Page 198 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Chapter 10
The TOPIC-3 study should clarify the clinical applicability of imiquimod cream as a treatment modality for high-grade CIN.
Future perspectives
Future perspectives of the issues addressed in this thesis include further development and implementation of prognostic biomarker profiles or prediction models in high-grade CIN and clarification of the clinical applicability of imiquimod in treatment of high-grade CIN, followed by strategies for actual clinical implementation.
Further biomarker research should be conducted according to the PROBE criteria for biomarker research, in order to improve interpretation, comparison and pooling of study outcomes. Ideally, given the distinct difference in natural history of CIN2 and CIN3 lesions, prognostic markers should be studied in these groups separately. Previously identified prognostic markers and the markers identified in our studies can be incorporated in future biomarker profiles or prediction models. Hopefully, this leads to the development of biomarker profiles or prediction models with adequate test characteristics for the prediction of disease outcome in CIN2 and CIN3. This offers the opportunity for an individualized treatment strategy, in which a wait-and-see policy could be applied in those cases in which regression is expected. Women with CIN 2/3 may benefit from this strategy, as they will be subject to less overtreatment and associated side effects. Clinical applicability of prognostic markers should then be further evaluated with regard to patient satisfaction with observational treatment and cost-effectiveness of this strategy. Finally, prognostic factors that can be influenced should be more actively addressed with patients. Based on the results of our study in hrHPV positive CIN2 lesions, which once again shows the important effect of smoking, we suggest that smoking cessation programs should be offered to smoking women with CIN2/3.
The TOPIC-3 study will clarify the clinical applicability of imiquimod cream as a treatment modality for high-grade CIN. It will provide additional evidence on short- and long-term treatment efficacy, side effects and quality of life of imiquimod treatment. Upon the establishment of adequate treatment efficacy and clinical applicability, we advocate the application in women with a future pregnancy desire. Other indications may be large CIN lesions requiring extensive excision, or recurrent CIN lesion with the aim to prevent repeated cervical surgery including hysterectomy. The efficacy of imiquimod in recurrent CIN lesions is currently being studied in the TOPIC-2 trial.[4] The identification of prognostic markers for imiquimod treatment outcome could enable selection of women in whom an adequate response to imiquimod treatment is expected. To this aim, the biological mechanisms behind imiquimod-associated clearance of high-grade CIN should be further elucidated. An intended study by the authors on cervical TLR expression and the immune response to imiquimod in high-grade CIN could contribute to this issue. After confirmation of the efficacy and clinical applicability of imiquimod, the awareness of this treatment modality should be increased among physicians and patients. Awareness among physicians could be achieved by incorporation in treatment guidelines, communication through gynecological associations and education. Awareness among patients could be achieved by
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