Zhao H, Zhu W, Zhao X, et al. 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;158(7):779-786.
To determine if a topical green tea extract solution containing epigallocatechin-3-gallate (EGCG) can reduce the incidence of radiation-induced dermatitis (RID) in breast cancer patients undergoing radiotherapy after surgery
Prophylactic use of a topical EGCG solution reduced the incidence and severity of RID in patients undergoing adjuvant radiotherapy for breast cancer.
Phase II double-blind, placebo-controlled, randomized clinical trial
The trial included women aged 18 years and older with histologically confirmed breast cancer, receiving postoperative radiotherapy between November 2014 and June 2019. Of the 180 eligible patients enrolled (aged 26–67 years, median age 46 years), 111 were treated with EGCG, and 54 were treated with placebo; these 165 were included in the final dataset.
There were no restrictions on neoadjuvant or adjuvant chemotherapy regimens. Exclusion criteria included patients with unhealed wounds in the radiation area and patients receiving anticancer therapies other than concurrent endocrine or anti-ERBB2/HER2 therapy or known hypersensitivity to EGCG.
Participants were randomly assigned (2:1) to receive either an EGCG solution (600 µmol/L) or placebo (0.9% sodium chloride [NaCl] saline) sprayed to the whole radiation field 3 times per day from day 2 of radiation until 2 weeks after radiation was completed.
Study Parameters Assessed
Patients reported RID-related symptoms (including pain, burning feeling, itching, pulling, and tenderness) using the Skin Toxicity Assessment Tool (0=no symptoms; 5=the worse symptoms) once per week. The highest score at each assessment was considered the highest symptom score.
The primary endpoint was incidence of grade 2 or worse radiation-induced dermatitis, as defined by the Radiation Therapy Oncology Group scale. The secondary endpoints included radiation-induced symptom index, changes in the skin temperature measured by infrared thermal images, and safety.
Of the participants treated with the topical EGCG solution, 50.5% had grade 2 or worse RID vs 72.2% of the participants treated with the placebo, which was statistically significant (P=0.008). Secondary outcomes included a significantly lower symptom index in the EGCG group.
Dr Zhu was supported by the National Natural Science Foundation of China, Jinan Science and Technology Plan Project (202019163), and Science and Technology Project of Traditional Chinese Medicine of Shandong Province (2021M013). Prof Yu was supported by the Academic Promotion Program of Shandong First Medical University (Shandong Academy of Medical Sciences) (2019ZL002) and the Innovation Project of Shandong First Medical University (Shandong Academy of Medical Sciences) (2019-04). Dr H. Zhao was supported by the Shandong Provincial Natural Science Foundation (No. ZR2016HM35). The authors had no conflict-of-interest disclosures.
Practice Implications & Limitations
Breast cancer represents about 30% (or 1 in 3) of all new cancer diagnoses in women each year.1
Radiotherapy is an essential part of the treatment plan in patients who have had breast-conserving surgery or in certain cases after a mastectomy to improve local control and overall survival.2 RID occurs in 95% of breast cancer patients3 and is characterized by pain, ulceration, swelling, itching, and burning of the skin in the radiation field, as well as physical and psychological discomfort.4 The risk from severe RID is interruption or early termination of radiation treatment, which can compromise outcomes, as well as the impact on patients’ quality of life during and after treatment.5
Radiotherapy affects the skin’s anatomy and physiology by causing DNA damage that disrupts normal skin cell turnover.6 In addition, an inflammatory response in the skin ensues, with the release of histamine and serotonin and a vascular response, leading to capillary dilation in the dermis. The skin responds to radiation with redness (erythema), changes in skin pigmentation, hair loss, and destruction of sweat and sebaceous glands.7
More recent advances in radiation techniques may lower the incidence and severity of radiation skin reactions. Skin-sparing techniques, including intensity-modulated radiotherapy, hypofractionated radiotherapy, accelerated partial breast irradiation, simultaneous integrated boost, and prone positioning, have consistently demonstrated decreased rates of radiation dermatitis.8
There is a lack of consensus for prophylaxis and management of RID. However, evidence-based guidelines have been published that emphasize skin washing with mild soap and application of barrier products (such as Aquaphor) after each radiation treatment to allow for a moist environment to promote wound healing, and/or use of a steroid cream.6
This study examined the use of a topical green tea extract (EGCG) solution sprayed on the breast area undergoing radiotherapy vs placebo. Previous studies have shown that EGCG facilitates the healing process in ultraviolet radiation–induced erythema in human skin.9 EGCG has also been shown to enhance the viability of skin cells and decrease apoptosis induced by ionizing irradiation.10 Furthermore, EGCG has been shown to enhance skin wound healing via antioxidant, anti-inflammatory, antimicrobial, and antifibrotic effects.11
The results of the study indicated significant improvement over placebo in patients who applied the EGCG spray.12 Given that there are common practices and guidelines but no high-level, evidence-based standards for prevention of RID,12 the implications of this study are important, especially for the patient population who prefers natural therapeutic interventions as much as possible.
The study has some important limitations. The placebo was a saline spray, and investigators did not allow a topical lotion or agent during radiotherapy.12 The saline spray is not considered an evidence-based recommendation for RID prevention, nor is the disallowance of the use of barrier creams.13 It would be helpful to compare the EGCG topical solution to the evidence-based preventive measures commonly used in practice to better understand the effectiveness of EGCG.
Furthermore, the study does not delineate whether the spray was applied before or after the radiation treatment each day, but only that it was utilized 3 times daily.12 Other research has indicated that EGCG can reach all the skin layers when in a cosmetic formulation,14 so it is unknown whether the antioxidant effects of EGCG could potentially interfere with DNA damage to cancer cells, thereby potentially decreasing the effectiveness of radiotherapy. For a patient whose intended radiation treatment field is relatively superficial, EGCG theoretically could interfere.
Another limitation is the form of radiotherapy used, conventional fractional radiotherapy. In contrast, hypofractionated radiotherapy is more widely used today and tends to have lower rates of RID.15 The investigators plan to study topical EGCG in prospective studies in patients undergoing hypofractionated radiotherapy.
Lastly, the EGCG solution was prepared fresh daily, which may not be practical for a patient, and it is unlikely that a patient could achieve the same concentration as the preparation used in the study.
Ideally, practitioners should inform patients of both the evidence for an intervention such as topical EGCG and the limitations of the research. In addition, it is important that radiation oncologists be included in the discussion of which natural therapeutics patients would like to use during radiotherapy. Lastly, a more cautious approach is to instruct patients to apply topical agents after radiation treatment each day and wash off well with soap and water prior to the next day’s radiation treatment to minimize any potential interference with radiotherapy.