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Originally published as JCO Early Release 10.1200/JCO.2008.20.1087 on December 15 2008 © 2009 American Society of Clinical Oncology.
Axitinib Induces Paradoxical Erythropoietin Synthesis in Metastatic Renal Cell Carcinoma
Department of Medical Oncology, Pitié-Salpetrière Hospital, Assistance Publique-Hôpitaux de Paris, University Paris 6, Paris, France
Centre d'Etudes et de Recours sur les Inhibiteurs de l'Angiogénése, Cochin Hospital, Paris, France
Department of Medical Oncology, Pitié-Salpetrière Hospital, Assistance Publique-Hôpitaux de Paris, University Paris 6, Paris, France
Génétique Oncologique École pratique des hautes études, Centre national de la recherché scientifique FRE 2939, Institut de cancérologie Gustave Roussy, Villejuif; and Faculté de Médecine Paris-Sud and Centre Pilote Tumeurs rares INCa/Assistance Publique-Hôpitaux de Paris, Service d'Urologie, Hôpital de Bicêtre, Le Kremlin-Bicêtre, France
Department of Medical Oncology, Pitié-Salpetrière Hospital, Assistance Publique-Hôpitaux de Paris, University Paris 6, Paris, France To the Editor: In a recent letter, Alexandrescu et al1 reported thoughtful data to address the occurrence of erythrocytosis after treatment with tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib for metastatic cancers. In addition, it has been previously reported that patients with von Hippel-Lindau (VHL) disease treated with semaxanib, a TKI targeting vascular endothelial growth factor receptor 2 (VEGFR-2) and cKit, may experience a supra-additive increase in hematocrit level.2 Experimental studies showing hepatic erythropoietin (EPO) synthesis related to VEGF blockage could explain this iatrogenic polycythemia.3 We report a case of polycythemia in a patient treated for metastatic renal cell carcinoma with axitinib, another TKI targeting VEGFR-2. Our findings were the opposite of those in the report by Alexandrescu et al. A 52-year-old man, with no significant past medical history, underwent a right radical nephrectomy for clear renal cell carcinoma. In October 2002, a partial response was achieved with interferon-alfa treatment for lung metastases. In March 2004, the lung metastases progressed in number and size, and the patient subsequently was enrolled onto an axitinib phase II trial. Oral axitinib was administered continuously at the fixed dose of 5 mg twice daily. Minor adverse effects were reported, including diarrhea and asthenia. During the initiation of the second cycle (week 5), we observed an increase in hematocrit, which was confirmed during the subsequent cycles. An isotopic measurement of RBCs confirmed the diagnosis of polycythemia. Treatment was continued for 36 months, with a documented complete response by the third cycle. However, repeated therapeutic phlebotomies for polycythemia remained necessary. There was no alternative cause of polycythemia, including the absence of clinical evidence of VHL disease. In addition, no somatic VHL mutation in the tumor sample was found in polymerase chain reaction analysis. Endogenous EPO blood levels and VEGF-A levels were monitored, and results are listed in Table 1.
Tam et al3 demonstrated that erythropoiesis is regulated by endogenous VEGF. In Tam's preclinical study, high-grade VEGF blockage induced the repression of adult hepatic EPO production. The absence of VEGFR-2 expression on hepatocytes suggests the participation of liver sinusoidal endothelial cells with homeostatic VEGFR-2–dependant paracrine signaling. In our observation, axitinib treatment was associated with a paradoxical VEGF increase, as reported both in vivo4 and in a cohort of patients with metastatic gastrointestinal stromal tumors treated with sunitinib,5 another TKI with VEGFR-2 inhibition. However, we speculate that axitinib mimics VEGF starvation in organs (such as the liver) through VEGFR-2 blockade, and leads to hepatic EPO production. Finally, we cannot exclude an axitinib interaction with the hypoxia-inducible factor pathway, which induces nitric oxide release, cutaneous vascular flow modification, and increased systemic EPO expression.6 Further investigation in clinical trials is warranted to determine the utility of EPO blood level as a marker of VEGF/VEGFR modulator activity. 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: Olivier Rixe, Pfizer Inc (C), GlaxoSmithKline (C) Stock Ownership: None Honoraria: Olivier Rixe, Pfizer Inc, GlaxoSmithKline Research Funding: None Expert Testimony: None Other Remuneration: None
NOTES published online ahead of print at www.jco.org on December 15, 2008 REFERENCES
1. Alexandrescu DT, McClure R, Farzanmehr H, et al: Secondary erythrocytosis produced by the tyrosine kinase inhibitors sunitinib and sorafenib. J Clin Oncol 26:4047-4048, 2008 2. Richard S, Croisille L, Yvart J, et al: Paradoxical secondary polycythemia in von Hippel-Lindau patients treated with anti-vascular endothelial growth factor receptor therapy. Blood 99:3851-3853, 2002 3. Tam BY, Wei K, Rudge JS, et al: VEGF modulates erythropoiesis through regulation of adult hepatic erythropoietin synthesis. Nat Med 12:793-800, 2006[CrossRef][Medline] 4. Ebos JM, Lee CR, Christensen JG, et al: Multiple circulating proangiogenic factors induced by sunitinib malate are tumor-independent and correlate with antitumor efficacy. Proc Natl Acad Sci U S A 104:17069-17074, 2007 5. Norden-Zfoni A, Desai J, Manola J, et al: Blood-based biomarkers of SU11248 activity and clinical outcome in patients with metastatic imatinib-resistant gastrointestinal stromal tumor. Clin Cancer Res 13:2643-2650, 2007 6. Boutin AT, Weidemann A, Fu Z, et al: Epidermal sensing of oxygen is essential for systemic hypoxic response. Cell 133:223-234, 2008[CrossRef][Medline]
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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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