This figure shows the proportion of patients with decreased Ki-67 and Bcl-2 expression after treatment, compared with baseline.
This figure shows the percentage of patients with moderate to severe local skin reactions during treatment for the sinecatechins, 10%, and placebo groups.
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Kessels J, Voeten L, Nelemans P, et al. Topical Sinecatechins, 10%, Ointment for Superficial Basal Cell Carcinoma: A Randomized Clinical Trial. JAMA Dermatol. 2017;153(10):1061–1063. doi:10.1001/jamadermatol.2017.2529
There is an ongoing search for noninvasive and targeted therapies in dermato-oncology. Superficial basal cell carcinoma (BCC), in particular, is accessible for topical treatments.
Epigallocatechin-3-gallate (EGCG) is an active constituent of green tea. It is assumed that EGCG has a cytotoxic effect, inhibits cell growth, induces apoptosis, and might inactivate β-catenin signaling of the Wingless (Wnt) pathway.1 Most sporadic BCCs have identifiable mutations in the patched (PTCH1) gene, an inhibitor of the Hedgehog (Hh) pathway. There is some evidence that the Wnt pathway might also be involved in BCC development.2 Deregulation of this pathway causes accumulation of nuclear β-catenin protein, leading to tumor development.3 This indicates that EGCG could possibly be a candidate for BCC treatment.
Sinecatechins ointment, 10%, contains EGCG and is currently registered to treat anogenital warts. To our knowledge, this is the first clinical study evaluating its efficacy in the treatment of superficial BCC.
The study was approved by the Maastricht University Medical Center institutional review board, registered at clinicaltrials.gov (NCT02029352), and conducted in a single university dermatology clinic. The protocol is available in the Supplement. Patients with a primary histologically proven superficial BCC of 4 to 20 mm in greatest diameter were included. Excluded were immunosuppressed patients or patients with genetic skin cancer disorders and tumors in the face and/or hairy scalp. After informed consent was given, patients were randomly assigned to either topical sinecatechins ointment, 10%, or placebo ointment. The ointment was applied twice daily for 6 weeks by patients at home. All tumors were excised after 8 weeks. Follow-up visits took place at baseline, 3, 6, and 8 weeks. All investigators were blinded to treatment allocation.
The primary outcome was the proportion of patients with complete histological tumor clearance. Secondarily, adverse events and the proportion of patients with decreased immunohistochemical expression of Ki-67 (proliferation) and Bcl-2 (B-cell lymphoma 2; anti-apoptosis) between excision and baseline biopsy were evaluated.
Between November 2014 and September 2015, 89 patients were assessed for eligibility. A total of 42 patients were included, and 39 completed follow-up. Complete histological tumor clearance was observed in 1 of 21 (5%) and 2 of 21 (10%) patients in the sinecatechins and placebo group, respectively (P > .99). Decrease in tumor size was slightly greater after sinecatechins application, but the difference was nonsignificant (P = .15). Decrease in Bcl-2 expression was nonsignificantly more frequent in the sinecatechins group than in the placebo group (7 of 17 [41%] vs 4 of 17 [24%]; P = .16) and decrease in Ki-67 occurred in similar proportions (5 of 17 [29%] vs 5 of 16 [31%]; P = .91) in patients for whom data were available (Figure 1). Use of the sinecatechins ointment led to a statistically significant higher frequency of erythema, edema, erosions, crusts, and itching (Figure 2).
No significant difference in histological tumor clearance between the sinecatechins and placebo groups was found in our study. The few complete tumor clearances that were observed probably reflect a biopsy-induced immune response.
Both Ki-67 and Bcl-2 were used in previous studies to assess the efficacy of BCC therapy, but results are not completely consistent between studies.4,5 We observed a slightly more frequent decrease in Bcl-2 expression in the sinecatechins group. Unexpectedly, we also observed a decrease in Bcl-2 and Ki-67 expression in a proportion of patients in the placebo group. A previously hypothesized biopsy-induced tumor regression could play a role.
The observed lack of efficacy in the present study might be because of insufficient EGCG uptake in the tumor cells. Encapsulation of EGCG in liposomes with deoxycholic acid and ethanol increased the drug deposition in a previous study.
In other studies, green tea polyphenols have been shown to reduce UV-induced inflammation, photoaging, and immunosuppression.6 Perhaps the suggested effect of EGCG is preventive rather than curative.
In conclusion, we did not observe supporting evidence for topical sinecatechins ointment, 10%, in the present formula to treat superficial BCC.
Corresponding Author: Janneke Kessels, MD, Maastricht University Medical Center, Department of Dermatology, P. Debyelaan 25, 6229 HX Maastricht, the Netherlands (firstname.lastname@example.org).
Accepted for Publication: May 30, 2017.
Published Online: August 9, 2017. doi:10.1001/jamadermatol.2017.2529
Author Contributions: Drs Kessels and Voeten had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Cleutjens, Hillen, Mosterd, Kelleners-Smeets.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Kessels, Voeten, Cleutjens, Hillen, Mosterd.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Kessels, Voeten, Nelemans.
Obtained funding: Kelleners-Smeets.
Administrative, technical, or material support: Kessels, Cleutjens, Hillen.
Supervision: Cleutjens, Hillen, Mosterd, Kelleners-Smeets.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was supported in part by Willpharma BV, the Netherlands, which supplied study medication (sinecatechins ointment, 10%, and placebo ointment).
Role of the Funder/Sponsor: The study sponsor had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Trial Registration: ClinicalTrials.gov Identifier: NCT02029352
Additional Contributions: We thank Maarten van Hoof, Department of Pathology, Maastricht University Medical Center, for collecting and preparing histopathology specimens and P.J. Steijlen, MD, PhD, Department of Dermatology, Maastricht University Medical Center, for his critical review of the manuscript. We are grateful to V. Winnepenninckx, MD, PhD, Department of Pathology, Maastricht University Medical Center, for her participation in study setup and assisting with the interpretation of histopathological specimens. We are especially thankful for the effort that Kiki Frencken, MD, Department of Dermatology, Maastricht Unversity Medical Center, put into the design and setup of this study. They did not receive compensation for their contributions.
Additional Information: Kiki Frencken died in 2015.