title: The reoxygenation of hypoxia and the reduction of glucose metabolism in head and neck cancer by fractionated radiotherapy with intensity-modulated radiation therapy.
abstract: OBJECTIVE
  The purpose of this study was to prospectively investigate reoxygenation in the early phase of fractionated radiotherapy and serial changes of tumoricidal effects associated with intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer (HNC) using F-18 fluoromisonidazole (FMISO) PET and F-18 fluorodeoxyglucose (FDG) PET.
  
  
  METHODS
  Patients with untreated HNC underwent FMISO-PET and FDG-PET studies prospectively. A PET evaluation was conducted before each IMRT (Pre-IMRT), during IMRT (at 30 Gy/15 fr) (Inter-IMRT), and after completion of IMRT (70 Gy/35 fr) (Post-IMRT). FMISO-PET images were scanned by a PET/CT scanner at 4 h after the FMISO injection. We quantitatively analyzed the FMISO-PET images of the primary lesion using the maximum standardized uptake (SUVmax) and tumor-to-muscle ratio (TMR). The hypoxic volume (HV) was calculated as an index of tumor hypoxia, and was defined as the volume when the TMR was ≥ 1.25. Each FDG-PET scan was started 1 h after injection. The SUVmax and metabolic tumor volume (MTV) values obtained by FDG-PET were analyzed.
  
  
  RESULTS
  Twenty patients finished the complete PET study protocol. At Pre-IMRT, 19 patients had tumor hypoxia in the primary tumor. In ten patients, the tumor hypoxia disappeared at Inter-IMRT. Another seven patients showed the disappearance of tumor hypoxia at Post-IMRT. Two patients showed tumor hypoxia at Post-IMRT. The FMISO-PET results showed that the reduction rates of both SUVmax and TMR from Pre-IMRT to Inter-IMRT were significantly higher than the corresponding reductions from Inter-IMRT to Post-IMRT (SUVmax: 27 % vs. 10 %, p = 0.025; TMR: 26 % vs. 12 %, p = 0.048). The reduction rate of SUVmax in FDG-PET from Pre-IMRT to Inter-IMRT was similar to that from Inter-IMRT to Post-IMRT (47 % vs. 48 %, p = 0.778). The reduction rate of the HV in FMISO-PET from Pre-IMRT to Inter-IMRT tended to be larger than that from Inter-IMRT to Post-IMRT (63 % vs. 40 %, p = 0.490). Conversely, the reduction rate of the MTV in FDG-PET from Pre-IMRT to Inter-IMRT was lower than that from Inter-IMRT to Post-IMRT (47 % vs. 74 %, p = 0.003).
  
  
  CONCLUSIONS
  Both the intensity and the volume of tumor hypoxia rapidly decreased in the early phase of radiotherapy, indicating reoxygenation of the tumor hypoxia. In contrast, the FDG uptake declined gradually with the course of radiotherapy, indicating that the tumoricidal effect continues over the entire course of radiation treatment.
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Shozo
authors.initials: S
authors.lastname: Okamoto
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan. tshiga@med.hokudai.ac.jp.
authors.forename: Tohru
authors.initials: T
authors.lastname: Shiga
authors.affiliation: Department of Radiology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Yasuda
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Watanabe
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Hirata
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Hokkaido, Japan.
authors.forename: Ken-Ichi
authors.initials: KI
authors.lastname: Nishijima
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Magota
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Kasai
authors.affiliation: Department of Radiology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Rikiya
authors.initials: R
authors.lastname: Onimaru
authors.affiliation: Department of Radiology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Tuchiya
authors.affiliation: Central Institute of Isotope Science, Hokkaido University, Hokkaido, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kuge
authors.affiliation: Department of Radiology, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Shirato
authors.affiliation: Department of Nuclear Medicine, Hokkaido University Graduate School of Medicine, Hokkaido, Japan.
authors.forename: Nagara
authors.initials: N
authors.lastname: Tamaki
mesh_terms: D000328:Adult; D000368:Aged; D019583:Dose Fractionation, Radiation; D015536:Down-Regulation / Q000528:radiation effects; D005260:Female; D019788:Fluorodeoxyglucose F18 / Q000493:pharmacokinetics*; D006258:Head and Neck Neoplasms / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008920:Misonidazole / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D010100:Oxygen / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics; D020266:Radiotherapy, Conformal / Q000379:methods*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D016896:Treatment Outcome; D000072258:Tumor Hypoxia / Q000528:radiation effects*
chemical_list: D019275:Radiopharmaceuticals; C031843:fluoromisonidazole; D019788:Fluorodeoxyglucose F18; D008920:Misonidazole; D010100:Oxygen
keywords: FDG-PET; FMISO-PET; Head and neck cancer; Radiotherapy; Reoxygenation; Tumor hypoxia