Sunitinib for the treatment of benign and malignant neoplasms from von Hippel-Lindau disease: A single-arm, prospective phase II clinical study from the PREDIR group

Abstract

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes affected individuals to the development of multiple benign and malignant tumors. One of the main manifestations of VHL is renal cell carcinoma (RCC). RCC is increasingly being treated with targeted therapies, which offer an alternative treatment option for patients with VHL disease. This study investigated the effectiveness of sunitinib in VHL patients with advanced tumors or tumors unsuitable for surgery.This multicenter, phase II, open-label study from the PREDIR VHL network, treated patients with genetically-confirmed advanced VHL disease with oral sunitinib (50 mg/day for 28 days then a 2-week rest period) until progression. Lesions were performed using magnetic resonance imaging (MRI) and computed tomographic (CT) scan. The primary endpoint was objective response rate; secondary endpoints included tolerability and overall survival.All five patients showed stable disease as best response at 6 months. Two patients showed impressive transitory clinical improvement during early cycles. No patient died during sunitinib treatment. Reasons for discontinuing sunitinib therapy were disease progression (n=1), unacceptable toxicity (n=3) and lack of clinical improvement after 7 cycles (10.5 months) with unacceptable toxicity (n=1).In conclusion, sunitinib was of limited benefit in patients with advanced VHL disease, but had better efficacy against metastatic RCC than other VHL-related lesions. Treatment-related toxicity is an important limiting factor in this frail patient population. New agents with different mechanisms of action are required to treat this disease.

A retrospective case study of sunitinib treatment in three patients with Von Hippel-Lindau disease

“…A multicenter, Phase-II, open-label study of sunitinib from the PREDIR VHL network has shown that all five enrolled patients with VHL disease exhibited stable disease as the best response at 6 months. This study also showed that sunitinib was more effective for VHL-related RCCs than for other VHL-related lesions 11 . More recently, a retrospective study by Roma et al showed that 9 of 14 (64%) patients with VHL who received sunitinib treatment as a first-line therapy exhibited radiological response not only in renal and hepatic lesions but also in pancreatic nodules 12 .…”

“…In 2009, Jimenez et al reported that a carrier of a VHL germline mutation with an aggressive malignant pheochromocytoma and several RCCs and pancreatic neuroendocrine tumors exhibited decreases in the sizes of most tumors after 6 months of treatment with sunitinib 14 . Furthermore, several other studies 7 , 8 , 11 , 15 have shown that sunitinib may be more effective in cRCCs arising from patients with VHL disease compared to sporadic non-VHL-related RCCs. Previous studies are equivocal, however, with respect to the effects of sunitinib on other VHL-related lesions.…”

Pazopanib in patients with von Hippel-Lindau disease: a single-arm, single-centre, phase 2 trial

“…Systemic therapy has been more broadly tested in patients with von Hippel-Lindau disease. Multiple studies reported outcomes in individuals treated with sunitinib(14-16). A 2011 study prospectively evaluated the safety and efficacy of sunitinib in 15 patients with von Hippel-Lindau disease(17).…”

Intermixed arteriovenous malformation and hemangioblastoma: case report and literature review

“…In terms of tyrosine kinase inhibitors, a single trial and multiple case reports exist in the use of multityrosine kinase inhibitor pozopanib for VHL disease associated HB, with moderate success [ 75–78 ]. Other multityrosine kinase inhibitor trials for HB were disappointing, with the dovitinib trial discontinued owing to toxicity, while erlotinib and sunitinib were found to be of limited benefit [ 79–82 ]. Emerging research into HB neovascularization mechanisms – such as Twist1 signaling, described above – may provide additional anti-angiogenic therapeutic targets [ 26 ].…”