Is Mini Beam Ready for Human Trials? Results of Randomized Study of Treating De-Novo Brain Tumors in Canines Using Linear Accelerator Generated Mini Beams

Abstract

The main challenge in treating malignant brain neoplasms lies in eradicating the tumor while minimizing treatment-related damage. Conventional radiation treatments are associated with considerable side effects. Synchrotron generated micro-beam radiation (SMBRT) has shown to preserve brain architecture while killing tumor cells, however physical characteristics and limited facility access restrict its use. We have created a new clinical device which produces mini beams on a linear accelerator, to provide a new type of treatment called mini-beam radiation therapy (MBRT). The objective of this study is to compare the treatment outcomes of linear accelerator based MBRT versus standard radiation treatment (SRT), to evaluate the tumor response and the treatment-related changes in the normal brain with respect to each treatment type. Pet dogs with de-novo brain tumors were accrued for treatment. Dogs were randomized between standard fractionated stereotactic (9 Gy in 3 fractions) radiation treatment vs. a single fraction of MBRT (26 Gy mean dose). Dogs were monitored after treatment for clinical assessment and imaging. When the dogs were euthanized, a veterinary pathologist assessed the radiation changes and tumor response. We accrued 16 dogs, 8 dogs in each treatment arm. In the MBRT arm, 71% dogs achieved complete pathological remission. The radiation-related changes were all confined to the target region. Structural damage was not observed in the beam path outside of the target region. In contrast, none of the dogs in control group achieved remission and the treatment related damage was more extensive. Therapeutic superiority was observed with MBRT, including both tumor control and the normal structural preservation. The MBRT findings are suggestive of an immune related mechanism which is absent in standard treatment. These findings together with the widespread availability of clinical linear accelerators make MBRT a promising research topic to explore further treatment and clinical trial opportunities.

Spatially fractionated radiation therapy: a critical review on current status of clinical and preclinical studies and knowledge gaps

“…Thereby, the superior tumor control in MRT can be challenged as due to a much higher integral dose than in standard RT. Most of the studies targeted brain tumors with a few experiments irradiating mouse melanoma Although MRT and MBRT are still in the preclinical stage, some recent veterinary clinical trials have been carried out with excellent results (Adam et al 2022, Kundapur et al 2022. A recent publication reports the shortterm results of the first MRT treatment of a dog with spontaneous glioma.…”

“…MRT and MBRT are still in the preclinical stage. The favorable preclinical data (Prezado 2022) along with the successful veterinary trials of de novo gliomas in dogs (Kundapur et al 2022) encourage the preparation of clinical trials in these two techniques. A detailed overview, including historical perspective about the different techniques can be found in the recent review by Prezado et al (Prezado 2022).…”

Development and characterization of a versatile mini‐beam collimator for pre‐clinical photon beam irradiation

“…Thereby, it was possible to show high normal brain tissue tolerance to several hundred Grays. [3][4][5] At the same time, significant tumor growth control could be achieved.The mechanism behind this so-called "mini-beam effect" is, however, not yet fully understood. Theories on the influence of the immune system, the abscopal effect, the vascular effect, or a combination of all three were already considered.…”

“…First applied using synchrotron radiation, mini‐beam irradiation introduces adjacent high‐dose and low‐dose regions in the target area referring to peaks and valleys, respectively. Thereby, it was possible to show high normal brain tissue tolerance to several hundred Grays 3–5 . At the same time, significant tumor growth control could be achieved.…”

Novel unconventional radiotherapy techniques: Current status and future perspectives – Report from the 2nd international radiation oncology online seminar

“…Firstly, the patterns of peak-and-valleys are not dependent on the cardio synchronous pulsations, and the technique could be implemented into conventional and low-cost equipment [117]. In addition, MBRT is not limited to the use of low energy X-rays beams but it can be implemented with higher energy X-rays [118], protons [119], carbon [120] and some other heavier ions [121]. The excellent results (71 % pathological complete remission without toxicity) of the first de novo brain tumor dog MBRT trial [122] opens the door to the transition towards clinical trials.…”