Abstract
Radiation-induced late side effects such as cognitive decline and normal tissue complications can severely affect quality of life and outcome in long-term survivors of brain tumors. Proton therapy offers a favorable depth-dose deposition with the potential to spare tumor-surrounding normal tissue, thus potentially reducing such side effects. In this study, we describe a preclinical model to reveal underlying biological mechanisms caused by precise high-dose proton irradiation of a brain subvolume. We studied the dose- and time-dependent radiation response of mouse brain tissue, using a high-precision image-guided proton irradiation setup for small animals established at the University Proton Therapy Dresden (UPTD). The right hippocampal area of ten C57BL/6 and ten C3H/He mice was irradiated. Both strains contained four groups (nirradiated = 3, ncontrol = 1) treated with increasing doses (0 Gy, 45 Gy, 65 Gy or 85 Gy and 0 Gy, 40 Gy, 60 Gy or 80 Gy, respectively). Follow-up examinations were performed for up to six months, including longitudinal monitoring of general health status and regular contrast-enhanced magnetic resonance imaging (MRI) of mouse brains. These findings were related to comprehensive histological analysis. In all mice of the highest dose group, first symptoms of blood-brain barrier (BBB) damage appeared one week after irradiation, while a dose-dependent delay in onset was observed for lower doses. MRI contrast agent leakage occurred in the irradiated brain areas and was progressive in the higher dose groups. Mouse health status and survival corresponded to the extent of contrast agent leakage. Histological analysis revealed tissue changes such as vessel abnormalities, gliosis, and granule cell dispersion, which also partly affected the non-irradiated contralateral hippocampus in the higher dose groups. All observed effects depended strongly on the prescribed radiation dose and the outcome, i.e. survival, image changes, and tissue alterations, were very consistent within an experimental dose cohort. The derived dose–response model will determine endpoint-specific dose levels for future experiments and may support generating clinical hypotheses on brain toxicity after proton therapy.
Highlights
Tumors of the central nervous system are still an entity with a very poor prognosis, with a current relative 5-year survival rate of around 19 – 22 % [1]
Preserving cognitive abilities and quality of life is of paramount importance to these patients. This requires the reduction of dose delivered to the tumorsurrounding normal tissue below a critical threshold dose
An advantage of proton therapy (PT) over photon radiotherapy is its inherent physical properties: Particles stop in the tissue after depositing their energy maximum (Bragg Peak), leading to a reduced integral dose [3] and sparing of normal tissue
Summary
Tumors of the central nervous system are still an entity with a very poor prognosis, with a current relative 5-year survival rate of around 19 – 22 % [1]. Preserving cognitive abilities and quality of life is of paramount importance to these patients. This requires the reduction of dose delivered to the tumorsurrounding normal tissue below a critical threshold dose. Brain tumors and pediatric patients are often treated with this modality [4, 5]. There has been a surge in PT treatment facilities [6], and several smaller cohort studies indicate beneficial effects of PT such as improved overall survival [7] or prevention of brain-volume loss [8]. Data from randomized multi-center clinical trials is still lacking [9]
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