A phase 1b trial of the combination of the antiangiogenic agent sunitinib and radiation therapy for patients with primary and metastatic central nervous system malignancies

Authors

  • Evan J. Wuthrick MD,

    1. Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
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  • Mitchell Kamrava MD,

    1. Radiation Oncology Branch, Section of Imaging and Molecular Therapeutics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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  • Walter J. Curran Jr MD,

    1. Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
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  • Maria Werner-Wasik MD,

    1. Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
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  • Kevin A. Camphausen MD,

    1. Radiation Oncology Branch, Section of Imaging and Molecular Therapeutics, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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  • Terry Hyslop PhD,

    1. Division of Biostatistics, Thomas Jefferson University, Philadelphia, Pennsylvania
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  • Rita Axelrod MD,

    1. Department of Medical Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
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  • David W. Andrews MD,

    1. Department of Neurological Surgery, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
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  • Jon Glass MD,

    1. Department of Neurological Surgery, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
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  • Mitchell Machtay MD,

    1. Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
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  • Adam P. Dicker MD, PhD

    Corresponding author
    1. Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania
    • Department of Radiation Oncology, Thomas Jefferson University Hospital, 111 South 11th Street, Philadelphia, PA 19107
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    • Fax: (215) 503-0013


  • Presented at the 44th Annual Meeting of the American Society of Clinical Oncology, Chicago, Illinois, May 30 to June 3, 2008.

Abstract

BACKGROUND:

In this phase 1 trial, the authors evaluated sunitinib combined with radiation therapy (RT) for the treatment of primary or metastatic central nervous system (CNS) malignancies.

METHODS:

Eligible patients had CNS malignancies that required a (minimum) 2-week course of RT. Sunitinib (37.5 mg) was administered daily for the duration of RT with optional treatment extension of 1 month. Urine was collected at 3 time points for correlative biomarker studies. The primary endpoint was acute toxicity defined according to Common Toxicity Criteria version 3.

RESULTS:

Fifteen patients were enrolled (12 with CNS metastasis and 3 with primary tumors). RT doses ranged from 14 Gray (Gy) to 70 Gy (1.8-3.5 Gy per fraction). Acute toxicities included hematologic, nausea, hyperglycemia, fatigue, hypocalcemia, and diarrhea. Six patients (40%) developed grade ≤2 toxicities. Grade 3 toxicities occurred in 7 patients (47%) and included hematologic toxicity, fatigue, deep vein thrombosis, dysphasia, hyperglycemia, and hyponatremia. No grade 3 through 5 hypertensive events or intracerebral hemorrhages occurred. Two grade 5 adverse events attributed to disease progression occurred. The median follow-up was 34.2 months. Two patients (13%) achieved a partial response, 9 patients (60%) had stable disease, and 2 patients (13%) patients had progressive disease. The 6-month progression-free survival rate for patients who had brain metastasis was 58%. Grade 3 hematologic toxicity was correlated with greater changes in vascular endothelial growth factor levels changes between baseline and the completion of RT.

CONCLUSIONS:

Continuous 37.5-mg sunitinib combined with RT in patients who had CNS malignancies yielded acceptable toxicities and adverse events. The current results indicated that changes in urine vascular endothelial growth factor levels are associated with hematologic toxicity, and this association should be analyzed in a larger cohort. The feasibility, safety, and early response results warrant a phase 2 trial. Cancer 2011;. © 2011 American Cancer Society.

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