Imiquimod is a good non-invasive treatment option for women with cervical high-grade squamous intraepithelial neoplasia (cHSIL), especially those with a possible (future) pregnancy wish. Complete response to imiquimod occurs in 55-73% of patients, however side-effects of imiquimod are common and can be extensive. Therefore, 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.
This prospective, multi-center cohort study aims to validate the potential of immune related biomarkers to predict the clinical response of patients with primary cHSIL to imiquimod, 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).
Primary cHSIL lesions (e.g. CIN3 or CIN 2), histologically confirmed by diagnostic biopsy Nota bene: In case of CIN 2, expectative management must be discussed according to the Dutch national guideline with the patient, if the patient prefers imiquimod therapy the patient can be treated with imiquimod and enrolled in the study, if the patient prefers expectative management they can be enrolled in the observational CIN 2 group.
Recurrent or residual cHSIL lesions after initial LLETZ treatment (e.g. CIN2 or CIN3), histologically confirmed by diagnostic biopsy
Age of 18 years or older
Concomitant diagnoses of VAIN (vaginal intraepithelial neoplasia e.g. vaginal HSIL)
PAP (Papanicolaou) 4 cytology as indication for the baseline colposcopy at study entrance
Adenocarcinoma in situ (AIS) diagnosis
Previous imiquimod therapy for cHSIL
Patients will be included in real-life outpatient clinic setting and treated according to standard Dutch therapy guidelines. We aim to enroll 310 patients with primary cHSIL and 50 patients with rrcHSIL treated with imiquimod and 50 cHSIL (CIN 2) patients not treated in the observational arm.
Cohort
Prospective
Imiquimod
DrugImiquimod 5% will be administered in the evening by either a vaginal applicator or administered on a vaginal tampon for three times a week during 16 weeks. Treatment efficacy will be evaluated after 20 weeks, by colposcopy with diagnostic biopsies, and at 6 months after completion of imiquimod therapy with cytology and if indicated histology.
3x vaginal swab for microbiome analysis
Diagnostic testA vaginal swab will be taken from all patients at inclusion (before start of imiquimod), at colposcopy 20 weeks after start of imiquimod and at 6 months after completion of imiquimod treatment during follow-up appointment.
Expectative management
Other interventionExpectative management of CIN 2 when preferred by the patient. Follow-up 6 months after baseline colposcopy with cytology and if indicated histology.
2x vaginal swab for microbiome analysis
Diagnostic testA vaginal swab will be taken from all patients at inclusion and at 6 months after inclusion during follow-up appointment.
Confirm association of 'hot signature' immune infiltrates in cHSIL with complete clinical responses to imiquimod
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 immune biomarker CIBI for imiquimod for predicting complete response in cHSIL
Defined as the sum of the numbers of either epithelial or stromal CD4+/CD11c+/M1+ cells per square millimeter minus the number of FoxP3+ cells per square millimeter, with a complete response to imiquimod treatment in primary cHSIL.
Determine the sensitivity and specificity of the CIBI in cHSIL
Determine the sensitivity and specificity of the CIBI in patients with primary cHSIL lesions to estimate the predictive value for therapy efficacy upon imiquimod treatment.
Explore the role of CIBI in therapy responses to imiquimod in rrcHSIL
Explore the CIBI as a predictive biomarker for therapy efficacy to imiquimod treatment in patients with residual/recurrent cHSIL (rrcHSIL).
Explore the role of CIBI in prediction of spontaneous regression of CIN 2
Explore the CIBI as a predictive biomarker for spontaneous regression of cHSIL (e.g. CIN2).
Determine treatment efficacy upon imiquimod therapy.
Treatment efficacy will be evaluated by determination of clinical responses at 20 weeks and at 6 months by either complete responder (CR), partial responder (PR), non-responder (NR) or progressive disease (PD) assessed by histology from biopsy and/or cytology from papsmear.
Determine therapy adherence upon imiquimod therapy.
Therapy adherence will be evaluated by patient reported use on the calendar by registrating the amount of imiquimod applications per week.
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Catharina Ziekenhuis Eindhoven
Lead sponsor
ZonMw: The Netherlands Organisation for Health Research and Development
Collaborator
Stichting Olijf: Dutch patient association for women with gynaecological cancer
Collaborator
Leids Universitair Medisch Centrum: Department of Medical Oncology and Department of Pathology
Collaborator
Maastricht Universitair Medisch Centrum: Department of Gynaecology and Department of Pathology
Collaborator
Erasmus Medisch Centrum: Department of Gynaecology
Collaborator
Radboud Medisch Centrum: Department of Gynaecology
Collaborator
