title: Concurrent whole brain radiotherapy and bortezomib for brain metastasis.
abstract: BACKGROUND
  Survival of patients with brain metastasis particularly from historically more radio-resistant malignancies remains dismal. A phase I study of concurrent bortezomib and whole brain radiotherapy was conducted to determine the tolerance and safety of this approach in patients with previously untreated brain metastasis.
  
  
  METHODS
  A phase I dose escalation study evaluated the safety of bortezomib (0.9, 1.1, 1.3, 1.5, and 1.7 mg/m2) given on days 1, 4, 8 and 11 of whole brain radiotherapy. Patients with confirmed brain metastasis were recruited for participation. The primary endpoint was the dose-limiting toxicity, defined as any ≥ grade 3 non-hematologic toxicity or grade ≥ 4 hematologic toxicity from the start of treatment to one month post irradiation. Time-to-Event Continual Reassessment Method (TITE-CRM) was used to determine dose escalation. A companion study of brain diffusion tensor imaging MRI was conducted on a subset of patients to assess changes in the brain that might predict delayed cognitive effects.
  
  
  RESULTS
  Twenty-four patients were recruited and completed the planned therapy. Patients with melanoma accounted for 83% of all participants. The bortezomib dose was escalated as planned to the highest dose of 1.7 mg/m2/dose. No grade 4/5 toxicities related to treatment were observed. Two patients had grade 3 dose-limiting toxicities (hyponatremia and encephalopathy). A partial or minor response was observed in 38% of patients. Bortezomib showed greater demyelination in hippocampus-associated white matter structures on MRI one month after radiotherapy compared to patients not treated with bortezomib (increase in radial diffusivity +16.8% versus 4.8%; p = 0.0023).
  
  
  CONCLUSIONS
  Concurrent bortezomib and whole brain irradiation for brain metastasis is well tolerated at one month follow-up, but MRI changes that have been shown to predict delayed cognitive function can be detected within one month of treatment.
authors: Christopher D
authors: CD
authors: Lao
authors: Judah
authors: J
authors: Friedman
authors: Christina I
authors: CI
authors: Tsien
authors: Daniel P
authors: DP
authors: Normolle
authors: Christopher
authors: C
authors: Chapman
authors: Yue
authors: Y
authors: Cao
authors: Oliver
authors: O
authors: Lee
authors: Matt
authors: M
authors: Schipper
authors: Catherine
authors: C
authors: Van Poznak
authors: Daniel
authors: D
authors: Hamstra
authors: Theodore
authors: T
authors: Lawrence
authors: James
authors: J
authors: Hayman
authors: Bruce G
authors: BG
authors: Redman
mesh_terms: D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects; D001897:Boronic Acids / Q000008:administration & dosage / Q000009:adverse effects; D000069286:Bortezomib; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000556:secondary* / Q000628:therapy*; D059248:Chemoradiotherapy / Q000379:methods*; D016371:Cranial Irradiation / Q000009:adverse effects / Q000379:methods; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D011719:Pyrazines / Q000008:administration & dosage / Q000009:adverse effects
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; D011719:Pyrazines; D000069286:Bortezomib
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