title: Hypofractionation results in reduced tumor cell kill compared to conventional fractionation for tumors with regions of hypoxia.
abstract: OBJECTIVE
  Tumor hypoxia has been observed in many human cancers and is associated with treatment failure in radiation therapy. The purpose of this study is to quantify the effect of different radiation fractionation schemes on tumor cell killing, assuming a realistic distribution of tumor oxygenation.
  
  
  METHODS
  A probability density function for the partial pressure of oxygen in a tumor cell population is quantified as a function of radial distance from the capillary wall. Corresponding hypoxia reduction factors for cell killing are determined. The surviving fraction of a tumor consisting of maximally resistant cells, cells at intermediate levels of hypoxia, and normoxic cells is calculated as a function of dose per fraction for an equivalent tumor biological effective dose under normoxic conditions.
  
  
  RESULTS
  Increasing hypoxia as a function of distance from blood vessels results in a decrease in tumor cell killing for a typical radiotherapy fractionation scheme by a factor of 10(5) over a distance of 130 μm. For head-and-neck cancer and prostate cancer, the fraction of tumor clonogens killed over a full treatment course decreases by up to a factor of ∼10(3) as the dose per fraction is increased from 2 to 24 Gy and from 2 to 18 Gy, respectively.
  
  
  CONCLUSIONS
  Hypofractionation of a radiotherapy regimen can result in a significant decrease in tumor cell killing compared to standard fractionation as a result of tumor hypoxia. There is a potential for large errors when calculating alternate fractionations using formalisms that do not account for tumor hypoxia.
authors.affiliation: Stanford University School of Medicine, Department of Radiation Oncology, Stanford, CA, USA. david.j.carlson@yale.edu
authors.forename: David J
authors.initials: DJ
authors.lastname: Carlson
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Keall
authors.forename: Billy W
authors.initials: BW
authors.lastname: Loo
authors.forename: Zhe J
authors.initials: ZJ
authors.lastname: Chen
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
mesh_terms: D000465:Algorithms; D002196:Capillaries / Q000033:anatomy & histology / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects*; D019583:Dose Fractionation, Radiation; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D006801:Humans; D016014:Linear Models; D008297:Male; D008920:Misonidazole / Q000494:pharmacology; D010101:Oxygen Consumption / Q000502:physiology*; D010313:Partial Pressure; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D011836:Radiation Tolerance / Q000187:drug effects / Q000502:physiology*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D017211:Treatment Failure
chemical_list: D011838:Radiation-Sensitizing Agents; D008920:Misonidazole