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Journal of Pediatric Hematology/oncology Aug 2018Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or...
Cardiotoxicity is a dose-limiting and potentially lethal complication of anthracycline administration. Previous studies failed to determine definitive toxic doses or cardioprotective factors. Current dosing strategies may utilize unnecessarily high anthracycline doses, such that survival benefit may not outweigh increased toxicity rates. A systematic review of randomized controlled trials and prospective/retrospective studies investigating anthracycline treatment in pediatric solid tumors was performed from PubMed/MEDLINE and Cochrane databases. Generalized linear models mapping survival, cardiotoxicity, and cardiotoxicity-free survival adjusted for male-to-female ratio, follow-up time, and concomitant chemotherapeutic drugs or cardioprotective agents (dexrazoxane) were generated using R. Survival rose linearly with increasing cumulative anthracycline dose whereas cardiotoxicity demonstrated exponential increases both without (dose, >200 mg/m) and with (dose, >400 mg/m) dexrazoxane. Maximum cardiotoxicity-free survival was 268.2 mg/m without and 431.8 mg/m with dexrazoxane. Despite increasing cardiotoxicity-free dose by >150 mg/m, dexrazoxane minimally improved projected survival (71.9% vs. 75.4%). Cardiotoxicity increased linearly as a function of follow-up time with rates doubling from 5 to 20 years, without evidence of plateau. On the basis of our model, current dosing regimens-doxorubicin doses >375 mg/m without dexrazoxane-overvalue increased anthracycline administration and may contribute to devastating cardiotoxicity. The linear increase of cardiotoxicity without evidence of plateau confirms the necessity for lifelong cardiac monitoring.
Topics: Adolescent; Anthracyclines; Cardiotoxicity; Child; Child, Preschool; Dexrazoxane; Disease-Free Survival; Female; Humans; Infant; Male; Neoplasms; Survival Rate
PubMed: 29432315
DOI: 10.1097/MPH.0000000000001118 -
British Journal of Cancer Jan 2007This review systematically assessed the evidence on the clinical and cost-effectiveness of cardioprotection against the toxic effects of anthracyclines given to children... (Review)
Review
This review systematically assessed the evidence on the clinical and cost-effectiveness of cardioprotection against the toxic effects of anthracyclines given to children with cancer. We searched eight electronic databases, including Medline and the Cochrane Library, from inception to January 2006 for systematic reviews and randomised controlled trials that reported death, heart failure, arrhythmias or measures of cardiac performance associated with cardioprotective technologies compared with standard treatment in children treated for cancer with anthracyclines. Economic evaluations were also sought. Inclusion criteria, data extraction and quality assessment were undertaken by standard methodology. Four randomised controlled trials met the inclusion criteria of the review; each had methodological limitations. No economic evaluations were identified. Studies were combined through narrative synthesis. One trial found that continuous infusion of doxorubicin did not offer any cardioprotection over rapid infusion. One suggested that continuous infusion of daunorubicin provoked less cardiotoxicity than rapid infusion. One concluded that dexrazoxane reduces cardiac injury during doxorubicin therapy and one reported a protective effect of coenzyme Q(10) on cardiac function during anthracycline therapy. The evidence on the effectiveness of cardioprotective technologies in children is limited in quality and quantity thus making conclusions difficult. This is surprising given the importance of anthracycline use in children with cancer. Further long-term research, which includes relevant outcome measures, is needed to determine whether technologies influence the development of cardiac damage without limiting the antitumour efficacy of anthracyclines.
Topics: Anthracyclines; Cardiotonic Agents; Child; Humans; State Medicine
PubMed: 17242696
DOI: 10.1038/sj.bjc.6603562 -
Interventions for preventing cardiomyopathy due to anthracyclines: a Bayesian network meta-analysis.Annals of Oncology : Official Journal... Mar 2017The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown. (Meta-Analysis)
Meta-Analysis
BACKGROUND
The relative efficacy of interventions for primary prevention of anthracycline-associated cardiotoxicity is unknown.
METHODS
We conducted a systematic review of randomized controlled trials for primary prevention of anthracycline-associated cardiotoxicity in adult cancer patients. We used hierarchal outcome definitions in the following order of priority: (1) composite of heart failure or decline in left ventricular ejection fraction, (2) decline in ejection fraction, or (3) heart failure. Data were analyzed using a Bayesian network meta-analysis with random effects.
RESULTS
A total of 16 trials reported cardiotoxicity as a dichotomous outcome among 1918 patients, evaluating dexrazoxane, angiotensin antagonists, beta-blockers, combination angiotensin antagonists and beta-blockers, statins, Co-enzyme Q-10, prenylamine, and N-acetylcysteine. Compared with control, dexrazoxane reduced cardiotoxicity with a pooled odds ratio (OR) of 0.26 (95% credible interval [CrI] 0.11-0.74) and had the highest probability (33%) of being most effective. No other agent was demonstrably better than placebo. Angiotensin antagonists had an 84% probability of being most effective in a sensitivity analysis excluding one outlying study (OR 0.06 [95% CrI 0.01- 0.24]). When the outcome was restricted to heart failure, dexrazoxane was associated with an OR of 0.12 (95% CrI 0.06-0.23) relative to control and had 58% probability of being most effective, while angiotensin antagonists had an OR of 0.18 (95% CrI 0.05-0.55). Available data suggested that dexrazoxane and angiotensin antagonists did not affect malignancy response rate or risk of death.
CONCLUSION
Moderate quality data suggest that dexrazoxane, and low quality data suggest angiotensin antagonists, are likely to be effective for cardiotoxicity prevention.
Topics: Acetylcysteine; Adrenergic beta-Antagonists; Angiotensins; Anthracyclines; Cardiomyopathies; Clinical Trials as Topic; Dexrazoxane; Heart Failure; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Neoplasms; Network Meta-Analysis; Prenylamine; Ventricular Dysfunction, Left
PubMed: 28028033
DOI: 10.1093/annonc/mdw671 -
Journal of Oncology Pharmacy Practice :... Mar 2021Doxorubicin- and epirubicin-induced cardiotoxicities are life threatening for those suffering from breast cancer. Comparing the effects of different strategies on the... (Meta-Analysis)
Meta-Analysis
OBJECTIVE
Doxorubicin- and epirubicin-induced cardiotoxicities are life threatening for those suffering from breast cancer. Comparing the effects of different strategies on the prevention of these agent-induced cardiotoxicities remains unexplored. A comprehensive review of clinical trials was performed on the prevention of epirubicin- and/or doxorubicin-induced cardiotoxicity in HER2-positive metastatic breast cancer patients. The reduction in ejection fraction was directed at evaluating cardiac toxicity. Fourteen articles evaluated cardiotoxicity as a condition among 2945 individuals, evaluating doxorubicin, epirubicin, Liposomal Doxorubicin (LD), Pegylated Liposomal Doxorubicin (PLD), dexrazoxane plus doxorubicin or epirubicin, and Angiotensin-Converting Enzyme Inhibitors (ACEIs) plus doxorubicin. Pooled Odds Ratio (OR) of 0.043 with a 95% credible interval (CrI) between 0.005 and 0.22 indicated that the dexrazoxane plus epirubicin reduced the number of cardiac events compared with doxorubicin. Furthermore, doxorubicin and epirubicin represented the most effective interventions with a 52% probability of success. Also, the best treatment for reducing Congestive Heart Failure (CHF) was dexrazoxane plus epirubicin with a probability of 43%. For the Left Ventricular Ejection Fraction (LVEF) reduction outcome, ACEIs plus doxorubicin was ranked first with a success probability of 61.2% and they could significantly prevent the reduction in LVEF compared with LD, epirubicin, or doxorubicin.
CONCLUSION
Our data suggested that angiotensin-converting enzyme inhibitors and dexrazoxane plus epirubicin were the most effective interventions for preventing cardiotoxicity and CHF. However, ACEIs plus doxorubicin was the best treatment for preventing LVEF reduction.
Topics: Angiotensin-Converting Enzyme Inhibitors; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiotoxicity; Dexrazoxane; Doxorubicin; Epirubicin; Female; Heart Failure; Humans; Network Meta-Analysis; Polyethylene Glycols; Randomized Controlled Trials as Topic; Stroke Volume; Ventricular Dysfunction, Left; Ventricular Function, Left
PubMed: 33081570
DOI: 10.1177/1078155220965674 -
Health Technology Assessment... Jul 2007To evaluate the technologies used to reduce anthracycline-induced cardiotoxicity in children. Also to evaluate cardiac markers to quantify cardiotoxicity, and identify... (Review)
Review
OBJECTIVES
To evaluate the technologies used to reduce anthracycline-induced cardiotoxicity in children. Also to evaluate cardiac markers to quantify cardiotoxicity, and identify cost-effectiveness studies and future research priorities.
DATA SOURCES
Eight electronic databases were searched from inception to January 2006. Bibliographies of related papers were assessed for relevant studies and experts contacted to identify additional published references.
REVIEW METHODS
A systematic review of the evidence was undertaken using a priori methods.
RESULTS
Four randomised controlled trials (RCTs) met the inclusion criteria of the review, each considering a different cardioprotective intervention; all trials included children with acute lymphoblastic leukaemia, and one also included children with non-Hodgkin's lymphoma. However, all had methodological limitations. No cost-effectiveness studies were identified. One RCT and six cohort studies on the use of cardiac markers met the inclusion criteria of the review, but also had methodological limitations. Of the two RCTs that considered continuous infusion versus bolus (rapid) infusion, one found that continuous infusion of doxorubicin did not offer any cardioprotection over bolus; the other suggested that continuous infusion of daunorubicin had less cardiotoxicity than bolus. Two studies considered cardioprotective agents, one concluded that dexrazoxane prevents or reduces cardiac injury without compromising the antileukaemic efficacy of doxorubicin and the other reported a protective effect of coenzyme Q10 on cardiac function during anthracycline therapy. One RCT suggested that cardiac troponin T can be used to assess the effectiveness of the cardioprotective agent dexrazoxane. Two cohort studies considering atrial natriuretic peptide and two considering brain (B-type) natriuretic peptide suggested that these chemicals are elevated in some subgroups of children treated with anthracyclines for cancer. N-terminal B-type natriuretic peptide levels were significantly elevated in children treated with anthracyclines who had cardiac dysfunction. One cohort study found that serum lipid peroxide was higher in younger children treated with doxorubicin than correspondingly aged children not receiving doxorubicin. No differences in carnitine levels were found in children treated with doxorubicin and a group of healthy children in one cohort study.
CONCLUSIONS
It is difficult to draw conclusions about the effectiveness of technologies for reducing or preventing cardiotoxicity and about the use of cardiac markers in children as the evidence is limited in quantity and quality. The lack of standardisation for monitoring and reporting cardiac performance is problematic. Not all studies report effectiveness in terms of cardiac outcomes and event-free survival with supporting statistical analyses. Studies are mostly small and of short duration, making generalisation difficult. Increasing numbers of survivors of childhood cancer treated with anthracyclines will experience cardiac damage and require long-term surveillance and management. This will have an impact on cardiac services and costs. Diverse medical problems and other late sequelae that affect cardiac outcome will have an impact on other specialist services. Mechanisms to reduce or prevent cardiotoxicity from anthracycline therapy and cardiac markers to improve monitoring could alter the extent of this impact on service provision. RCTs of the different methods for reducing or preventing cardiotoxicity in children treated with anthracyclines for cancer with long-term follow-up are needed to determine whether the technologies influence the development of cardiac damage. Cost-effectiveness research is also required.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Cardiovascular Agents; Child; Drug Administration Schedule; Heart Diseases; Heart Failure; Humans; Lymphoma, Non-Hodgkin; Precursor Cell Lymphoblastic Leukemia-Lymphoma
PubMed: 17610809
DOI: 10.3310/hta11270 -
European Journal of Cancer (Oxford,... Sep 2007To evaluate the effectiveness of cardiac markers to quantify anthracycline-induced cardiotoxicity in children with cancer. (Review)
Review
AIM
To evaluate the effectiveness of cardiac markers to quantify anthracycline-induced cardiotoxicity in children with cancer.
METHODS
Systematic review using a priori methods.
RESULTS
Seven studies, all with methodological limitations, were identified. One RCT suggests that cardiac troponin can be used to assess the effectiveness of the cardio-protective agent dexrazoxane. Cohort studies suggest that atrial natriuretic peptide and brain (B-type) natriuretic peptide are elevated in some subgroups of patients compared with healthy children; NT-pro-BNP levels are significantly elevated in children with cardiac dysfunction compared with those without; serum lipid peroxide is higher in children who have received doxorubicin compared with children not receiving doxorubicin; there are no differences in carnitine levels between children treated with doxorubicin and a healthy control group.
CONCLUSIONS
The limited evidence makes conclusions difficult. Research is needed to fill this important evidence gap and link short-term changes in cardiac markers to longer-term cardiac damage.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Biomarkers; Child, Preschool; Cohort Studies; Heart; Heart Diseases; Humans; Neoplasms; Randomized Controlled Trials as Topic; Survivors
PubMed: 17689066
DOI: 10.1016/j.ejca.2007.06.012 -
Oncology Research and Treatment 2019The effects of anthracycline-based chemical therapies on breast cancer are controversial and inconclusive. We undertook a network meta-analysis to assess the... (Comparative Study)
Comparative Study
The effects of anthracycline-based chemical therapies on breast cancer are controversial and inconclusive. We undertook a network meta-analysis to assess the cardiotoxicity and effects of anthracycline therapies in breast cancer. The PubMed, Embase, and Cochrane databases up to August 2018 were reviewed. We identified 19 randomized clinical trials including 3,484 patients with breast cancer which assessed both cardiotoxicity and the effects of anthracycline-based therapies. Eligible studies included the following five treatment strategies: doxorubicin, epirubicin, liposomal doxorubicin (LD), doxorubicin + dexrazoxane (DD), and epirubicin + dexrazoxane (ED). In a direct meta-analysis, epirubicin, LD, DD, and ED had significantly superior cardioprotective effects compared with doxorubicin with odds ratios and 95% CIs of 1.64 (1.04, 2.57), 3.75 (2.46, 5.70), 2.88 (1.93, 4.29), and 3.66 (1.09, 12.33), respectively. Doxorubicin showed no significant difference of response rate compared with epirubicin or LD or DD, respectively. In a network meta-analysis, the ranking order of cardiotoxicity was doxorubicin (worst), epirubicin, DD, LD, and ED (best). The ranking order of the response rate was LD (best), doxorubicin, epirubicin, ED, and DD (worst). The most favorable balance between benefit and risk was shown for ED (best) followed by LD, DD, epirubicin, and doxorubicin. In conclusion, LD or ED is the suitable anthracycline treatment for breast cancer in consideration of both cardiotoxicity and efficacy.
Topics: Anthracyclines; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cardiotoxicity; Female; Humans; Network Meta-Analysis; Treatment Outcome
PubMed: 31104059
DOI: 10.1159/000500204 -
Hellenic Journal of Cardiology : HJC =... 2019Medical advances in pediatric oncology have led to increases in survival but the long-term adverse effects of treatment in childhood cancer survivors have not yet been...
Medical advances in pediatric oncology have led to increases in survival but the long-term adverse effects of treatment in childhood cancer survivors have not yet been examined in depth. In this systematic review, we aimed to study the prevalence and risk factors of late-onset cardiomyopathy (LOCM) among survivors of childhood lymphoma treated with anthracyclines. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines we searched Pubmed/Medline, abstracted data and rated studies on quality regarding late-onset (>1 year following treatment) cardiotoxicity of anthracyclines in survivors of childhood lymphoma. Across 22 identified studies, the prevalence of anthracycline-induced LOCM among survivors of childhood lymphoma ranges from 0 to 40%. Anthracycline dose, administration and dose of mediastinal radiation, patient's age and era of diagnosis and evaluation, follow-up duration as well as disease relapse have been reported as risk factors for LOCM, whereas administration of dexrazoxane seems to act protectively. There was significant between-study heterogeneity with regards to lymphoma subtypes, follow-up duration, definition of outcomes, and anthracycline-based treatment protocols. The rates of anthracycline-induced LOCM among survivors of childhood lymphoma are high and dependent on study design. Future studies should explore whether modifying risk factors and suggested supportive care could decrease its prevalence among childhood lymphoma survivors. Until then, lifelong follow-up of these patients aiming to determinate the earliest signs of cardiac dysfunction is the most important measure towards primordial prevention of LOCM.
Topics: Age of Onset; Anthracyclines; Cancer Survivors; Cardiomyopathies; Cardiotoxicity; Child; Global Health; Humans; Incidence; Lymphoma; Risk Factors; Survival Rate; Time Factors
PubMed: 30273645
DOI: 10.1016/j.hjc.2018.09.004 -
European Journal of Cancer (Oxford,... Jul 2022Cardioprotective therapies represent an important avenue to reduce treatment-limiting cardiotoxicities in patients receiving chemotherapy. However, the optimal duration,... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Cardioprotective therapies represent an important avenue to reduce treatment-limiting cardiotoxicities in patients receiving chemotherapy. However, the optimal duration, strategy and long-term efficacy of empiric cardio-protection remains unknown.
METHODS
Leveraging the MEDLINE/Pubmed, CENTRAL and clinicaltrials.gov databases, we identified all randomised controlled trials investigating cardioprotective therapies from inception to November 2021 (PROSPERO-ID:CRD42021265006). Cardioprotective classes included ACEIs, ARBs, Beta-blockers, dexrazoxane (DEX), statins and mineralocorticoid receptor antagonists. The primary end-point was new-onset heart failure (HF). Secondary outcomes were the mean difference in left ventricular ejection fraction (LVEF) change, hypotension and all-cause mortality. Network meta-analyses were used to assess the cardioprotective effects of each therapy to deduce the most effective therapies. Both analyses were performed using a Bayesian random effects model to estimate risk ratios (RR) and 95% credible intervals (95% CrI).
RESULTS
Overall, from 726 articles, 39 trials evaluating 5931 participants (38.0 ± 19.1 years, 72.0% females) were identified. The use of any cardioprotective strategy associated with reduction in new-onset HF (RR:0.32; 95% CrI:0.19-0.55), improved LVEF (mean difference: 3.92%; 95% CrI:2.81-5.07), increased hypotension (RR:3.27; 95% CrI:1.38-9.87) and no difference in mortality. Based on control arms, the number-needed-to-treat for 'any' cardioprotective therapy to prevent one incident HF event was 45, including a number-needed-to-treat of 21 with ≥1 year of therapy. Dexrazoxane was most effective at HF prevention (Surface Under the Cumulative Ranking curve: 81.47%), and mineralocorticoid receptor antagonists were most effective at preserving LVEF (Surface Under the Cumulative Ranking curve: 99.22%).
CONCLUSION
Cardiotoxicity remains a challenge for patients requiring anticancer therapies. The initiation of extended duration cardioprotection reduces incident HF. Additional head-to-head trials are needed.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Bayes Theorem; Cardiotoxicity; Dexrazoxane; Female; Heart Failure; Humans; Hypotension; Male; Mineralocorticoid Receptor Antagonists; Network Meta-Analysis; Stroke Volume; Ventricular Function, Left
PubMed: 35524992
DOI: 10.1016/j.ejca.2022.03.024