Cardiotoxicity Associated With Monoclonal Antibody Chemotherapy

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Surveillance for cardiotoxicity must be a part of treating patients with monoclonal antibodies.
Surveillance for cardiotoxicity must be a part of treating patients with monoclonal antibodies.

Chemotherapeutic agents have a multitude of side effects that vary in timing and severity. Upon approval of a new medication, the full spectrum of adverse events may not be known, however there are established system-based categories of side effects that have been thoroughly studied and reported.

Cardiotoxicity represents one of the more worrisome side effects of chemotherapy, especially with the well-established reports associated with anthracycline-based chemotherapy. Monoclonal antibody (MAb)-based chemotherapy represents a newer class of medications that are continuing to accumulate data with respect to their cardiotoxicity profiles.

As with many side effects within oncology, the degree of cardiotoxicity of certain chemotherapy agents is multifactorial. Chemotherapy-based factors include the class of drug and molecular derivation, initial and cumulative dose, dosing schedule, route of administration (eg, oral, intravenous, intrathecal), potential polypharmacy, and combination with radiation therapy.

Patient-specific factors include age, sex, type of cancer, baseline hepatic and renal function, polypharmacy, baseline cardiovascular disease, and family history. The most common cardiotoxicities associated with certain chemotherapy agents include heart failure, arrhythmias, myocardial ischemia, thromboembolism, hypertension, and pericardial disease.1

Rituximab is an anti-CD20 monoclonal antibody that is used in chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL). The most lethal cardiac issues with rituximab are encountered during an infusion reaction, in which the patient may develop hypotension, hypoxia, acute myocardial infarction, arrythymias, and cardiogenic shock.

Patients can be premedicated with acetaminophen, antihistamines, and steroids prior to initiation of the infusion. More benign cardiac side effects of rituximab include hypertension (between approximately 6%-12% of patients) and transient hypotension (approximately 10% of patients).2

Pre-existing cardiovascular disease is not an absolute contraindication to rituximab use, however these patients should be monitored closely during all infusions, especially the first one.

Trastuzumab is a human epidermal growth factor receptor 2 (HER2) monoclonal antibody used in HER2-positive breast and gastric cancer.3

The most common cardiotoxicity associated with trastuzumab is decline in ejection fraction which can occur anywhere from 4% to 22% of patients.1,3 This decline in ejection fraction leads to clinical heart failure in between 2% to 7% of patients.1,3

Consequently, trastuzumab carries a black box warning for cardiomyopathy/heart failure, in which patients can be symptomatic or asymptomatic. Risk factors for trastuzumab-induced heart failure include prior cardiac history, older than age 50, depressed left ventricular ejection fraction, and concomitant administration with anthracyclines or prior radiation therapy.1,3

Cardiotoxicity is not dose-related, which is notably different than with anthracyclines. A baseline echocardiogram is recommended prior to initiation of therapy and should be monitored at regular 3 month intervals.3 The prescribing information recommends holding trastuzumab if the ejection fraction declines 16% or more from baseline.

Although there are no formal clinical studies on when and if trastuzumab should be restarted after a decline in ejection fraction, most clinicians would most be reluctant to do so. Additional cardiotoxicities associated with trastuzumab include hypertension, arrhythmias, and palpitations.

Bevacizumab is an antivascular endothelial growth factor (VEGF) monoclonal antibody approved to use in multiple cancers including colorectal, cervical, non-small cell lung (non-squamous cell), ovarian, and renal cell.4 Cardiotoxicities include hypertension (12% to 34%), myocardial ischemia (approximately 2%), and reduced ejection fraction (approximately 1% to 11%)1,4.

Monoclonal antibodies represent a relatively new and exciting class of medications being utilized more frequently in the field of oncology. The development of this class of drugs will undoubtedly continue, during which increased surveillance for adverse events including cardiotoxicity must be continued.

References

  1. Bovelli D, Plataniotis G, Roila F; ESMO Guidelines Working Group. Cardiotoxicity of chemotherapeutic agents and radiotherapy-related heart disease: ESMO Clinical Practice Guidelines. Ann Oncol. 2010 May;21 (Suppl 5):v277-v282.
  2. RITUXAN (rituximab) [package insert]. Genentech, Inc, South San Francisco, CA.  August 2014. http://www.gene.com/download/pdf/rituxan_prescribing.pdf.
  3. HERCEPTIN (trastuzumab) [package insert]. Genentech, Inc, South San Francisco, CA.  June 2014. http://www.gene.com/download/pdf/herceptin_prescribing.pdf. 
  4. AVASTIN (bevacizumab) [package insert]. Genentech, Inc, South San Francisco, CA.  November 2014. http://www.gene.com/download/pdf/avastin_prescribing.pdf.  

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