Title: Phase II clinical trial investigating the use of epigallocatechin-3-gallate (Veregen) in the treatment of vulval intraepithelial neoplasia (EPIVIN)
Funder: Department of Health (England)

Abstract: Aim To determine whether topical application of epigallocatechin-3-gallate (Veregen) can induce histological resolution of vulval intraepithelial neoplasia (VIN) Background The incidence of vulval intraepithelial neoplasia (VIN) has increased >3-fold in younger women. Not only are these women at risk of progression to vulval cancer but almost all present with symptoms, usually pain or vulval irritation. While surgical excision is the treatment most commonly offered to these women, more than one in three women treated in this way will have a recurrence, and surgery may itself result in additional physical and psychosexual problems New medical treatments which interrupt the natural history of VIN are needed. One potential new therapeutic agent is epigallocatechin-3-gallate (EGCG). EGCG is the major active polyphenol found in green tea and has been shown to prevent carcinogenesis in cell culture and animal models, and to reactivate the expression of tumour suppressor genes which are silenced during carcinogenesis. The topical application of EGCG (Veregen) has also been shown to be an efficacious treatment for vulval warts, and in a phase II RCT of patients with oral premalignant lesions – which like VIN, are associated with high-risk HPV types- higher doses of EGCG led to higher short-term response rates. Plan of investigation In a single centre, double-blind, randomised phase II trial, women with histologically proven VIN will be allocated either topical treatment with Veregen or a placebo ointment for 16 weeks, and re-assessed in the vulva clinic at 8, 16 and 32 weeks after study entry. The primary outcome measure will be histological resolution of VIN measured at 32 weeks. Secondary objectives include the measurement of compliance, clinical response, relief of symptoms, improvements in the quality of life, toxicity and the durability of the therapeutic response. The trial will run for 36 months; with recruitment completed in 2 years. The decision to proceed to a phase 3 RCT will be dependent on demonstrating an improvement in the rate of resolution of VIN to >30% in those allocated to treatment with Veregen as compared to placebo. Summary of potential benefits to patients and to the NHS As VIN is often characterised by the asynchronous appearance of dysplastic epithelium at multiple sites, an effective topical treatment, would offer the advantage of more effective long-term control of a disease which might otherwise require multiple surgical interventions. We believe that in the future, the active management of VIN will change from a predominantly surgically-oriented approach to one in which women are offered different topical medications which can be administered either sequentially dependent on patient response or according to predictive biomarkers identified at diagnosis, with surgery reserved for those who fail to respond to medical therapy. Although the risk of progressive disease in these women is small, clinicians cannot predict those in whom this will occur, and are therefore obliged to place all on extended surveillance with the result that ~80% of gynaecology out-patient appointments in women with vulval disease are follow-up visits. An effective medical treatment would not only help allay patient anxiety but also reduce this ever increasing burden on NHS resources. Finally, were such an agent shown to be effective in the treatment of VIN, there would be a compelling case for exploring its use in with invasive cancer. Here it would have the potential to reduce the incidence of recurrent disease ( ~25% at five years) in women with invasive vulval cancer and in so doing reduce the need for life-long follow-up in these often elderly patients who have serious co-morbidity.


Research activity codes: 6.1 PHARMACEUTICALS
Health categories: CANCER AND NEOPLASMS