Interpretation
Veregen® ointment comprises of 10% Epigallocatechin-3-gallate (EGCG), the primary bioactive polyphenol of green tea. EGCG has been shown to possess anti-carcinogenic effects in both cell culture systems in vitro and animal models of cancer in vivo .11-13 A meta-analysis by Tzellos et al . showed that application of Veregen® ointment to genital warts, a hyperproliferative disease caused by persistent infection with low-risk HPV strains (LR-HPV), is effective in eradicating the lesions with a relatively low recurrence rate.7 In addition, Veregen®, unlike Imiquimod, is well tolerated by most patients, with minimal localised side effects such as skin irritation, which is reversed after treatment cessation.
Here, we demonstrated that application of Veregen® ointment leads to at least partial clinical resolution to uVIN lesion with potential improvements in symptom of pain and quality of life. Scientific study has shown that EGCG down-regulates expression of the high risk-HPV-encoded E6 and E7 proteins, which are required for cell growth transformation and efficient replication during the HPV life cycle.12 As topical EGCG has been proven to be effective in the clinical treatment of HPV induced hyperproliferative disorders, coupled with the fact that several in vitro studies have shown a marked reduction in proliferation of HR-HPV driven cancerous cell lines11, presumably through downregulation of the viral oncogenes12,13, more prolonged-term treatment or maintenance therapy with Veregen® could potentially result in complete histological resolution of uVIN. With clinical evidence showing that patients with genital warts who achieved full disease resolution following Veregen® treatment were less likely to experience disease recurrence, we speculate that this effect may extend to uVIN7,14.
As the risk of progression from uVIN to vulval cancer is relatively low,5 and symptom control is often the primary treatment aim for these women, we propose that Veregen® may potentially be an alternative long-term treatment to surgery or act as an adjuvant treatment for surgery, given that surgical treatment does not offer a cure as optimal surgical resection margin was not often achieved, and most patients will recur within three years even if the disease was completely resected, and further surgery is associated with psychosexual comorbidities10. Furthermore, Veregen® treatment may reduce the frequency or even delay the need for surgical intervention.
Nevertheless, there was no observed difference in best histological response between Veregen® and the placebo group and this could be attributed to a number of reasons. Firstly, our study did not achieve the intended recruitment target within the allotted time, and we were unable to extend our recruitment time due to cost and time constrain. Secondly, as a tertiary referral centre, all the patients, except one, who were recruited into our study had a refractory disease as these patients had long-standing symptoms and had experienced multiple treatment failures in the past. Thus, patients with primary disease may show a better histological response to Veregen® treatment. Thirdly, extended treatment duration may be required to induce histological resolution of the disease. In two previous independent randomised control studies that evaluated the use of Imiquimod vs placebo15 and Imiquimod vs Cidofovir (RT3VIN study),16 respectively, these studies examined patients with VIN grade 1, 2 and 3. In the former study, there was a significant reduction in disease severity/grade following Imiquimod treatment, an observation which we were not able to undertake in our study as histological assessment in our study were based on The International Society for the Study of Vulval Disease which uses morphological criteria to classify vulval intraepithelial neoplasia into usual-type (HPV-related) or differentiated (non-HPV-related).17 Thus, women with low grade squamous intraepithelial neoplasia (LSIL) and VIN2 were excluded from our study; hence, the lack of observed difference in histological resolution, despite clinical symptoms and lesion size improvements, maybe because our patient had a higher-grade disease. Moreover, the RT3VIN study found that less than half of the patients treated with either Imiquimod or Cidofovir showed a complete histological response, thus highlighting that longer treatment duration or maintenance treatment may be required to facilitate histological resolution. Future study should consider including patients with LSIL and VIN2 as these patients also suffer from similar debilitating symptoms to that of VIN3 and surgery may be avoided in this group of patients.