Medulloblastoma is the most common malignant brain tumour in children, and radiotherapy to the whole brain and spine is an important component of treatment. Whilst several preclinical studies are exploring radiosensitising drug combinations, many utilise radiation doses and schedules that cannot reliably be translated into clinical practice. We aimed to develop a clinically-relevant radiotherapy protocol to treat mouse models of medulloblastoma, using Australia’s first conformal preclinical radiotherapy machine.
Four different radiotherapy beam plans were designed which targeted various areas of the brain and spinal cord. A comparison was also performed between single dose and fractionated radiotherapy approaches, whereby the single dose (8Gy) was calculated to be biologically equivalent to the fractionated dose (16-20Gy delivered as 2Gy daily fractions) based on a well-defined linear–quadratic mathematical model. Mice were implanted intracranially with D425 human medulloblastoma cells, treated with the different radiotherapy protocols, and survival measured. Brains were histologically assessed to determine the location of disease regrowth.
Mice treated with fractionated radiotherapy had significantly increased survival compared to those that received a single dose, therefore fractionated dosing was used in subsequent experiments. Focal radiotherapy did not increase survival compared to untreated controls. A treatment plan that irradiated most of the brain, except the olfactory bulbs and cerebellum, increased median survival compared to controls (23 days vs. 18 days, p<0.0001); however, the disease regrew in unexposed parts of the brain. Irradiation of the entire brain further increased survival (37 days, p<0.0001), however the mice succumbed to leptomeningeal metastases in the spinal cord. Lastly fractionated radiotherapy to the whole brain and spine markedly increased survival (42 days, p<0.0001). Moreover, the tumour regrew locally which is consistent with clinical relapse patterns.
This study has successfully optimised preclinical radiotherapy protocols in mouse models of medulloblastoma. Fractionated preclinical craniospinal radiotherapy most closely mimics clinical treatment protocols, clinical patterns of disease relapse, is well tolerated by animals, and is therefore recommended for future preclinical studies.