Skip to main content
NCBI home page
JACC: CardioOncology logoLink to JACC: CardioOncology
. 2019 Sep 24;1(1):68–79. doi: 10.1016/j.jaccao.2019.08.003

Efficacy of Dexrazoxane in Preventing Anthracycline Cardiotoxicity in Breast Cancer

Ariane VS Macedo a,b,∗, Ludhmila A Hajjar c, Alexander R Lyon d, Bruno R Nascimento a, Alessandro Putzu e, Lorenzo Rossi f, Rafael B Costa b, Giovanni Landoni g,h, Angélica Nogueira-Rodrigues i, Antonio LP Ribeiro a
PMCID: PMC8352186  PMID: 34396164

Abstract

Objectives

The authors performed a systematic review and meta-analysis of randomized and nonrandomized trials on the efficacy of dexrazoxane in patients with breast cancer who were treated with anthracyclines with or without trastuzumab.

Background

Breast cancer treatment with anthracyclines and trastuzumab is associated with an increased risk of cardiotoxicity. Among the various strategies to reduce the risk of cardiotoxicity, dexrazoxane is an option for primary prevention, but it is seldom used in clinical practice.

Methods

Online databases were searched from January 1990 up to March 1, 2019, for clinical trials on the use of dexrazoxane for the prevention of cardiotoxicity in patients with breast cancer receiving anthracyclines with or without trastuzumab. Risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model meta-analysis.

Results

Seven randomized trials and 2 retrospective trials with a total of 2,177 patients were included. Dexrazoxane reduced the risk of clinical heart failure (RR: 0.19; 95% CI: 0.09 to 0.40; p < 0.001) and cardiac events (RR: 0.36; 95% CI: 0.27 to 0.49; p < 0.001) irrespective of previous exposure to anthracyclines. The rate of a partial or complete oncological response, overall survival, and progression-free survival were not affected by dexrazoxane.

Conclusions

Dexrazoxane reduced the risk of clinical heart failure and cardiac events in patients with breast cancer undergoing anthracycline chemotherapy with or without trastuzumab and did not significantly impact cancer outcomes. However, the quality of available evidence is low, and further randomized trials are warranted before the systematic implementation of this therapy in clinical practice.

Key Words: cardiomyopathy, cardioprotection, cardiotoxicity, dexrazoxane, doxorubicin, heart failure, meta-analysis, survivorship, trastuzumab

Abbreviations and Acronyms: ANT, anthracycline; BC, breast cancer; CI, confidence interval; CTX, cardiotoxicity; DEX, dexrazoxane; HER2, anti–human epidermal growth factor 2; HR, hazard ratio; RR, risk ratio

Central Illustration

graphic file with name fx1.jpg

Open in a new tab

Breast cancer (BC) is the leading cause of cancer death in women (1). Significant progress has been made in both diagnostics and treatment improving survival. Cardiotoxicity (CTX) is a significant problem during or after BC treatment due to radiotherapy 2, 3, estrogen deprivation (4), cytotoxic chemotherapy (5), or related to targeted therapies, especially anti–human epidermal growth factor 2 (HER2) agents (6).

Among the commonly used cytotoxic drugs, anthracyclines (ANTs) are the main cardiotoxic chemotherapy responsible for acute and chronic cardiac damage (7). Acute damage related to ANTs appears to be a consequence of acute myocyte dysfunction and death and clinically manifests as arrhythmias, acute left ventricular dysfunction, and rarely as acute myocarditis. Conversely, chronic damage occurs months or years after treatment and can be either diagnosed clinically through heart failure symptoms or detected asymptomatically with echocardiography (8). In the myocardium, ANT metabolites bind to ferric cation (Fe3+) releasing free radicals, resulting in alteration in permeability and the induction of apoptosis (9). ANTs may also inhibit cardiac topoisomerase IIβ, causing double-stranded DNA breaks and activating death pathways (10). ANT administration is associated with dose-dependent cardiac dysfunction, although many additional factors influence risk including age, pre-existing cardiovascular disease 11, 12, 13, 14, and additional cancer therapies. For example, among targeted BC therapies, trastuzumab, a humanized monoclonal antibody targeting HER2, may lead to cardiomyopathy, especially when associated with ANT or taxanes 15, 16, 17, 18.

Dexrazoxane (DEX) might exert a protective effect against ANT-induced CTX 19, 20, 21. The proposed mechanisms of DEX include its ability to act as a strong iron chelator and to displace iron from ANTs via its active metabolite (ADR-925) (22). In addition, DEX prevents complex formation between topoisomerase IIβ and ANT, reducing CTX (23). Despite clinical evidence of cardioprotection and the recommendations of cardiology societies 24, 25, 26, 27, its use as a cardioprotective agent is limited. DEX was approved by the U.S. Food and Drug Administration in 1995 for use as a cardioprotective agent in patients with metastatic or advanced BC who have reached a cumulative ANT dose of 300 mg/m2 and are continuing to receive doxorubicin (28). In addition, the American Society of Clinical Oncology recommends considering DEX as one of the possible strategies to avoid CTX during the administration of high-dose ANTs in adult cancer (29).

There are concerns that DEX could mitigate the antitumor activity of ANT in BC patients and increase secondary malignancies in studies in childhood lymphoma and leukemia after DEX use (30). These controversial data led to the limited use of DEX in clinical practice. However, in 2017, the European Medical Agency concluded that DEX should not be contraindicated in children at the highest risk of CTX (31). The European Medical Agency found no data indicating that DEX was associated with an increase in second primary malignancies, interfered with chemotherapy, or increased the risk of early death in children 32, 33, 34. In addition, none of the systematic reviews have evaluated the cardioprotective effect of DEX exclusively in BC patients treated with ANT with or without trastuzumab.

The aim of this study was to provide the first comprehensive systematic review and meta-analysis incorporating studies that evaluated the cardioprotective efficacy of DEX exclusively in BC patients treated with ANT with or without trastuzumab in both early and metastatic settings.

Methods

The present systematic review was performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses 35, 36 and the Cochrane Handbook for Systematic Reviews of Interventions (37). A Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist is provided in Supplemental Table 1. This systematic review was registered in the PROSPERO database (CRD42017077462).

Search strategy

Two investigators (A.V.S.M. and A.P.) independently searched MEDLINE (access through PubMed), Cochrane Central Register of Controlled Trials, and Embase from January 1990 up to March 1, 2019. The search strategy for PubMed is available in the Supplemental Appendix.

Study selection

After the identification of all relevant studies, 2 authors (A.V.S.M. and A.P.) independently performed study selection, and discrepancies were resolved by consensus. Eligible studies met the following PICOS criteria: 1) Population: all-stage BC patients undergoing ANT-based chemotherapy; 2) Intervention: DEX; 3) Comparison intervention: placebo or any treatment; 4) Outcome: clinical heart failure (CHF) or cardiac event; and 5) Study design: randomized controlled trial (RCT) or observational trial. Exclusion criteria were pediatric studies and studies with overlapping populations. Eligible studies also had to contain complete data regarding the outcomes under evaluation in the meta-analysis.

The primary outcome was the development of symptomatic CHF (expressed as clinical heart failure according to study definition) or a cardiac event (expressed as subclinical heart failure defined as histopathological abnormal findings in endomyocardial biopsy, ventricular function abnormalities [assessed by echocardiography or radionuclide ventriculography], or hospital admission due to cardiac causes). We accepted each study’s definition of subclinical CTX, considering that it was plausible and sufficiently comparable to be pooled (Supplemental Table 2).

Secondary outcomes were interference in oncologic treatment associated with DEX exposure, such as the oncologic response rate, overall survival, and progression-free survival.

Studies evaluating other types of tumors or in which the outcomes in the BC group could not be assessed separately, case-control studies, studies in children, studies in which the use of DEX did not have a comparator group (placebo or no treatment), literature reviews, studies in animals, pharmacokinetic studies, pharmacoeconomic studies, case reports, and studies in which the outcomes of interest were not assessed were excluded from the analysis (Supplemental Table 3).

Data extraction

After the literature search, data from eligible studies were independently extracted by 2 authors (A.V.S.M. and A.P.) using standardized forms. Patients’ characteristics, treatment, regimens, outcomes of interest, and follow-up period were systematically collected by 2 investigators (A.V.S.M. and A.P.). Divergences were resolved by consensus.

Study quality assessment (risk of bias)

Two independent reviewers (A.V.S.M. and A.P.) assessed the quality of the included trials. For nonrandomized trials, the Good Research for Comparative Effectiveness checklist was used 38, 39 (Supplemental Table 4). For randomized controlled trials, we used the Cochrane Collaboration Group methods (37). Eventual divergences were resolved by consensus. We rated the potential risk of bias by applying a rating of “low,” “high,” or “unclear” to each study (Supplemental Figures 1 and 2).

Statistical analysis

We calculated the risk ratio (RR) with the 95% confidence interval (CI) for dichotomous variables. We reported the p value for the comparison between the groups, and a p value ≤0.05 was considered statistically significant. Heterogeneity between trials was explored by the chi-square test with significance set at a p value ≤0.10 and quantified with inconsistency measure (I2). The random-effects model was applied because significant heterogeneity (in populations, interventions, and settings) was anticipated; we used τ2 to quantify between-study variance. We performed publication bias plots for the overall primary outcomes (Supplemental Figures 2 and 3). We did not test publication bias because fewer than 10 trials were included in the analysis (37). The analysis was performed on an intention-to-treat basis whenever possible, as reported by the original studies. For overall survival and progression-free survival data, we applied the generic inverse variance function to combine logs of hazard ratios (HRs). We extracted the HR with 95% CI, and we obtained the log HR and standard deviation from the Kaplan-Meier curves using the Parmar method when HR was not presented (40). A prespecified subgroup analysis was performed hypothesizing that patients with previous exposure to ANT would have had greater benefit from DEX. Post hoc subgroup analyses were performed to assess possible differences in the effect estimates between randomized and retrospective trials and between patients with early or advanced/metastatic cancer. Post hoc sensitivity analysis comparing random- and fixed-effects models was performed (Supplemental Table 5).

We used the software Review Manager (RevMan [Computer program], Version 5.3, The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark) or Comprehensive Meta-Analysis software (Version 3.3.070, Biostat, Englewood, New Jersey).

Results

Search results

A total of 196 publications were selected from the initial search, and a total of 188 records were excluded (Figure 1). Finally, 7 randomized trials 20, 41, 42, 43, 44, 45 and 2 retrospective cohorts 46, 47, all evaluating BC patients, were included in the systematic review and the meta-analysis. One article reported the results of 2 randomized trials (44). Major exclusions (articles excluded 19, 21, 48, 49, 50, 51, 52, 53, 54, 55, 56 with reasons) are reported in Supplemental Table 3.

Figure 1.

Figure 1

Open in a new tab

Flow Diagram for the Selection of Studies

A flow diagram of the studies screened, assessed for eligibility, and included in the review, with reasons for exclusions.

Study characteristics

The characteristics of the 9 studies are reported in Table 1. We included a total of 2,177 female patients with metastatic/advanced BC (5 trials and 1,100 patients), nonmetastatic BC (1 trial and 822 patients), or early-stage BC (2 trials and 255 patients). All patients received doxorubicin or epirubicin as ANT-based chemotherapy. The average cumulative dose of ANTs ranged from 240 mg/m2 to 713 mg/m2, and the dose ratio of DEX to ANT was 10:1 or 20:1. Trastuzumab was part of the treatment only in the 2 retrospective cohorts included.

Table 1.

Characteristics of the Included Studies

First Author (Ref. #) Chemotherapy Regimen Design Population/Previous Anthracycline Yes/No N Dose of Dexrazoxane or Dose Ratio of Dexrazoxane to Anthracycline Control Trastuzumab Follow-Up Mean or Median Cumulative Dose of Anthracycline∗ in mg/m2 (Range) in Each Group if Available
Randomized controlled trials
 Lopez et al. (45) High-dose epirubicin Single center Advanced and metastatic BC/No 92 DEX 1,000 mg/m2 No therapy No NM Control: 489 mg/m2
DEX: 533 mg/m2
 Marty et al. (41) Doxorubicin or epirubicin-based chemotherapy Multicenter Advanced and metastatic BC/Yes 164 20:1 DEX:DOX dose ratio or 10:1 DEX:EPI No therapy No 5 yrs Control: 608 mg/m2 (244-900 mg/m2)
DEX: 669 mg/m2 (247-936 mg/m2)
 Speyer et al. (42) 5-fluorouracil, doxorubicin, cyclophosphamide (FAC) Multicenter Advanced and metastatic BC/No 150 20:1 DEX:DOX No therapy No 5 yrs Control: 407.4 mg/m2 (25-950 mg/m2)
DEX:558 mg/m2 (50-2,150 mg/m2)
 Sun et al. (43) Epirubicin and cyclophosphamide Single center Early-stage BC with concurrent type 2 diabetes mellitus/No 80 10:1 DEX:EPI Placebo No 126 days In both groups:
266 mg/m2
 Swain et al. (44) FAC Multicenter Advanced and metastatic BC/No 349 10:1 DEX:DOX Placebo No 3 yrs <100-2,700 mg/m2 anthracycline cumulative dose in each group; NM
 Swain et al. (44) FAC Multicenter Advanced and metastatic BC/No 185 10:1 DEX:DOX dose ratio Placebo No 3 yrs <100-1,750 mg/m2 anthracycline cumulative dose in each group; NM
 Venturini et al. (20) 5-flourouracil, epirubicin, and cyclophosphamide) or high-dose epirubicin Multicenter Advanced and metastatic BC/Yes 160 10:1 DEX:EPI dose ratio No therapy No NM Control: 488 mg/m2 (66-667 mg/m2)
DEX: 390 mg/m2 (33-800 mg/m2)
Retrospective trials
 Kim et al. (46) Doxorubicin, cyclophosphamide, taxol, and trastuzumab Single center Early-stage BC/No 175 10:1 DEX:DOX dose ratio No therapy Yes 32.3 months In both groups:
240 mg/m2
 Tahover et al. (47) Doxorubicin and cyclophosphamide Single center Nonmetastatic BC/No 822 10:1 DEX:DOX dose ratio No therapy Yes 7 yrs In both groups:
420 mg/m2
Open in a new tab

BC = breast cancer; DEX = dexrazoxane; DOX = doxorubicin; Epi = epirubicin; NM = not mentioned.

∗

The epirubicin dose was converted to a doxorubicin-equivalent dose: 50 mg doxorubicin = 90 mg epirubicin.

No randomized trials were judged as low risk of bias in all bias domains. Three trials had low risk of bias in the randomization process, 1 in allocation concealment, 1 in double blinding and blinding of outcome assessor, and 6 in selective reporting. All trials had at least 1 domain at high risk of bias (Figure 2, Supplemental Figure 1). The retrospective cohort studies were considered to be of moderate quality (Supplemental Table 4).

Figure 2.

Figure 2

Open in a new tab

Risk of Bias Summary

Authors' judgments about the risk of bias in each included randomized trial. Green symbol with + = low risk of bias; yellow symbol with question mark = unknown; red symbol with– = high risk of bias.

Cardiac toxicity

DEX therapy was associated with a lower risk of CHF compared with the control in patients receiving ANT-based chemotherapy alone (7 of 575 [1.22%] with DEX vs. 56 of 605 [9.26%] with control; RR: 0.19; 95% CI: 0.09 to 0.40; p < 0.001), with only RCTs reporting these data (Figure 3).

Figure 3.

Figure 3

Open in a new tab

Forest Plot for the Effect of DEX on the Risk of Clinical Heart Failure and Cardiac Events in BC Patients Treated With ANTs

Dexrazoxane (DEX) therapy reduced the risk of cardiac outcomes in patients receiving anthracycline (ANT)-based chemotherapy. CI = confidence interval; df = degree of freedom; M-H = Mantel-Haenszel.

Cardiac events were also lower in patients allocated to DEX when compared with the control (64 of 683 [9.4%] with DEX vs. 219 of 1,414 [15.5%] with the control; RR: 0.36; 95% CI: 0.27 to 0.49; p < 0.001). The effect estimate was similar when limiting the analysis to RCTs (RR: 0.36; 95% CI: 0.26 to 0.49; p < 0.001) or retrospective studies (RR: 0.33; 95% CI: 0.03 to 3.39; p = 0.35) (Figure 3).

In 2 of 9 studies 20, 41, patients had already received ANT-based chemotherapy months or years previously. Among these patients who were re-exposed to ANT, DEX possibly reduced the risk of CHF (RR: 0.27; 95% CI: 0.07 to 1.07; p = 0.06) and the risk of cardiac events (RR: 0.32; 95% CI: 0.19 to 0.54; p < 0.001). The benefit of adding DEX to ANT treatment was also consistent in the subgroup of patients who were exposed to ANT for the first time. The risk of CHF was significantly reduced (RR: 0.15; 95% CI: 0.06 to 0.39; p < 0.001) as well the risk of cardiac events (RR: 0.37; 95% CI: 0.24 to 0.58; p < 0.001) (Table 2).

Table 2.

Subgroup Analyses

Outcome Analysis Number of Trials Effect Estimate (95% CI) p Value p Value Between Groups
Clinical heart failure Primary analysis 7 RR: 0.19 (0.09-0.40) <0.001
RCTs 7 RR: 0.19 (0.09-0.40) <0.001 NA
Retrospective trials 0 — —
Previous ANT 2 RR: 0.27 (0.07-1.07) 0.06 0.51
No previous ANT 5 RR: 0.15 (0.06-0.39) <0.001
Early BC 1 Not estimable — NA
Advanced/metastatic BC 6 RR: 0.19 (0.09-0.40) <0.001
Cardiac events Primary analysis 8 RR: 0.36 (0.27-0.49) <0.001
RCTs 6 RR: 0.36 (0.26-0.49) <0.001 0.95
Retrospective trials 2 RR: 0.33 (0.03-3.39) 0.35
Previous ANT 2 RR: 0.32 (0.19-0.54) <0.001 0.67
No previous ANT 6 RR: 0.37 (0.24-0.58) <0.001
Early BC 1 RR: 0.08 (0.01-1.37) 0.08 0.30
Advanced/metastatic BC 7 RR: 0.37 (0.27-0.50) <0.001
Complete response Primary analysis 6 RR: 1.10 (0.75-1.61) 0.62
RCTs 6 RR: 1.10 (0.75-1.61) 0.62 NA
Retrospective trials 0 — —
Previous ANT 2 RR: 1.27 (0.60-2.68) 0.53 0.67
No previous ANT 4 RR: 1.05 (0.67-1.63) 0.83
Early BC 0 — — NA
Advanced/metastatic BC 6 RR: 1.10 (0.75-1.61) 0.62
Partial response Primary analysis 6 RR: 0.88 (0.75-1.02) 0.10
RCTs 6 RR: 0.88 (0.75, 1.02) 0.10 NA
Retrospective trials 0 — —
Previous ANT 2 RR: 0.96 (0.71-1.31) 0.81 0.49
No previous ANT 4 RR: 0.85 (0.70-1.02) 0.07
Early BC 0 — — NA
Advanced/metastatic BC 6 RR: 0.88 (0.75-1.02) 0.10
Stable disease Primary analysis 4 RR: 0.92 (0.70-1.20)
RCTs 4 RR: 0.92 (0.70-1.20) 0.54 NA
Retrospective trials 0 — —
Previous ANT 1 RR: 0.77 (0.50-1.19) 0.25 0.33
No previous ANT 3 RR: 1.02 (0.73-1.44) 0.90
Early BC 0 — — NA
Advanced/metastatic BC 4 RR: 0.92 (0.70-1.20) 0.54
Progression-free survival Primary analysis 5 HR:0.97 (0.75-1.24) 0.81
RCTs 5 HR:0.97 (0.75-1.24) 0.81 NA
Retrospective trials — — —
Previous ANT 2 HR:0.68 (0.49-0.94) 0.02 0.007
No previous ANT 3 HR: 1.13 (0.95-1.34) 0.17
Early BC — — — NA
Advanced/metastatic BC 5 HR: 0.97 (0.75-1.24) 0.81
Overall survival Primary analysis 6 HR: 1.01 (0.86-1.17) 0.92
RCTs 5 HR: 1.04 (0.88-1.22) 0.65 0.20
Retrospective trials 1 HR: 0.71 (0.41-1.24) 0.23
Previous ANT 2 HR: 1.06 (0.73-1.54) 0.75 0.76
No previous ANT 4 HR: 1.00 (0.84-1.18) 0.97
Early BC 1 HR: 1.04 (0.88-1.22) 0.23 0.20
Advanced/metastatic BC 5 HR: 0.71 (0.41-1.24) 0.65
Open in a new tab

ANT = anthracycline; BC = breast cancer; CI = confidence interval; HR = hazard ratio; RR = relative risk; NA = not applicable; RCT = randomized clinical trial.

The funnel plots addressing publication bias for the overall primary outcomes are reported in Supplemental Figures 2 and 3. In sensitivity analysis, results were similar when a fixed-effects model was used (Supplemental Table 5).

Oncologic outcomes and overall survival

In 5 randomized trials, the partial and complete response rates were assessed at different follow-up intervals. Similar results were noted in groups exposed or not to DEX (complete response rate [RR: 1.10; 95% CI: 0.75 to 1.61; p = 0.62] and partial response rate [RR: 0.88; 95% CI: 0.75 to 1.02; p = 0.10]). Stable disease was reported in only 3 randomized trials, and similar results were noted between groups (RR: 0.92; 95% CI: 0.70 to 1.20; p = 0.54) (Figure 4).

Figure 4.

Figure 4

Open in a new tab

Forest Plot for the Effect of DEX on Oncological Response in BC Patients Treated With ANTs

Oncological outcomes were similar in groups exposed or not exposed to dexrazoxane. Abbreviations as in Figure 3.

Overall survival was also similar between groups (HR: 1.01; 95% CI: 0.86 to 1.17; p = 0.91) (Figure 5). No subgroup effects were found when stratifying the trials according to previous ANT exposure (Table 2).

Figure 5.

Figure 5

Open in a new tab

Forest Plot for the Effect of DEX on the Overall Survival and Progression-Free Survival

Overall survival and progression free-survival were similar between the groups. IV = inverse variance; other abbreviations as in Figure 3.

Progression-free survival was similar between the groups (HR: 0.97; 95% CI: 0.76 to 1.25; p = 0.81) (Figure 5). However, in the subgroup of studies including patients with more advanced disease re-exposed to ANT chemotherapy, the use of DEX was associated with a decreased risk of disease progression (HR: 0.68; 95% CI: 0.49 to 0.94; p = 0.02). In the subgroup of studies without previous exposure to ANT, DEX was associated with no significant difference on progression-free survival (HR: 1.13; 95% CI: 0.95 to 1.34; p = 0.17) (Table 2).

Discussion

Our review is the first and largest meta-analysis performed to date to explore the potential of DEX in the prevention of cardiotoxicity in BC patients exposed to ANT. In our systematic review and meta-analysis including patients with both early and advanced/metastatic BC exposed to ANT, we observed a lower rate of clinical heart failure and cardiac events in patients receiving DEX compared with controls without a detrimental effect on the oncological response (Central Illustration).

Central Illustration.

Central Illustration

Open in a new tab

Dexrazoxane in Breast Cancer Patients Under Anthracycline-Based Chemotherapy

The present systematic review was performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 35, 36 and the Cochrane Handbook for Systematic Reviews of Interventions (37). We identified, in a universe of breast cancer patients evaluated in clinical studies (blue and red people), the population included in this review (red people). Studies analyzing the cardioprotective effect of dexrazoxane in breast cancer patients treated with anthracyclines were selected for meta-analysis. In 9 studies with a total of 2,177 breast cancer patients, dexrazoxane reduced the risk of heart failure and cardiac events without a significantly impact in cancer outcomes.

This study adds to the existing data an analysis of 2,177 BC patients exposed to anthracycline analyzing cardiovascular outcomes. Previous studies included both adult and pediatric populations 33, 57, 58, which limited the interpretation of the cardioprotective effect in BC patients.

An important question is whether cardioprotective drugs reduce the antitumor efficacy of ANT and thereby compromise oncology treatment and affect survival (59). A previous systematic review including several types of tumors in adults and children suggested that patients treated with DEX might have a reduced response rate (60). However, an update of the same meta-analysis did not confirm these findings (33), and our results are aligned to the contemporary data, which show DEX does not compromise cancer treatment.

For many years, trastuzumab-related CTX was considered to be predominantly temporary and reversible with drug interruption or discontinuation. More recent data partially modified this assumption 61, 62, reporting a non-negligible incidence of long-term CTX. A large, retrospective study of Chen et al. (63) reported on 45,537 elderly women with early BC have a higher risk of heart failure or cardiomyopathy in those who received trastuzumab after ANT therapy.

A significant reduction in the occurrence of cardiac events when DEX was added to the ANT-based chemotherapy in BC patients was confirmed by our analysis. Regarding BC patients exposed to both ANT and trastuzumab, the cardioprotective effect of DEX was similar, but it is important to acknowledge that evidence comes from 2 retrospective studies and that prospective RCTs are lacking.

Pharmacological prevention of CTX is not widely used. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and β-blockers 13, 64, 65, 66 have been tested as an option for primary prevention, but the level of existing evidence is not sufficiently strong to indicate these treatments routinely for BC patients treated with ANT and/or trastuzumab (67). Our study reinforces DEX as an effective cardioprotective agent in BC patients receiving ANT-based chemotherapy, and it is the only present option for primary prevention in this population.

When we analyzed the studied subgroups, we did not find any difference suggesting a higher cardioprotective effect of DEX in a specific subpopulation of BC patients. Nonetheless, most evidence is of low quality to allow definite recommendations. An assessment of the methodological quality of the studies included in this review was performed using the Cochrane “risk of bias” tool (37) for assessing the risk of bias in each included RCT. We found that no randomized trials were judged as low risk of bias in all bias domains. 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 RCTs should be performed on DEX in BC patients avoiding all potential source of bias, which could compromise the reliability of their results.

Uncertainty regarding oncological outcomes has also limited DEX prescribing (59). In the present meta-analysis, we found no difference between the DEX and control groups regarding the oncological response rate and survival, suggesting no influence of DEX on ANT-anticancer activity in the BC populations studied.

When assessing the meta-analysis data concerning progression-free survival, we found a substantial statistical heterogeneity and a large prediction interval for HR. As part of a possible explanation for this heterogeneity, we found a favorable effect for the use of DEX in the BC patient subgroup previously treated with ANT, with higher rate of progression-free survival. These findings should be considered with caution and hypothesis generating. In addition, it should be noted that some studies in preclinical models showed that DEX has an intrinsic antitumor activity and that its use can enhance the benefit of ANT, potentially also contributing to its therapeutic effect (68).

Study limitations

We highlight several limitations of our study. We relied on the reporting of CTX and/or clinical cardiac events, and there may be some patients with subclinical CTX who are not included. The definitions of CTX and cardiac events also vary widely between the studies included, and none reported cardiac biomarkers to detect CTX. We did not assess the impact of the use of DEX in combination with ANT on hematologic toxicities. The clinical significance of this excess of hematologic toxicity could impact antitumor efficacy. We believe that this is unlikely because there were no adverse effects on these parameters in our review.

Conclusions

DEX reduced the risk of clinical heart failure and cardiac events in BC patients undergoing ANT chemotherapy with or without trastuzumab and did not significantly impact cancer outcomes. 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.

Perspectives.

COMPETENCY IN MEDICAL KNOWLEDGE: In patients treated for both early and advanced/metastatic breast cancer exposed to anthracyclines, dexrazoxane reduces the occurrence of clinical heart failure and cardiac events without a detrimental effect on oncological outcomes.

TRANSLATIONAL OUTLOOK: Future, large-scale randomized trials are needed to establish the effects of dexrazoxane in breast cancer patients receiving anthracyclines with or without trastuzumab on both cardiovascular and oncological outcomes.

Footnotes

Dr. Macedo has received speaker, advisory board, or consultancy fees from Zodiac, Pfizer, Bayer, Daichii Sankyo, Roche, Novartis, Ferring Pharmaceuticals, and Servier. Dr. Lyon has received speaker, advisory board, or consultancy fees and/or research grants from Clinigen Group, Pfizer, Novartis, Servier, Amgen, Takeda, Roche, Eli Lilly, Eisai, Bristol-Myers Squibb, Ferring Pharmaceuticals, and Boehringer Ingelheim. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Appendix

For supplemental tables and figures, please see the online version of this paper.

Appendix

Supplemental Data
mmc1.docx (54.4KB, docx)

References

  • 1.Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68:394–424. doi: 10.3322/caac.21492. [DOI] [PubMed] [Google Scholar]
  • 2.Evans E.S., Prosnitz R.G., Yu X. Impact of patient-specific factors, irradiated left ventricular volume, and treatment set-up errors on the development of myocardial perfusion defects after radiation therapy for left-sided breast cancer. Int J Radiat Oncol Biol Phys. 2006;66:1125–1134. doi: 10.1016/j.ijrobp.2006.06.025. [DOI] [PubMed] [Google Scholar]
  • 3.Gagliardi G., Lax I., Ottolenghi A., Rutqvist L.E. Long-term cardiac mortality after radiotherapy of breast cancer--application of the relative seriality model. Br J Radiol. 1996;69:839–846. doi: 10.1259/0007-1285-69-825-839. [DOI] [PubMed] [Google Scholar]
  • 4.Amir E., Seruga B., Niraula S., Carlsson L., Ocana A. Toxicity of adjuvant endocrine therapy in postmenopausal breast cancer patients: a systematic review and meta-analysis. J Natl Cancer Inst. 2011;103:1299–1309. doi: 10.1093/jnci/djr242. [DOI] [PubMed] [Google Scholar]
  • 5.Ng R., Better N., Green M.D. Anticancer agents and cardiotoxicity. Semin Oncol. 2006;33:2–14. doi: 10.1053/j.seminoncol.2005.11.001. [DOI] [PubMed] [Google Scholar]
  • 6.Moslehi J.J. Cardiovascular toxic effects of targeted cancer therapies. N Engl J Med. 2016;375:1457–1467. doi: 10.1056/NEJMra1100265. [DOI] [PubMed] [Google Scholar]
  • 7.Bird B., Swain S. 2006 ASCO Educational Book. America Society of Clinical Oncology; Alexandria, VA: 2006. Cardiac toxicity in the new breast cancer survivors: review of potential cardiac problem in cured patients; pp. 45–47. [Google Scholar]
  • 8.Hilfiker-Kleiner D., Ardehali H., Fischmeister R., Burridge P., Hirsch E., Lyon A.R. Late onset heart failure after childhood chemotherapy. Eur Heart J. 2019;40:798–800. doi: 10.1093/eurheartj/ehz046. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Floyd J.D., Nguyen D.T., Lobins R.L., Bashir Q., Doll D.C., Perry M.C. Cardiotoxicity of cancer therapy. J Clin Oncol. 2005;23:7685–7696. doi: 10.1200/JCO.2005.08.789. [DOI] [PubMed] [Google Scholar]
  • 10.Zhang S., Liu X., Bawa-Khalfe T. Identification of the molecular basis of doxorubicin-induced cardiotoxicity. Nat Med. 2012;18:1639–1642. doi: 10.1038/nm.2919. [DOI] [PubMed] [Google Scholar]
  • 11.Pareek N., Cevallos J., Moliner P. Activity and outcomes of a cardio-oncology service in the United Kingdom-a five year experience. Eur J Heart Fail. 2018;20:1721–1731. doi: 10.1002/ejhf.1292. [DOI] [PubMed] [Google Scholar]
  • 12.Zamorano J.L., Lancellotti P., Muñoz D.R. 2016 ESC Position Paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC Committee for Practice Guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC) Eur Heart J. 2016;37:2768–2801. doi: 10.1093/eurheartj/ehw211. [DOI] [PubMed] [Google Scholar]
  • 13.Cardinale D., Colombo A., Bacchiani G. Early detection of anthracycline cardiotoxicity and improvement with heart failure therapy. Circulation. 2015;131:1981–1988. doi: 10.1161/CIRCULATIONAHA.114.013777. [DOI] [PubMed] [Google Scholar]
  • 14.Ky B., Carver J.R. Biomarker approach to the detection and cardioprotective strategies during anthracycline chemotherapy. Heart Fail Clin. 2011;7:323–331. doi: 10.1016/j.hfc.2011.03.002. [DOI] [PubMed] [Google Scholar]
  • 15.Keefe D.L. Trastuzumab-associated cardiotoxicity. Cancer. 2002;95:1592–1600. doi: 10.1002/cncr.10854. [DOI] [PubMed] [Google Scholar]
  • 16.Bengala C., Zamagni C., Pedrazzoli P. Cardiac toxicity of trastuzumab in metastatic breast cancer patients previously treated with high-dose chemotherapy: a retrospective study. Br J Cancer. 2006;94:1016–1020. doi: 10.1038/sj.bjc.6603060. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 17.Slamon D.J., Leyland-Jones B., Shak S. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783–792. doi: 10.1056/NEJM200103153441101. [DOI] [PubMed] [Google Scholar]
  • 18.Bowels E.J., Wellman R., Feigelson H.S. Risk of heart failure in breast cancer patients after anthracycline and trastuzumab treatment: a retrospective cohort study. J Natl Cancer Inst. 2012;104:1293–1305. doi: 10.1093/jnci/djs317. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.Speyer J.L., Green M.D., Kramer E. Protective effect of the bispiperazinedione ICRF-187 against doxorubicin-induced cardiac toxicity in women with advanced breast cancer. N Engl J Med. 1988;319:745–752. doi: 10.1056/NEJM198809223191203. [DOI] [PubMed] [Google Scholar]
  • 20.Venturini M., Michelotti A., Del Mastro L. Multicenter randomized controlled clinical trial to evaluate cardioprotection of dexrazoxane versus no cardioprotection in women receiving epirubicin chemotherapy for advanced breast cancer. J Clin Oncol. 1996;14:3112–3120. doi: 10.1200/JCO.1996.14.12.3112. [DOI] [PubMed] [Google Scholar]
  • 21.Kolaric K., Bradamante V., Cervek J. A phase-II trial of cardioprotection with cardioxane (ICRF-187) in patients with advanced breast-cancer receiving 5-fluorouracil, doxorubicin and cyclophosphamide. Oncology. 1995;52:251–255. doi: 10.1159/000227467. [DOI] [PubMed] [Google Scholar]
  • 22.Hasinoff B.B., Kuschak T.I., Yalowich J.C., Creighton A.M. A QSAR study comparing the cytotoxicity and DNA topoisomerase II inhibitory effects of bisdioxopiperazine analogs of ICRF-187 (dexrazoxane) Biochem Pharmacol. 1995;50:953–958. doi: 10.1016/0006-2952(95)00218-o. [DOI] [PubMed] [Google Scholar]
  • 23.Lyu Y.L., Kerrigan J.E., Lin C.P. Topoisomerase IIbeta mediated DNA double-strand breaks: implications in doxorubicin cardiotoxicity and prevention by dexrazoxane. Cancer Res. 2007;67:8839–8846. doi: 10.1158/0008-5472.CAN-07-1649. [DOI] [PubMed] [Google Scholar]
  • 24.Yancy C.W., Jessup M., Bozkurt B. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2013;62:e147–e239. doi: 10.1016/j.jacc.2013.05.019. [DOI] [PubMed] [Google Scholar]
  • 25.ESC Guidelines 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the task force for the diagnosis and treatment of acute and chronic heart failure 2012 of the European society of cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J. 2012;33:1787–1847. doi: 10.1093/eurheartj/ehs104. [DOI] [PubMed] [Google Scholar]
  • 26.Grupo de Estudos em Insuficiência Cardíaca da Sociedade Brasileira de Cardiologia (GEIC/SBC), Sociedade Brasileira de Oncologia Clínica, Instituto do Coração – Faculdade de Medicina da Universidade de São Paulo I Brazilian guideline for cardio-oncology from sociedade Brasileira de cardiologia. Arq Bras Cardiol. 2011;96:1–52. [PubMed] [Google Scholar]
  • 27.Schuchter L.M., Hensley M.L., Meropol N.J., Winer E.P. 2002 update of recommendations for the use of chemotherapy and radiotherapy protectants: clinical practice guidelines of the American Society of Clinical Oncology. J Clin Oncol. 2002;20:2895–2903. doi: 10.1200/JCO.2002.04.178. [DOI] [PubMed] [Google Scholar]
  • 28.Zinecard® (dexrazoxane for injection). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/020212s013lbl.pdf. Accessed July 9, 2019.
  • 29.Armenian S.H., Lacchetti C., Barac A. Prevention and monitoring of cardiac dysfunction in survivors of adult cancers: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;35:893–911. doi: 10.1200/JCO.2016.70.5400. [DOI] [PubMed] [Google Scholar]
  • 30.Tebbi C.K., London W.B., Friedman D. Dexrazoxane-associated risk for acute myeloid leukemia/myelodysplastic syndrome and other secondary malignancies in pediatric Hodgkin's disease. J Clin Oncol. 2007;25:493–500. doi: 10.1200/JCO.2005.02.3879. [DOI] [PubMed] [Google Scholar]
  • 31.European Medicines Agency. Cardioxane. Available at: https://www.ema.europa.eu/en/medicines/human/referrals/cardioxane. Accessed July 9, 2019.
  • 32.Lipshultz S.E., Adams M.J., Colan S.D. Long-term cardiovascular toxicity in children, adolescents, and young adults who receive cancer therapy: pathophysiology, course, monitoring, management, prevention, and research directions: a scientific statement from the American Heart Association. Circulation. 2013;17:1927–1995. doi: 10.1161/CIR.0b013e3182a88099. [DOI] [PubMed] [Google Scholar]
  • 33.Van Dalen E.C., Caron H.N., Dickinson H.O. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. 2011;6:CD003917. doi: 10.1002/14651858.CD003917.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 34.Chow E.J., Asselin B.L., Schwartz C.L. Late mortality after dexrazoxane treatment: a report from the Children's Oncology Group. J Clin Oncol. 2015;33:2639–2645. doi: 10.1200/JCO.2014.59.4473. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 35.Liberati A., Altman D.G., Tetzlaff J. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700. doi: 10.1136/bmj.b2700. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Moher D., Shamseer L., Clarke M. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement. Syst Rev. 2015;4:1. doi: 10.1186/2046-4053-4-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 37.Higgins J., Green S. The Cochrane Collaboration; Chichester, UK: 2011. Cochrane Handbook for Systematic Reviews of Interventions, Version 5. [Google Scholar]
  • 38.Dreyer N.A., Bryant A., Velentgas P. The GRACE checklist: a validated assessment tool for high quality observational studies of comparative effectiveness. J Manag Care Spec Pharm. 2016;22:1107–1113. doi: 10.18553/jmcp.2016.22.10.1107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 39.Dreyer N.A., Velentgas P., Westrich K., Dubois R. The GRACE checklist for rating the quality of observational studies of comparative effectiveness: a tale of hope and caution. J Manag Care Spec Pharm. 2014;20:301–308. doi: 10.18553/jmcp.2014.20.3.301. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 40.Parmar M.K., Torri V., Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–2834. doi: 10.1002/(sici)1097-0258(19981230)17:24<2815::aid-sim110>3.0.co;2-8. [DOI] [PubMed] [Google Scholar]
  • 41.Marty M., Espie M., Llombart A., Monnier A., Rapoport B.L., Stahalova V. Multicenter randomized phase III study of the cardioprotective effect of dexrazoxane (Cardioxane) in advanced/metastatic breast cancer patients treated with anthracycline-based chemotherapy. Ann Oncol. 2006;17:614–622. doi: 10.1093/annonc/mdj134. [DOI] [PubMed] [Google Scholar]
  • 42.Speyer J.L., Green M.D., Zeleniuch-Jacquotte A. ICRF-187 permits longer treatment with doxorubicin in women with breast cancer. J Clin Oncol. 1992;10:117–127. doi: 10.1200/JCO.1992.10.1.117. [DOI] [PubMed] [Google Scholar]
  • 43.Sun F., Qi X., Geng C., Li X. Dexrazoxane protects breast cancer patients with diabetes from chemotherapy-induced cardiotoxicity. Am J Med Sci. 2015;349:406–412. doi: 10.1097/MAJ.0000000000000432. [DOI] [PubMed] [Google Scholar]
  • 44.Swain S.M., Whaley F.S., Gerber M.C. Cardioprotection with dexrazoxane for doxorubicin-containing therapy in advanced breast cancer. J Clin Oncol. 1997;15:1318–1332. doi: 10.1200/JCO.1997.15.4.1318. [DOI] [PubMed] [Google Scholar]
  • 45.Lopez M., Vici P., Di Lauro K. Randomized prospective clinical trial of high-dose epirubicin and dexrazoxane in patients with advanced breast cancer and soft tissue sarcomas. J Clin Oncol. 1998;16:86–92. doi: 10.1200/JCO.1998.16.1.86. [DOI] [PubMed] [Google Scholar]
  • 46.Kim I.H., Lee J.E., Youn H.J., Song B.J., Chae B.J. Cardioprotective effect of dexrazoxane in patients with HER2-positive breast cancer who receive anthracycline based adjuvant chemotherapy followed by Trastuzumab. J Breast Cancer. 2017;20:82–90. doi: 10.4048/jbc.2017.20.1.82. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Tahover E., Segal A., Isacson R. Dexrazoxane added to doxorubicin-based adjuvant chemotherapy of breast cancer: a retrospective cohort study with a comparative analysis of toxicity and survival. Anticancer Drugs. 2017;28:787–794. doi: 10.1097/CAD.0000000000000514. [DOI] [PubMed] [Google Scholar]
  • 48.Binggao W., Xinyan Y., Li W., Hong H., Zhibo X., Zhenfeng L. Protective effect of dexrazoxane on the heart in elderly breast cancer patients after adjuvante chemotherapy. J Modern Oncol. 2016;15:2391–2393. [Google Scholar]
  • 49.Maral J., Vinke J., Oskam R., Cyrus R., Plas K.V., Herrera A. PP-7-16 Cardioxane still induces effective cardioprotection in anthracycline pretreated breast cancer patients. Eur J Cancer. 1996;32:48. [Google Scholar]
  • 50.Michelotti A., Venturini M., Tibaldi C. Single agent epirubicin as first line chemotherapy for metastatic breast cancer patients. Breast Cancer Res Treat. 2000;59:133–139. doi: 10.1023/a:1006394801389. [DOI] [PubMed] [Google Scholar]
  • 51.Rosing H., Huinink W.T.B., Van Gijn R. Comparative open, randomized, cross-over bioequivalence study of two intravenous dexrazoxane formulations (Cardioxane and ICRF-187) in patients with advanced breast cancer, treated with 5-fluorouracil-doxorubicin-cyclophosphamide (FDC) Eur J Drug Metab Pharmacokinet. 1999;24:69–77. doi: 10.1007/BF03190013. [DOI] [PubMed] [Google Scholar]
  • 52.Sun F., Shi J., Geng C. Dexrazoxane improves cardiac autonomic function in epirubicin-treated breast cancer patients with type 2 diabetes. Medicine. 2016;95:e5228. doi: 10.1097/MD.0000000000005228. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Tallarico D., Rizzo V., Di Maio F. Myocardial cytoprotection by trimetazidine against anthracycline-induced cardiotoxicity in anticancer chemotherapy. Angiology. 2003;54:219–227. doi: 10.1177/000331970305400212. [DOI] [PubMed] [Google Scholar]
  • 54.Vici P., Ferraironi A., Di L.L. Dexrazoxane cardioprotection in advanced breast cancer patients undergoing high-dose epirubicin treatment. Clin Ter. 1998;149:15–20. [PubMed] [Google Scholar]
  • 55.Wang P., Zhang S., Zhang X.B., Li W.J., Hao X.M., Zhang J. Protective effect of dexrazoxane on cardiotoxicity in breast cancer patients who received anthracycline-containing chemotherapy. Zhonghua Zhong Liu Za Zhi. 2013;35:135–139. doi: 10.3760/cma.j.issn.0253-3766.2013.02.013. [DOI] [PubMed] [Google Scholar]
  • 56.Jelic S., Radulovic S., Neskovic-Konstantinovic Z. Cardioprotection with ICRF-187 (cardioxane) in patients with advanced breast cancer having cardiac risk factors for doxorubicin cardiotoxicity, treated with the FDC regimen. Support Care Cancer. 1995;3:176–182. doi: 10.1007/BF00368887. [DOI] [PubMed] [Google Scholar]
  • 57.Schwartz C.L., Constine L.S., Villaluna D. A risk-adapted, response- based approach using ABVE-PC for children and adolescents with intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood. 2009;114:2051–2059. doi: 10.1182/blood-2008-10-184143. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.Lipshultz S.E., Rifai N., Dalton V.M. The effect of dexrazoxane on myocardial injury in doxorubicin-treated children with acute lymphoblastic leukemia. N Engl J Med. 2004;351:145–153. doi: 10.1056/NEJMoa035153. [DOI] [PubMed] [Google Scholar]
  • 59.Walker D.M., Fisher B.T., Seif A.E. Dexrazoxane use in pediatric patients with acute lymphoblastic or myeloid leukemia from 1999 and 2009: analysis of a national cohort of patients in the pediatric health information systems database. Pediatr Blood Cancer. 2013;60:616–620. doi: 10.1002/pbc.24270. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.Van Dalen E.C., Caron H.N., Dickinson H.O., Kremer L.C. Cardioprotective interventions for cancer patients receiving anthracyclines. Cochrane Database Syst Rev. 2008;2:CD003917. doi: 10.1002/14651858.CD003917.pub3. [DOI] [PubMed] [Google Scholar]
  • 61.Wang S.Y., Long J.B., Hurria A. Cardiovascular events, early discontinuation of trastuzumab, and their impact on survival. Breast Cancer Res Treat. 2014;146:411–419. doi: 10.1007/s10549-014-3029-0. [DOI] [PubMed] [Google Scholar]
  • 62.Witteles R.M., Bosch X. Myocardial protection during cardiotoxic chemotherapy. Circulation. 2015;132:1835–1845. doi: 10.1161/CIRCULATIONAHA.114.010486. [DOI] [PubMed] [Google Scholar]
  • 63.Chen J., Long J.B., Hurria A., Owusu C., Steingart R.M., Gross C.P. Incidence of heart failure or cardiomyopathy after adjuvant trastuzumab therapy for breast cancer. J Am Coll Cardiol. 2012;60:2504–2512. doi: 10.1016/j.jacc.2012.07.068. [DOI] [PubMed] [Google Scholar]
  • 64.Gulati G., Heck S.L., Ree A.H. Prevention of cardiac dysfunction during adjuvant breast cancer therapy (PRADA): a 2 x 2 factorial, randomized, placebo-controlled, double-blind clinical trial of candesartan and metoprolol. Eur Heart J. 2016;37:1671–1680. doi: 10.1093/eurheartj/ehw022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Boekhout A.H., Gietema J.A., Kerklaan B.M. Angiotensin II-receptor inhibition with candesartan to prevent trastuzumab-related cardiotoxic effects in patients with early breast cancer: a randomized clinical trial. JAMA Oncol. 2016;2:1030–1037. doi: 10.1001/jamaoncol.2016.1726. [DOI] [PubMed] [Google Scholar]
  • 66.Avila M.S., Ayub-Ferreira S.M., de Barros Wanderley M.R., Jr. Carvedilol for prevention of chemotherapy-related cardiotoxicity: the CECCY trial. J Am Coll Cardiol. 2018;71:2281–2290. doi: 10.1016/j.jacc.2018.02.049. [DOI] [PubMed] [Google Scholar]
  • 67.Payne D.L., Nohria A. Prevention of chemotherapy induced cardiomyopathy. Curr Heart Fail Rep. 2017;14:398–403. doi: 10.1007/s11897-017-0353-9. [DOI] [PubMed] [Google Scholar]
  • 68.Dickey J.S., Gonzalez Y., Aryal B. Mito-tempol and dexrazoxane exhibit cardioprotective and chemotherapeutic effects through specific protein oxidation and autophagy in a syngeneic breast tumor preclinical model. PLoS One. 2013;8 doi: 10.1371/journal.pone.0070575. [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplemental Data
mmc1.docx (54.4KB, docx)

Articles from JACC: CardioOncology are provided here courtesy of Elsevier

RESOURCES