Serum cardiovascular growth factors during doxorubicin chemotherapy in children with leukemia

  • Dr Steven Lipshultz, University of Miami Miller School of Medicine, United States
  • Ms Rebecca Scully, University of Miami Miller School of Medicine, United States
  • Ms Holly Smith, Vanderbilt University School of Medicine, United States
  • Mr Brent Anderson, Vanderbilt University School of Medicine, United States
  • Dr Tracie Miller, University of Miami Miller School of Medicine, United States
  • Dr Stuart Lipsitz, Brigham and Women's Hospital, United States
  • Dr Stephen Sallan, Dana-Farber Cancer Institute, United States
  • Dr Douglas Sawyer, Vanderbilt University School of Medicine, United States

    • Objective: To better understand individual susceptibility to doxorubicin (DOX) chemotherapy-related cardiotoxicity in children undergoing treatment for leukemia, we examined serum levels of neuregulin-1beta (NRG), cardiotrophin-1 (CT-1), vascular endothelial growth factor (VEGF), and interleukin-6 (IL-6), each of which alter myocardial responses to DOX in animals.
    Methods: Serum collected during treatment from 90 DOX-treated children (30 mg/m2 every 3 weeks for 10 cycles) at baseline, mid- and late-treatment was analyzed for NRG, CT-1, IL-6 and VEGF levels. Serum cardiac troponin T (cTnT) and high-sensitivity C-reactive protein levels (hsCRP) were assessed previously.
    Results: CT-1 and NRG levels decreased significantly with time; mean CT-1 was 800 pg/ml at baseline, 205 pg/ml mid-treatment and 19.1 pg/ml at late-treatment (p < .001). Mean NRG was 17.9 pg/ml at baseline, 13.5 pg/ml mid-treatment, and 7.7 pg/ml late (p < .001). VEGF was stable between baseline (145 pg/ml) and mid-treatment (177 pg/ml), but increased at late-treatment (292 pg/ml) compared to mid-treatment (p = 0.0035). Mean IL-6 decreased from baseline (32.3 pg/ml) to mid-treatment (9.2 pg/ml; p < 0.001), but not between baseline and late-treatment (21.5 pg/ml; p = 0.13). IL-6 correlated with hsCRP (r = .405, p < .001) and was higher when cTnT was elevated (cTnT ≥ 0.01 ng/ml; median IL-6: 17.6 vs. 4.1 pg/ml, p = 0.017).
    Conclusions: CT-1 and NRG decline with DOX-treatment promoting increased cardiac apoptosis, left ventricular remodeling, and decreased left ventricular function and mass. IL-6 and VEGF changes suggest DOX-related inflammation and angiogenesis, especially in the setting of myocardial injury.