Originally published as JCO Early Release 10.1200/JCO.2009.21.8263 on March 30 2009

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Reply to A. Bamias et al

Clinical Division of Oncology, Department of Medicine I and Cancer Center, Medical University of Vienna, Vienna, Austria

We read with great interest the correspondence of Bamias et al¹ on rigorous diagnosis and management of hypertension in patients with metastatic renal cell carcinoma treated with the tyrosine kinase inhibitor sunitinib. The authors prospectively assessed blood pressure on the basis of 24-hour monitoring at baseline and during the first cycle of sunitinib treatment. Fifteen of 18 patients (83%) had hypertension either at baseline or during treatment and were treated with an angiotensin II receptor antagonist plus thiazide, a highly cardioselective beta blocker and a calcium-channel blocker. The rate of cardiac toxicity was low (5%); however, the authors point out that ECG and biochemical markers of cardiac damage were not assessed regularly. In this context, it is questionable whether the low rate of cardiac toxicity reflects the true situation, given that the precise rate of cardiac events cannot be assessed without regular ECGs, echocardiograms, and frequent assessment of serum markers of myocardial damage. The authors refer to our published data on sunitinib and sorafenib patients presenting with relatively high rate of cardiac toxicity (33.8%) but relatively lower rate of hypertension (48.8%).² As pointed out by Bamias et al, differences in methodology, that is, more detailed blood pressure assessment in the work of Bamias et al and more precise cardiac assessment in our investigation, may account for the divergent results.

Presuming that hypertension is the most important trigger for a cardiac event in patients being treated with an inhibitor of the vascular endothelial growth factor receptor (VEGFR), it could be speculated from the data of Bamias et al¹ that the rate of hypertension inversely correlates with the rate of cardiac adverse effects. We could not detect a statistically significant correlation between the rate of hypertension and the occurrence of a cardiac event, but this might be the result of the less precise assessment of hypertension when compared with the work of Bamias et al. The relationship between hypertension, VEGF inhibition, and heart failure has been strikingly demonstrated in an animal model. In mice subjected to aortic constriction, the administration of an adenoviral vector encoding a decoy VEGFR led to a reduction in capillary density and reduction of hypertension-induced hypertrophy. This resulted in left myocardial fibrosis, left ventricle dilation, and loss in contractile dysfunction.³ Sunitinib not only induces hypertension but might, through VEGF inhibition, simultaneously impair physiologic compensatory hypertrophy, thereby contributing to heart failure. The data of Bamias et al indirectly confirm this relationship and are of tremendous clinical interest. However, conclusions drawn from a series of 18 patients only without regular cardiac assessment remain speculative.

To prevent sunitinib-induced cardiac adverse effects, rigorous monitoring and management of hypertension seem insufficient. Additional aspects that contribute to cardiac toxicity should be considered. Sunitinib, apart from being a VEGF inhibitor, also strongly inhibits the tyrosine kinase of the platelet growth factor receptor (PDGFR), which is expressed in cardiomyocytes. Physiologically, PDGF signals cardiomyocyte survival; thus, PDGFR inhibition may represent an additional challenge for the cardiomyocyte.⁴ Similarly, sunitinib inhibits KIT, the receptor for stem-cell factor. KIT is expressed on precursors of endothelial progenitor cells. Its functioning seems to be necessary for the mobilization of these cells to sites of myocardial injury, which could be relevant in patients with coronary artery disease.⁵ Finally, by indirectly affecting the phosphoinositide-3 kinase signaling pathway, sunitinib could modulate electrical and contractile function in the heart via regulation of ion channels.⁶

Whether all these potential risks for myocardial damage can be avoided by thorough cardiovascular monitoring is unclear, but creating increasing awareness seems crucial. Novel agents such as sunitinib have turned many types of cancer into a chronic disease. Reducing cancer-related mortality and treating a cancer population that ages also represent new challenges to oncologists. Age-related comorbidities such as coronary artery disease require that oncologists be permanently vigilant about other physical conditions that are not related to the cancer. Today, cancer patients benefit from therapies that are tailored to tumor- and patient-related factors. Similarly, cardiovascular treatment should be tailored to individual cardiovascular risk factors that are frequent in the elderly. Therefore, rigorous blood pressure assessment as well as electrocardiography and echocardiography should be part of cardiovascular monitoring in patients undergoing treatment with novel anticancer therapies. In addition, regular assessment of biochemical markers of myocardial damage might be useful in patients receiving tyrosine kinase inhibitors. Atrial natriuretic peptide and B-type natriuretic peptide have been shown to be sensitive markers in predicting early cardiac dysfunction.⁷ The success of novel cancer agents can be significantly enhanced by aiming for a tailored treatment of both the tumor and the cardiovascular comorbidites. Therefore, the involvement of cardiologists in the treatment of cancer patients seems crucial.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Manuela Schmidinger, Pfizer (C), Bayer Schering (C); Christoph C. Zielinski, Pfizer (C) Stock Ownership: None Honoraria: Manuela Schmidinger, Pfizer, Bayer Schering; Christoph C. Zielinski, Pfizer Research Funding: Manuela Schmidinger, Pfizer Expert Testimony: None Other Remuneration: None

REFERENCES

1. Bamias A, Lainakis G, Manios E, et al: Could rigorous diagnosis and management of hypertension reduce cardiac events in patients with renal cell carcinoma treated with tyrosine kinase inhibitors? J Clin Oncol 27:2567–2569, 2009.[Free Full Text]

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 26:5204–5212, 2008.[Abstract/Free Full Text]

3. Izumiya Y, Shiojima I, Sato K, et al: Vascular endothelial growth factor blockade promotes the transition from compensatory cardiac hypertrophy to failure in response to pressure overload. Hypertension 47:887–893, 2006.[Abstract/Free Full Text]

4. Hsieh PC, MacGillivray C, Gannon J, et al: Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity. Circulation 114:637–644, 2006.[Abstract/Free Full Text]

5. Wang CH, Anderson N, Li SH, et al: Stem cell factor deficiency is vasculoprotective: Unraveling a new therapeutic potential of imatinib mesylate. Circ Res 99:617–625, 2006.[Abstract/Free Full Text]

6. Steinberg SF: PI3King the L-type calcium channel activation mechanism. Circ Res 89:641–644, 2001.[Free Full Text]

7. Costello-Boerrigter LC, Boerrigter G, Redfield MM, et al: Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: Determinants and detection of left ventricular dysfunction. J Am Coll Cardiol 47:345–353, 2006.[Abstract/Free Full Text]

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• Could Rigorous Diagnosis and Management of Hypertension Reduce Cardiac Events in Patients With Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors?
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