Abstract
von Hippel–Lindau (VHL) disease is a genetically acquired multisystem tumor syndrome of the viscera and central nervous system (CNS). The most common tumors associated with this disease are histologically benign, slow-growing CNS hemangioblastomas affecting the retina, cerebellum, brainstem, spinal cord or nerve roots. With mean age at diagnosis of 30 years, CNS hemangioblastomas are usually the first manifestation of the disease. Ongoing clinical and radiological surveillance is required, with symptomatic lesions necessitating treatment. As tumor growth is inevitable during the lifetime of most VHL patients, and the multiplicity of tumors may preclude surgical cure, the search for effective therapies is ongoing. Here we provide the first report demonstrating clinical and radiological anti-tumor response using pazopanib, a small molecule multi-receptor tyrosine kinase inhibitor, in a patient with treatment-refractory VHL-associated CNS hemangioblastoma. Treatment initiation with daily oral pazopanib (800 mg/day) resulted in significant neurologic improvement and radiologic tumor volume reduction.
Similar content being viewed by others
References
Butman JA, Linehan WM, Lonser RR (2008) Neurologic manifestations of von Hippel–Lindau disease. JAMA 300:1334–1342
Lonser RR, Glenn GM, Walther M, Chew EY, Libutti SK, Linehan WM, Oldfield EH (2003) von Hippel–Lindau disease. Lancet 361:2059–2067
Wanebo JE, Lonser RR, Glenn GM, Oldfield EH (2003) The natural history of hemangioblastomas of the central nervous system in patients with von Hippel–Lindau disease. J Neurosurg 98(1 Suppl):82–94
Hes FJ, van der Luijt RB, Lips CM (2001) Clinical management of von Hippel–Lindau (VHL) disease. Neth J Med 59:225–234
Ammerman JM, Lonser RR, Dambrosia J, Butman J, Oldfield EH (2006) Long-term natural history of hemangioblastomas in von Hippel–Lindau disease: implications for treatment. Clin Neurosurg 53:324–331
Rogers LR, LoRusso P, Nadler P, Malik G, Shields A, Kaelin W (2011) Erlotinib therapy for central nervous system hemangioblastomatosis associated with von Hippel–Lindau disease: a case report. J Neuro Oncol 101:307–301
Niemela M, Maenpaa H, Salven P, Summanen P, Poussa K, Laatikainen L, Jaaskelainen J, Joensuu H (2001) Interferon-2a therapy in 18 hemangioblastomas. Clin Cancer Res 7:510–516
Madhusudan S, Deplanque G, Braybrooke JP, Cattell E, Harris AL (2004) Antiangiogenic therapy for von Hippel–Lindau disease. JAMA 291:943–944
Jonasch E, McCutcheon IE, Waguespack SG, Wen S, Do KA, Davis DW, Zhang Y, Smith L, Tamboli P, Tannir NM, Gombos DS, Fuller GN and Matin SF (2011) Pilot trial of sunitinib therapy in patients with von Hippel–Lindau disease. Ann Oncol, accepted
Gore ME, Larkin JMG (2011) Challenges and opportunities for converting renal cell carcinoma into a chronic disease with targeted therapies. Br J Cancer 104:399–406
Carmeliet P, Jain RK (2011) Molecular mechanisms and clinical applications of angiogenesis. Nature 473:298–307
Sanford M, Keating GM (2010) Pazopanib. BioDrugs 24:279–286
Friedman HS, Prados M, Wen PY, Mikkelsen T, Schiff D, Abrey LE, Yung WK, Paleologos N, Nicholas Mk, Jensen R, Vredenburgh J, Huang J, Zheng M, Cloughesy T (2009) Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma. J Clin Oncol 28:4733–4740
Batchelor T, Duda DG, di Tomaso E, Ancukiewicz M, Plotkin SR, Gerstner E, Eichler AF, Drappatz J, Hochberg FH, Benner T, Louis DN, Cohen KS, Chea H, Exarhopoulos A, Loeffler JS, Moses MA, Ivy P, Sorensen AG, Wen PY, Jain RK (2010) Phase II study of cediranib, an oral pan-endothelial growth factor receptor tyrosine kinase inhibitor, in patients with recurrent glioblastoma. J Clin Oncol 28:2817–2823
Iwamoto FM, Lamborn KR, Robins I, Mehta MP, Chang SM, Butowski NA, DeAngelis LM, Abrey LE, Zhang WT, Prados MD, Fine HA (2010) Phase II trial of pazopanib (GW786034), an oral multi-targeted angiogenesis inhibitor, for adults with recurrent glioblastoma (North America Brain Tumor Consortium Study 06-02). Neuro-Oncology 12:855–861
Bukowski RM (2010) Pazopanib: a multikinase inhibitor with activity in advanced renal cell carcinoma. Expert Rev Anticancer Ther 10:635–645
Mendel DM, Laird D, Xin X, Cherrington JM (2003) In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: determination of a pharmacokinetic pharmacodynamic relationship. Clin Cancer Res 9:327–337
Kaal EC, Vecht CJ (2004) The management of brain edema in brain tumors. Curr Opin Oncol 16:593–600
Jain RK (2005) Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science 307:58–62
De Groot JF, Fuller G, Kumar AJ, Piao Y, Eterovic K, Ji YJ, Conrad CA (2010) Tumor invasion after treatment of glioblastoma with bevacizumab: radiographic and pathologic correlation in humans and mice. Neuro-Oncology 12:233–242
Kumar R, Crouthamel MC, Rominger DH, Gontarek RR, Tummino PJ, Levin RA, King AG (2009) Myelosuppression and kinase selectivity of multikinase angiogenesis inhibitors. Br J Cancer 101:1717–1723
Acknowledgements
The authors thank Miao Li for performing manual segmentation on tumor images and volumetric analysis for this study. We thank Dr. Dawid Schellingerhout for assistance in technical discussions on brain imaging techniques.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Kim, B.Y.S., Jonasch, E. & McCutcheon, I.E. Pazopanib therapy for cerebellar hemangioblastomas in von Hippel–Lindau disease. Targ Oncol 7, 145–149 (2012). https://doi.org/10.1007/s11523-012-0214-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11523-012-0214-0