Particle Therapy Research Articles

Current status and future trends in particle therapy – lessons from an interdisciplinary workshop

PurposeTo provide an introduction to the special issue containing the proceedings of the workshop on cancer therapy using hadrons (proton, carbon ions or boron neutron capture therapy) that was held in Pavia in October 2023 and organized by CNAO and IAEA.MethodsPapers contained in the issue are briefly summarized.ResultsThis issue contains a collection of papers from the workshop that provide a great opportunity to learn about the status and progress of this technology.ConclusionsParticle therapy is exponentially growing worldwide. While several clinical trials are now providing convincing evidence of the effectiveness of the treatment in tumor control and reduced toxicity, the technology remains expensive and the cost effectiveness is still under debate. The IAEA-CNAO workshop provided a clear picture of the state of the art and future prospective of this technology.

Radiolysis of myoglobin concentrated gels by protons: specific changes in secondary structure and production of carbon monoxide

While particle therapy has been used for decades for cancer treatment, there is still a lack of information on the molecular mechanisms of biomolecules radiolysis by accelerated ions. Here, we examine the effects of accelerated protons on highly concentrated native myoglobin, by means of Fourier transform infrared and UV–Visible spectroscopies. Upon irradiation, the secondary structure of the protein is drastically modified, from mostly alpha helices conformation to mostly beta elements at highest fluence. These changes are accompanied by significant production of carbon monoxide, which was shown to come from heme degradation under irradiation. The radiolytic yields of formation of denatured protein, carbon monoxide, and of heme degradation were determined, and found very close to each other: G+denatured Mb ≈ G+CO ≈ G-heme = 1.6 × 10–8 ± 0.1 × 10–8 mol/J = 0.16 ± 0.01 species/100 eV. The denaturation of the protein to a beta structure and the production of carbon monoxide under ion irradiation are phenomena that may play an important role in the biological effects of ionizing radiation.

Particle Therapy for Cancer of the Head & Neck and Tracheoesophageal Region：Current Status and Future Prospects

Particle Therapy for Cancer of the Head & Neck and Tracheoesophageal Region：Current Status and Future Prospects

Impact of proton PBS machine operating parameters on the effectiveness of layer rescanning for interplay effect mitigation in lung SBRT treatment.

Rescanning is a common technique used in proton pencil beam scanning to mitigate the interplay effect. Advances in machine operating parameters across different generations of particle therapy systems have led to improvements in beam delivery time (BDT). However, the potential impact of these improvements on the effectiveness of rescanning remains an underexplored area in the existing research. We systematically investigated the impact of proton machine operating parameters on the effectiveness of layer rescanning in mitigating interplay effect during lung SBRT treatment, using the CIRS phantom. Focused on the Hitachi synchrotron particle therapy system, we explored machine operating parameters from our institution's current (2015) and upcoming systems (2025A and 2025B). Accumulated dynamic 4D dose were reconstructed to assess the interplay effect and layer rescanning effectiveness. Achieving target coverage and dose homogeneity within 2% deviation required 6, 6, and 20 times layer rescanning for the 2015, 2025A, and 2025B machine parameters, respectively. Beyond this point, further increasing the number of layer rescanning did not further improve the dose distribution. BDTs without rescanning were 50.4, 24.4, and 11.4s for 2015, 2025A, and 2025B, respectively. However, after incorporating proper number of layer rescanning (six for 2015 and 2025A, 20 for 2025B), BDTs increased to 67.0, 39.6, and 42.3s for 2015, 2025A, and 2025B machine parameters. Our data also demonstrated the potential problem of false negative and false positive if the randomness of the respiratory phase at which the beam is initiated is not considered in the evaluation of interplay effect. The effectiveness of layer rescanning for mitigating interplay effect is affected by machine operating parameters. Therefore, past clinical experiences may not be applicable to modern machines.

The MedAustron particle therapy accelerator facility

The MedAustron particle therapy accelerator facility

Comparing efficacy of charged-particle therapy with brachytherapy in treatment of uveal melanoma.

Uveal melanoma (UM) is the most common primary ocular tumour in adults. The most used eye-preserving treatments are charged-particle therapy (CPT) and brachytherapy. We performed a systematic review and meta-analysis to compare efficacies and complications of these two radiotherapies. We searched EMBASE, PubMed, MEDLINE, and the Cochrane Library from January 2012 to December 2022. Two independent reviewers identified controlled studies comparing outcomes of CPT versus brachytherapy. Case series that utilize either treatment modality were also reviewed. One hundred fifty studies met the eligibility criteria, including 2 randomized control trials, 5 controlled cohort studies, and 143 case series studies. We found significant reduction in local recurrence rate among patients treated with CPT compared to brachytherapy (Odds ratio[OR] 0.38, 95% Confidence interval [CI] 0.24-0.60, p < 0.01). Analysis also showed a trend of increased risks of secondary glaucoma after CPT. No statistically significant differences were found in analyzing risks of mortality, enucleation, and cataract. Our study suggested no difference in mortality, enucleation rate and cataract formation rate comparing the two treatments. Lower local recurrence rate and possibly higher secondary glaucoma incidence was noted among patients treated with CPT. Nevertheless, the overall level of evidence is limited, and further high-quality studies are necessary to provide a more definitive conclusion.

Data Processing Engine (DPE): data analysis tool for particle tracking and mixed radiation field characterization with pixel detectors Timepix

Hybrid semiconductor pixelated detectors from the Timepix family are advanced detectors for online particle tracking, offering energy measurement and precise time stamping capabilities for particles of various types and energies. This inherent capability makes them highly suitable for various applications, including imaging, medical fields such as radiotherapy and particle therapy, space-based applications aboard satellites and the International Space Station, and industrial applications. The data generated by these detectors is complex, necessitating the development and deployment of various analytical techniques to extract essential information.For this purpose, and to aid the Timepix user community, it was designed and developed the“Data Processing Engine” (DPE) as an advanced tool for data processing designed explicitly for Timepix detectors. The functionality of the DPE is structured into three distinct processing levels: i) Pre-processing: this phase involves clusterization and the application of necessary calibrations and corrections. ii) Processing: this stage includes particle classification, employing machine learning algorithms, and the recognition of radiation fields. iii) Post-processing: involves various analyses, such as directional analysis, coincidence analysis, frame analysis, Compton directional analysis, and the generation of physics products, are performed. The core of the DPE is supported by an extensive experimental database containing calibrations and referential radiation fields of typical environments, including protons, ions, electrons, gamma rays and X rays, as well as thermal and fast neutrons. To enhance accessibility, the DPE is implemented into various user interface platforms such as a command-line tool, an application programming interface, and as a graphical user interface in the form of a web portal. The DPE's broad utility is exemplified through its integration into various applications and developments.

Comprehensive beam delivery latency evaluation for gated proton therapy system using customized multi-channel signal acquisition platform.

Beam delivery latency in respiratory-gated particle therapy systems is a crucial issue to dose delivery accuracy. The aim of this study is to develop a multi-channel signal acquisition platform for investigating gating latencies occurring within RPM respiratory gating system (Varian, USA) and ProBeam proton treatment system (Varian, USA) individually. The multi-channel signal acquisition platform consisted of several electronic components, including a string position sensor for target motion detection, a photodiode for proton beam sensing, an interfacing board for accessing the trigger signal between the respiratory gating system and the proton treatment system, a signal acquisition device for sampling and synchronizing signals from the aforementioned components, and a laptop for controlling the signal acquisition device and data storage. RPM system latencies were determined by comparing the expected gating phases extracted from the motion signal with the trigger signal's state turning points. ProBeam system latencies were assessed by comparing the state turning points of the trigger signal with the beam signal. The total beam delivery latencies were calculated as the sum of delays in the respiratory gating system and the cyclotron proton treatment system. During latency measurements, simulated sinusoidal motion were applied at different amplitudes and periods for complete beam delivery latency evaluation under different breathing patterns. Each breathing pattern was repeated 30 times for statistical analysis. The measured gating ON/OFF latencies in the RPM system were found to be 104.20±13.64ms and 113.60±14.98ms, respectively. The measured gating ON/OFF delays in the ProBeam system were 108.29±0.85ms and 1.20±0.04ms, respectively. The total beam ON/OFF latencies were determined to be 212.50±13.64ms and 114.80±14.98ms. With the developed multi-channel signal acquisition platform, it was able to investigate the gating lags happened in both the respiratory gating system and the proton treatment system. The resolution of the platform is enough to distinguish the delays at the millisecond time level. Both the respiratory gating system and the proton treatment system made contributions to gating latency. Both systems contributed nearly equally to the total beam ON latency, with approximately 100ms. In contrast, the respiratory gating system was the dominant contributor to the total beam OFF latency.

Innovative approaches to enhance high-LETd tumor targeting in carbon ion radiotherapy

PurposeTo present novel approaches in particle therapy that could result in an improvement of patient outcome.MethodsTechnological/planning and biological innovations could bring particle therapy into a new area of precision medicine. However, several hurdles have to be overcome in order to transform these R&D opportunities into clinical advantages. In this contribution, we summarize the potential advantages of novel tumor targeting, through high-LETd boosting strategies with carbon ions, over standard IMPT: LETd-optimization for IMPT plan, IMPTLET, and spot-scanning hadron arc (SHArc) therapy. Two patient cases are presented to showcase the benefit: a pancreatic cancer patient (PATA) and a recurrent glioblastoma patient (PATB).ResultsFor both patients, the prescription dose and target/organs at risk (OARs) optimization goals were reached for the three techniques. In standard IMPT, the maximum LETd is placed outside of the target volume and extends into normal tissues. For the gross target volume (GTV), mean LETd values were, on average, around ∼40–60 keV/µm. IMPTLET allowed an increase in the GTV minimum LETd from 38.4 keV/µm to 48.6 keV/µm, and from 55.1 to 87.1 keV/µm, for PATA and PATB, respectively. SHArc led to an enhancement of the maximum LETd in the GTV up to at least 125 keV/µm, while the minimum GTV LETd were 47.2 keV/µm and 46.1 keV/µm, respectively. For PATA, SHArc lowers the maximum LETd in the gastrointestinal tract to 47.5 keV/µm compared to 88.0 keV/µm and 83.0 keV/µm found for the IMPT and IMPTLET plans, respectively.ConclusionsMany technological and biological innovations could enhance our current clinical approach. Following the current success of the IMPTLET introduction in clinic, SHARc will represent an interesting clinical option in carbon ion therapy.

Monitoring of carbon ion therapeutic beams with thin silicon sensors

Single ion counting in particle therapy may lead to new beam monitoring systems, enabling innovative delivery strategies that are faster and more sensitive than those currently used in clinics. Previous studies carried out by the University and the National Institute of Nuclear Physics (INFN) of Turin have demonstrated the feasibility of using thin silicon detectors to count single protons in clinical beams. The aim of this work is to report the performance of a strip-segmented 60-μm thick silicon PIN sensor used for single carbon ion discrimination. All measurements were performed using the CNAO synchrotron at different beam energies covering the clinical energy range (115–399 MeV/u). Signals from the sensor strips were read using a custom amplifier board and sampled with a 5 GS/s digitizer. The carbon ion signals were analyzed in terms of amplitude, duration, and deposited charge at different sensor bias voltages.

Current perspectives on radiotherapy in hepatocellular carcinoma management: a comprehensive review.

This review examines the transformative role of external beam radiotherapy (EBRT) in managing hepatocellular carcinoma (HCC), spotlighting the progression from traditional EBRT techniques to advanced modalities like intensity-modulated radiotherapy (RT), stereotactic body RT (SBRT), and innovative particle therapy, including proton beam therapy and carbon ion RT. These advancements have significantly improved the precision and efficacy of RT, marking a paradigm shift in the multimodal management of HCC, particularly in addressing complex cases and enhancing local tumor control. The review underscores the synergistic potential of integrating RT with other treatments like transarterial chemoembolization, systemic therapies such as sorafenib, and emerging immunotherapies, illustrating enhanced survival and disease control outcomes. The efficacy of RT is addressed for challenging conditions, including advanced HCC with macrovascular invasion, and RT modalities, like SBRT, are compared against traditional treatments like radiofrequency ablation for early-stage HCC. Additionally, the review accentuates the encouraging outcomes of particle therapy in enhancing local control and survival rates, minimizing treatment-related toxicity, and advocating for continued research and clinical trials. In conclusion, the integration of RT into multimodal HCC treatment strategies, coupled with the emergence of particle therapy, is crucial for advancing oncologic management, emphasizing the need for relentless innovation and personalized treatment approaches.

Evaluation of computed tomography artefacts of carbon-fiber and titanium implants in patients with spinal oligometastatic disease undergoing stereotactic ablative radiotherapy

This study evaluated artefacts on computed tomography (CT) images using Hounsfield units (HU) in patients with spinal oligometastatic disease who received carbon-fiber (CF; n = 11) or titanium (n = 11) spine implants and underwent stereotactic ablative radiotherapy (SABR). Pre- and postoperative HU were measured at the vertebral body, pedicle, and spinal cord at three different levels: the lower instrumented vertebra, the level of metastatic spinal cord compression, and an uninvolved level. Areas measured at each level were delicately matched pre- and postoperatively. Significant differences in HU were observed at the vertebral body, the pedicle, and the spinal cord at the lowest instrumented vertebra level for both CF and titanium (average increase 1.54-fold and 5.11-fold respectively). At the metastatic spinal cord compression level, a trend towards a higher HU-increase was observed in titanium compared with CF treated patients (average increase 2.51-fold and 1.43-fold respectively). The relatively high postoperative HU-increase after insertion of titanium implants indicated CT artefacts, while the relatively low HU-increase of CF implants was not associated with artefacts. Less CT artefacts could facilitate an easier contouring phase in radiotherapy planning. In addition, we propose a CT artefact grading system based on postoperative HU-increase. This system could serve as a valuable tool in future research to assess if less CT artefacts lead to time savings during radiotherapy treatment planning and, potentially, to better tumoricidal effects and less adverse effects if particle therapy would be administered.

Modeling hypoxia-induced radiation resistance and the impact of radiation sources

Hypoxia contributes significantly to resistance in radiotherapy. Our research rigorously examines the influence of microvascular morphology on radiotherapy outcome, specifically focusing on how microvasculature shapes hypoxia within the microenvironment and affects resistance to a standard treatment regimen (30×2GyRBE). Our computational modeling extends to the effects of different radiation sources. For photons and protons, our analysis establishes a clear correlation between hypoxic volume distribution and treatment effectiveness, with vascular density and regularity playing a crucial role in treatment success. On the contrary, carbon ions exhibit distinct effectiveness, even in areas of intense hypoxia and poor vascularization. This finding points to the potential of carbon-based hadron therapy in overcoming hypoxia-induced resistance to RT. Considering that the spatial scale analyzed in this study is closely aligned with that of imaging data voxels, we also address the implications of these findings in a clinical context envisioning the possibility of detecting subvoxel hypoxia.

ENLIGHT (European Network for Light Ion Hadron Therapy) and its role in Hadron therapy

PurposeThis study provides a comprehensive overview of the progress in hadron therapy within Europe, particularly highlighting the critical roles of the Proton Ion Medical Machine Study (PIMMS) and the European Network for Light Ion Hadron Therapy (ENLIGHT).MethodsOur approach includes a retrospective analysis of the advances in hadron therapy facilities, facilitated by a synthesis of interdisciplinary collaboration data gathered from ENLIGHT's annual meetings since 2002, and an assessment of European-funded projects and networks' contributions to the field.ResultsThe results showcase significant advancements in cancer treatment due to collective efforts in hadron therapy, underscored by ENLIGHT’s pivotal role in fostering interdisciplinary cooperation and the harmonization of treatment protocols across Europe.ConclusionThe evolution of hadron therapy, from its inception to its current impact on patient care, demonstrates the successful realization of complex medical technologies through sustained collaboration and standardized practices across European institutions and projects.

Review of the Book Particle Therapy Technology for Safe Treatment Edited by Jay Flanz, CRC Press—Taylor &amp; Francis Group, 2022, ISBN: 9780367643119

Review of the Book Particle Therapy Technology for Safe Treatment Edited by Jay Flanz, CRC Press—Taylor &amp; Francis Group, 2022, ISBN: 9780367643119

Neutron Capture Enhances Dose and Reduces Cancer Cell Viability in and out of Beam During Helium and Carbon Ion Therapy

Neutron capture enhanced particle therapy (NCEPT) is a proposed augmentation of charged particle therapy that exploits thermal neutrons generated internally, within the treatment volume via nuclear fragmentation, to deliver a biochemically targeted radiation dose to cancer cells. This work is the first experimental demonstration of NCEPT, performed using both carbon and helium ion beams with 2 different targeted neutron capture agents (NCAs). Human glioblastoma cells (T98G) were irradiated by carbon and helium ion beams in the presence of NCAs [10B]-BPA and [157Gd]-DOTA-TPP. Cells were positioned within a polymethyl methacrylate phantom either laterally adjacent to or within a 100 × 100 × 60 mm spread out Bragg peak (SOBP). The effect of NCAs and location relative to the SOBP on the cells was measured by cell growth and survival assays in 6 independent experiments. Neutron fluence within the phantom was characterized by quantifying the neutron activation of gold foil. Cells placed inside the treatment volume reached 10% survival by 2 Gy of carbon or 2 to 3 Gy of helium in the presence of NCAs compared with 5 Gy of carbon and 7 Gy of helium with no NCA. Cells placed adjacent to the treatment volume showed a dose-dependent decrease in cell growth when treated with NCAs, reaching 10% survival by 6 Gy of carbon or helium (to the treatment volume), compared with no detectable effect on cells without NCA. The mean thermal neutron fluence at the center of the SOBP was approximately 2.2 × 109 n/cm2/Gy (relative biological effectiveness) for the carbon beam and 5.8 × 109 n/cm2/Gy (relative biological effectiveness) for the helium beam and gradually decreased in all directions. The addition of NCAs to cancer cells during carbon and helium beam irradiation has a measurable effect on cell survival and growth in vitro. Through the capture of internally generated neutrons, NCEPT introduces the concept of a biochemically targeted radiation dose to charged particle therapy. NCEPT enables the established pharmaceuticals and concepts of neutron capture therapy to be applied to a wider range of deeply situated and diffuse tumors, by targeting this dose to microinfiltrates and cells outside of defined treatment regions. These results also demonstrate the potential for NCEPT to provide an increased dose to tumor tissue within the treatment volume, with a reduction in radiation doses to off-target tissue.

Kaplan lecture 2023: lymphopenia in particle therapy.

Lymphopenia is now generally recognized as a negative prognostic factor in radiotherapy. Already at the beginning of the century we demonstrated that high-energy carbon ions induce less damage to the lymphocytes of radiotherapy patients than X-rays, even if heavy ions are more effective per unit dose in the induction of chromosomal aberrations in blood cells irradiated ex-vivo. The explanation was based on the volume effect, i.e. the sparing of larger volumes of normal tissue in Bragg peak therapy. Here we will review the current knowledge about the difference in lymphopenia between particle and photon therapy and the consequences. There is nowadays an overwhelming evidence that particle therapy reduces significantly the radiotherapy-induced lymphopenia in several tumor sites. Because lymphopenia turns down the immune response to checkpoint inhibitors, it can be predicted that particle therapy may be the ideal partner for combined radiation and immunotherapy treatment and should be selected for patients where severe lymphopenia is expected after X-rays.

Commissioning and Validation of CT Number to SPR Calibration in Carbon Ion Therapy Facility

PurposeWe performed computed tomography (CT)—stopping power ratio (SPR) calibration in a carbon-ion therapy facility and evaluated SPR estimation accuracy. Materials and MethodsA polybinary tissue model method was used for the calibration of CT numbers and SPR. As a verification by dose calculation, we created a virtual phantom to which the CT-SPR calibration table was applied. Then, SPR was calculated from the change in the range of the treatment planning beam when changing to 19 different CT numbers, and the accuracy of the treatment planning system (TPS) calculation of SPR values from the CT-SPR calibration table was validated. As a verification by measurement, 5 materials (water, milk, olive oil, ethanol, 40% K2HPO4) were placed in a container, and the SPR was obtained by measurement from the change in the range of the beam that passed through the materials. ResultsThe results of the dose calculations of the TPS showed that the results agreed within 1% for the lower CT numbers up to 1000 HU, but there was a difference of 3.0% in the higher CT number volume. The difference between the SPR calculated by TPS and the SPR caused by the difference in the energy of the incident particles agreed within 0.51%. The accuracy of SPR estimation was measured, and the error was within 2% for all materials tested. ConclusionThese results indicate that the SPR estimation errors are within the range of errors that can be expected in particle therapy. From commissioning and verification results, the CT-SPR calibration table obtained during this commissioning process is clinically applicable.

P 16 - Is 180 the optimal gantry angle breakpoint for particle therapy?

P 16 - Is 180 the optimal gantry angle breakpoint for particle therapy?

Understanding Relative Biological Effectiveness and Clinical Outcome of Prostate Cancer Therapy Using Particle Irradiation: Analysis of Tumor Control Probability With the Modified Microdosimetric Kinetic Model

Purpose: Recent experimental studies and clinical trial results might indicate that - at least for some indications - continued use of the mechanistic model for relative biological effectiveness (RBE) applied at carbon ion therapy facilities in Europe for several decades (LEM-I) may be unwarranted. We present a novel clinical framework for prostate cancer treatment planning and tumor control probability (TCP) prediction based on the modified microdosimetric kinetic model (mMKM) for particle therapy. Methods: Treatment plans of 91 prostate tumor patients (proton: 46, carbon ions: 45) applying 66GyRBE [RBE=1.1 for protons and LEM-I, (α/β)x=2.0Gy, for carbon ions] in 20 fractions were recalculated using mMKM ((α/β)x=3.1Gy). Based solely on the response data of photon-irradiated patient groups stratified according to risk and usage of ADT, we derived parameters for an mMKM-based Poisson-TCP model. Subsequently, new carbon and helium ion plans, adhering to prescribed biological dose criteria, were generated. These were systematically compared to the clinical experience of Japanese centers employing an analogous fractionation scheme and existing proton plans. Results: mMKM predictions suggested significant biological dose deviation between proton and carbon ion arms. Patients irradiated with protons received 3.25±0.08GyRBEmMKM/Fx, while patients treated with carbon ions received 2.51±0.05GyRBEmMKM/Fx. TCP predictions were 86±3% for protons and 52±4% for carbon ions, matching the clinical outcome of 85% and 50%. Newly optimized carbon ion plans, guided by the mMKM/TCP model, effectively replicated clinical data from Japanese centers. Using mMKM, helium ions exhibited similar target coverage as proton and carbon ions and an improved rectum and bladder sparing compared to proton. Conclusions: Our mMKM-based model for prostate cancer treatment planning and TCP prediction was validated against clinical data for proton and carbon ion therapy and its application was extended to helium ion therapy. Based on the data presented in this work, mMKM seems to be a good candidate for clinical biological calculations in carbon ion therapy for prostate cancer.