Ion-beam radiography is a promising technique to verify the range of ion-beam radiotherapy treatments regularly. To detect and quantify the water-equivalent thickness (WET) of potential anatomical changes, ion-beam radiographs must provide a sufficient WET accuracy on the level of 1%.

In this work, we show an energy-painted helium-beam radiograph of an anthropomorphic head phantom acquired with thin silicon pixel detectors for the first time. Furthermore, we determine the WET accuracy of our helium-beam radiography system for the especially heterogeneous skull base region, which is highly relevant for the treatment of head and neck and skull base tumors.

With a detection system based on pixelated semiconducting Timepix detectors, we track single ions upstream and downstream of the head phantom. Furthermore, we measure their energy deposition in a thin Timepix detector behind the anthropomorphic phantom. To ensure a high precision of the image, we acquired a radiograph by using helium beams with five initial energies between 146.84 and 188.07 MeV/u following the energy painting algorithm. With a Siemens SOMATOM Confidence CT scanner, a single- and dual-energy CT were acquired with clinical protocols and translated to relative stopping power (RSP) values. After projecting these scans, the resulting WET maps were compared to the helium-beam radiograph. To evaluate the accuracy of all three modalities, a reference data set based on range-pullback measurements and a segmentation of a high-resolution CT scan was taken into account.

The mean absolute percentage error (MAPE) of all modalities was determined to be between 0.95% and 1.16%. Also, the root-mean-square percentage error (RMSPE) was similar for all modalities ranging from 1.19% to 1.46%. These deviations from the reference scan were found to mainly stem from an overestimation of air and sinus tissue and underestimation of cortical bone.

The helium-beam radiograph was shown to achieve a WET accuracy competitive with that of clinically used imaging methods. If certain technical aspects are addressed, helium-beam radiography may emerge as an auspicious imaging modality for on-couch range verification of ion-beam radiotherapy treatments allowing for regular detection and quantification of anatomical changes.

Objective.Secondary electron bremsstrahlung (SEB) imaging, along with prompt gamma (PG) and positron emission tomography (PET) imaging, has been proposed as anin vivorange verification tool for proton therapy. This study presents the first simulation based on patient computed tomography (CT) data to investigate the feasibility of SEB imaging for range verification in proton therapy, while comparing the characteristics of SEB imaging with those of PG and PET imaging.Approach.A Monte Carlo simulation was performed using patient CT data for the irradiation of monoenergetic pencil beams and spread-out Bragg peak proton beams. The physical characteristics of SEB imaging were analyzed at three different anatomical sites and compared with those of PG and PET imaging.Main results. In all the treatment cases, SEB imaging exhibited higher production rates than PG and PET imaging, particularly in the regions with high CT values along the beam path. Although the SEB signal was more affected by scattering and absorption than the PET or PG signals, sufficient statistical counts for range verification (∼3 × 10-3SEBs/proton) could potentially be detected outside the patient geometry. For pencil beam cases, the SEB and PET fall-offs were located 4-5 mm proximal to the dose fall-off, while the PG fall-off was located 0-1 mm distal to it.Significance.Results suggest that SEB imaging has the potential to offer a real-time range verification tool (by comparing measured and expected images), particularly for treating shallow-seated tumors using proton pencil-beam scanning delivery. Thus, this study represents a significant step towards the clinical application of range verification based on SEB imaging and promotes future efforts in this direction.

Objective. Due to higher dose conformality to the target, proton radiotherapy for cancer has received rapidly-growing interest. However, uncertainties in thein vivoproton range and methods to reduce them remain active areas of research. Based on 20 patients with head-and-neck cancer, this study aims to quantify the benefits of proton range uncertainty reductions in terms of the resulting improvements in quality-adjusted life expectancy (QALE).Approach. For each patient, two different proton therapy treatment plans were created, which assumed a current clinical range uncertainty of approximately 3.5% (IMPT3.5%) and a potentially achievable range uncertainty of 1.0% (IMPT1%). A Markov model considering the probability of tumor control and the development of xerostomia, larynx edema, secondary cancer, and/or metastases as well as death from primary cancer, secondary cancer, metastases, or unrelated causes was constructed, and for every patient and treatment plan, 10 000 simulations of the patient's entire lifetime from the time of treatment until death were performed.Main results.A 3.5%-1% range uncertainty reduction increased QALE by up to 0.4 quality-adjusted life years (QALYs) in the nominal and up to 0.6 QALY in the worst-case scenario, equivalent to 4.8 months and 7.2 months of life in perfect health. This was largely the result of a reduction in healthy tissue toxicity rates, which were reduced by up to 8.5 percentage points (pp) and 10.0 pp in the nominal and worst-case scenario, respectively.Significance. The benefits of a 3.5%-1% range uncertainty reduction in 20 patients with head-and-neck cancer were quantified in terms of the associated improvement in QALE. The highest QALE improvements were observed in patients in the top quartile of youngest patients at the time of treatment, due to the longer potential lifespan over which prevented healthy tissue toxicities would have impacted the patients' quality of life.

Intensity-modulated proton therapy (IMPT) holds promise for improving outcomes in head-and-neck cancer (HNC) patients by enhancing organ-at-risk (OAR) sparing. A key challenge in IMPT is ensuring an accurate dose delivery at the distal edge of the tumor, where the steep dose gradients make treatment precision highly sensitive to uncertainties in both proton range and patient setup. Thus, IMPT conformality is increased by incorporating robust margins in the treatment optimization. However, an increment in the plan robustness could lead to an OAR overdosing. Therefore, an accurate distal edge verification during dose delivery is crucial to increase IMPT conformality by reducing optimization settings in treatment planning.

This work aims to evaluate, in a quasi-clinical setting, a novel approach for accurate instantaneous proton beam distal edge verification in IMPT by means of spot-by-spot positron emission tomography (PET) imaging.

An anthropomorphic head and neck phantom CIRS-731 HN was irradiated at the head and neck region. The targets were defined as 4 cm diameter spheres. A 60-ms delay was introduced between the proton beam spots in order to enable the spot-by-spot coincidence detection of the 511-keV photons resulting from positron annihilation following the positron emission from very short-lived positron-emitting, mainly 12N (T1/2  = 11.0 ms). Additionally, modified irradiations were carried out using solid water slabs of 2 and 5 mm thickness in the beam path to assess the precision of the approach for detecting range deviations. The positron activity range (PAR) was determined from the 50% distal fall-off position of the 1D longitudinal positron activity profile derived from the 2D image reconstructions. Furthermore, Monte Carlo (MC) simulations were performed using an in-house RayStation/GATE MC framework to predict the positron activity images and verify the PAR measurements.

PAR measurements achieved a precision between 1.5 and 3.6 mm (at 1.5σ clinical level) at the beam spot level within sub-second time scales. Measured PAR shifts of 1.6-2.1  and 4.2--.7 mm were observed with the 2- and 5-mm thickness range shifters, respectively, aligning with the corresponding proton dose range (PDR) shifts of 1.3-1.8 and 3.9-4.3 mm. The simulated PAR agrees with the measured PARs, showing an average range difference of ∼0.4 mm.

This study demonstrated the feasibility of instantaneous distal edge verification using PET imaging by introducing beam spot delays during dose delivery. The findings represent a first step toward the clinical implementation of instantaneous in vivo distal edge verification. The approach contributes to the development of real-time range verification aimed at improving IMPT treatments by mitigating range and setup uncertainties, thereby reducing dose to organs-at-risk and ultimately enhancing patient outcomes.

In proton radiotherapy, the steep dose deposition profile near the end of the proton's track, the Bragg peak, ensures a more conformed deposition of dose to the tumor region when compared with conventional radiotherapy while reducing the probability of normal tissue complications. However, uncertainties, as in the proton range, patient geometry, and positioning pose challenges to the precise and secure delivery of the treatment plan (TP). In vivo range determination and dose distribution are pivotal for mitigation of uncertainties, opening the possibility to reduce uncertainty margins and for adaptation of the TP.

This study aims to explore the feasibility of utilizing gadolinium (Gd), a highly used contrast agent in MRI, as a surrogate for in vivo dosimetry during the course of scanning proton therapy, tracking the delivery of a TP and the impact of uncertainties intra- and inter-fraction in the course of treatment.

Monte Carlo simulations (Geant4 11.1.1) were performed, where a Gd-filled volume was placed within a water phantom and underwent treatment with a scanning proton TP delivering 4 Gy. The secondary photons emitted upon proton-Gd interaction were recorded and assessed for various tumor displacements. The spectral response of Gd to each pencil beam irradiation is therefore used as a surrogate for dose measurements during treatment.

Results show that the deposited dose at the target volume can be tracked for each TP scanning point by correlating it with the recorded Gd signal. The analyzed Gd spectral line corresponded to the characteristic X-rayk α $\text{k}_\alpha$ line at 43 keV. Displacements from the planned geometry could be distinguished by observing changes in the Gd signal induced by each pencil beam. Moreover, the total 43 keV signal recorded subsequently to the full TP delivery reflected deviations from the planned integral dose to the target.

The study suggests that the spectral response of a Gd-based contrast agent can be used for in vivo dosimetry, providing insights into the TP delivery. The Gd 43 keV spectral line was correlated with the dose at the tumor, its volume, and its position. Other variables that can impact the method, such as the kinetic energy of the incident protons and Gd concentration in the target were also discussed.

Objective.Monolithic active pixel sensors are used for charged particle tracking in many applications, from medical physics to astrophysics. The Bergen pCT collaboration designed a sampling calorimeter for proton computed tomography, based entirely on the ALICE PIxel DEtector (ALPIDE). The same telescope can be used for in-situ range verification in particle therapy. An accurate charge diffusion model is required to convert the deposited energy from Monte Carlo simulations to a cluster of pixels, and to estimate the deposited energy, given an experimentally observed cluster.Approach.We optimize the parameters of different charge diffusion models to experimental data for both proton computed tomography and proton range verification, collected at the Danish Centre for Particle Therapy. We then evaluate the performance of downstream tasks to investigate the impact of charge diffusion modeling.Main results.We find that it is beneficial to optimize application-specific models, with a power law working best for proton computed tomography, and a model based on a 2D Cauchy-Lorentz distribution giving better agreement for range verification. We further highlight the importance of evaluating the downstream tasks with multiple approaches to obtain a range of expected performance metrics for the application.Significance.This work demonstrates the influence of the charge diffusion model on downstream tasks, and recommends a new model for proton range verification with an ALPIDE-based pixel telescope.

Radiotherapy using very-high-energy electron (VHEE) beams (50-300 MeV) has attracted considerable attention due to its advantageous dose deposition characteristics, enabling deep penetration and easy manipulation by magnetic components. One promising approach to compactly delivering these high energy electron beams in a cost-effective manner is laser wakefield acceleration (LWFA), which offers ultra-strong accelerating gradients. However, the transition from this concept to a functional machine intended for tumor treatment remains elusive. Here we present the self-developed pro- totype for LWFA-based VHEE radiotherapy, exhibiting compactness (occupying less than 5 m2) and long-term operational stability (validated over a period of one month). Subsequently, we employ this device to irradiate a tumor implanted in a mouse model. Following a dose delivery of 5.8 ± 0.2 Gy with precise tumor conformity, all irradiated mice exhibit pronounced control of tumor growth. For comparison, this tumor-control efficacy is similar to that achieved using commercial X-ray radiotherapy equipment operating at equivalent doses. These results demonstrate a compact and stable laser-driven VHEE system dedicated for preclinical studies involving small animal models and its promising prospects for future clinical translation in cancer therapy.

Gold nanoparticles (GNPs) have gained significant attention as multifunctional agents in biomedical applications, particularly for enhancing radiotherapy. Their advantages, including low toxicity, high biocompatibility, and excellent conductivity, make them promising candidates for improving treatment outcomes across various radiation sources, such as femtosecond lasers, X-rays, Cs-137, and proton beams. However, a deeper understanding of their precise mechanisms in radiotherapy is essential for maximizing their therapeutic potential. This review explores the role of GNPs in enhancing reactive oxygen species (ROS) generation through plasmon-induced hot electrons or radiation-induced secondary electrons, leading to cellular damage in organelles such as mitochondria and the cytoskeleton. This additional pathway enhances radiotherapy efficacy, offering new therapeutic possibilities. Furthermore, we discuss emerging trends and future perspectives, highlighting innovative strategies for integrating GNPs into radiotherapy. This comprehensive review provides insights into the mechanisms, applications, and potential clinical impact of GNPs in cancer treatment.

This work presents an effort to extend the capabilities of the previously introduced GPU-based Monte Carlo code ARCHER for helium ion therapy.

ARCHER performs helium ion transport simulations in voxelized geometry, covering kinetic energy levels up to 220 MeV/u. The physical processes are modeled using a class II condensed-history algorithm, considering ionization, energy straggling, multiple scattering, and elastic and inelastic nuclear interactions. A new nuclear-event-repeat algorithm is proposed to generate inelastic nuclear reaction products. Secondary protons, deuterons, tritons, and 3He particles are tracked, while other particles either deposit their energy locally or are ignored. The code is developed under the compute unified device architecture (CUDA) platform to improve computational efficiency. Validations are conducted by benchmarking our code against TOPAS in different phantoms.

Dose distribution comparisons demonstrate strong agreement between our code and TOPAS. The mean point-by-point local relative errors in the region where the dose exceeds 10% of the maximum dose range from 0.25% to 1.31% for all phantoms. In the strict 1%/1 mm criterion, gamma passing rates for a head-neck case, chest case, and prostate case are 99.8%, 96.9%, and 99.6%, respectively. Except for the lung phantom, ARCHER takes less than 10 s to simulate 10 million primary helium ions using a single NVIDIA GeForce RTX 3080 card (NVIDIA Corporation, Santa Clara, USA), while TOPAS requires several minutes on a computational platform with two Intel Xeon Gold 6348 CPUs (Intel Corporation, Santa Clara, USA) with 56 cores.

This work presents the development and benchmarking of the first GPU-based dose engine for helium ion therapy. The code has been proven to achieve high levels of accuracy and efficiency.

Glioblastoma multiforme (GBM) is the most malignant brain tumor, with radiotherapy frequently employed following surgical resection. However, conventional radiation therapies often yield suboptimal results. This study investigated the effects of X-ray and carbon ion irradiation on the glioblastoma cell line U251 to assess the distinctive advantages of carbon ion treatment and explore mechanisms for overcoming radiation resistance. The findings indicated that carbon ion irradiation more effectively inhibited colony formation and induced more severe apoptosis and cell cycle disorder in U251 cells. Immunofluorescence assays revealed larger and more abundant ϒ-H2AX and 53BP1 foci in the carbon ion irradiation group. Western blot analysis demonstrated that carbon ion-induced DNA damage repair involved a complex array of pathways, with the RAD51-mediated homologous recombination (HR) pathway being predominant, while the Rad23B-mediated nucleotide excision repair (NER) pathway and XRCC1-mediated base excision repair (BER) were more relevant in response to X-ray irradiation. These results suggest that carbon ion irradiation may overcome radioresistance by inducing more complex DNA damage and apoptosis, thus providing insights for targeting new strategies in combining gene therapy with radiotherapy.

The battle against cancer remains a top priority for society, with an urgent need to develop therapies capable of targeting challenging tumours while preserving patient's quality of life. Hadron Therapy (HT), which employs accelerated beams of protons, carbon ions, and other charged particles, represents a significant frontier in cancer treatment. This modality offers superior precision and efficacy compared to conventional methods, delivering therapeutic the dose directly to tumours while sparing healthy tissue. Even though 350,000 patients have already been treated worldwide with protons and 50,000 with carbon ions, HT is still a relatively young field and more research as well as novel, cost-effective and compact accelerator technologies are needed to make this treatment more readily available globally. Interestingly the very first patient was irradiated with protons in September 1954, the same month and year CERN was founded. Both of these endeavours are embedded in cutting edge technologies and multidisciplinary collaboration. HT is finally gaining ground and, even after 70 years, the particle therapy field continues innovating and improving for the benefits of patients globally. Developing technologies that are both affordable and easy to use is key and would allow access to more patients. Advances in accelerator-driven Boron Neutron Capture Therapy (BNCT), image-guided hadron beams delivery, clinical trials and immunotherapy, together with the recent interest and advances in FLASH therapy, which is currently an experimental treatment modality that involves ultrahigh-dose rate delivery, are just a few examples of innovation that may eventually help to provide access to a larger number of patients.

Radiotherapy is indicated for nearly all cancers and at all stages in one form or another. More than half of all cancer patients are treated with radiation at some point in their cancer treatment. Conventional X-ray (photon) based radiotherapy does have a number of physical limitations which were theorized to be overcome by instead employing proton based radiotherapy. The late 1990s and early 2000s saw a rapid adoption in proton therapy as many speculated a greatly improved therapeutic window compared with photon therapy. Only a few randomized clinical trials have been reported, but to-date proton therapy has not shown to improve cancer control metrics. There is improved treatment related toxicity which may be clinically meaningful in some scenarios, but further expansion and wide spread utilization of the technology may be drastically limited by the substantially higher start up and operational costs of a proton center. Nonetheless, proton therapy may be beneficial in select scenarios which warrant individualized consideration.

Pencil-beam scanning proton therapy has been considered a potential modality for the 3D form of spatially fractionated radiation therapy called lattice therapy. However, few practical solutions have been introduced in the clinic. Existing limitations include degradation in plan quality and robustness when using single-field versus multifield lattice plans, respectively. We propose a practical and robust proton lattice (RPL) planning method using multifield and evaluate its dosimetric characteristics compared to clinically acceptable photon lattice plans.

Seven cases previously treated with photon lattice therapy were used to evaluate a novel RPL planning technique using 2-orthogonal beams: a primary beam (PB) and a robust complementary beam (RCB) that deliver 67% and 33%, respectively, of the prescribed dose to vertices inside the gross target volume (GTV). Only RCB is robustly optimized for setup and range uncertainties. The number and volume of vertices, peak-to-valley dose ratios (PVDRs), and volume of low dose to GTV of proton and photon plans were compared. The RPL technique was then used in the treatment of 2 patients and their dosimetric parameters were reported.

The RPL strategy was able to achieve the clinical planning goals. Compared to previously treated photon plans, the average number of vertices increased by 30%, the average vertex volume by 49% (18.2 ± 25.9 cc vs 12.2 ± 14.5 cc, P = .21), and higher PVDR (10.5 ± 4.8 vs 2.5 ± 0.9, P < .005) was achieved. In addition, RPL plans show more conformal dose with less low dose to GTV (V30%, 60.9% ± 7.2% vs 81.6% ± 13.9% and V10%, 88.3% ± 4.5% vs 98.6% ± 3.6% [P < .01]). The RPL plan for 2 treated patients showed PVDRs of 4.61 and 14.85 with vertices-to-GTV ratios of 1.52% and 1.30%, respectively.

A novel RPL planning strategy using a pair of orthogonal beams was developed and successfully translated to the clinic. The proposed method can generate better quality plans, a higher number of vertices, and higher PVDRs than currently used photon lattice plans.

Particle therapy is a promising treatment technique that is becoming more commonly used. Although proton beam therapy remains the most commonly used particle therapy, multiple other heavier ions have been used in the preclinical and clinical settings, each with its own unique properties. This practical review aims to summarize the differences between the studied particles, discussing their radiobiological and physical properties with additional review of the available clinical data.

A search was carried out on the PubMed databases with search terms related to each particle. Relevant radiobiology, physics, and clinical studies were included. The articles were summarized to provide a practical resource for practicing clinicians.

A total of 113 articles and texts were included in our narrative review. Currently, proton beam therapy has the most data and is the most widely used, followed by carbon, helium, and neutrons. Although oxygen, neon, silicon, and argon have been used clinically, their future use will likely remain limited as monotherapy.

This review summarizes the properties of each of the clinically relevant particles. Protons, helium, and carbon will likely remain the most commonly used, although multi-ion therapy is an emerging technique.

Particle therapy presents a promising alternative to conventional photon therapy for treating non-small cell lung cancer (NSCLC). However, the heterogeneous structure of lung tissue leads to the degradation of the Bragg peak and thereby to the degradation of the dose distribution. This review offers a comprehensive overview of the models developed to account for these modulation effects. It summarizes studies focused on determining modulation power as a predictor of this so-called lung modulation. In addition, the review covers early investigations on dose uncertainties caused by lung modulation in CT-based lung phantoms and patient anatomies and discusses future challenges in integrating these solutions into clinical treatment planning routines.

Particle therapy (PT) represents a significant advancement in cancer treatment, precisely targeting tumor cells while sparing surrounding healthy tissues thanks to the unique depth-dose profiles of the charged particles. Furthermore, their linear energy transfer and relative biological effectiveness enhance their capability to treat radioresistant tumors, including hypoxic ones. Over the years, extensive research has paved the way for PT's clinical application, and current efforts aim to refine its efficacy and precision, minimizing the toxicities. In this regard, radiobiology research is evolving toward integrating biotechnology to advance drug discovery and radiation therapy optimization. This shift from basic radiobiology to understanding the molecular mechanisms of PT aims to expand the therapeutic window through innovative dose delivery regimens and combined therapy approaches. This review, written by over 30 contributors from various countries, provides a comprehensive look at key research areas and new developments in PT radiobiology, emphasizing the innovations and techniques transforming the field, ranging from the radiobiology of new irradiation modalities to multimodal radiation therapy and modeling efforts. We highlight both advancements and knowledge gaps, with the aim of improving the understanding and application of PT in oncology.

Although access to proton beam therapy (PBT) is limited worldwide, its use for the treatment of hepatocellular carcinoma (HCC) is gradually increasing with the expansion of new facilities. Therefore, we conducted a systematic review and metaanalysis to investigate the updated evidence of PBT for HCC.

The MEDLINE, EMBASE, Cochrane Library, and Web of Science databases were systematically searched for studies that enrolled patients with liver-confined HCC that were treated with PBT for a cure up to February 2024.

A total of 1,858 HCC patients receiving PBT from 22 studies between 2004 and 2023 were selected for this meta-analysis. The median proportion of Child-Pugh class A was 86% (range, 41-100), and the median tumor size was 3.6 cm (range, 1.2-9.0). The median total dose ranged from 55 GyE to 76 GyE (median, 69). The pooled rates of 3- and 5-year local progression-free survival after PBT were 88% (95% confidence interval [CI], 85-91) and 86% (95% CI, 82-90), respectively. The pooled 3- and 5-year overall rates were 60% (95% CI, 54-66) and 46% (95% CI, 38-54), respectively. The pooled rates of grade 3 hepatic toxicity, classic radiationinduced liver disease (RILD), and non-classic RILD were 1%, 2%, and 1%, respectively.

The current study supports PBT for HCC and demonstrates favorable long-term survival and low hepatic toxicities compared with other published studies on other radiotherapy modalities. However, further studies are needed to identify the subgroups that will benefit from PBT.

This practice parameter for the performance of proton beam radiation therapy was revised collaboratively by the American College of Radiology (ACR) and the American Radium Society (ARS). This practice parameter was developed to serve as a tool in the appropriate application of proton therapy in the care of cancer patients or other patients with conditions in which radiation therapy is indicated. It addresses clinical implementation of proton radiation therapy, including personnel qualifications, quality assurance (QA) standards, indications, and suggested documentation.

This practice parameter for the performance of proton beam radiation therapy was developed according to the process described under the heading The Process for Developing ACR Practice Parameters and Technical Standards on the ACR website (https://www.acr.org/Clinical-Resources/Practice-Parameters-and-Technical-Standards) by the Committee on Practice Parameters - Radiation Oncology of the ACR Commission on Radiation Oncology in collaboration with the ARS.

The qualifications and responsibilities of personnel, such as the proton center Chief Medical Officer or Medical Director, Radiation Oncologist, Radiation Physicist, Dosimetrist and Therapist, are outlined, including the necessity for continuing medical education. Proton therapy standard clinical indications and methodologies of treatment management are outlined by disease site and treatment group (e.g. pediatrics) including documentation and the process of proton therapy workflow and equipment specifications. Additionally, this proton therapy practice parameter updates policies and procedures related to a quality assurance and performance improvement program (QAPI), patient education, infection control, and safety.

As proton therapy becomes more accessible to cancer patients, policies and procedures as outlined in this practice parameter will help ensure quality and safety programs are effectively implemented to optimize clinical care.

Radiation research is a multidisciplinary field, and among its many branches, mathematical and computational modelers have played a significant role in advancing boundaries of knowledge. A fundamental contribution is modelling cellular response to ionizing radiation as that is the key to not only understanding how radiation can kill cancer cells, but also cause cancer and other health issues. The invention of microdosimetry in the 1950s by Harold Rossi paved the way for brilliant scientists to study the mechanism of radiation at cellular and sub-cellular scales. This paper reviews some snippets of ingenious mathematical and computational models published in microdosimetry symposium proceedings and publications of the radiation research community. Among these are simulations of radiation tracks at atomic and molecular levels using Monte Carlo methods, models of cell survival, quantification of the amount of energy required to create a single strand break, and models of DNA-damage-repair. These models can broadly be categorized into mechanistic, semi-mechanistic, and phenomenological approaches, and this review seeks to provide historical context of their development. We salute pioneers of the field and great teachers who supported and educated the younger members of the community and showed them how to build upon their work.

Background and purpose: Proton therapy has been shown to provide dosimetric benefits in comparison with IMRT when treating prostate cancer with whole pelvis radiation; however, the optimal proton beam arrangement has yet to be established. The aim of this study was to evaluate three different intensity-modulated proton therapy (IMPT) beam arrangements when treating the prostate bed and pelvis in the postoperative setting. Materials and Methods: Twenty-three post-prostatectomy patients were planned using three different beam arrangements: two-field (IMPT2B) (opposed laterals), three-field (IMPT3B) (opposed laterals inferiorly matched to a posterior-anterior beam superiorly), and four-field (IMPT4B) (opposed laterals inferiorly matched to two posterior oblique beams superiorly) arrangements. The prescription was 50 Gy radiobiological equivalent (GyE) to the pelvis and 70 GyE to the prostate bed. Comparisons were made using paired two-sided Wilcoxon signed-rank tests. Results: CTV coverages were met for all IMPT plans, with 99% of CTVs receiving ≥ 100% of prescription doses. All organ at risk (OAR) objectives were met with IMPT3B and IMPT4B plans, while several rectum objectives were exceeded by IMPT2B plans. IMPT4B provided the lowest doses to OARs for the majority of analyzed outcomes, with significantly lower doses than IMPT2B +/- IMPT3B for bladder V30-V50 and mean dose; bowel V15-V45 and mean dose; sigmoid maximum dose; rectum V40-V72.1, maximum dose, and mean dose; femoral head V37-40 and maximum dose; bone V40 and mean dose; penile bulb mean dose; and skin maximum dose. Conclusion: This study is the first to compare proton beam arrangements when treating the prostate bed and pelvis. four-field plans provided better sparing of the bladder, bowel, and rectum than 2- and three-field plans. The data presented herein may help inform the future delivery of whole pelvis IMPT for prostate cancer.

Objective.Prompt gamma (PG) radiation generated from nuclear reactions between protons and tissue nuclei can be employed for range verification in proton therapy. A typical clinical workflow for PG range verification compares the detected PG profile with a predicted one. Recently, a novel analytical PG prediction algorithm based on the so-called filtering formalism has been proposed and implemented in a research version of RayStation (RaySearch Laboratories AB), which is a widely adopted treatment planning system. This work validates the performance of the filtering PG prediction approach.Approach.The said algorithm is validated against experimental data and benchmarked with another well-established PG prediction algorithm implemented in a MATLAB-based software REGGUI. Furthermore, a new workflow based on several PG profile quality criteria and analytical methods is proposed for data selection. The workflow also calculates sensitivity and specificity information, which can help practitioners to decide on irradiation course interruption during treatment and monitor spot selection at the treatment planning stage. With the proposed workflow, the comparison can be performed on a limited number of selected high-quality irradiation spots without neighbouring-spot aggregation.Main results.The mean shifts between the experimental data and the predicted PG detection (PGD) profiles (ΔPGD) by the two algorithms are estimated to be1.5±2.1mm and-0.6±2.2mm for the filtering and REGGUI prediction methods, respectively. The ΔPGD difference between two algorithms is observed to be consistent with the beam model difference within uncertainty. However, the filtering approach requires a much shorter computation time compared to the REGGUI approach.Significance.The novel filtering approach is successfully validated against experimental data and another widely used PG prediction algorithm. The workflow designed in this work selects spots with high-quality PGD shift calculation results, and performs sensitivity and specificity analyses to assist clinical decisions.

An increase in plan robustness leads to a higher dose to organs-at-risk (OARs), and an increased chance of post-treatment toxicities. In contrast, more conformal plans lead to sparing of healthy surrounding tissue at the expense of a higher sensitivity to anatomical changes, requiring costly adaptations. In this study, we assess the trade-off and impact of treatment plan robustness on the adaptation rate.

Treatment planning was performed for 40 lung cancer patients, each having a planning 4DCT and up to eight weekly repeated 4DCTs (reCTs). For each patient, plans were made with three different levels of robustness based on setup uncertainty of 3, 6 and 9 mm. These plans were robustly re-evaluated on all reCTs to assess whether the clinical constraints were met.

For the 3, 6 and 9 mm robustness levels, adaptation rates of 87.5 %, 70.0 % and 57.5 %, respectively, were observed. A mean absolute normal tissue complication probability (NTCP) gain of 2.9 percentage points (pp) was calculated for pneumonitis grade ≥ 2 when transitioning from 9 mm plans to 3 mm plans, 7.6 pp for esophagitis grade ≥ 2, and 2.5 pp for mortality risk 2 years post-treatment.

The lowered risk of post treatment toxicities at lower robustness levels is clinically relevant but comes at the expense of more treatment adaptations, particularly in cases where meeting our clinical goals is not compromised by having a dose that is more conformal to the target. The trade-off between workload and reduced NTCP needs to be individually assessed.

The highly heterogeneous dose delivery of spatially fractionated radiation therapy (SFRT) is a profound departure from standard radiation planning and reporting approaches. Early SFRT studies have shown excellent clinical outcomes. However, prospective multi-institutional clinical trials of SFRT are still lacking. This NRG Oncology/American Association of Physicists in Medicine working group consensus aimed to develop recommendations on dosimetric planning, delivery, and SFRT dose reporting to address this current obstacle toward the design of SFRT clinical trials.

Working groups consisting of radiation oncologists, radiobiologists, and medical physicists with expertise in SFRT were formed in NRG Oncology and the American Association of Physicists in Medicine to investigate the needs and barriers in SFRT clinical trials.

Upon reviewing the SFRT technologies and methods, this group identified challenges in several areas, including the availability of SFRT, the lack of treatment planning system support for SFRT, the lack of guidance in the physics and dosimetry of SFRT, the approximated radiobiological modeling of SFRT, and the prescription and combination of SFRT with conventional radiation therapy.

Recognizing these challenges, the group further recommended several areas of improvement for the application of SFRT in cancer treatment, including the creation of clinical practice guidance documents, the improvement of treatment planning system support, the generation of treatment planning and dosimetric index reporting templates, and the development of better radiobiological models through preclinical studies and through conducting multi-institution clinical trials.

Esophageal cancer is among the top causes of cancer-related mortality worldwide, and the main treatment modality for locally advanced esophageal cancer is concurrent chemoradiotherapy. The current photon-based radiotherapy modalities and procedures have increased the incidence of treatment-related cardiac and pulmonary complications. Additionally, anatomical changes in the esophagus resulting from diaphragmatic movement, weight loss, and tumor progression present challenges for radiotherapy. These challenges have spurred interest in particle therapies, such as proton beam therapy (PBT) and heavy-ion therapy, for esophageal cancer. This paper comprehensively reviews the dosimetric advantages, clinical efficacy, and limitations of PBT and heavy-ion therapy for esophageal cancer and discusses their prospects. This highlights the unique dosimetric benefits of these therapies, particularly their ability to deliver high-dose radiation precisely to the tumor while sparing the surrounding normal organs and tissues. Although PBT and heavy-ion therapy demonstrate superior clinical efficacy compared to photon therapy, they are not without limitations. Multiple studies are needed to further validate and supplement the existing clinical and preclinical data to better exploit the benefits of PBT and thereby provide improved survival advantages to these patients.

Oncologic surgical resection is the standard of care for extremity and truncal soft tissue sarcoma (STS), often accompanied by the addition of pre- or postoperative radiation therapy (RT). Preoperative RT may decrease the risk of joint stiffness and fibrosis at the cost of higher rates of wound complications. Hypofractionated, preoperative RT has been shown to provide acceptable outcomes in prospective trials. Proton beam therapy (PBT) provides the means to decrease dose to surrounding organs at risk, such as the skin, bone, soft tissues, and adjacent joint(s), and has not yet been studied in patients with extremity and truncal sarcoma.

Our study titled "PROspective phase II trial of preoperative hypofractionated protoN therapy for extremity and Truncal soft tissue sarcOma (PRONTO)" is a non-randomized, prospective phase II trial evaluating the safety and efficacy of preoperative, hypofractionated PBT for patients with STS of the extremity and trunk planned for surgical resection. Adult patients with Eastern Cooperative Group Performance Status ≤ 2 with resectable extremity and truncal STS will be included, with the aim to accrue 40 patients. Treatment will consist of 30 Gy radiobiological equivalent of PBT in 5 fractions delivered every other day, followed by surgical resection 2-12 weeks later. The primary outcome is rate of major wound complications as defined according to the National Cancer Institute of Canada Sarcoma2 (NCIC-SR2) Multicenter Trial. Secondary objectives include rate of late grade ≥ 2 toxicity, local recurrence-free survival and distant metastasis-free survival at 1- and 2-years, functional outcomes, quality of life, and pathologic response.

PRONTO represents the first trial evaluating the use of hypofractionated PBT for STS. We aim to prove the safety and efficacy of this approach and to compare our results to historical outcomes established by previous trials. Given the low number of proton centers and limited availability, the short course of PBT may provide the opportunity to treat patients who would otherwise be limited when treating with daily RT over several weeks. We hope that this trial will lead to increased referral patterns, offer benefits towards patient convenience and clinic workflow efficiency, and provide evidence supporting the use of PBT in this setting.

NCT05917301 (registered 23/6/2023).

Proton beam therapy (PBT) has great advantages as tumor radiotherapy and is progressively becoming a more prevalent choice for individuals undergoing radiation therapy. The objective of this review is to pinpoint collaborative efforts among countries and institutions, while also exploring the hot topics and future outlook in the field of PBT. Data from publications were downloaded from the Web of Science Core Collection. CiteSpace and Excel 2016 were used to conduct the bibliometric and knowledge map analysis. A total of 6516 publications were identified, with the total number of articles steadily increasing and the United States being the most productive country. Harvard University took the lead in contributing the highest number of publications. Paganetti Harald published the most articles and had the most cocitations. PHYS MED BIOL published the greatest number of PBT-related articles, while INT J RADIAT ONCOL received the most citations. Paganetti Harald, 2012, PHYS MED BIOL can be classified as classic literature due to its high citation rate. We believe that research on technology development, dose calculation and relative biological effectiveness were the knowledge bases in this field. Future research hotspots may include clinical trials, flash radiotherapy, and immunotherapy.

The synchrotron is a circular particle accelerator used for high energy physics experiments, material and life science, as well as hadron cancer therapy. After acceleration to the desired energies, particle beams are commonly extracted from the synchrotron using the method of resonant slow extraction. The goal is to deliver a steady particle flux-referred to as spill-to experiments and treatment facilities over the course of seconds while slowly emptying the storage ring. Any uncontrolled intensity fluctuations in the spill are detrimental to the efficiency of beam usage, as they lead to detector pileups or detector interlocks, hindering experiments and cancer treatment. Among the most widely used extraction scheme in medical facilities is the Radio Frequency Knock Out (RF-KO) driven resonant slow extraction, where the stored beam is transversely excited with a radio frequency (RF) field and the spill intensity is controlled by the excitation signal strength. This article presents particle dynamics simulations of the RF-KO system with the focus on finding effective mechanism for minimizing the intensity fluctuations while maintaining a good extraction efficiency and other advantages of KO extraction. An improved beam excitation signal which optimizes these main objectives is found, and is rigorously compared experimentally with other commonly applied techniques.

This paper provides insights into the use of Proton Beam Therapy (PBT) in pediatric patients with non-rhabdomyosarcoma soft tissue sarcomas (NRSTS). NRSTS are a heterogeneous group of rare and aggressive mesenchymal extraskeletal tumors, presenting complex and challenging clinical management scenarios. The overall survival rate for patients with NRSTS is around 70%, but the outcome is strictly related to the presence of various variables, such as the histological subtype, grade of malignancy and tumor stage at diagnosis. Multimodal therapy is typically considered the preferred treatment for high-grade NRSTS. Radiotherapy plays a key role in the treatment of children and adolescents with NRSTS. However, the potential for radiation-induced side effects partially limits its use. Therefore, PBT represents a very suitable therapeutic option for these patients. The unique depth-dose characteristics of protons can be leveraged to minimize doses to healthy tissue significantly, potentially allowing for increased tumor doses and enhanced preservation of surrounding tissues. These benefits suggest that PBT may improve local control while reducing toxicity and improving quality of life. While clear evidence of therapeutic superiority of PBT over other modern photon techniques in NRSTS is still lacking-partly due to the limited data available-PBT can be an excellent treatment option for young patients with these tumors. A dedicated international comprehensive collaborative approach is essential to better define its role within the multidisciplinary management of NRSTS. Shared guidelines for PBT indications-based on the patient's age, estimated outcome, and tumor location-and centralization in high-level referral centers are needed to optimize the use of resources, since access to PBT remains a challenge due to the limited number of available proton therapy facilities.

Uncertainties in the relative biological effectiveness (RBE) of proton remains a major barrier to the biological optimization of proton therapy. A large amount of experimental data suggest that proton RBE is variable. As an evolving Monte Carlo code toolkit, Geant4-DNA is able to simulate the initial DNA damage caused by particle beams through physical and chemical interactions at the nanometer scale over a short period of time. This contributes to evaluating the radiobiological effects induced by ionizing radiation. Based on the Geant4-DNA toolkit, this study constructed a DNA geometric model containing 6.32Gbp, simulated the relationship between radiochemical yields (G-values) and their corresponding chemical constructors, and calculated a detailed calculation of the sources of damage and the complexity of damage in DNA strand breaks. The damage model constructed in this study can simulate the relative biological effectiveness (RBE) in the proton Bragg peak region. The results indicate that: (1) When the electron energy is below 400 keV, the yield of OH·account for 18.1% to 25.3% of the total water radiolysis yields. (2) Under the influence of histone clearance function, the yield of indirect damage account for over 72.93% of the yield of DNA strand breaks (SBs). When linear energy transfer (LET) increased from 29.79 (keV/μm) to 64.29 (keV/μm), the yield of double strand breaks (DSB) increased from 17.27% to 32.65%. (3) By investigating the effect of proton Bragg peak depth on the yield of direct DSB (DSBdirect) and total DSB (DSBtotal), theRBEDSBtotandRBEDSBdirlevels of cells show that the RBE value of protons reaches 2.2 in the Bragg peak region.

The present study aimed to develop a porous structure with plug-ins (PSP) to broaden the Bragg peak width (BPW, defined as the distance in water between the proximal and distal 80% dose) of the carbon ion beam while maintaining a sharp distal falloff width (DFW, defined as the distance along the beam axis where the dose in water reduces from 80% to 20%).

The binary voxel models of porous structure (PS) and PSP were established in the Monte Carlo code FLUKA and the corresponding physical models were manufactured by 3D printing. Both experiment and simulation were performed for evaluating the modulation capacity of PS and PSP. BPWs and DFWs derived from each integral depth dose curves were compared. Fluence homogeneity of 430 MeV/u carbon-ion beam passing through the PSP was recorded by analyzing radiochromic films at six different locations downstream the PSP in the experiment. Additionally, by changing the beam spot size and incident position on the PSP, totally 48 different carbon-ion beams were simulated and corresponding deviations of beam metrics were evaluated to test the modulating stability of PSP.

According to the measurement data, the use of PSP resulted in an average increase of 0.63 mm in BPW and a decrease of 0.74 mm in DFW compared to PS. The 2D radiation field inhomogeneities were lower than 3 % when the beam passing through a ≥ 10 cm PMMA medium. Furthermore, employing a spot size of ≥ 6 mm ensures that beam metric deviations, including BPW, DFW, and range, remain within a deviation of 0.1 mm across various incident positions.

The developed PSP demonstrated its capability to effectively broaden the BPW of carbon ion beams while maintaining a sharp DFW comparing to PS. The superior performance of PSP, indicates its potential for clinical use in the future.

Australia has taken a collaborative nationally networked approach to achieve particle therapy capability. This supports the under-construction proton therapy facility in Adelaide, other potential proton centres and an under-evaluation proposal for a hybrid carbon ion and proton centre in western Sydney. A wide-ranging overview is presented of the rationale for carbon ion radiation therapy, applying observations to the case for an Australian facility and to the clinical and research potential from such a national centre.

Proton radiography is a promising development in proton therapy, and researchers are currently exploring optimal detector materials to construct proton radiography detector arrays. High-density glass scintillators may improve integrating-mode proton radiography detectors by increasing spatial resolution and decreasing detector thickness. We evaluated several new scintillators, activated with europium or terbium, with proton response measurements and Monte Carlo simulations, characterizing relative luminosity, ionization quenching, and proton radiograph spatial resolution. We applied a correction based on Birks's analytical model for ionization quenching. The data demonstrate increased relative luminosity with increased activation element concentration, and higher relative luminosity for samples activated with europium. An increased glass density enables more compact detector geometries and higher spatial resolution. These findings suggest that a tungsten and gadolinium oxide-based glass activated with 4% europium is an ideal scintillator for testing in a full-size proton radiography detector.

Objective.Compton camera imaging shows promise as a range verification technique in proton therapy. This work aims to assess the performance of a machine learning model in Compton camera imaging for proton beam range verification improvement.Approach.The presented approach was used to recognize Compton events and estimate more accurately the prompt gamma (PG) energy in the Compton camera to reconstruct the PGs emission profile during proton therapy. This work reports the results obtained from the Geant4 simulation for a proton beam impinging on a polymethyl methacrylate (PMMA) target. To validate the versatility of such an approach, the produced PG emissions interact with a scintillating fiber-based Compton camera.Main results.A trained multilayer perceptron (MLP) neural network shows that it was possible to achieve a notable three-fold increase in the signal-to-total ratio. Furthermore, after event selection by the trained MLP, the loss of full-energy PGs was compensated by means of fitting an MLP energy regression model to the available data from true Compton (signal) events, predicting more precisely the total deposited energy for Compton events with incomplete energy deposition.Significance.A considerable improvement in the Compton camera's performance was demonstrated in determining the distal falloff and identifying a few millimeters of target displacements. This approach has shown great potential for enhancing online proton range monitoring with Compton cameras in future clinical applications.

Objective. Proton therapy reduces the integral dose to the patient compared to conventional photon treatments. However,in vivoproton range uncertainties remain a considerable hurdle. Range uncertainty reduction benefits depend on clinical practices. During intensity-modulated proton therapy (IMPT), the target is irradiated from only a few directions, but proton arc therapy (PAT), for which the target is irradiated from dozens of angles, may see clinical implementation by the time considerable range uncertainty reductions are achieved. It is therefore crucial to determine the impact of PAT on range uncertainty reduction benefits.Approach. For twenty head-and-neck cancer patients, four different treatment plans were created: an IMPT and a PAT treatment plan assuming current clinical range uncertainties of 3.5% (IMPT3.5%and PAT3.5%), and an IMPT and a PAT treatment plan assuming that range uncertainties can be reduced to 1% (IMPT1%and PAT1%). Plans were evaluated with respect to target coverage and organ-at-risk doses as well as normal tissue complication probabilities (NTCPs) for parotid glands (endpoint: parotid gland flow <25%) and larynx (endpoint: larynx edema).Main results. Implementation of PAT (IMPT3.5%-PAT3.5%) reduced mean NTCPs in the nominal and worst-case scenario by 3.2 percentage points (pp) and 4.2 pp, respectively. Reducing range uncertainties from 3.5% to 1% during use of IMPT (IMPT3.5%-IMPT1%) reduced evaluated NTCPs by 0.9 pp and 2.0 pp. Benefits of range uncertainty reductions subsequently to PAT implementation (PAT3.5%-PAT1%) were 0.2 pp and 1.0 pp, with considerably higher benefits in bilateral compared to unilateral cases.Significance. The mean clinical benefit of implementing PAT was more than twice as high as the benefit of a 3.5%-1% range uncertainty reduction. Range uncertainty reductions are expected to remain beneficial even after PAT implementation, especially in cases with target positions allowing for full leveraging of the higher number of gantry angles during PAT.

This study aimed to explore the potential of metal oxides such as Titanate Scrolled Nanosheets (TNs) in improving the radiosensitivity of sarcoma cell lines. Enhancing the response of cancer cells to radiation therapy is crucial, and one promising approach involves utilizing metal oxide nanoparticles. We focused on the impact of exposing two human sarcoma cell lines to both TNs and ionizing radiation (IR). Our research was prompted by previous in vitro toxicity assessments, revealing a correlation between TNs' toxicity and alterations in intracellular calcium homeostasis. A hydrothermal process using titanium dioxide powder in an alkaline solution produced the TNs. Our study quantified the intracellular content of TNs and analyzed their impact on radiation-induced responses. This assessment encompassed PIXE analysis, cell proliferation, and transcriptomic analysis. We observed that sarcoma cells internalized TNs, causing alterations in intracellular calcium homeostasis. We also found that irradiation influence intracellular calcium levels. Transcriptomic analysis revealed marked disparities in the gene expression patterns between the two sarcoma cell lines, suggesting a potential cell-line-dependent nano-sensitization to IR. These results significantly advance our comprehension of the interplay between TNs, IR, and cancer cells, promising potential enhancement of radiation therapy efficiency.

The proton irradiation modality has transitioned from passive scattering (PS) to pencil beam scanning. Nevertheless, the documented outcomes predominantly rely on PS.

Thirty patients diagnosed with prostate cancer were selected to assess treatment planning across line scanning (LS), PS, and volumetric modulated arc therapy (VMAT). Dose constraints encompassed clinical target volume (CTV) D98 ≥ 73.0 Gy (RBE), rectal wall V65 < 17% and V40 < 35%, and bladder wall V65 < 25% and V40 < 50%. The CTV, rectal wall, and bladder wall dose volumes were calculated and evaluated using the Freidman test.

The LS technique adhered to all dose limitations. For the rectal and bladder walls, 10 (33.3%) and 21 (70.0%) patients in the PS method and 5 (16.7%) and 1 (3.3%) patients in VMAT, respectively, failed to meet the stipulated requirements. The wide ranges of the rectal and bladder wall volumes (V10-70) were lower with LS than with PS and VMAT. LS outperformed VMAT across all dose-volume rectal and bladder wall indices.

The LS method demonstrated a reduction in rectal and bladder doses relative to PS and VMAT, thereby suggesting the potential for mitigating toxicities.

Objective.Proton radiograph has been broadly applied in proton radiotherapy which is affected by scattered protons which result in the lower spatial resolution of proton radiographs than that of x-ray images. Traditional image denoising method may lead to the change of water equivalent path length (WEPL) resulting in the lower WEPL measurement accuracy. In this study, we proposed a new denoising method of proton radiographs based on energy resolved dose function curves.Approach.Firstly, the corresponding relationship between the distortion of WEPL characteristic curve, and energy and proportion of scattered protons was established. Then, to improve the accuracy of proton radiographs, deep learning technique was used to remove scattered protons and correct deviated WEPL values. Experiments on a calibration phantom to prove the effectiveness and feasibility of this method were performed. In addition, an anthropomorphic head phantom was selected to demonstrate the clinical relevance of this technology and the denoising effect was analyzed.Main results.The curves of WEPL profiles of proton radiographs became smoother and deviated WEPL values were corrected. For the calibration phantom proton radiograph, the average absolute error of WEPL values decreased from 2.23 to 1.72, the mean percentage difference of all materials of relative stopping power decreased from 1.24 to 0.39, and the average relative WEPL corrected due to the denoising process was 1.06%. In addition, WEPL values correcting were also observed on the proton radiograph for anthropomorphic head phantom due to this denoising process.Significance.The experiments showed that this new method was effective for proton radiograph denoising and had greater advantages than end-to-end image denoising methods, laying the foundation for the implementation of precise proton radiotherapy.