title: A proliferation saturation index to predict radiation response and personalize radiotherapy fractionation.
abstract: BACKGROUND
  Although altered protocols that challenge conventional radiation fractionation have been tested in prospective clinical trials, we still have limited understanding of how to select the most appropriate fractionation schedule for individual patients. Currently, the prescription of definitive radiotherapy is based on the primary site and stage, without regard to patient-specific tumor or host factors that may influence outcome. We hypothesize that the proportion of radiosensitive proliferating cells is dependent on the saturation of the tumor carrying capacity. This may serve as a prognostic factor for personalized radiotherapy (RT) fractionation.
  
  
  METHODS
  We introduce a proliferation saturation index (PSI), which is defined as the ratio of tumor volume to the host-influenced tumor carrying capacity. Carrying capacity is as a conceptual measure of the maximum volume that can be supported by the current tumor environment including oxygen and nutrient availability, immune surveillance and acidity. PSI is estimated from two temporally separated routine pre-radiotherapy computed tomography scans and a deterministic logistic tumor growth model. We introduce the patient-specific pre-treatment PSI into a model of tumor growth and radiotherapy response, and fit the model to retrospective data of four non-small cell lung cancer patients treated exclusively with standard fractionation. We then simulate both a clinical trial hyperfractionation protocol and daily fractionations, with equal biologically effective dose, to compare tumor volume reduction as a function of pretreatment PSI.
  
  
  RESULTS
  With tumor doubling time and radiosensitivity assumed constant across patients, a patient-specific pretreatment PSI is sufficient to fit individual patient response data (R(2) = 0.98). PSI varies greatly between patients (coefficient of variation >128 %) and correlates inversely with radiotherapy response. For this study, our simulations suggest that only patients with intermediate PSI (0.45-0.9) are likely to truly benefit from hyperfractionation. For up to 20 % uncertainties in tumor growth rate, radiosensitivity, and noise in radiological data, the absolute estimation error of pretreatment PSI is <10 % for more than 75 % of patients.
  
  
  CONCLUSIONS
  Routine radiological images can be used to calculate individual PSI, which may serve as a prognostic factor for radiation response. This provides a new paradigm and rationale to select personalized RT dose-fractionation.
authors.affiliation: Departments of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Sotiris
authors.initials: S
authors.lastname: Prokopiou
authors.affiliation: Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.|Department of Cancer Imaging and Metabolism, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Eduardo G
authors.initials: EG
authors.lastname: Moros
authors.affiliation: Departments of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Poleszczuk
authors.affiliation: Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Jimmy
authors.initials: J
authors.lastname: Caudell
authors.affiliation: Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Javier F
authors.initials: JF
authors.lastname: Torres-Roca
authors.affiliation: Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Kujtim
authors.initials: K
authors.lastname: Latifi
authors.affiliation: Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, USA.
authors.forename: Jae K
authors.initials: JK
authors.lastname: Lee
authors.affiliation: Department of Radiation Oncology, Washington University School of Medicine, St. Louis, MO, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Myerson
authors.affiliation: Department of Radiation Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA.
authors.forename: Louis B
authors.initials: LB
authors.lastname: Harrison
authors.affiliation: Departments of Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, 12902 Magnolia Drive, Tampa, FL, 33612, USA. Heiko.Enderling@Moffitt.org.
authors.forename: Heiko
authors.initials: H
authors.lastname: Enderling
mesh_terms: D000465:Algorithms; D002289:Carcinoma, Non-Small-Cell Lung / Q000532:radiotherapy; D002455:Cell Division / Q000528:radiation effects*; D015687:Cell Hypoxia; D003198:Computer Simulation; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007157:Immunologic Surveillance; D008175:Lung Neoplasms / Q000532:radiotherapy; D008954:Models, Biological; D057285:Precision Medicine / Q000379:methods*; D011836:Radiation Tolerance; D011897:Random Allocation; D012062:Relative Biological Effectiveness; D012189:Retrospective Studies; D047368:Tumor Burden; D059016:Tumor Microenvironment