First Evaluation of Temporal and Spatial Fractionation in Proton Minibeam Radiation Therapy of Glioma-Bearing Rats

Abstract

(1) Background: Proton minibeam radiation therapy (pMBRT) is a new radiotherapy technique using spatially modulated narrow proton beams. pMBRT results in a significantly reduced local tissue toxicity while maintaining or even increasing the tumor control efficacy as compared to conventional radiotherapy in small animal experiments. In all the experiments performed up to date in tumor bearing animals, the dose was delivered in one single fraction. This is the first assessment on the impact of a temporal fractionation scheme on the response of glioma-bearing animals to pMBRT. (2) Methods: glioma-bearing rats were irradiated with pMBRT using a crossfire geometry. The response of the irradiated animals in one and two fractions was compared. An additional group of animals was also treated with conventional broad beam irradiations. (3) Results: pMBRT delivered in two fractions at the biological equivalent dose corresponding to one fraction resulted in the highest median survival time, with 80% long-term survivors free of tumors. No increase in local toxicity was noted in this group with respect to the other pMBRT irradiated groups. Conventional broad beam irradiations resulted in the most severe local toxicity. (4) Conclusion: Temporal fractionation increases the therapeutic index in pMBRT and could ease the path towards clinical trials.

Preclinical dosimetry in proton minibeam radiation therapy: Robustness analysis and guidelines

“…The increase or reduction of peak and valley doses also plays a crucial role in the normal tissue sparing, especially valley doses since strong indications suggest that these low‐dose regions are responsible for the preservation of normal tissue architecture and survival of progenitor cells 5 . In addition, an undesirable variation in the absolute dose may also affect the comparison of pMBRT with conventional broad beam PT since the average dose of lateral profiles is used as the dose prescription parameter in previous and current preclinical trials 21 . A displacement of the profile caused by the variation of some of the parameters studied may also affect the overall response of animals to treatments since normal tissue volumes and tumors may be irradiated or underirradiated, respectively, which is especially relevant in pMBRT due to the high doses employed.…”

“…5,12 pMBRT has shown a significant reduction in neurotoxicity in both brain [13][14][15] and skin 16,17 and an equivalent or superior tumor control, as compared to standard proton therapy (PT) in glioma-bearing rats. [18][19][20][21] The widening of the therapeutic window provided by pMBRT has raised interest in initiating preclinical investigations at several centers worldwide. Along this line, robust and reproducible dosimetry for preclinical trials is crucial to reliably correlate the physical quantities that characterize pMBRT dose distributions and biological endpoints.…”

Proton Minibeam Radiation Therapy and Arc Therapy: Proof of Concept of a Winning Alliance

“…Further evaluations considering more complex geometries and tumor types are needed to assess in depth the benefits of pMBAT. Finally, pMBAT could be implemented using technologies and protocols similar to those already implemented at our institution for pre-clinical trials in pMBRT [ 39 ].…”

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy

“…The results are even more remarkable considering that these results were obtained after a single fraction delivery of a highly heterogeneous dose. The impact of temporal fractionation was also evaluated in a subsequent study, where the initial radiation dose was administered in two fractions having the same biologically equivalent dose as the single fraction [ 101 ]. This resulted in 83% tumour-free long-term survival, which is 2.2-times higher than the survivals in the single-dose group and 3.3-times higher than the percentage of long-term survival after conventional proton irradiation, showing that temporal fractionation can further widen the therapeutic index of proton minibeam therapy in aggressive tumours.…”