Page 171 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

3. To assess Quality of life (QoL) for both arms before, during and after treatment (at 0 and 20 weeks and after 1 year) by the following QoL questionnaires: (1) Medical Outcomes Study 36-Item Short-Form General Health Survey (RAND 36), to assess generic health-related quality of life, (2) the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, to assess cancer-specific health-related quality of life, and (3) the European Organization for Research and Treatment of Cancer (EORTC) QLQ-CX24, to assess cervical cancer specific quality of life, including sexual functioning.
Interventions
After informed consent is obtained, patients are equally randomized into one of two arms:
1. Experimental arm. Patients in this arm are treated by a 16-week regime of imiquimod 5%
cream.
2. Standard arm. Patients in this arm receive standard treatment by LLETZ.
Follow-up visits are anchored to the start of the treatment (either imiquimod or LLETZ).
Cytological assessment will be performed by two independent trained cytology analysts,
according to the Papanicolaou system. In case of inconsistent results, a consensus will be reached
by discussion. The histopathological assessment of cervical biopsies will be performed by two independent pathologists according to national guidelines, based on the WHO guidelines. In case
of inconsistent results, a consensus will be reached by discussion. CIN diagnosis will be based on
evaluation of histological features concerned with differentiation, maturation and stratification 9 of cells and nuclear abnormalities, in combination with p16 staining. In CIN 1 there is good a maturation with minimal nuclear abnormalities and few mitotic figures. Undifferentiated cells
are confined to the deeper layers (lower third) of the epithelium. Mitotic figures are present, but not very numerous. Cytopathic changes due to HPV infection may be observed in the full thickness of the epithelium. CIN 2 is characterized by dysplastic cellular changes mostly restricted to the lower half or the lower two-thirds of the epithelium, with more marked nuclear abnormalities than in CIN 1. Mitotic figures may be seen throughout the lower half of the epithelium. In CIN 3, differentiation and stratification may be totally absent or present only in the superficial quarter of the epithelium with numerous mitotic figures. Nuclear abnormalities extend throughout the thickness of the epithelium. Many mitotic figures have abnormal forms.
Patients in the experimental arm are treated with imiquimod 5% cream during 16 weeks. Imiquimod 5% cream is administered in a vaginal applicator, containing 12,5 mg of imiquimod (one sachet). The cream is administered three times per week. The cream is administered by patients themselves at night, before going to bed. A vaginal shower is performed in the morning in order to remove cream remainders. In case of mild systemic drug-related side effects, patients are offered a prescription for anti-inflammatory drugs (paracetamol or NSAID). In case of more severe or persistent systemic or severe local side effects (Common Terminology Criteria for Adverse Events grade 2 or higher), the frequency of imiquimod application is decreased to twice per week, and subsequently to once per week if side effects persist. Imiquimod treatment is discontinued if side effects are unacceptable to patients hereafter. Subjects should use adequate contraception in order to prevent pregnancy. Subjects should not have vaginal sexual intercourse from the time
TOPIC trial
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