title: Effect of [(18)F]FMISO stratified dose-escalation on local control in FaDu hSCC in nude mice.
abstract: OBJECTIVE
  To investigate the effect of radiation dose-escalation on local control in hypoxic versus non-hypoxic hypoxic tumours defined using [(18)F]fluoromisonidazole ([(18)F]FMISO) PET.
  
  
  METHODS
  FaDu human squamous cell carcinomas (hSCCs) growing subcutaneously in nude mice were subjected to [(18)F]FMISO PET before irradiation with single doses of 25 or 35Gy under normal blood flow conditions. [(18)F]FMISO hypoxic volume (HV) and maximum standardised uptake value (SUVmax) were used to quantify tracer uptake. The animals were followed up for at least 120days after irradiation. The endpoints were permanent local tumour control and time to local recurrence.
  
  
  RESULTS
  HV varied between 38 and 291mm(3) (median 105mm(3)). Non-hypoxic tumours (HV below median) showed significantly better local control after single dose irradiation than hypoxic tumours (HV above median) (p=0.046). The effect of dose was significant and not different in non-hypoxic and in hypoxic tumours (HR=0.82 [95% CI 0.71; 0.93], p=0.002 and HR=0.86 [0.78; 0.95], p=0.001, respectively). Dose escalation resulted in an incremental increase of local tumour control from low-dose hypoxic, over low-dose non-hypoxic and high-dose hypoxic to high-dose non-hypoxic tumours. SUVmax did not reveal significant association with local control at any dose level.
  
  
  CONCLUSIONS
  The negative effect of [(18)F]FMISO HV on permanent local tumour control supports the prognostic value of the pre-treatment [(18)F]FMISO HV. Making the assumption that variable [(18)F]FMISO uptake in different FaDu tumours which all have the same genetic background may serve as an experimental model of intratumoural heterogeneity, the data support the concept of dose-escalation with inhomogeneous dose distribution based on pre-treatment [(18)F]FMISO uptake. This result needs to be confirmed in other tumour models and using fractionated radiotherapy schedules.
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Schütze
authors.affiliation: PET Centre, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Bergmann
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Brüchner
authors.affiliation: Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Mosch
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Dept. of Radiation Oncology (MAASTRO Lab), GROW - School for Oncology and Developmental Biology, Maastricht University Medical Centre, The Netherlands.
authors.forename: Ala
authors.initials: A
authors.lastname: Yaromina
authors.affiliation: Department of Radiation Oncology, Eberhard Karls University Tübingen, Germany; German Cancer Consortium (DKTK), Site Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Zips
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Hessel
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; German Cancer Consortium (DKTK), Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Mechthild
authors.initials: M
authors.lastname: Krause
authors.affiliation: University of Texas, M.D. Anderson Cancer Centre, Department of Biostatistics and Applied Mathematics, Houston, United States.
authors.forename: Howard
authors.initials: H
authors.lastname: Thames
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Nuclear Medicine, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; PET Centre, Helmholtz-Zentrum Dresden-Rossendorf, Germany; German Cancer Consortium (DKTK), Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Kotzerke
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; PET Centre, Helmholtz-Zentrum Dresden-Rossendorf, Germany; Institute of Radiopharmaceutical Cancer Research, Helmholtz-Zentrum Dresden-Rossendorf, Germany; German Cancer Consortium (DKTK), Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Steinbach
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Radiation Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; Institute of Radiation Oncology, Helmholtz-Zentrum Dresden-Rossendorf, Germany; German Cancer Consortium (DKTK), Site Dresden and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Baumann
authors.affiliation: OncoRay - National Centre for Radiation Research in Oncology, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, Germany; Department of Nuclear Medicine, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Germany; PET Centre, Helmholtz-Zentrum Dresden-Rossendorf, Germany. Electronic address: b.beuthien@hzdr.de.
authors.forename: Bettina
authors.initials: B
authors.lastname: Beuthien-Baumann
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D015687:Cell Hypoxia / Q000528:radiation effects; D045744:Cell Line, Tumor; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005462:Fluorine Radioisotopes / Q000008:administration & dosage*; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D007012:Hypopharyngeal Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy*; D051379:Mice; D008819:Mice, Nude; D008920:Misonidazole / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009364:Neoplasm Recurrence, Local / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology / Q000532:radiotherapy; D011838:Radiation-Sensitizing Agents / Q000008:administration & dosage*; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals / Q000008:administration & dosage*; D011897:Random Allocation; D000077195:Squamous Cell Carcinoma of Head and Neck; D023041:Xenograft Model Antitumor Assays
chemical_list: D005462:Fluorine Radioisotopes; D011838:Radiation-Sensitizing Agents; D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D008920:Misonidazole
keywords: Dose escalation; Human tumour xenografts; Hypoxic volume; Local control; Single dose irradiation; Squamous cell carcinoma; [(18)F]FMISO positron emission tomography