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To the Editor: The von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome caused by mutation in the VHL tumor suppressor gene that results in enhanced transcription of several hypoxia-inducible genes, including the gene for vascular endothelial growth factor (VEGF). Patients with VHL disease often develop highly vascular hemangioblastomas and solid tumors¹ with aberrant angiogenesis.^2-3 The compound SU5416, which inhibits vascular endothelial growth factor receptor 2, has been reported to slow tumor angiogenesis and growth⁴ and has been investigated in patients with advanced cancer.⁵ We conducted a phase I/phase II study of SU5416 in patients with VHL disease.

Methods
Participants were 6 patients with progressive VHL disease despite standard treatment. (Clinical details are available from the authors.) Patients were excluded if they had a neutrophil count of less than1500 cells/mm³, hemoglobin level less than 9.0 g/dL, platelet count of less than 100 000 cells/mm³, abnormal liver or renal function test results, surgery within 4 weeks, known allergy to study medications, or Karnofsky Performance Status less than 80% (unless due to complications of the disease). Patients were either sterile or were using contraception. Two patients were started on intravenous SU5416 at a dosage of 145 mg/m² weekly; the other 4 patients received 145 mg/m² twice weekly. All patients were premedicated intravenously with 10 mg of chlorpheniramine, 50 mg of ranitidine, and 4 mg of dexamethasone. Each cycle consisted of 4 weeks of therapy.

Radiological and retinal assessment of disease response was performed every 24 weeks using World Health Organization response criteria.⁶ Stable disease was defined as a less than 25% decrease or a less than 25% increase in the size of all lesions (measured by the sum of the products of the greatest length and the maximum width). Progressive disease was defined as an increase of 25% or more in the size of any measured lesion or the appearance of any new lesion(s). Toxicity was evaluated every 4 weeks, using National Cancer Institute criteria.⁷ Plasma levels of VEGF were measured at baseline and then monthly (Quantikine, R & D Systems Inc, Minneapolis, Minn).

Results
The median age of the 6 patients was 34.5 (range, 26-42) years. A total of 51 cycles were administered with a median of 5.8 (range, 1.5-22.4) cycles per patient.

Two of the 6 patients had stabilization of disease. The first patient had hemangioblastomas in the brain and spinal cord, and numerous cysts, for which she had previously undergone neurosurgery, radiotherapy, pancreatectomy, and splenectomy. Because the patient wanted to become pregnant, SU5416 was discontinued after 22.4 months. At that time, she had radiological stabilization of the lesions and resolution of numbness and reduction of weakness and ataxia in her legs. Her pretreatment plasma VEGF level of 210 pg/mL had decreased to 160 pg/mL at 6 months. She had a normal pregnancy and delivered a healthy infant. Her disease remained stable 19 months after completion of treatment.

The second patient had hemangioblastomas in the brain, spinal cord, and retina, as well as renal, pancreatic, and epididymal cysts, for which he had undergone 2 neurosurgical procedures, 4 retinal laser treatments, and unilateral nephrectomy. The patient had complete regression of the right retinal lesion after 10 months of treatment. Visual acuity in that eye was 20/20 and remained stable. He also noticed improvement in strength (grade 3 at baseline to grade 2) and sexual function. The radiological appearance of his tumors remained stable for 14 months. This patient's pretreatment VEGF level of 91 pg/mL, increased to 116 pg/mL at 6 months.

Serial measurements of plasma levels of VEGF were available for 2 of the 4 patients who did not have a clinical response. In 1 patient, VEGF level decreased from 166 pg/mL to 51 pg/mL by the end of treatment, but in the other it increased from 15 pg/mL to 26 pg/mL.

Common adverse effects included headache, vomiting, nausea, fatigue, diarrhea, arthralgia, and pruritus. Treatment was discontinued in 1 patient because of severe uncontrollable pruritus.

Comment
We found that SU5416 was associated with improved clinical status in 2 of 6 patients with advanced VHL disease. Although it was also associated with reduction in serum levels of VEGF in some patients, this did not correlate with clinical response.

Recovery of visual function with SU5416 has been reported in a patient with VHL disease and optic nerve hemangioblastoma⁸ and in another patient with retinal hemangioblastoma and associated cystoid macular edema.⁹ We found evidence for the regression of a retinal lesion, as well as possible clinical benefit of SU5416 in lesions outside the retina. Further evaluation of inhibitors of VEGF receptor 2 in VHL disease is needed.

Dr Deplanque is currently affiliated with the Départment d'Oncologie, Hôpital Claude Bernard, Metz, France.—ED.

Funding/Support: Sugen Inc (a subsidiary of Pharmacia Corp) provided SU5416 free of cost under the United Kingdom DDX Certificate regulations.

Role of Sponsor: The study was the responsibility of the investigator. Sugen Inc had no role in data collection, data analysis, data interpretation, or the writing of the report. The ownership of all data is with Dr Harris, who had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses.

Acknowledgment: We thank Dylan Jones, PhD, of the Cancer Research UK, Weatherall Institute of Molecular Medicine, Oxford, England, for performing the plasma VEGF assays.

Srinivasan Madhusudan, MBBS, MRCP; Gaël Deplanque, MSc, MD, PhD; Jeremy P. Braybrooke, MRCP, PhD; Emma Cattell, MBBS, MRCP; Marian Taylor, BSc
Cancer Research UK Medical Oncology Unit
Oxford Radcliffe Hospitals
Oxford, England

Pat Price, MD, FRCR, FRCP
Academic Department of Radiation Oncology
Christie Hospital
Manchester, England

Marie D. Tsaloumas, FRCOphth
Department of Ophthalmology
Birmingham & Midland Eye Clinic
Birmingham, England

Niall Moore, FRCR
Department of Radiology

Susan M. Huson, MD, FRCP
Department of Clinical Genetics

Chris Adams, MA, MChir, FRCS
Department of Neurosurgery

Peggy Frith, FRCOphth
Department of Ophthalmology
Oxford Radcliffe Hospitals

Paul Scigalla, MD, PhD
SUGEN Inc
San Francisco, Calif

Adrian L. Harris, FRCP, DPhil
aharris.lab{at}cancer.org.uk
Cancer Research UK Medical Oncology Unit
Oxford Radcliffe Hospitals

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Letters Section Editor: Stephen J. Lurie, MD, PhD, Senior Editor.

JAMA. 2004;291:943-944.

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