Michael S. Ewer, MD
Concerns about cardiotoxicity of molecularly targeted anticancer therapies may be overblown, according to Michael S. Ewer, MD, from The University of Texas MD Anderson Cancer Center in Houston. Although molecularly targeted agents can cause cardiac damage, it appears to be reversible and related to cellular dysfunction, as distinct from agents such as anthracyclines that cause cellular death and irreversible cardiac dysfunction.
“The ‘Big Bad Wolf’ [in terms of cardiotoxicity] is still anthracyclines. Type II agents [ie, molecularly targeted agents] are generally much safer, but instances of heart failure can still occur. The risk is related to prior damage, which adds insult to injury,” Ewer said in a session at the 2012 Multinational Association of Supportive Care in Cancer Symposium.
Patients on targeted therapy need cardiac monitoring, but perhaps extensive monitoring is not rational, he suggested. Also, aggressive treatment of reduced left ventricular ejection fraction (LVEF) may not be rational, Ewer noted.
“There is considerable confusion and almost paranoia in some settings [about the cardiac safety of targeted therapy]. Many patients can be given a rest from targeted therapy and restarted safely,” Ewer said.
Targeted therapies change the vascular milieu by causing hypertension, fluid retention, and thromboembolic phenomenon. Although a Cochrane review suggested that trastuzumab (Herceptin, Genentech) significantly increased the risk of heart failure and decline in LVEF, in adjuvant breast cancer trials with a total of more than 10,000 women, only two cardiac deaths were reported, Ewer said.
“A 7-year follow-up of an NSABP [National Surgical Adjuvant Breast and Bowel Project] trial of trastuzumab will be reported soon and shows a different picture, with great safety. Maybe the Cochrane analysis is not complete,” he said. “My two cents is that molecularly targeted therapy is generally safe.”
Targeted therapies cause much less cardiotoxicity than type I drugs like anthracyclines, which are widely used to treat breast cancer. With type I agents, damage is cumulative, dose-related, and involves cell destruction.
“But not all damaged cells die. When we damage myocytes, some die and some repair,” Ewer said.
The newer type II targeted agents cause cellular dysfunction, but the cell does not die. Predictable risk factors for type I and type II cardiac injury include prior chemotherapy and prior radiation, or “anything that damages the heart or leads to vascular or ischemic injury.”
Studies have shown that incipient heart failure due to reduced LVEF in patients treated with trastuzumab is reversible with standard heart failure treatment. Many patients could be rechallenged with trastuzumab successfully after heart failure treatment, Ewer told listeners.
“Anthracyclines damage myocytes, and trastuzumab interferes with cell repair. When you add trastuzumab to an anthracycline, it blocks the repair mechanism. These drugs cause problems when given close together in time. Timing is important [in terms of cardiotoxicity],” he commented.
Cardiotoxicity concerns have been raised about combining targeted therapies, such as pertuzumab (Perjeta, Genentech) and trastuzumab, which bind to distinct epitopes on the HER2 extracellular domain and work synergistically. The CLEOPATRA trial enrolled more than 800 patients and randomized them to either placebo plus trastuzumab plus docetaxel or pertuzumab plus trastuzumab plus docetaxel (N Engl J Med
. 2012;366:109-119). However, no cardiac safety signals were raised in this trial when the two targeted agents were combined. The percentages for left ventricular systolic dysfunction were all lower in the combination arm than in the control group.
Turning to specific targeted therapies, Ewer mentioned sunitinib (Sutent, Pfizer), bevacizumab (Avastin, Genentech), and lapatinib (Tykerb, GlaxoSmithKline). In clinical trials, sunitinib has been shown to increase the risk of hypertension, yet hypertension is associated with longer survival. Symptomatic and asymptomatic LVEF both increase initially on sunitinib and then plateau over time. “This shows that sunitinib does not destroy myocytes,” Ewer said.
“Patients who develop hypertension on sunitinib should be treated with blood pressure lowering medications, and they do well. The incidence of cardiovascular death is low on sunitinib,” he said.
Bevacizumab causes hypertension as well, and the hypertension should be treated. There is a risk of malignant hypertension with the treatment, and if that occurs, bevacizumab should be withdrawn.