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Originally published as JCO Early Release 10.1200/JCO.2008.18.5439 on October 6 2008 © 2008 American Society of Clinical Oncology.
Tyrosine Kinase Inhibitors: Can Promising New Therapy Associated With Cardiac Toxicity Strengthen the Concept of Teamwork?
Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX 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.1 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.2 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 considerably3,4 (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,2 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.7-9 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 therapy10 and also is present at the onset of cancer therapy more often than anticipated.11 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.12 The complexity of newly developing cancer therapy with expected vascular effects, the aging of the general population who are undergoing such treatments, and the effectiveness of standard cardiovascular treatment in controlling identified cardiac conditions13,14 demand effective and integrated patient care. It should be incumbent on cardiovascular specialists to actively participate in close collaboration with oncologists and provide such care. As demonstrated by the authors in this report, cardiac conditions identified early can be managed to allow continued aggressive cancer therapy. Third, the incidence of hypertension with TKIs is high and deserves attention early in the course of therapy. Hypertension is an easily treated and often ignored coexistent condition, and severe hypertension can be induced by a variety of TKIs. This is a clearly defined risk factor for the development of heart failure and other cardiovascular events. In this study, the details of antihypertensive therapy in patients with cardiovascular events can be seen in Table 2 (of Schmidinger et al2) and includes the use of angiotensin-converting enzyme inhibitors and beta-blockers. This approach is consistent with the American Heart Association/American College of Cardiology guidelines for the treatment of heart failure or those at high risk for the development of heart failure.15 However, it is not clear in the nonevent population which hypertensive medications were used, nor how often titration of doses was necessary. This area of clinical research needs to be improved, and ultimately, data that demonstrate which agent(s) are most beneficial should be forthcoming.16 Hopefully, mechanistic studies in animal models will also provide conceptual guidance as to which antihypertensive therapy is preferred. Additionally, recommendations for following blood pressure recordings frequently during therapy with vascular-active drugs need to be developed immediately.17 In conclusion, the report by Schmidinger et al2 is an important addition to our collective knowledge about cardiovascular toxicity associated with sunitinib and sorafenib. Aggressive management of cardiovascular comorbidities to allow continued optimal cancer therapy is a principle that must be embraced by cardiovascular specialists and oncologists alike. The tremendous success of cancer therapy in general over the past two decades can be significantly enhanced if cardiac issues are identified early and controlled. In this manner, the future of TKI therapy may actually promote true teamwork and communication in the medical care of our patients. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest.
NOTES published online ahead of print atwww.jco.org on October 13, 2008 REFERENCES
1. Chen MH, Kerkelä R, Force T: Mechanisms of cardiac dysfunction associated with tyrosine kinase inhibitor cancer therapeutics. Circulation 118:84-95, 2008 2. Schmidinger M, Zielinski CC, Vogl UM, et al: Cardiac toxicity of sunitinib and sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol doi:10.1200/JCO.2007.15.6331 [epub ahead of print on October 6, 2008] 3. Chu TF, Rupnick MA, Kerkela R, et al: Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011-2019, 2007[CrossRef][Medline] 4. Khakoo AY, Kassiotis CM, Tannir N, et al: Heart failure associated with sunitinib malate: A multitargeted receptor tyrosine kinase inhibitor. Cancer 112:2500-2508, 2008[Medline] 5. Pfizer: SUTENT (sunitinib malate) package insert. New York, NY, Pfizer, 2006 6. Bayer: NEXAVAR (sorafenib) package insert. Wayen, NJ, Bayer, 2005 7. Ewer MS, Lenihan DJ: Left ventricular ejection fraction and cardiotoxicity: Is our ear really to the ground? J Clin Oncol 26:1201-1203, 2008 8. Bhatia RS, Tu JV, Lee DS, et al: Outcome of heart failure with preserved ejection fraction in a population-based study. N Engl J Med 355:260-269, 2006 9. Owan TE, Hodge DO, Herges RM, et al: Trends in prevalence and outcome of heart failure with preserved ejection fraction. N Engl J Med 355:251-259, 2006 10. Hanrahan EO, Gonzalez-Angulo AM, Giordano SH, et al: Overall survival and cause-specific mortality of patients with stage T1a,bN0M0 breast carcinoma. J Clin Oncol 25:4952-4960, 2007 11. Doyle JJ, Neugut AI, Jacobson JS, et al: Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study. J Clin Oncol 23:8597-8605, 2005 12. van Heeckeren WJ, Bhakta S, Ortiz J, et al: Promise of new vascular-disrupting agents balanced with cardiac toxicity: Is it time for oncologists to get to know their cardiologists? J Clin Oncol 24:1485-1488, 2006 13. Sarkiss MG, Yusuf SW, Warneke CL, et al: Impact of aspirin therapy in cancer patients with thrombocytopenia and acute coronary syndromes. Cancer 109:621-627, 2007[CrossRef][Medline] 14. Ewer MS, Vooletich MT, Durand JB, et al: Reversibility of trastuzumab-related cardiotoxicity: New insights based on clinical course and response to medical treatment. J Clin Oncol 23:7820-7826, 2005 15. Hunt SA, Abraham WT, Chin MH, et al: ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure)—Developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation 112:e154-e235, 2005 16. Sica DA: Angiogenesis inhibitors and hypertension: An emerging issue. J Clin Oncol 24:1329-1331, 2006 17. Maitland ML, Ratain MJ: Terminal ballistics of kinase inhibitors: There are no magic bullets. Ann Intern Med 145:702-703, 2006
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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