Page 173 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

The imiquimod treatment period was set at 20 weeks, in order to realize adequate treatment efficacy of imiquimod, while minimizing the risk of progression of cervical dysplasia to invasive disease. Progression of CIN into cervical cancer is considered to be a slow process. The annual risk of progression of CIN 3 to invasive cervical cancer is estimated to be less than 1%.[17] We identified ten studies in which patients with high-grade CIN underwent watchful waiting for a set period of time.[4, 6, 7, 18-24] A total of 637 patients were included either as a control group, receiving no treatment during 6 weeks to 15 months, or followed during the period between diagnosis and LLETZ. Three cases of invasive disease were identified: all occurred in the same study after 16 weeks of observation. The possibility of invasive disease already present at the initial colposcopy (due to biopsy error) cannot be excluded. Based on these results, we set the maximum treatment period at 20 weeks and we included an additional control colposcopy with diagnostic biopsies after ten weeks. When no disease progression is detected during this colposcopy, the imiquimod treatment can be continued until the 20 weeks colposcopy.
Sample size calculation
The sample size calculation was based on a regression rate of 73% at 20 weeks follow-up after immunotherapy and a 95% treatment efficacy of LLETZ. Using 80% power and alpha = 5%, the
estimated sample size required is 42 women in both arms. Allowing for a withdrawal rate of approximately 20%, 53 women will have to be recruited in each arm. Sample size calculations for
the secondary outcome measures indicated that roughly 70 patients per treatment arm would
be necessary. Although the sample size calculation should be based on the primary outcome 9 measure, we decided to recruit a total of 140 patients (70 per arm). a
Randomization
Randomization is performed by the principal investigator to prevent selection and allocation bias, by use of a computerized randomization tool. Sampling is stratified according to the following age categories: 18-24, 25-39, and 40 years and older. Sampling will be stratified according to study centre.
Data collection
Coded data are stored both on paper and in an electronic database. Collected data are stored in a digital case report form (CRF). Raw data is available only to the principal and coordinating investigator. The following data are recorded:
Baseline
- Patients characteristics: age, ethnical background, education, medical history, smoking, sexual behaviour
- HPV genotyping for all patients
- Histological biomarkers on biopsies of patients in the experimental arm: markers of
lymphoproliferative response: CD4, CD8, CD25, CD138, fox p3; cell cycle markers: p16, Rb,
p53, Ki67, CK 13, CK 14, IMP3
- Quality of life
TOPIC trial
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