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Dexrazoxane may reduce cardiotoxicity from breast cancer treatment
Dexrazoxane reduced the risk for cardiac events and clinical heart failure among women with breast cancer who underwent anthracycline chemotherapy, according to results of a systematic review and meta-analysis published in JACC: Cardio-Oncology.
The benefit persisted regardless of whether women received trastuzumab (Herceptin, Genentech) as part of their breast cancer therapy, results showed.
“Nonetheless, due to the low quality of the actual evidence available, further randomized trials are warranted before the systematic implementation of this therapy for primary cardioprotection,” Ariane V.S. Macedo, MD, MSc, cardiologist at Hospital das Clínicas Federal University of Minas Gerais and Oncoclínicas Group — the largest network of oncology clinics in Brazil — and colleagues wrote.
Cardiotoxicity is a considerable problem during and after breast cancer treatment.
Anthracyclines have been linked to acute and chronic cardiac damage. In addition, trastuzumab — a humanized monoclonal antibody that targets HER2 — may contribute to cardiomyopathy, particularly when used with anthracyclines or taxanes, according to study background.
Dexrazoxane — approved by the FDA in 1995 as a cardioprotective agent for certain patients with metastatic or advanced breast cancer — is one option for primary prevention of cardiotoxicity; however, dexrazoxane is rarely used in clinical practice due to concerns it may mitigate the antitumor activity of anthracyclines or elevate risk for secondary malignancies.
Macedo and colleagues searched the MEDLINE, Cochrane Central Register of Controlled Trials and Embase databases from January 1990 through March 1 of this year to identify trials that evaluated the efficacy of dexrazoxane for cardiotoxicity prevention among women with breast cancer who received anthracyclines with or without trastuzumab.
Investigators excluded pediatric studies and those with overlapping populations.
The analysis included seven randomized trials and two retrospective trials that enrolled a combined 2,177 women with breast cancer. Approximately half (n = 1,100; 50.5%) had metastatic or advanced disease, whereas 822 (37.7%) had nonmetastatic disease and 255 (11.7%) had early-stage disease.
All women received anthracycline-based chemotherapy with doxorubicin or epirubicin. Average cumulative doses ranged from 240 mg/m2 to 713 mg/m2. The dose ratio of dexrazoxane to anthracyclines was 10:1 or 20:1.
The women in the two retrospective cohorts also received trastuzumab.
Development of symptomatic clinical heart failure or a cardiac event — defined as subclinical heart failure, ventricular function abnormalities or hospital admission due to cardiac causes — served as the primary outcome. Secondary outcomes included dexrazoxane interference with oncologic treatment as determined by effect on response rate, OS or PFS.
Analysis of randomized trial results showed women who received dexrazoxane demonstrated lower risk for clinical heart failure (1.22% vs. 9.26%; RR = 0.19; 95% CI, 0.09-0.4).
Researchers also determined cardiac events were lower among women who received dexrazoxane (9.4% vs. 15.5%; RR = 0.36; 95% CI, 0.27-0.49). The benefit persisted when analyses were limited to randomized controlled trials (RR = 0.36; 95% CI, 0.26-0.49) or retrospective studies (RR = 0.33; 95% CI, 0.03-3.39).
Among women exposed to anthracycline-based chemotherapy for the first time, dexrazoxane significantly reduced risk for clinical heart failure (RR = 0.15; 95% CI, 0.06-0.39) and cardiac events (RR = 0.37; 95% CI, 0.24-0.58).
Patients in two of the nine studies analyzed had received anthracycline-based chemotherapy months or years earlier. Among this group, dexrazoxane demonstrated the potential to reduce the risk for clinical heart failure (RR = 0.27; 95% CI, 0.07-1.07) and risk for cardiac events (RR = 0.32; 95% CI, 0.19-0.54).
Analysis of five randomized trials in which response rates were assessed revealed no difference between dexrazoxane-exposed or -unexposed women with regard to complete response rate (RR = 1.1; 95% CI, 0.75-1.61) or partial response rate (RR = 0.88; 95% CI, 0.75-1.02).
Investigators reported no significant difference in rates of stable disease (RR = 0.92; 95% CI, 0.7-1.2), OS (HR = 1.01; 95% CI, 0.86-1.17) or PFS (HR = 0.97; 95% CI, 0.76-1.25). However, analysis of studies that included women with more advanced disease who were re-exposed to anthracyclines showed dexrazoxane was associated with reduced risk for disease progression (HR = 0.68; 95% CI, 0.49-0.94).
Investigators acknowledged limitations to their study, including their reliance on reporting of cardiotoxicity and/or clinical cardiac events, and the possibility that some patients with subclinical cardiotoxicity were not included. Also, the definitions of cardiotoxicity and cardiac events varied greatly between the studies analyzed, and the study did not include an assessment of the impact of dexrazoxane use on hematologic toxicities.
The results support the rationale of dexrazoxane as an effective cardioprotective agent for patients with breast cancer who receive anthracycline-based chemotherapy, Macedo and colleagues concluded. However, additional study is necessary because the quality of most evidence is too low to provide definitive recommendations, they added.
The researchers used the Cochrane “risk of bias” tool to assess the methodological quality of the randomized controlled trials included in their analysis.
“We found that no randomized trials were judged as low risk of bias in all bias domains,” they wrote. “The domains with more studies classified as high risk of bias were ‘performance bias’ due to knowledge of the allocated interventions by participants and personnel during the studies, and ‘attrition bias’ due to the amount, nature or handling of incomplete outcome data.
“Future high-quality randomized controlled trials should be performed [to evaluate dexrazoxane for patients with breast cancer] avoiding all potential source of bias, which could compromise the reliability of their results,” the researchers wrote.
Although the study suggests dexrazoxane has a role as a cardioprotective agent for women undergoing anthracycline-based breast cancer treatment, it is unclear which patients derive the greatest benefit, Christine E. Simmons, MD, MSc, FRCPC, medical oncologist at BC Cancer Agency, wrote in an accompanying editorial.
“The studies summarized in this most recent meta-analysis have used quite a wide range of doses of anthracyclines, as well as a wide range of disease stages — from very early and highly curable to overtly metastatic and incurable,” Simmons write. “We also do not have the ability to tease out the baseline cardiovascular risk for the individuals included in this study, which may also factor heavily into predicting those who would appreciate the most gain from such a cardioprotectant. Wouldn’t it be great if we could derive a test or a nomogram with reliable likelihood ratios to predict future risk of anthracycline cardiotoxicity for patients with breast cancer?”
Future efforts to study and clarify the potential benefit of dexrazoxane for patients with breast cancer requires careful planning and collaboration, Simmons wrote.
“As with many preventive strategies in medicine, the inertia of adopting a new treatment is victim to the competing motivations of oncologists, patients and cardiologists at the time of initial consultation,” she wrote. “We know that there are risks, but they seem a long way off in the moment when an immediate life-threatening illness is faced. For the time being, is there harm in adopting its use more widely? This meta-analysis would suggest not.” – by Mark Leiser
Disclosure: Macedo reports speakers bureau, advisory board or consultant fees from Bayer, Daiichi Sankyo, Ferring Pharmaceuticals, Novartis, Pfizer, Roche, Servier and Zodiac. Please see the study for all other authors’ relevant financial disclosures. Simmons reports honoraria from Amgen, AstraZeneca, Eli Lilly, Mylan, Novartis, Pfizer and Sandoz, as well as education or research grants from Amgen, Eli Lilly, Merck, Novartis, Pfizer and Roche.