title: 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.
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.
authors.affiliation: Department of Radiation Oncology, Jefferson Medical College of Thomas Jefferson University, Kimmel Cancer Center, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Evan J
authors.initials: EJ
authors.lastname: Wuthrick
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kamrava
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Curran
authors.forename: Maria
authors.initials: M
authors.lastname: Werner-Wasik
authors.forename: Kevin A
authors.initials: KA
authors.lastname: Camphausen
authors.forename: Terry
authors.initials: T
authors.lastname: Hyslop
authors.forename: Rita
authors.initials: R
authors.lastname: Axelrod
authors.forename: David W
authors.initials: DW
authors.lastname: Andrews
authors.forename: Jon
authors.initials: J
authors.lastname: Glass
authors.forename: Mitchell
authors.initials: M
authors.lastname: Machtay
authors.forename: Adam P
authors.initials: AP
authors.lastname: Dicker
mesh_terms: D000368:Aged; D020533:Angiogenesis Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000652:urine; D001932:Brain Neoplasms / Q000188:drug therapy / Q000532:radiotherapy* / Q000556:secondary / Q000652:urine; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000652:urine; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000652:urine; D008875:Middle Aged; D011758:Pyrroles / Q000009:adverse effects / Q000627:therapeutic use*; D011879:Radiotherapy Dosage; D000077210:Sunitinib; D016019:Survival Analysis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000652:urine
chemical_list: D020533:Angiogenesis Inhibitors; D014408:Biomarkers, Tumor; D007211:Indoles; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000077210:Sunitinib