Translational Research in FLASH Radiotherapy—From Radiobiological Mechanisms to In Vivo Results

Marcu, Loredana G.; Bezak, Eva; Peukert, Dylan; Wilson, Puthenparampil

doi:10.3390/biomedicines9020181

Cited by 28 publications

(34 citation statements)

References 58 publications

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“…Strikingly, FLASH irradiation (intra-pulse dose rates of ~10 6 -10 7 Gy/s with mean values in excess of 40-100 Gy/s) spares the surrounding healthy tissue while maintaining the same anti-tumor activity compared to conventional-dose-rate radiotherapy (~0.03 Gy/s) as shown in several animal model and pre-clinical studies (for reviews, see refs. [45][46][47][48][49]. Moreover, a recent first human patient treatment with FLASH-RT 50 has demonstrated that this technique may be transferable to the clinic.…”

Section: The Flash Effectmentioning

confidence: 99%

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Generation of ultrafast, transient, highly acidic pH spikes in the radiolysis of water at very high dose rates: relevance for FLASH radiotherapy

et al. 2022

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Monte Carlo multi-track chemistry simulations were carried out to study the effects of high dose rates on the transient yields of hydronium ions (H3O+) formed during low linear energy transfer (LET) radiolysis of both pure, deaerated and aerated liquid water at 25 °C, in the interval ~1 ps–10 μs. Our simulation model consisted of randomly irradiating water with N interactive tracks of 300-MeV incident protons (LET ~ 0.3 keV/μm), which simultaneously impact perpendicularly on the water within a circular surface. The effect of the dose rate was studied by varying N. Our calculations showed that the radiolytic formation of H3O+ causes the entire irradiated volume to temporarily become very acidic. The magnitude and duration of this abrupt “acid-spike” response depend on the value of N. It is most intense at times less than ~10–100 ns, equal to ~3.4 and 2.8 for N = 500 and 2000 (i.e., for dose rates of ~1.9 × 109 and 8.7 × 109 Gy/s, respectively). At longer times, the pH gradually increases for all N values and eventually returns to the neutral value of seven, which corresponds to the non-radiolytic, pre-irradiation concentration of H3O+. It is worth noting that these early acidic pH responses are very little dependent on the presence or absence of oxygen. Finally, given the importance of pH for many cellular functions, this study suggests that these acidic pH spikes may contribute to the normal tissue-sparing effect of FLASH radiotherapy.

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Section: The Flash Effectmentioning

confidence: 99%

“…(70) FLASH-RT has become a hot topic in radiotherapy. The field has grown very quickly and several promising explanations of FLASH have been proposed (for a recent review, see, for example, ref 49…”

mentioning

confidence: 99%

Generation of ultrafast, transient, highly acidic pH spikes in the radiolysis of water at very high dose rates: relevance for FLASH radiotherapy

et al. 2022

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“…The two main variants of SFRT with photons that have been studied and implemented include GRID radiotherapy (GRID RT) and lattice radiotherapy (LRT)—a 3D configuration of GRID, delivering spherical subvolumes of a high dose within the tumour. Ultra-high-dose-rate methods, including FLASH and microbeam radiotherapy, and LRT are beyond the scope of this review and can be found elsewhere in the literature [ 2 , 10 , 31 , 38 , 39 , 40 ].…”

Section: Preclinical and Clinical Evidence With Spatially Fractionate...mentioning

confidence: 99%

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy

Moghaddasi

Reid²,

Bezak

et al. 2022

IJMS

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The continuously evolving field of radiotherapy aims to devise and implement techniques that allow for greater tumour control and better sparing of critical organs. Investigations into the complexity of tumour radiobiology confirmed the high heterogeneity of tumours as being responsible for the often poor treatment outcome. Hypoxic subvolumes, a subpopulation of cancer stem cells, as well as the inherent or acquired radioresistance define tumour aggressiveness and metastatic potential, which remain a therapeutic challenge. Non-conventional irradiation techniques, such as spatially fractionated radiotherapy, have been developed to tackle some of these challenges and to offer a high therapeutic index when treating radioresistant tumours. The goal of this article was to highlight the current knowledge on the molecular and radiobiological mechanisms behind spatially fractionated radiotherapy and to present the up-to-date preclinical and clinical evidence towards the therapeutic potential of this technique involving both photon and proton beams.

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“…X-ray microbeams of average 100 KeV beam energy (spectrum 50–600 keV) are delivered at dose rates of 10 4 Gy/s up to 16 kGy/s [ 43 , 44 ]. Such dose rates trigger FLASH effects that confer additional biological benefits [ 45 ]. The biological FLASH effect was found to be reproducible when the whole dose of radiation is delivered in less than 200 milliseconds [ 46 ].…”

Section: Melanoma and Radiation Therapymentioning

confidence: 99%

Microbeam Radiotherapy—A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma

Trappetti

Fazzari

Fernández-Palomo

et al. 2021

IJMS

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Melanoma is the deadliest type of skin cancer, due to its invasiveness and limited treatment efficacy. The main therapy for primary melanoma and solitary organ metastases is wide excision. Adjuvant therapy, such as chemotherapy and targeted therapies are mainly used for disseminated disease. Radiotherapy (RT) is a powerful treatment option used in more than 50% of cancer patients, however, conventional RT alone is unable to eradicate melanoma. Its general radioresistance is attributed to overexpression of repair genes in combination with cascades of biochemical repair mechanisms. A novel sophisticated technique based on synchrotron-generated, spatially fractionated RT, called Microbeam Radiation Therapy (MRT), has been shown to overcome these treatment limitations by allowing increased dose delivery. With MRT, a collimator subdivides the homogeneous radiation field into an array of co-planar, high-dose microbeams that are tens of micrometres wide and spaced a few hundred micrometres apart. Different preclinical models demonstrated that MRT has the potential to completely ablate tumours, or significantly improve tumour control while dramatically reducing normal tissue toxicity. Here, we discuss the role of conventional RT-induced immunity and the potential for MRT to enhance local and systemic anti-tumour immune responses. Comparative gene expression analysis from preclinical tumour models indicated a specific gene signature for an ‘MRT-induced immune effect’. This focused review highlights the potential of MRT to overcome the inherent radioresistance of melanoma which could be further enhanced for future clinical use with combined treatment strategies, in particular, immunotherapy.

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Translational Research in FLASH Radiotherapy—From Radiobiological Mechanisms to In Vivo Results

Cited by 28 publications

References 58 publications

Generation of ultrafast, transient, highly acidic pH spikes in the radiolysis of water at very high dose rates: relevance for FLASH radiotherapy

Generation of ultrafast, transient, highly acidic pH spikes in the radiolysis of water at very high dose rates: relevance for FLASH radiotherapy

Radiobiological and Treatment-Related Aspects of Spatially Fractionated Radiotherapy

Microbeam Radiotherapy—A Novel Therapeutic Approach to Overcome Radioresistance and Enhance Anti-Tumour Response in Melanoma

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