title: Loss of biological effect in prolonged fraction delivery.
abstract: OBJECTIVE
  The decrease of biologic effect if delivery of dose fractions takes more than a few minutes has been occasionally recognized in the literature but has been insufficiently studied. It has been recognized as a problem in the long exposures necessary for stereotactic radiotherapy and is also a potential problem in some applications of IMRT. Modeling repair rates is a complex function of dose per fraction, dose rate, half-times of repair, and nature of the tissue of interest (the alpha/beta ratio of intrinsic radiosensitivity to repair capacity). In this article, we model repair rates for a range of doses per fraction and draw conclusions.
  
  
  METHODS
  We review the data on half-times of repair in tissues in situ in animals and human patients and conclude that a single first-order (exponential) repair rate is no longer an appropriate assumption for most tissues. At least 2 half-times of repair, and perhaps a distribution of half-times, are required. The faster components have a median half-time of 0.3 h (range, 0.08-1.2 h), and the longer components have a median of 4 h (range, 2.4->6 h). Modeling repair rates by a two-component model is the simplest approach. We have used two models of repair to represent these ranges, one with equal proportions of 0.2 h + 4.0 h half-times, the other with 0.4 h + 4.0 h half-times of repair. Data are also reviewed on the few experiments that have been reported with cell culture that investigate this problem.
  
  
  RESULTS
  Computations indicate that any fraction delivery that lasts more than half an hour might experience a clinically significant loss of cell-sterilizing effect. We suggest that a loss of more than 10% in biologically effective dose should be compensated for and show modeled doses and fraction durations for which this situation seems to be likely. It will be dose, tissue, and system dependent and will require more investigation at the clinical level.
  
  
  CONCLUSIONS
  It is suggested that any radiotherapy schedule that requires more than half an hour for the delivery of 1 fraction should have careful records made and reported, to look for a possible decrease of biologic effect with fraction duration.
authors.affiliation: Department of Human Oncology, Medical School, University of Wisconsin, Madison, WI 53792, USA. jffowler@humonc.wisc.edu
authors.forename: Jack F
authors.initials: JF
authors.lastname: Fowler
authors.forename: James S
authors.initials: JS
authors.lastname: Welsh
authors.forename: Steven P
authors.initials: SP
authors.lastname: Howard
mesh_terms: D000818:Animals; D004260:DNA Repair; D019583:Dose Fractionation, Radiation; D004307:Dose-Response Relationship, Radiation; D011832:Radiation Injuries / Q000503:physiopathology; D020266:Radiotherapy, Conformal; D012062:Relative Biological Effectiveness; D013997:Time Factors