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Advances in Experimental Medicine and... 2020Doxorubicin is an anthracycline and one of the more effective chemotherapy agents used in the treatment of children, adolescents, and adults with osteosarcoma. Despite... (Review)
Review
Doxorubicin is an anthracycline and one of the more effective chemotherapy agents used in the treatment of children, adolescents, and adults with osteosarcoma. Despite its effectiveness, cardiotoxicity is a major late effect that compromises the survival and quality of life of survivors of this and other cancers. Cardiotoxicity is the inability of the heart to pump blood through the body effectively. Doxorubicin-induced cardiotoxicity is dose dependent. Additionally, the age of the patients plays a role in susceptibility with younger patients having a greater risk for cardiotoxicity and heart failure years after treatment is complete. The exact mechanism(s) responsible for doxorubicin-induced cardiotoxicity is poorly understood, and further research needs to be done to elucidate the mechanisms. This chapter summarizes the identified mechanisms that may play a role in anthracycline-induced cardiotoxicity. We will also summarize the types of cardiomyopathies that have been described in survivors treated with doxorubicin and the current recommendations for monitoring survivor for the development of cardiomyopathies. Included will be the important search for defining early biomarkers to identify patients and survivors at risk. Finally, we will summarize some of the interventions proposed for decreasing anthracycline-induced cardiotoxicity.
Topics: Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Humans; Neoplasms; Osteosarcoma; Quality of Life
PubMed: 32483740
DOI: 10.1007/978-3-030-43032-0_15 -
Aging Jan 2021Treatment of thoracic tumors with radiotherapy can lead to severe cardiac injury. We investigated the effects of dexrazoxane, a USFDA-approved cardioprotective drug...
Treatment of thoracic tumors with radiotherapy can lead to severe cardiac injury. We investigated the effects of dexrazoxane, a USFDA-approved cardioprotective drug administered with chemotherapy, on radiation-induced heart disease (RIHD) in a rat model. Male Sprague-Dawley rats were irradiated with a single dose of 20 Gy to the heart and treated with dexrazoxane at the time of irradiation and for 12 subsequent weeks. Dexrazoxane suppressed radiation-induced myocardial apoptosis and significantly reversed changes in serum cardiac troponin I levels and histopathological characteristics six months post-radiation. Treatment with dexrazoxane did not alter the radiosensitivity of thoracic tumors in a tumor formation experiment using male nude Balb/C mice with tumors generated by H292 cells. Dexrazoxane reduced the accumulation of reactive oxygen species in rat cardiac tissues, but not in tumors in nude mice. Transcriptome sequencing showed that and , which are involved in Toll-like receptor signaling, may be associated with the anti-RIHD effects of dexrazoxane. Immunohistochemistry revealed that dexrazoxane significantly decreased NF-κB p65 expression in cardiomyocytes. These findings suggest dexrazoxane may protect against RIHD by suppressing apoptosis and oxidative stress in cardiomyocytes.
Topics: Animals; Apoptosis; Dexrazoxane; Heart; Heart Diseases; Male; Mice; Mice, Nude; Protective Agents; Radiation Injuries, Experimental; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species
PubMed: 33406500
DOI: 10.18632/aging.202332 -
Future Oncology (London, England) Oct 2018Dexrazoxane can prevent anthracycline-associated cardiotoxicity. However, in 2011, its use in children was contraindicated by the EMA over concerns of increased risk of... (Review)
Review
Dexrazoxane can prevent anthracycline-associated cardiotoxicity. However, in 2011, its use in children was contraindicated by the EMA over concerns of increased risk of infection, myelosuppression and second primary malignancies, and because its efficacy in children had not then been established. We review here the evidence published since 2011, which confirms that dexrazoxane is an effective cardioprotectant in children and adolescents, is not associated with an increased risk of second primary malignancies or excess early or late mortality and does not impair chemotherapy efficacy. Based on this evidence, the contraindication for children and adolescents requiring high doses of anthracyclines and at risk for cardiotoxicity was removed from the European labeling for dexrazoxane.
Topics: Adolescent; Anthracyclines; Antibiotics, Antineoplastic; Cardiotoxicity; Child; Dexrazoxane; Humans; Neoplasms, Second Primary
PubMed: 29747541
DOI: 10.2217/fon-2018-0210 -
Drugs 2005Dexrazoxane (Cardioxane, Zinecard, a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced... (Meta-Analysis)
Meta-Analysis Review
Dexrazoxane (Cardioxane, Zinecard, a cyclic derivative of edetic acid, is a site-specific cardioprotective agent that effectively protects against anthracycline-induced cardiac toxicity. Dexrazoxane is approved in the US and some European countries for cardioprotection in women with advanced and/or metastatic breast cancer receiving doxorubicin; in other countries dexrazoxane is approved for use in a wider range of patients with advanced cancer receiving anthracyclines. As shown in clinical trials, intravenous dexrazoxane significantly reduces the incidence of anthracycline-induced congestive heart failure (CHF) and adverse cardiac events in women with advanced breast cancer or adults with soft tissue sarcomas or small-cell lung cancer, regardless of whether the drug is given before the first dose of anthracycline or the administration is delayed until cumulative doxorubicin dose is > or =300 mg/m2. The drug also appears to offer cardioprotection irrespective of pre-existing cardiac risk factors. Importantly, the antitumour efficacy of anthracyclines is unlikely to be altered by dexrazoxane use, although the drug has not been shown to improve progression-free and overall patient survival. At present, the cardioprotective efficacy of dexrazoxane in patients with childhood malignancies is supported by limited data. The drug is generally well tolerated and has a tolerability profile similar to that of placebo in cancer patients undergoing anthracycline-based chemotherapy, with the exception of a higher incidence of severe leukopenia (78% vs 68%; p < 0.01). Dexrazoxane is the only cardioprotective agent with proven efficacy in cancer patients receiving anthracycline chemotherapy and is a valuable option for the prevention of cardiotoxicity in this patient population.
Topics: Anthracyclines; Antineoplastic Agents; Cardiovascular Agents; Cardiovascular Diseases; Humans; Neoplasms; Randomized Controlled Trials as Topic; Razoxane
PubMed: 15892593
DOI: 10.2165/00003495-200565070-00008 -
The Annals of Pharmacotherapy Sep 1994To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention. (Comparative Study)
Comparative Study Review
OBJECTIVE
To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention.
DATA SOURCES
All animal and human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant papers.
DATA EXTRACTION
Animal, in vitro cellular, and human data are thoroughly reviewed with particular emphasis on doxorubicin-induced cardiotoxicity, including clinical manifestations, risk factors, and mechanisms of toxicity. The role of dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity is reviewed, including mechanism of effect, animal data, and human trials.
DATA SYNTHESIS
Anthracyclines are associated with a cumulative, dose-dependent, irreversible cardiomyopathy that can lead to congestive heart failure and death. The incidence of cardiotoxicity rises sharply at a total lifetime dose of more than 550 mg/m2. Through its semiquinone metabolite, doxorubicin appears to generate superoxide anion and superhydroxide free radicals with iron as a cofactor. Because of poor myocardial concentrations of superoxide dismutase, catalase, and glutathione peroxidase, these free radicals cause extensive lipid peroxidation and mitochondrial destruction.
CONCLUSIONS
Dexrazoxane is hydrolyzed to its active form intracellularly and binds iron to prevent the formation of superhydroxide radicals, thus preventing mitochondrial destruction. The effect of dexrazoxane on the prevention of doxorubicin-induced cardiotoxicity is impressive in both animal and human studies. Further research is needed to clearly demonstrate the effect dexrazoxane has on the antitumor effects of combination chemotherapy while defining optimal dosing strategies to minimize myelosuppression and maximize cardioprotection.
Topics: Animals; Cardiomyopathies; Dogs; Doxorubicin; Drug Synergism; Humans; Randomized Controlled Trials as Topic; Rats; Razoxane; Swine; Swine, Miniature
PubMed: 7803884
DOI: 10.1177/106002809402800912 -
Nederlands Tijdschrift Voor Geneeskunde 2010Cardiotoxicity and extravasation injuries are extremely serious complications of anthracycline use. Both complications are probably caused by oxidative stress.... (Review)
Review
Cardiotoxicity and extravasation injuries are extremely serious complications of anthracycline use. Both complications are probably caused by oxidative stress. Dexrazoxane has been approved as a cardioprotective agent and as an antidote in extravasation of anthracyclines. Randomized clinical trials have shown that dexrazoxane is the only cardioprotective agent proven to be effective in the treatment of anthracycline-induced cardiotoxicity. In these clinical studies dexrazoxane decreased the incidence of cardiac events and heart failure. Possible adverse effects of dexrazoxane when administered as a cardioprotective agent are a decreased antitumor effect of anthracyclines and the onset of secondary malignancies in children. As an antidote in anthracycline extravasation, clinical studies showed dexrazoxane to be highly efficacious in preventing the need for surgical resection. Dexrazoxane can be considered as the treatment of first choice for this indication. Dexrazoxane is well tolerated in general. The most commonly reported side effects are leukopenia, thrombocytopenia and local reactions at the infusion site.
Topics: Anthracyclines; Cardiovascular Agents; Heart Diseases; Heart Failure; Humans; Randomized Controlled Trials as Topic; Razoxane
PubMed: 20619024
DOI: No ID Found -
Cardiovascular Toxicology 2007Dexrazoxane is highly effective in reducing anthracycline-induced cardiotoxicity and extravasation injury and is used clinically for these indications. Dexrazoxane has... (Review)
Review
Dexrazoxane is highly effective in reducing anthracycline-induced cardiotoxicity and extravasation injury and is used clinically for these indications. Dexrazoxane has two biological activities: it is a prodrug that is hydrolyzed to an iron chelating EDTA-type structure and it is also a strong inhibitor of topoisomerase II. Doxorubicin is able to be reductively activated to produce damaging reactive oxygen species. Iron-dependent cellular damage is thought to be responsible for its cardiotoxicity. The available experimental evidence supports the conclusion that dexrazoxane reduces doxorubicin cardiotoxicity by binding free iron and preventing site-specific oxidative stress on cardiac tissue. However, it cannot be ruled out that dexrazoxane may also be protective through its ability to inhibit topoisomerase II.
Topics: Animals; Antineoplastic Agents; Cardiovascular Agents; Clinical Trials as Topic; Doxorubicin; Enzyme Inhibitors; Heart Diseases; Humans; Neoplasms; Prodrugs; Razoxane; Topoisomerase II Inhibitors
PubMed: 17652819
DOI: 10.1007/s12012-007-0023-3 -
British Journal of Nursing (Mark Allen...This article reviews the efficacy and place in therapy of dexrazoxane (Savene®) for the treatment of anthracycline extravasation, highlighting the lack of inclusion of... (Review)
Review
AIMS
This article reviews the efficacy and place in therapy of dexrazoxane (Savene®) for the treatment of anthracycline extravasation, highlighting the lack of inclusion of Savene in most UK cancer network and organisational treatment guidelines. Here we offer advice to nurses on making a case to ensure the availability of Savene.
KEY FINDINGS
In 2010, the UK National Extravasation Information Service (NEXIS) green card scheme reported that anthracyclines were the second most common agent involved in extravasations, but they carry the greatest risk to the patient because of their potentially serious consequences. Anthracycline extravasations therefore require prompt and effective treatment. Due to the infrequent occurrence of anthracycline extravasations, their accidental nature and ethical considerations, conducting randomised controlled clinical trials in this therapy area is not possible. As treatment decisions should always be made on patient-specific factors, health professionals need to demonstrate the rationale for choosing a particular course of action when presented with an anthracycline extravasation, especially when we are moving into an era of increased medical litigation. There are several possible treatment options, some of which require demonstrable local core competencies in order to be considered for a particular patient. Based on the available evidence, Savene-the only licensed antidote-is recommended as an effective management strategy for anthracycline extravasation and should be made available in all settings where chemotherapy is administered. However, a high percentage of nurses administering chemotherapy still do not have access to Savene, as it has not been included in their local guidelines for the management of extravasations. Thus, in a large part of the UK, this important treatment option is not available, leaving a significant unmet need (Figure 1).
CONCLUSIONS
As nurses play a key role in the prevention, detection, and management of extravasations, they should also assume a key role in ensuring that their local protocols include all appropriate management strategies. Where appropriate, if Savene is not included in the treatment guidelines, nurses should feel empowered to encourage their trust and Specialist Commissioning Groups (SCGs) to make it available, and thus minimise the serious risks associated with anthracycline extravasations.
Topics: Anthracyclines; Antineoplastic Agents; Dexrazoxane; Extravasation of Diagnostic and Therapeutic Materials; Humans; Neoplasms; Oncology Nursing; Practice Guidelines as Topic; Risk Factors; Topoisomerase II Inhibitors; United Kingdom
PubMed: 24067273
DOI: 10.12968/bjon.2013.22.Sup17.S6 -
Clinical & Translational Oncology :... Jan 2014Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane... (Review)
Review
Extravasation of cytotoxic agents is a true medical emergency. Dexrazoxane is the only licensed drug for the treatment of anthracycline extravasations. Dexrazoxane proved to be effective and moderately well tolerated. However, alternative approaches for the management of anthracycline extravasations are available such as topical DMSO and cooling. There appears to be general agreement about dexrazoxane usefulness when extravasations involve large volumes of anthracycline and/or central venous access device. Nevertheless, the non-invasive combination of DMSO and cooling is the most commonly described therapy, particularly in small anthracycline extravasations. Further research is still needed to establish unequivocal situations where dexrazoxane must be initiated.
Topics: Animals; Anthracyclines; Antineoplastic Agents; Dexrazoxane; Extravasation of Diagnostic and Therapeutic Materials; Humans; Infusions, Intravenous
PubMed: 23949792
DOI: 10.1007/s12094-013-1100-7 -
Drugs Sep 1998Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced... (Review)
Review
UNLABELLED
Dexrazoxane has been used successfully to reduce cardiac toxicity in patients receiving anthracycline-based chemotherapy for cancer (predominantly women with advanced breast cancer). The drug is thought to reduce the cardiotoxic effects of anthracyclines by binding to free and bound iron, thereby reducing the formation of anthracycline-iron complexes and the subsequent generation of reactive oxygen species which are toxic to surrounding cardiac tissue. Clinical trials in women with advanced breast cancer have found that patients given dexrazoxane (about 30 minutes prior to anthracycline therapy; dexrazoxane to doxorubicin dosage ratio 20:1 or 10:1) have a significantly lower overall incidence of cardiac events than placebo recipients (14 or 15% vs 31%) when the drug is initiated at the same time as doxorubicin. Cardiac events included congestive heart failure (CHF), a significant reduction in left ventricular ejection fraction and/or a > or = 2-point increase in the Billingham biopsy score. These results are supported by the findings of studies which used control groups (patients who received only chemotherapy) for comparison. The drug appears to offer cardiac protection irrespective of pre-existing cardiac risk factors. In addition, cardiac protection has been shown in patients given the drug after receiving a cumulative doxorubicin dose > or = 300 mg/m2. It remains to be confirmed that dexrazoxane does not affect the antitumour activity of doxorubicin: although most studies found that clinical end-points (including tumour response rates, time to disease progression and survival duration) did not differ significantly between treatment groups, the largest study did show a significant reduction in response rates in dexrazoxane versus placebo recipients. Dexrazoxane permits the administration of doxorubicin beyond standard cumulative doses; however, it is unclear whether this will translate into prolonged survival. Preliminary results (from small nonblind studies) indicate that dexrazoxane reduces cardiac toxicity in children and adolescents receiving anthracycline-based therapy for a range of malignancies. The long term benefits with regard to prevention of late-onset cardiac toxicity remain unclear. With the exception of severe leucopenia [Eastern Cooperative Oncology Group (ECOG) grade 3/4 toxicity], the incidence of haematological and nonhaematological adverse events appears similar in patients given dexrazoxane to that in placebo recipients undergoing anthracycline-based chemotherapy. Although preliminary pharmacoeconomic analyses have shown dexrazoxane to be a cost-effective agent in women with advanced breast cancer, they require confirmation.
CONCLUSIONS
Dexrazoxane is a valuable drug for protecting against cardiac toxicity in patients receiving anthracycline-based chemotherapy. Whether it offers protection against late-onset cardiac toxicity in patients who received anthracycline-based chemotherapy in childhood or adolescence remains to be determined. Further clinical experience is required to confirm that it does not adversely affect clinical outcome, that it is a cost-effective option, and to determine the optimal treatment regimen.
Topics: Animals; Antibiotics, Antineoplastic; Antineoplastic Agents; Cardiovascular Agents; Chelating Agents; Heart Diseases; Humans; Neoplasms; Razoxane
PubMed: 9777314
DOI: 10.2165/00003495-199856030-00009