title: Sorafenib Increases Tumor Hypoxia in Cervical Cancer Patients Treated With Radiation Therapy: Results of a Phase 1 Clinical Study.
abstract: OBJECTIVE
  Preclinical studies have shown that angiogenesis inhibition can improve response to radiation therapy (RT). The purpose of this phase 1 study was to examine the angiogenesis inhibitor sorafenib in patients with cervical cancer receiving radical RT and concurrent cisplatin (RTCT).
  
  
  METHODS
  Thirteen patients with stage IB to IIIB cervical cancer participated. Sorafenib was administered daily for 7 days before the start of standard RTCT in patients with early-stage, low-risk disease and also during RTCT in patients with high-risk disease. Biomarkers of tumor vascularity, perfusion, and hypoxia were measured at baseline and again after 7 days of sorafenib alone before the start of RTCT. The median follow-up time was 4.5 years.
  
  
  RESULTS
  Initial complete response was seen in 12 patients. One patient died without achieving disease control, and 4 experienced recurrent disease. One patient with an extensive, infiltrative tumor experienced pelvic fistulas during treatment. The 4-year actuarial survival was 85%. Late grade 3 gastrointestinal toxicity developed in 4 patients. Sorafenib alone produced a reduction in tumor perfusion/permeability and an increase in hypoxia, which resulted in early closure of the study.
  
  
  CONCLUSIONS
  Sorafenib increased tumor hypoxia, raising concern that it might impair rather than improve disease control when added to RTCT.
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada. Electronic address: mike.milosevic@rmp.uhn.ca.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Milosevic
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Carol A
authors.initials: CA
authors.lastname: Townsley
authors.affiliation: Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Naz
authors.initials: N
authors.lastname: Chaudary
authors.affiliation: Department of Pathology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada.
authors.forename: Blaise
authors.initials: B
authors.lastname: Clarke
authors.affiliation: Department of Clinical Study Coordination and Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Melania
authors.initials: M
authors.lastname: Pintilie
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Stacy
authors.initials: S
authors.lastname: Fan
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Rachel
authors.initials: R
authors.lastname: Glicksman
authors.affiliation: Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Canada; Department of Medical Imaging, University of Toronto, Toronto, Canada.
authors.forename: Masoom
authors.initials: M
authors.lastname: Haider
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada.
authors.forename: Sunmo
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Helen
authors.initials: H
authors.lastname: MacKay
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Yeung
authors.affiliation: Department of Radiation Oncology, University of Toronto, Toronto, Canada; Department of Advanced Molecular Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hill
authors.affiliation: Radiation Medicine Program, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Radiation Oncology, University of Toronto, Toronto, Canada.
authors.forename: Anthony
authors.initials: A
authors.lastname: Fyles
authors.affiliation: Department of Medical Oncology, Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Department of Medicine, University of Toronto, Toronto, Canada.
authors.forename: Amit M
authors.initials: AM
authors.lastname: Oza
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D000970:Antineoplastic Agents / Q000008:administration & dosage; D015415:Biomarkers; D001918:Brachytherapy / Q000379:methods; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D015687:Cell Hypoxia; D059248:Chemoradiotherapy / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D057239:Early Termination of Clinical Trials; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D009536:Niacinamide / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D010100:Oxygen / Q000378:metabolism; D010313:Partial Pressure; D010671:Phenylurea Compounds / Q000008:administration & dosage / Q000009:adverse effects*; D011836:Radiation Tolerance / Q000187:drug effects; D000077157:Sorafenib; D013997:Time Factors; D047368:Tumor Burden; D002583:Uterine Cervical Neoplasms / Q000098:blood supply / Q000473:pathology / Q000628:therapy*
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D015415:Biomarkers; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D002945:Cisplatin; D010100:Oxygen