Page 189 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman

Treatment of high-grade CIN lesions is an effective method to prevent the development of cervical carcinoma. However, since not all lesions will progress to cervical cancer, overtreatment of high- grade CIN is common.[1] This leads to unnecessary side effects of surgical treatment, of which an increased risk of premature birth in subsequent pregnancy is the most severe.[2] With 5,000 women being treated for high-grade CIN yearly in the Netherlands, this is a relevant problem. The current HPV vaccination program will not eradicate all high-grade CIN lesions. At the same time, recent implementation of HPV-based cervical cancer screening leads to an increase in diagnosed high-grade CIN lesions.[3] Consequently, a substantial number of women will remain exposed to potential side effects of surgical treatment of high-grade CIN. Moreover, approximately 15% of high-grade CIN lesions are recurrent, leading to repeated surgical intervention, further increasing the risk of premature birth in future pregnancies.[4] Non-surgical treatment modalities could improve management of high-grade CIN, with the aim to reduce side effects of surgical treatment. This thesis provides evidence and tools for such alternative management strategies in high-grade CIN, focusing on the prediction of spontaneous regression with prognostic biomarkers and immunotherapy with imiquimod.
Prognostic biomarkers for spontaneous regression of high-grade CIN
Biomarker research in cancer is a hot topic and extensive research is being conducted in various fields of medicine, including in CIN and cervical carcinoma. Useful diagnostic markers have been identified and implemented to aid cytological triage and histological diagnosis of high-grade CIN. Among these are HPV-genotype for cytological triage and p16 /Ki67 staining for histological diagnosis.[5, 6] Various other cytological diagnostic markers have been studied, some with promising results such as combined CADM1/MAL methylation testing, but none have reached the stage of clinical implementation.[7, 8] Research on prognostic biomarkers in high-grade CIN has also proven challenging, as is shown in this thesis. We reviewed previously studied prognostic biomarkers in high-grade CIN and assessed their prognostic value and clinical applicability, according to their role in the natural history of CIN and the PROBE criteria for biomarker research. We concluded that none of the reviewed biomarkers is currently eligible for implementation in clinical practice for prediction of disease outcome in high-grade CIN.
Prognostic biomarker research in high-grade CIN faces several important challenges. One of these challenges is the inability to conduct long-term prospective observational studies, due to the risk of malignant evolution of high-grade CIN lesions. This is most clearly illustrated by a historical and unethical clinical study at the National Women’s Hospital, Auckland, New Zealand, in which treatment of CIN3 was withheld from a substantial number of women between 1965 and 1974.[9] The cumulative incidence of invasive cancer of the cervix or vaginal vault was 31% in these women. Consequently, in order to prevent the development of cervical carcinoma, a certain maximum follow-up term should be determined for prognostic biomarker studies in CIN3. A natural history model based on cervical screening practice in the UK showed that the annual risk of progression of a CIN 3 lesion to invasive cervical cancer is 0.99%.[10] The short term natural history of high- grade CIN can be further derived from randomized controlled therapeutic trials, which include a control group of histologically confirmed CIN 2/3 patients, and from short-term follow-up studies.
10
Discussion
187