In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFβ1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues.Significance: These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.

Ultra-high dose rate FLASH proton radiotherapy (F-PRT) has been shown to reduce normal tissue toxicity compared to standard dose rate proton radiotherapy (S-PRT) in experiments using the entrance portion of the proton depth dose profile, while proton therapy uses a spread-out Bragg peak (SOBP) with unknown effects on FLASH toxicity sparing. To investigate, the biological effects of F-PRT using an SOBP and the entrance region were compared to S-PRT in mouse intestine. In this study, 8–10-week-old C57BL/6J mice underwent 15 Gy (absorbed dose) whole abdomen irradiation in four groups: (1) SOBP F-PRT, (2) SOBP S-PRT, (3) entrance F-PRT, and (4) entrance S-PRT. Mice were injected with EdU 3.5 days after irradiation, and jejunum segments were harvested and preserved. EdU-positive proliferating cells and regenerated intestinal crypts were quantified. The SOBP had a modulation (width) of 2.5 cm from the proximal to distal 90%. Dose rates with a SOBP for F-PRT or S-PRT were 108.2 ± 8.3 Gy/s or 0.82 ± 0.14 Gy/s, respectively. In the entrance region, dose rates were 107.1 ± 15.2 Gy/s and 0.83 ± 0.19 Gy/s, respectively. Both entrance and SOBP F-PRT preserved a significantly higher number of EdU + /crypt cells and percentage of regenerated crypts compared to S-PRT. Moreover, tumor growth studies showed no difference between SOBP and entrance for either of the treatment modalities.

Research efforts in FLASH radiotherapy (FLASH-RT) have increased at an accelerated pace recently. FLASH-RT involves ultra-high dose rates and has been shown to reduce toxicity to normal tissue while maintaining tumor response in preclinical studies when compared to conventional dose rate radiotherapy. The goal of this review is to summarize the studies performed to date with proton, electron, and heavy-ion FLASH-RT, with particular emphasis on the physical aspects of each study and the advantages and disadvantages of each modality. Beam delivery parameters, experimental setup, and the dosimetry tools used are described for each FLASH modality. In addition, modeling efforts and treatment planning for FLASH-RT are discussed along with potential drawbacks when translated into the clinical setting. The final section concludes with further questions that have yet to be answered before safe clinical implementation of FLASH-RT.

Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients’ quality of life. The ability of FLASH proton radiotherapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared with standard proton radiotherapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating radiation-induced salivary gland dysfunction and oral mucositis and controlling orthotopic head and neck tumor growth has not been reported. The head and neck area of C57BL/6 mice was irradiated with a single dose of radiotherapy (ranging from 14–18 Gy) or a fractionated dose of 8 Gy × 3 of F-PRT (128 Gy/second) or S-PRT (0.95 Gy/second). Following irradiation, the mice were studied for radiation-induced xerostomia by measuring their salivary flow. Oral mucositis was analyzed by histopathologic examination. To determine the ability of F-PRT to control orthotopic head and neck tumors, tongue tumors were generated in the mice and then irradiated with either F-PRT or S-PRT. Mice treated with either a single dose or fractionated dose of F-PRT showed significantly improved survival than those irradiated with S-PRT. F-PRT–treated mice showed improvement in their salivary flow. S-PRT–irradiated mice demonstrated increased fibrosis in their tongue epithelium. F-PRT significantly increased the overall survival of the mice with orthotopic tumors compared with the S-PRT–treated mice. The demonstration that F-PRT decreases radiation-induced normal tissue toxicity without compromising tumor control, suggests that this modality could be useful for the clinical management of patients with head and neck cancer.

The Halcyon is Varian’s latest linear accelerator that offers a single 6X flattening-filter-free beam with a jawless design that features a new dual layer multileaf collimator system with faster speed and reduced transmission. Dosimetric characteristics of the dual layer multileaf collimator system including transmission, dosimetric leaf gap, and tongue and groove effects were measured. Ionization chambers, diode arrays, and an electronic portal imaging device were used to measure various multileaf collimator characteristics. Transmission through both multileaf collimator banks was found to be 0.008%, while the distal and proximal banks alone had transmission values of 0.4%. The penumbra was slightly sharper for fields using only the distal multileaf collimator bank but found to be largely independent of leaf position with values between 2.7 to 3.0 mm at d_max for the combined multileaf collimator banks. The dosimetric leaf gap was measured for the proximal and distal multileaf collimator banks both individually and together and found to have values of −0.216 mm, −0.225 mm, and 0.964 mm, respectively. Measurements of dosimetric leaf gap at the leaf edge and midline were also performed. Tongue and groove effects were investigated with both the electronic portal imaging device and a 2-dimensional array of diodes.