Littérature scientifique sur le sujet « Ultra-High dose rate FLASH therapy »

Proton pencil-beam scanning (PBS) Bragg peak FLASH combines ultra-high dose rate delivery and organ-at-risk (OAR) sparing. This proof-of-principle study compared dosimetry and dose rate coverage between PBS Bragg peak FLASH and PBS transmission FLASH in head and neck reirradiation. PBS Bragg peak FLASH plans were created via the highest beam single energy, range shifter, and range compensator, and were compared to PBS transmission FLASH plans for 6 GyE/fraction and 10 GyE/fraction in eight recurrent head and neck patients originally treated with quad shot reirradiation (14.8/3.7 CGE). The 6 GyE/fraction and 10 GyE/fraction plans were also created using conventional-rate intensity-modulated proton therapy techniques. PBS Bragg peak FLASH, PBS transmission FLASH, and conventional plans were compared for OAR sparing, FLASH dose rate coverage, and target coverage. All FLASH OAR V40 Gy/s dose rate coverage was 90–100% at 6 GyE and 10 GyE for both FLASH modalities. PBS Bragg peak FLASH generated dose volume histograms (DVHs) like those of conventional therapy and demonstrated improved OAR dose sparing over PBS transmission FLASH. All the modalities had similar CTV coverage. PBS Bragg peak FLASH can deliver conformal, ultra-high dose rate FLASH with a two-millisecond delivery of the minimum MU per spot. PBS Bragg peak FLASH demonstrated similar dose rate coverage to PBS transmission FLASH with improved OAR dose-sparing, which was more pronounced in the 10 GyE/fraction than in the 6 GyE/fraction. This feasibility study generates hypotheses for the benefits of FLASH in head and neck reirradiation and developing biological models.

FLASH radiotherapy is the delivery of ultra-high dose rate radiation several orders of magnitude higher than what is currently used in conventional clinical radiotherapy, and has the potential to revolutionize the future of cancer treatment. FLASH radiotherapy induces a phenomenon known as the FLASH effect, whereby the ultra-high dose rate radiation reduces the normal tissue toxicities commonly associated with conventional radiotherapy, while still maintaining local tumor control. The underlying mechanism(s) responsible for the FLASH effect are yet to be fully elucidated, but a prominent role for oxygen tension and reactive oxygen species production is the most current valid hypothesis. The FLASH effect has been confirmed in many studies in recent years, both in vitro and in vivo, with even the first patient with T-cell cutaneous lymphoma being treated using FLASH radiotherapy. However, most of the studies into FLASH radiotherapy have used electron beams that have low tissue penetration, which presents a limitation for translation into clinical practice. A promising alternate FLASH delivery method is via proton beam therapy, as the dose can be deposited deeper within the tissue. However, studies into FLASH protons are currently sparse. This review will summarize FLASH radiotherapy research conducted to date and the current theories explaining the FLASH effect, with an emphasis on the future potential for FLASH proton beam therapy.

Abstract FLASH-RT represents a novel therapeutic radiation modality that holds remarkable potential for mitigating radiation therapy's adverse side effects. This cutting-edge technology allows for sparing healthy tissue while precisely targeting cancerous cells. This is possible by administering an ultra-high-dose-rate in less than a few hundred milliseconds. FLASH-RT has demonstrated impressive results in small-animal models, prompting scientists to adapt and advance existing technologies to make it a viable treatment option for humans. However, producing the ultra-high-dose-rate radiation required for the therapy remains a significant challenge. Several radiation sources, such as very high energy electrons (VHEEs), low energy electrons, x-rays, and protons, have been studied for their ability to deliver the necessary dose. Among them, FLASH-x-ray has gained the most attention owing to its capacity to penetrate deep-seated tumors. Despite the complexity of the process, the potential advantages of FLASH-RT made it an exciting area of research. To achieve the FLASH effect, high-frequency, pulsed irradiated accelerator technology can be employed. Sparing healthy tissue may allow for more aggressive and effective cancer treatments, leading to a better quality of life for patients. Ongoing research and development will be necessary to refine and optimize this approach to radiation therapy.

FLASH-radiotherapy (RT) presents great potential as an alternative to conventional radiotherapy methods in cancer treatment. In this paper, we focus on simulation studies for a linear particle accelerator injector design using the ASTRA code, which permits beam generation and particle tracking through electromagnetic fields. Space charge-dominated beams were selected with the aim of providing an optimized generated beam profile and accelerator lattice with minimized emittance. The main results of the electron beam and ultra-high dose rate (UHDR) simulation dosimetry studies are reported for the FLASH mode radiobiological treatment. Results for the percentage depth dose (PDD) at electron beam energies of 5, 7, 15, 25, 50, 100 MeV and 1.2 GeV for Poly-methyl-methacrylate (PMMA) and water phantom vs. the penetration depth are presented. Additionally, the PDD transverse profile was simulated for the above energies, delivering the beam to the phantom. The simulation dosimetry results provide an UHDR electron beam under the conditions of the FLASH-RT. The performance of the beam inside the phantom and the dose depth depends on the linear accelerator beam’s energy and stability.

Abstract Radiation cancer therapy with ultra-high dose rate exposure, so called FLASH radiotherapy, appears to reduce normal tissue damage without compromising tumor response. The aim of this study was to clarify whether FLASH exposure of proton beam would be effective in reducing the DNA strand break induction. We applied a simple model system, pBR322 plasmid DNA in aqueous 1 × TE solution, where DNA single strand breaks (SSBs) and double strand breaks (DSBs) can be precisely quantified by gel electrophoresis. Plasmid DNA were exposed to 27.5 MeV protons in the conventional dose rate of 0.05 Gy/s (CONV) and ultra-high dose rate of 40 Gy/s (FLASH). With both dose rate, the kinetics of the SSB and DSB induction were proportional to absorbed dose. The SSB induction of FLASH was significantly less than CONV, which were 8.79 ± 0.14 (10−3 SSB per Gy per molecule) and 10.8 ± 0.68 (10−3 SSB per Gy per molecule), respectively. The DSB induction of FLASH was also slightly less than CONV, but difference was not significant. Altogether, 27.5 MeV proton beam at 40 Gy/s reduced SSB and not DSB, thus its effect may not be significant in reducing lethal DNA damage that become apparent in acute radiation effect.

The general concept of radiation therapy used in conventional cancer treatment is to increase the therapeutic index by creating a physical dose differential between tumors and normal tissues through precision dose targeting, image guidance, and radiation beams that deliver a radiation dose with high conformality, e.g., protons and ions. However, the treatment and cure are still limited by normal tissue radiation toxicity, with the corresponding side effects. A fundamentally different paradigm for increasing the therapeutic index of radiation therapy has emerged recently, supported by preclinical research, and based on the FLASH radiation effect. FLASH radiation therapy (FLASH-RT) is an ultra-high-dose-rate delivery of a therapeutic radiation dose within a fraction of a second. Experimental studies have shown that normal tissues seem to be universally spared at these high dose rates, whereas tumors are not. While dose delivery conditions to achieve a FLASH effect are not yet fully characterized, it is currently estimated that doses delivered in less than 200 ms produce normal-tissue-sparing effects, yet effectively kill tumor cells. Despite a great opportunity, there are many technical challenges for the accelerator community to create the required dose rates with novel compact accelerators to ensure the safe delivery of FLASH radiation beams.

Bragg peak FLASH-RT can deliver highly conformal treatment and potentially offer improved normal tissue protection for radiotherapy patients. This study focused on developing ultra-high dose rate (≥40 Gy × RBE/s) intensity-modulated proton therapy (IMPT) for hypofractionated treatment of early-stage breast cancer. A novel tracking technique was developed to enable pencil beaming scanning (PBS) of single-energy protons to adapt the Bragg peak (BP) to the target distally. Standard-of-care PBS treatment plans of consecutively treated early-stage breast cancer patients using multiple energy layers were reoptimized using this technique, and dose metrics were compared between single-energy layer BP FLASH and conventional IMPT plans. FLASH dose rate coverage by volume (V40Gy/s) was also evaluated for the FLASH sparing effect. Distal tracking can precisely stop BP at the target distal edge. All plans (n = 10) achieved conformal IMPT-like dose distributions under clinical machine parameters. No statistically significant differences were observed in any dose metrics for heart, ipsilateral lung, most ipsilateral breast, and CTV metrics (p > 0.05 for all). Conventional plans yielded slightly superior target and skin dose uniformities with 4.5% and 12.9% lower dose maxes, respectively. FLASH-RT plans reached 46.7% and 61.9% average-dose rate FLASH coverage for tissues receiving more than 1 and 5 Gy plan dose total under the 250 minimum MU condition. Bragg peak FLASH-RT techniques achieved comparable plan quality to conventional IMPT while reaching adequate dose rate ratios, demonstrating the feasibility of early-stage breast cancer clinical applications.

Recent preclinical evidence has shown that ionizing radiation given at an ultra-high dose rate (UHDR), also known as FLASH radiation therapy (FLASH-RT), can selectively reduce radiation injury to normal tissue while remaining isoeffective to conventional radiation therapy (CONV-RT) with respect to tumor killing. Unresectable pancreatic cancer is challenging to control without ablative doses of radiation, but this is difficult to achieve without significant gastrointestinal toxicity. In this review article, we explore the propsed mechanisms of FLASH-RT and its tissue-sparing effect, as well as its relevance and suitability for the treatment of pancreatic cancer. We also briefly discuss the challenges with regard to dosimetry, dose rate, and fractionation for using FLASH-RT to treat this disease.

Le développement de méthodes innovantes susceptibles de réduire la sensibilité des tissus sains aux radiations, tout en maintenant l'efficacité du traitement sur la tumeur, est un aspect central de l'amélioration de l'efficacité de la radiothérapie pour le traitement du cancer. Parmi les développements et innovations méthodologiques possibles, la combinaison d'une irradiation à ultra-haut débit de dose (FLASH) et d'électrons de très haute énergie (VHEE) pourrait permettre d'exploiter les avantages radiobiologiques de l'effet FLASH pour le traitement des tumeurs profondes. En particulier, les VHEEs dans la gamme d'énergie de 100 à 250 MeV seraient particulièrement intéressants d'un point de vue balistique et biologique pour l'application des irradiations FLASH en radiothérapie. Cette thèse étudie donc l'utilisation possible des VHEEs en radiothérapie et en particulier leur utilisation à ultra-haut débit de dose, évaluant ainsi la faisabilité de la radiothérapie FLASH-VHEE. Bien que prometteuse, plusieurs aspects de cette technique doivent être étudiés avant qu'elle puisse être employée dans un contexte clinique. Une première partie du travail étudie les paramètres de la machine nécessaires pour répondre aux contraintes des irradiations FLASH. À cette fin, un modèle analytique de calcul de la dose basé sur la théorie de la diffusion multiple de Fermi-Eyges a été développé et testé. Ce modèle analytique a également été utilisé pour concevoir et optimiser un système de double diffusion pour la thérapie VHEE et ainsi obtenir des tailles de champ supérieures à 15x15 cm², et pour évaluer la possible adaptation des méthodes de conformation conventionnelles du faisceau de particules pour la thérapie FLASH-VHEE. La deuxième partie de ce travail porte sur la planification du traitement par VHEE et l'évaluation des plans cliniques. Quatre cas cliniques représentatifs ont été étudiés, pour lesquels des plans de traitement par balayage de mini-faisceau (PBS) et par double diffusion (DS) ont été calculés. L'influence de l'énergie du faisceau sur la qualité du plan a été étudiée et les techniques PBS et DS ont été comparées. Une description temporelle de l'irradiation a également été réalisée ainsi que l'incorporation d'un facteur de modification FLASH lors de l'évaluation du plan et de son effet sur les tissus sains en mode FLASH. Enfin, l'estimation des doses liées aux particules secondaires et les questions de radioprotection ont été abordées. Un calcul de la dose secondaire due aux photons de Bremsstrahlung et aux neutrons provenant des deux systèmes de délivrance de la dose a été développé dans l'eau. La dose dues aux particules secondaires reçues par divers organes a également été évaluée dans le cadre de traitements intracrâniens et afin de démontrer l'avantage des faisceaux VHEE par rapport aux faisceaux de protons en terme de dose neutrons hors champ. En résumé, les modèles analytiques accélérés et paramétrés dans cette étude permettent une estimation de la distribution de la dose produite par un système VHEE avec une bonne précision, ce qui fournit des informations importantes pour la conception éventuelle d'un système VHEE. Les résultats de ce travail pourraient soutenir le développement de la radiothérapie FLASH-VHEE
The development of innovative methods capable of reducing the sensitivity of healthy tissue to radiation, while maintaining the effectiveness of the treatment on the tumour, is a central aspect of improving the effectiveness of radiotherapy in the treatment of cancer. Among possible developments and methodological innovations, the combination of ultra-high dose rate irradiation (FLASH) and very high energy electrons (VHEE) could make it possible to exploit the radiobiological advantages of the FLASH effect for the treatment of deep tumours. In particular, VHEEs in the 100 to 250 MeV energy range would be particularly interesting from a ballistic and biological point of view for the application of FLASH irradiation in radiotherapy. This thesis therefore studies the possible use of VHEEs in radiotherapy, and in particular their use at ultra-high dose rates, thus assessing the feasibility of FLASH-VHEE radiotherapy. Although promising, several aspects of this technique need to be studied before it can be used in a clinical context. The first part of this work studies the machine parameters required to meet the constraints of FLASH irradiation. To this end, an analytical model for calculating the dose based on Fermi-Eyges multiple scattering theory was developed and tested. This analytical model has also been used to design and optimise a double-scattering system for VHEE therapy, in order to obtain field sizes greater than 15x15 cm², and to assess the possible adaptation of conventional particle beam conformation methods for FLASH-VHEE therapy. The second part of this work focuses on VHEE treatment planning and the evaluation of clinical plans. Four representative clinical cases were studied, for which pencil-beam scanning (PBS) and double scattering (DS) treatment plans were calculated. The influence of beam energy on plan quality was studied and the PBS and DS techniques were compared. A temporal description of the irradiation was also carried out, as well as the incorporation of a FLASH modification factor when evaluating the plan and its effect on healthy tissue in FLASH mode. Finally, the estimation of doses from secondary particles and radiation protection issues were addressed. A calculation of the secondary dose due to Bremsstrahlung photons and neutrons from the two dose delivery systems was developed in water. The secondary particle dose received by various organs was also assessed in the context of intracranial treatments and in order to demonstrate the advantage of VHEE beams over proton beams in terms of out-of-field neutron dose. In summary, the fast analytical models parameterised in this study allow the dose distribution produced by a VHEE system to be estimated with good accuracy, providing important information for the potential design of a VHEE system. The results of this work could support the development of FLASH-VHEE radiotherapy

A significant portion of cancer patients receive radiotherapy as part of their curative or palliative treatment plan. Radiotherapy is however greatly limited by radiation induced toxicities in healthy tissue surrounding the tumour, which can lead to long-term or acute complications for a patient. In response to this issue, recent studies have considered a new technique called FLASH radiotherapy, where ultra-high dose rates have been shown to effectively reduce toxicity in normal cells whilst maintaining a tumour response equivalent to conventional dose rates. However, the exact mechanism for this effect is not yet well understood. This project seeks to investigate if certain dose delivery patterns exist where there is an increase or reduction of concentration of the toxic radical hydroxyl, which is known to play a key role in the damage of DNA in the cell, for unchanged total dose. This was done by simulating the chemical reactions which take place when water is irradiated with ionizing radiation using a simple model system consisting of water with free oxygen dissolved into it, called RadChemModel. Using basic reaction laws from chemistry, the concentration of each chemical species involved was solved for from a system of linear and non-linear ordinary differential equations. The concentration of hydroxyl was calculated as a function of time for a range of irradiation beam patterns. This model supports that there could be a difference in toxicity between FLASH and conventional beam parameters. Furthermore, a shift in the behaviour of hydroxyl suggesting reduced toxicity was observed at FLASH dose rates with very high beam pulse frequencies. However, the results obtained do not provide enough information to confirm that the concentration of hydroxyl is reduced with FLASH beam parameters.
En stor andel cancerpatienter får strålterapi som läkande eller palliativ behandling. Strålterapi kan ge upphov till allvarliga skador i den friska vävnaden i närheten av tumörområdet. För att förebygga omedelbara så väl som långsiktiga skadliga effekter av strålterapi, har nyligen pulicerade studier undersökt en ny teknik som kallas för FLASH strålterapi. Man har påvisat att ultra-höga doshastigheter kan minska strålskadorna i friska celler samtidigt som tumörkontrollen bevaras. Emellertid finns ännu ingen tillräcklig förklaring för den exakta mekanismen bakom fenomenet. Målet med detta projekt är att undersöka om en ökning eller minskning av koncentrationen hos radikalen hydroxyl, som är känd för att spela en kritisk roll i framkallandet av DNA skador, kunde upptäckas för särskilda doseringsmönster med en oförändrad total dos. Detta studerades med en enkel matematisk modell (RadChemModel) för vatten med upplöst syre. Med denna modell simulerades de kemiska reaktioner som äger rum när vatten bestrålas med joniserande strålning. Från fundamentala kemiska reaktionslagar, kunde koncentrationen av hydroxyl som funktion av tid fås genom att lösa ett system av linjära och icke-linjära ordinära differentialekvationer. Den här modellen visar att det kan finnas en skillnad i strålinducerade skador mellan FLASH och vanlig strålterapi. Resultaten från väldigt höga pulsfrekvenser med FLASH antydde också att mindre hydroxyl producerades och därmed att strålskador kan vara beroende av både doshastighet och pulsfrekvens. Däremot är resultaten inte tillräckliga för bekräfta att koncentrationen av hydroxyl är reducerad för FLASH.

AbstractIn this chapter, we address the role of radiation as treatment modality in the context of oncological treatments given to patients. Physical aspects of the use of ionizing radiation (IR)—by either photons, neutrons, or charged (high linear energy transfer) particles—and their clinical application are summarized. Information is also provided regarding the radiobiological rationale of the use of conventional fractionation as well as alternative fractionation schedules using deviating total dose, fraction size, number of fractions, and the overall treatment time. Pro- and contra arguments of hypofractionation are discussed. In particular, the biological rationale and clinical application of Stereotactic Body Radiation Therapy (SBRT) are described. Furthermore, background information is given about FLASH radiotherapy (RT), which is an emerging new radiation method using ultra-high dose rate allowing the healthy, normal tissues and organs to be spared while maintaining the antitumor effect. Spatial fractionation of radiation in tumor therapy, another method that reduces damage to normal tissue is presented. Normal tissue doses could also be minimized by interstitial or intraluminal irradiation, i.e., brachytherapy, and herein an overview is given on the principles of brachytherapy and its clinical application. Furthermore, details are provided regarding the principles, clinical application, and limitations of boron neutron capture therapy (BNCT). Another important key issue in cancer therapy is the combination of RT with other treatment modalities, e.g., chemotherapy, targeted therapy, immunotherapy, hyperthermia, and hormonal therapy. Combination treatments are aimed to selectively enhance the effect of radiation in cancer cells or to trigger the immune system but also to minimize adverse effects on normal cells. The biological rationale of all these combination treatments as well as their application in clinical settings are outlined. To selectively reach high concentrations of radionuclides in tumor tissue, radioembolization is a highly interesting approach. Also, radioligand therapy which enables specific targeting of cancer cells, while causing minimal harm surrounding healthy tissues is presented. A brief overview is provided on how nanotechnology could contribute to the diagnosis and treatment of cancer. Last but not least, risk factors involved in acquiring secondary tumors after RT are discussed.

Radiation oncology- the branch of medicine that treats cancer by use of ionizing radiations, is an ever-evolving subject. Rapid technological advancements and expansion of scientific knowledge on biology of cancer has brought forth many exciting new techniques in radiotherapy. Here we discuss about three such promising latest advances in the field of radiation oncology. Firstly, we elaborate on MR-LINAC, that integrates Magnetic Resonance Imaging with a medical Linear Accelerator for therapeutic purpose- that enables better adaptation of radiation delivery with change in patient’s anatomy as well as tumor response during treatment. Next, we briefly highlight on FLASH radiotherapy- another novel radiation technique that is still investigational clinically. This technique that uses ultra-high dose rates for radiation delivery, may be a potential game changer to overcome tumor radioresistance. Lastly, we discuss the upcoming technique of Lattice radiation therapy that aims to redefine the conventional norms of dose prescription and distribution for photon beam treatments. These techniques warrant further clinical research and constitute the latest advancements in the field of radiotherapy.

Electron beams used in laser-Compton X-ray sources can be utilized as ultra-high dose rate (UHDR) ionizing radiation sources if the architecture provides sufficient peak current and beam energy. Using a multi-step simulation workflow, we identify commensurate X-ray and electron beam profiles for image-guided UHDR (FLASH) radiotherapy experiments.

We present a straightforward method to generate MeV-ranged high dose-rate electron beams in ambient air through the tight focusing of a mJ-class femtosecond laser. We demonstrate that relativistic intensities are reached through an intensity clamping suppression effect and that the technique is promising for performing FLASH radiation therapy.