title: Phase 1 trial of bevacizumab with concurrent chemoradiation therapy for squamous cell carcinoma of the head and neck with exploratory functional imaging of tumor hypoxia, proliferation, and perfusion.
abstract: OBJECTIVE
  A phase 1 trial was completed to examine the safety and feasibility of combining bevacizumab with radiation and cisplatin in patients with locoregionally advanced squamous cell carcinoma of the head and neck (HNSCC) treated with curative intent. Additionally, we assessed the capacity of bevacizumab to induce an early tumor response as measured by a series of biological imaging studies.
  
  
  METHODS
  All patients received a single induction dose of bevacizumab (15 mg/kg) delivered 3 weeks (±3 days) before the initiation of chemoradiation therapy. After the initial dose of bevacizumab, comprehensive head and neck chemoradiation therapy was delivered with curative intent to 70 Gy in 33 fractions with concurrent weekly cisplatin at 30 mg/m(2) and bevacizumab every 3 weeks (weeks 1, 4, 7) with dose escalation from 5 to 10 to 15 mg/kg. All patients underwent experimental imaging with [(18)F]fluorothymidine positron emission tomography (FLT-PET) (proliferation), [(61)Cu]Cu-diacetyl-bis(N4-methylthiosemicarbazone) PET (Cu-ATSM-PET) (hypoxia), and dynamic contrast-enhanced computed tomography (DCE-CT) (perfusion) at 3 time points: before bevacizumab monotherapy, after bevacizumab monotherapy, and during the combined therapy course.
  
  
  RESULTS
  Ten patients were enrolled. All had stage IV HNSCC, all achieved a complete response to treatment, and 9 of 10 remain alive, with a mean survival time of 61.3 months. All patients experienced grade 3 toxicity, but no dose-limiting toxicities or significant bleeding episodes were observed. Significant reductions were noted in tumor proliferation (FLT-PET), tumor hypoxia (Cu-ATSM-PET), and DCE-CT contrast enhancement after bevacizumab monotherapy, with further decreases in FLT-PET and Cu-ATSM-PET during the combined therapy course.
  
  
  CONCLUSIONS
  The incorporation of bevacizumab into comprehensive chemoradiation therapy regimens for patients with HNSCC appears safe and feasible. Experimental imaging demonstrates measureable changes in tumor proliferation, hypoxia, and perfusion after bevacizumab monotherapy and during chemoradiation therapy. These findings suggest opportunities to preview the clinical outcomes for individual patients and thereby design personalized therapy approaches in future trials.
authors: Department of Radiation Oncology, University of Washington, Seattle, Washington. Electronic address: nyflot@uw.edu.
authors: Matthew J
authors: MJ
authors: Nyflot
authors: Department of Radiation Oncology, Cadence Cancer Center at Delnor Hospital, Geneva, Illinois.
authors: Tim J
authors: TJ
authors: Kruser
authors: Department of Medicine, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Anne M
authors: AM
authors: Traynor
authors: Varian Medical Systems, Palo Alto, California.
authors: Deepak
authors: D
authors: Khuntia
authors: Departments of Pathology and Laboratory Medicine, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: David T
authors: DT
authors: Yang
authors: Department of Surgery-Otolaryngology, H&N Surgery Division, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Gregory K
authors: GK
authors: Hartig
authors: Department of Surgery-Otolaryngology, H&N Surgery Division, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Timothy M
authors: TM
authors: McCulloch
authors: Department of Human Oncology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Peggy A
authors: PA
authors: Wiederholt
authors: Department of Radiology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Lindell R
authors: LR
authors: Gentry
authors: Department of Medicine, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Tien
authors: T
authors: Hoang
authors: Department of Human Oncology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin; Department of Radiology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin; Department of Medical Physics, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Robert
authors: R
authors: Jeraj
authors: Department of Human Oncology, University of Wisconsin Carbone Cancer Center and School of Medicine and Public Health, Madison, Wisconsin.
authors: Paul M
authors: PM
authors: Harari
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D000068258:Bevacizumab; D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D015687:Cell Hypoxia; D049109:Cell Proliferation; D059248:Chemoradiotherapy / Q000009:adverse effects / Q000379:methods*; D002945:Cisplatin / Q000008:administration & dosage; D056831:Coordination Complexes; D004334:Drug Administration Schedule; D005260:Female; D006258:Head and Neck Neoplasms / Q000098:blood supply / Q000000981:diagnostic imaging / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000628:therapy*; D006801:Humans; D060828:Induction Chemotherapy / Q000379:methods; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009942:Organometallic Compounds; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals; D000077195:Squamous Cell Carcinoma of Head and Neck; D013882:Thiosemicarbazones
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D056831:Coordination Complexes; D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; D013882:Thiosemicarbazones; C089548:copper (II) diacetyl-di(N(4)-methylthiosemicarbazone); D000068258:Bevacizumab; D002945:Cisplatin