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

Purpose: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy. Methods: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45–60 Gy (RBE) (1.5–2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan–Meier method. Results: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm3 and 1630 cm3. Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm3, respectively. At the end of particle therapy, G 1–2 skin reactions (n = 16/21) and fatigue (n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively. Conclusions: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed.

Purpose/objective To understand the role of relative biological effectiveness (RBE) and dose-averaged linear energy transfer (LETd) distributions in the treatment of sacral chordoma (SC) patients with carbon ion radiotherapy (CIRT). Material/methods 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 (DRBE|50%), near-to-minimum- (DRBE|95%) and near-to-maximum- (DRBE|2%) doses were compared between the two cohorts in both RBE systems. LETd distribution was evaluated for in-field relapsed cases with respect to the control group. Results Target DMKM|50% and DMKM|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 LETd 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. Conclusion 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.

Large doses of ionizing radiation delivered to tumors at ultra-high dose rates (i.e., in a few milliseconds) paradoxically spare the surrounding healthy tissue while preserving anti-tumor activity (compared with conventional radiotherapy delivered at much lower dose rates). This new modality is known as “FLASH radiotherapy” (FLASH-RT). Although the molecular mechanisms underlying FLASH-RT are not yet fully understood, it has been suggested that radiation delivered at high dose rates spares normal tissue via oxygen depletion followed by subsequent radioresistance of the irradiated tissue. To date, FLASH-RT has been studied using electrons, photons, and protons in various basic biological experiments, pre-clinical studies, and recently in a human patient. However, the efficacy of heavy ions, such as energetic carbon ions, under FLASH-RT conditions remains unclear. Given that living cells and tissues consist mainly of water, we set out to study, from a pure radiation chemistry perspective, the effects of ultra-high dose rates on the transient yields and concentrations of radiolytic species formed in water irradiated by 300-MeV per nucleon carbon ions (LET ∼ 11.6 keV/µm). This mimics irradiation in the “plateau” region of the depth–dose distribution of ions, i.e., in the “normal” tissue region in which the LET is rather low. We used Monte Carlo simulations of multiple, simultaneously interacting radiation tracks together with an “instantaneous pulse” irradiation model. Our calculations show a pronounced oxygen depletion around 0.2 μs, strongly suggesting, as with electrons, photons, and protons, that irradiation with energetic carbon ions at ultra-high dose rates is suitable for FLASH-RT.

Localized hepatocellular carcinoma (HCC) that is unresectable and non-transplantable can be treated by several liver-directed therapies. External beam radiation therapy (EBRT) is an increasingly accepted and widely utilized treatment modality in this setting. Accelerated charged particles such as proton beam therapy (PBT) and carbon ion radiation therapy (CIRT) offer technological advancements over conventional photon radiotherapy. In this review, we summarize the distinct advantages of CIRT use for HCC treatment, focusing on physical and biological attributes, and outline dosimetric and treatment planning caveats. Based on these considerations, we posit that HCC may be among the best indications for use of CIRT, as it allows for maximizing tumoricidal doses to the target volume while minimizing the dose to the organs at risk.

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

Purpose We present the nanoCluE model, which uses nano- and microdosimetric quantities to model RBE for protons and carbon ions. Under the hypothesis that nano- and microdosimetric quantities correlates with the generation of complex DNA double strand breakes, we wish to investigate whether an improved accuracy in predicting LQ parameters may be achieved, compared to some of the published RBE models. Methods The model is based on experimental LQ data for protons and carbon ions. We generated a database of track structure data for a number of proton and carbon ion kinetic energies with the Geant4-DNA Monte Carlo code. These data were used to obtain both a nanodosimetric quantity and a set of microdosimetric quantities. The latter were tested with different parameterizations versus experimental LQ-data to select the variable and parametrization that yielded the best fit. Results For protons, the nanoCluE model yielded, for the ratio of the linear LQ term versus the test data, a root mean square error (RMSE) of 1.57 compared to 1.31 and 1.30 for two earlier other published proton models. For carbon ions the RMSE was 2.26 compared to 3.24 and 5.24 for earlier published carbon ion models. Conclusion These results demonstrate the feasibility of the nanoCluE RBE model for carbon ions and protons. The increased accuracy for carbon ions as compared to two other considered models warrants further investigation.

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

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

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

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

Purpose The heavy‐ion medical machine (HIMM), which is the first commercial medical accelerator designed and built independently by the institute of modern physics (IMP) in Wuwei, Gansu Province, China, had officially completed clinical trials at the time of this article's writing. Three types of detector systems were developed based on the ionization‐chamber principle to monitor the beam parameters during treatment in real time, quickly verify the beam performance during a routine checkup, and ensure patient safety. Methods and materials The above‐mentioned detector systems were used for beam monitoring and quality assurance in the treatment system. The beam‐monitoring system is composed of three integral ionization chambers (ICs) and two multistrip ionization chambers (MSICs) as a redundant design. The irradiation dose, beam position, and homogeneity of a lateral profile are monitored online by the beam‐monitoring system, and safety interlocks are established to keep the test results under the predefined tolerance limitation. The quality‐assurance equipment was composed of one MSIC and one IC stack. The IC stack was used for energy verification. Results The off‐axis response of ICs is within a tolerance of 2%, and the dose interlock system (DIS) response time is less than 7 ms during the treatment process. The positioning resolution of MSICs reached 73 µm. The IC stack can verify the beam range within one spill and the measurement resolution is less than 0.2 mm. Conclusions The beam‐monitoring system (BMS) and quality‐assurance equipment (QAE) have been installed and run successfully within HIMM for two years and are associated with the HIMM treatment system to deliver the right dose to the correct position precisely. Furthermore, the daily QA task is simplified by it. Above all, the system has passed the performance test of the China Food and Drug Administration (CFDA).

Die Kohlenstoffionentherapie (CIRT) bietet neben einer vorteilhaften Dosisverteilung auch eine h��here relative biologische Wirksamkeit (RBE) als Photonen oder Protonen. Die RBE von Kohlenstoffionen variiert je nach Position innerhalb der Teilchenspur erheblich, sodass komplexe mathematische Modelle f��r die Bestrahlungsplanung ben��tigt werden, um eine gleichm����ige biologische Wirkung im Zielvolumen zu erzielen. Aus historischen Gr��nnden werden in CIRT-Zentren weltweit zwei verschiedene Modelle, MKM und LEM, verwendet.W��hrend japanische Einrichtungen einen Gro��teil der klinischen Erfahrungen f��r die CIRT mit MKM eingebracht haben, ist LEM das fuhrende RBE-Modell in Europa und China.Um von den japanischen Erfahrungen zu proftieren, wenden viele europ��ische Zentren japanische Behandlungsschemata an, obwohl deren Bestrahlungsplanung auf LEM basiert.Dies erfordert Anpassungen der geplanten Dosiswerte f��r das Tumorvolumen sowie der maximalen Grenzwerte f��r die Risikoorgane (OAR). Da davon ausgegangen wird, dass LEM eine h��here RBE liefert als MKM, w��rde die direkte Anwendung von MKM-Werten in Kombination mit dem LEM-Modell zu einer Unterdosierung im Zielbereich und einer ��berdosierung in den Risikoorganen f��hren.Ziel dieser Arbeit war es, die bei MedAustron angewandten OAR-Dosisbeschr��nkungen f��r die Kopf- und Halsregion bzw. die OARs Hirnparenchym, Hirnstamm und optisches System zu validieren, indem Vergleiche zwischen LEM und MKM erstellt wurden.31 bereits mit japanischen Behandlungsschemata bei MedAustron therapierte Patienten wurden f��r diese Studie selektiert. Die klinischen, LEM-basierten Pl��ne wurden im Bestrahlungsplanungssystem RayStation v9A mit MKM neu berechnet. Basierend auf extrahierten Dosispunkten f��r einzelne OARs wurden Translationskurven generiert und f��r den Vergleich der jeweiligen Dosisgrenzwerte herangezogen. Anhand einfacher Zielstrukturenwurden beide Modelle im Bestrahlungsplanungssystem einander gegen��bergestellt. Diese Vorgehensweise f��hrte zu einem tieferen Verst��ndnis der Modelle und l��sst R��ckschl��sse auf ihre Anwendung zu.Die aktuell verwendeten LEM-Grenzwerte konnten erfolgreich validiert werden, da sie mit den empfohlenen MKM-Werten ��bereinstimmen. Es konnte gezeigt werden, dass die Anwendbarkeit nicht in jedem Fall automatisch gegeben ist. Verschiedene Bestrahlungsplanungsparameter, z.B. Variationen in der Dosis pro Fraktion oder in den verwendeten Einstrahlwinkeln, f��hren dazu, dass das Verh��ltnis der beiden Modelle variiert. Diese generierten Abweichungen sind unter klinischen Bedingungen zu ber��cksichtigen und sorgf��ltig zu bewerten., Carbon ion radiotherapy (CIRT) others, besides benefcial dose distribution, an increased relative biological effectiveness (RBE) compared to photons or protons. However, RBE of carbon ions varies significantly depending on the position within the particle track, creating the necessity for application of sophisticated mathematical models in treatment planning to achieve homogeneous biological effects within target volumes. Due to historical reasons, two different models, namely MKM and LEM, are in use in CIRT-centres around the world. While Japanese facilities created the largest amount of clinical evidence for CIRT applying MKM, LEM is the prominent RBE model in Europe and China. To benefit from Japanese experience, many European centres apply Japanese treatment schemes, though actual planning is performed in LEM. This requires modifcations of nominal doses for target prescriptions as well as constraints to organs at risk (OARs) as LEM is assumed to estimate higher RBE than MKM, i.e. application of MKM numerical values would cause underdosage of targets and increased dose to healthy tissues. The aim of this thesis was tovalidate dose constraints applied at MedAustron for the head and neck region, by creating translations between RBE models and comparing achieved translations with recommended values. Emphasis was placed on the OARs brain parenchyma, brainstem and optic system.31 patients treated with Japanese treatment schedules at MedAustron were selected retrospectively and clinical LEM-based plans were recalculated with MKM in the treatment planning system RayStation v9A. Based on extracted dose statistics for individual OARs, translation curves were generated and applied to translate respective constraints. Additionally, several investigations on simple target structures in articial plans were created to properly understand dependences of both models. Currently applied LEM constraints were successfully validated as they correspond to recommended MKM values according to the derived translations. However, translated constraintshave been shown to have limited applicability. For specific treatment planning parameters, including dose per fraction and applied beam angles, the relation between models varies from the expected translation profile, creating outlier cases for which an application of the presented constraints in LEM does not automatically imply a fulfilment of the corresponding MKM values. Such cases need to be considered and carefully evaluated in clinical routine of CIRT.

Simple Summary Skull-base chondrosarcoma is a rare locally aggressive or malignant group of cartilaginous neoplasm. The standard of care consists of surgery and high-dose radiation therapy, better if with particle, due to their radioresistance and proximity to organs at risk such as brainstem and optic pathways. Due to the rarity of the tumor and its site, outcomes in terms of local control and toxicity of patients with this malignancy after receiving particle therapy has been documented only in a limited number of series with a restricted number of patients, in particular with regard to carbon ions. The aim of our retrospective study is to assess the role of particle therapy (protons and carbon ions) after surgery in our Institute in skull-base chondrosarcomas. Abstract Background: The standard treatment for skull base chondrosarcoma (SB-CHS) consists of surgery and high-dose radiation therapy. Our aim was to evaluate outcome in terms of local control (LC) and toxicity of proton therapy (PT) and carbon ion (CIRT) after surgery. Materials and methods: From September 2011 to July 2020, 48 patients underwent particle therapy (67% PT, 33% CIRT) for SB-CHS. PT and CIRT total dose was 70 GyRBE (relative biological effectiveness) in 35 fractions and 70.4 GyRBE in 16 fractions, respectively. Toxicity was assessed using the Common Terminology Criteria for Adverse Events (CTCAE v5). Results: After a median follow-up time of 38 months, one local failure (2%) was documented and the patient died for progressive disease. Overall, 3-year LC was 98%. One (2%) and 4 (8%) patients experienced G3 acute and late toxicity, respectively. White-matter brain changes were documented in 22 (46%) patients, but only 7 needed steroids (G2). No patients had G3 brain toxicity. No G4–5 complications were reported. We did not find any correlation between high-grade toxicity or white-matter changes and characteristics of patients, disease and surgery. Conclusions: PT and CIRT appeared to be effective and safe treatments for patients with SB-CHS, resulting in high LC rates and an acceptable toxicity profile.

International audience; 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.

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 (

Clinical and translational radiation oncology 13, 57 - 63 (2018). doi:10.1016/j.ctro.2018.10.002, Background and purpose:Chromosomal aberrations in peripheral blood lymphocytes are a biomarker for radiation exposure and are associated with an increased risk for malignancies. To determine the long-term cytogenetic effect of radiotherapy, we analyzed the persistence of different aberration types up to 2.5 years after C-ion boost + IMRT treatment.Materials and Methods:Cytogenetic damage was analyzed in lymphocytes from 13 patients that had undergone C-ion boost + IMRT treatment for prostate cancer. Samples were taken immediately, 1 year and 2.5 years after therapy. Aberrations were scored using the mFISH technique and grouped according to their transmissibility to daughter cells.Results:Dicentric chromosomes (non-transmissible) and translocations (transmissible) were induced with equal frequencies. In the follow-up period, the translocation yield remained unchanged while the yield of dicentrics decreased to ≈40% of the initial value (p=0.011 and p=0.001 for 1 and 2.5 years after compared to end of therapy). In 2 patients clonal aberrations were observed; however they were also found in samples taken before therapy and thus were not radiotherapy induced.Conclusion:The shift in the aberrations spectrum towards a higher fraction of translocations indicates the exposure of hematopoietic stem and progenitor cells underlining the importance of a careful sparing of bone marrow during radiotherapy to minimize the risk for secondary cancers., Published by Elsevier, Amsterdam

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.

PurposeThere 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.MethodsA 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).ResultsA 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.ConclusionsThe 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.

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.

Ping Li,1– 3,* Chang Liu,4– 6,* Shuang Wu,2,3,7 Lin Deng,2,3,8 Guangyuan Zhang,2,3,8 Xin Cai,1– 3 Silong Hu,4– 6 Jingyi Cheng,2,3,6,9 Xiaoping Xu,4– 6 Bin Wu,2,3,10 Xiaomao Guo,2,3,7 Yingjian Zhang,4– 6 Shen Fu,5,11 Qing Zhang1– 3 1Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 2Shanghai Key Laboratory of Radiation Oncology, Shanghai, People’s Republic of China; 3Shanghai Engineering Research Center of Proton and Heavy ion Radiation Therapy, Shanghai, People’s Republic of China; 4Department of Nuclear Medicine, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China; 5Key Laboratory of Nuclear Physics and Ion-Beam Application (MOE), Fudan University, Shanghai, People’s Republic of China; 6Shanghai Engineering Research Center for Molecular Imaging Probes, Shanghai, People’s Republic of China; 7Department of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of China; 8Department of Radiology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of China; 9Department of Nuclear Medicine, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of China; 10Department of Radiology, Shanghai Proton and Heavy Ion Center, Fudan University Cancer Hospital, Shanghai, People’s Republic of China; 11Department of Radiation Oncology, Shanghai Concord Cancer Hospital, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qing ZhangDepartment of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of ChinaTel +86 139 1737 4609Fax +86 2138296518Email qing.zhang@hotmail.comShen FuDepartment of Radiation Oncology, Shanghai Proton and Heavy Ion Center, Shanghai, People’s Republic of ChinaEmail shen_fu@hotmail.comPurpose: The purpose of this study was to assess the potential of 99mTc-labeled PSMA-SPECT/CT and diffusion-weighted image (DWI) for predicting treatment response after carbon ion radiotherapy (CIRT) in prostate cancer.Patients and Methods: We prospectively registered 26 patients with localized prostate cancer treated with CIRT. All patients underwent 99mTc-labeled PSMA-SPECT/CT and multiparametric magnetic resonance imaging (MRI) before and after CIRT. The tumor/background ratio (TBR) and mean apparent diffusion coefficient (ADCmean) were measured on the tumor and the percentage changes before and after therapy (ΔTBR and ΔADCmean) were calculated. Patients were divided into two groups: good response and poor response according to clinical follow-up.Results: The median follow up time was 38.3months. The TBR was significantly decreased (p=0.001), while the ADCmean was significantly increased compared with the pretreatment value (p< 0.001). The ΔTBR and ΔADCmean were negatively correlated with each other (p = 0.002). On ROC curve analysis for predicting treatment response, the area under the ROC curve (AUC) of ΔTBR (0.867) for predicting good response was higher than that of ΔADCmean (0.819). The AUC of combined with ΔTBR and ΔADCmean (0.895) was higher than that of either ΔADCmean or ΔTBR alone. The combined use of ΔTBR and ΔADCmean showed 91.4% sensitivity and 95.2% specificity.Conclusion: Our preliminary data indicate that the changes of TBR and ADCmean maybe an early bio-marker for predicting prognosis after CIRT in localized prostate cancer patients. In addition, the ΔTBR seems to be a more powerful prognostic factor than ΔADCmean in prostate cancer treated with CIRT.Keywords: PSMA, DWI, prostate cancer, carbon ion radiotherapy

In radiotherapy, a quantity asked for by clinics when calculating a treatment plan, along withdose, is linear energy transfer. Linear energy transfer is defined as the absorbed energy intissue per particle track length and has been shown to increase with relative biologicaleffectiveness untill the overkilling effect. In this master thesis the dose averaged linear energytransfer from proton and carbon ion beams was simulated using the FLUKA multi purposeMonte Carlo code. The simulated distributions have been compared to algorithms fromRaySearch Laboratories AB in order to investigate the agreement between the computationmethods. For the proton computation algorithm improvements to the current scoring algorithmwere also implemented. A first version of the linear energy transfer validation code was alsoconstructed. Scoring of linear energy transfer in the RaySearch algorithm was done with theproton Monte Carlo dose engine and the carbon pencil beam dose engine. The results indicatedthat the dose averaged linear energy transfer from RaySearch Laboratories agreed well for lowenergies for both proton and carbon beams. For higher energies shape differences were notedwhen using both a small and large field size. The protons, the RaySearch algorithm initiallyoverestimates the linear energy transfer which could result from fluence differences in FLUKAcompared to the RaySearch algorithm. For carbon ions, the difference could stem from someloss of information in the tables used to calculate the linear energy transfer in the RaySearchalgorithm. From validation γ-tests the proton linear energy transfer passed for (3%/3mm) and(1%/1mm) with no voxels out of tolerance. γ-tests for the carbon linear energy transfer passedwith no voxels out of tolerance for (5%/5mm) and a fail rate of 2.92% for (3%/3mm).

Carbon ion therapy has several advantages over proton therapy in terms of target depth precision, biological effectiveness, and patient outcome. Despite these advantages, there are far fewer carbon ion therapy facilities in operation around the world compared to proton therapy facilities. The adoption of carbon ion therapy has been severely limited by the cost and size of dedicated infrastructure and facilities in order to accommodate the heavier ion species. The Next Ion Medical Machine Study (NIMMS) project led by CERN aims to design the next generation hadron therapy system including a compact synchrotron and an efficient beam delivery method for future clinical use. In collaboration with CERN, this work presents a comparison of current synchrotron designs used at carbon ion therapy facilities and motivates the need for a new, efficient future design. While normal conducting and superconducting options are being considered, here we propose a compact, normal-conducting synchrotron based on the double-bend achromat structure.

Particle therapy has progressed over 40 years and there are now many results for outcomes for hepatocellular carcinoma (HCC). The local control rate of HCC by particle therapy is expected to be 85–90% at 3 years and 80–90% at 5 years. Overall survival rate is expected to be 55–65% at 2 years and 20–50% at 5 years. The prognostic factors for survival considered are hepatic function and number and size of tumors.

Objective: Carbon ion radiation therapy (CIRT) is an emerging radiation technique with advantageous physical and radiobiologic properties compared to conventional radiotherapy (RT) providing better response in case of radioresistant and hypoxic tumors. Our aim is to critically review if functional imaging techniques could play a role in predicting outcome of CIRT-treated tumors, as already proven for conventional RT. Methods: 14 studies, concerning Magnetic resonance imaging (MRI) and Positron Emission Tomography (PET), were selected after a comprehensive search on multiple electronic databases from January 2000 to March 2020. Results: MRI studies (n = 5) focused on diffusion-weighted MRI and, even though quantitative parameters were the same in all studies (apparent diffusion coefficient, ADC), results were not univocal, probably due to different imaging acquisition protocols and tumoral histology. For PET studies (n = 9), different tracers were used such as [18F]FDG and other uncommon tracers ([11C]MET, [18F]FLT), with a relevant heterogeneity regarding parameters used for outcome assessment. Conclusion: No conclusion can be drawn on the predictive value of functional imaging in CIRT-treated tumors. A standardization of image acquisition, multi-institutional large trials and external validations are needed in order to establish the prognostic value of functional imaging in CIRT and to guide clinical practice. Advances in knowledge: Emerging studies focused on functional imaging’s role in predicting CIRT outcome. Due to the heterogeneity of images acquisition and studies, results are conflicting and prospective large studies with imaging standardized protocol are needed.

In radiotherapy, a quantity asked for by clinics when calculating a treatment plan, along withdose, is linear energy transfer. Linear energy transfer is defined as the absorbed energy intissue per particle track length and has been shown to increase with relative biologicaleffectiveness untill the overkilling effect. In this master thesis the dose averaged linear energytransfer from proton and carbon ion beams was simulated using the FLUKA multi purposeMonte Carlo code. The simulated distributions have been compared to algorithms fromRaySearch Laboratories AB in order to investigate the agreement between the computationmethods. For the proton computation algorithm improvements to the current scoring algorithmwere also implemented. A first version of the linear energy transfer validation code was alsoconstructed. Scoring of linear energy transfer in the RaySearch algorithm was done with theproton Monte Carlo dose engine and the carbon pencil beam dose engine. The results indicatedthat the dose averaged linear energy transfer from RaySearch Laboratories agreed well for lowenergies for both proton and carbon beams. For higher energies shape differences were notedwhen using both a small and large field size. The protons, the RaySearch algorithm initiallyoverestimates the linear energy transfer which could result from fluence differences in FLUKAcompared to the RaySearch algorithm. For carbon ions, the difference could stem from someloss of information in the tables used to calculate the linear energy transfer in the RaySearchalgorithm. From validation γ-tests the proton linear energy transfer passed for (3%/3mm) and(1%/1mm) with no voxels out of tolerance. γ-tests for the carbon linear energy transfer passedwith no voxels out of tolerance for (5%/5mm) and a fail rate of 2.92% for (3%/3mm).

High-frequency linear accelerators are very suitable for carbon ion therapy, thanks to the reduced operational costs and the high beam quality with respect to synchrotrons, which are presently the only available technology for this application. In the framework of the development of a new linac for carbon ion therapy, this article describes the design of a compact 750 MHz Radio Frequency Quadrupole (RFQ) with trapezoidal vanes. A new semi-analytic approach to design the trapezoidal-vane RFQ is introduced together with the relevant beam dynamics properties. The RFQ is split into two decoupled rf cavities, both of which make use of a novel dipole detuning technique by means of length adjustment. The splitting is described both from the rf and the beam dynamics point of view. The paper concludes with the rf design of the full structure, including maximum surface field and thermal studies., Comment: Revised version published in Physical Review Accelerators and Beams on 31 December 2020

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

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.

Intensity modulated particle therapy (IMPT) with carbon ions can generate highly conformal treatment plans; however, IMPT is limited in robustness against range and positioning uncertainty. This is particularly true for moving targets, even though all motion states of a 4DCT are considered in 4D-IMPT. Here, we expand 4D-IMPT to include robust non-linear RBE-weighted optimization to explore its potential in improving plan robustness and sparing critical organs. In this study, robust 4D-optimization—based on worst-case optimization on 9 scenarios—was compared to conventional 4D-optimization with PTV margins using 4D dose calculation and robustness analysis for 21 uncertainty scenarios. Slice-by-slice rescanning was used for motion mitigation. Both 4D-optimization strategies were tested on a cohort of 8 multi-lesion lung cancer patients with the goal of prioritizing OAR sparing in a hypofractionated treatment plan. Planning objectives were to keep the OAR volume doses below corresponding limits while simultaneously achieve CTV coverage with D95% ≥ 95 %. For the conventional plans, average D95% was at 98.7% which fulfilled the target objective in 83.2% of scenarios. For the robust plans, average D95% was reduced to 97.6% which still fulfilled the target objective in 80.7% of cases, but led to significantly improved overall OAR sparing: Volume doses were below the limits in 96.2% of cases for the conventional and 99.5% for the robust plans. When considering the particularly critical smaller airways only, fulfillment rates could be increased from 76.2% to 96% for the robust plans. This study has shown that plan robustness of 4D-IMPT could be improved by using robust 4D-optimization, offering greater control over uncertainties in the actual delivered dose. In some cases, this required sacrificing target coverage for the benefit of better OAR sparing.

Background The purpose of this study was to assess the potential of 99mTc-labeled PSMA-SPECT/CT and Diffusion-Weighted Image (DWI) for predicting treatment response after carbon ion radiotherapy (CIRT) in prostate cancer. Methods We prospectively registered 26 patients with localized prostate cancer treated with CIRT. All patients underwent 99m Tc-labeled PSMA-SPECT/CT and multiparametric MRI before and after CIRT. The tumor/background ratio (TBR) and mean apparent diffusion coefficient (ADC mean ) were measured on the tumor and the percentage changes between 2 time points (ΔTBR and ΔADC mean ) were calculated. Patients were divided into two groups: good response and poor response according to clinical follow-up. Results The median follow up time was 38.3months. The TBR was significantly decreased ( p =0.001), while the ADC mean was significantly increased compared with the pretreatment value ( p

Hadron therapy has been first proposed in 1946 by Robert Wilson as an advanced form of radiotherapy. Hadrons, such as protons and light ions, release the largest part of their energy in a narrow space range, called Bragg peak, allowing to target the tumor cells more precisely than photon beams. Despite this advantage, the number of proton and carbon ion therapy centers is still small compared to conventional radiotherapy. One of the reasons for this disparity can be found in the treatment costs of hadron therapy, which is three to four times higher than for conventional radiotherapy, due to the larger and more complex accelerators needed, which imply typically the construction of entirely new buildings, with the associated medical and technical personnel. The limited availability of hadron therapy has also consequences on the number of patients that can be enrolled in clinical trials, that are necessary to assess the effective clinical advantages with respect to other, less costly, therapies. The main goal in the development of hadron therapy technology is to reduce as much as possible the cost of the machines, by proposing smaller and more efficient solutions, easing the access to this treatment. Proton therapy has already moved in this direction, bringing the accelerator technology to industrialization and offering compact turn-key solutions that reduce the cost gap with respect to radiotherapy. The few carbon ion centers worldwide, on the contrary, are still based on bespoke solutions: the development of carbon ion machines is still carried out, in most of the cases, in the framework of research laboratories and is far from the industrialization step needed to improve the accessibility to the service. Synchrotrons are the only technology used in carbon ion therapy centers. However, in the past years, the idea of using linear accelerators has been developed, initially for proton therapy, due to the advantages it would bring in terms of costs and therapeutic beam quality. At present, there are worldwide two medical proton linacs being commissioned, while linacs for carbon ions are still at a conceptual stage in a handful of research centers. The general purpose of this thesis work is to propose the beam dynamics design of a 3 GHz bent linear accelerator for carbon ion therapy from the pre-injector, based on the pioneering work done at the European Organization fro Nuclear Research (CERN) on a proton machine, to the very end of the linac.

Radiation therapy is one of the most widely used therapies for malignancies. The therapeutic use of heavy ions, such as carbon, has gained significant interest due to advantageous physical and radiobiologic properties compared to photon based therapy. By taking advantage of these unique properties, carbon ion radiotherapy may allow dose escalation to tumors while reducing radiation dose to adjacent normal tissues. There are currently 13 centers treating with carbon ion radiotherapy, with many of these centers publishing promising safety and efficacy data from the first cohorts of patients treated. To date, carbon ion radiotherapy has been studied for almost every type of malignancy, including intracranial malignancies, head and neck malignancies, primary and metastatic lung cancers, tumors of the gastrointestinal tract, prostate and genitourinary cancers, sarcomas, cutaneous malignancies, breast cancer, gynecologic malignancies, and pediatric cancers. Additionally, carbon ion radiotherapy has been studied extensively in the setting of recurrent disease. We aim to provide a comprehensive review of the studies of each of these disease sites, with a focus on the current trials using carbon ion radiotherapy.

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

Introduction: Despite improvements in radiation therapy, chemotherapy and surgical procedures over the last 30 years, pancreatic cancer 5-year survival rate remains at 9%. Reduced stroma permeability and heterogeneous blood supply to the tumour prevent chemoradiation from making a meaningful impact on overall survival. Hypoxia-activated prodrugs are the latest strategy to reintroduce oxygenation to radioresistant cells harbouring in pancreatic cancer. This paper reviews the current status of photon and particle radiation therapy for pancreatic cancer in combination with systemic therapies and hypoxia activators. Methods: The current effectiveness of management of pancreatic cancer was systematically evaluated from MEDLINE® database search in April 2019. Results: Limited published data suggest pancreatic cancer patients undergoing carbon ion therapy and proton therapy achieve a comparable median survival time (25.1 months and 25.6 months, respectively) and 1-year overall survival rate (84% and 77.8%). Inconsistencies in methodology, recording parameters and protocols have prevented the safety and technical aspects of particle therapy to be fully defined yet. Conclusion: There is an increasing requirement to tackle unmet clinical demands of pancreatic cancer, particularly the lack of synergistic therapies in the advancing space of radiation oncology. Refereed/Peer-reviewed

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.

Purpose In image-guided particle radiotherapy of abdominal lesions, respiratory motion hinders treatment accuracy. In this study, 2D cineMRI data were used to quantify the tumor (GTV) motion and to evaluate the clinical approach based on deriving an internal target volume (ITV) from a planning 4DCT for gating treatments. Methods Seven patients with abdominal lesions were treated with carbon-ion therapy at the National Centre of Oncological Hadron-therapy (Italy). The MR scan was performed on the same day of the 4DCT acquisition. For four patients, an additional MR was acquired approximately after 1 week. The cineMRI combined with deformable image registration algorithm was used to quantify tumor motion. Afterwards, two ITVs were defined considering (1) all phases (ITVFB) and (2) only phases within the gating window (ITVG), and then compared with the clinical (4DCT-derived) ITVs (ITVCG and ITVCFB). Results Tumor residual motion estimated by cineMRI data in the two MRI sessions resulted not significantly different from 4DCT, although cineMRI accounted for cycle-to-cycle variations. The ITV normalized for the GTV median values were higher for ITVFB with respect to ITVG, ITVCFB and ITVCG. The Hausdorff distances with respect to the GTV were up to 10.55 mm, 3.13 mm, 5.56 mm and 2.51 mm, for ITVFB, ITVG, ITVCFB and ITVCG, respectively. According to both metrics, ITVCG and ITVG were not found significantly different. Conclusions CineMRI acquisitions allowed to quantify organ motion without delivering additional dose to the patient and to verify treatment margins in gated carbon-ion therapy of abdominal lesions.

The success of checkpoint inhibitors has expanded the treatment regimens significantly for patients with solid tumors. As such, emerging data suggests that immunotherapy may play a role in the treatment of recurrent and high-grade meningiomas. There are several immunotherapy agents currently under active investigation in clinical trials. In addition to immunotherapy, novel radiotherapy techniques, including carbon ion therapy, brachytherapy, peptide receptor radionuclide therapy, and radiosensitizers may support improvements in clinical outcomes for meningioma patients. The efficacy of many of these techniques is being investigated in clinical trials. In this chapter, we will discuss these novel therapeutic approaches, as well as other novel experimental avenues, such as tumor treatment fields, and ideas for additional clinical trials that warrant investigation.

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. ispartof: FRONTIERS IN ONCOLOGY vol:10 ispartof: location:Switzerland status: published

The clinical application of different relative biological effectiveness (RBE) models for carbon ion RBE-weighted dose calculation hinders a global consensus in defining normal tissue constraints. This work aims to update the local effect model (LEM)-based constraints for the rectum using microdosimetric kinetic model (mMKM)-defined values, relying on RBE translation and the analysis of long-term clinical outcomes. LEM-optimized plans of treated patients, having suffered from prostate adenocarcinoma (n = 22) and sacral chordoma (n = 41), were recalculated with the mMKM using an in-house developed tool. The relation between rectum dose-volume points in the two RBE systems (DLEM|v and DMKM|v) was fitted to translate new LEM-based constraints. Normal tissue complication probability (NTCP) values, predicting late rectal toxicity, were obtained by applying published parameters. No late rectal toxicity events were reported within the patient cohort. The rectal toxicity outcome was confirmed using dosimetric analysis: DMKMVHs lay largely below original constraints, the translated DLEM|v values were 4.5%, 8.3%, 18.5%, and 35.4% higher than the nominal DMKM|v of the rectum volume, v&mdash, 1%, 5%, 10% and 20%. The average NTCP value ranged from 5% for the prostate adenocarcinoma, to 0% for the sacral chordoma group. The redefined constraints, to be confirmed prospectively with clinical data, are DLEM|5cc &le, 61 Gy(RBE) and DLEM|1cc &le, 66 Gy(RBE).

Sinonasal cancers (SNCs) represent 3–5% of all head and neck carcinomas and less than 1% of all tumors. The majority of sinonasal tumors has epithelial origin and is generally diagnosed at advanced stages. Multimodal approaches, including chemotherapy and loco-regional approaches, notably surgery and/or radiotherapy (RT), are the mainstay of treatment of locally advanced disease. In particular, RT is a cornerstone in the treatment of this pathology, either in a definitive setting for unresectable disease or in a postoperative one, with a role in recurrent disease as well. The employment of high conformal radiation techniques, such as intensity-modulated radiation therapy or charged particle therapy, proton or carbon ion therapy, may improve outcome and reduce late effects. With regard to chemotherapy, as it occurs in a potentially curable disease, the choice of systemic treatments is tailored on the single patient global performance status, and it is histology driven.

Purpose To evaluate the short-term outcomes in terms of tumor control and toxicity of patients with skull base or cervical spine chordoma and chondrosarcoma treated with intensity-modulated proton or carbon-ion radiation therapy. Methods Between 6/2014 and 7/2018, a total of 91 patients were treated in our Center. The median age was 38 (range, 4–70) years. Forty-six (50.5%) patients were treated definitively for their conditions as initial diagnosis, 45 (49.5%) patients had recurrent tumors including 14 had prior radiotherapy. The median gross tumor volume was 37.0 (range, 1.6–231.7) cc. Eight patients received proton therapy alone, 28 patients received combined proton and carbon ion therapy, 55 patients received carbon-ion therapy alone. Results With a median follow-up time of 28 (range, 8–59) months, the 2-year local control (LC), progression free (PFS) and overall survival (OS) rates was 86.2, 76.8, and 87.2%, respectively. Those rates for patients received definitive proton or carbon-ion therapy were 86.7, 82.8, and 93.8%, respectively. On multivariate analyses, tumor volume of > 60 cc was the only significant factor for predicting PFS (p = 0.045), while re-irradiation (p = 0.012) and tumor volume (> vs p = 0.005) were significant prognosticators for OS. Grade 1–2 late toxicities were observed in 11 patients, and one patient developed Grade 3 acute mucositis. Conclusions Larger tumor volume and re-irradiation were related to inferior survival for this group of patients. Further follow-up is needed for long-term efficacy and safety.

OBJECTIVE Long-term local control in patients with primary chordoma and sarcoma of the spine and sacrum is increasingly reliant upon en bloc resection with negative margins. At many institutions, adjuvant radiation is recommended; definitive radiation is also recommended for the treatment of unresectable tumors. Because of the high off-target radiation toxicities associated with conventional radiotherapy, there has been growing interest in the use of proton and heavy-ion therapies. The aim of this study was to systematically review the literature regarding these therapies. METHODS The PubMed, OVID, Embase, and Web of Science databases were queried for articles describing the use of proton, combined proton/photon, or heavy-ion therapies for adjuvant or definitive radiotherapy in patients with primary sarcoma or chordoma of the mobile spine and sacrum. A qualitative synthesis of the results was performed, focusing on overall survival (OS), progression-free survival (PFS), disease-free survival (DFS), and disease-specific survival (DSS); local control; and postradiation toxicities. RESULTS Of 595 unique articles, 64 underwent full-text screening and 38 were included in the final synthesis. All studies were level III or IV evidence with a high risk of bias; there was also significant overlap in the reported populations, with six centers accounting for roughly three-fourths of all reports. Five-year therapy outcomes were as follows: proton-only therapies, OS 67%–82%, PFS 31%–57%, and DFS 52%–62%; metastases occurred in 17%–18% and acute toxicities in 3%–100% of cases; combined proton/photon therapy, local control 62%–85%, OS 78%–87%, PFS 90%, and DFS 61%–72%; metastases occurred in 12%–14% and acute toxicities in 84%–100% of cases; and carbon ion therapy, local control 53%–100%, OS 52%–86%, PFS (only reported for 3 years) 48%–76%, and DFS 50%–53%; metastases occurred in 2%–39% and acute toxicities in 26%–48%. There were no studies directly comparing outcomes between photon and charged-particle therapies or comparing outcomes between radiation and surgical groups. CONCLUSIONS The current evidence for charged-particle therapies in the management of sarcomas of the spine and sacrum is limited. Preliminary evidence suggests that with these therapies local control and OS at 5 years are comparable among various charged-particle options and may be similar between those treated with definitive charged-particle therapy and historical surgical cohorts. Further research directly comparing charged-particle and photon-based therapies is necessary.

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.

At National Institute of Radiological Sciences (NIRS), we have been commissioning a rotating-gantry system for carbon-ion radiotherapy. This rotating gantry can transport heavy ions at 430 MeV/u to an isocenter with irradiation angles of ±180° that can rotate around the patient so that the tumor can be irradiated from any direction. A three-dimensional pencil-beam scanning irradiation system equipped with the rotating gantry enables the optimal use of physical characteristics of carbon ions to provide accurate treatment. To ensure the treatment quality using such a complex system, the calibration of the primary dose monitor, output check, range check, dose rate check, machine safety check, and some mechanical tests should be performed efficiently. For this purpose, we have developed a measurement system dedicated for quality assurance (QA) of this gantry system: the Daily QA system. The system consists of an ionization chamber system and a scintillator system. The ionization chamber system is used for the calibration of the primary dose monitor, output check, and dose rate check, and the scintillator system is used for the range check, isocenter, and gantry angle. The performance of the Daily QA system was verified by a beam test. The stability of the output was within 0.5%, and the range was within 0.5 mm. The coincidence of the coordinates between the patient-positioning system and the irradiation system was verified using the Daily QA system. Our present findings verified that the new Daily QA system for a rotating gantry is capable of verifying the irradiation system with sufficient accuracy.