Journal of Neuro-Oncology 48: 27–40, 2000. © 2000 Kluwer Academic Publishers. Printed in the Netherlands. Laboratory Investigation Tolerance of the normal canine brain to epithermal neutron irradiation in the presence of p-boronophenylalanine Jeffrey A. Coderre 1 , Patrick R. Gavin 2 , Jacek Capala 1,∗ , Ruimei Ma 1 , Gerard M. Morris 3 , Terry M. Button 4 , Tariq Aziz 5,† and Nancy S. Peress 5 1 Medical Department, Brookhaven National Laboratory, Upton, NY, USA; 2 Washington State University, Veterinary Clinical Sciences, Pullman, WA, USA; 3 Research Institute, University of Oxford, Churchill Hospital, Oxford, UK; 4 Department of Radiology, 5 Department of Pathology, Neuropathology Division, School of Medicine, State University of New York at Stony Brook, Stony Brook, NY, USA; ∗ Current address: Unit of Biomedical Radiation Sciences, Rudbeck Laboratory, Uppsala University, Uppsala, Sweden; † Current address: Dalhousie University, Department of Laboratory Medicine, Saint John Regional Hospital, Saint John, Canada Key words: boron neutron capture therapy, boronophenylalanine, BNCT, brain, epithermal neutrons, irradiation, normal tissue tolerance Summary Twelve normal dogs underwent brain irradiation in a mixed-radiation, mainly epithermal neutron field at the Brookhaven Medical Research Reactor following intravenous infusion of 950 mg of 10 B-enriched BPA/kg as its fructose complex. The 5 × 10 cm irradiation aperture was centered over the left hemisphere. For a subgroup of dogs reported previously, we now present more detailed analyses including dose–volume relationships, longer follow-ups, MRIs, and histopathological observations. Peak doses (delivered to 1 cm 3 of brain at the depth of maximum thermal neutron flux) ranged from 7.6 Gy (photon-equivalent dose: 11.8 Gy-Eq) to 11.6 Gy (17.5 Gy-Eq). The average dose to the brain ranged from 3.0 Gy (4.5 Gy-Eq) to 8.1 Gy (11.9 Gy-Eq) and to the left hemisphere, 6.6 Gy (10.1 Gy-Eq) to 10.0 Gy (15.0 Gy-Eq). Maximum tolerated ‘threshold’ doses were 6.7 Gy (9.8 Gy-Eq) to the whole brain and 8.2 Gy (12.3 Gy-Eq) to one hemisphere. The threshold peak brain dose was 9.5 Gy (14.3 Gy-Eq). At doses below threshold, some dogs developed subclinical MRI changes. Above threshold, all dogs developed dose-dependent MRI changes, neurological deficits, and focal brain necrosis. Introduction The radiation tolerance of the normal brain is the lim- iting factor in radiotherapy of malignant brain tumors. For glioblastoma multiforme, in particular, both fast neutron therapy [1,2] and stereotactic radiosurgery [3] have been reported to sterilize tumor regions at the center of a treatment volume but normal tissue compli- cations and local recurrence have limited the effective- ness of both of these modalities. Boron neutron capture therapy (BNCT) is a binary technique that relies upon the preferential accumula- tion of a boronated drug in the tumor to selectively irra- diate tumor cells during exposure to slow (‘epithermal’ or ‘thermal’) neutrons. Epithermal neutrons have the advantage of thermalizing as they penetrate normal tissues toward deeper tumor-bearing tissues. Thermal neutrons are much more likely to be ‘captured’ by boron-10 nuclei via the 10 B(n,α) 7 Li reaction than by the nuclei of elements that normally constitute mam- malian tissues. Immediately after neutron capture, the resultant metastable boron-11 nucleus splits into two densely ionizing high-energy particles, an α particle and a Li ion, which have a combined track length in soft tissues of only ∼14 μm, i.e., the diameter of one or two cells. The short ranges of the α and Li par- ticles (9 and 5 μm, respectively) confine most radia- tion damage to boron-loaded cells. This ‘biochemical