Page 170 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 9a
treatment is compared to standard treatment by LLETZ. The trial was designed according to the CONSORT guidelines.
Methods
Setting and study population
The study will be started at the outpatient clinic of gynecologic oncology, Maastricht University Medical Center, the Netherlands and is intended as a multi-center trial in the future. Inclusion criteria are newly diagnosed, histologically confirmed high-grade CIN lesions (CIN 2-3) and age above 18 years. Exclusion criteria are previous histologically confirmed high-grade CIN (CIN 2-3), concomitant vulvar and/or vaginal intraepithelial neoplasia, previous cervical malignancy, current malignant disease, immunodeficiency (including HIV/AIDS and immunodepressive medication), pregnancy or lactation and legal incapability.
Study objectives and outcome measures
The primary study objectives and outcome measures are:
1. Assessment of treatment efficacy of imiquimod treatment for high-grade CIN, as compared
to LLETZ treatment. Successful treatment for the experimental (imiquimod) arm is defined as regression to CIN 1 or less in diagnostic biopsies at 20 weeks follow-up. Successful treatment for the LLETZ arm is defined as normal cytology at 6 months follow-up. Based upon earlier studies, we hypothesize that 50-75% of patients in the experimental (imiquimod) arm will show regression to CIN 1 or less.
These two different outcome measures (cytology in the LLETZ arm and histology in the experimental arm) were selected in order to optimize the assessment of treatment efficacy, whilst limiting overtreatment of patients (performing unnecessary biopsies or LLETZ treatments). For the experimental arm, it is assessed by colposcopy with diagnostic biopsies and for the LLETZ arm it is assessed by cytology. Regarding efficacy of LLETZ treatment, the significance of resection margins of the LLETZ specimen is controversial and is not advised in guidelines as outcome measure of LLETZ efficacy. Therefore, regular follow-up cytology at six months was selected as outcome measure, as is also done in clinical practice and by other authors. Regarding imiquimod treatment, histological assessment of treatment efficacy was selected as outcome measure, in order to optimize the assessment of potential residual disease. Biopsies were chosen rather than a standard LLETZ procedure to evaluate residual disease, to prevent overtreatment.
2. Development of a biomarker model to predict adequate response to imiquimod treatment.
Secondary study objectives and outcome measures are:
1. To determine the incidence and severity of side effects of LLETZ and imiquimod therapy,
scored by the Common Terminology Criteria for Adverse Events guidelines.
2. To estimate disease recurrence rates for both arms at 6, 12 and 24 months follow-up, defined
as abnormal cervical cytology. The follow-up term starts after treatment is finished.
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