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.