It has been postulated that the delivery of radiotherapy at ultra-high dose rates ("FLASH") reduces normal tissue toxicities by depleting them of oxygen. The fraction of normal tissue and cancer cells surviving radiotherapy depends on dose and oxygen levels in an exponential manner and even a very small fraction of tissue at low oxygen levels can determine radiotherapy response. The effect of FLASH on radiation-induced normal and tumour tissue cell killing was studied by simulating oxygen diffusion, metabolism, and radiolytic oxygen depletion over domains with simulated capillary architectures. Two architectural models were used: 1.) randomly distributed capillaries and 2.) capillaries forming a regular square lattice array. The resulting oxygen partial pressure distribution histograms were used to simulate normal and tumour tissue cell survival using the linear quadratic model of cell survival, modified to incorporate oxygen-enhancement ratio (OER) effects. Tumour cell survival was found to be increased by FLASH as compared to conventional radiotherapy, with a 0-1 order of magnitude increase for expected levels of tumour hypoxia, depending on the relative magnitudes of radiolytic oxygen depletion and tissue oxygen metabolism. Interestingly, for the random capillary model, the impact of FLASH on well-oxygenated (normal) tissues was found to be much greater, with an estimated increase in cell survival by up to 10 orders of magnitude, even though reductions in mean tissue partial pressure were modest, less than 7 mmHg for the parameter values studied. The presence of very small nearly hypoxic regions in otherwise well-perfused normal tissues with high mean oxygen levels resulted in a greater proportional sparing of normal tissue than tumour cells during FLASH irradiation, possibly explaining empirical normal tissue sparing and iso-tumour control results.
An in-silico study of conventional and FLASH radiotherapy iso-effectiveness: Radiolytic oxygen depletion and its potential impact on tumor control probability
Purpose: Recent studies suggest ultra-high dose rate (FLASH) irradiation can spare normal tissues from radiotoxicity, while efficiently controlling the tumor, and this is known as the FLASH effect. This study performed theoretical analyses about the impact of radiolytic oxygen depletion (ROD) on the cellular responses after FLASH irradiation. Methods: Monte Carlo simulation was used to model the ROD process, determine the DNA damage, and calculate the amount of oxygen depleted (LROD) during FLASH exposure. A mathematical model was applied to analyze oxygen tension (pO2) distribution in human t…
Recent results from animal irradiation studies have rekindled interest in the potential of ultra-high dose rate irradiation (also known as FLASH) for reducing normal tissue toxicity. However, despite mounting evidence of a "FLASH effect", a mechanism has yet to be elucidated. This article hypothesizes that the radioprotecting effect of FLASH irradiation could be due to the specific sparing of hypoxic stem cell niches, which have been identified in several organs including the bone marrow and the brain. To explore this hypothesis, a new computational model is presented that frames transient rad…
Current Views on Mechanisms of the FLASH Effect in Cancer Radiotherapy
Peking University（北京大学）；the Second Affiliated Hospital of Wenzhou Medical University（温州医科大学附属第二医院）；College of Chemistry and Molecular Engineering, Peking University（北京大学化学与分子工程学院）；Sun Yat-sen University（中山大学）；KIRI Precision Particle Therapy Flash Technologies Research Center（基锐精准粒子治疗闪速技术研究中心）；The University of Hong Kong-Shenzhen Hospital（香港大学深圳医院）
FLASH is a new treatment modality that requires optimization of dose, dose rate, and LET. Here we validate these three quantities under FLASH conditions, which includes the quantum uncertainty in the time-dependent instantaneous dose rate (IDR) curves and LET spectra that underlie the newly proposed integrated optimization framework. Measurements of dose, IDR, and LET were performed at the Emory Proton Therapy Center using a FLASH proton beam with a nominal energy of 250 MeV and a 3D printed ridge filter. Because 3D printing resin is made from a proprietary chemical formula, we developed a met…
Purpose: A Monte Carlo (MC) beam model and its implementation in a clinical treatment planning system (TPS, Varian Eclipse) are presented for a modified ultra-high dose-rate electron FLASH radiotherapy (eFLASH-RT) LINAC. Methods: The gantry head without scattering foils or targets, representative of the LINAC modifications, was modelled in Geant4. The energy spectrum (σE) and beam source emittance cone angle (θcone) were varied to match the calculated and Gafchromic film measured central-axis percent depth dose (PDD) and lateral profiles. Its Eclipse configuration was validated with measured p…
While spatial dose conformity delivered to a target volume has been pushed to its practical limits with advanced treatment planning and delivery, investigations in novel temporal dose delivery are unfolding new mechanisms. Recent advances in ultra-high dose radiotherapy, abbreviated as FLASH, indicate the potential for reduction in healthy tissue damage while preserving tumor control. FLASH therapy relies on very high dose rate of > 40Gy/sec with sub-second temporal beam modulation, taking a seemingly opposite direction from the conventional paradigm of fractionated therapy. FLASH brings uniqu…
Beam monitoring for radiotherapy from conventional to FLASH dose rates using Low Gain Avalanche Silicon detectors
Universidad de Sonora（索诺拉大学）；University of Kansas（堪萨斯大学）；Washington University School of Medicine（华盛顿大学医学院）；Rice University（莱斯大学）；University of Kansas Cancer Center（堪萨斯大学癌症中心）；The University of Texas MD Anderson Cancer Center（德克萨斯大学安德森癌症中心）
We present a microscopic mechanism that accounts for the outward burst of "cold" ion species (IS) in a high-energy particle track due to coupling with ''hot" non-ion species (NIS). IS refers to radiolysis products of ionized molecules, whereas NIS refers to non-ionized excitations of molecules in a medium. The interaction is mediated by a quantized field of acoustic phonons, a channel that allows conversion of thermal energy of NIS to kinetic energy of IS, a flow of heat from the outer to the inner core of the track structure. We demonstrate the coexistence of "hot" NIS with "cold" IS in the r…
Review of oxygen measurement and relevance to the mechanisms of FLASH radiotherapy
Thayer School of Engineering at Dartmouth（达特茅斯学院泰耶尔工程学院）；Giesel School of Medicine at Dartmouth（达特茅斯学院吉塞尔医学院）；University of Wisconsin School of Medicine and Public Health（威斯康星大学医学院和公共卫生学院）
The mechanism responsible for the FLASH effect, normal tissue sparing by ultra-high dose rate (UHDR) irradiation with isoeffective tumor control compared to conventional dose rate (CDR) irradiation, remains undetermined. Here we investigate the contribution of interspur interactions (interactions between radiolytic species of individual particle tracks) to overall radiochemical interactions as a function of irradiation parameters, and suggest an increase in interspur interaction as a potential mechanism for tissue sparing in FLASH radiation therapy. We construct a model that analytically repre…
FLASH radiation has been reported to efficiently suppress tumor growth while sparing normal tissue, however, the mechanism of the differential tissue sparing effect is still not known. Oxygen has long been known to profoundly impact radiobiological responses, and radiolytic oxygen depletion has been considered to be a possible cause or contributor to the FLASH phenomenon. This work investigates the impact of tissue pO2 profiles, oxygen depletion per unit dose (g), and the oxygen concentration yielding half-maximal radiosensitization (k) in tumor and normal tissue. We developed a model that con…
We present a first-principles molecular dynamics (MD) simulation and expound upon a mechanism of oxygen depletion hypothesis to explain the mitigation of normal tissue injury observed in ultra-high-dose-rate (UHDR) FLASH radiotherapy. We simulated damage to a segment of DNA (also representing other bio-molecules such as RNA and proteins) in a simulation box filled with H$_2$O and O$_2$ molecules. Attoseconds physical interactions (ionizations, electronic and vibrational excitations) were simulated by using the Monte Carlo track structure code Geant4-DNA. Immediately after ionization, {\it ab i…
Purpose: To investigate experimentally, if FLASH irradiation depletes oxygen within water for different radiation types such as photons, protons and carbon ions. Methods: This study presents measurements of the oxygen consumption in sealed, 3D printed water phantoms during irradiation with X-rays, protons and carbon ions at varying dose rates up to 340 Gy/s. The oxygen measurement was performed using an optical sensor allowing for non-invasive measurements. Results: Oxygen consumption in water only depends on dose, dose rate and linear energy transfer (LET) of the irradiation. The total amount…
