(P003) Delivery of Ultra-Rapid Flash Radiation Therapy and Demonstration of Normal Tissue Sparing After Abdominal Irradiation of Mice

Loo, Billy W.; Schüler, Emil; Lartey, Frederick M.; Rafat, Marjan; King, Gregory J.; Trovati, Stefania; Koong, Albert C.; Maxim, Peter G.

doi:10.1016/j.ijrobp.2017.02.101

Cited by 103 publications

(92 citation statements)

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“…Thus, FLASH may be able to disrupt and bypass ROS-mediated pathogenic cascades that normally lead to neurocognitive complications and associated pathology typically found after CONV irradiation of the brain. The absence of normal tissue toxicity observed after FLASH irradiation and reported here corroborates recent and older work from our laboratories and others on the normal brain, lung, skin, and gut (18,19,23,24) and, as recently reviewed (25), point to the general applicability of FLASH irradiation to avoid normal tissue injury. Normal tissue sparing reported here is especially relevant in the context of current treatment regimens for adult and pediatric brain tumors that elicit significant toxicities that negatively impact patient care and quality of life (5,26).…”

Section: Discussionsupporting

confidence: 91%

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species

Montay‐Gruel

Acharya

Petersson

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

349

414

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Here, 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.ultra-high dose-rate irradiation | cognitive dysfunction | neuronal morphology | neuroinflammation | reactive oxygen species R adiation therapy (RT) remains an essential part of cancer treatment, and, today, the benefit of RT would increase dramatically if normal tissues surrounding the tumor could tolerate higher doses of radiation (1-3). In the last decade, major advances in high-precision treatment delivery and multimodal imaging have improved tolerance to RT (4), but the selective protection of normal tissue remains a significant clinical challenge and the radiation-induced toxicities still adversely impact the patient's quality of life. This latter fact largely remains an unmet medical need, and points to the urgency of developing improved RT modalities for combating those cancers refractory to treatment.This issue is especially critical for those afflicted with brain tumors, including glioblastoma multiforme (GBM), for which standard treatment consists of surgical resection followed by RT and concomitant chemotherapy (temozolomide). Typical radiotherapeutic protocols for GBM induce neurocognitive complications, including impairments in learning and memory, attention, and executive function and a variety of mood disorders (5-8). A breadth of past work from our laboratories has linked adverse neurocognitive outcomes following cranial irradiation to a range of neuropathologies, including reductions in dendritic complexity and spine density (9-12), reductions in microvascular density (13-15), reduced myelination and synapse density, and increased neuroinflammation (16,17). These changes are persistent and problematic in the conventionally irradiated brain and have prompted efforts to more fully develop a truly innovative approach to RT, where we have concept...

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Section: Discussionsupporting

confidence: 91%

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species

Montay‐Gruel

Acharya

Petersson

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

349

414

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“…Limiting the induction of toxicities to normal tissue would subsequently increase the therapeutic index of RT regimes (7). A number of recent studies have demonstrated that irradiation at ultra-high dose rates (FLASH) diminishes the severity of toxicities in normal tissues compared to irradiation at the conventional dose rates (CONV) currently used in clinical practice (8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18). Notably, limited data also shows that FLASH-RT reduces normal tissue toxicities whilst maintaining the anti-tumor response of CONV-RT (8-10, 15, 17, 19).…”

Section: Introductionmentioning

confidence: 99%

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

et al. 2020

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Radiotherapy is a cornerstone of both curative and palliative cancer care. However, radiotherapy is severely limited by radiation-induced toxicities. If these toxicities could be reduced, a greater dose of radiation could be given therefore facilitating a better tumor response. Initial pre-clinical studies have shown that irradiation at dose rates far exceeding those currently used in clinical contexts reduce radiation-induced toxicities whilst maintaining an equivalent tumor response. This is known as the FLASH effect. To date, a single patient has been subjected to FLASH radiotherapy for the treatment of subcutaneous T-cell lymphoma resulting in complete response and minimal toxicities. The mechanism responsible for reduced tissue toxicity following FLASH radiotherapy is yet to be elucidated, but the most prominent hypothesis so far proposed is that acute oxygen depletion occurs within the irradiated tissue. This review examines the tissue response to FLASH radiotherapy, critically evaluates the evidence supporting hypotheses surrounding the biological basis of the FLASH effect, and considers the potential for FLASH radiotherapy to be translated into clinical contexts.

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“…8 Using electron or photon RT, FLASH dose rateedependent normal tissue radioprotection has been demonstrated for functional and pathophysiologic outcomes in brain, lung, bowel, and skin. 1,4,[9][10][11][12][13] Although normal tissues are protected by FLASH RT, studies of orthotopic lung and ectopic head and neck cancers demonstrated no evidence of FLASH radioprotection. 1,4,14 In terms of dose rate thresholds, electron RT >60 Gy/s demonstrated complete or nearly complete protection against cognitive decline induced by 10 Gy whole brain irradiation in mice.…”

Section: Introductionmentioning

confidence: 99%

Design, Implementation, and in Vivo Validation of a Novel Proton FLASH Radiation Therapy System

Diffenderfer

Verginadis

Kim

et al. 2020

International Journal of Radiation Oncology*Biology*Physics

291

370

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In this article, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with CT guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. Purpose: Recent studies suggest that ultrahigh-dose-rate, "FLASH," electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection. Methods and Materials: Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup. Real-time dose rate was obtained using a NaI detector to measure prompt gamma rays. The effect of FLASH versus standard dose rate PRT on tumors and normal tissues was measured using pancreatic flank tumors (MH641905) derived from the KPC autochthonous PanCa model in syngeneic C57BL/6J mice with analysis of fibrosis and stem cell repopulation in small intestine after abdominal irradiation.

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(P003) Delivery of Ultra-Rapid Flash Radiation Therapy and Demonstration of Normal Tissue Sparing After Abdominal Irradiation of Mice

Cited by 103 publications

References 0 publications

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species

Long-term neurocognitive benefits of FLASH radiotherapy driven by reduced reactive oxygen species

Ultra-High Dose Rate (FLASH) Radiotherapy: Silver Bullet or Fool's Gold?

Design, Implementation, and in Vivo Validation of a Novel Proton FLASH Radiation Therapy System

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