Search Results (24)

Background/Objectives: Proton therapy has emerged as an advanced radiotherapy modality due to its unique physical dose distribution and its distinct radiobiological properties. The finite range of protons in tissue enables highly conformal dose delivery with minimal exit dose, significantly reducing irradiation of surrounding normal tissues compared to photon-based radiotherapy. Beyond these physical advantages, proton beams exhibit a spatially varying linear energy transfer that increases toward the distal edge of the spread-out Bragg peak, leading to clustered and complex DNA damage that is more difficult for cancer cells to repair. Methods: This review integrates experimental, computational, and clinical evidence to examine how proton-induced DNA damage, relative biological effectiveness, oxygen effects, and non-targeted responses contribute to tumor control and normal tissue sparing. Results: Comparative analyses with photon intensity-modulated radiotherapy demonstrate consistent reductions in acute and late toxicities across multiple tumor sites, particularly in pediatric patients and in tumors located near critical organs. The review also discusses emerging technologies, including pencil beam scanning, image-guided and adaptive proton therapy, compact accelerator systems, and ultra-high dose rate FLASH proton therapy, which collectively aim to enhance treatment precision, biological effectiveness, and accessibility. Conclusions: Together, these developments support proton therapy as a rapidly evolving modality with significant potential to improve therapeutic outcomes in modern oncology. Full article

Background/Objectives: The PEER beamline at the ANSTO Australian Synchrotron has been developed to enable VHEE FLASH radiotherapy studies, both dosimetric and biological. Featuring a 100 MeV electron linac, it delivers single or multi-pulse irradiations consisting of 100 ps bunches with a 2 ns spacing, resulting in average dose-rates and instantaneous dose-rates as high as ${10}^8$ Gy/s and ${10}^9$ Gy/s, respectively. Much work has been conducted to realise a stable accelerator facility, complete with the tooling and diagnostics required to undertake such studies. However, to truly confirm its suitability required a successful biological benchmarking. Methods: Three cell lines were irradiated utilising real-time dosimetry to compare linear quadratic cell survival curves with other facilities. Also, mouse cadavers were transported and irradiated, mimicking live animals, to assess the feasibility and logistics of small animal experiments. Results: By comparing the trends of the linear quadratic model, evident in the $\alpha$ and $\beta$ parameters, the PEER cell survival results were shown to be in agreement with VHEE results from the ARES beamline at DESY, Hamburg, Germany. Evident in the survival trends, VHEE produced more cell sparing in all cell lines compared to 2 Gy/s X-rays delivered on the IMBL, another beamline at the Australian Synchrotron. The results of the mouse cadaver irradiations showed that PEER can safely and efficiently irradiate small animals. Conclusions: The PEER beamline is shown to possess suitable capabilities, including real-time dosimetry, repeatable alignment, and linac diagnostics, rendering it suitable for future in vivo VHEE UHDR FLASH radiotherapy investigations. Full article

The global cancer burden continues to increase worldwide. Among the various treatment options, radiotherapy (RT), which employs high-energy ionizing radiation to destroy cancer cells, is one of the primary modalities for cancer. However, increasing the absorbed dose to the target volume also increases the risk of damage to surrounding healthy tissues. This radiation-induced toxicity to normal tissues limits the desirable dosage that can be delivered to the tumor, thereby constraining the effectiveness of radiation therapy in achieving tumor control. FLASH radiotherapy (FLASH-RT) has emerged as a promising technique due to its biological advantages. FLASH-RT involves the delivery of radiation at an ultra-high dose rate (≥40 Gy/s). Unlike conventional RT, FLASH-RT achieves comparable tumor control rates while significantly reducing damage to surrounding normal tissues, a phenomenon known as the FLASH effect. Although the mechanism behind the FLASH effect is not fully understood, this approach shows considerable promise for future cancer treatment. The development of specialized treatment planning systems (TPS) becomes imperative to facilitate the clinical implementation of FLASH-RT from experimental studies. These systems must account for the unique characteristics of FLASH-RT, including ultra-high dose rate delivery and its distinctive radiobiological effects. Critical reassessment and optimization of treatment planning protocols are essential to fully leverage the therapeutic potential of the FLASH effect. This review examines key considerations for the TPS development of electron and proton FLASH-RT, including electron and proton FLASH techniques, biological models, crucial beam parameters, and dosimetry, providing essential insights for optimizing TPS and advancing the clinical implementation of this promising therapeutic modality. Full article

Objectives: Ultra-high dose-rate FLASH radiotherapy has demonstrated strong potential in reducing normal tissue toxicity while maintaining effective tumor control. However, its underlying radiobiological mechanisms remain unclear, highlighting the need for novel approaches to probe the effects of radiation during and immediately after delivery. This study presents the first exploration of 3D PET imaging of positron-emitting nuclei (PENs) generated by a FLASH proton beam. Methods: A home-built 12-panel preclinical small-animal PET system was employed for recording coincidence events. A 142.4 MeV FLASH proton beam with a 100 ms delivery time was directed into a solid water phantom. PET coincidence signals were recorded during the first 1 s and up to 11 min. The system’s capability for 3D localization was also assessed, and Monte Carlo simulations were performed for validation. Results: The PET system successfully recorded coincidence data within the first second, including the 100 ms beam delivery interval. Detector dead-time effects under the high beam flux were observed, leading to underestimated event counts. Following irradiation, the measured activity and decay behavior were consistent with simulations. The PET system accurately reconstructed the spatial distribution of PEN activities, with discrepancies in measured versus calculated line profiles ranging from 3.35–6.85%. Reconstructed PET images enabled reliable 3D localization with sub-millimeter accuracy in both lateral and depth dimensions. Conclusions: Our findings demonstrate that a multi-detector PET system is a promising tool for investigating the radiation effects of FLASH beams. Full article

Background/Objectives: Radiotherapy, radiobiology, and oncology have evolved rapidly over the past six decades. This progress has generated vast but fragmented bodies of scientific evidence. The present study aimed to systematically map and interpret their conceptual and temporal development using artificial intelligence (AI)-based methods. It highlights the integration between molecular mechanisms, clinical applications, and technological innovation within a precision radiotherapy framework. Methods: A corpus of 3343 unique articles (1964–2025) was retrieved from Scopus, PubMed, and Web of Science. Records were harmonized through deduplication, lemmatization, and metadata normalization. Topic modeling using Latent Dirichlet Allocation (LDA) and co-occurrence network analysis were applied to identify dominant research axes. Semantic and temporal analyses were conducted to reveal patterns, emerging trends, and translational connections across decades. Results: Three historical phases were identified. The first was a period of limited production (1964–1990). The second showed moderate growth (1991–2010). The third, from 2011 to 2024, represented exponential expansion, with publication peaks in 2020 and 2023. LDA revealed two principal axes. The first, a clinical–anatomical axis, focused on cancer sites, treatment modalities, and prognosis. The second, a mechanistic–molecular axis, centered on DNA repair, radiosensitivity, and biomarkers. Case synthesis from 2014–2025 defined five operational classes: DNA repair and molecular response; precision oncology and genomic modeling; individual radiosensitivity; mechanisms of radioresistance; and advanced technologies such as FLASH radiotherapy and optimized brachytherapy. Conclusions: AI-driven semantic and temporal analyses showed that radiotherapy has matured into an interconnected and interdisciplinary domain. The derived Precision Radiotherapy Implementation Plan translates molecular and computational insights into clinically actionable strategies. These approaches can enhance survival, reduce toxicity, and inform equitable health policies for advanced cancer care. Full article

Among the methods for increasing the specificity of tumor radiotherapy, FLASH radiotherapy (FLASH-RT) stands out, having recently entered clinical trials. A distinctive feature of this treatment method is the delivery of a therapeutic dose in a fraction of a second with a typical mean dose rate greater than 40 Gy/s. In addition to improved patient comfort and a shorter hospital stay, this therapy potentially carries a lower risk of radiation-related side effects due to reduced damage to normal tissues. Numerous preclinical and in vivo laboratory trials of FLASH-RT have demonstrated that, in addition to reducing the severity of radiation-related complications, FLASH radiotherapy has antitumor efficacy similar to conventional radiotherapy. Partly reduced radiotoxicity after such a dose rate delivery obtained, in a broader radiobiological sense, an eponymous term FLASH effect. Although the first clinical trials aimed to evaluate the safety and efficiency of FLASH-RT against bone metastases (FAST-01/02), melanoma skin metastases (IMPulse, Flash-Skin I), Squamous Cell Carcinoma, or Basal Cell Carcinoma (LANCE) have already started or even finished and showed promising results (FAST-01), the radiobiological basis of the FLASH effect is far from a complete explanation. The fundamental factors explaining the nature of the FLASH effect are mainly considered to be the following: (1) changes in the balance of water radiolysis products and a decrease in the generation of stable reactive oxygen species (ROS), (2) differential oxygen depletion, depending on the initial oxygen concentration in tissues, and (3) physiological and metabolic, gene expression and probably epigenetic shifts in response to irradiation in normal and tumor cells. The main purpose of this review is the systematization of the radiobiological manifestations of the FLASH effect together with a consideration of the elementary processes laying in the basis of the FLASH effect in order to actualize rationale and future application developments of FLASH-RT. Full article

Laser-accelerated electron beams, in the so-called Very High-Energy Electron (VHEE) energy range, are of great interest for biomedical applications. For instance, laser-driven VHEE beams are envisaged to offer suitable compact accelerators for the promising field of FLASH radiotherapy. Radiobiology experiments carried out using laser-driven beams require the real-time knowledge of the dose delivered to the sample. We have developed an online dose monitoring procedure, using an Integrating Current Transformer (ICT) coupled to a suitable collimator, that allows the estimation of the delivered dose on a shot-to-shot basis under suitable assumptions. The cross-calibration of the measured charge with standard offline dosimetry measurements carried out with RadioChromic Films (RCFs) is discussed, demonstrating excellent correlation between the two measurements. Full article

Objectives: To investigate how the FLASH effect modulates radiation response on multiple developmental endpoints of zebrafish embryos under normoxic and hypoxic conditions, after irradiation with proton beams at a conventional and an ultra-high dose rate (UHDR). Methods: Embryos were obtained from adult zebrafish and irradiated with a 228 MeV proton beam 24 h post-fertilization (hpf) at a dose rate of 0.6 and 317 Gy/s. For the hypoxic group, samples were kept inside a hypoxic chamber prior to irradiation, while standard incubation was adopted for the normoxic group. After irradiation, images of single embryos were acquired, and radiation effects on larval length, yolk absorption, pericardial edema, head size, eye size, and spinal curvature were assessed at specific time points. Results: Data indicate a general trend of significantly reduced toxicity after exposure to a UHDR compared to conventional regimes, which is maintained under both normoxic and hypoxic conditions. Differences are significant for the levels of pericardial edema induced by a UHDR versus conventional irradiation in normoxic conditions, and for eye and head size in hypoxic conditions. The toxicity scoring analysis shows a tendency toward a protective effect of the UHDR, which appears to be associated with a lower percentage of embryos in the high score categories. Conclusions: A radioprotective effect at a UHDR is observed both for normoxic (pericardial edema) and hypoxic (head and eye size) conditions. These results suggest that while the UHDR may preserve a potential to reduce radiation-induced damage, its protective effects are endpoint-dependent; the role of oxygenation might also be dependent on the tissue involved. Full article

Modern oncology increasingly relies on personalized strategies that aim to customize medical interventions, using both tumor biology and clinical features to enhance efficacy and minimize adverse effects. In recent years, precision medicine has been implemented as part of systemic therapies; however, its integration into radiation therapy (RT) is still a work in progress. Conventional RT treatment plans are based on the Linear Quadratic (LQ) model and utilize standardized alpha and beta ratios (α/β), which ignore the high variability in terms of treatment response between and within patients. Recent advances in radiobiology, as well as general medical technologies, have also driven a shift toward more tailored approaches, including in RT. This review provides an overview of current knowledge and future perspectives for the personalization of RT, highlighting the role of tumor and patient-specific biomarkers, advanced imaging techniques, and novel therapeutic approaches. As an alternative to conventional RT modalities, hadron therapy and Flash RT are discussed as innovative approaches with the potential to improve tumor targeting while sparing normal tissues. Furthermore, the synergistic combination of RT with immunotherapy is discussed as a potential strategy to support antitumor immune responses and overcome resistance. By integrating biological insights, technological innovation, and clinical expertise, personalized radiation therapy may significantly advance the precision oncology paradigm. Full article

The discrete physics models available in the Geant4-DNA Monte Carlo toolkit are a subject of continuous evolution and improvement in order to meet the needs of state-of-the-art radiobiological research for medical and space applications. The current capabilities of Geant4-DNA for event-by-event electron transport extend up to 1 MeV. In this work, Geant4-DNA’s most accurate electron inelastic model for sub-keV energies is improved and extended up to 10 MeV via the Relativistic Plane Wave Born Approximation and other theoretical considerations. Benchmark simulations of the electronic stopping power and range of electrons in liquid water using the new model show almost excellent agreement (at the few % level) with the recommendations of the International Commission on Radiation Units and Measurements (ICRU) up to 10 MeV, offering notable improvement (by a factor of ~2) over the default Geant4-DNA inelastic model and an order-of-magnitude higher electron limit. The present development will allow Geant4-DNA users to perform electron track-structure simulations up to 10 MeV, thus, covering a wider range of radiotherapeutic applications (including FLASH-RT) as well as space applications involving MeV electrons which are not currently reachable. Full article

Among the most investigated hypotheses for a radiobiological explanation of the mechanism behind the FLASH effect in ultra-high dose rate radiotherapy, intertrack recombination between particle tracks arriving at a close spatiotemporal distance has been suggested. In the present work, we examine these conditions for different beam qualities and energies, defining the limits of both space and time where a non-negligible chemical effect is expected. To this purpose the TRAX-CHEM chemical track structure Monte Carlo code has been extended to handle several particle tracks at the same time, separated by pre-defined spatial and temporal distances. We analyzed the yields of different radicals as compared to the non-interacting track conditions and we evaluated the difference. We find a negligible role of intertrack for spatial distances larger than 1 $\mu$m, while for temporal distances up to $\mu$s, a non-negligible interaction is observed especially at higher LET. In addition, we emphasize the non-monotonic behavior of some relative yield as a function of the time separation, in particular of ${\mathrm{H}}_2{\mathrm{O}}_2$, due to the onset of a different reaction involving solvated electrons besides well-known $\mathrm{O}{\mathrm{H}}^{·}$ recombination. Full article

The use of very high energy electron (VHEE) beams, with energies between 50 and 400 MeV, has drawn considerable interest in radiotherapy due to their deep tissue penetration, sharp beam edges, and low sensitivity to tissue density. VHEE beams can be precisely steered with magnetic components, positioning VHEE therapy as a cost-effective option between photon and proton therapies. However, the clinical implementation of VHEE therapy (VHEET) requires advances in several areas: developing compact, stable, and efficient accelerators; creating sophisticated treatment planning software; and establishing clinically validated protocols. In addition, the perspective of VHEE to access ultra-high dose–rate regime presents a promising avenue for the practical integration of FLASH radiotherapy of deep tumors and metastases with VHEET (FLASH-VHEET), enhancing normal tissue sparing while maintaining the inherent dosimetric advantages of VHEET. However, FLASH-VHEET systems require validation of time-dependent dose parameters, thus introducing additional technological challenges. Here, we discuss recent progress in VHEET research, focusing on both conventional and FLASH modalities, and covering key aspects including dosimetric properties, radioprotection, accelerator technology, beam focusing, radiobiological effects, and clinical outcomes. Furthermore, we comprehensively analyze initial VHEET in silico studies on coverage across various tumor sites. Full article

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. Full article

Major strides have been made in the development of FLASH radiotherapy (FLASH RT) in the last ten years, but there are still many obstacles to overcome for transfer to the clinic to become a reality. Although preclinical and first-in-human clinical evidence suggests that ultra-high dose rates (UHDRs) induce a sparing effect in normal tissue without modifying the therapeutic effect on the tumor, successful clinical translation of FLASH-RT depends on a better understanding of the biological mechanisms underpinning the sparing effect. Suitable in vitro studies are required to fully understand the radiobiological mechanisms associated with UHDRs. From a technical point of view, it is also crucial to develop optimal technologies in terms of beam irradiation parameters for producing FLASH conditions. This review provides an overview of the research progress of FLASH RT and discusses the potential challenges to be faced before its clinical application. We critically summarize the preclinical evidence and in vitro studies on DNA damage following UHDR irradiation. We also highlight the ongoing developments of technologies for delivering FLASH-compliant beams, with a focus on laser-driven plasma accelerators suitable for performing basic radiobiological research on the UHDR effects. Full article

Flash radiotherapy (Flash-RT) is an innovative technique used in radiotherapy for cancer treatment because it delivers an extremely high dose of radiation (>40 Gy/s) to the tumour in a very short period of time, typically within a fraction of a second. This ultra-fast delivery of radiation distinguishes Flash-RT from conventional radiotherapy, which typically involves the delivery of radiation over a longer time period, often several minutes. Studies conducted in cell and preclinical models suggested that Flash-RT may spare normal tissues from radiation-related side effects, such as skin toxicity, gastrointestinal complications, and damage to organs-at-risk. This is believed to be due to the unique normal tissue response to the ultra-high dose rate. Nevertheless, while Flash-RT shows promising results in preclinical and early clinical studies, one should note that the technique is still in the early stages of development. This entry provides a comprehensive exploration of the immense potentials of Flash-RT, covering its background, mechanisms, radiation sources, recent experimental findings based on cell and preclinical models, and future prospects. It aims to provide valuable insights into this innovative radiotherapy technology for anyone interested in the subject. Full article