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Objective: 3D printing has seen use in many fields of imaging and radiation oncology, but applications in (anthropomorphic) phantoms, especially for particle therapy, are still lacking. The aim of this work was to characterize various available 3D printing methods and epoxy-based materials with the specific goal of identifying suitable tissue surrogates for dosimetry applications in particle therapy. Methods: 3D-printed and epoxy-based mixtures of varying ratios combining epoxy resin, bone meal, and polyethylene powder were scanned in a single-energy computed tomography (CT), a dual-energy CT, and a μCT scanner. Their CT-predicted attenuation was compared to measurements in a 148.2 MeV proton and 284.7 MeV/u carbon ion beam. The sample homogeneity was evaluated in the respective CT images and in the carbon beam, additionally via widening of the Bragg peak. To assess long-term stability attenuation, size and weight measurements were repeated after 6-12 months. Results: Four 3D-printed materials, acrylonitrile butadiene styrene polylactic acid, fused deposition modeling printed nylon, and selective laser sintering printed nylon, and various ratios of epoxy-based mixtures were found to be suitable tissue surrogates. The materials' predicted stopping power ratio matched the measured stopping power ratio within 3% for all investigated CT machines and protocols, except for μCT scans employing cone beam CT technology. The heterogeneity of the suitable surrogate samples was adequate, with a maximum Bragg peak width increase of 11.5 ± 2.5%. The repeat measurements showed no signs of degradation after 6-12 months. Conclusion: We identified surrogates for soft tissue and low- to medium-density bone among the investigated materials. This allows low-cost, adaptable phantoms to be built for quality assurance and end-to-end tests for particle therapy. [ABSTRACT FROM AUTHOR]

Abstract Background The quality of life of patients is an important consideration when selecting treatments for localized prostate cancer (PCa). We retrospectively compared sexual function after robot-assisted radical prostatectomy (RARP) and carbon-ion radiotherapy (CIRT) using propensity score matching. Methods In total, 127 Japanese PCa patients treated with RARP and 190 treated with CIRT monotherapy were evaluated. We evaluated the Expanded Prostate Cancer Index Composite (EPIC) score before treatment and 12 and 24 months after treatment. After propensity score matching, data from 101 patients from each group were analyzed. The study protocol was approved by the Institutional Review Board of Gunma University Hospital (no. IRB2020-050, 1839). Results After propensity score matching, the mean EPIC sexual function summary scores in the RARP and CIRT groups were 46.4 and 48.2, respectively. At 12 and 24 months after treatment, these scores were 27.9 (39.9% decrease) and 28.2 (39.2% decrease) in the RARP group and 41.4 (14.1% decrease) and 41.6 (13.7% decrease) in the CIRT group, respectively. Both groups demonstrated significantly decreased scores after 12 and 24 months of treatment compared to before treatment (all p

Background: Proton and carbon‐ion therapy may spare normal tissues in regions with many critical structures surrounding the target volume. As toxicity outcome data are emerging, we aimed to synthesize the published data for the toxicity outcomes of proton or carbon‐ion therapy (together known as particle beam therapy [PBT]) for primary nasopharyngeal carcinoma (NPC). Materials and methods: We searched PubMed and Scopus electronic databases to identify original studies reporting toxicity outcomes following PBT of primary NPC. Quality assessment was performed using NIH's Quality Assessment Tool. Reports were extracted for information on demographics, main results, and clinical and dose factors correlates. Meta‐analysis was performed using the random‐effects model. Results: Twelve studies were selected (six using mixed particle‐photon beams, five performed comparisons to photon‐based therapy). The pooled event rates for acute grade ≥2 toxicities mucositis, dermatitis, xerostomia weight loss are 46% (95% confidence interval [95% CI]—29%–64%, I2 = 87%), 47% (95% CI—28%–67%, I2 = 87%), 16% (95% CI—9%–29%, I2 = 76%), and 36% (95% CI—27%–47%, I2 = 45%), respectively. Only one late endpoint (xerostomia grade ≥2) has sufficient data for analysis with pooled event rate of 9% (95% CI—3%–29%, I2 = 77%), lower than intensity‐modulated radiotherapy 27% (95% CI—10%–54%, I2 = 95%). For most endpoints with significant differences between the PBT and photon‐based therapies, PBT resulted in better outcomes. In two studies where dose distribution was studied, doses to the organs at risk were independent risk factors for toxicities. Conclusion: PBT may reduce the risk of acute toxicities for patients treated for primary NPC, likely due to dose reduction to critical structures. The pooled event rate for toxicities derived in this study can be a guide for patient counseling. [ABSTRACT FROM AUTHOR]

Background: The quality of life of patients is an important consideration when selecting treatments for localized prostate cancer (PCa). We retrospectively compared sexual function after robot-assisted radical prostatectomy (RARP) and carbon-ion radiotherapy (CIRT) using propensity score matching. Methods: In total, 127 Japanese PCa patients treated with RARP and 190 treated with CIRT monotherapy were evaluated. We evaluated the Expanded Prostate Cancer Index Composite (EPIC) score before treatment and 12 and 24 months after treatment. After propensity score matching, data from 101 patients from each group were analyzed. The study protocol was approved by the Institutional Review Board of Gunma University Hospital (no. IRB2020-050, 1839). Results: After propensity score matching, the mean EPIC sexual function summary scores in the RARP and CIRT groups were 46.4 and 48.2, respectively. At 12 and 24 months after treatment, these scores were 27.9 (39.9% decrease) and 28.2 (39.2% decrease) in the RARP group and 41.4 (14.1% decrease) and 41.6 (13.7% decrease) in the CIRT group, respectively. Both groups demonstrated significantly decreased scores after 12 and 24 months of treatment compared to before treatment (all p < 0.05). At 12 and 24 months, the sexual function summary score was significantly higher in the CIRT group than in the RARP group (p < 0.001). Conclusions: There was a smaller decrease in the EPIC sexual function score in the CIRT group than in the RARP group. These results provide useful information for treatment decision-making of Japanese PCa patients. [ABSTRACT FROM AUTHOR]

Chordomas originate from remnant tissue of the notochord during embryonic development, with a relatively low incidence rate. Furthermore, chordomas, being resistant to radiotherapy, are primarily treated by resection; however, in some cases, particularly in those that involve the skull base or upper cervical spine, chordomas are unresectable. In recent years, carbon ion/proton beam therapy has shown significant efficacy in such cases. However, it is not sufficiently curative and is commonly associated with recurrence. Moreover, there is no consensus regarding the treatment of recurrent cases, resulting in several uncertainties pertaining to it. Here, we present the case of a 55-year-old male patient with axial chordoma who experienced recurrence after carbon ion therapy and underwent tumor reduction surgery for a longer life span. Two months postoperatively, dehiscence was found in the posterior pharyngeal wall, probably due to heavy ion therapy. Salvage surgery was performed using an osteocutaneous radial forearm free flap, and the patient's postoperative course was uneventful.

Objective3D printing has seen use in many fields of imaging and radiation oncology, but applications in (anthropomorphic) phantoms, especially for particle therapy, are still lacking. The aim of this work was to characterize various available 3D printing methods and epoxy-based materials with the specific goal of identifying suitable tissue surrogates for dosimetry applications in particle therapy.Methods3D-printed and epoxy-based mixtures of varying ratios combining epoxy resin, bone meal, and polyethylene powder were scanned in a single-energy computed tomography (CT), a dual-energy CT, and a µCT scanner. Their CT-predicted attenuation was compared to measurements in a 148.2 MeV proton and 284.7 MeV/u carbon ion beam. The sample homogeneity was evaluated in the respective CT images and in the carbon beam, additionally via widening of the Bragg peak. To assess long-term stability attenuation, size and weight measurements were repeated after 6–12 months.ResultsFour 3D-printed materials, acrylonitrile butadiene styrene polylactic acid, fused deposition modeling printed nylon, and selective laser sintering printed nylon, and various ratios of epoxy-based mixtures were found to be suitable tissue surrogates. The materials’ predicted stopping power ratio matched the measured stopping power ratio within 3% for all investigated CT machines and protocols, except for µCT scans employing cone beam CT technology. The heterogeneity of the suitable surrogate samples was adequate, with a maximum Bragg peak width increase of 11.5 ± 2.5%. The repeat measurements showed no signs of degradation after 6–12 months.ConclusionWe identified surrogates for soft tissue and low- to medium-density bone among the investigated materials. This allows low-cost, adaptable phantoms to be built for quality assurance and end-to-end tests for particle therapy.

Background and Purpose: Nuclear interaction correction (NIC) and trichrome fragment spectra modelling improve relative biological effectiveness-weighted dose (DRBE) and dose-averaged linear energy transfer (LETd) calculation for carbon ions. The effect of those novel approaches on the clinical dose and LET distributions was investigated. Materials and Methods: The effect of the NIC and trichrome algorithm was assessed, creating single beam plans for a virtual water phantom with standard settings and NIC + trichrome corrections. Reference DRBE and LETd distributions were simulated using FLUKA version 2021.2.9. Thirty clinically applied scanned carbon ion treatment plans were recalculated applying NIC, trichrome and NIC + trichrome corrections, using the LEM low dose approximation and compared to clinical plans (base RS). Four treatment sites were analysed: six prostate adenocarcinoma, ten head and neck, nine locally advanced pancreatic adenocarcinoma and five sacral chordoma. The FLUKA and clinical plans were compared in terms of DRBE deviations for D98%, D50%, D2% for the clinical target volume (CTV) and D50% in ring-like dose regions retrieved from isodose curves in base RS plans. Additionally, region-based median LETd deviations and global gamma parameters were evaluated. Results: Dose deviations comparing base RS and evaluation plans were within ± 1% supported by γ-pass rates over 97% for all cases. No significant LETd deviations were reported in the CTV, but significant median LETd deviations were up to 80% for very low dose regions. Conclusion: Our results showed improved accuracy of the predicted DRBE and LETd. Considering clinically relevant constraints, no significant modifications of clinical protocols are expected with the introduction of NIC + trichrome.

Background: Treatment planning is essential for in silico particle therapy studies. matRad is an open‐source research treatment planning system (TPS) based on the local effect model, which is a type of relative biological effectiveness (RBE) model. Purpose: This study aims to implement a microdosimetric kinetic model (MKM) in matRad and develop an automation algorithm for Monte Carlo (MC) dose recalculation using the TOPAS code. In addition, we provide the developed MKM extension as open‐source tool for users. Methods: Carbon beam data were generated using TOPAS MC pencil beam irradiation. We parameterized the TOPAS MC beam data with a double‐Gaussian fit and modeled the integral depth doses and lateral spot profiles in the range of 100–430 MeV/u. To implement the MKM, the specific energy data table for Z = 1–6 and integrated depth‐specific energy data were acquired based on the Kiefer–Chatterjee track structure and TOPAS MC simulation, respectively. Generic data were integrated into matRad, and treatment planning was performed based on these data. The optimized plan parameters were automatically converted into MC simulation input. Finally, the matRad TPS and TOPAS MC simulations were compared using the RBE‐weighted dose calculation results. A comparison was made for three geometries: homogeneous water phantom, inhomogeneous phantom, and patient. Results: The RBE‐weighted dose (DRBE) distribution agreed with TOPAS MC within 1.8% for all target sizes for the homogeneous phantom. For the inhomogeneous phantom, the relative difference in the range of 80% of the prescription dose in the distal fall‐off region (R80) between the matRad TPS and TOPAS MC was 0.6% (1.1 mm). DRBE between the TPS and the MC was within 4.0%. In the patient case, the difference in the dose–volume histogram parameters for the target volume between the TPS and the MC was less than 2.7%. The relative difference in R80 was 0.7% (1.2 mm). Conclusions: The MKM was successfully implemented in matRad TPS, and the RBE‐weighted dose was comparable to that of TOPAS MC. The MKM‐implemented matRad was released as an open‐source tool. Further investigations with MC simulations can be conducted using this tool, providing a good option for carbon ion research. [ABSTRACT FROM AUTHOR]

Biomaterials are indispensable elements for improving human health and quality of life. Applications of biomaterials include the use of phantoms as tissue replacement in diagnostics (biosensors), medical supplies (blood bags and surgical instruments), therapeutic treatments (medical implants and devices), regenerative medicine (tissue engineered skin and cartilage), and radiation dosimetric studies. Since polymers are organic, they offer a much more versatile usage area than metals and ceramic biomaterials, particularly in soft tissue substitutes. The wide physical, mechanical, and chemical properties provided by polymers have encouraged extensive research, development, and application of polymeric biomaterials. Their usage as a soft tissue phantom is at the forefront of these applications. In this study, the ionization, recoils, phonon release, collision events, and lateral straggle properties of polymeric biomaterials [e.g., polymethylmetacrylate (PMMA), polystyrene, polyethylene, polypropylene, and polyvinylchloride] closest to soft tissue are investigated in carbon therapy application. The Brag peak location achieved for PMMA is quite close to that of soft tissue, within 4.8%, average recoils within 0.5%, and collision event parameter within 0.6%, however, lateral scattering is comparatively larger by roughly 6.8%, according to TRIM-based Monte Carlo simulation results. Thus, when carbon ion is taken into account, the current findings show that PMMA is one of the possible polymeric biomaterials to simulate soft tissue in terms of radiation interaction properties. [ABSTRACT FROM AUTHOR]

As an important part of radiation therapy quality assurance, dose verification can verify the accuracy of the treatment dose to the patient’s tumor target area before treatment. At present, the dose verification technology has developed to the stage of three-dimensional dose verification. However, the existing clinical dose verification tools cannot meet the demand for three-dimensional dose verification in heavy ion therapy. In order to quickly and accurately realize three-dimensional dose verification of carbon ion therapy plan, a three-dimensional ionization chamber array was designed by using plexiglass PMMA(polymethyl methacrylate) as the ionization chamber wall and water equivalent phantom. And the structural design of the three-dimensional ionization chamber array was thoroughly studied and verified by Geant4 software. Firstly, by simulating the depth dose distribution of carbon ion beam deposited in water and PMMA phantom with different energies, the distal range ratio of the Bragg peak of the carbon ion beam in water and PMMA phantom was calculated, and the water equivalent thickness factor of PMMA phantom was characterized. Its value is 1.151. Then the effects of the spacing between adjacent ionization chambers and the signal leads on the accuracy of the dose measurement in the three-dimensional ionization chamber array were investigated. The signal crosstalk between adjacent ionization chambers mainly originates from the front ionization chamber, and the degree of crosstalk is inversely proportional to the spacing, the degree of crosstalk accounts for 3% of the dose within the ionization chamber at spacing of 1 mm, and the crosstalk effect can be completely eliminated at spacing of 30 mm. And the interference effect of the signal leads on the dose within the rear ionization chamber is about 1%. Finally, the dose distribution of 100 MeV/u and 200 MeV/u carbon ion beams deposited in the three-dimensional ionization chamber array was simulated, and the distal range of the Bragg peak was obtained in which the carbon ion beam was deposited. It has good agreement compared to the distal range of the Bragg peak in the PMMA phantom, and the deviation is 0.5 mm. The research show that the three-dimensional ionization chamber array can realize the three-dimensional dose verification of heavy ion therapy at the same time, and provides a reference for the development of three-dimensional ionization chamber array. The quality assurance level of carbon ion therapy should be further improved.

The use of high-energy charged particles in radiotherapy has evolved into an advanced cancer treatment. Even though proton beams and carbon ions are currently the popular particles used for radiotherapy in cancer, ions such as pions, helium, argon, and neon were previously used. To prepare this article, reviewed the literature relevant to the history, current status, and clinical outcomes of particle therapy for specific types of tumors by searching in PubMed and Google Scholar using specific search terms. This article reviews the history, current status, physics, and radiobiological advantages of particle therapy. Outcomes of particle therapy for sites such as the head-and-neck, central nervous system, lung, and prostate have been discussed. The physical and biological properties of particle therapy have been shown to be effective in reducing radiation-induced acute toxicities to a large extent as well as reducing the integral dose, i.e., the sum of dose delivered at every point in a patient's body, multiplied by the volume of tissue at each point and then added up over the entire treated volume. It is used to assess the potential risks associated with radiation therapy. The advantages of particle therapy over conventional photon therapy in terms of overall survival and local control rates have been described. Advances in image guidance and newer particle acceleration technologies have improved the efficiency of particle therapy treatment.

Simple Summary: Chordomas are rare tumors of the embryologic spinal cord remnant. They are locally aggressive and typically managed with surgery in combination with radiation therapy. However, there is great variability in practice patterns including different radiation treatment types and approaches, and limited high-level data to drive decision making. The purpose of this manuscript was to summarize the current literature specific to radiotherapy in the management of spine and sacral chordoma and to provide a practical guide on behalf of the Spine Tumor Academy, an international group of spinal oncology experts. Chordomas are rare tumors of the embryologic spinal cord remnant. They are locally aggressive and typically managed with surgery and either adjuvant or neoadjuvant radiation therapy. However, there is great variability in practice patterns including radiation type and fractionation regimen, and limited high-level data to drive decision making. The purpose of this manuscript was to summarize the current literature specific to radiotherapy in the management of spine and sacral chordoma and to provide practice recommendations on behalf of the Spine Tumor Academy. A systematic review of the literature was performed using the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) approach. Medline and Embase databases were utilized. The primary outcome measure was the rate of local control. A detailed review and interpretation of eligible studies is provided in the manuscript tables and text. Recommendations were defined as follows: (1) consensus: approved by >75% of experts; (2) predominant: approved by >50% of experts; (3) controversial: not approved by a majority of experts. Expert consensus supports dose escalation as critical in optimizing local control following radiation therapy for chordoma. In addition, comprehensive target volumes including sites of potential microscopic involvement improve local control compared with focal targets. Level I and high-quality multi-institutional data comparing treatment modalities, sequencing of radiation and surgery, and dose/fractionation schedules are needed to optimize patient outcomes in this locally aggressive malignancy. [ABSTRACT FROM AUTHOR]

Simple Summary: Oncologic gross total resection of skull base chordoma remains elusive in many patients. Dose-escalated radiotherapy, preferably by proton therapy, is frequently used. We present the early analysis of a mono-institutional experience using proton or carbon ion therapy for skull base chordomas. Our initial 4-year clinical outcomes suggest excellent local control. Large tumor volume was related with worse local tumor control, underlining the importance of maximum debulking of large lesions. Background: Skull base chordomas are radio-resistant tumors that require high-dose, high-precision radiotherapy, as can be delivered by particle therapy (protons and carbon ions). We performed a first clinical outcome analysis of particle therapy based on the initial 4-years of operation. Methods: Between August 2017 and October 2021, 44 patients were treated with proton (89%) or carbon ion therapy (11%). Prior gross total resection had been performed in 21% of lesions, subtotal resection in 57%, biopsy in 12% and decompression in 10%. The average prescription dose was 75.2 Gy RBE in 37 fractions for protons and 66 Gy RBE in 22 fractions for carbon ions. Results: At a median follow-up of 34.3 months (range: 1–55), 2-, and 3-year actuarial local control rates were 95.5% and 90.9%, respectively. The 2-, and 3-year overall and progression-free survival rates were 97.7%, 93.2%, 95.5% and 90.9%, respectively. The tumor volume at the time of particle therapy was highly predictive of local failure (p < 0.01), and currently, there is 100% local control in patients with tumors < 49 cc. No grade ≥3 toxicities were observed. There was no significant difference in outcome or side effect profile seen for proton versus carbon ion therapy. Five patients (11.4%) experienced transient grade ≤2 radiation-induced brain changes. Conclusions: The first analysis suggests the safety and efficacy of proton and carbon ion therapy at our center. The excellent control of small to mid-size chordomas underlines the effectiveness of particle therapy and importance of upfront maximum debulking of large lesions. [ABSTRACT FROM AUTHOR]

Background: In a recent study, we reported beam quality correction factors, fQ, in carbon ion beams using Monte Carlo (MC) methods for a cylindrical and a parallel-plate ionization chamber (IC). A non-negligible perturbation effect was observed;however, the magnitude of the perturbation correction due to the specific IC subcomponents was not included. Furthermore, the stopping power data presented in the International Commission on Radiation Units and Measurements (ICRU) report 73 were used, whereas the latest stopping power data have been reported in the ICRU report 90. Purpose: The aim of this study was to extend our previous work by computing fQ correction factors using the ICRU 90 stopping power data and by reporting ICspecific perturbation correction factors. Possible energy or linear energy transfer (LET) dependence of the fQ correction factor was investigated by simulating both pristine beams and spread-out Bragg peaks (SOBPs). Methods: The TOol for PArticle Simulation (TOPAS)/GEANT4 MC code was used in this study. A 30 × 30 × 50 cm3 water phantom was simulated with a uniform 10 × 10 cm2 parallel beam incident on the surface. A Farmer-type cylindrical IC (Exradin A12) and two parallel-plate ICs (Exradin P11 and A11) were simulated in TOPAS using the manufacturer-provided geometrical drawings. The fQ correction factor was calculated in pristine carbon ion beams in the 150-450 MeV/u energy range at 2 cm depth and in the middle of the flat region of four SOBPs. The kQ correction factor was calculated by simulating the fQo correction factor in a 60Co beam at 5 cm depth. The perturbation correction factors due to the presence of the individual IC subcomponents, such as the displacement effect in the air cavity, collecting electrode, chamber wall, and chamber stem, were calculated at 2 cm depth for monoenergetic beams only. Additionally, the mean dose-averaged and track-averaged LET was calculated at the depths at which the fQ was calculated. Results: The ICRU 90 fQ correction factors were reported. The pdis correction factor was found to be significant for the cylindrical IC with magnitudes up to 1.70%. The individual perturbation corrections for the parallel-plate ICs were <1.0% except for the A11 pcel correction at the lowest energy. The fQ correction for the P11 IC exhibited an energy dependence of >1.00% and displayed differences up to 0.87% between pristine beams and SOBPs. Conversely, the fQ for A11 and A12 displayed a minimal energy dependence of <0.50%. The energy dependence was found to manifest in the LET dependence for the P11 IC. A statistically significant LET dependence was found only for the P11 IC in pristine beams only with a magnitude of <1.10%. Conclusions: The perturbation and kQ correction factor should be calculated for the specific IC to be used in carbon ion beam reference dosimetry as a function of beam quality. [ABSTRACT FROM AUTHOR]

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Abstract Background Some cancers such as sarcomas (bone and soft tissue sarcomas) and adenoid cystic carcinomas are considered as radioresistant to low linear energy transfer radiation (including photons and protons) and may therefore beneficiate from a carbon ion therapy. Despite encouraging results obtained in phase I/II trials compared to historical data with photons, the spread of carbon ions has been limited mainly because of the absence of randomized medical data. The French health authorities stressed the importance of having randomized data for carbon ion therapy. Methods The ETOILE study is a multicenter prospective randomized phase III trial comparing carbon ion therapy to either advanced photon or proton radiotherapy for inoperable or macroscopically incompletely resected (R2) radioresistant cancers including sarcomas and adenoid cystic carcinomas. In the experimental arm, carbon ion therapy will be performed at the National Center for Oncological Hadrontherapy (CNAO) in Pavia, Italy. In the control arm, photon or proton radiotherapy will be carried out in referent centers in France. The primary endpoint is progression-free survival (PFS). Secondary endpoints are overall survival and local control, toxicity profile, and quality of life. In addition, a prospective health-economic study and a radiobiological analysis will be conducted. To demonstrate an absolute improvement in the 5-year PFS rate of 20% in favor of carbon ion therapy, 250 patients have to be included in the study. Discussion So far, no clinical study of phase III has demonstrated the superiority of carbon ion therapy compared to conventional radiotherapy, including proton therapy, for the treatment of radioresistant tumors. Trial registration ClinicalTrials.gov identifier: NCT02838602 . Date of registration: July 20, 2016. The posted information will be updated as needed to reflect protocol amendments and study progress.

Abstract Background The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration. Methods Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5–6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life. Discussion The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control. Trial registration ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021.

Simple Summary: Radiotherapy is a crucial component in the multimodal treatment of Ewing sarcoma; it can be applied for local disease in addition to surgery or as definitive treatment for inoperable disease. Particularly in pelvic Ewing sarcoma, definitive radiotherapy offers the possibility of avoiding extensive and potentially mutilating resections and preserving crucial neurological functions. Adult patients with primary or locally recurrent pelvic Ewing sarcoma treated with curative intent with protons for primary disease and carbon ions for recurrent disease at the Heidelberg Ion-Beam Therapy Center (HIT) were considered for this retrospective analysis. We report excellent dosimetric characteristics in the treatment with protons in comparison to photon IMRT and promising early clinical outcomes. Particle therapy in adult pelvic Ewing sarcoma is shown to be feasible in a consecutive patient cohort. However, further long-term follow-up is needed to assess late toxicity and clinical outcomes. Purpose: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy. Methods: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45–60 Gy (RBE) (1.5–2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan–Meier method. Results: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm3 and 1630 cm3. Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm3, respectively. At the end of particle therapy, G 1–2 skin reactions (n = 16/21) and fatigue (n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively. Conclusions: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed. [ABSTRACT FROM AUTHOR]

Transition-edge sensor (TES) calorimeters will contribute to reducing the uncertainty in the dosimetry of carbon ion beams. A TES coupled to a large graphite absorber was designed to measure the energy deposited on materials which are similar to body tissues. We have demonstrated that a TES with a graphite absorber can be applied to the detection of particles. [ABSTRACT FROM AUTHOR]

Purpose: To generate virtual 4DCT from 4DMRI with field of view (FOV) extended to the entire involved patient anatomy, in order to evaluate its use in carbon ion radiation therapy (CIRT) of the abdominal site in a clinical scenario. Materials and methods: The virtual 4DCT was generated by deforming a reference CT in order to (1) match the anatomy depicted in the 4DMRI within its FOV, by calculating deformation fields with deformable image registration to describe inter-fractional and breathing motion, and (2) obtain physically plausible deformation outside of the 4DMRI FOV, by propagating and modulating the previously obtained deformation fields. The implemented method was validated on a digital anthropomorphic phantom, for which a ground truth (GT) 4DCT was available. A CIRT treatment plan was optimized at the end-exhale reference CT and the RBE-weighted dose distribution was recalculated on both the virtual and GT 4DCTs. The method estimation error was quantified by comparing the virtual and GT 4DCTs and the corresponding recomputed doses. The method was then evaluated on 8 patients with pancreas or liver tumors treated with CIRT using respiratory gating at end-exhale. The clinical treatment plans adopted at the National Center for Oncological Hadrontherapy (CNAO, Pavia, Italy) were considered and the dose distribution was recomputed on all respiratory phases of the planning and virtual 4DCTs. By comparing the two datasets and the corresponding dose distributions, the geometrical and dosimetric impact of organ motion was assessed. Results: For the phantom, the error outside of the 4DMRI FOV was up to 4.5 mm, but it remained sub-millimetric in correspondence to the target within the 4DMRI FOV. Although the impact of motion on the target D95% resulted in variations ranging from 22% to 90% between the planned dose and the doses recomputed on the GT 4DCT phases, the corresponding estimation error was ≤2.2%. In the patient cases, the variation of the baseline tumor position between the planning and the virtual end-exhale CTs presented a median (interquartile range) value of 6.0 (4.9) mm. For baseline variations larger than 5 mm, the tumor D95% variation between the plan and the dose recomputed on the end-exhale virtual CT resulted larger than 10%. Median variations higher than 10% in the target D95% and gastro-intestinal OARs D2% were quantified at the end-inhale, whereas close to the end-exhale phase, limited variations of relevant dose metrics were found for both tumor and OARs. Conclusions: The negligible impact of the geometrical inaccuracy in the estimated anatomy outside of the 4DMRI FOV on the overall dosimetric accuracy suggests the feasibility of virtual 4DCT with extended FOV in CIRT of the abdominal site. In the analyzed patient group, inter-fractional variations such as baseline variation and breathing variability were quantified, demonstrating the method capability to support treatment planning in gated CIRT of the abdominal site.

The advantageous depth dose profile of ion beams together with state of the art beam delivery and treatment planning systems allow for highly conformal tumor treatments in patients. First treatments date back to 1954 at the Lawrence Berkeley Laboratory (LBL) and in Europe, ion beam therapy started in the mid-1990s at the Paul-Scherrer Institute (PSI) with protons and at the Helmholtz Center for Heavy Ion Research (GSI) with carbon ions, followed by the Heidelberg Ion Therapy Center (HIT) in Heidelberg. This review describes the historical development of ion beam therapy in Germany based on the pioneering work at LBL and in the context of simultaneous developments in other countries as well as recent developments.

Range uncertainty that reduces the dosimetric advantage of carbon ion therapy is a major problem limiting its treatment precision. To address this issue, high-precision monitoring of the in-beam range is essential. This paper proposes a method for range verification using a secondary particle intensity (SPI) system consisting of a cerium bromide (CeBr 3) scintillation detector and an integrated ionization chamber (IC). This method uses the secondary particle intensity produced by the primary particles per monitor unit (MU) observed by the SPI system to convert the carbon ion range. Secondary particles, including gamma rays, neutrons, and charged particles, can be detected in the CeBr 3 detector as long as their signal exceeds the threshold, and no discrimination by particle type is required. The Heavy Ion Medical Machine (HIMM) terminal, situated in Lanzhou, China, provided the 12C6+ beam with energies ranging from 160.86 to 211.44 MeV/u. The experiment demonstrated that the carbon ion range accuracy of the 12C6+ beam in a polymethyl methacrylate (PMMA) target can reach 0.92 ± 0.67 mm under a 10 ms measurement period. The secondary particle energy spectrum was recorded during both the in-beam and off-beam phases, clearly recognizing the 511 keV annihilation photopeak with a full width at half maximum (FWHM) of 31.37 keV. The photopeak of annihilation confirmed the accumulation of activated products. During the 15 min continuous irradiation process, the effect of activated product accumulation on the range verification is about 1.15 mm. This paper illustrates the feasibility of SPI method for fast measurement of carbon ion range, which could potentially reduce the effects of range uncertainty in carbon ion therapy. [ABSTRACT FROM AUTHOR]

At the Heidelberg Ion-Beam Therapy Center, the track structure of carbon ions of therapeutic energy after penetrating layers of simulated tissue was investigated for the first time. Measurements were conducted with carbon ion beams of different energies and polymethyl methacrylate (PMMA) absorbers of different thicknesses to realize different depths in the phantom along the pristine Bragg peak. Ionization cluster size (ICS) distributions resulting from the mixed radiation field behind the PMMA absorbers were measured using an ion-counting nanodosimeter. Two different measurements were carried out: (i) variation of the PMMA absorber thickness with constant carbon ion beam energy and (ii) combined variation of PMMA absorber thickness and carbon ion beam energy such that the kinetic energy of the carbon ions in the target volume is constant. The data analysis revealed unexpectedly high mean ICS values compared to stopping power calculations and the data measured at lower energies in earlier work. This suggests that in the measurements the carbon ion kinetic energies behind the PMMA absorber may have deviated considerably from the expected values obtained by the calculations. In addition, the results indicate the presence of a marked contribution of nuclear fragments to the measured ICS distributions, especially if the carbon ion does not cross the target volume., (Creative Commons Attribution license.)

Belal Abousaida,1,&ast; Danushka Seneviratne,1,&ast; Bradford S Hoppe,1 Stephen J Ko,1 Aroumougame Asaithamby,2 Francis A Cucinotta,3 Jessica M Kirwan,4 Kabir Mody,5 Beau Toskich,6 Jonathan B Ashman,7 Christopher L Hallemeier,8 Sunil Krishnan1 1Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, USA; 2Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA; 3School of Integrated Health Sciences, University of Las Vegas, Las Vegas, NV, USA; 4Department of Radiation Oncology, University of Florida, Gainesville, FL, USA; 5Division of Hematology and Medical Oncology, Department of Internal Medicine, Mayo Clinic Florida, Jacksonville, FL, USA; 6Division of Interventional Radiology, Department of Radiology, Mayo Clinic Florida, Jacksonville, FL, USA; 7Department of Radiation Oncology, Mayo Clinic Arizona, Phoenix, AZ, USA; 8Department of Radiation Oncology, Mayo Clinic Rochester, Rochester, MN, USA&ast;These authors contributed equally to this workCorrespondence: Sunil KrishnanDepartment of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, 32224, USATel +1 713-202-8063Email krishnan.sunil@mayo.eduAbstract: Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.Keywords: carbon ion therapy, hepatocellular carcinoma, hypofractionation

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Background: The dose distribution of carbon ion radiotherapy (CIRT) for locally advanced non‐small cell lung cancer (LANSCLC) is highly sensitive to anatomical changes. Purpose: To demonstrate the dosimetric benefits of adaptive CIRT for LANSCLC and compare the differences between patients with and without adaptive plans based on dosimetry and clinical effect factors. Materials and methods: Of the 98 patients with LANSCLC receiving CIRT, 31 patients underwent replanning following re‐evaluations that revealed changes that would have compromised the dose coverage of the target volume or violated dose constraints. Dosimetric parameters and clinical factors were compared between patients with and without adaptive plans. Multivariate analysis identified factors influencing the adaptive planning. Results: The median number of fractions delivered using adaptive plans was eight (range: 2‐18). Adaptive plans ensured target coverage, and the maximum spinal cord dose was significantly decreased (p = 0.02). The median reduction in the maximum spinal cord dose was 10.4 Gy (relative biological effectiveness). Patients with adaptive plans had larger tumor volumes (p < 0.001); the median initial internal gross tumor volumes (iGTVs) of patients with adaptive and nonadaptive plans were 125.9 and 49.79 cm3, respectively. Tumor volumes of patients with adaptive plans were altered to a greater extent (p < 0.001); the median absolute percentage of volume changes in patients in the adaptive and in nonadaptive groups were 20.76% and 3.63%, respectively, while the median movements of iGTV centers were 5.75 and 2.44 mm, respectively. Binary logistic regression analysis revealed that the iGTV volume change and iGTV center movements were significantly different between the groups. Conclusions: An adaptive plan can effectively ensure target area coverage and protect normal tissues, especially in patients with large tumor volumes and substantial changes. iGTV volume changes and iGTV center movements are the main factors influencing adaptive planning. Weekly simulation computed tomography scans are necessary for treatment evaluation in patients with LANSCLC treated with CIRT. [ABSTRACT FROM AUTHOR]

Administering reirradiation for the treatment of recurrent head and neck cancers is extremely challenging. These tumors are hypoxic and radioresistant and require escalated radiation doses for adequate control. The obstacle to delivering this escalated dose of radiation to the target is its proximity to critical organs at risk (OARs) and possible development of consequent severe late toxicities. With the emergence of highly sophisticated technologies, intensity-modulated radiotherapy (IMRT) and stereotactic body radiotherapy have shown promising outcomes. Proton beam radiotherapy has been used for locally recurrent head and neck cancers because of its excellent physical dose distribution, exploring sharp Bragg peak properties with negligible entrance and exit doses. To further improve these results, carbon ion radiotherapy (CIRT) has been explored in several countries across Europe and Asia because of its favorable physical properties with minimal entrance and exit doses, sharper lateral penumbra, and much higher and variable relative biological efficacy, which cannot be currently achieved with any other form of radiation. Few studies have described the role of CIRT in recurrent head and neck cancers. In this article, we have discussed the different aspects of carbon ions in reirradiation of recurrent head and neck cancers, including European and Asian experiences, different dose schedules, dose constraints of OARs, outcomes, and toxicities, and a brief comparison with proton beam radiotherapy and IMRT. [ABSTRACT FROM AUTHOR]

Background: The standard of care treatment for soft tissue sarcoma of the extremities is a wide resection in combination with pre- or postoperative radiotherapy with high local control rates, sparing patients the necessity of amputation without compromising on overall survival rates. The currently preferred timing of radiotherapy is under debate. Albeit having higher rates of acute wound complications, late side effects like fibrosis, joint stiffness or edema are less frequent in preoperative compared to postoperative radiotherapy. This can be explained in smaller treatment volumes and a lower dose in the preoperative setting. Particles allow better sparing of surrounding tissues at risk, and carbon ions additionally offer biologic advantages and are preferred in less radiosensitive tumors. Hypofractionation allows for a significantly shorter treatment duration.Methods: Extrem-ion is a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the extremities will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5-6 fractions per week] in each arm). The primary objective is the proportion of therapies without wound healing disorder the first 120 days after surgery or discontinuation of treatment for any reason related to the treatment. The secondary endpoints of the study consist of local control, local progression-free survival, disease-free survival, overall survival, and quality of life.Discussion: The aim of this study is to confirm that hypofractionated, preoperative radiotherapy is safe and feasible. The potential for reduced toxicity by the utilization of particle therapy is the rational of this trial. A subsequent randomized phase III trial will compare the hypofractionated proton and carbon ion irradiation in regards to local control.Trial Registration: ClinicalTrials.gov Identifier: NCT04946357 ; Retrospectively registered June 30, 2021. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the outcomes of particle therapy in cancer patients with cardiac implantable electronic devices (CIEDs). Materials and methods: From April 2001 to March 2013, 19,585 patients were treated with proton beam therapy (PBT) or carbon ion therapy (CIT) at 8 institutions. Of these, 69 patients (0.4%, PBT 46, CIT 22, and PBT + CIT 1) with CIEDs (64 pacemakers, 4 implantable cardioverter defibrillators, and 1 with a cardiac resynchronization therapy defibrillator) were retrospectively reviewed. All the patients with CIEDs in this study were treated with the passive scattering type of particle beam therapy. Results: Six (13%) of the 47 PBT patients, and none of the 23 CIT patients experienced CIED malfunctions (p = 0.105). Electrical resets (7) and over-sensing (3) occurred transiently in 6 patients. The distance between the edge of the irradiation field and the CIED was not associated with the incidence of malfunctions in 20 patients with lung cancer. A larger field size had a higher event rate but the test to evaluate trends as not statistically significant (p = 0.196). Conclusion: Differences in the frequency of occurrence of device malfunctions for patients treated with PBT and patients treated with CIT did not reach statistical significance. The present study can be regarded as a benchmark study about the incidence of malfunctioning of CIED in passive scattering particle beam therapy and can be used as a reference for active scanning particle beam therapy. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the clinical outcomes and treatment related toxicities of charged particle-based re-irradiation (reRT; protons and carbon ions) for the definitive management of recurrent or second primary skull base and head and neck tumors. Materials and Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied for the conduct of this systematic review. Published work in English language evaluating the role of definitive charged particle therapies in the clinical setting of reRT for recurrent or second primary skull base and head and neck tumors were eligible for this analysis. Results: A total of 26 original studies (15 protons, 10 carbon ions, and 1 helium/neon studies) involving a total of 1,118 patients (437 with protons, 670 with carbon ions, and 11 with helium/neon) treated with curative-intent charged particle reRT were included in this systematic review. All studies were retrospective in nature, and the majority of them (n=23, 88 %) were reported as single institution experiences (87% for protons, and 90% for carbon ion-based studies). The median proton therapy reRT dose was 64.5 Gy (RBE 1.1) (range, 50.0 – 75.6 Gy ), while the median carbon ion reRT dose was 53.8 Gy (RBE 2.5 – 3.0) (range, 44.8 – 60 Gy ). Induction and/or concurrent chemotherapy was administered to 232 (53%) of the patients that received a course of proton reRT, and 122 (18%) for carbon ion reRT patients. ReRT with protons achieved 2-year local control rates ranging from 50% to 86%, and 41% to 92% for carbon ion reRT. The 2-year overall survival rates for proton and carbon ion reRT ranged from 33% to 80%, and 50% to 86% respectively. Late ≥ G3 toxicities ranged from 0% to 37%, with brain necrosis, ototoxicity, visual deficits, and bleeding as the most common complications. Grade 5 toxicities for all treated patients occurred in 1.4% (n = 16/1118) with fatal bleeding as the leading cause. Conclusions: Based on current data, curative intent skull base and head and neck reRT with charged particle radiotherapy is feasible and safe in well-selected cases, associated with comparable or potentially improved local control and toxicity rates compared to historical reRT studies using photon radiotherapy. Prospective multi-institutional studies reporting oncologic outcomes, toxicity, and dosimetric treatment planning data are warranted to further validate these findings and to improve the understanding of the clinical benefits of charged particle radiotherapy in the reRT setting.

Skull base tumors constitute one of the established indications for particle therapy, specifically proton therapy. However, a number of prognostic factors, practical clinical management issues, and the emerging role of carbon ion therapy remain subjects of active clinical investigation. This review summarizes these topics, assesses the present status, and reflects on future research directions focusing on the management of chordomas, one of the most aggressive skull base tumors. In addition, the role of particle therapy for benign tumors of the skull base, including pituitary adenoma and acoustic neuroma, is reviewed.

In vivo treatment monitoring in ion therapy is one of the key issues for improving the treatment quality assurance procedures. Range verification is one of the most relevant and yet complex task used for in vivo treatment monitoring. In carbon ion therapy, positron emission tomography is the most widely used method. This technique exploits the β + -activity of positron emitters created by nuclear interactions between the incoming beam and the irradiated tissue. Currently, high computational efforts and time-consuming Monte Carlo simulation platforms are typically used to predict positron emitter distributions. In order to avoid time-consuming simulations, an extended filtering approach was suggested to analytically predict positron emitter profiles from depth dose distributions in carbon ion therapy. The purpose of this work is to investigate such an analytical prediction model in patient anatomies of varying complexity, highlighting its potential and the need of further improvements, especially in highly heterogeneous anatomies where many air cavities are present in the beam path. The accuracy of range verification showed a mean relative error of ∼ 3 % and a deviation between the simulation and the prediction below 2 mm for the three patient cases analysed: a brain case and two head and neck cases. Additional investigations demonstrated the region of applicability of the method for cases of patient data. The analytical method enables range verification in carbon ion therapy by replacing computing-intensive Monte Carlo simulations and thus minimize the PET monitoring burden on the clinical workflow. • Fast prediction of positron emitter distributions in carbon ion therapy is necessary. • The present analytical approach allows for fast and accurate prediction. • Tests with clinical data are shown. • Differences between analytical approach and Monte Carlo simulations below 2 mm. • Improvements to the method are proposed. [ABSTRACT FROM AUTHOR]

Administering reirradiation for the treatment of recurrent head and neck cancers is extremely challenging. These tumors are hypoxic and radioresistant and require escalated radiation doses for adequate control. The obstacle to delivering this escalated dose of radiation to the target is its proximity to critical organs at risk (OARs) and possible development of consequent severe late toxicities. With the emergence of highly sophisticated technologies, intensity-modulated radiotherapy (IMRT) and stereotactic body radiotherapy have shown promising outcomes. Proton beam radiotherapy has been used for locally recurrent head and neck cancers because of its excellent physical dose distribution, exploring sharp Bragg peak properties with negligible entrance and exit doses. To further improve these results, carbon ion radiotherapy (CIRT) has been explored in several countries across Europe and Asia because of its favorable physical properties with minimal entrance and exit doses, sharper lateral penumbra, and much higher and variable relative biological efficacy, which cannot be currently achieved with any other form of radiation. Few studies have described the role of CIRT in recurrent head and neck cancers. In this article, we have discussed the different aspects of carbon ions in reirradiation of recurrent head and neck cancers, including European and Asian experiences, different dose schedules, dose constraints of OARs, outcomes, and toxicities, and a brief comparison with proton beam radiotherapy and IMRT.

Abstract Background Following surgery for soft tissue sarcoma of the retroperitoneum, the predominant pattern of failure is local recurrence, which remains the main cause of death. Radiotherapy is utilized to reduce recurrence rates but the efficacy of this strategy has not been definitely established. As treatment tolerability is more favorable with preoperative radiotherapy, normofractionated neoadjuvant treatment is the current approach. The final results of the prospective, randomized STRASS (EORTC 62092) trial, which compared the efficacy of this combined treatment to that of surgery alone, are still awaited; preliminary results presented at the 2019 ASCO Annual Meeting indicated that combined treatment is associated with better local control in patients with liposarcoma (74.5% of the cohort, 11% benefit in abdominal progression free survival after 3 years, p = 0.049). Particles allow better sparing of surrounding tissues at risk, e.g., bowel epithelium, and carbon ions additionally offer biologic advantages and are preferred in slow growing tumors. Furthermore, hypofractionation allows for a significantly shorter treatment interval with a lower risk of progression during radiotherapy. Methods and design We present a prospective, randomized, monocentric phase II trial. Patients with resectable or marginally resectable, histologically confirmed soft tissue sarcoma of the retroperitoneum will be randomized between neoadjuvant proton or neoadjuvant carbon ion radiotherapy in active scanning beam application technique (39 Gy [relative biological effectiveness, RBE] in 13 fractions [5–6 fractions per week] in each arm). The primary objective is the safety and feasibility based on the proportion of grade 3–5 toxicity (CTCAE, version 5.0) in the first 12 months after surgery or discontinuation of treatment for any reason related to the treatment. Local control, local progression-free survival, disease-free survival, overall survival, and quality of life are the secondary endpoints of the study. Discussion The aim of this study is to confirm that hypofractionated, accelerated preoperative radiotherapy is safe and feasible. The rationale for the use of particle therapy is the potential for reduced toxicity. The data will lay the groundwork for a randomized phase III trial comparing hypofractionated proton and carbon ion irradiation with regard to local control. Trial registration ClinicalTrials.gov NCT04219202 . Retrospectively registered on January 6, 2020

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. [ABSTRACT FROM AUTHOR]

We describe a way to include biologically based objectives in plan optimization specific for carbon ion therapy, beyond the standard voxel-dose-based criteria already implemented in TRiP98, research planning software for ion beams. The aim is to account for volume effects—tissue architecture-dependent response to damage—in the optimization procedure, using the concept of generalized equivalent uniform dose (gEUD), which is an expression to convert a heterogeneous dose distribution (e.g., in an organ at risk (OAR)) into a uniform dose associated with the same biological effect. Moreover, gEUD is closely related to normal tissue complication probability (NTCP). The multi-field optimization problem here takes also into account the relative biological effectiveness (RBE), which in the case of ion beams is not factorizable and introduces strong non-linearity. We implemented the gEUD-based optimization in TRiP98, allowing us to control the whole dose–volume histogram (DVH) shape of OAR with a single objective by adjusting the prescribed gEUD 0 and the volume effect parameter a , reducing the volume receiving dose levels close to mean dose when a = 1 (large volume effect) while close to maximum dose for a >> 1 (small volume effect), depending on the organ type considered. We studied the role of gEUD 0 and a in the optimization, and we compared voxel-dose-based and gEUD-based optimization in chordoma cases with different anatomies. In particular, for a plan containing multiple OARs, we obtained the same target coverage and similar DVHs for OARs with a small volume effect while decreasing the mean dose received by the proximal parotid, thus reducing its NTCP by a factor of 2.5. Further investigations are done for this plan, considering also the distal parotid gland, obtaining a NTCP reduction by a factor of 1.9 for the proximal and 2.9 for the distal one. In conclusion, this novel optimization method can be applied to different OARs, but it achieves the largest improvement for organs whose volume effect is larger. This allows TRiP98 to perform a double level of biologically driven optimization for ion beams, including at the same time RBE-weighted dose and volume effects in inverse planning. An outlook is presented on the possible extension of this method to the target. [ABSTRACT FROM AUTHOR]

The advantageous depth dose profile of ion beams together with state of the art beam delivery and treatment planning systems allow for highly conformal tumor treatments in patients. First treatments date back to 1954 at the Lawrence Berkeley Laboratory (LBL) and in Europe, ion beam therapy started in the mid-1990s at the Paul-Scherrer Institute (PSI) with protons and at the Helmholtz Center for Heavy Ion Research (GSI) with carbon ions, followed by the Heidelberg Ion Therapy Center (HIT) in Heidelberg. This review describes the historical development of ion beam therapy in Germany based on the pioneering work at LBL and in the context of simultaneous developments in other countries as well as recent developments. [ABSTRACT FROM AUTHOR]

To generate virtual 4DCT from 4DMRI with field of view (FOV) extended to the entire involved patient anatomy, in order to evaluate its use in carbon ion radiation therapy (CIRT) of the abdominal site in a clinical scenario. The virtual 4DCT was generated by deforming a reference CT in order to (1) match the anatomy depicted in the 4DMRI within its FOV, by calculating deformation fields with deformable image registration to describe inter-fractional and breathing motion, and (2) obtain physically plausible deformation outside of the 4DMRI FOV, by propagating and modulating the previously obtained deformation fields. The implemented method was validated on a digital anthropomorphic phantom, for which a ground truth (GT) 4DCT was available. A CIRT treatment plan was optimized at the end-exhale reference CT and the RBE-weighted dose distribution was recalculated on both the virtual and GT 4DCTs. The method estimation error was quantified by comparing the virtual and GT 4DCTs and the corresponding recomputed doses. The method was then evaluated on 8 patients with pancreas or liver tumors treated with CIRT using respiratory gating at end-exhale. The clinical treatment plans adopted at the National Center for Oncological Hadrontherapy (CNAO, Pavia, Italy) were considered and the dose distribution was recomputed on all respiratory phases of the planning and virtual 4DCTs. By comparing the two datasets and the corresponding dose distributions, the geometrical and dosimetric impact of organ motion was assessed. For the phantom, the error outside of the 4DMRI FOV was up to 4.5 mm, but it remained sub-millimetric in correspondence to the target within the 4DMRI FOV. Although the impact of motion on the target D 95% resulted in variations ranging from 22% to 90% between the planned dose and the doses recomputed on the GT 4DCT phases, the corresponding estimation error was ≤2.2%. In the patient cases, the variation of the baseline tumor position between the planning and the virtual end-exhale CTs presented a median (interquartile range) value of 6.0 (4.9) mm. For baseline variations larger than 5 mm, the tumor D 95% variation between the plan and the dose recomputed on the end-exhale virtual CT resulted larger than 10%. Median variations higher than 10% in the target D 95% and gastro-intestinal OARs D 2% were quantified at the end-inhale, whereas close to the end-exhale phase, limited variations of relevant dose metrics were found for both tumor and OARs. The negligible impact of the geometrical inaccuracy in the estimated anatomy outside of the 4DMRI FOV on the overall dosimetric accuracy suggests the feasibility of virtual 4DCT with extended FOV in CIRT of the abdominal site. In the analyzed patient group, inter-fractional variations such as baseline variation and breathing variability were quantified, demonstrating the method capability to support treatment planning in gated CIRT of the abdominal site. [ABSTRACT FROM AUTHOR]

We describe a way to include biologically based objectives in plan optimization specific for carbon ion therapy, beyond the standard voxel-dose-based criteria already implemented in TRiP98, research planning software for ion beams. The aim is to account for volume effects—tissue architecture-dependent response to damage—in the optimization procedure, using the concept of generalized equivalent uniform dose (gEUD), which is an expression to convert a heterogeneous dose distribution (e.g., in an organ at risk (OAR)) into a uniform dose associated with the same biological effect. Moreover, gEUD is closely related to normal tissue complication probability (NTCP). The multi-field optimization problem here takes also into account the relative biological effectiveness (RBE), which in the case of ion beams is not factorizable and introduces strong non-linearity. We implemented the gEUD-based optimization in TRiP98, allowing us to control the whole dose–volume histogram (DVH) shape of OAR with a single objective by adjusting the prescribed gEUD0 and the volume effect parameter a, reducing the volume receiving dose levels close to mean dose when a = 1 (large volume effect) while close to maximum dose for a >> 1 (small volume effect), depending on the organ type considered. We studied the role of gEUD0 and a in the optimization, and we compared voxel-dose-based and gEUD-based optimization in chordoma cases with different anatomies. In particular, for a plan containing multiple OARs, we obtained the same target coverage and similar DVHs for OARs with a small volume effect while decreasing the mean dose received by the proximal parotid, thus reducing its NTCP by a factor of 2.5. Further investigations are done for this plan, considering also the distal parotid gland, obtaining a NTCP reduction by a factor of 1.9 for the proximal and 2.9 for the distal one. In conclusion, this novel optimization method can be applied to different OARs, but it achieves the largest improvement for organs whose volume effect is larger. This allows TRiP98 to perform a double level of biologically driven optimization for ion beams, including at the same time RBE-weighted dose and volume effects in inverse planning. An outlook is presented on the possible extension of this method to the target.

Purpose: To evaluate the dose difference between measurement and double Gaussian beam model prediction according to the field size and correct the measurements in patient‐specific quality assurance (QA). Methods: The field size dependence of the dose was evaluated with volumes of 20 × 20 × 80 mm3, 40 × 40 × 80 mm3, 60 × 60 × 80 mm3, and 80 × 80 × 80 mm3 of 1 Gy uniform dose at three depths. Additional two 80 × 80 × 80 mm3 volumes of nonuniform fields were created: one high‐dose field was given 1 Gy at the central 40 × 40 mm2 and 0.5 Gy in its surrounding, and the other low‐dose field was given 0.5 Gy in the middle and 1 Gy at the periphery. The dose in the center of the spread‐out Bragg peak (SOBP) was measured in a water phantom and compared with the treatment planning system (TPS) predication. A field factor based on the two‐dimensional (2D) dose distribution was proposed to estimate the field size. The field factor was first evaluated against the dose difference in the square fields, and then used to analyze and correct the patient‐specific QA results. Results: TPS overestimated dose for fields smaller than 80 × 80 mm2. A practically positive correlation was observed between the measured dose and the field factor. In the patient‐specific QA, measured doses were lower than the TPS predication as they were calculated a relatively small field factor. The corrected dose differences were no longer field factor dependent. Conclusions: Using the proposed field factor, we have shown that all the measurements with a large dose deviation were due to the small‐sized field. It is clinically relevant to take into consideration the field size in the QA analysis as long as the double Gaussian beam model being used for the dose calculation. Correction to the measurement can be made based on the field factor. [ABSTRACT FROM AUTHOR]

• Implemented RBE-weighted 4D particle dose alculation for irregular motion. • Enables dose calculations on arbitrarily long series of CT images. • Impact of irregular motion studied on simulated human phantom CT sequences. • Experimental validation of dose calculation algorithm with moving IC array detector. • Will enable exploration of effects and study of motion mitigation strategies. Purpose: Highly conformal scanned Carbon Ion Radiotherapy (CIRT) might permit dose escalation and improved local control in advanced stage thoracic tumors, but is challenged by target motion. Dose calculation algorithms typically assume a periodically repeating, regular motion. To assess the effect of realistic, irregular motion, new algorithms of validated accuracy are needed. Methods: We extended an in-house treatment planning system to calculate RBE-weighted dose distributions in CIRT on non-periodic CT image sequences. Dosimetric accuracy was validated experimentally on a moving, time-resolved ionization chamber array. Log-file based dose reconstructions were compared by gamma analysis and correlation to measurements at every intermediate detector frame during delivery. The impact of irregular motion on treatment quality was simulated on a virtual 4DCT thorax phantom. Periodic motion was compared to motion with varying amplitude and period ± baseline drift. Rescanning as a mitigation strategy was assessed on all scenarios. Results: In experimental validation, average gamma pass rates were 99.89+-0.30% for 3%/3 mm and 88.2+-2.2% for 2%/2 mm criteria. Average correlation for integral dose distributions was 0.990 ± 0.002. Median correlation for single 200 ms frames was 0.947 ± 0.006. In the simulations, irregular motion deteriorated V95 target coverage to 81.2%, 76.6% and 79.0% for regular, irregular motion and irregular motion with base-line drift, respectively. Rescanning restored V95 to > 98% for both scenarios without baseline drift, but not with additional baseline drift at 83.7%. Conclusions: The validated algorithm permits to study the effects of irregular motion and to develop and adapt appropriate motion mitigation techniques. [ABSTRACT FROM AUTHOR]