title: Phase 1 pharmacogenetic and pharmacodynamic study of sorafenib with concurrent radiation therapy and gemcitabine in locally advanced unresectable pancreatic cancer.
abstract: OBJECTIVE
  To define the safety, efficacy, and pharmacogenetic and pharmacodynamic effects of sorafenib with gemcitabine-based chemoradiotherapy (CRT) in locally advanced pancreatic cancer.
  
  
  METHODS
  Patients received gemcitabine 1000 mg/m(2) intravenously weekly × 3 every 4 weeks per cycle for 1 cycle before CRT and continued for up to 4 cycles after CRT. Weekly gemcitabine 600 mg/m(2) intravenously was given during concurrent intensity modulated radiation therapy of 50 Gy to gross tumor volume in 25 fractions. Sorafenib was dosed orally 400 mg twice daily until progression, except during CRT when it was escalated from 200 mg to 400 mg daily, and 400 mg twice daily. The maximum tolerated dose cohort was expanded to 15 patients. Correlative studies included dynamic contrast-enhanced MRI and angiogenesis genes polymorphisms (VEGF-A and VEGF-R2 single nucleotide polymorphisms).
  
  
  RESULTS
  Twenty-seven patients were enrolled. No dose-limiting toxicity occurred during induction gemcitabine/sorafenib followed by concurrent CRT. The most common grade 3/4 toxicities were fatigue, hematologic, and gastrointestinal. The maximum tolerated dose was sorafenib 400 mg twice daily. The median progression-free survival and overall survival for 25 evaluable patients were 10.6 and 12.6 months, respectively. The median overall survival for patients with VEGF-A -2578 AA, -1498 CC, and -1154 AA versus alternate genotypes was 21.6 versus 14.7 months. Dynamic contrast-enhanced MRI demonstrated higher baseline K(trans) in responding patients.
  
  
  CONCLUSIONS
  Concurrent sorafenib with CRT had modest clinical activity with increased gastrointestinal toxicity in localized unresectable pancreatic cancer. Select VEGF-A/VEGF-R2 genotypes were associated with favorable survival.
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana; Department of Medicine, University of Washington, Seattle, Washington. Electronic address: gchiorea@uw.edu.
authors.forename: E Gabriela
authors.initials: EG
authors.lastname: Chiorean
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Bryan P
authors.initials: BP
authors.lastname: Schneider
authors.affiliation: Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Fatih M
authors.initials: FM
authors.lastname: Akisik
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Susan M
authors.initials: SM
authors.lastname: Perkins
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Stephen
authors.initials: S
authors.lastname: Anderson
authors.affiliation: Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Cynthia S
authors.initials: CS
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: John
authors.initials: J
authors.lastname: DeWitt
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Paul
authors.initials: P
authors.lastname: Helft
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Romnee
authors.initials: R
authors.lastname: Clark
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Erica L
authors.initials: EL
authors.lastname: Johnston
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: A John
authors.initials: AJ
authors.lastname: Spittler
authors.affiliation: Department of Radiation Oncology, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Jill
authors.initials: J
authors.lastname: Deluca
authors.affiliation: Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Guixue
authors.initials: G
authors.lastname: Bu
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Safi
authors.initials: S
authors.lastname: Shahda
authors.affiliation: Department of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Loehrer
authors.affiliation: Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sandrasegaran
authors.affiliation: Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, Indiana.
authors.forename: Higinia R
authors.initials: HR
authors.lastname: Cardenes
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D003841:Deoxycytidine / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D018572:Disease-Free Survival; D019583:Dose Fractionation, Radiation; D004334:Drug Administration Schedule; D005260:Female; D005838:Genotype; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011446:Prospective Studies; D050397:Radiotherapy, Intensity-Modulated / Q000379:methods*; D000077157:Sorafenib; D047368:Tumor Burden; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D009536:Niacinamide; D000077157:Sorafenib; D040301:Vascular Endothelial Growth Factor Receptor-2; D000093542:Gemcitabine