Year : 2017 | Volume
: 6 | Issue : 2 | Page : 68--69
Dexrazoxane in anthracycline cardiotoxicity
Abhijit S Nair
Department of Anaesthesia and Pain Medicine, Basavatarakam Indo American Cancer Hospital and Research Centre, Hyderabad, Telangana, India
Abhijit S Nair
Department of Anaesthesia and Pain Medicine, Basavatarakam Indo American Cancer Hospital and Research Centre, Hyderabad - 500 034, Telangana
Anthracycline group of antineoplastic agents is notorious for causing cumulative dose induced cardiotoxicity which is more pronounced in elderly patients and in patients with preexisting cardiac comorbidities. Several preventive strategies have been explored with variable success and without randomized studies and insufficient data. Dexrazoxane is an ethylenediaminetetraacetic acid analog which has been found to be effective when used before or along with anthracycline infusion. The drug is also found to be useful in counteracting injuries caused due to anthracycline extravasation in the tissues.
|How to cite this article:|
Nair AS. Dexrazoxane in anthracycline cardiotoxicity.J Clin Prev Cardiol 2017;6:68-69
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Nair AS. Dexrazoxane in anthracycline cardiotoxicity. J Clin Prev Cardiol [serial online] 2017 [cited 2022 May 26 ];6:68-69
Available from: https://www.jcpconline.org/text.asp?2017/6/2/68/203533
Anthracyclines belong to a group of antineoplastic drugs, which is indicated and approved for use as a chemotherapeutic agent in several malignancies. Doxorubicin, daunorubicin, idarubicin, and epirubicin are the drugs under anthracycline group. Although the drugs are very effective in cancer chemotherapy, the cardiotoxicity associated with their use is the limiting factor. The cardiotoxic effect can present clinically within the initial 1 year after exposure which is called as early toxicity or after 20 years of exposure called as late toxicity. Therefore, it is very important for the patients to remember the use and always narrate it in medical history as anthracycline exposure at any time in one's life is a risk factor.
Anthracyclines and the Heart
The upper safe limit of cumulative dose of anthracycline is suggested to be 500 mg/m 2. However, in elderly patients, i.e., more than 65 years of age, patient's with cardiac comorbidities (long-standing hypertension, coronary artery disease, diabetes mellitus), or concomitant radiation exposure to mediastinum, the cumulative dose should be even lesser. Cumulative anthracycline dose more than the recommended or allowable dose leads to mitochondrial disruption, swelling of sarcoplasmic reticulum, and degeneration of myocardial myofilament due to excessive free radicals in myocardial cells and formation of reactive oxygen (hydrogen peroxide and superoxide anion) which predisposes the patient to decrease in left ventricular (LV) function, reduced exercise tolerance, and heart failure. The cardiac mitochondrial damage is seen due to the formation of anthracycline-iron complexes. These complexes also predispose the cells to oxidative stress and lead to apoptosis of cardiac myocytes.
Echocardiographic Findings in Anthracycline Toxicity
A baseline echocardiogram is a must in patients of all age groups before starting anthracycline-based chemotherapy. A drop of more than 10% in the baseline ejection fraction should be taken seriously and regular follow-ups should be carried out. The oncologist may need to make changes in the chemotherapy plan in such patients. A three-dimensional echocardiography or a contrast echocardiography can give more information compared to the conventional echo. Diastolic abnormalities such as a decreased early peak flow velocity to atrial peak flow velocity (E/A) ratio, impaired deceleration time, isovolumetric relaxation time, and an increased Tei index have been found to be common presentation of anthracycline toxicity. Strain imaging with two-dimensional echocardiography is helpful in detection of subclinical LV dysfunction compared to the regular imaging., A cardiac magnetic resonance imaging is helpful in selected patients as it can pick up myocardial inflammation, fibrosis, and edema early. Equilibrium radionucleotide angiocardiography and single-photon emission computer tomography are specific imaging modalities used to assess cardiac insult after anthracyclines.
the Usual Strategies to Prevent Anthracycline Cardiotoxicity
The strategies practiced by medical oncologists to reduce cardiotoxicity are to administer the prescribed anthracycline over a longer duration (more than 6 h) which in some studies has been shown to reduce risk of heart failure later. Another way is to use liposomal encapsulated anthracyclines to target the delivery of the drug to the malignant organ and thereby reduce chances of cardiotoxicity. Drugs such as angiotensin-converting enzyme inhibitors, beta blockers, fluvastatin, erythropoietin, Vitamin E, N-acetyl cysteine, coenzyme-Q10, L-carnitine, statins, glutathione, and selenium have been used with variable success as prophylaxis against anthracycline-induced cardiotoxicity. However, the efficacy is anecdotal and when a meta-analysis was performed, pooling of data was not possible as the number of studies was too less.
Dexrazoxane is an iron chelating agent belonging to bisdioxopiperazine group of drugs which is closely related to ethylenediaminetetraacetic acid. After hydrolysis, dexrazoxane displaces the iron from the anthracycline compound by its chelating action. Interestingly, dexrazoxane also inhibits the enzyme DNA topoisomerase II just like anthracycline and other antineoplastic agents such as anthracenedione group (example mitoxantrone) and podophyllotoxins (example etoposide). However, dexrazoxane does not lead to the breaks in the double strands of DNA which contributes to the antineoplastic activity of other agents. However, using dexrazoxane with anthracyclines is associated with a higher risk of leukopenia.
Van Dalen et al. in Cochrane Database Systematic Review assessed the several cardioprotective strategies practiced to reduce anthracycline-induced cardiotoxicity in cancer patients by searching different databases and a statistically significant benefit was revealed in favor of dexrazoxane. However, there was no evidence found for a difference in response rate or survival between the dexrazoxane and control groups. The authors thus suggested the use of dexrazoxane concomitantly with anthracyclines to reduce cardiotoxicity in high-risk patients by carefully weighing risk versus benefit ratio. The recommended dosing is in a ratio of 10:1, i.e., 500 mg/m 2 of dexrazoxane for 50 mg/m 2 of anthracycline. The chemotherapy should be started 30 min after dexrazoxane infusion has started or once the infusion is over. The safety of dexrazoxane has not been established in pediatric patients.
Dexrazoxane is also used to counteract the toxicity encountered due to accidental anthracycline extravasation during infusion either through peripheral line or through a central venous catheter in the subcutaneous tissue. The recommended dosing is 1000 mg/m 2 within 6 h of extravasation as an infusion over 1–2 h, to repeat in same dose after 24 h and 500 mg/m 2 after another 24 h.
Dexrazoxane should be used concomitantly with anthracyclines in patients who already have cardiac ailments and in patients who have associated risk factors for serious cardiac problems. A baseline echocardiogram should be done before starting anthracyclines irrespective of patients' age and comorbidities. Special cardiac imaging should be considered during or after treatment by selecting the patient appropriately.
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