title: Stereotactic ablative radiotherapy should be combined with a hypoxic cell radiosensitizer.
abstract: OBJECTIVE
  To evaluate the effect of tumor hypoxia on the expected level of cell killing by regimens of stereotactic ablative radiotherapy (SABR) and to determine the extent to which the negative effect of hypoxia could be prevented using a clinically available hypoxic cell radiosensitizer.
  
  
  CONCLUSIONS
  We have calculated the expected level of tumor cell killing from regimens of SABR, both with and without the assumption that 20% of the tumor cells are hypoxic, using the standard linear quadratic model and the universal survival curve modification. We compare the results obtained with our own clinical data for lung tumors of different sizes and with published data from other studies. We also have calculated the expected effect on cell survival of adding the hypoxic cell sensitizer etanidazole at clinically achievable drug concentrations. Modeling tumor cell killing with any of the currently used regimens of SABR produces results that are inconsistent with the majority of clinical findings if tumor hypoxia is not considered. However, with the assumption of tumor hypoxia, the expected level of cell killing is consistent with clinical data. For only some of the smallest tumors are the clinical data consistent with no tumor hypoxia, but there could be other reasons for the sensitivity of these tumors. The addition of etanidazole at clinically achievable tumor concentrations produces a large increase in the expected level of tumor cell killing from the large radiation doses used in SABR.
  
  
  CONCLUSIONS
  The presence of tumor hypoxia is a major negative factor in limiting the curability of tumors by SABR at radiation doses that are tolerable to surrounding normal tissues. However, this negative effect of hypoxia could be overcome by the addition of clinically tolerable doses of the hypoxic cell radiosensitizer etanidazole.
authors.affiliation: Department of Radiation Oncology, Stanford University School of Medicine, California 94305, USA. mbrown@stanford.edu
authors.forename: J Martin
authors.initials: JM
authors.lastname: Brown
authors.forename: Maximilian
authors.initials: M
authors.lastname: Diehn
authors.forename: Billy W
authors.initials: BW
authors.lastname: Loo
mesh_terms: D015687:Cell Hypoxia / Q000187:drug effects*; D002470:Cell Survival; D003131:Combined Modality Therapy / Q000379:methods; D017341:Etanidazole / Q000627:therapeutic use*; D006801:Humans; D016014:Linear Models; D008175:Lung Neoplasms / Q000473:pathology / Q000601:surgery*; D011838:Radiation-Sensitizing Agents / Q000627:therapeutic use*; D016634:Radiosurgery / Q000379:methods*; D047368:Tumor Burden
chemical_list: D011838:Radiation-Sensitizing Agents; D017341:Etanidazole