Unexpected changes of rat cervical spinal cord tolerance caused by inhomogeneous dose distributions

Purpose: The effects of dose distribution on dose-effect relationships have been evaluated and, from this, iso-effective doses (ED(50)) established. Methods and Materials: Wistar rats were irradiated on the cervical spinal cord with single doses of unmodulated protons (150MeV) 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 ED50 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 intensitymodulated radiotherapy. (C) 2003 Elsevier Inc.