Pilot trial of sunitinib therapy in patients with von Hippel-Lindau disease

Abstract

Background: Von Hippel-Lindau (VHL) disease induces vascular neoplasms in multiple organs. We evaluated the safety and efficacy of sunitinib in VHL patients and examined the expression of candidate receptors in archived tissue.

Methods: Patients with VHL were given four cycles of 50 mg sunitinib daily for 28 days, followed by 14 days off. Primary end point was toxicity. Modified RECIST were used for efficacy assessment. We evaluated 20 archival renal cell carcinomas (RCCs) and 20 hemangioblastomas (HBs) for biomarker expression levels using laser-scanning cytometry (LSC).

Results: Fifteen patients were treated. Grade 3 toxicity included fatigue in five patients. Dose reductions were needed in 10 patients. Eighteen RCC and 21 HB lesions were evaluable. Six of the RCCs (33%) responded partially, versus none of the HBs (P = 0.014). LSC revealed that mean levels of phosphorylated vascular endothelial growth factor receptor-2 were lower in HB than in RCC endothelium (P = 0.003) and mean phosphorylated fibroblast growth factor receptor substrate-2 (pFRS2) levels were higher in HB (P = 0.003).

Conclusions: Sunitinib treatment in VHL patients showed acceptable toxicity. Significant response was observed in RCC but not in HB. Greater expression of pFRS2 in HB tissue than in RCC raises the hypothesis that treatment with fibroblast growth factor pathway-blocking agents may benefit patients with HB.

Figures

Figure 1.

Pancreatic NETs after sunitinib therapy. At study initiation (06/19/2006), this patient had two pancreatic NETs (arrows) on CT scanning. Post-treatment scans (obtained 08/17/2006 and 11/14/2006) of tumors show a slight decrease in size and central necrosis. After the patient had completed the therapy regimen, scans (obtained 07/19/2007) show centripetal and centrifugal regrowth. Reinitiation of sunitinib therapy outside the bounds of the study resulted in redevelopment of central necrosis and a decrease in outside diameter (06/19/2008 and 10/19/2009). NETs, neuroendocrine tumors; CT, computed tomography.