Skin toxicity following radiotherapy in patients with breast carcinoma: is anthocyanin supplementation beneficial?

Summary

Background

The EU-supported ATHENA project stems from a previous study suggesting that moderate wine consumption reduced the side-effects of radiotherapy (RT) in breast cancer patients, an effect possibly due to non-alcoholic anthocyanin fractions of wine.

Objective

To evaluate the role of anthocyanins on RT skin side effects in breast cancer patients.

Methods

Randomized, controlled, double-blind clinical trial. Patients were assigned to an intensity modulated radiation therapy (IMRT) either for three or five weeks, then randomized to receive three times a day a water-soluble anthocyanin (125 mg)-rich extract of corn cob or a placebo. Supplementation started one week before till the end of RT. Skin characteristics were detected by a standardized, non-invasive Cutometer® dual-MPA580, providing quantitative indices of skin maximal distensibility (R0), elasticity (R2, R5, R7) and viscoelasticity (R6); a Mexameter® MX18 probe evaluated the skin erythema (Er) and melanin (M). Measures were performed before (T0), at the end of RT and of supplementation (T1), and 1, 6 and 12 months after RT (T2-T4). Acute and late skin toxicity were scored according to the RTOG/EORTG scale. Selected biomarkers were measured at T0 and T1.

Results

193 patients previously assigned to 3- or 5-week RT schedules were randomized to either anthocyanin (97) or placebo (96) supplementation. RT induced changes in skin parameters: R0, R2, R5 and R7 decreased, while R6 increased; the changes in R0 and R6 continued in the same direction up to one year, while the others recovered towards basal values; Er and M peaked at T1 and T2, respectively, and returned to basal values at T4. Comparable skin changes were apparent in anthocyanin and placebo groups. A moderate RT-induced increase in total and HDL cholesterol and triglycerides was prevented by anthocyanins.

Conclusions

Anthocyanin supplementation did not prevent RT-induced local skin toxicity. The supplementation was well tolerated and safe.

Introduction

Adhesion to the Mediterranean diet reduces the risk of chronic degenerative diseases and of total mortality [1]. Bioactive polyphenols, of which fruit and vegetables contributing to the Mediterranean dietary pattern are particularly rich, possess antioxidant activities and contribute to reduce oxidative stress and to down-regulate the inflammatory response to injury. Within polyphenols, anthocyanins are a subclass of flavonoids, responsible for the red, purple and blue colors of plants and fruits, widely recognized for their anti-inflammatory and antioxidant properties [[2], [3], [4]].

In the frame of two EU-funded projects, FLORA (FLavonoids and related phenolics for healthy living using ORally recommended Antioxidants, STREP 007130) and ATHENA (AnTHocyanin and polyphenol bioactives for Health Enhancement through Nutritional Advancement, FP7-KBBE-2009-3), foods enriched in anthocyanins by genetic engineering or by genetic selection or classical breeding, have been tested in different experimental models and shown health-promoting activities against cardiovascular, cancer and neurodegenerative diseases [[5], [6], [7], [8]].

In healthy volunteers, four-week ingestion of anthocyanin-rich red orange juice resulted in measurable urine excretion of the main anthocyanin metabolites, but did not affect platelet activation nor cell inflammation markers of cardiovascular disease [9]. On the other hand, a single drink of orange juice prevented in human volunteers the post-prandial inflammatory response to a standardized fatty meal, a condition similar to a low-grade inflammatory status [10]. This finding is in keeping with the epidemiological observation that polyphenol intake was inversely associated with low-grade inflammation in the Moli-sani cohort [11].

Moving from healthy subjects and a general population to patients, moderate wine consumption was reported in a retrospective observational study to be protective from skin toxicity induced by radiotherapy (RT) in breast cancer patients; such effect was ascribed to the possible antioxidant activity of polyphenols contained in wine [12].

The skin response to ionizing radiation may involve multiple inflammatory outbreaks: vascular damage, with consequent thrombin generation, which induces circulating inflammatory cells to release cytokines; within the latter, the transforming growth factor (TGF)-β is responsible of dermal fibroblasts activation and skin fibrosis, interleukin (IL)-1 and tumor necrosis factor (TNF)-α stimulate metalloproteinase production and disruption of the basal cell layer, while adhesion molecules and TNF-α contribute to the inflammatory process. Anthocyanins have been shown to stimulate extracellular matrix proteins, such as collagen and elastin, in human skin fibroblasts [13]; to inhibit UV radiation-induced human dermal fibroblast injury by upregulating autophagy [14], to alter inflammatory cytokine release and actions and to blunt the excess of oxygen radicals generated by radiations [15].

The present trial was designed to test the possible beneficial effect on skin toxicity of anthocyanins derived from purple corn cobs in breast cancer patients undergoing RT [5].