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

Abstract

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.

LhARA: The Laser-hybrid Accelerator for Radiobiological Applications

“…Extending the range of beam characteristics used in PBT delivery may have significant therapeutic benefits. Delivery of RT at high dose rates has led to noticeably reduced lung fibrosis in mice, reduced skin toxicity in mini-pigs, and reduced side-effects in cats with nasal squamous-cell carcinoma, effects currently thought to be mediated via local oxygen depletion [10,27]. In fact, the first patient with CD30 + T-cell cutaneous lymphoma has been safely treated with electrons delivered at FLASH dose rates [28].…”

“…PBT today is routinely delivered in fractions of ∼ 2 Gy per day over several weeks; each fraction being delivered at a rate of < ∼ 5 Gy/min deposited uniformly over the target treatment volume. There is evidence of therapeutic benefit when dose is delivered at ultrahigh rate, > ∼ 40 Gy/s, in "FLASH" RT [6][7][8][9][10] or when multiple micro-beams with diameter <1 mm distributed over a grid with inter-beam spacing ∼ 3 mm are used [11][12][13][14][15][16]. However, the radiobiological mechanisms by which the therapeutic benefit is generated using these approaches are not entirely understood.…”

Immunomodulatory Effects of Radiotherapy

“…In fact, multiple studies have found that FLASH therapy can deplete local oxygen and induce a short-lived protective hypoxic environment within normal healthy tissues that increases radioresistance. FLASH therapy may also modulate immune responses, which could contribute to its effect, but this needs more research [105]. FLASH-RT may directly affect immune cells or indirectly influence the tumor microenvironment.…”

Solving the Issue of Ionizing Radiation Induced Neurotoxicity by Using Novel Cell Models and State of the Art Accelerator Facilities

“…Montay-Gruel et al [205] demonstrated that spatial memory of mice is preserved after 10 Gy FLASH-whole-brain irradiation with mean dose rates above 100 Gy/s, whereas 10 Gy whole-brain irradiation at a conventional dose rate (0.1 Gy/s) impairs spatial memory [105]. Due to the limited number of suitable accelerator facilities providing the necessary technology to perform FLASH irradiations [106] and the lack of suitable human biological models, studies regarding FLASH radiotherapy are rare and translation to the clinics remains a challenge. High throughput, organoid based studies could shed light on the molecular mechanisms of the observed effects, particularly the contribution of hypoxia, and overcome these challenges.…”