Page 19 - Strategies for non-invasive managementof high-grade cervical intraepithelial neoplasia - prognostic biomarkers and immunotherapy Margot Maria Koeneman
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While counseling of patients for conservative management of CIN3 cannot yet be adequately 1 applied, this is already a matter of common practice for CIN2. Nevertheless, not all young women
with CIN2 receive conservative treatment. The reasons for this are unknown, but may be found
in patient factors (fear of progression, desire for a fast solution) or physician factors (fear of progression, performing surgical treatment by habit). A better individual prediction of disease
outcome would enable a more adequate patient counseling with regard to management options. As conservative treatment of CIN2 is already implemented in clinical practice, it is undesirable to use complex and expensive biomarkers to predict disease outcome. Rather, simple clinical parameters – based on patient and lesion characteristics – may be applied to predict individual disease outcome and thus enable a more personalized counseling with regard to management options. Since the implementation of HPV-based screening for cervical cancer, nearly all newly diagnosed CIN2 lesions are now hrHPV positive. Identification of prognostic factors for disease outcome in exclusively hrHPV positive CIN2 is therefore vital, in order to provide with clinically applicable prognostic factors.
Taken together, the identification of prognostic markers in high-grade CIN may enable individual prediction of disease outcome, in order to select those women with a high likelihood of spontaneous regression for conservative management.
Non-surgical treatment of CIN
Another strategy to reduce side effects of surgical treatment of CIN lesions is the application of non-surgical treatment modalities. Non-surgical ablative methods (electrocautery, cryotherapy and laser ablation) have been proven effective and were widely used until the 1990s. After the introduction of LLETZ treatment in the 1990s, several first studies indicated a potential undertreatment of invasive cancer by ablative methods, for which reason these methods were abandoned and replaced by surgical excision.[41] The fact that meta-analytic data shows that cryotherapy and laser ablation have comparable efficacy to excisional techniques has not lead to their re-introduction.[41, 42] More recently, several other non-surgical approaches have been evaluated in the treatment of CIN.[43] Among these are photodynamic therapy and 5-fluorouracil (5-FU), which are applied as direct cervical irritants. Both have not reached clinical implementation, due to limited evidence but also high costs and toxicity. Other research is focusing on immunotherapy for CIN, with the aim to enhance the immune response to CIN lesions in order to promote disease regression. Several forms of immunotherapy have been studied: local and systemic treatment with antiviral drugs, local treatment with interferon and imiquimod and therapeutic HPV vaccination. Regarding antiviral drugs, local application of cidofovir has been shown to be moderately effective in small trials. It is not likely to be clinically applied due to potential mutagenic and carcinogenic effects and high costs. Local and systemic application of HIV protease inhibitors has shown promising results in vitro and in small trials, but has not yet been studied beyond a phase II trial. Intralesional injection of interferon has been proven very effective in CIN lesions in one study, but has not been investigated further. This may be due to high costs and significant side effects. HPV vaccination is now extensively studied as systemic immunotherapy in CIN.[44-46] The currently available prophylactic HPV vaccines have not been successful in treating established HPV infections. These prophylactic vaccines prevent HPV infection by targeting the humoral immune response through delivering virus-
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