Randomized controlled phase II trial of simvastatin as prophylaxis against radiation-induced skin toxicity in breast cancer patients.

Abstract

TPS1143 Background: Most women receiving adjuvant radiation (RT) for breast cancer (BC) have significant acute skin toxicities ranging from erythema to moist desquamation. Late skin toxicities include fibrosis and telangiectasia. The inflammatory response to RT is mediated by RT-induced endothelial cell expression of the cell adhesion molecule E-selectin, to which neutrophils and monocytes adhere and then infiltrate into tissues. Blockade of this mechanism could interrupt the inflammatory cascade at an early stage. Preclinical studies have shown that statins can inhibit RT-induced E-selectin expression and skin and intestinal inflammation in vivo without impairing DNA damage or tumour response to RT. Retrospective clinical studies have shown reduced relapse rates with statins in breast cancer patients. Thus statins have the potential to reduce the acute RT-induced inflammatory component without compromising the DNA-damaging effects essential to cancer cell death. This is the only registered trial evaluating the effects of statins on acute RT toxicity. Methods: Randomised open controlled phase II trial of simvastatin 40mg daily during and for 3 weeks after RT. Eligibility: women with invasive or in-situ BC receiving whole-breast +/- lymphatic RT; dose fractionation schedules include 50Gy/25 #, 45Gy/20#, 42.5Gy/16 # or 40Gy/15#, with or without a boost; may have had prior chemotherapy, and be on hormonal or Trastuzumab therapy during RT; no prior statins within 6 weeks of starting RT. Stratification by breast conserving surgery vs mastectomy, use of boost and fraction size (<2 Gy vs >2 Gy). Primary endpoint: incidence of > grade 2 acute RT-related skin toxicity. Secondary endpoints: time to onset of skin toxicity, proportion requiring additional topical treatment, compliance with trial medication, statin-related toxicities and subjective RT-related toxicities (breast discomfort and fatigue). Statistical design: 130 randomised patients gives 90% power (one-sided a 0.20) to detect a reduction in > grade 2 acute skin toxicity from 55% to 35%. Enrolment opened January 2013, planned to complete by April 2014. Clinical trial information: ACTRN12612000662864.