Ryan JL, Heckler CE, Ling M, et al. Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res. 2013;180(1):34-43.
A randomized, double-blind, placebo-controlled clinical trial. Weekly assessments were conducted to assess occurrence/severity/progression of radiation dermatitis.
Thirty adult females with non-inflammatory breast cancer or carcinoma in situ who received radiation therapy without chemotherapy. All patients were prescribed radiation therapy without concurrent chemotherapy. The average age of subjects was 58.1 years, and 90% were Caucasian.
Study Medication and Dosage
Patients were randomized to receive either 6 g of curcumin per day (divided into 2 g doses 3 times daily) or matching placebo capsules containing 500 mg dicalcium phosphate and a yellow food coloring. The total prescribed radiation dose ranged from 42.6 to 50.4 Gy. The total number of sessions ranged from 16 to 33.
Radiation dermatitis (RDS) was assessed using a radiation severity score (a scoring system adapted by the Radiation Treatment Oncology Group), redness measurement (via colorimeter), digital imaging of skin changes, and completion of 2 self-report questionnaires: Symptom Inventory (SI) (symptoms included, but were not limited to, nausea, vomiting, diarrhea, and disturbed sleep) and McGill Pain Questionnaire-Short Form (MPQ-SF). Patients were assessed at baseline, weekly after every fifth radiation therapy (RT) session, at the end of RT, and at 2 post-RT appointments (at 1 month and 6 months post last RT session).
In those subjects assigned to the use 6 g curcumin, daily, there was a significant reduction in radiation dermatitis at the end of RT compared to placebo (P=0.008). Average RDS scores for patients treated with curcumin were 0.8 lower (scale range: 1–4) than placebo group. (Of note: this is more than 1 increment on the RDS scale). Furthermore, differences of RDS scores were evident at week 4 of treatment. The most significant effect was noted when measuring moist desquamation. Fewer patients in the curcumin arm experienced moist desquamation than those receiving placebo (P=0.002). Furthermore, although there was no significant difference in incidence of pain, the quality of pain was significantly different between study groups. Examination of each individual pain descriptor—“gnawing,” “aching,” and “splitting”—resulted in this difference (P=0.021). Due to the size of the study and high P value, it may be impossible to attribute this trend to artifact or true correlation.
Remaining study measures showed insignificant benefit between curcumin and placebo. In those patients who had undergone prior mastectomy (2 in curcumin arm and 1 in placebo arm), curcumin provided no significant benefit and, in fact, all 3 patients experienced the most severe skin reaction. A larger study is needed to verify the significance of this finding. Skin color changes were noted in both arms of the study. Curcumin was not found to protect from or decrease erythema. Although previous studies have reported mild to moderate diarrhea associated with the use of curcumin, in this case, no effect was evident. This suggests that curcumin, at a dose of 6 g/day was well tolerated by all patients.
Radiation dermatitis is a problem for most patients undergoing RT. The local side effects consist of and are not limited to: erythema, pain, moist desquamation, compromise of mucosal membranes (most notable in those patients undergoing radiation of the head and neck), pruritis, 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. Other effects may occur months to years post treatment. These may involve abnormal skin reactions and the possibility of developing a second cancer.1 Radiation remains an effective and important mainstay in the treatment of several cancers. It therefore behooves us as practitioners to incorporate means to prevent and manage side effects associated with the RT.
As of August 2013, clinical practice guidelines for the prevention and treatment of acute and late radiation reactions, from the Multinational Association for Supportive Care in Cancer (MASCC) Skin Toxicity Study Group, recommend the adoption of washing with water, with or without a mild soap, and that only topical corticosteroids, pentoxifylline, and vitamin E be employed for the management of RDS.2 These conservative recommendations have been made due to insufficient clinical evidence for other substances, even those that are commonly employed to many radiation centers.
A small pool of research exists on the management of radiation dermatitis with natural treatments. Unlike the current study, most of these previous research studies have focused on the use of topical treatments to manage local skin reactions. The results are conflicting and a clear outlier remains elusive.
One potential treatment is the use of a topical platelet gel. A January 2013 study reported that a once per week application of this gel (described as “home-made,” produced by treating platelets with autologous thrombin) was beneficial in 7 of 10 patients in a small open-label study.3 Researchers conducting the study hypothesize that the use of platelet gel may promote tissue regeneration (through the production and action of various growth factors) and provide antibacterial benefits.
A second, in vitro study, published in February 2013, reports platelet gel is effective in the treatment diabetic foot ulcers. This study found antibacterial properties against Staphylococcus aureus but not against Escherichia coli or Pseudomonas aeruginosa.4 While intriguing, the evidence for using platelet gel is still weak and there is valid concern about using any treatment that stimulates growth factors, specifically around a site of tumor growth.
In August 2011 a study was published evaluating the use of a silymarin-based preparation (Laviaderm) to prevent radiation dermatitis. This non-randomized, observational trial, evaluated the benefit of the silymarin preparation in postsurgical breast cancer patients. The sample size was 101. Fifty-one patients were treated with the silymarin-based cream. The remaining 50 received “standard of care” during RT. Study results reflected a significantly prolonged time to toxicity in those patients who used the silymarin-based cream compared to those who did not.5 Although promising, the study design (non-blind, non-randomized) compromises the validity, and therefore the understanding of the effectiveness of silymarin-based cream in the management/prevention of RDS.
Some people have used hyaluronic acid for the management of radiation dermatitis. However, its benefits remain unclear. In a single-blind randomized phase III clinical trial of 74 patients, hyaluronic acid was compared to a petroleum-based gel. Unexpectedly, 62% of patients using hylaruonic acid developed a significantly higher rate of grade II dermatitis, compared to 48% of those in the petroleum arm.6 In this case, the use of hyaluronic acid provided no benefit, and may hasten the development of radiation dermatitis.
Pot marigold (Calendula officinalis) is frequently suggested for the prevention of skin damage during radiation treatment. Recent studies are inconclusive. A randomized controlled clinical study, published in March of 2013, demonstrated its potential effectiveness in decreasing the intensity of radiotherapy-induced oral mucositis in those undergoing RT or concurrent chemoradiation for head and neck cancers within 4–7 weeks. Forty subjects received either calendula mouthwash as oral gel or placebo. Mucositis severity was measured with the oral mucositis assessment scale (OMAS). A significant difference was found week 2 (score: 11.4 vs. 13.35), week 3 (score: 8.25 vs. 10.95, P<0.0001), and week 6 (score: 11.4 vs. 13.35, P=0.031).7 A second study, published in August of 2013, showed no effect with topical calendula for those undergoing adjuvant RT for breast cancer. In this blinded, randomized clinical trial, 420 patients were randomized to receive either calendula cream or Essex™cream (the latter an aqueous-based solution). No statistically relevant differences were found in skin-related symptoms between groups.8
Xenaderm™, an ointment specifically manufactured for the treatment of ulcers and wounds, and has been studied for its benefits in alleviating and preventing radiation dermatitis. Active ingredients include castor oil, trypsin, and Balsam Peru. A meta-analysis from 2010 found the ointment to be efficacious and adequate in the treatment of radiation-induced skin damage, effectively healing wounds twice as fast as saline-based treatments.9 It is important to note that, because this is an oil-based treatment, its use must be restricted to post-radiation skin changes. Oil potentiates radiation-induced burns.10
Study incorporates the use of an herb that has been studied and found statistically valuable in the management/prevention of several cancers.
In recent years, there has been increased use of complementary and alternative treatments (CAM) in breast cancer patients during radiation. A prospective, multi-dimensional study published in 2013 found those who did employ CAM practices reported significantly lower skin toxicity scores.11 So although it remains unclear which CAM therapy is superior, it is evident that patients are experiencing some relief with their use. Studies similar to the evaluation of curcumin during RT offer some insight and direction into how and why these practices may be highly efficacious and, in the long run, may provide established standards of care in the prevention and management of RDS.
Curcumin remains a leading armament in naturopathic oncology. We know that this constituent of the spice turmeric (Curcuma longa) offers preventative properties and has been studied in the management of numerous cancers.12–16 Some of its actions are (1) the inhibition of certain genes that trigger cancer, (2) the prevention of metastases and angiogenesis, (3) the stimulation of apoptosis in malignant cells, (4) the enhancement of chemotherapy and radiation without potentiating toxic side effects and now, (5) the potential management of skin damage caused by radiation.
Curcumin was dosed as a single aggregate in this study, without piperine and/or an emulsifier, 2 means of increasing the bioavailability of curcumin without compromising its biological activity.17 A future study incorporating curcumin in a formulation, with an increased bioavailability, may be practical. It is possible that if curcumin provides benefit, it could do so at a potentially lower dose.
In India, the use of turmeric on bandages to promote wound healing is and has been a common practice for hundreds of years.12 Perhaps this centuries-old practice offers insight into current and efficacious medical interventions in the treatment of wounds caused by radiation. This traditional topical use, coupled with the current abstract suggesting some benefit from oral consumption of curcumin, leaves us with many questions and directions for future research. Might we apply curcumin (in a non-oil based form) to address radiation-induced skin damage? How effective might it be locally?
So, what does all of this mean for our practices and management of radiation dermatitis? Certainly, a larger study is needed to assess the effects of curcumin for those undergoing radiation therapy. In addition, the outcome of radiation in these women is not known. A follow-up study, perhaps 5 years or more, would serve to elucidate a post-radiation recurrence rate. While rodent studies suggest curcumin may enhance radiation cytotoxicity,18,19 it is best for us practitioners to first see the clinical data that an oral agent that lessens a side effect does not do so at the expense of efficacy. However, the current study is useful in several ways. Primarily, it provides further direction into a potentially efficacious and relatively inexpensive means of managing RDS. Secondly, the study incorporates the use of an herb that has been studied and found statistically valuable in the management/prevention of several cancers, making it a potential asset for those patients diagnosed with cancer and undergoing radiation treatment. And finally, its topical use for the management of RDS remains to be determined.