LAS VEGAS – When it comes to discussing the cardiotoxicity of cancer pharmacotherapies, it often seems that oncologists and cardiologists are on different planets.
“You will see wildly different toxicity numbers. … One trial will report 3% cardiotoxicity; another studying the same regimen will report 30%. It’s usually because they’re using vastly different definitions of toxicity,” Dr. Ronald M. Witteles said at the annual meeting of the Heart Failure Society of America.
“The typical clinical trial definition of a cardiac event in a cancer treatment trial is new symptomatic NYHA class III or IV heart failure or cardiac death; that’s it,” added Dr. Witteles, a cardiologist at Stanford (Calif.) University.
The consensus within the emerging field of cardio-oncology is that that simply isn’t good enough. A reasonable definition of cancer treatment–related cardiotoxicity must be far broader, encompassing a drop in left ventricular ejection fraction (LVEF) of greater than 10% from normal-range pretreatment to below the threshold of normal, regardless of whether that decline is accompanied by symptoms, as well as the development of an acute coronary syndrome or symptomatic arrhythmia, according to Dr. Daniel J. Lenihan, president of the International Cardioncology Society, an organization devoted to closer collaboration between the two medical specialties.
“Development of cardiomyopathy during cancer therapy is a lot more common than most people think,” emphasized Dr. Lenihan, professor of medicine and director of clinical research in the division of cardiovascular medicine at Vanderbilt University, Nashville, Tenn.
Dr. Witteles noted that the product labeling for doxorubicin quotes a preposterously low 1%-2% probability of developing impaired myocardial function at a total cumulative dose of 300 mg/m2, which is what’s typically used in treating lymphoma. That’s because the primary source of that estimate is 35-year-old data in which there was no routine measurement of LVEF and the diagnosis of impaired myocardial function was made by the treating oncologist on the basis of clinical signs and symptoms.
There are far better data available, but they’re not in the product label. Dr. Witteles cited as an example a more recent study featuring routine LVEF monitoring, where the incidence of a greater than 10% fall from normal to below normal at a cumulative dose of 300 mg/m2 wasn’t 1%-2%; it was 16% (Cancer 2003;97:2869-79).
He added that current evidence indicates that a fall in LVEF of more than 10%, taking a patient from normal range to below normal, occurs in 7%-8% of patients on an anthracycline such as doxorubicin at a cumulative dose of 240 mg/m2, as is typical in treating breast cancer. The incidence with trastuzumab (Herceptin) when prescribed after completion of anthracycline-based chemotherapy is about 25%; however, when trastuzumab is given in an anthracycline-free regimen, the rate drops to 9%-10%. A study by Dr. Witteles and his coworkers pegged the rate in cancer patients treated with sunitinib (Sutent) or other tyrosine kinase inhibitors at about 15% (JACC Heart Fail. 2013;1:72-8).
“Any way you slice it, that’s a whole lot of people,” he commented.
Dr. Lenihan reported receiving research support from Singulex, Millenium, and Acorda as well as serving as a consultant to Onyx and Roche. Dr. Witteles declared having no financial conflicts.