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Therapies for prevention of cardiotoxicity in breast cancer confer mixed results
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ORLANDO, Fla. — Two studies of medications for prevention of cardiotoxicity-induced myocardial injury in patients with breast cancer did not meet their primary outcomes, but suggested benefits in certain patients.
The CECCY study found carvedilol did not prevent reduction in left ventricular ejection fraction; however, treatment conferred less of an increase in troponin I and less diastolic dysfunction compared with placebo. In another trial, carvedilol and lisinopril did not improve cardiotoxicity-free survival in the overall cohort of patients treated with trastuzumab (Herceptin, Genentech), but was associated with improvement in patients also treated with anthracyclines.
“This is a tremendous advancement,” Ana Barac, MD, PhD, director of the cardio-oncology program at the MedStar Heart and Vascular Institute in Washington, D.C., said during a panel discussion of these trials at the American College of Cardiology Scientific Session. “We’re increasing [our ability] to help patients at the beginning of the initiation of cancer therapy, and there’s scarce data in this.”
Findings from the CECCY trial
The CECCY trial evaluated the effectiveness of carvedilol in the prevention of early-onset chemotherapy-induced cardiomyopathy in patients with breast cancer. The trial enrolled women with breast cancer and an indication for chemotherapy including doxorubicin (mean age, 51 to 53 years). Women were assigned to treatment with carvedilol (n = 96) or placebo (n = 96) for 20 weeks while receiving anthracycline infusion. Physical exam, biomarker analysis and echocardiography were performed during follow-up through 24 weeks.
Therapies for prevention of cardiotoxicity in breast cancer confer mixed results
At 6 months, the primary endpoint — 10% or greater reduction in LVEF — occurred in 15% of the carvedilol group vs. 14% of the placebo group. Changes in systolic dysfunction, LVEF or B-type natriuretic peptide were not different in both groups, according to data presented by Mônica Samuel Avila, MD, cardiologist assistant in the heart transplant and heart failure department at the Heart Institute of Clinical Hospital at the University of São Paulo in Brazil.
Over time, troponin I levels were significantly lower in the carvedilol group vs. the placebo group (P = .003).
Patients assigned placebo showed a progressive increase in diastolic dysfunction vs. those assigned carvedilol. In the carvedilol group, diastolic dysfunction increased from 22.9% at baseline to 30.2% at 24 weeks, whereas in the placebo group, diastolic dysfunction increased from 15.2% at baseline to 39.3% at 24 weeks (P = .039 for comparison). The carvedilol group was more likely to exhibit reduction in end-diastolic diameter compared with the placebo group (44.1 mm to 45.2 mm vs. 44.9 mm to 46.4 mm, respectively; P = .057).
Clinical events were similar in both groups, with two deaths reported in each group during follow-up.
“Our findings suggest that carvedilol might reduce myocardial injury, might influence the LV remodeling process in the cardiotoxicity setting and might decrease the appearance of diastolic dysfunction also in this setting,” Avila said.
Trastuzumab cohort
For the second study, Maya Guglin, MD, professor of medicine at the University of Kentucky and director of the VAD program at University of Kentucky Gill Heart and Vascular Institute, and colleagues analyzed 468 patients with early stage breast cancer (mean age, 51 years) who received trastuzumab for 1 year as part of multimodality breast cancer treatment. All patients were followed for an additional year after their treatment ended. Patients were stratified by whether they were also receiving anthracycline treatment. Both the anthracycline and non-anthracycline groups were randomly assigned carvedilol, lisinopril or placebo.
“The primary objective was to determine if administration of lisinopril or carvedilol results in a decrease in the rate of cardiotoxicity compared with placebo,” Guglin said during a presentation.
Cardiotoxicity was defined as a decrease of at least 10% in LVEF or, if LVEF dropped below 50% during the study, a decrease of at least 5%.
When all patients were analyzed together, there was no significant difference between carvedilol, lisinopril or placebo in rate of cardiotoxicity.
However, among patients who were also treated with anthracyclines, carvedilol (HR = 0.49; P = .009) and lisinopril (HR = 0.53; P = .015) were both associated with a lower rate of cardiotoxcity compared with placebo.
“Unfortunately, this study did not have centralized echocardiogram review and relied on field reports of echocardiography results for primary endpoint, not providing an opportunity for assessment of LV remodeling and most importantly quality control,” Barac said.
“Cardiotoxcity associated with trastuzumab superimposed on prior or current exposure to anthracyclines can be prevented with carvedilol or lisinopril,” Guglin said. “In high-risk patients who may benefit from an anthracycline-containing regimen,” the use of lisinopril or carvedilol is justified and should be considered to offset cardiotoxic events by the use of anthracyclines in combination with trastuzumab.” – by Darlene Dobkowski and Erik Swain
References:
Avila M, et al.
Guglin M, et al. Late-Breaking Clinical Trials III. Both presented at: American College of Cardiology Scientific Session; March 10-12, 2018; Orlando, Fla.
Avila MS, et al. J Am Coll Cardiol. 2018;doi:10.1016/j.jacc.2018.02.049.
Disclosures:
Avila, Barac and Guglin report no relevant financial disclosures.