title: Unexpected changes of rat cervical spinal cord tolerance caused by inhomogeneous dose distributions.
abstract: OBJECTIVE
  The effects of dose distribution on dose-effect relationships have been evaluated and, from this, iso-effective doses (ED(50)) established.
  
  
  METHODS
  Wistar rats were irradiated on the cervical spinal cord with single doses of unmodulated protons (150 MeV) to obtain sharp lateral penumbras, using the shoot-through technique, which employs the plateau of the depth-dose profile rather than the Bragg peak. Two types of inhomogeneous dose distributions have been administered: (1) 2 4-mm fields with 8- or 12-mm spacing between the center of the fields (referred to as split-field) were irradiated with variable single doses and (2) cervical spinal cord was irradiated with various combinations of relatively low doses to a large volume (20 mm) combined with high doses to a small volume (4 mm) (referred to as bath and shower). The endpoint for estimating the dose-response relationships was paralysis of the fore or hind limbs.
  
  
  RESULTS
  The split-field experiments (2 x 4 mm) showed a shift in the dose-response curves, giving significant higher ED(50) values of 45.4 Gy and 41.6 Gy for 8- and 12-mm spacing, respectively, compared with the ED(50) of 24.9 Gy for the single 8 mm (same total tissue volume irradiated). These values were closer to the ED(50) for a single 4-mm field of 53.7 Gy. The bath and shower experiments showed a large decrease of the ED(50) values from 15-22 Gy when compared with the 4-mm single field, even with a bath dose as low as 4 Gy. There were no histologic changes found in the low dose bath regions of the spinal cord at postmortem.
  
  
  CONCLUSIONS
  Not only the integral irradiated volume is a determining factor for the ED(50) of rat cervical spinal cord, but also the shape of the dose distribution is of great importance. The high ED(50) values of a small region or shower (4 mm) decreases significantly when the adjacent tissue is irradiated with a subthreshold dose (bath), even as low as 4 Gy. The significant shift to lower ED(50) values for induction of paralysis of the limbs by adding a low-dose bath was not accompanied by changes in histologic lesions. These observations may have implications for the interpretation of complex treatment plans and normal tissue complication probability in intensity-modulated radiotherapy.
authors.affiliation: Department of Radiation Oncology, University Hospital Groningen, Groningen, The Netherlands. h.p.bijl@rt.azg.nl
authors.forename: Hendrik P
authors.initials: HP
authors.lastname: Bijl
authors.forename: Peter
authors.initials: P
authors.lastname: van Luijk
authors.forename: Rob P
authors.initials: RP
authors.lastname: Coppes
authors.forename: Jacobus M
authors.initials: JM
authors.lastname: Schippers
authors.forename: Antonius W T
authors.initials: AW
authors.lastname: Konings
authors.forename: Albert J
authors.initials: AJ
authors.lastname: van der Kogel
mesh_terms: D000818:Animals; D002574:Cervical Vertebrae; D005552:Forelimb / Q000294:innervation / Q000528:radiation effects; D006614:Hindlimb / Q000294:innervation / Q000528:radiation effects; D033162:Incidental Findings; D007928:Lethal Dose 50; D008297:Male; D010243:Paralysis / Q000209:etiology*; D011829:Radiation Dosage; D011836:Radiation Tolerance; D011874:Radiometry / Q000379:methods*; D011880:Radiotherapy Planning, Computer-Assisted; D051381:Rats; D017208:Rats, Wistar; D013116:Spinal Cord / Q000473:pathology* / Q000528:radiation effects*