title: Theoretical effectiveness of cell survival in fractionated radiotherapy with hypoxia-targeted dose escalation.
abstract: OBJECTIVE
  The goal of this article is to compute the cell survival during fractionated radiotherapy with non-uniform hypoxia-targeted dose distribution relative to cell survival for a uniform dose distribution with equal integral tumor dose. The analysis is performed for different parameters of radiotherapy with conventional and hypofractionated dose regimens.
  
  
  METHODS
  Our analysis is done using a parsimonious tumor response model that describes the major components of tumor response to radiotherapy such as radiosensitivity, cell proliferation, and hypoxia using as few variables as possible. Two levels of oxygenated and hypoxic cells with the survival curves described by the linear quadratic (LQ) model are implemented in the model. The model allows for analytical solutions for relative cell survival in a single fraction simulation which can be used for additional validation of our numerical simulations. The relative cell survival was computed for conventional and hypofractionated dose regimens in a model problem with radiobiological parameters for the non-small-cell lung cancer. Sensitivity of cell survival to different parameters of radiotherapy such as the relative volume of hypoxic fraction, boost dose ratio, re-oxygenation rate, and delivery errors was investigated.
  
  
  RESULTS
  Our computational and analytical results show that relative cell survival for non-uniform and uniform dose distributions is larger than 1.0 during the first few fractions of radiotherapy with conventional fractionation. This indicates that the uniform dose distribution produces a higher cell killing effect for the equal integral dose. This may stem from domination of linear contribution to the cell killing effect seen in the dose range of 1-2 Gy and a steeper slope of survival curve in the oxygenated tumor region. This effect can only happen if the distribution of clonogens is nearly uniform; therefore, after the first few fractions, the non-uniform dose distributions outperform the uniform dose distribution and relative cell survival becomes less than 1.0. However, re-oxygenation and delivery errors can also reduce the effectiveness of hypoxia-targeted non-uniform dose distributions toward the end of treatment. For hypofractionated radiotherapy with fractional dose >3 Gy, the relative cell survival was always below 1.0, which means the non-uniform dose distributions produced higher cell killing effect than the uniform dose distribution during the entire treatment.
  
  
  CONCLUSIONS
  The data obtained in this work suggest that non-uniform hypoxia-targeted dose distributions are less effective at cell killing than uniform dose distributions at the beginning of radiotherapy with conventional fractionation. However; non-uniform dose distributions can outperform uniform dose distribution by the end of the treatment if the effects of re-oxygenation and delivery errors are reduced. In hypofractionated radiotherapy, non-uniform hypoxia-targeted dose distributions are more efficient than uniform dose distributions during the entire treatment.
authors.affiliation: Department of Radiation Oncology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195-6043, USA.
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Chvetsov
authors.affiliation: Department of Radiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195-6043, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Rajendran
authors.affiliation: Department of Radiation Oncology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195-6043, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zeng
authors.affiliation: Department of Radiation Oncology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195-6043, USA.
authors.forename: Shilpen A
authors.initials: SA
authors.lastname: Patel
authors.affiliation: Departments of Radiation Oncology and Radiology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195-6043, USA.
authors.forename: Stephen R
authors.initials: SR
authors.lastname: Bowen
authors.affiliation: Department of Radiation Oncology, University of Washington, 1959 NE Pacific Street, Seattle, WA, 98195-6043, USA.
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Kim
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000532:radiotherapy*; D002470:Cell Survival; D019583:Dose Fractionation, Radiation; D006801:Humans; D000860:Hypoxia; D008175:Lung Neoplasms / Q000532:radiotherapy*; D008954:Models, Biological; D011853:Radiobiology; D014407:Tumor Cells, Cultured
keywords: cell survival; dose escalation; hypofractionation; hypoxia