Reference
Zhu W, Jia L, Chen G, et al. Epigallocatechin-3-gallate ameliorates radiation-induced acute skin damage in breast cancer patients undergoing adjuvant radiotherapy. Oncotarget. 2016;30:48607-48613.
Design
A single-arm, non-randomized, Phase II clinical trial to assess the occurrence, severity, and progression of radiation dermatitis (RDS)
Participants
The study included 49 patients diagnosed with breast carcinoma who had undergone modified radical mastectomy followed by external beam radiation therapy (RT) to the chest wall, including the surgical scar and regional lymph nodes. The use of neoadjuvant or adjuvant chemotherapy was not mentioned in this study.
Study Medication and Dosage
All patients were given the epigallocatechin-3-gallate (EGCG) solutions from the onset of Grade 1 toxicity until 2 weeks after the last radiation treatment. The EGCG concentration was 660 μmol per liter of saline; this dilution was selected based on an earlier Phase I trial.1 The EGCG solution was sprayed onto the skin 3 times a day, 10 to 20 cm from the skin, at 0.05 mL/cm2 to the entire radiation field. In an effort to ensure full skin exposure, all skin folds were fully stretched prior to administration of the solution. All patients were advised to avoid the use of deodorants, lotions, creams, perfumes, or any other products on radiation-exposed skin during the course of RT. The mean duration of EGCG treatment was 4 weeks. The RT fraction was 2 Gy per treatment, given 5 days per week, for a total of 50 Gy in 2 Gy to 50 Gy, for 5 days a week.
Outcome Measures
Radiation dermatitis was assessed with the use of a radiation severity score, a combined score that includes a patient score using the skin toxicity assessment tool (STAT) and a score given by a healthcare practitioner based on the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer (RTOG/EORTC) scoring system. The STAT scores range from 0 to 5, with 0 representing no symptoms and 5 representing the worst symptoms. Symptoms were characterized as pain, burning, itching, pulling, and tenderness. Education was provided to all staff on how to use this scale. The severity of RDS was assessed by 2 radiation oncologists. If their scores were inconsistent, a senior doctor was asked to determine the score. The presence and severity of dermatitis was measured before and 3 hours after the EGCG application (based on the EGCG half-life, which is approximately 3 hours). The National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events was used to assess the development of any adverse events or toxicity associated with EGCG.
Key Findings
All radiation treatments were delivered to all study participants without interruptions or treatment delays.
Of the 49 patients assigned to this study, 35 (71.4%) sustained Grade 1 dermatitis, 14 (28.6%) experienced Grade 2 dermatitis, and none exhibited Grade 3-4 dermatitis. The average RTOG/EORTC scores for patients treated with EGCG were Grade 1 (scale range 0-4). Per the RTOG/EORTC scale, Grade 1 toxicity is associated with follicular, faint, or dull erythema, epilation, dry desquamation, and/or decreased sweating. Grade 2 reflects tender or bright erythema, moist patchy desquamation, and/or moderate edema.
Grade I dermatitis was exhibited by 17 patients in the second week, 24 in the third week, and 8 in the fourth week. As soon as Grade I dermatitis was documented, the EGCG solution was applied. The average duration of EGCG treatment was 4 weeks. Of note, 15 patients regressed to Grade 0 skin toxicity (meaning no symptoms) with the use of EGCG. Per RTOG scores, a significant difference was found between scores measured at the onset (documentation of Grade 1 dermatitis) and at the end of the study (2 weeks post-radiation; n=49, t=4.38, P<0.05). Of note, the RTOG score did not increase in 35 patients (71%) during RT, meaning that RDS worsened in only 10 patients.
The patient self-assessment scores (STAT scores) suggest that EGCG application was associated with rapid relief of RDS symptoms. Within 1 week the symptoms of pain, burning, itching, pulling, and tenderness had all decreased (pain: t=5.229, P<0.05; burning: t=7.167, P<0.05; itching: t=9.478, P<0.05; pulling: t=2.14, P<0.038; tenderness: t=4.499, P<0.05). Patient-reported symptom scores were also significantly reduced at the end of the study (pain: t=3.347, P=0.004; burning: t=6.126, P<0.05; itching: t=4.968, P<0.05; and tenderness: t=3.043, P=0.008). The STAT scores appear to demonstrate that application of topical EGCG has the ability to control symptoms associated with pain in 85.7% of patients, burning in 89.8%, itching in 87.8%, and pulling in 71.4%.
All patients tolerated the use of topical EGCG without problems, and no acute toxicity was reported. This study indicates that application of topical EGCG at a dose of 660 μmol/L may be beneficial in the treatment and management of acute RDS.
Practice Implications
Radiation dermatitis remains a significant issue for many patients undergoing external beam radiation treatment. According to previous studies, 12% to 17% of patients who receive 50 Gy of skin radiation will develop Grade 3-4 dermatitis.2 The risk for dermatitis tends to be greater for patients with breast cancer, head and neck cancer, lung cancer, and sarcoma.3 The incidence of dermatitis is higher for these patient populations due to the higher radiation doses typically employed for these cancers. In fact, approximately 95% of cancer patients who receive radiotherapy with or without chemotherapy for these conditions will develop RDS and 20% to 25% will experience moist desquamation and ulceration.4
When the mechanism of ionizing radiation and the subsequent development of RDS are taken into account, the use of EGCG as a therapeutic tool makes sense.
In breast cancer alone, more than 50% of those diagnosed will undergo radiation.5 In fact, current guidelines recommend radiation be given within 6 months after surgery.6,7 The local side effects of radiation include erythema, pain, moist desquamation, compromise of mucosal membranes (most notable in patients undergoing radiation of the head and neck), pruritus, edematous tissue, alopecia, and xerosis. Systemic effects may include fatigue, lymphocytopenia, anemia, diarrhea, nausea, emesis, and depression. Erythema alone typically presents within the first week of treatment.4
If radiation-induced dermatitis is not managed properly, preferably at its onset, other effects may occur months to years later. Potential late effects include not only abnormal skin reactions, but also the development of a second cancer.8 The prolonged and toxic effects associated with radiation are most notable and most significant in patients who are also undergoing additional forms of cytotoxic therapy (eg, chemotherapy, surgery), are receiving implants or reconstructive surgery, or have comorbidities such as anemia, diabetes, and immunosuppression. However, despite its risks and associated skin toxicities, radiation remains an effective and important mainstay in the treatment of several cancers. As practitioners, it behooves us to incorporate therapies that prevent or reduce side effects associated with RT.
The current clinical practice guidelines for the prevention and treatment of acute and late radiation reactions recommend washing with water, with or without a mild soap, and using only topical corticosteroids, pentoxifylline, and vitamin E to manage RDS.9 The recommendations are conservative because there is insufficient clinical evidence to support the use of other substances, even those commonly employed by many radiation centers. No major changes to these guidelines have been made since they were adopted in 2013.
Understanding the pathophysiology of radiation-induced dermatitis may help explain why EGCG, one of the primary constituents found in green tea, is beneficial.
Ionizing radiation is the most common type of radiation used in cancer treatment. As the ionizing radiation passes through molecules, it removes electrons and forms short-lived free radicals. The free radicals cause immediate and significant structural damage and, most importantly, irreversible double-stranded DNA breaks.10 This tissue damage triggers inflammation, resulting in erythema, one of the first hallmarks of RD. Continued exposure to radiation results in the destruction of mitotic divisibility of the stem cells at the basal level of the skin. This may result in long-term cutaneous toxicity.4,11
When the mechanism of ionizing radiation and the subsequent development of RDS are taken into account, the use of EGCG as a therapeutic tool makes sense. Previous studies have demonstrated that EGCG has the ability to scavenge superoxide anions, hydroxyl radicals, and hydrogen peroxide. In addition, it has the ability to bind free radicals, protecting DNA from radiation-induced damage.12 By inhibiting the activity of proteasome, a key regulator of inflammation, EGCG can suppress pro-inflammatory cytokines including but not limited to interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor (TNF)-α. Notably, tea polyphenols have been shown to suppress NFkappa-B, one of the most notorious proteasome-dependent transcription factors associated with the inflammatory response.13 The blockage of proteasome and transcription factors is likely why curcumin, another herbal treatment we have previously discussed, has also displayed a significant positive effect on RDS.
In clinical practice, a dose of 660 μmol EGCG per liter, as used in the study under review, is achievable. This dose equates to 0.303 grams of EGCG per liter (302.5 mg/L). The typical EGCG supplement contains about 175 mg per capsule (higher quality supplements typically contain a higher concentration of EGCG). Therefore, to achieve this concentration, roughly 2 capsules of a given EGCG supplement can be mixed in 1 liter of solution (in this case, saline). In addition, the administration device could be something as simple as a nasal spray mister. Adding in 1 or 2 capsules of curcumin and/or boswellia, which have also been studied and proven effective in the amelioration of RDS,14-16 could also be considered. Of course, this provides the idea for yet another study—a study to assess the use of topical EGCG, curcumin, and boswellia for the treatment of RDS. There may be a synergistic benefit here. The bottom line is that the nontoxic nature and potential efficacy of EGCG for the amelioration of RDS make it a desirable therapy.
Of course, this provides the idea for yet another study—a study to assess the use of topical EGCG, curcumin, and boswellia for the treatment of RDS.
The study at hand is not the first time EGCG has been identified as a potentially effective treatment for RDS. While the pool of research is small, the 4 studies that follow also support its effectiveness.
The earliest, a retrospective study in 2006, found that topical green and black tea extracts restored skin integrity in patients (n=60) undergoing head and neck radiotherapy. The EGCG-containing tea extracts modulated production of IL-1β, IL-6, IL-8, and TNF-α, and also appeared to protect macrophages.17
A second study (Phase I), published in 2014, assessed the effect of oral EGCG in patients with advanced stage III non-small cell lung cancer (NSCLC) undergoing concurrent chemotherapy and thoracic RT. The authors concluded that the oral administration of EGCG was feasible, safe, and effective and found that it produced a dramatic regression of esophagitis to Grade 0/1 in 22 of 24 patients. Grade 2 esophagitis persisted in 2 of 24 patients at the end of radiotherapy.18 Although this study did not use topical EGCG, the mechanisms of action may be similar, especially given that EGCG did bypass the esophageal tissue on intake. It is uncertain whether or not the tissue was directly exposed to the compound.
This study was followed in 2015 by a Phase II study of 37 patients, which again measured the effectiveness of oral EGCG for the reduction and management of acute radiation-induced esophagitis in those with stage III NSCLC. The RTOG scores (as assessed by healthcare practitioners) from weeks 1 to 5 of RT and the 2 weeks following RT decreased significantly with the use of oral EGCG. In addition, the weekly pain scores were significantly lower than baseline scores.19
A fourth study, also a Phase I trial, preceded the current study under review. The study evaluated the effectiveness of topical EGCG in 24 patients. Grade 2 RDS was observed in 8 patients during or after RT and all cases decreased to Grade 1 after EGCG treatment. In addition, patient-reported symptom scores were significantly decreased at 2 weeks after the end of RT. The dose of EGCG was escalated to 660 μmol/L with no adverse effects (although it is notable that no maximum dose was found), and this dose was elected as the concentration employed for the subsequent Phase II study.1 The Phase I study, like the one under review, was not placebo-controlled.
While the current Phase II study by Zhu et al appears to support the use of EGCG as an adequate and safe therapy in the management of RDS, several limitations remain. First and foremost, this study was not a placebo-controlled randomized trial. In fact, none of the studies that assessed the use of EGCG in the management/amelioration of RDS mentioned in this review were placebo-controlled. Without a control group it is not possible to determine whether the reduction in RDS was solely associated with the use of EGCG or simply a result of the self-restoring capacity of the skin itself. As noted above, decreased immunity and skin integrity are associated with increased propensity for radiation-induced skin damage and are also associated with increased age.
A second limitation is the inability of researchers to ensure a standard radiation dosimetry. Three-dimensional planning radiotherapy was not employed.
A third important factor regards the topical EGCG solution itself: the use of saline as the solvent.1 Saline is recommended as a treatment for radiation burns, specifically for the reduction of swelling, irritation, redness, and itchiness.20 It is possible that saline was the active ingredient in the spray, and absent a saline-only placebo group we cannot be sure the EGCG was the active agent.
Fourth, the sample size of this study (and the studies discussed above, and most of the studies regarding natural therapies) is small. So, although the results do appear to be “significant” (P= >0.05) this may or may not be the case with a larger study sample. A study of a larger sample will help to confirm or negate our confidence that EGCG offers amelioration and potential prevention of radiation-induced dermatitis. What we can say now, with reasonable confidence, is that EGCG appears to be a safe, nontoxic, and potentially effective armament in the management of RDS.
Finally, any effort to reduce symptoms associated with cytotoxic therapy may also result in the negation of its very therapeutic efficacy. While the use of topical green tea does not likely counteract or change radiation cytotoxicity, oral EGCG may. A 2011 in vitro study of EGCG application to prostate cancer cells also treated with ionizing radiation found that EGCG acted as an antioxidant, reducing apoptosis induced by radiation.21 However, a 2012 study in human subjects found the opposite effect.22 This study suggests that oral EGCG may actually prove synergistic with ionizing radiation. It found that 400 mg of oral EGCG, given 3 times a day to breast cancer patients undergoing radiotherapy, not only reduced NF-kappaB but also seemed to augment the apoptosis-inducing effects of the RT itself. More data is needed to assess potential risks associated with the use of oral EGCG during ionizing radiation.
In conclusion, EGCG can be placed among other natural therapies as a potentially effective tool in an area lacking clear therapeutic guidelines. The 2013 clinical practice guidelines for the prevention and treatment of acute and late radiation reactions may be due for a warranted revision in the near future. Until then, practitioners must weigh the risks and benefits of EGCG for each individual patient, using the best information available.
