore the
value of these immune biomarkers in recurrent/residual cHSIL to predict treatment responses
for imiquimod and aims to explore their potential in spontaneous regression of cHSIL (CIN2).
STUDY DESIGN: Multicenter, real-life prospective cohort validation study.
STUDY POPULATION: We aim to include 316 women with a primary histological diagnosis of cHSIL,
50 patients with residual/recurrent histological diagnosis of cHSIL treated with imiquimod
and 50 patients with cHSIL (e.g. CIN 2) not treated to await potential spontaneous regression
according to the real life setting.
INTERVENTION: Patients are included in the study if they prefer imiquimod treatment, as
standard care, for their cHSIL lesion or choose for expectative management of cHSIL (e.g.
CIN2), according to the real-life clinical setting in the Netherlands. Patients are treated
by a 16-week regime of imiquimod 5% cream, applied three times a week. Treatment efficacy
will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies, and at 6 months
after completion of imiquimod therapy with cytology or if indicated histology. At inclusion,
at 20 weeks and after 6 months a vaginal swab will be taken to evaluate the vaginal
microbiome. Therapy adherence and side effects will be registered.
PRIMARY STUDY OBJECTIVES:
Confirm the relationship between a complete clinical response to imiquimod and the
increased epithelial and stromal infiltration of CD4+ T cells, CD11c+ cells and/or
M1-like macrophages as well as the decreased infiltration with FoxP3+ Tregs in primary
cHSIL.
Validate the association of CIBI to a complete response to imiquimod treatment in
primary cHSIL.
Determine the sensitivity and specificity of CIBI in patients with primary cHSIL lesions
to estimate the predictive value for therapy efficacy upon imiquimod treatment.
SECONDARY STUDY OBJECTIVES:
Explore the CIBI as a predictive biomarker for therapy efficacy to imiquimod treatment
in patients with residual/recurrent cHSIL (rrcHSIL).
Explore the CIBI as a predictive biomarker for spontaneous regression of cHSIL (e.g.
CIN2).
Determine the vaginal microbiome in cHSIL patients treated with imiquimod or not treated
to explore the potential interaction of the vaginal microbiome and composition of immune
infiltrates in relation to imiquimod treatment and the relation to spontaneous
regression.
NATURE AND EXTENT OF THE BURDEN AND RISKS ASSOCIATED WITH PARTICIPATION, BENEFIT AND GROUP
RELATEDNESS: The burden associated with participation to this study is minimal since patients
are included in accordance to real-life selection. If patients prefer imiquimod treatment for
the therapy for their cHSIL lesion after consultation with the gynecologist they will be
treated following a standard protocol, following the national guideline for cHSIL (CIN, AIS
en VAIN.pdf). The burden for patients to participate in the study lies in an extra biopsy
taken at colposcopy at 20 weeks and taking vaginal cultures for microbiome analysis. The
benefit for the patients lies in extra support via telephonic consultation and close
monitoring. For the patients in the observational arm with no treatment, no extra
examinations will be performed according to the national guideline for cHSIL, only data and
tissue will be used and two vaginal swabs taken. For the study cohort the benefit is limited
but if we are able to identify a clinical predictive biomarker for spontaneous regression or
imiquimod in cHSIL, this may increase therapy efficacy for future cHSIL patients by patient
selection preventing unnecessary imiquimod therapy.