A Prospective, Randomized, Placebo-Controlled Study of a Combination of Simvastatin and Chemotherapy in Metastatic Breast Cancer

Preclinical studies support the anticancer activity of statins; however, the existing clinical evidence is inconsistent and not definitive. Our study aimed at evaluating a postulated cancer chemo-sensitizing effect of statin (simvastatin) in a cohort of metastatic breast cancer (MBC) patients. We designed a prospective, single-centered, randomized, double blinded, placebo-controlled trial that encompassed MBC patients with an ECOG Performance Status Scale ≤2 and scheduled to be treated with a chemotherapy regimen consisting of carboplatin and vinorelbine every 3 weeks at Al-Baironi Hospital, Damascus, Syria. Patients were enrolled between August 2011 and July 2012 and randomly allocated to receive a 15-day course of either simvastatin (40 mg) or placebo seven days prior to the first day of each chemotherapy cycle and then continued for eight days in each individual cycle. Primary endpoints were objective response rate (ORR) and toxicity, and the secondary endpoint was overall survival (OS). Eighty-two patients met the inclusion criteria and consented. ORR (35% vs. 32.5%) and predominant toxicity and grade ≥3 neutropenia (occurred in 30% vs. 40% of the patients) were not significantly different between simvastatin and placebo groups, respectively. Over a median follow-up of 44 months (range, 10–60), median OS was 15 months in the simvastatin group and 17 the in placebo group (hazard ratio (HR) = 1.16, 95% CI (0.70–1.91), P=0.57). Elevated baseline values of high-sensitivity C-reactive protein (hsCRP >10 mg/l), lactate dehydrogenase (LDH >480 U/L), and chemotherapy being ≥2nd line were significantly associated with shorter OS for the total cohort in both Univariate and multivariate analyses. Our data prove a safe profile of simvastatin at 40 mg per day combined with carboplatin and vinorelbine in MBC patients but without any beneficial increase of tumor sensitivity to chemotherapy. Moreover, we demonstrated a strong clinical advantage of baseline values of hsCRP and LDH as useful prognostic tools in MBC patients. This trial is registered with ISRCTN12964275