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Journal of Clinical Oncology, Vol 24, No 28 (October 1), 2006: pp. e48 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.08.4608
Reversible Posterior Leukoencephalopathy Syndrome Induced by RAF Kinase Inhibitor BAY 43-9006University of Arkansas for Medical Sciences, Little Rock, AR To the Editor: Reversible posterior leukoencephalopathy syndrome (RPLS) is a clinical condition characterized by headache, seizures, impaired vision, acute hypertension, and typical magnetic resonance imaging (MRI) findings.1 Bevacizumab (Avastin; Genentech Inc, South San Francisco, CA), an antiangiogenic agent, was recently reported to be associated with RPLS.2,3 We report a case of RPLS induced by BAY 43-9006, a RAF kinase inhibitor, with antiangiogenic activity. A 49-year-old woman with metastatic cholangiocarcinoma was enrolled in a phase II clinical trial using 400 mg of oral BAY 43-9006 twice daily. Three weeks after starting treatment, she developed grade 1 hypertension which resolved spontaneously. She did not have a history of hypertension. After 4 months of therapy, with one brief interruption for a procedure, she developed severe headache. Several hours later, she experienced sudden loss of vision (she could see only bright light), followed by generalized tonic-clonic seizure and loss of consciousness. She presented to the emergency department with blood pressure of 188/103 mmHg. Her blood pressure remained high, the highest being 197/131 mmHg. She was hospitalized; BAY 43-9006 was withheld and she was treated with intravenous hydralazine and oral metoprolol. Her blood pressure returned to normal (113/77 mmHg) within 2 days. She regained her visual acuity within a few hours. There was no evidence of lateralizing or focal features on neurological examination. MRI of the brain revealed typical signal changes in the posterior cerebral white matter, consistent with the diagnosis of RPLS (Figure 1). There was no MRI evidence of stroke or metastatic disease. She recovered completely and was discharged on the third hospital day. A repeat MRI scan of the brain 1 week later showed complete resolution of previous changes.
Hypertension is a known adverse effect of BAY 43-9006, a RAF kinase inhibitor, that interferes with signal transduction downstream in the RAS proliferation pathway.4 In addition BAY 43-9006 is also an inhibitor of proangiogenic receptor tyrosine kinases, such as vascular endothelial growth factor receptor 2, platelet derived growth factor receptor beta, and vascular endothelial growth factor receptor 3.5 In a trial of BAY 43-9006 (sorafenib) in metastatic renal cell carcinoma, 43% of patients developed hypertension, with 31% developing grade 3 hypertension.6 BAY 43- 9006 is approved by the US Food and Drug Administration for treatment of renal cell carcinoma and is being investigated in the treatment of other solid tumors. RPLS is a serious adverse effect that should be considered by physicians caring for these patients. Whether the underlying mechanism of RPLS in patients receiving BAY 43-9006 is its antiangiogenic effect(s) or simply mediated by severe acute hypertension remains unknown. Authors' Disclosures of Potential Conflicts of Interest The authors indicated no potential conflicts of interest.
REFERENCES
1. Hinchey J, Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome. N Engl J Med 334:494-500, 1996 2. Stott VL, Hurrell MA, Anderson TJ: Reversible posterior leukoencephalopathy syndrome: A misnomer reviewed. Int Med J. 35:83-90, 2005 3. Glusker P: Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 354:980-981, 2006 4. Oczan C: Reversible posterior leukoencephalopathy syndrome and bevacizumab. N Engl J Med 354:981, 2006 5. Wilhelm SM, Carter C, Tang LY, et al: BAY 43-9006 exhibits broad spectrum oral anti-tumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res 64:7099-7109, 2004 6. Ratain MJ, Eisen T, Stadler WM, et al: Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma. J Clin Oncol 24:2505-2512, 2006
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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