No abstract

Background: Despite aggressive treatment regimens comprising surgery and radiochemotherapy, glioblastoma (GBM) remains a cancer entity with very poor prognosis. The development of novel, combined modality approaches necessitates adequate preclinical model systems and therapy regimens that closely reflect the clinical situation. So far, image-guided, fractionated radiotherapy of orthotopic GBM models represents a major limitation in this regard. Methods: GL261 mouse GBM cells were inoculated into the right hemispheres of C57BL/6 mice. Tumor growth was monitored by contrast-enhanced conebeam CT (CBCT) scans. When reaching an average volume of approximately 7 mm 3 , GBM tumors were irradiated with daily fractions of 2 Gy up to a cumulative dose of 20 Gy in different beam collimation settings. For treatment planning and tumor volume follow-up, contrast-enhanced CBCT scans were performed twice per week. Daily repositioning of animals was achieved by alignment of bony structures in native CBCT scans. When showing neurological symptoms, mice were sacrificed by cardiac perfusion. Brains, livers, and kidneys were processed into histologic sections. Potential toxic effects of contrast agent administration were assessed by measurement of liver enzyme and creatinine serum levels and by histologic examination. Results: Tumors were successfully visualized by contrast-enhanced CBCT scans with a detection limit of approximately 2 mm 3 , and treatment planning could be performed. For daily repositioning of the animals, alignment of bony structures in native CT scans was well feasible. Fractionated irradiation caused a significant delay in tumor growth translating into significantly prolonged survival in clear dependence of the beam collimation setting and margin size. Brain sections revealed tumors of similar appearance and volume on the day of euthanasia. Importantly, the repeated contrast agent injections were well tolerated, as liver enzyme and creatinine serum levels were only subclinically elevated, and liver and kidney sections displayed normal histomorphology.

Purpose: Mimicking state‐of‐the‐art patient radiotherapy with high precision irradiators for small animals allows advanced dose‐effect studies and radiobiological investigations. One example is the implementation of pre‐clinical IMRT‐like irradiations, which requires the development of inverse planning for keV photon beams. As a first step, we present a novel kernel‐based dose calculation engine for keV x‐rays with explicit consideration of energy and material dependencies. Methods: We follow a superposition‐convolution approach adapted to keV x‐rays, based on previously published work on micro‐beam therapy. In small animal radiotherapy, we assume local energy deposition at the photon interaction point, since the electron ranges in tissue are of the same order of magnitude as the voxel size. This allows us to use photon‐only kernel sets generated by MC simulations, which are pre‐calculated for six energy windows and ten base materials. We validate our stand‐alone dose engine against Geant4 MC simulations for various beam configurations in water, slab phantoms with bone and lung inserts, and on a mouse CT with (0.275mm)3 voxels. Results: We observe good agreement for all cases. For field sizes of 1mm2 to 1cm2 in water, the depth dose curves agree within 1% (mean), with the largest deviations in the first voxel (4%) and at depths>5cm (<2.5%). The out‐of‐field doses at 1cm depth agree within 8% (mean) for all but the smallest field size. In slab geometries, the mean agreement was within 3%, with maximum deviations of 8% at water‐bone interfaces. The γ‐index (1mm/1%) passing rate for a single‐field mouse irradiation is 71%. Conclusion: The presented dose engine yields an accurate representation of keV‐photon doses suitable for inverse treatment planning for IMRT. It has the potential to become a significantly faster yet sufficiently accurate alternative to full MC simulations. Further investigations will focus on energy sampling as well as calculation times. Research at ICR is also supported by Cancer Research UK under Programme C33589/A19727 and NHS funding to the NIHR Biomedical Research Centre at RMH and ICR. MFF is supported by Cancer Research UK under Programme C33589/A19908.