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Chronic encapsulated intracerebral hematoma is a rare type of intracerebral hemorrhage. Reportedly, it is associated with vascular malformations, including arteriovenous malformations, cavernous hemangiomas, microaneurysms, and venous malformations. Recently, an association between chronic encapsulated intracerebral hematoma and stereotactic radiosurgery for arteriovenous malformations has been reported. In general, as the hematoma enlarges, symptoms progress slowly. In this report, we present a case of a 50-year-old woman who had undergone clivus chordoma resection and carbon ion therapy for the clivus respectively 27 and 20 years before developing chronic encapsulated intracerebral hematoma with rapidly progressing disturbance of consciousness. She was referred to our hospital because of difficulty walking due to left hemiparesis. Head computed tomography and magnetic resonance imaging showed a cystic lesion in the right temporal lobe with perifocal edema. On the second day of hospitalization, the patient's consciousness worsened. We suspected a malignant glioma and performed an emergency craniotomy; however, the pathological diagnosis was chronic encapsulated intracerebral hematoma. After the rehabilitation therapy, the patient became ambulatory and was discharged. To the date of reporting, the patient remained recurrence-free. Chronic encapsulated intracerebral hematoma may be due to invasive craniotomy or carbon ion therapy. It usually progresses slowly; however, in some cases, such as this one, it may cause rapid deterioration of consciousness., Competing Interests: The authors have no conflicts of interest to declare., (© 2024 The Japan Neurosurgical Society.)

Radiation therapy is part of recommendations in the adjuvant settings for advanced stage or as exclusive treatment in unresectable thymic epithelial tumors (TETs). However, first-generation techniques delivered substantial radiation doses to critical organs at risk (OARs), such as the heart or the lungs, resulting in noticeable radiation-induced toxicity. Treatment techniques have significantly evolved for TET irradiation, and modern techniques efficiently spare normal surrounding tissues without negative impact on tumor coverage and consequently local control or patient survival. Considering its dosimetric advantages, hadrontherapy (which includes proton therapy and carbon ion therapy) has proved to be worthwhile for TET irradiation in particular for challenging clinical situations such as cardiac tumoral involvement. However, clinical experience for hadrontherapy is still limited and mainly relies on small-size proton therapy studies. This critical review aims to analyze the current status of hadrontherapy for TET irradiation to implement it at a larger scale. [ABSTRACT FROM AUTHOR]

• RBE modeling and dose-averaged LET distributions can affect treatment outcomes of CIRT. • The large size of sacral chordomas increases RBE modeling related uncertainties in CIRT. • Efforts should be focused on carbon ions LET optimization for large radioresistent tumors. To understand the role of relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LET d) distributions in the treatment of sacral chordoma (SC) patients with carbon ion radiotherapy (CIRT). Clinical plans of 50 SC patients consecutively treated before August 2018 with a local effect model-based optimization were recalculated with the modified microdosimetric kinetic RBE model (mMKM). Twenty-six patients were classified as progressive disease and the relapse volume was contoured on the corresponding follow-up diagnostic sequence. The remaining 24 patients populated the control group. Target prescription dose (D RBE|50%), near-to-minimum- (D RBE|95%) and near-to-maximum- (D RBE|2%) doses were compared between the two cohorts in both RBE systems. LET d distribution was evaluated for in-field relapsed cases with respect to the control group. Target D MKM|50% and D MKM|95% were respectively 10% and 18% lower than what we aimed at. Dosimetric evaluators showed no significant difference, in neither of the RBE frameworks, between relapsed and control sets. Half of the relapse volumes were located in a well-covered high dose region. On average, over these cases, median target LET d was significantly lower than the control cohort mean value (27 vs 30 keV/μm). Most notably, the volume receiving dose from high-LET particles (>50 keV/μm) lay substantially below recently reported data in the literature. A combined multi model RBE- and LET-based optimization could play a key role in the enhancement of the therapeutic ratio of CIRT for large radioresistant tumors such as sacral chordomas. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study was to validate the dosimetric performance of scanned ion beam deliveries with motion-synchronization to heterogenous targets. Methods: A 4D library of treatment plans, comprised of up to 10 3D sub-plans, was created with robust and conventional 4D optimization methods. Each sub-plan corresponded to one phase of periodic target motion. The plan libraries were delivered to a test phantom, comprising plastic slabs, dosimeters, and heterogenous phantoms. This phantom emulated range changes that occur when treating moving tumors. Similar treatment plans, but without motion synchronization, were also delivered to a test phantom with a stationary target and to a moving target; these were used to assess how the target motion degrades the quality of dose distributions and the extent to which motion synchronization can improve dosimetric quality. The accuracy of calculated dose distributions was verified by comparison with corresponding measurements. Comparisons utilized the gamma index analysis method. Plan quality was assessed based on conformity, dose coverage, overdose, and homogeneity values, each extracted from calculated dose distributions. Results: High pass rates for the gamma index analysis confirmed that the methods used to calculate and reconstruct dose distributions were sufficiently accurate for the purposes of this study. Calculated and reconstructed dose distributions revealed that the motion-synchronized and static deliveries exhibited similar quality in terms of dose coverage, overdose, and homogeneity for all deliveries considered. Motion-synchronization substantially improved conformity in deliveries with moving targets. Importantly, measurements at multiple locations within the target also confirmed that the motion-synchronized delivery system satisfactorily compensated for changes in beam range caused by the phantom motion. Specifically, the overall planning and delivery approach achieved the desired dose distribution by avoiding range undershoots and overshoots caused by tumor motion. Conclusions: We validated a dose delivery system that synchronizes the movement of the ion beam to that of a moving target in a test phantom. Measured and calculated dose distributions revealed that this system satisfactorily compensated for target motion in the presence of beam range changes due to target motion. The implication of this finding is that the prototype system is suitable for additional preclinical research studies, such as irregular anatomic motion. [ABSTRACT FROM AUTHOR]

Radiation therapy is part of recommendations in the adjuvant settings for advanced stage or as exclusive treatment in unresectable thymic epithelial tumors (TETs). However, first-generation techniques delivered substantial radiation doses to critical organs at risk (OARs), such as the heart or the lungs, resulting in noticeable radiation-induced toxicity. Treatment techniques have significantly evolved for TET irradiation, and modern techniques efficiently spare normal surrounding tissues without negative impact on tumor coverage and consequently local control or patient survival. Considering its dosimetric advantages, hadrontherapy (which includes proton therapy and carbon ion therapy) has proved to be worthwhile for TET irradiation in particular for challenging clinical situations such as cardiac tumoral involvement. However, clinical experience for hadrontherapy is still limited and mainly relies on small-size proton therapy studies. This critical review aims to analyze the current status of hadrontherapy for TET irradiation to implement it at a larger scale.

PurposeThe purpose of this study was to validate the dosimetric performance of scanned ion beam deliveries with motion-synchronization to heterogenous targets.MethodsA 4D library of treatment plans, comprised of up to 10 3D sub-plans, was created with robust and conventional 4D optimization methods. Each sub-plan corresponded to one phase of periodic target motion. The plan libraries were delivered to a test phantom, comprising plastic slabs, dosimeters, and heterogenous phantoms. This phantom emulated range changes that occur when treating moving tumors. Similar treatment plans, but without motion synchronization, were also delivered to a test phantom with a stationary target and to a moving target; these were used to assess how the target motion degrades the quality of dose distributions and the extent to which motion synchronization can improve dosimetric quality. The accuracy of calculated dose distributions was verified by comparison with corresponding measurements. Comparisons utilized the gamma index analysis method. Plan quality was assessed based on conformity, dose coverage, overdose, and homogeneity values, each extracted from calculated dose distributions.ResultsHigh pass rates for the gamma index analysis confirmed that the methods used to calculate and reconstruct dose distributions were sufficiently accurate for the purposes of this study. Calculated and reconstructed dose distributions revealed that the motion-synchronized and static deliveries exhibited similar quality in terms of dose coverage, overdose, and homogeneity for all deliveries considered. Motion-synchronization substantially improved conformity in deliveries with moving targets. Importantly, measurements at multiple locations within the target also confirmed that the motion-synchronized delivery system satisfactorily compensated for changes in beam range caused by the phantom motion. Specifically, the overall planning and delivery approach achieved the desired dose distribution by avoiding range undershoots and overshoots caused by tumor motion.ConclusionsWe validated a dose delivery system that synchronizes the movement of the ion beam to that of a moving target in a test phantom. Measured and calculated dose distributions revealed that this system satisfactorily compensated for target motion in the presence of beam range changes due to target motion. The implication of this finding is that the prototype system is suitable for additional preclinical research studies, such as irregular anatomic motion.

• A novel variable cycle-based respiratory guidance method was proposed. • The patterns between the breathing and synchrotron magnet excitation cycle could be synchronized. • The raITV and motion-induced dose distortion were included in the 4D dose calculations. • Both the treatment precision and efficiency were improved significantly. A novel variable cycle-based respiratory guidance method was proposed to synchronize the patterns between patients' breathing and the magnetic excitation of synchrotron under the mode of full-energy depth scanning beam delivery, in order to improve the treatment precision and efficiency for carbon ion therapy. Audio-visual biofeedback system with variable cycle-based respiratory guidance method was developed. We enrolled 6 healthy volunteers and a simulation study of the fixed cycle-based and variable cycle-based respiratory guidance with three treatment fractions was performed. A total of 72 breathing curves were collected for 4D dose calculations with three 4DCT datasets of lung tumor cases. Target dose coverage (D95: the percent dose covering 95% of the target), dose homogeneity (D5-D95), and treatment time were analyzed. The Wilcoxon signed-rank test was used for statistical difference analysis, and p < 0.05 was considered significant. With the variable cycle-based respiratory guidance method, the breath hold phase of breathing curve could be synchronized with the synchrotron flat-top phase over time. The dose homogeneity was improved by factors of 1.94–2.92 compared to the fixed cycle-based respiratory guidance maneuvers alone or in combination with gating technique. Moreover, the treatment efficiency increased by 11–23%, depending on the duty cycle settings of the gating window. The proposed variable cycle-based respiratory guidance method could improve both the treatment efficiency and precision under the mode of the full-energy depth scanning beam delivery for synchrotron-based carbon ion therapy. [ABSTRACT FROM AUTHOR]

Purpose: There is high-level evidence for addition of androgen deprivation therapy to photon-based radiotherapy of the prostate in intermediate- and high-risk prostate cancer. Little is known about the value of ADT in particle therapy of prostate cancer. We are conducting a systematic review on biochemical disease-free survival, overall survival, and morbidity after combined particle therapy and ADT for prostate cancer. Methods: A thorough search in PubMed, Embase, Scopus, and Web of Science databases were conducted, searching for relevant studies. Clinical studies on prostate cancer and the treatment combination of particle therapy and androgen deprivation therapy were included. The review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered on PROSPERO (CRD42021230801). Results: A total of 298 papers were identified. Fifteen papers reporting on 7,202 patients after proton or carbon-ion therapy for localized prostate cancer where a fraction or all patients received ADT were selected for analysis. Three thousand five hundred and nineteen (49%) of the patients had received combined ADT and particle therapy. Primarily high-risk (87%), to a lesser extent intermediate-risk (34%) and low-risk patients (12%) received ADT. There were no comparative studies on the effect of ADT in patients treated with particles and no studies identified ADT as an independent prognostic factor related to survival outcomes. Conclusions: The review found no evidence to support that the effects on biochemical disease-free survival and morbidity of combining ADT to particle therapy differs from the ADT effects in conventional photon based radiotherapy. The available data on the topic is limited. [ABSTRACT FROM AUTHOR]

• Combined ion-beam radiotherapy for osteosarcoma is a novel local therapeutic approach • Despite unfavorable size/localization toxicity was moderate/local control promising • FDG PET might serve as a surrogate for grading histopathologic regression in future. 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. 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. 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. CIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma. [ABSTRACT FROM AUTHOR]

Abstract Purpose To assess toxicity and quality-of-life (QOL) after carbon ion radiotherapy (CIRT) at the Shanghai Proton and Heavy Ion Center (SPHIC) and identify clinical factors that correlate with urinary, bowel and sexual function. Methods Sixty-four patients with localized prostate cancer admitted from July 2015 to January 2018 underwent CIRT. At baseline and 5 time-points after radiotherapy, we assessed patients’ QOL using the 26-item edition of the Expanded Prostate Cancer Index-Composite (EPIC-26) Chinese version. Logistic regression was performed to identify clinical factors associated with acute genitourinary (GU) toxicity and relative QOL. Results By the end of CIRT, urinary irritation/obstruction temporarily declined (− 7.92 ± 1.76, p

Abstract Background The usefulness of particle therapy for skull base chordoma has not been established. The aim of this retrospective study was to analyse the treatment outcomes of proton therapy (PT) and carbon ion therapy (CIT) in patients with skull base chordoma at a single institution. Methods All patients who underwent PT or CIT with curative intent between 2003 and 2014 at Hyogo Ion Beam Medical Center were included in this study. Twenty-four patients were enrolled. Eleven (46%) received PT and 13 (54%) received CIT. Overall survival (OS), progression-free survival (PFS) and local control (LC) were calculated using the Kaplan–Meier method. Late toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.0. Results The median follow-up was 71.5 months (range, 14–175 months). The five-year LC, PFS and OS rates were 85, 81, and 86%, respectively. The LC (P = 0.048), PFS (P = 0.028) and OS (P = 0.012) were significantly improved in patients who had undergone surgery before particle therapy. No significant differences were observed in the LC rate and the incidence of grade 2 or higher late toxicities between patients who received PT and CIT. Conclusions Both PT and CIT appear to be effective and safe treatments and show potential to become the standard treatments for skull base chordoma. To increase the local control, surgery before particle therapy is preferable.

BackgroundQuality management and safety are integral to modern radiotherapy. New radiotherapy technologies require new consensus guidelines on quality and safety. Established analysis strategies, such as the failure modes and effects analysis (FMEA) and incident learning systems have been developed as tools to assess the safety of several types of radiation therapies. An extensive literature documents the widespread application of risk analysis methods to photon radiation therapy. Relatively little attention has been paid to performing risk analyses of nascent radiation therapy systems to treat moving tumors with scanned heavy ion beams. The purpose of this study was to apply a comprehensive safety analysis strategy to a motion-synchronized dose delivery system (M-DDS) for ion therapy.MethodsWe applied a risk analysis method to new treatment planning and treatment delivery processes with scanned heavy ion beams. The processes utilize a prototype, modular dose delivery system, currently undergoing preclinical testing, that provides new capabilities for treating moving anatomy. Each step in the treatment process was listed in a process map, potential errors for each step were identified and scored using the risk probability number in an FMEA, and the possible causes of each error were described in a fault tree analysis. Solutions were identified to mitigate the risk of these errors, including permanent corrective actions, periodic quality assurance (QA) tests, and patient specific QA (PSQA) tests. Each solution was tested experimentally.ResultsThe analysis revealed 58 potential errors that could compromise beam delivery quality or safety. Each of the 14 binary (pass-or-fail) tests passed. Each of the nine QA and four PSQA tests were within anticipated clinical specifications. The modular M-DDS was modified accordingly, and was found to function at two centers.ConclusionWe have applied a comprehensive risk analysis strategy to the M-DDS and shown that it is a clinically viable motion mitigation strategy. The described strategy can be utilized at any ion therapy center that operates with the modular M-DDS. The approach can also be adapted for use at other facilities and can be combined with existing safety analysis systems.

Background: Quality management and safety are integral to modern radiotherapy. New radiotherapy technologies require new consensus guidelines on quality and safety. Established analysis strategies, such as the failure modes and effects analysis (FMEA) and incident learning systems have been developed as tools to assess the safety of several types of radiation therapies. An extensive literature documents the widespread application of risk analysis methods to photon radiation therapy. Relatively little attention has been paid to performing risk analyses of nascent radiation therapy systems to treat moving tumors with scanned heavy ion beams. The purpose of this study was to apply a comprehensive safety analysis strategy to a motion-synchronized dose delivery system (M-DDS) for ion therapy. Methods: We applied a risk analysis method to new treatment planning and treatment delivery processes with scanned heavy ion beams. The processes utilize a prototype, modular dose delivery system, currently undergoing preclinical testing, that provides new capabilities for treating moving anatomy. Each step in the treatment process was listed in a process map, potential errors for each step were identified and scored using the risk probability number in an FMEA, and the possible causes of each error were described in a fault tree analysis. Solutions were identified to mitigate the risk of these errors, including permanent corrective actions, periodic quality assurance (QA) tests, and patient specific QA (PSQA) tests. Each solution was tested experimentally. Results: The analysis revealed 58 potential errors that could compromise beam delivery quality or safety. Each of the 14 binary (pass-or-fail) tests passed. Each of the nine QA and four PSQA tests were within anticipated clinical specifications. The modular M-DDS was modified accordingly, and was found to function at two centers. Conclusion: We have applied a comprehensive risk analysis strategy to the M-DDS and shown that it is a clinically viable motion mitigation strategy. The described strategy can be utilized at any ion therapy center that operates with the modular M-DDS. The approach can also be adapted for use at other facilities and can be combined with existing safety analysis systems. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background and Purpose: Nuclear interaction correction (NIC) and trichrome fragment spectra modelling improve relative biological effectiveness-weighted dose (D RBE ) and dose-averaged linear energy transfer (LET d ) 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 D RBE and LET d 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 D RBE deviations for D 98% , D 50% , D 2% for the clinical target volume (CTV) and D 50% in ring-like dose regions retrieved from isodose curves in base RS plans. Additionally, region-based median LET d 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 LET d deviations were reported in the CTV, but significant median LET d deviations were up to 80% for very low dose regions., Conclusion: Our results showed improved accuracy of the predicted D RBE and LET d . Considering clinically relevant constraints, no significant modifications of clinical protocols are expected with the introduction of NIC + trichrome., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Lars Glimelius, Daniel Simon Colomar, Walter Ikegami Andersson reports financial support was provided by RaySearch Laboratories AB. Barbara Knäusl is associate editor in phiRO. The remaining authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Radiotherapy plays a central role in the treatment of cancer patients. Over the past decades, remarkable technological progress has been made in the field of conventional radiotherapy. In addition, the use of charged particles (e.g., protons and carbon ions) makes it possible to further improve dose deposition to the tumor, while sparing the surrounding healthy tissues. Despite these improvements, radioresistance and tumor recurrence are still observed. Although the mechanisms underlying resistance to conventional radiotherapy are well-studied, scientific evidence on the impact of charged particle therapy on cancer cell radioresistance is restricted. The purpose of this review is to discuss the potential role that charged particles could play to overcome radioresistance. This review will focus on hypoxia, cancer stem cells, and specific signaling pathways of EGFR, NFκB, and Hedgehog as well as DNA damage signaling involving PARP, as mechanisms of radioresistance for which pharmacological targets have been identified. Finally, new lines of future research will be proposed, with a focus on novel molecular inhibitors that could be used in combination with charged particle therapy as a novel treatment option for radioresistant tumors.

Abstract Background With the advance of modern irradiation techniques, the role of radiotherapy (RT) for intracranial meningioma has increased significantly throughout the past years. Despite that tumor’s generally favorable outcome with local control rates of up to 90% after ten years, progression after RT does occur. In those cases, re-irradiation is often difficult due to the limited radiation tolerance of the surrounding tissue. The aim of this analysis is to determine the value of particle therapy with its better dose conformity and higher biological efficacy for re-irradiating recurrent intracranial meningioma. It was performed within the framework of the “clinical research group heavy ion therapy” and funded by the German Research Council (DFG, KFO 214). Methods Forty-two patients treated with particle RT (protons (n = 8) or carbon ions (n = 34)) for recurrent intracranial meningioma were included in this analysis. Location of the primary lesion varied, including skull base (n = 31), convexity (n = 5) and falx (n = 6). 74% of the patients were categorized high-risk according to histology with a WHO grading of II (n = 25) or III (n = 6), in the remaining cases histology was either WHO grade I (n = 10) or unknown (n = 1). Median follow-up was 49,7 months. Results In all patients, re-irradiation could be performed safely without interruptions due to side effects. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered good overall local control rates with 71% progression-free survival (PFS) after 12 months, 56,5% after 24 months and a median PFS of 34,3 months (95% CI 11,7–56,9). Histology had a significant impact on PFS yielding a median PFS of 25,7 months (95% CI 5,8–45,5) for high-risk histology (WHO grades II and III) while median PFS was not reached for low-risk tumors (WHO grade I) (p = 0,03). Median time to local progression was 15,3 months (Q1-Q3 8,08–34,6). Overall survival (OS) after re-irradiation was 89,6% after 12 months and 71,4% after 24 months with a median OS of 61,0 months (95% CI 34,2–87,7). Again, WHO grading had an effect, as median OS for low-risk patients was not reached whereas for high-risk patients it was 45,5 months (95% CI 35,6–55,3). Conclusion Re-irradiation using particle therapy is an effective method for the treatment of recurrent meningiomas. Interdisciplinary decision making is necessary to guarantee best treatment for every patient.

Abstract Background Meningiomas of the skull base account for 25–30% of all meningiomas. Due to the complex structure of the cranial base and its close proximity to critical structures, surgery is often associated with substantial morbidity. Treatment options include observation, aggressive surgical intervention, stereotactic or conventional radiotherapy. In this analysis we evaluate the outcome of 110 patients with meningiomas of the skull base treated with particle therapy. It was performed within the framework of the “clinical research group heavy ion therapy” and supported by the German Research Council (DFG, KFO 214). Methods Between May 2010 and November 2014, 110 Patients with skull base meningioma were treated with particle radiotherapy at the Heidelberg Ion Therapy Center (HIT). Primary localizations included the sphenoid wing (n = 42), petroclival region (n = 23), cavernous sinus (n = 4), sella (n = 10) and olfactory nerve (n = 4). Sixty meningiomas were benign (WHO °I); whereas 8 were high-risk (WHO °II (n = 7) and °III (n = 1)). In 42 cases histology was not examined, since no surgery was performed. Proton (n = 104) or carbon ion (n = 6) radiotherapy was applied at Heidelberg Ion Therapy Center (HIT) using raster-scanning technique for active beam delivery. Fifty one patients (46.4%) received radiotherapy due to tumor progression, 17 (15.5%) after surgical resection and 42 (38.2%) as primary treatment. Results Median follow-up in this analysis was 46,8 months (95% CI 39,9–53,7; Q1-Q3 34,3–61,7). Particle radiotherapy could be performed safely without toxicity-related interruptions. No grade IV or V toxicities according to CTCAE v4.0 were observed. Particle RT offered excellent overall local control rates with 100% progression-free survival (PFS) after 36 months and 96.6% after 60 months. Median PFS was not reached due to the small number of events. Histology significantly impacted PFS with superior PFS after 5 years for low-risk tumors (96.6% vs. 75.0%, p = 0,02). Overall survival was 96.2% after 60 months and 92.0% after 72 months from therapy. Of six documented deaths, five were definitely not and the sixth probably not meningioma-related. Conclusion Particle radiotherapy is an excellent treatment option for patients with meningiomas of the skull base and can lead to long-term tumor control with minimal side effects. Other prospective studies with longer follow-up will be necessary to further confirm the role of particle radiotherapy in skull base meningioma.

Abstract Background The present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the “clinical research group ion beam therapy” funded by the German Research Foundation (DFG, KFO 214). Methods and materials Dose–response curves for the endpoint radiation-induced myelopathy were determined at 6 different positions (LET 16–99 keV/μm) within a 6 cm spread-out Bragg peak using either 1, 2 or 6 fractions of carbon ions. Based on the tolerance dose TD50 of carbon ions and photons, the relative biological effectiveness (RBE) was determined and compared with predictions of the local effect model (LEM I and IV). Within a longitudinal magnetic resonance imaging (MRI)-based study the temporal development of radiation-induced changes in the spinal cord was characterized. To test the protective potential of the ACE (angiotensin converting enzyme)-inhibitor ramipril™, an additional dose–response experiment was performed. Results The RBE-values increased with LET and the increase was found to be larger for smaller fractional doses. Benchmarking the RBE-values as predicted by LEM I and LEM IV with the measured data revealed that LEM IV is more accurate in the high-LET, while LEM I is more accurate in the low-LET region. Characterization of the temporal development of radiation-induced changes with MRI demonstrated a shorter latency time for carbon ions, reflected on the histological level by an increased vessel perforation after carbon ion as compared to photon irradiations. For the ACE-inhibitor ramipril™, a mitigative rather than protective effect was found. Conclusions This comprehensive study established a large and consistent RBE data base for late effects in the rat spinal cord after carbon ion irradiation which will be further extended in ongoing studies. Using MRI, an extensive characterization of the temporal development of radiation-induced alterations was obtained. The reduced latency time for carbon ions is expected to originate from a dynamic interaction of various complex pathological processes. A dominant observation after carbon ion irradiation was an increase in vessel perforation preferentially in the white matter. To enable a targeted pharmacological intervention more details of the molecular pathways, responsible for the development of radiation-induced myelopathy are required.

Owing to its physical properties, particle therapy (PT), including proton beam therapy (PBT) and carbon ion therapy (CIT), can enhance the therapeutic ratio in radiation therapy. The major factor driving PT implementation is the reduction in exit and integral dose compared to photon plans, which is expected to translate to reduced toxicity and improved quality of life. This study extends the findings from a recent systematic review by the current authors which concentrated on tumour outcomes for PT, to now examine toxicity as a separate focus. Together, these reviews provide a comprehensive collation of the evidence relating to PT outcomes in clinical practice. Three major databases were searched by two independent researchers, and evidence quality was classified according to the National Health and Medical Research Council evidence hierarchy. One hundred and seventy-nine studies were included. Most demonstrated acceptable and favourable toxicity results. Comparative evidence reported reduced morbidities and improvement in quality of life in head and neck, paediatrics, sarcomas, adult central nervous system, gastrointestinal, ocular and prostate cancers compared to photon radiotherapy. This suggestion for reduced morbidity must be counterbalanced by the overall low quality of evidence. A concerted effort in the design of appropriate comparative clinical trials is needed which takes into account integration of PT's pace of technological advancements, including evolving delivery techniques, image guidance availability and sophistication of planning algorithms. [ABSTRACT FROM AUTHOR]

Particle therapy (PT) offers the potential for reduced normal tissue damage as well as escalation of target dose, thereby enhancing the therapeutic ratio in radiation therapy. Reflecting the building momentum of PT use worldwide, construction has recently commenced for The Australian Bragg Centre for Proton Therapy and Research in Adelaide - the first PT centre in Australia. This systematic review aims to update the clinical evidence base for PT, both proton beam and carbon ion therapy. The purpose is to inform clinical decision-making for referral of patients to PT centres in Australia as they become operational and overseas in the interim. Three major databases were searched by two independent researchers, and evidence quality was classified according to the National Health and Medical Research Council evidence hierarchy. One hundred and thirty-six studies were included, two-thirds related to proton beam therapy alone. PT at the very least provides equivalent tumour outcomes compared to photon controls with the possibility of improved control in the case of carbon ion therapy. There is suggestion of reduced morbidities in a range of tumour sites, supporting the predictions from dosimetric modelling and the wide international acceptance of PT for specific indications based on this. Though promising, this needs to be counterbalanced by the overall low quality of evidence found, with 90% of studies of level IV (case series) evidence. Prospective comparative clinical trials, supplemented by database-derived outcome information, preferably conducted within international and national networks, are strongly recommended as PT is introduced into Australasia. [ABSTRACT FROM AUTHOR]

In radiation therapy, it is very important to ensure that the radiation dose is correctly delivered to the patient. This is achieved by obtaining quantitative dose measurements for beam calibration in the treatment planning system. Dose calculations should be performed with the required accuracy to a degree of uncertainty of less than 1%. The measurement of the absorbed dose in and around body tissues irradiated with carbon ions requires careful use of materials selected from established phantom and radiation detectors. The main advantage of such materials is that when information on the energy and nature of charged particles at the desired point is incomplete or inaccurate, they can allow determination of the absorbed dose. In general, radiation interactions in a tissue representation caused by carbon ions can be characterized by calculating the linear stopping power. Carbon ions have a limited penetration depth within human tissues that depends on the energy and stopping power of these ions as they penetrate into the body. The purpose of the present study was to calculate the stopping power, range and dose to intestinal and prostate tissues of carbon ions. The stopping power values of these tissues were specified by the effective charge approach method. The 5ZaPa-NR-CV, pcemd-4 and pcSseg-4 sets of Gaussian-type functions were employed for the calculation of electronic charge density. Range calculations were made by means of the Gaussian quadrature method, making use of the continuous slowing down approximation. Flux-based dose calculations were also carried out in accordance with the Bragg–Gray theorem using the Geant4 and FLUKA simulation toolkits. The results were compared with each other and with the SRIM and CasP datasets. Then, depth–dose distributions and range values were verified by positron emission activity using the GATE toolkit. Among the different types of Gaussian functions used here, the best semi-analytical result was found for the 5ZaPa-NR-CV set. The results obtained in the present study can be used for dose verification and dose reconstruction in charged particle radiotherapy and for radiation research on the interaction of radiation with matter. The results calculated here will be useful for quantifying uncertainties associated with stopping power, range, and reconstruction of dose in charged particle therapy. [ABSTRACT FROM AUTHOR]

Purpose: To model four‐dimensional (4D) relative biological effectiveness (RBE)‐weighted dose variations in abdominal lesions treated with scanned carbon ion beam in case of irregular breathing motion. Methods: The proposed method, referred to as bioWED method, combines the simulation of tumor motion in a patient‐ and beam‐specific water equivalent depth (WED)‐space with RBE modeling, aiming at the estimation of RBE‐weighted dose changes due to respiratory motion. The method was validated on a phantom, simulating gated and free breathing dose delivery, and on a patient case, for which free breathing irradiation was assumed and both amplitude and baseline breathing irregularities were simulated through a respiratory motion model. We quantified (a) the effect of motion on the equivalent uniform dose (EUD) and the RBE‐weighted dose–volume histograms (DVH), by comparing the planned dose distribution with "ground truth" 4D RBE‐weighted doses computed using 4D computed tomography data, and (ii) the estimation error, by comparing the doses estimated with the bioWED method to "ground truth" 4D RBE‐weighted doses. Results: In the phantom validation, the estimation error on the EUD was limited with respect to the motion effect and the median estimation error on relevant RBE‐weighted DVH metrics remained within 5%. In the patient study, the estimation error as computed on the EUD was smaller than the corresponding motion effect, exhibiting the largest values in the baseline irregularity simulation. However, the median estimation error over all simulations was below 3.2% considering relevant DVH metrics. Conclusions: In the evaluated cases, the bioWED method showed proper accuracy when compared to deformable image registration‐based 4D dose calculation. Therefore, it can be seen as a tool to test treatment plan robustness against irregular breathing motion, although its accuracy decreases as a function of increasing soft tissue deformation and should be evaluated on a larger patient dataset. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate a method for generating virtual four‐dimensional computed tomography (4DCT) from four‐dimensional magnetic resonance imaging (4DMRI) data in carbon ion radiotherapy with pencil beam scanning for abdominal tumors. Methods: Deformable image registration is used to: (a) register each respiratory phase of the 4DMRI to the end‐exhale MRI; (b) register the reference end‐exhale CT to the end‐exhale MRI volume; (c) generate the virtual 4DCT by warping the registered CT according to the obtained deformation fields. A respiratory‐gated carbon ion treatment plan is optimized on the planning 4DCT and the corresponding dose distribution is recalculated on the virtual 4DCT. The method was validated on a digital anthropomorphic phantom and tested on eight patients (18 acquisitions). For the phantom, a ground truth dataset was available to assess the method performances from the geometrical and dosimetric standpoints. For the patients, the virtual 4DCT was compared with the planning 4DCT. Results: In the phantom, the method exhibits a geometrical accuracy within the voxel size and Dose Volume Histograms deviations up to 3.3% for target V95% (mean dose difference ≤ 0.2% of the prescription dose, gamma pass rate > 98%). For patients, the virtual and the planning 4DCTs show good agreement at end‐exhale (3% median D95% difference), whereas other respiratory phases exhibit moderate motion variability with consequent dose discrepancies, confirming the need for motion mitigation strategies during treatment. Conclusions: The virtual 4DCT approach is feasible to evaluate treatment plan robustness against intra‐ and interfraction motion in carbon ion therapy delivered at the abdominal site. [ABSTRACT FROM AUTHOR]

Radiotherapy plays a central role in the treatment of cancer patients. Over the past decades, remarkable technological progress has been made in the field of conventional radiotherapy. In addition, the use of charged particles (e.g., protons and carbon ions) makes it possible to further improve dose deposition to the tumor, while sparing the surrounding healthy tissues. Despite these improvements, radioresistance and tumor recurrence are still observed. Although the mechanisms underlying resistance to conventional radiotherapy are well-studied, scientific evidence on the impact of charged particle therapy on cancer cell radioresistance is restricted. The purpose of this review is to discuss the potential role that charged particles could play to overcome radioresistance. This review will focus on hypoxia, cancer stem cells, and specific signaling pathways of EGFR, NFκB, and Hedgehog as well as DNA damage signaling involving PARP, as mechanisms of radioresistance for which pharmacological targets have been identified. Finally, new lines of future research will be proposed, with a focus on novel molecular inhibitors that could be used in combination with charged particle therapy as a novel treatment option for radioresistant tumors. [ABSTRACT FROM AUTHOR]

Atypical and anaplastic meningiomas, unlike their benign counterparts, are highly aggressive, locally destructive, and likely to recur after treatment. These diseases are difficult to definitively treat with traditional radiotherapy without injuring adjacent brain parenchyma. The physical properties of ion radiotherapy allows for treatment plans that avoid damaging critical neural structures. The objectives of this systematic review were to evaluate the use and efficacy of ion radiotherapy in the treatment of atypical and anaplastic meningiomas. We performed a systematic review of the literature by querying the PubMed and Ovid databases to identify and examine literature addressing the efficacy of ion radiotherapy in maintaining long-term local tumor control for patients with atypical or anaplastic meningiomas. The outcome of interest was rate of local tumor control at 5 years after ion radiotherapy. Across the included studies, proton therapy delivered a mean local control rate of 59.62% after 5 years. Carbon ion radiotherapy studies showed local control rates of 95% and 63% at 2 years for grade II and III meningiomas, respectively. In contrast, carbon ion radiotherapy studies that failed to differentiate between atypical and anaplastic meningiomas produced a local control rate of 33% at 2 years. Proton and carbon ion radiotherapy maintain comparable rates of local control to conventional photon therapy and allow for more targeted treatment plans that may limit excess radiation damage. Although additional prospective trials are needed, ion therapy represents a burgeoning field in the treatment of atypical and anaplastic meningiomas. [ABSTRACT FROM AUTHOR]

• mMKM to LEM conversion of dose prescription/constraints affects treatment outcomes. • LEM-68.8 Gy(RBE) correctly reproduces mMKM-64 Gy(RBE) for ACC patients. • ACC relapses were mainly related to CTV under-dosage due to OARs sparing. • mMKM OARs constraints require correction when applied to LEM plans. The purpose of this study is to assess the impact of the conversion scheme for relative biological effectiveness (RBE)-weighted dose (D RBE), implemented at our center, on treatment outcomes of adenoid cystic carcinoma (ACC) patients. Treatment plans of 78 ACC patients, optimized with the Local Effect Model (LEM), were recalculated with the modified Microdosimetric Kinetic Model (mMKM). D RBE to 95%, 50% and 2% (D V%) of the clinical target volume (CTV), were selected as relevant parameters to compare LEM and mMKM D RBE. The pattern of failure of ACC treatments was analyzed in relation to uncertainties involved in the D RBE translation methodology. mMKM recalculations of LEM plans, optimized to a prescription dose of 68.8 Gy(RBE), showed a D 50% 8% higher, on average, than the expected value (60.8 Gy(RBE)), closer to the most frequently used mMKM prescription D RBE (64 Gy(RBE)). D 95% and D 2% deviations, with respect to the optimization goals in the two RBE systems, increased of 0.5% and 14.2%, respectively, due to the steeper mMKM RBE variation along the beam path. Local recurrences were mainly (63%) reported in areas where CTV coverage was not satisfactory in the original LEM plan and the mMKM analysis showed that OARs constraints were too conservative. No case of local recurrence could be explained by inadequate mMKM target coverage that was not already present in the LEM plan. New constraints have been defined for optic pathways and brainstem to improve target coverage with no expected increase in tissue complications. [ABSTRACT FROM AUTHOR]

Range uncertainty in carbon ion therapy can diminish treatment efficacy because it may cause deviation from the planned dose distribution. The precise and accurate determination of relative stopping power (RSP) maps of carbon ions in the patient is a direct solution to this problem. To obtain RSP maps in patients undergoing carbon ion radiography, our team developed a preliminary prototype of a composite ionization chamber detection (CICD) system. The CICD prototype employs synchronously gated integral electronics with the ability to measure the depth-to-dose curve and the beam profile simultaneously. Carbon ion radiography experiments were performed on hemispherical, sloped, and stepped phantoms using the Heavy Ion Medical Machine (HIMM) beam. The beam energy was 190.19 MeV/μ and the beam spot full width at half maximum (FWHM) was 7.42 mm. The radiographic image of the sloped phantom, the thickness prediction accuracy of each pixel (2 mm) is 88.25%, its absolute mean error (AME) is 1.07 mm, and the maximum absolute deviation (MAD) is 2.64 mm. The prediction accuracy of the CICD prototype is mainly affected by electronic noise, with a noise-to-signal ratio (NSR) of about 14.36 dB. Carbon ion radiography simulations were performed in this study using Geant4 software to eliminate the effect of the electronic noise. The thickness prediction accuracy is 98.54%, 98.62%, and 99.07% per pixel for hemispherical, sloped and stepped phantoms, respectively, with AME of 0.09 mm, 0.27 mm, and 0.48 mm. Carbon ion radiography utilizing the CICD prototype scheme has the ability to refine the accuracy and resolution of radiographic images, consequently establishing a scientific foundation for diminishing the effects of range uncertainty and fully exploiting the advantages of precision particle therapy. • In this paper, we propose a method that can effectively reduce the range uncertainty in carbon ion therapy. • The proposed method effectively reduces the range uncertainty of carbon therapy, as proven by experiments and simulations • Geant4 verifies that by optimizing and upgrading the prototype, higher resolution radiographic images can be obtained. [ABSTRACT FROM AUTHOR]

The FLASH effect of carbon ion therapy has recently attracted significant attention from the scientific community. However, the radiobiological mechanism of the effect and the exact therapeutic conditions are still under investigation. Therefore, the dosimetry accuracy is critical for testing hypotheses about the effect and quantifying FLASH Radiotherapy. In this paper, the FLASH ionization chamber at low-pressure was designed, and its dose rate dependence was verified with the Faraday cup. In addition, the dose response was tested under the air pressure of the ionization chamber of 10 mbar, 80 mbar and 845 mbar, respectively. The results showed that when the pressure was 10 mbar, the dose linearity was verified and calibrated at the dose rate of ∼50 Gy s -1 , and the residuals were less than 2%. In conclusion, the FLASH ionization chamber is a promising instrument for online dose monitoring., (© 2024 Institute of Physics and Engineering in Medicine.)

Carbon ion therapy has received increasing attention because of its excellent physical dose distribution and high biological effect comparing against the conventional radiotherapy. However, the range uncertainty is still a major issue that limits further improvement of the treatment efficiency. Hence, we propose a novel method for reducing the range uncertainty in carbon ion therapy based on the Doppler Shift Effect of prompt gamma (PG), which can quantify the average carbon energy by the significant energy shift of the 4.44 MeV PG in the spectrum and then calibrate the range. Specifically, the influences of heterogeneity, initial carbon beam configuration, and detected direction are thoroughly discussed using the Monte Carlo simulation in this paper. Results show a moderate difference (<3.5%) between the Monte Carlo simulation and the analytical calculation, which verify the theoretical feasibility and veracity of the proposed method. The different initial energies (200, 225, 250, 300, and 400 MeV/u) and energy spreads (0%, 0.5%, 1%, 2%) of carbon beam have a not obvious influence on the accuracy of this method. When the detected direction changes from 90° to 50°, the PG energy shift overturns from "red shift" to "blue shift" and the difference value increases significantly. Moreover, for inhomogeneous phantoms, this method can distinguish the different ranges with blocks filled by different materials (bone, adipose, and air) in the beam path. Finally, through the analysis of range verification error with cavities of different thicknesses (0–30 mm) in the water phantom, the precision of the proposed method in theory is determined to be 0.008%–6.253%, and this value can be less than 3% with an appropriate detection site. These results indicate that the measurement of the PG energy shift could be applied to reduce the range uncertainty on the basis of the Doppler Shift Effect in carbon ion therapy. • A novel carbon ion range verification method based on the Doppler Shift Effect of prompt gamma is proposed. • The feasibility and accuracy of the proposed method are tested by Monte Carlo simulation. • The influences of heterogeneity, initial carbon beam configuration, and detected direction are thoroughly discussed. [ABSTRACT FROM AUTHOR]

Highlights • CPT offers favorable dose distribution due to the physical properties of charged particles. This can potentially lead to high efficacy with low treatment morbidity. • In this review we summarized 16 studies, 17 cohorts and 1516 patients treated for HCC with CPT, with following findings: • Mean weighted overall survival across studies was 86%, 62%, 59% and 35% at 1, 2, 3 and 5 years, respectively. Mean weighted local control was 86%, 89%, 87% and 89% at 1, 2, 3 and 5 years, respectively. • Adjusted morbidity rates were: 54% for acute G1-2 toxicities and 6% for acute ≥G3 toxicities; 9% for late G1-2 toxicities and less than 4% for late ≥G3 toxicities. Abstract Hepatocellular carcinoma (HCC) is a raising condition world-wide. Most of patients are ineligible for surgery at diagnosis due to the advanced stage of the disease or poor medical condition of the patient. Charged particle therapy (CPT) is a radiotherapy modality showing promising results. The aim of this systematic review was to summarize current knowledge on patient-specific outcomes of CPT for HCC, including overall survival, local control, the effect of radiation dose and the toxicity burden. The systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). After comprehensive database search 17 cohorts (16 studies, 1516 patients) were included into qualitative and quantitative analyses; 11 of 16 studies were retrospective. Eleven studies were on protons, 2 studies were on protons and carbon ions and 4 on carbon ions alone, were identified. Median BED10 (biologically equivalent dose) range was 68.75–122.5 GyE. Mean weighted overall survival across studies was 86%, 62%, 59% and 35% at 1, 2, 3 and 5 years, respectively. Mean weighted local control was 86%, 89%, 87% and 89% at 1, 2, 3 and 5 years, respectively. Adjusted morbidity rates were: 54% for acute G1-2 toxicities and 6% for acute ≥G3 toxicities; 9% for late G1-2 toxicities and less than 4% for late ≥G3 toxicities. There was no treatment-associated mortality. Conclusions CPT offers high local control, acceptable overall survival and low post-treatment morbidity. Quality of findings, especially on toxicities, is decreased by incomplete reporting and retrospective designs of available studies. Therefore, there is a strong need for better reporting and prospective studies. [ABSTRACT FROM AUTHOR]

Prognosis is usually grim for those with liver metastasis from colorectal cancer (CRC) who cannot receive resection. Radiation therapy can be an option for those unsuitable for resection, with carbon ion radiotherapy (CIRT) being more effective and less toxic than X‐ray due to its physio‐biological characteristics. The objective of this study is to identify the optimal dose of single fraction CIRT for colorectal cancer liver metastasis. Thirty‐one patients with liver metastasis from CRC were enrolled in the present study. Twenty‐nine patients received a single‐fraction CIRT, escalating the dose from 36 Gy (RBE) in 5% to 10% increments until unacceptable incidence of dose‐limiting toxicity was observed. Dose‐limiting toxicity was defined as grade ≥3 acute toxicity attributed to radiotherapy. The prescribed doses were as follows: 36 Gy (RBE) (3 cases), 40 Gy (2 cases), 44 Gy (4 cases), 46 Gy (6 cases), 48 Gy (3 cases), 53 Gy (8 cases) and 58 Gy (3 cases). Dose‐limiting toxicity was not observed, but late grade 3 liver toxicity due to biliary obstruction was observed in 2 patients at 53 Gy (RBE). Both cases had lesions close to the hepatic portal region, and, therefore, the dose was escalated to 58 Gy (RBE), limited to peripheral lesions. The 3‐year actuarial overall survival rate of all 29 patients was 78%, and the median survival time was 65 months. Local control improved significantly at ≥53 Gy (RBE), with a 3‐year actuarial local control rate of 82%, compared to 28% in lower doses. Treatment for CRC liver metastasis with single‐fraction CIRT appeared to be safe up to 58 Gy (RBE) as long as the central hepatic portal region was avoided. This is a dose escalation study for single fraction carbon ion radiotherapy. Treatment for CRC liver metastasis with single‐fraction CIRT appeared to be safe up to 58 Gy (RBE) as long as the central hepatic portal region was avoided. [ABSTRACT FROM AUTHOR]

Carbon ion radiotherapy (CIRT) is developing toward a versatile tool in radiotherapy; however, the increased relative biological effectiveness (RBE) of carbon ions in tumors and normal tissues with respect to photon irradiation has to be considered by mathematical models in treatment planning. As a consequence, dose prescription and definition of dose constraints are performed in terms of RBE weighted rather than absorbed dose. The RBE is a complex quantity, which depends on physical variables, such as dose and beam quality as well as on normal tissue‐ or tumor‐specific factors. At present, three RBE models are employed in CIRT: (a) the mixed‐beam model, (b) the Microdosimetric Kinetic Model (MKM), and (c) the local effect model. While the LEM is used in Europe, the other two models are employed in Japan, and unfortunately, the concepts of how the nominal RBE‐weighted dose is determined and prescribed differ significantly between the European and Japanese centers complicating the comparison, transfer, and reproduction of clinical results. This has severe impact on the way treatments should be prescribed, recorded, and reported. This contribution reviews the concept of the clinical application of the different RBE models and the ongoing clinical CIRT trials in Japan and Europe. Limitations of the RBE models and the resulting radiobiological issues in clinical CIRT trials are discussed in the context of current clinical evidence and future challenges. [ABSTRACT FROM AUTHOR]

Radiation therapy (RT), an integral component of curative treatment for many malignancies, can be administered via an increasing array of techniques. In this review, we summarize the properties and application of different types of RT, specifically, conventional therapy with x-rays, stereotactic body RT, and proton and carbon particle therapies. We highlight how low-linear energy transfer (LET) radiation induces simple DNA lesions that are efficiently repaired by cells, whereas high-LET radiation causes complex DNA lesions that are difficult to repair and that ultimately enhance cancer cell killing. Additionally, we discuss the immunogenicity of radiation-induced tumor death, elucidate the molecular mechanisms by which radiation mounts innate and adaptive immune responses and explore strategies by which we can increase the efficacy of these mechanisms. Understanding the mechanisms by which RT modulates immune signaling and the key players involved in modulating the RT-mediated immune response will help to improve therapeutic efficacy and to identify novel immunomodulatory drugs that will benefit cancer patients undergoing targeted RT.

The factors influencing carbon ion therapy can be predicted from accurate knowledge about the production of secondary particles from the interaction of carbon ions in water/tissue-like materials, and subsequently the interaction of the secondary particles in the same materials. The secondary particles may have linear energy transfer (LET) values that potentially increase the relative biological effectiveness of the beam. Our primary objective in this study was to classify and quantify the secondary particles produced, their dose averaged LETs, and their dose contributions in the absorbing material. A 1 mm diameter carbon ion pencil beam with energies per nucleon of 155, 262, and 369 MeV was used in a geometry and tracking 4 Monte Carlo simulation to interact in a 27 L water phantom containing 3000 rectangular detector voxels. The dose-averaged LET and the dose contributions of primary and secondary particles were calculated from the simulation. The results of the simulations show that the secondary particles that contributed a major dose component had LETs 600 keV/µm contributed only

Starting from the birth of high linear energy transfer (LET) radiotherapy in USA in the mid-1970s, the field has continuously evolved and to date over 20,000 patients have been treated with 12C ions worldwide. The purpose of this contribution is to review the advancements in clinical fractionated radiotherapy using high LET radiation in the last decades, with special focus on biological treatment planning. Along with technological developments for ion acceleration and beam delivery, progress in radiation biology and computational modeling has enabled a remarkable evolution in the planning capabilities of highly conformal, biologically optimized treatment with high LET radiation. In particular, recent efforts have provided the possibility of direct comparison between treatment plans obtained at different facilities with different biological models for the same ion species. This achievement represents an important step forward to gather better understanding of the remaining uncertainties in biological modeling and the impact of fractionation for optimal dose prescriptions, ultimately aiming to promote clinical exploitation of the anticipated, yet not fully demonstrated advantages of high LET-charged particles. [ABSTRACT FROM AUTHOR]

Charged particle therapy (proton beam therapy and carbon ion therapy) is a form of radiotherapy which has the unique characteristic of superior depth dose distribution, and has been used for the treatment of hepatocellular carcinoma (HCC) in a limited number of patients, especially in Japan. We undertook a systematic review to define the clinical utility of charged particle therapy for patients with HCC. We searched the MEDLINE database from 1983 to June 2016 to identify clinical studies on charged particle therapy for HCC. Primary outcomes of interest were local control, overall survival, and late radiation morbidities. A total of 13 cohorts from 11 papers were selected from an initial dataset of 78 papers. They included a randomized controlled trial comparing proton beam therapy with transarterial chemoembolization, 9 phase I or II trials and 2 retrospective studies. The reported actuarial local control rates ranged from 71.4-95% at 3 years, and the overall survival rates ranged from 25-42.3% at 5 years. Late severe radiation morbidities were uncommon, and a total of 18 patients with grade ≥3 late adverse events were reported among the 787 patients included in this analysis. Charged particle therapy for HCC was associated with good local control with limited probability of severe morbidities. The cost-effectiveness and the distinctive clinical advantages of charged particle therapies should be clarified in order to become a socially accepted treatment modality for HCC. [ABSTRACT FROM AUTHOR]

Background: The present work summarizes the research activities on radiation-induced late effects in the rat spinal cord carried out within the "clinical research group ion beam therapy" funded by the German Research Foundation (DFG, KFO 214).Methods and Materials: Dose-response curves for the endpoint radiation-induced myelopathy were determined at 6 different positions (LET 16-99 keV/μm) within a 6 cm spread-out Bragg peak using either 1, 2 or 6 fractions of carbon ions. Based on the tolerance dose TD50 of carbon ions and photons, the relative biological effectiveness (RBE) was determined and compared with predictions of the local effect model (LEM I and IV). Within a longitudinal magnetic resonance imaging (MRI)-based study the temporal development of radiation-induced changes in the spinal cord was characterized. To test the protective potential of the ACE (angiotensin converting enzyme)-inhibitor ramipril™, an additional dose-response experiment was performed.Results: The RBE-values increased with LET and the increase was found to be larger for smaller fractional doses. Benchmarking the RBE-values as predicted by LEM I and LEM IV with the measured data revealed that LEM IV is more accurate in the high-LET, while LEM I is more accurate in the low-LET region. Characterization of the temporal development of radiation-induced changes with MRI demonstrated a shorter latency time for carbon ions, reflected on the histological level by an increased vessel perforation after carbon ion as compared to photon irradiations. For the ACE-inhibitor ramipril™, a mitigative rather than protective effect was found.Conclusions: This comprehensive study established a large and consistent RBE data base for late effects in the rat spinal cord after carbon ion irradiation which will be further extended in ongoing studies. Using MRI, an extensive characterization of the temporal development of radiation-induced alterations was obtained. The reduced latency time for carbon ions is expected to originate from a dynamic interaction of various complex pathological processes. A dominant observation after carbon ion irradiation was an increase in vessel perforation preferentially in the white matter. To enable a targeted pharmacological intervention more details of the molecular pathways, responsible for the development of radiation-induced myelopathy are required. [ABSTRACT FROM AUTHOR]