Objective.The LET trilemma-an inherent conflict between target dose homogeneity, range robustness, and high dose-averaged linear energy transfer (LETd)-poses a major challenge in treatment optimization. To ensure accurate beam delivery in multi-ion therapy, this study evaluated the effects of range and setup uncertainties on LETd-optimized treatment plans and explored strategies to overcome this trilemma, framed within the phase I LETdescalation trial for head and neck cancers.Approach.Six head and neck cancer patients representing diverse tumors were selected. Multi-ion therapy plans using carbon-, oxygen-, and neon-ion beams were optimized to achieve a target LETdof 90 keV μm-1(the final LETdlevel of the phase I trial). These plans were recalculated to incorporate systematic range uncertainty (±2.5%) and random daily setup variations (mean, 0.45 mm; standard deviation, 0.23 mm) across the 16 fractions, and their combined effects on the dose and LETddistributions were evaluated. Additionally, to explore strategies to enhance plan robustness, five modified plans were evaluated for one patient identified as particularly susceptible to these uncertainties.Main Results.Range uncertainty was the dominant contributor to degraded plan quality, substantially outweighing setup uncertainty. A small, centrally located tumor was most susceptible, exhibiting dose inhomogeneity of approximately 11%, while LETdvariations were approximately 3 keV μm-1. The most effective mitigation strategy involved replacing the original carbon-oxygen combination with oxygen ions for two beam ports, reducing dose inhomogeneity by more than 7% while maintaining normal tissue sparing adjacent to the target.Significance.Optimization toward achieving higher LETdmakes treatment plans susceptible to range uncertainty, leading to dose degradation within small, deep-seated tumors. Employing heavier ions is an effective strategy to overcome this challenge, enabling robust target coverage by leveraging their inherently higher LETdwhile sparing normal tissues. These findings provide a key rationale for ion selection in the design of robust multi-ion therapy.

This work investigates the radiation shielding efficiency of high-density polyethylene (HDPE) graphene, carbon fiber (CF), and polyethylene materials. The composite HDPE graphene was studied both as a substitute layer in the ISS wall/Columbus shielding configuration and as an additional layer serving as intravehicular spacesuits for astronauts. The average quality factors ( Q(sic) ) for C-12, Ar-40, and Fe-56 ion beams were evaluated using the silicon-on-insulator (SOI) Mushroom microdosimeter behind various realistic ISS Columbus wall configurations at the Heavy Ion Medical Accelerator in Chiba (HIMAC), Japan. Moreover, the individual dose equivalent, Hp(10), was calculated for astronaut personal monitoring. The SOI microdosimeter's response to the monoenergetic ion beams behind these shielding configurations enabled comparison of the shielding efficiencies for the tested materials. The results indicate that the shielding efficiency of HDPE graphene is similar to that of CF and Kevlar.

Neon ion (20Ne) beam radiotherapy was one of the primary particle therapy candidates investigated during the clinical trials beginning in the 1970s at the Lawrence Berkely National Laboratory (LBNL), which shut down in the early 1990s. Currently, therapeutic neon ion beams are available at only one clinical facility worldwide, the National Institutes for Quantum Science and Technology (QST) in Chiba, Japan. Recently, neon ion beams were commissioned at QST Hospital as part of the first clinical multi-ion therapy (MIT) program, which aims to improve clinical outcomes by escalating higher linear energy transfer (LET) radiation in the tumor for treating therapy-resistant disease. With the advancement of high-precision scanning delivery techniques, neon ion treatments in the present day could be delivered more safely and with greater precision compared to the first and only clinical application decades prior at LBNL using passive scattering technology. Despite their promising results, preclinical investigations of neon ions are scarce outside of Japan and further independent studies are needed. Clinically, neon ion therapy may offer benefits in treating certain malignancies by escalating LET in the tumor, but its limited availability and high costs restrict its current use and adoption. Studies have shown that20Ne or multi-ion mixtures (4He,12C,16O and/or20Ne) can provide larger degrees of freedom in optimization of dose, LET and relative biological effectiveness, otherwise unattainable with other single ion techniques. Neon ion beams are under investigation in the ongoing MIT clinical trials which will establish their broader applicability. In this review, the technology, physics, radiobiology, and potential clinical applications of neon ion beams are outlined. The status of therapeutic neon ion beams is provided while discussing future research and clinical directions, including technological development of novel particle therapy delivery techniques, such as multi-ion, mini-beam, arc, and ultra-high dose rate.

BACKGROUND:Carbon ion radiotherapy (CIRT) in the upright posture is a treatment technique which delivers carbon ion beams from a fixed direction to patients who sit or stand on a rotating chair. Although various potential advantages of the upright positioning have been discussed, feasibility of upright CIRT for prostate cancer has not been quantitatively evaluated. PURPOSE:This study demonstrated prostate cancer CIRT in the upright posture and evaluated its feasibility by comparing anatomy and dosimetric metrics between the supine and upright postures. METHODS:A total of 12 pairs of computed tomography (CT) images of asymptomatic volunteers in the supine and upright postures were retrospectively analyzed. Based on a clinical treatment protocol, clinical target volume (CTV) was defined as being a prostate gland and proximal seminal vesicle. Other target and organ-at-risk (OAR) contours within a planning volume were also delineated. A CIRT plan was calculated for each CT volume with the same dose prescription and evaluation criteria. The delineated contour volumes, 16 dosimetric metrics, dose-volume histograms (DVHs) of CTV and OARs, and robustness against setup and range uncertainties were compared between the supine and upright postures. RESULTS:No significant differences in the contour volumes were found between the two postures (p > 0.05). The CTV and rectum contour volumes were 34.30 ± 7.76 and 36.35 ± 13.53 cm3 for the supine posture and 35.89 ± 7.37 and 32.96 ± 8.08 cm3 for the upright posture, respectively. Moreover, mean absolute differences of five CTV dosimetric metrics (D2%, D5%, D50%, D95%, and D98%) were all less than 0.15 Gy (0.29% of the prescription dose of 51.6 Gy). Nine other dosimetric metrics in the upright posture were also equivalent to those in the supine posture. The DVHs and robustness in the upright posture were in agreement with those in the supine posture. CONCLUSIONS:The upright CIRT provided dose distributions with target dose coverage and OAR dose sparing equivalent to those of the conventional supine CIRT. Upright CIRT for prostate cancer is expected to have equivalent treatment effectiveness while offering reduced installation costs and simple system management of platforms.

The exploitation of the high relative biological effectiveness (RBE) of carbon ions is one of the major rationales for their use as a radiation therapy modality. As the RBE depends on many physical and biological factors, biophysical models are used to compute it for the complex radiation fields used in clinical settings. However, the models currently applied in clinics or used to interpret clinical results make different RBE predictions. This creates difficulties for direct comparability of RBE-weighted doses delivered and reported within different approaches. Additional conventions on how these models are applied also differ and further complicate the comparison. Consequently, it is crucial to understand the impact of RBE modeling on the delivered absorbed doses and the reported RBE-weighted doses. Translation concepts between dose prescription systems, that is, the models and the context in which they are used, are needed to exchange treatment protocols between centers with different planning methods and to establish joint clinical studies or meta-studies. Although many of these problems are solved for specific cases, a broad perspective is lacking on how to transparently proceed with multiple RBE models and corresponding concepts of RBE-weighted dose. The present publication is a product of an initiative within the subcommittee on Guidelines in Carbon Ion Radiation Therapy of the Particle Therapy Co-operative group (PTCOG). It aims to (1) raise awareness of the problem; (2) demonstrate the impact of different models used for RBE predictions; (3) provide information on how RBE is currently accounted for; and (4) give an overview of approaches toward the translation of doses. Along this route, we provide several expert consensus statements agreed on by all authors, which provide insights into the complexity of understanding and comparing different dose prescription systems. Despite this complexity, transforming treatment plans between any 2 systems is feasible, opening up novel planning strategies that consider multiple models and paving the way for multi-institutional clinical studies .

To clarify the mechanisms of FLASH radiotherapy using C ion beams (373 MeV/u and 90 MeV/u), we investigated the dose rate dependence of yields of water radiolysis species (OH radicals, hydrated electrons, and hydrogen peroxide). Additionally, we evaluated changes in the induction rate of DNA strand breaks as a function of dose rate using pBR322 plasmid DNA in solutions. Average dose rates were 0.2 Gy/s [conventional (CONV)] and 75 Gy/s [ultra-high dose rate (UHDR)] for 373 MeV/u, and 0.3 Gy/s (CONV) and 100 Gy/s (UHDR) for 90 MeV/u. The G values of water radiolysis species decreased with UHDR irradiation compared to CONV dose rate, except for hydrogen peroxide exposed to 90 MeV/u C ions, whose yield remained independent of dose rate. Furthermore, the induction rate of single-strand breaks (SSB) was unaffected by dose rate, while the induction of double-strand breaks (DSB) decreased after UHDR irradiation. These findings suggest that radical-radical reactions occur more efficiently with increasing dose rate, resulting in a reduced contribution of water radiolysis species to DNA strand breaks, especially DSBs, after irradiation with C ions. Therefore, changes in the contribution of water radiolysis species to DNA strand breaks could play a crucial role in the sparing effects observed after UHDR irradiation.

BACKGROUND:Conducting carbon ion radiotherapy (CIRT) in upright posture has several technical advantages over that in conventional supine posture for pancreatic cancer treatment. However, few studies have investigated effects of upright positioning on anatomy and CIRT dose distributions. PURPOSE:This study compared anatomy and dose distributions in CIRT for pancreatic cancer between supine and upright postures. METHODS:Fourteen pairs of computed tomography (CT) images obtained from asymptomatic volunteers in these postures were analyzed. Clinical target volume (CTV), organs-at-risk (OARs), and gastrointestinal gas contours were delineated within a planning volume for each CT image, and a CIRT dose distribution was calculated. The anatomical differences between these postures were evaluated by comparing volumes and 3D rendered images of the contours, while the dosimetric differences were assessed with 12 dosimetric metrics. Moreover, a proximal overlap volume of the OARs and possible change in water-equivalent path length due to gastrointestinal gas were calculated for all coplanar beam angles to compare ranges of applicable beam angles and potential range uncertainty between these postures. RESULTS:The bowel contour volumes in the upright posture were more than 46% smaller than those in the supine posture because the bowel was shifted. The upright posture provided a smaller dose to the bowel and higher dose coverage to the CTV than the supine posture. The possible water-equivalent path length changes due to the stomach and duodenum gas decreased at most beam angles in the upright posture. CONCLUSIONS:The upright CIRT had several anatomical and dosimetric advantages for pancreatic cancer treatment over conventional supine CIRT. This technique will be useful in applying the patient-specific beam angle arrangement and precise dose delivery with reduced range uncertainty.

PURPOSE:This study quantified inter- and intra-fractional setup accuracies in the upright posture and compared them among setups with different immobilization methods. METHODS:Two and four setups were examined for abdominal and head and neck (HN) cancer treatments, respectively. Fifteen asymptomatic volunteers were positioned to a replicated chair of an upright radiotherapy platform with leg immobilization devices, backrest attachments, thermoplastic masks, and vacuum cushions. The 3D positions of the subject body and masks were monitored by calculating 3D point clouds of 26 surface markers from three camera images. The inter-fractional setup errors were calculated by repeating the same setup five times. The intra-fractional displacements were evaluated while the subjects remained in the setups for 20 min. These setup errors and displacements were compared among the setups with different immobilization methods. The intra-fractional displacements were also compared between this study and previous studies in the supine posture. RESULTS:Inter-fractional setup errors in the abdominal setups were reduced from 6.6 ± 3.3 to 3.9 ± 1.7 mm by using the masks. The HN setup using both the leg immobilization devices and backrest attachments had the setup errors of 2.9 ± 1.7 mm. This was smaller than the setup errors observed in three other HN setups that did not use either or both of the devices together. Intra-fractional displacements of these abdominal and HN setups with the immobilization devices were 1.9 ± 1.1 and 1.8 ± 1.5 mm, respectively, which were smaller than those in the other setups. These displacements were equivalent to those in the previous studies. CONCLUSIONS:Utilizing the masks increased upright setup accuracy in the abdominal setup. The leg immobilization devices and backrest attachments provided the highest setup accuracy in the upright HN setup. These findings will be useful to expand the applicability of upright radiotherapy for various cancer treatments.

Purpose Modeling relative biological effectiveness (RBE) is central to carbon ion radiotherapy treatment planning. The modified Microdosimetric Kinetic Model (mMKM) is a clinically established RBE framework that has guided treatment protocols at many existing carbon centers, while the Mayo Clinic Florida Microdosimetric Kinetic Model (MCF MKM) is a recently developed alternative. This work aims to implement the MCF MKM in the open-source treatment planning system matRad and to quantitatively compare its RBE-weighted dose predictions with those of the clinically established mMKM using identical physical dose distributions across multiple disease sites. These findings will help assess their dosimetric equivalence and inform protocol development for carbon ion radiotherapy at MCF.Methods Monte Carlo simulations of the MCF carbon beamline were performed to generate physical (IDD, LET, lateral spread) and biological base data for integration of each RBE model into matRad. Treatment plans were generated for six patients, each corresponding to a different disease site, using clinical beam configurations with carbon-reference dose prescriptions, and plans were optimized using the MCF MKM. To isolate differences attributable solely to the RBE model, the resulting physical dose distributions were held fixed and RBE-weighted doses were recalculated using the mMKM. Dose volume histogram (DVH) metrics and spatial dose-difference maps were used to compare target coverage and organ-at-risk doses between the two models.Results Across patient cases, RBE-weighted dose distributions from MCF MKM and mMKM showed strong agreement. Differences in target coverage were small, with CTV D95% differing by less than 1.6% across all disease sites and maximum target dose differences not exceeding 0.88%. Organ-at-risk dose deviations were limited, with differences of 3.0% or less across evaluated DVH metrics. Spatial dose-difference maps showed that the largest discrepancies occurred in regions of steep dose gradients near target to organ-at-risk interfaces, while overall dose conformity and plan quality remained comparable between the two models.Conclusions: This study served as the first systematic model comparison of the MCF MKM and mMKM within a treatment planning environment. These findings suggest that the MCF MKM and mMKM produce dosimetrically consistent RBE-weighted dose predictions under realistic planning conditions using carbon-reference parameters. Accordingly, the fractionation schemes developed from years of clinical experience with mMKM implementations may serve as a practical foundation for protocol development at MCF.

BACKGROUND:Multi-ion radiotherapy using carbon, oxygen, and neon ions aims to improve local control by increasing dose-averaged linear energy transfer (LETd) in the target. However, there has been limited understanding of how to utilize variables for multi-ion treatment planning such as the selection and arrangement of ion species. PURPOSE:An in silico study was conducted to explore the feasibility of increasing a minimum LETd, and the optimal selection and arrangement of ion species in multi-ion therapy for increasing LETd in tumors of varying sizes mimicking bone and soft tissue sarcomas (BSTS). Additionally, the robustness of multi-ion therapy against setup and range errors was evaluated. METHODS:Spherical targets of 500, 1000, and 1500-mL volumes were placed at the center or 80 mm horizontally displaced from the center of a numerical phantom to simulate BSTS treatments. Treatment plans were made for these targets with two orthogonal fields of carbon-only, oxygen+carbon, and neon+carbon ions with a total dose of 70.4 Gy (RBE). The treatment parameters were optimized to increase the LETd in the targets while ensuring adequate target dose coverage and dose homogeneity. The plans were evaluated based on the dose covering 95% of the target (D95%), skin dose (Dskin), and the minimum LETd excluding the 1 mL volume with the lowest LETd (L1mL). Multi-ion radiotherapy treatment plans were also developed for 12 patients with BSTS who had previously received carbon-ion radiotherapy. D95% and L1m of the target, and the dose to organs at risk (OARs) such as the rectum, intestine, and spinal cord were assessed. The robustness of the plans created in the phantom against setup and range errors was evaluated under 2 mm shifts in six directions combined with 2.5% variation of the stopping power ratio, resulting in 12 scenarios. Differences in the target D95% and L1mL, and Dskin in each scenario from those in the nominal plan were evaluated. RESULTS:The target dose coverage was comparable for any ion species combinations regardless of target size and position. The L1mL in the target increased by 7-9 and 15-20 keV/µm with the oxygen+carbon and neon+carbon plans, respectively, compared to the carbon-only plans, while maintaining homogeneity index values below 0.10. Additionally, the skin dose increased by 2.2-7.0 and 9.2-14.6 Gy (RBE) for the oxygen+carbon and neon+carbon plans. The L1mL was greater than or equal to 40 keV/µm in all phantom targets and most clinical cases for the oxygen+carbon and neon+carbon plans, while meeting the target and OAR dose requirements. In the robustness evaluation, the variations in D95% were comparable or smaller in the oxygen+carbon and neon+carbon plans than in the carbon-only plan. The maximum decrease in L1mL in the target was 1.5 keV/µm. The maximum increase in Dskin was 2.4 Gy (RBE) in the target closest to the skin. CONCLUSIONS:The LETd was successfully increased with the oxygen+carbon and neon+carbon ions, while meeting the dose requirements. The multi-ion therapy plans created using the method presented in this study were robust to setup and range errors.

Objective.The tumor microenvironment characterized by heterogeneously organized vasculatures causes intra-tumoral heterogeneity of oxygen partial pressurepat the cellular level, which cannot be measured by current imaging techniques. The intra-tumoral cellularpheterogeneity may lead to a reduction of therapeutic effects of radiation. The purpose of this study was to investigate the effects of the heterogeneity on biological effectiveness of H-, He-, C-, O-, and Ne-ion beams for different oxygenation levels, prescribed dose levels, and cell types.Approach.The intra-tumoral cellularpdistributions were simulated with a numerical tumor model for average oxygen pressuresp¯tranging from 2.5 to 15 mmHg. The relative biological effectiveness (RBE)-weighted dose distributions of 3-15 Gy prescribed doses were planned for a cuboid target with the five ion species for constantp¯tvalues. Radiosensitivities of human salivary gland tumor (HSG) and Chinese hamster ovary (CHO) cells were investigated. The planned dose distributions were then recalculated by taking thepheterogeneity into account.Main results.Asp¯tdecreased and prescribed dose increased, the biological effectiveness of the ion beams decreased due to thepheterogeneity. The reduction in biological effectiveness was pronounced for lighter H- and He-ion beams compared to heavier C-, O-, and Ne-ion beams. The RBE-weighted dose in the target for HSG (CHO) cells decreased by 41.2% (44.3%) for the H-ion beam, while it decreased by 16.7% (14.7%) for the Ne-ion beam at a prescribed dose of 15 Gy under ap¯tof 2.5 mmHg.Significance.The intra-tumoral cellularpheterogeneity causes a significant reduction in biological effectiveness of ion beams. These effects should be considered in estimation of therapeutic outcomes.

Particle beam therapy is becoming increasingly popular as an advanced cancer treatment method, and currently proton and (stable) carbon ion beams are used clinically. Recently, in-beam positron emission tomography (PET) has been investigated for dose monitoring technique during particle therapy. However, the signal-to-noise ratio of in-beam PET images is poor due to the low yield of positron emitters. On the contrary, radioactive ion (RI) beams is ideally suited to particle therapy using in-beam PET due to its high signal-to-noise ratio. In addition, RI beams enable more accurate analysis of the biological washout effect than conventional stable beam irradiations do. These advantages have been clearly demonstrated in many animal studies with prototyped PET systems. On the other hand, there are several issues that limit clinical use of RI beams such as the low RI beam intensity, large momentum distribution, and the limited number of RI beam facilities. This article reviews the state-of-the-art research and development for applications of RI beams to particle beam therapy.

BACKGROUND:Understanding respiratory motions of liver and its surrogate organs is crucial for precise dose delivery in liver cancer radiotherapy. Although these motions have been studied for respiratory motion management in the supine posture, few studies have quantified them and evaluated their correlations in the upright posture. PURPOSE:This study quantified the respiratory motions of liver and surrogate organs and evaluated the correlations between the liver motions and surrogate signals for respiratory motion monitoring in both the supine and upright postures. METHODS:4D dynamic volume computed tomography (CT) images were acquired from 13 asymptomatic volunteers in both supine and upright postures while free breathing. The 4D liver motions were calculated by performing deformable image registration. Subsequently, superior-inferior (SI) motion at the right diaphragm apex and anterior-posterior (AP) motion at the abdominal skin surface were obtained as surrogate signals from the 4D CT images. The average displacements and maximum magnitudes of liver motions and surrogate signals were compared between the postures. Moreover, the correlations between the liver motions and surrogate signals were evaluated based on correlation models. RESULTS:The average liver displacements from the end-exhalation along the SI, AP, and left-right directions were -6.1, 2.1, and -0.4 mm in the supine posture and -4.6, 2.5, and 0.1 mm in the upright posture, respectively. The maximum motion range along the SI direction significantly decreased from 16.3 ± 6.6 mm in the supine posture to 11.0 ± 2.7 mm in the upright posture. Similar to the supine posture, the correlation models also reproduced the liver motions with high fitting accuracy in the upright posture. CONCLUSIONS:Compared to the conventional supine posture, the liver SI motion became smaller in the upright posture while keeping evident correlations with the surrogate signals, which suggests the upright posture will allow precise dose delivery with reduced internal target margins.

Objective. In order to initiate multi-ion therapy for head and neck cancers, it is necessary to predetermine the target dose-averaged linear energy transfer (LETd) prescription to the gross tumor volume (GTV). This study investigated LETdoptimized treatment plans with carbon-, oxygen-, and neon-ion beams and demonstrated their potential efficacy against tumor hypoxia.Approach. Sixteen head and neck cancer patients with GTV sizes ranging from 5.5 to 143.1 cm3were selected for this retrospective planning study. Carbon, oxygen, and neon ions were used alone or in combination with two ion species. The treatment plans were optimized to increase LETdwithin the GTV and to make the LETddistribution uniform while maintaining the relative biological effectiveness weighted dose distributions of conventional intensity modulated carbon-ion therapy (IMIT). The effective dose improvement rate against IMIT was then estimated by changing oxygen partial pressure within the GTV to 0 mmHg because a substantial number of anoxic cancer cells is predicted to exist in a hypoxic tumor microenvironment.Main results. The target LETdof 90 keVμm-1was prescribable without deteriorating the dose distributions when: for example, carbon- and oxygen-ion beams were used for small tumors (around 20 cm3); oxygen-ion beams alone were used for medium tumors (around 50 cm3); and carbon- and neon-ion beams were used for large tumors (around 100 cm3). The uniformity of the LETddistributions within the GTV was about 10%. With the LETdprescription, the improvement rate of the effective dose covering 98% (i.e.D98%) of the GTV against anoxic cancer cells was about 30%.Significance. For the application to the first multi-ion therapy program, the target LETdprescription to the GTV was determined to be 90 keVμm-1. If tumor hypoxia contributes to the cause of recurrence, the proposed treatment may offer better local tumor control without compromising normal tissue sparing.

Objective: the recently developed V79-RBE10 biological weighting function (BWF) model is a simple and robust tool for a fast relative biological effectiveness (RBE) assessment for comparing different exposure conditions in particle therapy. In this study, the RBE10 derived by this model (through the particle and heavy ion transport code system (PHITS) simulated d(y) spectra) is compared with values of RBE10 using experimentally derived d(y) spectra from a silicon-on-insulator (SOI) microdosimeter. Approach: experimentally measured d(y) spectra are used to calculate an RBE10 value utilizing the V79-RBE10 BWF model as well as the modified microdosimetric kinetic model (MKM) to produce an RBE10-vs-yD trend for a wide range of ions. In addition, a beamline specific PHITS simulation was conducted which replicated the exact experimental conditions that were used with the SOI microdosimeter at the heavy ion medical accelerator in Chiba biological beamline with 12C ions. Main Results: the RBE10-vs-yD trend for 1H, 4He, 7Li, 12C, 14N, 16O, 20Ne, 28Si, 56Fe, and 124Xe ions is examined with good agreement found between the SOI microdosimeter derived RBE10 values with the V79-RBE10 BWF model and MKM, as well as the PHITS simulations for 1H, 4He, 7Li, 12C, 16O, and 56Fe ions while some discrepancies were seen for 14N, 20Ne, and 28Si ions. Deviations have been attributed to the difference in the derivation of the d(y) spectra based on the different methods utilized. Good agreement was found between yD values and an over estimation was observed for RBE10 values for the beamline specific simulation of the 12C ion beam. Significance: overall, this study shows that the SOI microdosimeter is a valuable tool that can be utilized for quick and accurate experimental derivation of the d(y) spectra, which can then be convoluted with the weighting function of the V79-RBE10 BWF model to derive RBE10. The SOI microdosimeter is able to derive experimental values of yD and RBE10 for various ions in any irradiation condition utilizing other radiobiological models.

INTRODUCTION:The standard treatment for unresectable head and neck cancer typically involves radiotherapy (RT) alone or chemoradiotherapy (chemo-RT). Non-squamous cell carcinomas exhibit relatively low radiosensitivity, limiting the efficacy of conventional photon RT. Carbon-ion (C-ion) RT, characterised by high linear energy transfer (LET) and high relative biological effectiveness (RBE), has shown promising outcomes in treating radioresistant head and neck cancers. However, local recurrences still occur, and further improvements in treatment outcomes are needed. To enhance the local control rate, an increase in dose-averaged LET (LETd) to the tumour was considered.Following a simulation study, a clinical trial was conducted to optimise LETd using only C-ion therapy, and its safety was confirmed. However, in this clinical trial, LETd could only be increased to approximately 70 keV/μm. To further escalate LETd, multi-ion therapy using ions heavier than carbon was developed. Simulation studies demonstrated that multi-ion therapy incorporating carbon, oxygen and neon ions could increase LETd up to 90 keV/μm, regardless of tumour size, while maintaining high-dose uniformity within the tumour. Based on these results, a clinical study was planned to evaluate the safety of escalating LETd from 70 keV/μm to 90 keV/μm using multi-ion therapy. The primary objective of this study is to evaluate the safety of escalating LETd to the tumour using multi-ion therapy for head and neck cancer, with the secondary goal of identifying the maximum tolerated LETd. METHODS AND ANALYSIS:This is a non-randomised, open-label, phase 1 study focused on LETd escalation. A maximum of 18 patients with histologically confirmed inoperable head and neck malignancies will be enrolled. All patients will receive multi-ion therapy using helium, carbon, oxygen or neon ions, either alone or in combination, at an RBE-weighted dose ranging from 57.6 to 70.4 Gy, delivered in 16 fractions (4 fractions per week) over 4 weeks. The specific dose will be determined according to histology. LETd escalation will begin at 70 keV/μm and will increase by 10 keV/μm increments, reaching a maximum of 90 keV/μm. The safety of multi-ion therapy will be assessed based on the frequency and severity of dose-limiting toxicities, monitored up to 90 days after the initial irradiation. Patients will be followed up according to the protocol for 180 days after the initial multi-ion therapy irradiation. ETHICS AND DISSEMINATION:The study protocol has been approved by the National Institutes for Quantum Science and Technology Certified Review Board (#L24-002). The results will be published in a peer-reviewed journal and presented at a scientific conference. TRIAL REGISTRATION NUMBER:jRCTs032240451.

BACKGROUND:Increasing evidence of the great normal tissue sparing effect in ultra-high dose-rate (UHDR) irradiation points to the potential for improving the therapeutic ratio. However, limited accumulation of data still prevents further understanding of the normal tissue sparing effect mechanism and its subsequent clinical translation. PURPOSE:This study aimed to be the first to provide in vivo data for intestinal toxicity in UHDR carbon-ion irradiation. METHODS:The abdominal part of eight week old C3H/HeSlc female mice was locally irradiated at an entrance region of 400-MeV/u monoenergetic carbon-ion beams either with a conventional dose rate (CONV) or UHDR. The CONV and UHDR irradiations had mean dose rates (MDRs) of ∼0.3 Gy/s and ∼96 Gy/s, respectively. Multiple dose levels (12-18 Gy) were used under the dedicated dosimetry system for UHDR irradiation. Acute intestinal toxicity was evaluated by monitoring the survival of 96 irradiated mice for 30 days post-irradiation. To investigate the influence of dose rate on intestinal crypts, CONV, and UHDR irradiations were conducted for an additional six mice for each. These mice were autopsied 6 or 84 h after irradiation along with two non-irradiated mice and their immunohistochemically stained intestines were used to count the apoptotic cells in crypts or regenerating crypts. RESULTS:Survival fractions of mice were comparable for both dose rates. At the sub-lethal dose, 14 Gy, normal tissue complication probabilities (NTCPs) for the endpoint of survival were 0.78 and 0.89 for CONV and UHDR irradiations, respectively. The 13 Gy dose resulted in NTCP of 0.11 for both dose rates. Doses leading to 50% NTCP were 13.6 and 13.5 Gy for CONV and UHDR irradiations, respectively, which produced a dose modifying factor of 1.008. The percentages of apoptotic crypts at 6 h post-irradiation were 36% for CONV and 34% for UHDR irradiations, showing a small difference (p = 0.782). The percentages of remaining crypts at 84 h post-irradiation were 7.9% for CONV and 5.8% for UHDR irradiations (p = 0.214), indicating a slightly worse result for UHDR irradiation, albeit without statistical significance. CONCLUSION:The intestinal toxicity in UHDR carbon-ion irradiation was investigated for the first time. UHDR carbon-ion irradiation did not produce a substantial sparing effect for intestinal toxicity at least under the beam conditions tested here, i.e., a 400-MeV/u carbon-ion beam at an MDR of ∼96 Gy/s. Additional experiments with different endpoints and beam conditions are mandatory to assess the potential of FLASH carbon-ion therapy.

\emph{Objective.} This study conceptualizes the ionization dose to water as the dose absorbed to water and expended exclusively on ionization, which is essential for radiation therapy, and formulates its dosimetric procedures for high-energy photon, electron, proton, and ion beams. It also aims to design optimal ionization chambers to reduce large dosimetric uncertainty for proton and ion beams. \emph{Approach.} Based on the international code of practice, the dosimetric procedure without the $W$-value correction was formulated for all beams, and that without the stopping-power-ratio correction was formulated for proton and ion beams. For the latter, water-equivalent gas was considered for gas-sealed ionization chambers. Reference dosimetry was performed virtually for test beams. \emph{Main results.} For photon and electron beams, the ionization dose was essentially equivalent to the absorbed dose. For proton and ion beams, dosimetric uncertainties were greatly reduced, especially with water-equivalent gas, to \SI{0.7}{\%} and \SI{1.0}{\%}, respectively. Nitrogen-based water-equivalent gas mixtures were designed with helium, methane, and ethane. Dosimetry with the helium mixture was prone and sensitive to leakage, while the methane and ethane mixtures were flammable. \emph{Significance.} The ionization dose with reduced beam quality corrections provides dose representations of improved accuracy and relevance to radiation therapy, particularly for proton and ion beams.