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Originally published as JCO Early Release 10.1200/JCO.2008.21.6028 on March 30 2009 © 2009 American Society of Clinical Oncology.
Could Rigorous Diagnosis and Management of Hypertension Reduce Cardiac Events in Patients With Renal Cell Carcinoma Treated With Tyrosine Kinase Inhibitors?Department of Clinical Therapeutics, University of Athens Medical School, Athens, Greece To the Editor: We read with great interest the valuable work by Schmidinger et al1 regarding the incidence of cardiac toxicity of two tyrosine kinase inhibitors (TKIs) used in the treatment of advanced renal cell carcinoma (RCC). We believe that this article raises several important issues. First, the incidence of many serious adverse effects (including cardiac and hypertension) has been underestimated by the data reported in the recent randomized studies, mainly because it was based on self-reporting toxicities and office measurements in predefined visits. Therefore, prospective and more detailed evaluation may be necessary to reveal the true incidence, at least for some of them. Second, current toxicity grading systems used in clinical trials (and subsequent action on the basis of such grading) is far from ideal, especially for treatable conditions such as coronary artery disease, asymptomatic left ventricular ejection fraction decline, or hypertension. This is emphatically shown by the fact that all patients with a cardiac event were re-treated with TKIs after management of the cardiac event. Although all events are not described in detail, it is certain that many of the 13 patients who developed cardiac symptoms would qualify for at least grade 3 toxicity, which might have resulted in permanent discontinuation or dose reductions of TKIs, according to common rules in clinical studies. Third, diagnosis and correction of precipitating factors may result in lowering the incidence of cardiac events. More specifically, hypertension (HT), a well-established risk factor for coronary artery disease and heart failure, is frequent in RCC but also may remain unrecognized if its diagnosis depends on self- or office measurements. We have been applying a protocol of prospective evaluation of diagnosis and management of HT on the basis of current guidelines of the European Society of Hypertension2 in patients with advanced RCC treated with sunitinib.3 Baseline diagnosis and control of HT is based on 24-hour blood pressure monitoring (BPM), whereas monitoring during the first cycle of treatment is based on 24-hour BPM and home measurement. Only home measurement is applied thereafter. Management of HT is based on the successive use of hydrochlorothiazide plus irbesartan, nebivolol, and amlodipine, which can all be used with TKIs.4 The aim is to achieve normal 24-hour BPM before initiation of sunitinib and aggressive correction of uncontrolled HT during the first cycle of sunitinib, when most problems occur. Up to now, 18 patients have been included. All patients have received sunitinib starting at 50 mg daily for 4 weeks, followed by a 2-week interval. No TKI or bevacizumab had been previously administered. The median number of cycles administered has been four (range, one to seven cycles). One cardiac event (5%) has occurred. Although the accuracy of our estimation is limited by the relatively small number of our patients, it is strikingly lower than the 33.8% reported by Schmidinger et al.1 This difference can be partially attributed to methodological differences, given that we did not apply regular monitoring of electrocardiogram and markers of cardiac damage in asymptomatic patients. Nevertheless, 13 patients (18%) had symptomatic cardiac events; hence, more events would have been expected in our series. Patients' selection should also be taken into consideration, given that we only included patients treated with sunitinib. Nevertheless, no data suggest that the incidence of cardiac events might be more frequent with sorafenib. Finally, an important difference in the methodology between the two studies is the rigorous assessment and monitoring of blood pressure in our series. We therefore believe that a comparison with Schmidinger et al's data is worthwhile to attempt to extract any conclusions as to whether a tighter control of HT might have reduced the incidence of cardiac events in her population. Looking at the cardiovascular-related baseline characteristics (Table 1), the major difference between the two series is the higher incidence of uncontrolled hypertension in our population, although the total percentage of baseline HT is similar. This difference could be a result of the more sensitive method of 24-hour BPM we used to diagnose and control baseline HT. If applied, this method may have detected more instances of uncontrolled hypertension in the study by Schmidinger et al.1 Detection and correction of uncontrolled hypertension may prevent cardiac events. Interestingly, the only cardiac event we observed was hypertensive crisis in a patient with uncontrolled HT despite the use of all four anti-HT agents. In Table 2, the authors state that only three patients who experienced cardiac events had baseline cardiac abnormalities. Apparently, HT was not grouped under this term. It would be therefore interesting to know if any relationship between the occurrence of cardiac events and the preexistence of HT was observed.
In addition to uncontrolled HT, detection of HT occurring during treatment with TKIs is equally important. In our analysis, two of 10 patients with no previous history had baseline HT, while another five developed HT during therapy. Therefore, 15 (83%) of 18 patients had at baseline or developed HT during treatment with sunitinib and required anti-HT management. This high incidence has also been reported by Azizi et al.5 Seven patients also required intensification of anti-HT medication during sunitinib therapy. These modifications were based not only on home measurements but also on the more sensitive 24-hour BPM during the first cycle of therapy. We speculate that some patients in the study by Schmidinger et al1 had undiagnosed (and therefore untreated) HT (either at baseline or during TKI therapy), which might have been responsible for some of the cardiac manifestations reported. Again, it would be interesting to know whether HT was newly diagnosed in any of the patients with cardiac events. In conclusion, prospective studies like the one of Schmidinger et al1 are necessary to accurately evaluate recently described important adverse effects of novel (but probably to be more widely used) biologic agents. It also underlines the importance of the multidisciplinary approach in the management of cancer patients not only regarding the application of antineoplastic therapies, but also their adverse effects. Specifically, cardiac events are potentially life-threatening and should receive more attention. It is now well established that HT may well be a precipitating factor for a number of them. We believe that easy-to-apply protocols, which can ensure high diagnostic sensitivity and effective management of this condition, might result in reduction of cardiac and other related (ie, renal) serious adverse effects. 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: Aristotle Bamias, Pfizer (C), Bayer Pharmaceuticals (C) Stock Ownership: None Honoraria: Aristotle Bamias, Pfizer, Bayer Pharmaceuticals Research Funding: None Expert Testimony: None Other Remuneration: None REFERENCES
1. 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. 2. Mancia G, De Backer G, Dominiczak A, et al: Management of arterial hypertension of the European Society of Hypertension; European Society of Cardiology. 2007 Guidelines for the management of arterial hypertension: The task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 25:1105–1187, 2007.[CrossRef][Medline] 3. Lainakis G, Bamias A, Manios E, et al: 24-hour arterial blood pressure monitoring in patients with renal cell carcinoma treated with sunitinib results in control of hypertension without dose reduction in the majority of patients. Ann Oncol 18:195; 2008 (suppl) abstr 603P. 4. Bhojani N, Jeldres C, Patard JJ, et al: Toxicities associated with the administration of sorafenib, sunitinib, and temsirolimus and their management in patients with metastatic renal cell carcinoma. Eur Urol 53:917–930, 2008.[CrossRef][Medline] 5. Azizi M, Chedid A, Oudard S: Home blood-pressure monitoring in patients receiving sunitinib. N Engl J Med 358:95–96, 2008.
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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