Novel Therapies in Advanced Renal Cell Carcinoma – Management of Adverse Events from Sorafenib and Sunitinib: In Reply

by Dr. med. Philipp Ivanyi, Dr. med. Thomas Winkler, Prof. Dr. med. Arnold Ganser, Priv.-Doz. Dr. med. Christoph Reuter, Dr. med. Viktor Grünwald in volume 13/2008

We thank Professor Meyer for his remarks about the adverse effects associated with the novel tyrosine kinase inhibitors (TKI), which address the particular problem of cardiotoxicity. Chu et al. investigated the incidence of cardiotoxicity with sunitinib in patients with gastrointestinal stromal tumor (GIST). All patients were refractory to treatment with imatinib, whose cardiotoxic potential is being controversially discussed. All patients therefore received two potentially cardiotoxic substances, which renders the results indistinguishable with regard to an individual substance, but which certainly underlines the fundamental relevance of cardiotoxicity of TKI.
In the Expanded Access Program (EAP) for sunitinib in renal cell carcinoma, clinically manifest heart failure was observed in 0.5% (n = 2341) of patients (1). In the licensing study for sunitinib, the proportion of severe impairments of left ventricular ejection fraction was 2% (n = 375). Methodologically, the two results can be compared only to a limited degree as in contrast to the EAP, myocardial function was evaluated prospectively in the licensing study. Further, prior immunotherapy is an additional risk factor for developing cardiomyopathy (3) and therefore influences the clinical presentation of heart failure with regard to first line or second line treatment.
In addition to direct cardiotoxic mechanisms, insufficient blood pressure regulation favors clinically manifest heart failure, which prompted us at our clinic to strictly regulate blood pressure to normal values. From three years' experience with sunitinib in renal cell carcinoma, we can report only one case of severe heart failure, which we think underlines the importance of blood pressure regulation.
The author's recommendation for antidepressants for fatigue is certainly an individual decision and entails the risk of drug interactions. However, the same is true for St John's wort, a known cytochrome inhibitor.
DOI: 10.3238/arztebl.2008.0500b

Dr. med. Viktor Grünwald
Abteilung Hämatologie, Hämostaseologie und Onkologie
Medizinische Hochschule Hannover
Carl-Neuberg Str. 1
30625 Hannover, Germany
[e-mail]

References

1. Gore M, Porta C, Oudard S et al.: Sunitinib in metastatic renal cell carcinoma (mrcc): Preliminary assessment of toxicity in an expanded access trial with subpopulation analysis. J Clin Oncol ASCO Annual Meeting Proceedings 2007; 25: 5010.

2. Motzer RJ, Hutson TE, Tomczak P et al.: Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356: 115–24.

3. Reifenberg K, Lehr HA, Torzewski M et al.: Interferon-gamma induces chronic active myocarditis and cardiomyopathy in transgenic mice. Am J Pathol 2007; 171: 463–72.