Comparison of linear energy transfer measurement for therapeutic carbon beam using CR-39 and TLD.

The measurement of linear energy transfer (LET) is crucial for the evaluation of the radiation effect in heavy ion therapy. As two detectors which are convenient to implant into the phantom, the performance of CR-39 and thermoluminescence detector (TLD) for LET measurement was compared by experiment and simulation in this study. The results confirmed the applicability of both detectors for LET measurements, but also revealed that the CR-39 detector would lead to potential overestimation of dose-averaged LET compared with the simulation by PHITS, while the TLD would have a large uncertainty measuring ions with LET larger than 20 keVµm-1. The results of this study were expected to improve the detection method of LET for therapeutic carbon beam and would finally be benefit to the quality assurance of heavy ion radiotherapy.

Trajectories of fear of progression in nasopharyngeal carcinoma patients receiving proton and heavy ion therapy.

OBJECTIVE: The study examined the growth trajectory of fear of progression(FOP) in nasopharyngeal carcinoma (NPC) patients. In addition, sociodemographic and clinical variables of each trajectory class were analyzed. METHOD: Two hundred sixteen NPC patients undergoing proton and heavy ion therapy were measured beginning (T0) and end of a 4-week proton and heavy ion therapy (T1), 3 months (T2) and 6 months (T3) after discharge. And data from the final 197 NPC patients were analyzed. NPC patients' FOP was investigated by the Fear of Progression Questionnaire-Short Form (FOP-Q-SF) form T0 to T3. SPSS and Mplus were used for statistical analysis. The LGMM was used to analyze the trajectory of FOP followed up over 6 months after proton and heavy ion therapy. The logistic regression was utilized to compare the differences in sociodemographic and clinical characteristics of patients in different trajectory groups of FOP. RESULTS: One hundred ninety-seven NPC patients were analyzed. LGMM analysis showed that three-group trajectory solution was the best fitting (low-fear decline FOP (14.21%), the moderate-fear stable FOP(43.15%), and high-fear rising FOP (42.64%). Significant positive associations were found between age < 30 years (ß = 3.399, p = 0.023), with or without children (ß = 3.1, p = 0.002), primary/recurrence (ß = -6.196, p < 0.001), diagnosis < 3 months (ß = 4.435, p = 0.031), high school education (ß = 2.98, p = 0.048), and high fear rising FOP. Patients who had moderate financial stress (ß = 2.51, p = 0.041), with or without children (ß = 1.564, p = 0.003), primary/recurrence (ß = -2.578, p = 0.005), less than 30 radiotherapy times (ß = 0.979, p = 0.046) tended to report significant moderate-fear stable FOP over time. CONCLUSION: 42.64% of the NPC patients showed high-fear rising FOP over the 6 months after treatment. Age 18-30 years, with or without children, relapsed, diagnosis < 3 months, and high school education and reporting being a pessimist predicts higher FOP scores. Early identification of age 18-30 years, with or without children, relapsed, diagnosis < 3 months, and high school education might help to identify populations experiencing long-term FOP. Clinical teams responsible to develop the target interventions for management of FCR in clinical practice.

Spindle cell oncocytoma of the neurohypophysis with metastasis to the sphenoparietal sinus and immunohistochemical negativity for S100 and epithelial membrane antigen (EMA).

We report the case of a 61-year-old male with spindle cell oncocytoma of the hypophysis. On presentation to the Department of Neurosurgery at the German Armed Forces Hospital of Ulm, the patient reported a history of several years of left sixth nerve palsy, right ptosis, increased sensitivity to light, and a bilateral retrobulbar pressure sensation. Pituitary function was normal. A chromophobe non-functioning pituitary adenoma was initially suspected. The diagnosis was established on the basis of examination at a histopathology reference laboratory using immunohistochemistry to identify cell surface markers. During two years of follow-up, there were two clinical recurrences requiring surgery. To our knowledge, this is the 35th documented case of spindle cell oncocytoma of the pituitary gland and the first that was immunohistochemically negative for epithelial membrane antigen (EMA) and S100; and the first that displayed haematogenous metastasis to the right sphenoparietal sinus. The three surgical procedures were associated with massive intraoperative bleeding and thus resulted in subtotal tumor resection. Following surgery for the recurrences, the patient underwent radiotherapy.

Neoadjuvant irradiation of extremity soft tissue sarcoma with ions (Extrem-ion): study protocol for a randomized phase II pilot trial.

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.

Effects of cellular radioresponse on therapeutic helium-, carbon-, oxygen-, and neon-ion beams: a simulation study.

Objective. Helium, oxygen, and neon ions in addition to carbon ions will be used for hypofractionated multi-ion therapy to maximize the therapeutic effectiveness of charged-particle therapy. To use new ions in cancer treatments based on the dose-fractionation protocols established in carbon-ion therapy, this study examined the cell-line-specific radioresponse to therapeutic helium-, oxygen-, and neon-ion beams within wide dose ranges.Approach. Response of cells to ions was described by the stochastic microdosimetric kinetic model. First, simulations were made for the irradiation of one-field spread-out Bragg peak beams in water with helium, carbon, oxygen, and neon ions to achieve uniform survival fractions at 37%, 10%, and 1% for human salivary gland tumor (HSG) cells, the reference cell line for the Japanese relative biological effectiveness weighted dose system, within the target region defined at depths from 90 to 150 mm. The HSG cells were then replaced by other cell lines with different radioresponses to evaluate differences in the biological dose distributions of each ion beam with respect to those of carbon-ion beams.Main results. For oxygen- and neon-ion beams, the biological dose distributions within the target region were almost equivalent to those of carbon-ion beams, differing by less than 5% in most cases. In contrast, for helium-ion beams, the biological dose distributions within the target region were largely different from those of carbon-ion beams, more than 10% in several cases.Significance.From the standpoint of tumor control evaluated by the clonogenic cell survival, this study suggests that the dose-fractionation protocols established in carbon-ion therapy could be reasonably applied to oxygen- and neon-ion beams while some modifications in dose prescription would be needed when the protocols are applied to helium-ion beams. This study bridges the gap between carbon-ion therapy and hypofractionated multi-ion therapy.

Minimum data elements for the Australian Particle Therapy Clinical Quality Registry.

INTRODUCTION: Construction of the first Australian particle therapy (PT) centre is underway. Establishment of a national registry, to be known as the Australian Particle Therapy Clinical Quality Registry (ASPIRE), has been identified as a mandatory requirement for PT treatment to be reimbursed by the Australian Medicare Benefits Schedule. This study aimed to determine a consensus set of Minimum Data Elements (MDEs) for ASPIRE. METHODS: A modified Delphi and expert consensus process was completed. Stage 1 compiled currently operational English-language international PT registries. Stage 2 listed the MDEs included in each of these four registries. Those included in three or four registries were automatically included as a potential MDE for ASPIRE. Stage 3 interrogated the remaining data items, and involved three rounds - an online survey to a panel of experts, followed by a live poll session of PT-interested participants, and finally a virtual discussion forum of the original expert panel. RESULTS: One hundred and twenty-three different MDEs were identified across the four international registries. The multi-staged Delphi and expert consensus process resulted in a total of 27 essential MDEs for ASPIRE; 14 patient factors, four tumour factors and nine treatment factors. CONCLUSIONS: The MDEs provide the core mandatory data items for the national PT registry. Registry data collection for PT is paramount in the ongoing global effort to accumulate more robust clinical evidence regarding PT patient and tumour outcomes, quantifying the magnitude of clinical benefit and justifying the relatively higher costs of PT investment.

The SINTART 2 Study. A phase II non-randomised controlled trial of induction chemotherapy, photon-, proton- and carbon-ion-based radiotherapy integration in patients with locally advanced unresectable sinonasal tumours.

PURPOSE: Unresectable, locally advanced sinonasal epithelial tumours are rare diseases with poor prognosis. Multimodal approach is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT. METHODS: Patients with untreated, unresectable sinonasal epithelial tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enroled in a single-arm, open-label, phase II, multicentre clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype. Photon and/or proton/carbon-ion-based RT was employed according to disease site, stage and ICT response. Primary end-point was 5-years progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate per RECIST 1.1 and safety. RESULTS: Twenty-five patients were evaluable for primary end-point. Five-year PFS was 26.8% (95% confidence interval [CI]: 12.6-57.1), with a median PFS of 18 months. Five-year OS was 23.8% (95% CI: 9.5-59.3), with a median OS of 27 months. The overall response rate to ICT was 40%. Three-year PFS for patients achieving major volumetric partial response (mPRv) versus non-mPRv was 40% (95% CI: 13.7-100%) versus 23.1% (95% CI: 8.3-64.7%) (P = 0.318) and 3-year OS was 53.3% (95% CI: 21.4-100%) versus 37.7% (95% CI: 20.0-71.0%) (P = 0.114). CONCLUSION: Multimodal combination of ICT and innovative RT did not provide a significant improvement in survival rates with respect to previous experiences. This finding underscores the need for future research in this rare disease, still characterised by a heavy burden and poor prognosis. We observed longer survival in subjects achieving response to ICT. The overall treatment safety is acceptable.

The SINTART 1 study. A phase II non-randomised controlled trial of induction chemotherapy, surgery, photon-, proton- and carbon ion-based radiotherapy integration in patients with locally advanced resectable sinonasal tumours.

PURPOSE: Sinonasal tumours are rare diseases with poor prognosis. Multimodal approach including surgery is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment-induction chemotherapy (ICT), surgery and radiotherapy (RT)-modulated by histology and response to ICT. METHODS: Patients with untreated, operable sinonasal tumours with selected histotypes (squamous cell carcinoma, intestinal-type adenocarcinoma, sinonasal undifferentiated and neuroendocrine carcinoma, olfactory neuroblastoma) were enrolled in a single-arm, phase II, multicenter clinical trial. Patients were treated with up to 5 ICT cycles, whose regimen was selected according to histotype, followed either by curative chemo-RT for pts with ≥80% reduction of initial tumour diameter or surgery and adjuvant (chemo)RT. Photon and/or proton/carbon ion-based RT was employed according to the disease site and stage. Primary end-point was 5-year progression-free survival (PFS), secondary end-points were overall survival (OS), ICT objective response rate (ORR) per RECIST 1.1 and safety. RESULTS: Thirty-five patients were evaluable for primary end-point. Fourteen patients (40%) were treated with definitive (CT)RT and 20 (57%) underwent surgery. Five-year PFS was 38% (95% confidence interval [CI], 21-69), with a median PFS of 26 months. Five-year OS was 46% (95% CI, 28-75), with a median OS of 36 months. Three-year PFS-OS for pts achieving PR/CR versus stable disease (SD)/PD to ICT were 49.8-57% versus 43.2-53%, respectively. Three-year PFS for patients achieving major volumetric partial response (≥80% reduction of initial tumour volume, major partial volumetric response [mPRv]) versus non-mPRv were 82% versus 28% and 3-year OS were 92% versus 36% (p value 0.010 and 0.029, respectively). The ORR to ICT was 54% and 60% across all histotypes and in the sinonasal undifferentiated carcinoma (SNUC) subpopulation, respectively, with 6/15 SNUCs (40%) achieving mPRv. CONCLUSION: Treatment of advanced sinonasal cancer with histology-driven ICT followed by (CT)RT in responsive patients was feasible. Overall, these findings suggest a possible role of ICT as the primary approach in newly diagnosed, resectable sinonasal tumours-especially SNUC-to select patients with favourable prognosis. Histology heterogeneity limits generalisation of trial results.

Radiotherapy for Mobile Spine and Sacral Chordoma: A Critical Review and Practical Guide from the Spine Tumor Academy.

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.

FLASH radiotherapy with carbon ion beams.

FLASH radiotherapy is considered a new potential breakthrough in cancer treatment. Ultra-high dose rates (>40 Gy/s) have been shown to reduce toxicity in the normal tissue without compromising tumor control, resulting in a widened therapeutic window. These high dose rates are more easily achievable in the clinic with charged particles, and clinical trials are, indeed, ongoing using electrons or protons. FLASH could be an attractive solution also for heavier ions such as carbon and could even enhance the therapeutic window. However, it is not yet known whether the FLASH effect will be the same as for sparsely ionizing radiation when densely ionizing carbons ions are used. Here we discuss the technical challenges in beam delivery and present a promising solution using 3D range-modulators in order to apply ultra-high dose rates (UHDR) compatible with FLASH with carbon ions. Furthermore, we will discuss the possible outcome of C-ion therapy at UHDR on the level of the radiobiological and radiation chemical effects.

FLASH with carbon ions: Tumor control, normal tissue sparing, and distal metastasis in a mouse osteosarcoma model.

BACKGROUND AND PURPOSE: The FLASH effect is a potential breakthrough in radiotherapy because ultra-high dose-rate irradiation can substantially widen the therapeutic window. While the normal tissue sparing at high doses and short irradiation times has been demonstrated with electrons, photons, and protons, so far evidence with heavy ions is limited to in vitro cell experiments. Here we present the first in vivo results with high-energy 12C-ions delivered at an ultra-high dose rate. MATERIALS AND METHODS: LM8 osteosarcoma cells were subcutaneously injected in the posterior limb of female C3H/He mice 7 days before radiation exposure. Both hind limbs of the animals were irradiated with 240 MeV/n 12C-ions at ultra-high (18 Gy in 150 ms) or conventional dose rate (∼18 Gy/min). Tumor size was measured until 28 days post-exposure, when animals were sacrificed and lungs, limb muscles, and tumors were collected for further histological analysis. RESULTS: Irradiation with carbon ions was able to control the tumour both at conventional and ultra-high dose rate. FLASH decreases normal tissue toxicity as demonstrated by the reduced structural changes in muscle compared to conventional dose-rate irradiation. Carbon ion irradiation in FLASH conditions significantly reduced lung metastasis compared to conventional dose-rate irradiation and sham-irradiated animals. CONCLUSIONS: We demonstrated the FLASH effect in vivo with high-energy carbon ions. In addition to normal tissue sparing, we observed tumor control and a substantial reduction of lung metastasis in an osteosarcoma mouse model.

Spot-scanning hadron arc (SHArc) therapy: A proof of concept using single- and multi-ion strategies with helium, carbon, oxygen, and neon ions.

PURPOSE: To present particle arc therapy treatments using single and multi-ion therapy optimization strategies with helium (4 He), carbon (12 C), oxygen (16 O), and neon (20 Ne) ion beams. METHODS AND MATERIALS: An optimization procedure and workflow were devised for spot-scanning hadron arc therapy (SHArc) treatment planning in the PRECISE (PaRticle thErapy using single and Combined Ion optimization StratEgies) treatment planning system (TPS). Physical and biological beam models were developed for helium, carbon, oxygen, and neon ions via FLUKA MC simulation. SHArc treatments were optimized using both single-ion (12 C, 16 O, or 20 Ne) and multi-ion therapy (16 O+4 He or 20 Ne+4 He) applying variable relative biological effectiveness (RBE) modeling using a modified microdosimetric kinetic model (mMKM) with (α/ß)x values of 2, 5, and 3.1 Gy, respectively, for glioblastoma, pancreatic adenocarcinoma, and prostate adenocarcinoma patient cases. Dose, effective dose, linear energy transfer (LET), and RBE were computed with the GPU-accelerated dose engine FRoG and dosimetric/biophysical attributes were evaluated in the context of conventional particle and photon-based therapies (e.g., volumetric modulated arc therapy [VMAT]). RESULTS: All SHArc plans met the target optimization goals (3GyRBE) and demonstrated increased target conformity and substantially lower low-dose bath to surrounding normal tissues than VMAT. SHArc plans using a singleion species (12 C, 16 O, or 20 Ne) exhibited favorable LET distributions with the highest-LET components centralized in the target volume, with values ranging from ∼80-170 keV/µm, ∼130-220 keV/µm, and ∼180-350 keV/µm for 12 C, 16 O, or 20 Ne, respectively, exceeding mean target LET of conventional particle therapy (12 C:∼55, 16 O:∼75 20 Ne:∼95 keV/µm). Multi-ion therapy with SHArc delivery (SHArcMIT ) provided a similar level of target LET enhancement as SHArc compared to conventional planning, however, with additional benefits of homogenous physical dose and RBE distributions. CONCLUSION: Here, we demonstrate that arc delivery of light and heavy ion beams, using either a single-ion species (12 C, 16 O, or 20 Ne) or combining two ions in a single fraction (16 O+4 He or 20 Ne+4 He) affords enhanced physical and biological distributions (e.g., LET) compared with conventional delivery with photons or particle beams. SHArc marks the first single- and multi-ion arc therapy treatment optimization approach using light and heavy ions.

Is Thoracic Radiotherapy an Absolute Contraindication for Treatment of Lung Cancer Patients With Interstitial Lung Disease? A Systematic Review.

Thoracic radiotherapy decisions in patients with interstitial lung disease (ILD) are complex due to concerns about severe or even fatal radiation pneumonitis. This systematic review analysed the published evidence regarding the incidence of radiation pneumonitis and mortality after thoracic radiotherapy and investigated clinical and dosimetric predictors of radiation pneumonitis in lung cancer patients with ILD. A systematic search was carried out in PubMed, Medline, Embase and the Cochrane database for articles published between January 2000 and April 2021. Two authors independently screened eligible studies that met our predefined criteria. Studies were assessed for design and quality and a qualitative data synthesis was carried out. The search strategy resulted in 1750 articles. After two rounds of screening, 24 publications were included. The median overall incidence of grade ≥3 radiation pneumonitis was 19.7% (range 8-46%). The incidence was greater in conventional radical radiotherapy-treated patients (median 31.8%) compared with particle beam therapy- or stereotactic ablative radiotherapy-treated patients (median 12.5%). The median rate of grade 5 radiation pneumonitis was 11.9% (range 0-60%). The presence of ILD was an independent predictor of severe radiation pneumonitis. Severe radiation pneumonitis was more common in the presence of usual interstitial pneumonia (UIP) pattern or idiopathic pulmonary fibrosis (IPF) than non-UIP or non-IPF subtype. Several other clinical predictors were reported in the literature. V5, V10, V20 and mean lung dose were the most common dosimetric predictors for severe radiation pneumonitis, often with stricter dose constraints than conventionally used. Patients with lung cancer associated with ILD had a poorer overall survival compared with patients without ILD. In conclusion, patients with lung cancer associated with ILD have a poor prognosis. They are at high risk of severe and even fatal radiation pneumonitis. Careful patient selection is necessary, appropriate high-risk consenting and strict lung dose-volume constraints should be used, if these patients are to be treated with thoracic radiotherapy.

The role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma.

BACKGROUND: To investigate the role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma; final analysis of a one-armed, single center phase I/II trial. METHODS: Between August 2011 until September 2018, 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) inoperable pelvic (70%) or craniofacial (30%) osteosarcoma were treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) and followed until May 2019. A Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed before CIBRT in search for a prognostic factor. The primary endpoint was toxicity. Secondary endpoints included treatment response, global, local and distant progression free survival (PFS, LPFS and DPFS) and overall (OS), among others. RESULTS: The median age was 20; all patients finished treatment per protocol. LPFS, DPFS, PFS and OS were 73%, 74%, 60% and 75% after one year and 55%, 65% 65.3%, 45% and 68% after two years, respectively. The median clinical target volume (CTV) was 1042 cc and 415 cc for the primary and boost plan, respectively. Craniofacial localization, lower uptake of FDG in PET/CT and boost plan CTV ≤ median were associated with improved overall survival (p = 0.039, p = 0.016 and p = 0.0043, respectively). No acute toxicities > grade III were observed. We observed one case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss. CONCLUSION: CIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma.

Intra- and inter-fraction relative range verification in heavy-ion therapy using filtered interaction vertex imaging.

Heavy-ion therapy, particularly using scanned (active) beam delivery, provides a precise and highly conformal dose distribution, with maximum dose deposition for each pencil beam at its endpoint (Bragg peak), and low entrance and exit dose. To take full advantage of this precision, robust range verification methods are required; these methods ensure that the Bragg peak is positioned correctly in the patient and the dose is delivered as prescribed. Relative range verification allows intra-fraction monitoring of Bragg peak spacing to ensure full coverage with each fraction, as well as inter-fraction monitoring to ensure all fractions are delivered consistently. To validate the proposed filtered interaction vertex imaging (IVI) method for relative range verification, a16O beam was used to deliver 12 Bragg peak positions in a 40 mm poly-(methyl methacrylate) phantom. Secondary particles produced in the phantom were monitored using position-sensitive silicon detectors. Events recorded on these detectors, along with a measurement of the treatment beam axis, were used to reconstruct the sites of origin of these secondary particles in the phantom. The distal edge of the depth distribution of these reconstructed points was determined with logistic fits, and the translation in depth required to minimize theχ2statistic between these fits was used to compute the range shift between any two Bragg peak positions. In all cases, the range shift was determined with sub-millimeter precision, to a standard deviation of the mean of 220(10)µm. This result validates filtered IVI as a reliable relative range verification method, which should be capable of monitoring each energy step in each fraction of a scanned heavy-ion treatment plan.

A Potential Renewed Use of Very Heavy Ions for Therapy: Neon Minibeam Radiation Therapy.

(1) Background: among all types of radiation, very heavy ions, such as Neon (Ne) or Argon (Ar), are the optimum candidates for hypoxic tumor treatments due to their reduced oxygen enhancement effect. However, their pioneering clinical use in the 1970s was halted due to severe side effects. The aim of this work was to provide a first proof that the combination of very heavy ions with minibeam radiation therapy leads to a minimization of toxicities and, thus, opening the door for a renewed use of heavy ions for therapy; (2) Methods: mouse legs were irradiated with either Ne MBRT or Ne broad beams at the same average dose. Skin toxicity was scored for a period of four weeks. Histopathology evaluations were carried out at the end of the study; (3) Results: a significant difference in toxicity was observed between the two irradiated groups. While severe da-mage, including necrosis, was observed in the broad beam group, only light to mild erythema was present in the MBRT group; (4) Conclusion: Ne MBRT is significantly better tolerated than conventional broad beam irradiations.

Evidence Mapping of Proton Therapy, Heavy Ion Therapy, and Helical Tomotherapy for Gastric Cancer.

PURPOSE: This study aimed to systematically present application situation and therapeutic effect of proton therapy (PT), heavy ion therapy, and helical tomotherapy (TOMO) for gastric cancer (GC), and to find gaps of existing studies. METHODS: PubMed, EMBASE, the Cochrane Library, Web of Science, and Chinese Biological Medical Database were searched. Tables, bubble plot, and heat map were conducted to display results. RESULTS: Fourteen studies were included. About PT, 7 single-arm studies showed median overall survival (OS) within 2-66 months and 1 study reported 40% of patients happened moderate degree of radiation gastritis. About TOMO, 1 study reported longer median OS and progression-free survival, lower occurrence of Grade III toxicity, and late toxicity compared to 3D-CRT, while another study remained neutral. About heavy ion therapy, there was no clinical study was found. CONCLUSIONS: Existing studies presented good clinic treatment effect about PT and TOMO for GC, and furthermore clinical studies are needed.

Physical characterization of3He ion beams for radiotherapy and comparison with4He.

There is increasing interest in using helium ions for radiotherapy, complementary to protons and carbon ions. A large number of patients were treated with4He ions in the US heavy ion therapy project and novel4He ion treatment programs are under preparation, for instance in Germany and Japan.3He ions have been proposed as an alternative to4He ions because the acceleration of3He is technically less difficult than4He. In particular, beam contaminations have been pointed out as a potential safety issue for4He ion beams. This motivated a series of experiments with3He ion beams at Gesellschaft für Schwerionenforschung (GSI), Darmstadt. Measured3He Bragg curves and fragmentation data in water are presented in this work. Those experimental data are compared with FLUKA Monte Carlo simulations. The physical characteristics of3He ion beams are compared to those of4He, for which a large set of data became available in recent years from the preparation work at the Heidelberger Ionenstrahl-Therapiezentrum (HIT). The dose distributions (spread out Bragg peaks, lateral profiles) that can be achieved with3He ions are found to be competitive to4He dose distributions. The effect of beam contaminations on4He depth dose distribution is also addressed. It is concluded that3He ions can be a viable alternative to4He, especially for future compact therapy accelerator designs and upgrades of existing ion therapy facilities.

Neoadjuvant irradiation of retroperitoneal soft tissue sarcoma with ions (Retro-Ion): study protocol for a randomized phase II pilot trial.

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.

Estimations of relative biological effectiveness of secondary fragments in carbon ion irradiation of water using CR-39 plastic detector and microdosimetric kinetic model.

PURPOSE: To estimate relative biological effectiveness (RBE) ascribed to secondary fragments in a lateral distribution of carbon ion irradiation. The RBE was estimated with the microdosimetric kinetic (MK) model and measured linear energy transfer (LET) obtained with CR-39 plastic detectors. METHODS: A water phantom was irradiated by a 12 C pencil beam with energy of 380 MeV/u at the Gunma University Heavy Ion Medical Center (GHMC), and CR-39 detectors were exposed to secondary fragments. Because CR-39 was insensitive to low LET, we conducted Monte Carlo simulations with Geant4 to calculate low LET particles. The spectra of low LET particles were combined with experimental spectra to calculate RBE. To estimate accuracy of RBE, we calculated RBE by changing yield of low LET particles by ± 10% and ± 40%. RESULTS: At a small angle, maximum RBE by secondary fragments was 1.3 for 10% survival fractions. RBE values of fragments gradually decreased as the angle became larger. The shape of the LET spectra in the simulation reproduced the experimental spectra, but there was a discrepancy between the simulation and experiment for the relative yield of fragments. When the yield of low LET particles was changed by ± 40%, the change in RBE was smaller than 10%. CONCLUSIONS: An RBE of 1.3 was expected for secondary fragments emitted at a small angle. Although, we observed a discrepancy in the relative yield of secondary fragments between simulation and experiment, precision of RBE was not so sensitive to the yield of low LET particles.