Teatime for radiation dermatitis (and beyond)

By Warren R. Heymann, MD, FAAD
June 14, 2023
Vol. 5, No. 24

I am biased — as a coffee lover, I only believe articles demonstrating coffee’s benefits, while finding flaws in any study deriding its use. I can be more objective about tea — especially green tea — a staple of Chinese herbal medicine. As a dermatologist, however, all of us might become enamored with the potential use of topical epigallocatechin-3-gallate (EGCG), a polyphenol, which is the most abundant catechin found in green tea leaves (Camellia sinensis). (1)

EGCG sounds like a miracle drug with antioxidant, anti-inflammatory, antimicrobial, anti-angiogenic, and anticarcinogenic properties. A major reason for its limited topical use in dermatology is because the molecule is unstable, especially when retained at high temperatures and pH. (2) Why not just drink enough green tea to derive its vast benefit? According to Braegelmann et al: “The plasma concentration of EGCG detected upon intake of green tea extraction in 350 mL water, however, is far from the concentration needed to achieve anti-inflammatory effects. Consumption of EGCG dietary supplements, resulting in much higher plasma and tissue concentrations of EGCG than upon intake of tea beverages, has been shown to be associated with hepatotoxicity. Topical application can thus be considered a much safer and more effective delivery approach than oral intake.” (1)

I first became familiar with EGCG after reading the article by Katiyar et al, demonstrating that green tea could protect against UVB-induced immunosuppression and cutaneous inflammatory responses in C3H mice. (3) Over the past few decades, scores of manuscripts about green tea EGCG providing benefit in psoriasis, atopic dermatitis, scars, lichenoid reactions, acne, vitiligo, HPV infection, skin cancers (including melanoma) have been published. (1-8) Camellia sinensis extract/Sinecatechins, with EGCG as the main component, (9) is approved for use to treat condyloma acuminata.

Mechanistically, EGCG has vast biological effects. It is a good anti-oxidant that scavenges free radicals, partially by enhancing antioxidant enzymes such as superoxide dismutase. This correlates with reactive oxygen species removal, thereby affecting NF-κB, Akt, MAPK, and cell cycle regulation. From an oncologic perspective, EGCG therapy decreases cell proliferation by repressing ERK1/2, STAT3, Akt/PI3K, NF-κB, and Wnt pathways. EGCG demonstrates its chemopreventive effect through the activation of p53 and PTEN/p21 regulation of apoptosis and inhibition of signaling molecules. (10)

Radiation-induced dermatitis (RID) is a common problem encountered by dermatologists, especially in women treated for breast cancer. The usual therapeutic approach is with topical steroids and emollients, which may not offer much relief. Zhao et al sought to determine if topical EGCG solution can reduce the incidence of RID in patients undergoing radiotherapy after breast cancer surgery. The authors performed a phase 2 double-blind, placebo-controlled randomized clinical trial enrolling 180 patients with breast cancer who were to receive postoperative radiotherapy — 165 participants were evaluable. Patients were randomly assigned (2:1) to receive either EGCG solution (660 μmol/L) or placebo (0.9% NaCl saline) sprayed to the whole radiation field from day 1 of the radiation until 2 weeks after radiation completion. The primary end point was an incidence of grade 2 or worse RID, defined by the Radiation Therapy Oncology Group scale. The secondary end points included RID index (RIDI), symptom index, changes in the skin temperature measured by infrared thermal images, and safety. The occurrence of grade 2 or worse RID was significantly lower (50.5%; 95% CI, 41.2%-59.8%) in the EGCG group than in the placebo group (72.2%; 95% CI, 60.3%-84.1%) (P = .008). The mean RIDI in the EGCG group was significantly lower than that in the placebo group. Symptom indexes were significantly lower in patients receiving EGCG. Four patients (3.6%) had adverse events related to the EGCG treatment, including a grade 1 pricking skin sensation (3 [2.7%]) and pruritus (1 [0.9%]). The authors concluded that prophylactic use of EGCG solution may significantly reduce the incidence and severity of RID in patients receiving adjuvant radiotherapy for breast cancer. It may potentially become a new choice of skin care for patients receiving radiotherapy. (11)

According to the website Healthline: “Green tea is touted to be one of the healthiest beverages on the planet. It’s loaded with antioxidants that have many health benefits, which may include: improved brain function, fat loss, protecting against cancer [and] lowering the risk of heart disease. There may be even more potential health benefits.” (12) Despite these enticements, coffee will remain my beverage of choice. For topical use, however, when the right formulation is determined, I will be delighted to start prescribing EGCG.

Point to Remember: Epigallocatechin-3-gallate, derived from green tea, has many properties with the potential for multiple uses in dermatology when used topically. It may prove especially useful for patients with radiation-induced dermatitis.

Our expert’s viewpoint

Craig A. Elmets, MD, FAAD
Professor, Department of Dermatology
University of Alabama at Birmingham

Green tea is a brewed drink, the consumption of which is widespread in Asian countries. It is becoming more popular as a beverage worldwide. (13) Green tea is also one of a handful of herbs and supplements that has received serious scientific scrutiny for its health effects. Epidemiological studies and a few clinical trials have suggested that it has beneficial effects in the prevention of some cancers (e.g. prostate cancer). (14) However, the large amounts required for its antioxidant effect and the unpleasant side effects associated with ingestion of the large amounts of green tea required for its health benefits make its use as a systemic agent unfeasible in most instances.

Because of its accessibility, topical formulations can deliver large amounts of EGCG without the requirement for ongoing consumption and the concern for side effects. Although topical application of green tea or epigallocatechin-3-gallate (EGCG), the most potent polyphenolic green tea constituent, prevents UV-induced sunburn in humans (15) and photoaging and UV-induced skin cancer in mice (14), several factors limit its use as a medicinal agent when chronically applied to the skin as a medicinal agent. The formulations cause a greenish discoloration of the skin, which is often cosmetically unacceptable; the SPF value is low (15); and it easily degrades into an inactive form making the shelf-life short. However, the positive biological characteristics (potent antioxidant effects, anti-inflammatory actions, anti-microbial activities, anti-fibrotic properties), make it attractive for short term use as an anti-inflammatory and antioxidant.

The recent report by Zhao et al provides evidence that EGCG may be beneficial in the prevention of radiation-induced dermatitis. (11) Because the incidence of dermatitis is high and the treatments are given for a limited time, this is an ideal situation in which to exploit the medicinal properties of this botanical product. The carefully conducted randomized controlled phase 2 clinical trial of 180 breast cancer patients showed that EGCG applied to the skin site through which radiation was being delivered significantly reduced the percentage of patients with severe radiation dermatitis and reached several secondary endpoints as well. The treatment was well tolerated with only 2% of patients having mild adverse cutaneous reactions. EGCG solution was prepared immediately prior to topical application, thereby precluding its oxidation into an inactive compound.

In addition to identification of a new preventive agent for radiation dermatitis, this is one of only a few randomized controlled clinical trials demonstrating the efficacy and safety of topical EGCG. It may therefore be the impetus for its investigation in other diseases, both dermatologic and non-dermatologic, in which it can be given locally. Larger, multicenter trials are necessary to confirm these findings of the Zhao study, but the results from this study are encouraging.

1. Braegelmann C, Niebel D, Ferring-Schmitt S, Fetter T, Landsberg J, Hölzel M, Effern M, Glodde N, Steinbuch S, Bieber T, Wenzel J. Epigallocatechin-3-gallate exhibits anti-inflammatory effects in a human interface dermatitis model-implications for therapy. J Eur Acad Dermatol Venereol. 2022 Jan;36(1):144-153. doi: 10.1111/jdv.17710. Epub 2021 Oct 12. PMID: 34585800.

2. Frasheri L, Schielein MC, Tizek L, Mikschl P, Biedermann T, Zink A. Great green tea ingredient? A narrative literature review on epigallocatechin gallate and its biophysical properties for topical use in dermatology. Phytother Res. 2020 Sep;34(9):2170-2179. doi: 10.1002/ptr.6670. Epub 2020 Mar 18. PMID: 32189392.

3. Katiyar SK, Elmets CA, Agarwal R, Mukhtar H. Protection against ultraviolet-B radiation-induced local and systemic suppression of contact hypersensitivity and edema responses in C3H/HeN mice by green tea polyphenols. Photochem Photobiol. 1995 Nov;62(5):855-61. doi: 10.1111/j.1751-1097.1995.tb09147.x. PMID: 8570723.

4. Kim S, Park TH, Kim WI, Park S, Kim JH, Cho MK. The effects of green tea on acne vulgaris: A systematic review and meta-analysis of randomized clinical trials. Phytother Res. 2021 Jan;35(1):374-383. doi: 10.1002/ptr.6809. Epub 2020 Aug 19. PMID: 32812270.

5. Hu W, Zhang L, Lin F, Lei J, Zhou M, Xu A. Topical epigallocatechin-3-gallate in the treatment of vitiligo. Australas J Dermatol. 2021 Aug;62(3):e404-e407. doi: 10.1111/ajd.13612. Epub 2021 May 28. PMID: 34046892.

6. Hu W, Jin R, Lin F, Lei J, Ma Y, Xu AE. Repigmentation in two patients with vitiligo on AcEGCG 0.5% cream. Clin Exp Dermatol. 2022 Jun 22. doi: 10.1111/ced.15211. Epub ahead of print. PMID: 35731108.

7. Song JY, Han JH, Song Y, Lee JH, Choi SY, Park YM. Epigallocatechin-3-gallate Can Prevent Type 2 Human Papillomavirus E7 from Suppressing Interferon-Stimulated Genes. Int J Mol Sci. 2021 Feb 28;22(5):2418. doi: 10.3390/ijms22052418. PMID: 33670861; PMCID: PMC7957673.

8. Ravindran Menon D, Li Y, Yamauchi T, Osborne DG, Vaddi PK, Wempe MF, Zhai Z, Fujita M. EGCG Inhibits Tumor Growth in Melanoma by Targeting JAK-STAT Signaling and Its Downstream PD-L1/PD-L2-PD1 Axis in Tumors and Enhancing Cytotoxic T-Cell Responses. Pharmaceuticals (Basel). 2021 Oct 26;14(11):1081. doi: 10.3390/ph14111081. PMID: 34832863; PMCID: PMC8618268.

9. de Vries HJC, Soltanipoor M, Kezic S, Vergunst CE. Sinecatechins ointment 10% (Veregen®) for genital warts: percutaneous penetration of epigallocatechin gallate concentrations in the stratum corneum collected by adhesive tape stripping method. J Eur Acad Dermatol Venereol. 2018 Sep;32(9):e357-e358. doi: 10.1111/jdv.14933. Epub 2018 Mar 30. PMID: 29524277.

10. Alam M, Ali S, Ashraf GM, Bilgrami AL, Yadav DK, Hassan MI. Epigallocatechin 3-gallate: From green tea to cancer therapeutics. Food Chem. 2022 Jun 15;379:132135. doi: 10.1016/j.foodchem.2022.132135. Epub 2022 Jan 11. PMID: 35063850.

11. Zhao H, Zhu W, Zhao X, Li X, Zhou Z, Zheng M, Meng X, Kong L, Zhang S, He D, Xing L, Yu J. Efficacy of Epigallocatechin-3-Gallate in Preventing Dermatitis in Patients With Breast Cancer Receiving Postoperative Radiotherapy: A Double-Blind, Placebo-Controlled, Phase 2 Randomized Clinical Trial. JAMA Dermatol. 2022 Jun 1:e221736. doi: 10.1001/jamadermatol.2022.1736. Epub ahead of print. PMID: 35648426; PMCID: PMC9161122.

12. https://www.healthline.com/nutrition/top-10-evidence-based-health-benefits-of-green-tea (accessed July 9, 2022)

13. Yusuf N, Irby C, Katiyar SK , Elmets CA. Photoprotective effects of green tea polyphenols. Photodermatol Photoimmunol Photomed 2007;23:48-56.

14. Filippini T, Malavolti M, Borrelli F, Izzo AA, Fairweather-Tait SJ, Horneber M et al. Green tea (Camellia sinensis) for the prevention of cancer. Cochrane Database Syst Rev 2020;3:Cd005004.

15. Elmets CA, Singh D, Tubesing K, Matsui M, Katiyar S , Mukhtar H. Cutaneous photoprotection from ultraviolet injury by green tea polyphenols. J Am Acad Dermatol 2001;44:425-32.

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