Cardio-oncology

1

What is type I versus type II cardiotoxicity?

• Type I drugs cause irreversible cell loss and cumulative dose-related cardiotoxicity. Anthracyclines are type I drugs. Clinical manifestations of irreversible damage may not present for years owing to compensatory mechanisms. Stress factors such as hypertension and coronary artery disease (CAD) might later lead to cardiac decompensation. Other type I drugs include mitoxantrone and cyclophosphamide.

• Type II drugs can cause cellular dysfunction by altering mitochondrial and protein function and can thereby induce reversible cardiotoxicity. Trastuzumab, a monoclonal antibody against the HER2/erbB2 receptor, is a type II drug, although irreversible damage can occur with trastuzumab in the setting of preexisting cardiac disease or with concomitant use of anthracyclines. Concomitant use of trastuzumab with an anthracycline greatly increases the risk of cardiotoxicity (16% vs. 0%–3.9% New York Health Association [NYHA] class III–IV heart failure). A time interval of 3 months is recommended before starting trastuzumab after anthracycline. Other type II drugs include angiogenesis inhibitors such as bevacizumab, sunitinib, and sorafenib.

2

What is the mechanism of anthracycline-induced cardiotoxicity?

• The cellular target for doxorubicin is topoisomerase II (Top 2). There are two Top 2 enzymes, Top 2 alpha and Top 2 beta. Top 2 alpha is overexpressed in tumors and is the molecular basis of anticancer activity. Cardiomyocytes express Top 2 beta but not Top 2 alpha. Doxorubicin also targets Top 2 beta and forms a complex that induces DNA double-stranded breaks and leads to cell death as well as an increase in reactive oxygen species.

3

What is a safe dose of anthracycline?

• There is no safe dose of anthracycline. The risk of cardiac dysfunction increases with increasing cumulative dose. The risk is less than 5% for doses of less than 250 mg/m ² , 10% for doses between 250 mg/m ² and 600 mg/m ² , and greater than 30% for doses greater than 600 mg/m ² .

4

What are primary prevention strategies for anthracycline-induced cardiotoxicity?

• Several strategies are utilized:

• Continuous infusion. Bolus administration of anthracycline leads to a higher cardiac concentration and higher cardiac toxicity. Continuous infusion does not compromise antitumor efficacy but does reduce cardiac toxicity. This finding does not apply to children. In children, cardiac toxicity is the same with a bolus or a continuous infusion.

• Liposomal doxorubicin. Liposomal encapsulation does not penetrate healthy vasculature as readily as tumor vasculature and thus provides an equivalent antitumor effect with less cardiac toxicity. Use is limited owing to cost and is approved by the US Food and Drug Administration (FDA) only for ovarian cancer, HIV-related Kaposi sarcoma, and multiple myeloma after failure of another therapy.

• Dexrazoxane. Dexrazoxane prevents anthracyclines from binding to the Top 2 complex and thereby provides cardioprotection. Dexrazoxane is FDA-approved only for breast cancer patients who have already received 300 mg/m ² of anthracyclines. There is concern that dexrazoxane might interfere with the antitumor effect of anthracyclines. In children, there is concern that there could be an increased risk for the development of a secondary malignancy.

• It is uncertain whether beta-blockers or angiotensin-converting enzyme (ACE) inhibitors are useful in primary prevention. There are short-term studies suggesting benefit, but further study is needed.

5

How should cardiac function be monitored in patients receiving anthracyclines?

• Prior to treatment patients should have a history and physical, electrocardiogram (ECG), and measurement of left ventricular ejection fraction (LVEF), preferably by echocardiogram. Patients under age 65 with normal EF are considered to be at low risk. Those with prior cardiac disease are at intermediate or high risk, and the oncologist and cardiologist must weigh the risk and benefit of treatment with anthracyclines versus using a less cardiotoxic regimen. If the LVEF is less than 40%, anthracyclines should not be used.

• Cardiac function should be reassessed at 3, 6, and 9 months during treatment and at 12 and 18 months after initiation of treatment. If the EF decreases to less than 40%, the anthracycline should be discontinued. If the EF decreases to 40% to 50%, recommendations are slightly variable. At MD Anderson, if the EF is less than 45%, chemotherapy is held, treatment with an ACE inhibitor and beta-blocker is initiated, and the LVEF is reassessed after 1 month. If the LVEF is 45% to 49%, treatment with an ACE inhibitor and beta-blocker is initiated. Chemotherapy is held if the LVEF decrease is greater than 10% from baseline and continued if the LVEF decrease is less than 10% from baseline. LVEF is reassessed after 1 month.

6

How long is cardiac monitoring recommended after anthracyclines and/or radiation therapy for treatment of childhood, adolescent, and young adult cancer?

• Lifelong cardiac monitoring is advised because the incidence of cardiac toxicity increases with length of time since treatment. There is no time limit on the development of cardiac toxicity. Assessment of LVEF by echocardiography (or comparable imaging) is recommended as follows:

• Anthracycline dose less than 250 mg/m ² : every 5 years.

• Anthracycline dose greater than or equal to 250 mg/m ² : every 2 years.

• Radiation dose between 15 Gy and 35 Gy: every 5 years.

• Radiation dose greater than 35 Gy: every 2 years.

• Radiation dose greater than or equal to 15 Gy plus anthracycline dose less than 250 mg/m ² : every 2 years.

• Any radiation dose and anthracycline greater than or equal to 250 mg/m ² : every 2 years.

  • Evaluation by a cardiologist for stress testing is recommended 5 to 10 years after radiation therapy for patients who received greater than or equal to 35 Gy or greater than 15 Gy plus any anthracyclines.

7

How should cardiac function be monitored in patients receiving trastuzumab?

• Baseline evaluation and discontinuation for EF less than 40% is the same as for anthracyclines. If the EF decreases to 40% to 50%, management is different and slightly variable. At MD Anderson, if the EF decrease is less than 15% compared with baseline, trastuzumab is continued with initiation of an ACE inhibitor and a beta-blocker. If the EF decrease is greater than 15% compared with baseline, trastuzumab is held, an ACE inhibitor and beta-blocker are started, and the EF is reassessed after 1 month.

8

What tyrosine kinase inhibitor was featured on the cover of TIME magazine as “the magic bullet” against cancer?

• Imatinib (Gleevec). Chronic myelogenous leukemia (CML) was the first cancer treated with a tyrosine kinase inhibitor (TKI). CML is caused by the Philadelphia chromosome, which creates the BCR-ABL protein. Imatinib is a “breakpoint cluster region”—Abelson (BCR-ABL) inhibitor. Treatment with imatinib improved 5-year survival in CML patients from 40% to 50% initially to 90%, essentially converting a fatal cancer into a manageable chronic condition. Imatinib has been associated with a low incidence of cardiomyopathy and asymptomatic cardiac dysfunction. However, patients can develop resistance to imatinib. Thus, newer generation BCR-ABL kinase inhibitors have been developed.

9

What are tyrosine kinase inhibitors?

• TKIs are the most common targeted cancer drugs. Kinases are enzymes that control diverse cellular functions by transferring a phosphate group from adenosine triphosphate (ATP). Most cancers are associated with an overactivation of kinases. Drugs that target kinases have less toxic side effects than older chemotherapies. There are 20 lipid kinases and 518 protein kinases. Tyrosine kinases are protein kinases and can be categorized into receptor tyrosine kinases (RTKs) and nonreceptor tyrosine kinases.