By Van Selby, MD
Assistant Professor of Medicine, UCSF Cardiology Division, Advanced Heart Failure Section, San Francisco, CA
Dr. Selby reports no financial relationships relevant to this field of study.
SOURCE: Cardinale D, et al. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation 2015;131:1981-1988.
Anthracyclines are used to treat a broad range of malignancies. Cardiotoxicity is a well-known complication that leads to substantial morbidity and often limits the utility of these agents. Current understanding of anthracycline cardiotoxicity is primarily based on retrospective studies, with wide variation in reported incidence and prognosis. As a result, evidence-based consensus recommendations for the identification and treatment of anthracycline cardiotoxicity are lacking.
Cardinale et al prospectively measured left ventricular ejection fraction (LVEF) at baseline and at regular intervals before, during, and after treatment in 2625 adult patients receiving an anthracycline-containing regimen. Patients were followed for a median of 5.2 years. Cardiotoxicity was defined as a decrease in LVEF > 10 points and to < 50%. All patients with cardiotoxicity were started on heart failure therapy with enalapril and beta-blockers titrated to maximal tolerated doses.
The overall incidence of cardiotoxicity was 9%. The median time elapsed between the completion of chemotherapy and development of cardiotoxicity was 3.5 months, and 98% of all cardiotoxicity occurred within the first year after chemotherapy was completed. Key predictors of cardiotoxicity were LVEF at the end of chemotherapy and cumulative anthracycline dose. With medical therapy for heart failure, 11% of patients had full recovery and 71% had partial recovery (defined as an increase in LVEF of at least 5 points and > 50% with no heart failure symptoms). Severity of LV dysfunction and NYHA functional class were the strongest predictors of recovery. The authors conclude that cardiotoxicity is a relatively common complication of anthracycline-based chemotherapy in adults, almost always occurs within the first year after chemotherapy is completed, and usually recovers with prompt initiation of heart failure therapies.
With improvements in the detection and treatment of malignancies, cancer patients are living longer and side effects of chemotherapy, such as anthracycline cardiotoxicity, are gaining importance. This study marks a major advancement in our understanding of the incidence, risk factors, and time course of anthracycline cardiotoxicity, as well as the response to treatment. Chronic anthracycline cardiotoxicity traditionally has been divided into early-onset and late-onset progressive disease. The findings of Cardinale suggest the vast majority of cardiotoxicity actually occurs early on, within the first year after treatment. Most patients were asymptomatic (NYHA class I or II) at the time of diagnosis. Rather than separate disease entities, anthracycline cardiotoxicity may represent a continuum, with most “late” cardiotoxicity actually developing much earlier. Patients are often only diagnosed with cardiotoxicity once they become symptomatic from their LV dysfunction. In fact, all of the five patients who developed late-onset LV dysfunction (more than 1 year after finishing chemotherapy) in this study had other risk factors for heart failure. It is possible the prior anthracycline exposure was not the only cause of cardiotoxicity in these patients.
The response to heart failure therapy observed in this cohort is impressive and highlights the importance of early detection. Anthracycline cardiotoxicity is traditionally thought of as a type I cardiotoxicity, characterized by irreversible cardiomyocyte death. Cardinale et al challenge this notion and prove, at least in the early stages, that anthracycline-mediated LV dysfunction does not appear to be an irreversible process.
There are several important limitations to this study. All patients were treated with heart failure therapy once cardiotoxicity was identified, so we cannot make definite conclusions regarding the natural history of this early, often asymptomatic LV dysfunction. It is possible that many of the patients who were treated with beta-blockers and ACE inhibitors never would have gone on to develop clinically significant heart failure. The study also doesn’t discuss what adjustments were made to the chemotherapy regimen after cardiotoxicity was identified nor what impact any changes may have had on their oncologic outcome.
Current guidelines from the AHA/ACC recommend echocardiography at baseline and for re-evaluation to monitor patients exposed to anthracyclines. The guidelines do not specify how frequently monitoring should be done, which echocardiographic parameter to use, or how treating physicians should respond to a decrease in LV systolic function. The FDA recommends discontinuing doxorubicin in all patients with a 10% decrease in LVEF or to < 55%.
Although more research is still needed in the emerging field of cardio-oncology, this study provides valuable insights into anthracycline cardiotoxicity and may ultimately change the current classification system and understanding of the underlying pathophysiology. The key lessons are that cardiotoxicity occurs early on, and with prompt initiation of standard medical therapy for systolic heart failure, most patients can usually recover LV function. Surveillance based solely on symptoms may miss this early window during which patients are responsive to treatment.