Page 218 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 12
an imiquimod treatment arm, a LLETZ treatment arm and an observational arm, in which women were followed for a maximum of 20 weeks with a control colposcopy after 10 weeks. The purpose of this observational arm was to study prognostic biomarkers in high-grade CIN. The inclusion of women into the study was first hampered by this observational arm, which was therefore removed from the study. Thereafter, inclusions were hampered by a strong preference of women for either of the two treatment modalities: most women did not want to be randomized between imiquimod and LLETZ treatment. The study was therefore prematurely terminated, as is described in chapter 9b, and converted to a non-randomized trial (TOPIC-3 study). In this study, women could choose the treatment modality of their preference. In addition to treatment efficacy, side- effects and quality of life, the TOPIC-3 also studies predictive biomarkers for treatment outcome of imiquimod. This would enable identification of women in whom an adequate response to imiquimod is expected. The TOPIC-3 study is currently running in three centers in the Netherlands. All 120 women have been included at the time of writing. The first study results are expected in the spring of 2019.
In chapter 10, the findings of this thesis are discussed in a general perspective and with regard to their implications for clinical care and future research. This thesis provides evidence and tools for alternative management strategies in high-grade CIN, focusing on the prediction of spontaneous regression with prognostic biomarkers and immunotherapy with imiquimod.
Conclusions, recommendations and future perspectives
- Prognostic biomarker research is challenging, but short-term observational studies do provide an opportunity for further research in this field. Future prognostic biomarker research should focus on the development of biomarker panels or prediction models, instead of individual markers, and should be performed according to the PROBE criteria for biomarker research.
- Future prognostic biomarker research should distinguish between CIN2 and CIN3 lesions, given the distinct difference in spontaneous regression rates. This distinction should be based on conventional histopathological assessment, until better methods are available.
- 3q26 gain, smoking status and parity could be considered as part of a biomarker profile or prediction model for spontaneous regression of high-grade CIN.
- Based on physician’s opinions and patient preferences, imiquimod qualifies as a non-surgical treatment alternative to LLETZ treatment, mainly for women with a future pregnancy desire, to avoid the risk of premature birth in subsequent pregnancies caused by conventional surgical treatment.
- Additional evidence on the clinical applicability of imiquimod in high-grade CIN (including treatment efficacy and side effects) is necessary and will be provided by the TOPIC3 study.
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