title: Gemcitabine Plus Radiation Therapy for High-Grade Glioma: Long-Term Results of a Phase 1 Dose-Escalation Study.
abstract: OBJECTIVE
  To evaluate the tolerability and efficacy of gemcitabine plus radiation therapy (RT) in this phase 1 study of patients with newly diagnosed malignant glioma (HGG).
  
  
  METHODS
  Between 2004 and 2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method, 5 dose levels were evaluated starting at 500 mg/m(2) during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended phase 2 dose of gemcitabine plus RT. Secondary objectives included progression-free survival, overall survival (OS), and long-term toxicity.
  
  
  RESULTS
  Median follow-up was 38.1 months (range, 8.9-117.5 months); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with World Health Organization grade 4 tumors were no longer enrolled. Median progression-free survival for 22 patients with grade 3 tumors was 26.0 months (95% confidence interval [CI] 15.6-inestimable), and OS was 48.5 months (95% CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95% CI 32.8-inestimable). Six nonmutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended phase 2 dose of gemcitabine plus RT was 750 mg/m(2)/wk given the last 4 weeks of RT. Dose reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen.
  
  
  CONCLUSIONS
  Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG.
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan. Electronic address: michekim@med.umich.edu.
authors: Michelle M
authors: MM
authors: Kim
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Sandra
authors: S
authors: Camelo-Piragua
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors: Matthew
authors: M
authors: Schipper
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Department of Biostatistics, University of Michigan, Ann Arbor, Michigan.
authors: Yebin
authors: Y
authors: Tao
authors: Department of Biostatistics, University of Pittsburgh, Pittsburgh, Pennsylvania.
authors: Daniel
authors: D
authors: Normolle
authors: Department of Neurology, University of Michigan, Ann Arbor, Michigan.
authors: Larry
authors: L
authors: Junck
authors: Department of Neurology, University of Michigan, Ann Arbor, Michigan.
authors: Aaron
authors: A
authors: Mammoser
authors: Department of Pathology, University of Michigan, Ann Arbor, Michigan.
authors: Bryan L
authors: BL
authors: Betz
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan; Department of Radiology, University of Michigan, Ann Arbor, Michigan; Department of Biomedical Engineering, University of Michigan, Ann Arbor, Michigan.
authors: Yue
authors: Y
authors: Cao
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Christopher J
authors: CJ
authors: Kim
authors: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan.
authors: Jason
authors: J
authors: Heth
authors: Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan.
authors: Oren
authors: O
authors: Sagher
authors: Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.
authors: Theodore S
authors: TS
authors: Lawrence
authors: Department of Radiation Oncology, Washington University, St. Louis, Missouri.
authors: Christina I
authors: CI
authors: Tsien
mesh_terms: D000328:Adult; D000368:Aged; D001932:Brain Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D005910:Glioma / Q000188:drug therapy / Q000235:genetics / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009503:Neutropenia / Q000209:etiology / Q000473:pathology; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage* / Q000009:adverse effects; D011879:Radiotherapy Dosage; D055815:Young Adult; D000093542:Gemcitabine
chemical_list: D011838:Radiation-Sensitizing Agents; D003841:Deoxycytidine; D000093542:Gemcitabine