FLASH Proton Pencil Beam Scanning Irradiation Minimizes Radiation-Induced Leg Contracture and Skin Toxicity in Mice

Abstract

Ultra-high dose rate radiation has been reported to produce a more favorable toxicity and tumor control profile compared to conventional dose rates that are used for patient treatment. So far, the so-called FLASH effect has been validated for electron, photon and scattered proton beam, but not yet for proton pencil beam scanning (PBS). Because PBS is the state-of-the-art delivery modality for proton therapy and constitutes a wide and growing installation base, we determined the benefit of FLASH PBS on skin and soft tissue toxicity. Using a pencil beam scanning nozzle and the plateau region of a 250 MeV proton beam, a uniform physical dose of 35 Gy (toxicity study) or 15 Gy (tumor control study) was delivered to the right hind leg of mice at various dose rates: Sham, Conventional (Conv, 1 Gy/s), Flash60 (57 Gy/s) and Flash115 (115 Gy/s). Acute radiation effects were quantified by measurements of plasma and skin levels of TGF-β1 and skin toxicity scoring. Delayed irradiation response was defined by hind leg contracture as a surrogate of irradiation-induced skin and soft tissue toxicity and by plasma levels of 13 different cytokines (CXCL1, CXCL10, Eotaxin, IL1-beta, IL-6, MCP-1, Mip1alpha, TNF-alpha, TNF-beta, VEGF, G-CSF, GM-CSF and TGF- β1). Plasma and skin levels of TGF-β1, skin toxicity and leg contracture were all significantly decreased in FLASH compared to Conv groups of mice. FLASH and Conv PBS had similar efficacy with regards to growth control of MOC1 and MOC2 head and neck cancer cells transplanted into syngeneic, immunocompetent mice. These results demonstrate consistent delivery of FLASH PBS radiation from 1 to 115 Gy/s in a clinical gantry. Radiation response following delivery of 35 Gy indicates potential benefits of FLASH versus conventional PBS that are related to skin and soft tissue toxicity.

Quantitative Assessment of 3D Dose Rate for Proton Pencil Beam Scanning FLASH Radiotherapy and Its Application for Lung Hypofractionation Treatment Planning

“…The duration of each spot is at an order of magnitude ~10 −3 s, the radiation-induced events like the DNA damage begin over a time scale of 10 −12 –10 −7 s [ 44 , 45 ], the rapid consumption of local oxygen occurs on the scale of 10 −3 s [ 46 ], and oxygen diffusion in a time-scale of ~10 −2 s [ 47 ]. Different researchers have proposed that either the mean dose rate over the entire field delivery time [ 12 , 22 , 24 ] or the instantaneous dose rate of the pulse [ 21 ] is more relevant to the FLASH sparing effect based on their understanding of the currently available experimental data. DADR and DTDR, using the instantaneous dose rate, ignore the dwelling time of spots and scanning time between spots which may overestimate the dose–rate effect.…”

“…More recently, researchers from the University of Pennsylvania reported their FLASH progress on an IBA proton system, where a dose rate > 100 Gy/s was reached on a small animal radiation therapy platform via scattering systems [ 11 ]. The effects of FLASH irradiation using pencil beam scanning (PBS) proton irradiation in a Varian ProBeam system were then reported by Cunningham et al [ 12 ].…”

Intensity Modulated Proton Beam Therapy versus Volumetric Modulated Arc Therapy for Patients with Nasopharyngeal Cancer: A Propensity Score-Matched Study

“…RD caused physical, emotional, and functional discomfort that impaired patients’ QoL, with pronounced effects in high-grade dermatitis [ 29 ]. Although all RD healed after intensive interventions in this study, further proton therapy studies should focus on reducing RD [ 30 ].…”

Models for Translational Proton Radiobiology—From Bench to Bedside and Back

“…Using clinically relevant settings is crucial in developing protocols that reduce normal tissue complications. Amongst others, this includes the development of proton minibeam therapy [28,29] and proton FLASH irradiation [50,57,218,219]. Further studies on normal tissue toxicities have focused on processes, such as the peripheral inflammatory response [220], radiation-induced thoracic injuries [19,221], radiation-induced abdominal injury [207,222], as well as tumor incidence after irradiation of a healthy brain [223] and dorsal skin [224].…”

“…This research is especially interesting for preclinical studies with proton FLASH irradiation, which promises normal tissue protection at unvarying tumor control rates. Indeed, two recent studies could prove this effect in C57BL/6 mice [218,219]. Moreover, this valuable preclinical research has already culminated in the first feasibility study of proton FLASH irradiation in patients [240].…”