FLASH Radiotherapy: Electron-beam FLASH

Summary/Conclusion

Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.

Summary/Conclusion

This is the first study to demonstrate the physical and biological effects of FLASH RT achieved with a FLASH Mobetron unit. Two independent institutions were able to demonstrate similar biological sparing effects resulting from high-dose, single-fraction abdominal irradiation delivered with FLASH RT versus CONV RT. The FLASH Mobetron was available to both institutions, and the beam parameters used were nearly identical. The most striking finding was that, despite differences in selected endpoints and in euthanasia criteria, both institutions found that FLASH RT produced significantly different responses than CONV RT. When comparing to and including previously published literature using similar endpoints and with similar irradiation beam parameters but on different irradiation units, we can show that the FLASH effect is robust and reproducible regardless of the unit used, as long as the same set of beam parameters are used.

Summary/Conclusion

The BCTs were implemented and validated on a pulsed electron beam medical LINAC, thus improving current dosimetric procedures and allowing for a more complete analysis of beam characteristics. BCTs were shown to be a valid method for beam monitoring for UHDR (and therefore FLASH) experiments.

Summary/Conclusion

The dual BCT system integrated within the FLASH Mobetron was shown to be a reliable monitoring system able to quantify accelerator performance and capture all essential physical beam parameters on a pulse-by-pulse basis, and the ratio between the two BCTs was strongly correlated with beam energy. The fast signal readout and processing enables the BCTs to provide real-time information on beam output and energy and is proposed as a system suitable for accurate beam monitoring and control of eFLASH beams.

Summary/Conclusion

The Mobetron device was evaluated with electron beams of 9 MeV in conventional (CONV) mode and of 6 and 9 MeV in UHDR mode (nominal energy). The acceptance was performed according to the acceptance protocol of the company. The commissioning consisted of determining the short- and long-term stability of the device, the measurement of percent depth dose curves (PDDs) and profiles at two different positions (with two different dose per pulse regimen) and for different collimator sizes, and the evaluation of the variability of these parameters when changing the pulse width and pulse repetition frequency. Measurements were performed using a redundant and validated dosimetric strategy with alanine and radiochromic films, as well as Advanced Markus ionization chamber for some measurements.

Summary/Conclusion

When compared to conventional radiotherapy (RT) in pre-clinical studies, FLASH-RT was shown to reproducibly spare normal tissues, while preserving the anti-tumor activity. This marked increase of the differential effect between normal tissues and tumors prompted its clinical translation. In this context, we present here the treatment of a first patient with FLASH-RT.

Summary/Conclusion

We highlight the potential translational benefits of delivering FLASH radiotherapy using ultra-high dose rates (>100 Gy·s−1). Compared with conventional dose-rate (CONV; 0.07–0.1 Gy·s−1) modalities, we showed that FLASH did not cause radiation-induced deficits in learning and memory in mice. Moreover, 6 months after exposure, CONV caused permanent alterations in neurocognitive end points, whereas FLASH did not induce behaviors characteristic of anxiety and depression and did not impair extinction memory.

Mechanistic investigations showed that increasing the oxygen tension in the brain through carbogen breathing reversed the neuroprotective effects of FLASH, while radiochemical studies confirmed that FLASH produced lower levels of the toxic reactive oxygen species hydrogen peroxide. In addition, FLASH did not induce neuroinflammation, a process described as oxidative stress-dependent, and was also associated with a marked preservation of neuronal morphology and dendritic spine density. The remarkable normal tissue sparing afforded by FLASH may someday provide heretofore unrealized opportunities for dose escalation to the tumor bed, capabilities that promise to hasten the translation of this groundbreaking irradiation modality into clinical practice.

Summary/Conclusion

This study shows for the first time that normal brain tissue toxicities after WBI can be reduced with increased dose rate. Spatial memory is preserved after WBI with mean dose rates above 100 Gy/s, whereas 10 Gy WBI at a conventional radiotherapy dose rate (0.1 Gy/s) totally impairs spatial memory.

Summary/Conclusion

Pulsed irradiation (FLASH) was performed using the 4.5 MeV linear electron accelerator (LINAC) described in (34). The system allows exposure of cells or animals to a single submicrosecond pulse, to any sequence of pulses, or to split-dose irradiation with an interval between fractions ranging from fractions of seconds to a few minutes.