Introduction
Anthracycline is a class of anti-cancer drugs derived from the Streptomyces bacterium. Anthracyclines are widely used as a chemotherapy regimen to treat cancer. Chemotherapy is a highly specialized field for oncologists. Anthracyclines are the most effective chemotherapeutic drug used to treat children and adult patients with osteosarcoma. Studies show that more than 60 percent of children receive an Anthracycline regimen to treat cancer. Anthracycline is also used to treat other sarcomas like lymphoma, leukemia, and breast cancer. Heart diseases and heart failure are the most common complications associated with the toxicity and exposure to anthracyclines, compromising the patient's quality of life. It also decreases the survival rate of patients with cancer. The proper intervention of drugs, reduction of Doxorubin dose, and exercise can prevent Anthracycline-induced cardiotoxicity.
What Is Anthracycline?
Anthracycline is a class of anti-cancer drugs used in chemotherapy to treat cancer. Anthracyclines are antibiotics derived from the Streptomyces bacterium. Idarubicin, Daunorubicin, Epirubicin, and Doxorubicin are important drugs under anthracycline. The anti-cancer drug either kills the cancerous cells or inhibits their growth. However, the selection of drugs for treating cancer by chemotherapy is limited. The role of anti-cancer drugs is important in treating various cancer. Chemotherapeutic drugs are combined with surgery, radiotherapy, and immunotherapy as a combined modality approach for many metastatic tumors (groups of cell masses that grow abnormally). Metastatic tumors are those tumors which can spread to different parts of the body.
Anthracycline treats the following diseases:
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Leukemia (blood cancer).
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Lymphoma (cancer of lymph node).
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Breast cancer.
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Gastrointestinal cancer (stomach cancer).
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Uterine cancer (cancer of the female reproductive organ, uterus).
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Ovarian cancer.
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Lung cancer.
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Anthracyclines are used as adjuvant chemotherapy to kill any remnant of the malignant cell after surgery or radiotherapy.
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Osteosarcoma (bone cancer).
How does Anthracycline Treat Cancer?
Anthracyclines are effective anti-cancer drugs. Anthracyclines drugs such as Doxorubicin are classified as cytotoxic drugs. Cytotoxic (cyto means cell) drugs are a class of drugs that kill fast-growing cancerous cells. Anthracyclines have more effect on multiplying cells, which grow rapidly. Anthracyclines interfere with the rapid nucleic acid synthesis (deoxyribonucleic acid and ribonucleic acid metabolism), which occurs during cell division leading to cell death. Hence, Anthracyclines modify the growth of cancer cells by shrinking tumor size, thereby prolonging the life of patients.
What Is Anthracycline Cardiotoxicity?
Anthracyclines are widely used as chemotherapy, but the tissue is affected in a dose-dependent manner. Anthracyclines have a limited role in chemotherapy due to their adverse effect. Myelosuppression and cardiotoxicity are major toxicities of high-dose anthracycline.
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Cardiotoxicity - Cardiotoxicity is the inability of the heart’s muscles to pump blood (cardiomyopathy) through the body. Doxorubicin mainly causes cardiomyopathy. Doxorubicin-induced cardiotoxicity can be fatal after successful tumor treatment as it is late cardiotoxicity. Doxorubicin can also cause acute heart muscle damage, putting the heart at risk of ischemic (insufficient oxygen supply) damage.
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Myelosuppression - Anthracyclines can cause depression of bone marrow resulting in aplastic anemia. This is the most serious toxicity and often limits the dose of Anthracyclines employed for cancer patients.
What Are the Types of Anthracycline-Induced Cardiotoxicity?
The researchers have classified the stages of Anthracycline-induced cardiotoxicity:
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Acute Cardiotoxicity - Acute cardiotoxicity is rare and reversible. Acute cardiotoxicity occurs during or within a week of anthracycline administration. Acute failure of the heart, inflammation of layers of the heart, and hypotension (low blood pressure) due to dilatation of blood vessels (vasodilatation) are the symptoms of acute cardiotoxicity.
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Subchronic Cardiotoxicity - Following the administration of Anthracyclines, subchronic cardiotoxicity is seen within a year.
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Early Chronic Cardiotoxicity - Early chronic cardiotoxicity is seen within one year after cessation of anthracycline. Congestive heart failure and heart dysfunctions are symptoms of early chronic cardiotoxicity.
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Late Chronic Cardiotoxicity - Late chronic cardiotoxicity most commonly occurs after successful tumor treatment. Late chronic cardiotoxicity is seen after one year or more than a year of cessation of anthracycline. Congestive heart failure and cardiomyopathies are the symptoms of late chronic cardiotoxicity.
What Are the Risk Factors for Anthracycline-Induced Cardiotoxicity?
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Age - Children under four years and adults over 65 years of age are at higher risk for developing anthracycline-induced cardiotoxicity. Studies have shown that 10 percent of pediatric patients develop late cardiotoxicity up to 15 years after completing therapy.
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Sex - Females are more susceptible to cardiotoxicity than males.
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Dose of Anthracyclines - The risk of cardiotoxicity is correlated to drug dose. Studies show a 63 percent prevalence of heart dysfunction after ten years of follow-up in patients who received a cumulative dose of more than 500 milligrams per meter square of anthracyclines.
How Anthracycline-Induced Cardiotoxicity Detected?
Signs and symptoms of heart failure can detect cardiotoxicity. It can also be detected by a reduced blood volume ejected by the heart (left ventricular ejection fraction). Normal LVEF for males is 52 to 72 percent , while for females, it is 54 to 74 percent . Heart dysfunction shows less than 52 percent LVF.
The following are the investigation by which anthracycline-induced cardiotoxicity can be detected:
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Endomyocardial Biopsy - Endomyocardial biopsy is the most successful technique to detect heart functions. However, it has some limitations as it is an invasive technique.
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Echocardiography - Echocardiography is a non-invasive investigation detecting LVEF, which can indicate heart dysfunction. In addition, three dimensional echocardiography has reduced analysis time and enhanced the quality of diagnosis.
How to Prevent Anthracycline-Induced Cardiotoxicity?
Late cardiotoxicity most commonly occurs after successful post-treatment of cancer. The proper intervention of drugs, reduction of Doxorubin dose, and exercise can prevent Anthracycline-induced cardiotoxicity.
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Medication - Dexrazoxane is approved by the Food and Drug Administration (FDA) as a cardioprotective agent for anthracycline-induced cardiotoxicity. Dexrazoxane is an adjunctive agent used as a scavenger. Enalapril, Zofenopril, and Lisinopril (ACE inhibitors) are used to treat heart failure. Beta-blockers such as Carvedilol help to preserve heart function after cessation of Doxorubicin in patients with cancer.
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Reduction of Dose - Studies have shown that adults who receive cumulative doses of more than 600mg/m2 anthracyclines are at higher risk of toxicity.
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Follow-Up - The regular follow-up until 5 years after cessation of anthracycline is important to detect signs and symptoms of heart dysfunction.
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Exercise - Aerobic exercise is recommended in cancer survival patients after cessation of anthracyclines as exercise shows cardioprotective effects. The reduced ejected blood volume by the heart can be prevented by exercise in doxorubicin-treated patients. In addition, the exercise intervention help to combat the weight loss seen in patients treated with Doxorubicin.
Conclusion
Anthracyclines are most commonly used in treating patients with osteosarcoma. Late Doxorubicin-induced cardiotoxicity is seen in sarcoma survivors. The exact mechanism of anthracycline-induced cardiotoxicity is not known. Early detection of heart dysfunction and drug intervention can prevent anthracycline-induced cardiotoxicity. The alternative new way to prevent anthracycline-induced cardiotoxicity is aerobic exercise. In the case of childhood sarcoma survival, prompt follow-up should be done to prevent side effects, as Doxorubicin-induced cardiotoxicity can occur several years after the completion of treatment.
