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Originally published as JCO Early Release 10.1200/JCO.2008.20.6151 on February 2 2009 © 2009 American Society of Clinical Oncology.
Sunitinib-Induced Hemoglobin Changes Are Related to the Dosing ScheduleDepartment of Medical Oncology, VU University Medical Center, Amsterdam, the Netherlands
Department of Medical Oncology, the Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands To the Editor: We read with interest the correspondence by Alexandrescu et al1 reporting the occurrence of erythrocytosis in five of 21 patients treated with sorafenib or sunitinib. We also observed erythrocytosis during sunitinib treatment, although we detected that hemoglobin and erythrocyte changes occurred in a cyclic pattern. In an expanded access program, 82 patients with metastatic renal cell cancer were treated with sunitinib 50 mg daily, 4 weeks on, 2 weeks off.2 We measured hemoglobin levels on days 1 and 28 of each cycle and on day 14 of the first cycle. In 90% of patients, we observed a transient increase in hemoglobin during the first cycle. The median hemoglobin level of 7.5 mmol/L (range, 5.2 to 10.4 mmol/L) at baseline increased to 8.4 mmol/L (range, 6.0 to 10.9 mmol/L; Wilcoxon signed-rank test, P < .001) on day 14 and 8.0 mmol/L (range, 5.7 to 10.7 mmol/L; P < .001) on day 28 of the first cycle. After the 2-week rest period, the median hemoglobin level returned to baseline of 7.8 mmol/L (range, 5.2 to 10.0 mmol/L; P = .127). This transient increase in hemoglobin occurred in all subsequent cycles (Fig 1). In 69% of patients, the maximum level was reached during the first cycle (range, cycle 1 to cycle 10) with a median increase of 1.2 mmol/L. In 46 patients in the expanded access program, hemoglobin-associated variables, including hematocrit, erythrocytes, mean corpuscular volume, mean cellular hemoglobin, and mean corpuscular hemoglobin concentration, as well as vascular endothelial growth factor (VEGF), were available (Table 1). The incidence of erythrocytosis (erythrocytes above the upper limit of normal) was 26% during the first cycle, whereas a significant increase in erythrocyte numbers occurred in 81% of these patients.
The cyclic kinetics in hemoglobin values and erythrocyte numbers indicate that sunitinib scheduling is the cause of these changes. Thus far, its mechanism is not known. Tam et al3 have described that neutralization of VEGF in mouse and primate models can result in an increase in the secretion of erythropoietin from the liver, leading to erythropoiesis and erythrocytosis. Another study in mice has demonstrated that sunitinib can increase erythropoietin levels.4 Therefore, we measured erythropoietin at baseline and on day 14 of the first cycle in 20 unselected patients and indeed found an increase from a median of 12 U/L (range, 1.2 to 119.9) to 26 U/L (range, 12.9 to 54.2; P < .002). Although the difference in erythropoietin levels is significant, an erythropoietin-induced increase in erythrocytes is not expected to diminish rapidly within the 2 weeks of rest.
We propose another mechanism for the transient hemoglobin changes during sunitinib treatment. Like other inhibitors of VEGF signaling, sunitinib is known to raise blood pressure.5 In 39 of our patients, blood pressure was consistently monitored with a Dinamap Dash 4000 (GE Medical Systems, Milwaukee, WI). In these patients, we detected a significant increase in blood pressure on day 14 and 28 of the first cycle, which was reversible after the rest period (Table 1). On day 28, changes in mean arterial blood pressure were significantly correlated with changes in hemoglobin levels (n = 25; Spearman's In summary, we describe a zig-zag pattern in hemoglobin levels and erythrocyte numbers during sunitinib treatment in metastatic renal cell cancer patients. On the basis of previous studies and our findings, we hypothesize that the cyclic kinetics of hemoglobin and erythrocytes is the result of a temporary loss of intravascular fluid caused by inhibition of VEGFR-2 and subsequent reduction of NO, rather than an increase in erythropoiesis. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. 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. Van der Veldt AA, Boven E, Helgason HH, et al: Predictive factors for severe toxicity of sunitinib in unselected patients with advanced renal cell cancer. Br J Cancer 99:259–265, 2008.[CrossRef][Medline] 3. Tam BYY, 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. Zhu X, Stergiopoulos K, Wu S: Risk of hypertension and renal dysfunction with an angiogenesis inhibitor sunitinib: Systematic review and meta-analysis. Acta Oncol 48:9–17, 2009.[CrossRef][Medline] 6. Mourad JJ, des Guetz G, Debbabi H, et al: Blood pressure rise following angiogenesis inhibition by bevacizumab. A crucial role for microcirculation. Ann Oncol 19:927–934, 2008. 7. Van Heeckeren WJ, Ortiz J, Cooney MM, et al: Hypertension, proteinuria, and antagonism of vascular endothelial growth factor signaling: Clinical toxicity, therapeutic target, or novel biomarker? J Clin Oncol 25:2993–2995, 2007. 8. Jin ZG, Ueba H, Tanimoto T, et al: Ligand-independent activation of vascular endothelial growth factor receptor 2 by fluid shear stress regulates activation of endothelial nitric oxide synthase. Circ Res 93:354–363, 2003. 9. Van Cruijsen H, Van der Veldt AA, Hoekman K: Tyrosine kinase inhibitors of VEGF receptors: Clinical issues and remaining questions. Front Biosci 14:2248–2268, 2009.[Medline] 10. Filep JG: Endogenous endothelin modulates blood pressure, plasma volume, and albumin escape after systemic nitric oxide blockade. Hypertension 30:22–28, 1997.
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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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= 0.552; P = .004). Sunitinib-induced increase in blood pressure is thought to be caused by increased peripheral resistance.
