title: Severe hypofractionation: non-homogeneous tumour dose delivery can counteract tumour hypoxia.
abstract: BACKGROUND
  The current rationale for severely hypofractionated schedules (3-5 fractions) used in stereotactic-body-radiotherapy (SBRT) of non-small-cell lung cancer (NSCLC) is the small size of the irradiated volumes. Being the dose prescribed to the 60-80% isodose line enclosing the PTV, a non-homogeneous tumour-dose-delivery results which might impact on tumour hypoxia. A comparison between homogeneous and SBRT-like non-homogeneous tumour-dose-delivery is then proposed here, using severe hypofractionation on large tumour volumes where both dose prescription strategies are applicable.
  
  
  METHODS
  For iso-NTCP hypofractionated schedules (1f/d*5d/w) with respect to standard fractionation (d=2Gy), computed from the individual DVHs for lungs, oesophagus, heart and spinal cord (Lyman-Kutcher-Burman NTCP-model), TCP values were calculated (α-averaged Poissonian-LQ model) for homogeneous and SBRT-like non-homogeneous plans both with and without tumour hypoxia. Two different estimates of the oxygen-enhancement-ratio (OER) in combination with two distinct assumptions on the kinetics of reoxygenation were considered. Homogeneous and SBRT-like non-homogeneous plans were finally compared in terms of therapeutic ratio (TR), as the product of TCP and the four (1-NTCP(i)) values.
  
  
  RESULTS
  For severe hypofractionation (3-5 fractions) and for any of the hypotheses on the kinetics of reoxygenation and the OER, there was a significant difference between the computed TRs with or without inclusion of tumour hypoxia (anova, p=0.01) for homogeneous tumour-dose-delivery, but no significant difference for the SBRT-like non-homogeneous one. Further, a significantly increased mean TR for the group of SBRT-like non-homogeneous plans resulted (t-test, p=0.05) with respect to the group with homogeneous target-dose-coverage.
  
  
  CONCLUSIONS
  SBRT-like dose-boosting seems to counterbalance the loss of reoxygenation within a few fractions. For SBRT it then seems that, in addition to the high level of dose-sparing to the adjacent normal tissues, when severe hypofractionation is adopted it is probably the intrinsic ability of stereotactic techniques to perform intra-tumour simultaneous dose-boosting which yields the reported high clinical efficacy.
authors.affiliation: Medical Physics Department, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, Meldola, FC, Italy. ruggieri.ruggero@gmail.com
authors.forename: Ruggero
authors.initials: R
authors.lastname: Ruggieri
authors.forename: Stefania
authors.initials: S
authors.lastname: Naccarato
authors.forename: Alan E
authors.initials: AE
authors.lastname: Nahum
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000532:radiotherapy*; D015687:Cell Hypoxia / Q000528:radiation effects*; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy*; D008432:Mathematical Computing; D015233:Models, Statistical; D016012:Poisson Distribution; D016634:Radiosurgery / Q000379:methods*; D011880:Radiotherapy Planning, Computer-Assisted