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In Reply

Departments of Medical Oncology, Cardiology and Vascular Medicine, University of Groningen and University Medical Center Groningen, Groningen, the Netherlands

An increased incidence of cardiovascular risk factors and ischemic cardiovascular events has been reported in long-term survivors of testicular cancer, as well as during and shortly after chemotherapy.^1-3 It seems conceivable that the cardiovascular damage finds its origin during chemotherapy. As cardiovascular changes during bleomycin, etoposide, and cisplatin (BEP) chemotherapy might have a prognostic value for the development of cardiovascular complications, we investigated in a prospective cohort study whether standard tests, including measurement of cardiac troponin I (TnI), can be used to detect acute chemotherapy-induced cardiovascular changes in testicular cancer patients.

Ten (27%) of 37 patients showed an elevation of TnI (any value > 0.0 ng/mL) during chemotherapy. Three patients with an increase in TnI developed an acute cardiovascular event during the treatment period. In one of these patients, an acute myocardial infarction was preceded by a slight increase in TnI (0.4 ng/mL; for TnI levels between 0.2 and 0.8 ng/mL in this assay myocardial damage cannot be excluded). However, in the two other patients with a cardiovascular event (one myocardial infarction and one pulmonary embolism) the TnI elevation did not precede the event, but actually followed it and was most probably secondary to the event. Furthermore, the cardiovascular events developed while patients were at home. Based on these observations, we are not convinced that standardized measurement of TnI during BEP chemotherapy is of value for early detection of acute cardiovascular complications.

Although measurement of TnI seems to have a limited predictive value for acute cardiovascular complications, some interesting issues raised by Cardinale et al in their letter remain. These issues relate to the underlying mechanism of the myocardial damage, suggested by the increase in TnI, and to the predictive value of TnI for long-term cardiovascular complications. BEP chemotherapy might cause myocardial damage via other mechanisms than a direct cardiotoxic effect, as known for anthracyclines.⁴ While cardiomyopathy, leading to left ventricular systolic dysfunction and congestive heart failure, forms a serious long-term complication in treatment with anthracyclines, long-term cardiovascular complications in testicular cancer survivors mainly exist of accelerated atherosclerosis and ischemic events.^1,2,4-6

Cardinale et al described the prognostic relevance of TnI elevation for cardiac events in patients treated with high-dose chemotherapy, in the majority containing anthracyclines.⁷ Most of these events occurred within 1 year after chemotherapy. After chemotherapy for testicular cancer, the majority of the cardiac events occur about 15 years after treatment suggesting another mechanism.⁶ Subclinical cardiac damage on echocardiography in testicular cancer survivors, not treated with anthracyclines, seems to be limited to a left diastolic dysfunction (up to 33% of patients with a median follow-up duration of 14 years).^2,7,8 Although a direct cardiotoxicity of cisplatin-based chemotherapy cannot be excluded, a correlation was found with systolic blood pressure.^2,7,8 In addition, the increased prevalence of cardiovascular risk factors, such as obesity and dyslipidemia, might contribute to cardiac damage.⁸ In accordance with these observations, BEP chemotherapy-induced vascular toxicity, in our study reflected by an increase in von Willebrand factor in plasma and an increase in the intima-media thickness of the common carotid artery, might contribute to myocardial ischemia and consequently TnI elevation.

However, irrespective of the underlying mechanism of cardiac damage, a prolonged follow-up in a larger population of testicular cancer patients treated with BEP chemotherapy, as suggested by Cardinale et al, is a good suggestion to expand the data on the potential value of TnI elevation as a predictor of long-term cardiovascular complications.

Authors' Disclosures of Potential Conflicts of Interest

The authors indicated no potential conflicts of interest.

ACKNOWLEDGMENTS

Supported by Grant No. RUG2000-2177 from the Dutch Cancer Society.

REFERENCES

1. Huddart RA, Norman A, Shahidi M, et al: Cardiovascular disease as a long-term complication of treatment for testicular cancer. J Clin Oncol 21:1513-1523, 2003[Abstract/Free Full Text]

2. Meinardi MT, Gietema JA, van der Graaf WT, et al: Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol 18:1725-1732, 2000[Abstract/Free Full Text]

3. Weijl NI, Rutten MF, Zwinderman AH, et al: Thromboembolic events during chemotherapy for germ cell cancer: A cohort study and review of the literature. J Clin Oncol 18:2169-2178, 2000[Abstract/Free Full Text]

4. Adams MJ, Lipshultz SE: Pathophysiology of anthracycline- and radiation-associated cardiomyopathies: Implications for screening and prevention. Pediatr Blood Cancer 44:600-606, 2005[CrossRef][Medline]

5. Nuver J, Smit AJ, Sleijfer DT, et al: Microalbuminuria, decreased fibrinolysis, and inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer. Eur J Cancer 40:701-706, 2004[CrossRef][Medline]

6. van den Belt-Dusebout AW, Nuver J, de Wit R, et al: Long-term risk of cardiovascular disease in 5-year survivors of testicular cancer. J Clin Oncol 24:467-475, 2006[Abstract/Free Full Text]

7. Cardinale D, Sandri MT, Colombo A, et al: Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high dose chemotherapy. Circulation 109:2749-2754, 2004[Abstract/Free Full Text]

8. Nuver J, Smit AJ, Sleijfer DT, et al: Left ventricular and cardiac autonomic function in survivors of testicular cancer. Eur J Clin Invest 35:99-103, 2005[CrossRef][Medline]

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Related Correspondence

• Troponin I and Cardiovascular Risk Stratification in Patients With Testicular Cancer
  Daniela Cardinale, Giuseppina Lamantia, and Carlo M. Cipolla
  JCO 2006 24: 3508 [Full Text]

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