A 67-year-old female patient with history of non-ischemic cardiomyopathy (baseline left ventricular ejection fraction of 35%) presents with recent unintentional weight loss, night sweats, and low-grade fever. She has baseline New York Heart Association Class I heart failure (HF), and had implantable cardioverter defibrillator placement several years ago, and has been on target doses of lisinopril, carvedilol, and spironolactone without the need for a loop diuretic. Further workup with computed tomography scan of abdomen and pelvis reveal diffuse lymphadenopathy. Based on biopsy of an affected lymph node, she is diagnosed with stage III-B Hodgkin's lymphoma with high-risk features. Anthracycline-based chemotherapy is thought to have greatest curative potential; however, given her preexisting cardiomyopathy, she is considered very high risk for development of worsened HF with use of anthracyclines. Her physical examination is unremarkable; she appears euvolemic.
Which of the following is the most efficient strategy for cardioprotection?
The correct answer is: B. Administer intravenous dexrazoxane prior to anthracycline infusion
Anthracyclines are some of the most commonly used chemotherapeutic agents. However, due to a high incidence of cardiotoxicity, their utility is limited in patients with a pre-existing cardiomyopathy or HF.1 Although the cumulative dose of anthracyclines is an independent predictor of cardiotoxicity, there is no minimum safe dose.2 This patient, who had a preexisting cardiomyopathy, is at higher risk for anthracycline-related cardiotoxicity. Dexrazoxane protects against the cardiotoxic effects of anthracyclines3 but is underutilized given its narrow Food and Drug Administration (FDA) approval for adults with advanced breast cancer with a cumulative treatment dose of at least 300 mg/m2 and concern for reduced anti-tumor response rates. This does not address the challenge faced by patients with pre-existing cardiomyopathy who require anthracyclines, like this patient. Although there was initial concern regarding the reduced anti-cancer effects of anthracycline when used with dexrazoxane, this finding has not been reproduced in multiple clinical studies.4 The current FDA approval is based on the original study done in patients with breast cancer,5 but the protective effect of dexrazoxane is specific to anthracycline-induced cardiotoxicity and not related to any specific cancer. In patients who are at higher risk given preexisting cardiomyopathy and require anthracycline-based chemotherapy, it is reasonable to consider concomitant use of dexrazoxane from the beginning of the therapy regardless of type of cancer or cumulative anthracycline dose. Of course, these high-risk patients should be monitored closely for the development of cardiotoxicity with cardiac biomarkers and echocardiography prior to beginning of each cycle of treatment.
Neither amlodipine nor aspirin have shown any significant protective effects against anthracycline-induced cardiotoxicity. The only effective way to avoid late cardiotoxic effects appears to be to prevent cardiac injury during chemotherapy. Although this patient is considered high risk for worsening of left ventricular systolic dysfunction and development of HF with anthracycline therapy given her pre-existing cardiomyopathy, refraining from the best available treatment for her malignancy may not be ideal. The first line therapy should be considered after collaboration with cardio-oncology under close surveillance.
Ganatra S, Majithia A, Shah S. Expanding the Role of Dexrazoxane For Cardioprotection: Use in a Patient with Pre-Existing Systolic Dysfunction and No Prior Anthracycline Exposure. J Am Coll Cardiol 2017;69:2389.
Cardinale D, Colombo A, Bacchiani G, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-8.
Lipshultz SE, Rifai N, Dalton VM, et al. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med 2004;351:145-53.
Chow EJ, Asselin BL, Schwartz CL, et al. Late Mortality After Dexrazoxane Treatment: A Report From the Children's Oncology Group. J Clin Oncol 2015;33:2639-45.
Swain SM, Whaley FS, Gerber MC, et al. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol 1997;15:1318-32.