Late radiation effects in the dog brain: correlation of MRI and histological changes

Abstract

Purpose: To determine the correlation between sequential changes in the brain of dogs after irradiation, as detected by magnetic resonance imaging (MRI), with the eventual appearance of histological lesions. Histology was performed 77–115 weeks after irradiation.

Materials and methods: Groups of five beagle dogs were irradiated to the brain with single doses of 10, 12, 14 or 16 Gy of 6 MV photons, at the 100% iso-dose. Sequential MRIs were taken to detect changes in the brain for 77–115 weeks after irradiation. Dose–effect relationships were established for changes in the brain as detected by MRI, computerized tomography (CT), gross morphology and histology. The doses that caused a specified response in 50% of the animals (ED₅₀±SE) were calculated from these dose–effect relationships for each endpoint.

Results: The ED₅₀ values (±SE) for focal and diffuse changes on T2-weighted MR images were 11.0±1.1 and 10.8±0.9 Gy, respectively. The ED₅₀ values (±SE) for contrast enhancement on T1-weighted MR images and on CT were 13.4±0.6 and 13.0±0.6 Gy, respectively. It was 11.4±0.6 Gy for any type of histological lesion (haemorrhage, reactive change or glial scar) 77–115 weeks after irradiation. For a macroscopic lesion the ED₅₀ (±SE) value was 13.0±1.1 Gy.

Conclusions: The presence of focal or diffuse changes on T2-weighted MR images was the best indicator for the eventual appearance of any type of histological lesion in the dog brain after irradiation with single doses of photons. The ED₅₀ for any histological lesion did not differ significantly from the ED₅₀ for a focal (P>0.35) or diffuse (P=0.3) change on T2-weighted MR images.

Introduction

The tolerance of the central nervous system (CNS) is an important consideration when planning radiation therapy for head and neck tumours, including those of the brain. Tissue necrosis has often been selected as the appropriate endpoint in studies of the tolerance of the brain to irradiation. In a review [12] of patients irradiated with 1.8–2.0 Gy daily fractions, given five times a week, normal tissue tolerance was defined as the probability of 5% of patients developing brain necrosis or infarction within 5 years of irradiation (TD 5/5). The tolerated total dose was found to depend on the volume of the brain irradiated. The TD 5/5 varied from 45 Gy for the entire brain, to 60 Gy for one-third of the brain within the target volume. The probability of a 50% incidence of brain necrosis/infarction within 5 years, for the same dose fractionation schedule (TD 50/5), was estimated to be in the range 60–75 Gy for the different target volumes considered. These estimates of normal brain tolerance should be viewed with caution because of the difficult differential diagnosis between brain necrosis and tumour recurrence if no autopsy is performed or if multiple tissue biopsies are not available. Autopsy rates are low, particularly in brain tumour patients, and many of these patients either die early or may receive other cancer therapies, which may confound the radiation-related effects. Moreover, the anatomical distribution of critical radiosensitive CNS structures is perhaps more important than the relative tissue volume irradiated [22].

Experiments to study the acute and late effects of radiation on normal CNS tissue have, with few exceptions, involved rodents. In these studies severe neurological or histological changes have been evaluated and neither computerized tomography (CT) nor magnetic resonance imaging (MRI) were used in most cases. In an extensive review of the literature up until 1979 [19] it was proposed, based on histological endpoints, that both vascular and glial cell changes were important in the development of late radiation-induced damage. More recently, others have reported on the time- and dose-related histological changes seen in the vasculature and associated astrocytes in the latent period before the onset of white matter necrosis in the rat brain [9]. It was concluded that reactive changes in these tissue elements, as a result of endothelial cell loss, were the causative factor in the development of necrosis. The conclusion of a recent review [21] was that the underlying mechanism for selective white matter necrosis after irradiation, with doses close to tolerance, was clearly related to initial damage to the vasculature. This was based on the results of histological studies supplemented by studies of glial progenitor cell survival after irradiation with thermal neutrons in the presence of different boron-10 capture agents. The marked variation in the reduction in glial progenitor cells did not influence the observed effects using the different radiation protocols.

There have been few studies in large animals designed to examine the response of the normal brain to photon irradiation with doses in the therapeutic range. Functional, clinical, gross morphological and ultrastructural changes have been studied in brains of Macaca mulatta monkeys after both single and fractionated doses of X-rays [10]. Neurological symptoms, animal survival and histological findings were the endpoints evaluated in the brains of dogs irradiated with fractionated doses of photons [30]. Fike et al. [13], [14] were the first to use CT, in addition to neurological examinations and histology, to study the late effects of single doses of photons on the hemi-brain of dogs. MRI was not widely available for diagnostic purposes at the time the studies by Fike et al. [13], [14] were initiated, although in modern clinical imaging it is used predominantly for the CNS. Therefore, there is a need to examine, in an experimental model, the development of radiation-induced late effects in the normal brain using MRI. The clinical significance of the radiation-related MRI findings also needs to be evaluated and compared with neurological signs and histological changes.

The tolerance of the brain to single doses of irradiation has aroused interest recently with the introduction of new radiation modalities, such as boron neutron capture therapy (BNCT), which is frequently delivered as a single treatment. An additional objective of the present study was to provide baseline data for comparison with the effects of irradiation of the whole brain of dogs with epithermal neutrons from a 250 kW light-water moderated Triga Mark II nuclear reactor [4]. The objective was to provide relative biological effectiveness (RBE) factors for this reactor beam, which is used for the treatment of patients with BNCT [5].

In the present study, a range of single doses of 6 MV photons (10–16 Gy) were used to investigate both the time- and dose-related changes on MR images after irradiation of dogs and to compare these with the dose–effect relationships for CT, macroscopic and histological lesions. This study was planned based on the data provided by Fike (pers. commun.), which included his treatment plans. To ascertain comparability of the previously published and the present data a dosimetry inter-comparison was made between the Department of Oncology, HUCH, Helsinki, Finland and the Department of Radiation Oncology, UCSF Medical Center, San Francisco, USA.