Tyrosine Kinase Inhibitors: Can Promising New Therapy Associated With Cardiac Toxicity Strengthen the Concept of Teamwork?

Abstract

The use of tyrosine kinase inhibitors (TKIs) for cancer therapy has dramatically increased in recent years, and this trend is likely to continue in an explosive fashion. Sunitinib and sorafenib are two important recent additions to the TKI family of clinically effective chemotherapeutic options. These two therapies have shown substantial benefits in renal cell carcinoma, GI stromal tumor, and liver cancer and are being investigated in a variety of other cancers, including lung cancer, prostate cancer, thyroid cancer, and certain leukemias. Not only are these therapies attractive because of their clinical effectiveness in certain cancers, but also because they are oral medications that are relatively easy to administer and monitor for typical side effects. However, this simplistic summary of these two new therapeutic agents does not tell the whole story. In this issue of Journal of Clinical Oncology, a careful study of the cardiac effects of these two newer TKIs is reported. The authors describe the cardiovascular risk factors and established cardiac disease in a group of patients (n 86) not enrolled onto a clinical trial who have metastatic renal cell carcinoma and are starting either sunitinib or sorafenib. Although some of these patients (n 12) are lost to follow-up, 74 patients were ultimately observed closely for cardiac events. From this analysis, several points emerge that are worth contemplating. First, the incidence of cardiac events is quite a bit higher than previously reported, at least as it relates to sunitinib in particular. Two studies now have reported an association between sunitinib and heart failure and/or reduction in left ventricular ejection fraction (LVEF), but the rates differ considerably (Table 1). In the case of sorafenib, there are not as many reports of heart failure or reduced LVEF, but clinical observation would certainly suggest that these occur. In the study by Schmidinger at al, the incidence of reduced LVEF during sunitinib therapy of at least 10 percentage points is 14%, but a clear description of those who developed heart failure is lacking. This is an important point, principally because the presence of heart failure portends a much more serious effect on prognosis than a change in LVEF, and heart failure can occur independently of the findings of a normal LVEF. The incidence of reduced LVEF for sorafenib in this study is reported at 5%, but again, no clear description of the presence or absence of heart failure is given. These findings underscore the need to revise the reporting of cardiovascular toxicity in oncology clinical trials, especially to include an understandable and practical grading system for the clinical diagnosis of heart failure not based solely on investigator reporting of symptoms or serial changes in LVEF. Furthermore, clinically important findings that have an effect on outcomes should be reported, not just laboratory-based findings that serve as surrogate markers. Second, the prevalence of treatable cardiovascular risk factors is high in this study population, with 49% having hypertension, 22% having diabetes, 39% having hyperlipidemia, 13% having obesity, and 9% having established coronary artery disease. Generally speaking, most oncology clinical trials do not report a careful cardiac assessment at baseline, because that is not the focus of an oncology trial. However, recent retrospective studies suggest that cardiovascular disease can have a dramatic effect on long-term survival after cancer therapy and also is present at the onset of cancer therapy more often than anticipated. These data emphasize the need for management of serious comorbidities throughout the course of cancer therapy; involvement of cardiovascular specialists in the care of these patients is paramount. The complexity of newly developing cancer therapy with