Search

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.

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.

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

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.

Purpose Locoregional control (LC) in malignant salivary gland tumors is dose-dependent, initial results with particle therapy were promising. We report our experience with raster-scanned, intensity-controlled carbon ion therapy (C12) and IMRT in 309 patients with pathologically confirmed adenoid cystic carcinoma (ACC) of the head and neck. Patients and methods Treatment records of patients treated with C12 between 08/1998 and 05/2013 were evaluated regarding tumor stage, treatment, toxicity (CTCAE v3), LC, progression-free survival (PFS) and overall survival (OS). Response assessment was carried out according to RECIST1.1. Results Tumor stages were mostly advanced (T4a/b: 60%, macroscopic disease: 71%), most common sites of origin were the paranasal sinus (37%). At a median follow-up at 33.9 months, LC, PFS, and OS at 3 and 5 year estimates are 83.7%/58.5%, 67.8%/56.1%, and 88.9%/74.6%. LC correlates with T-stage but neither nodal stage, age, relapse state, nor margin status. RECIST did not correlate with LC or survival rates. Conclusion IMRT plus C12 boost results in good control and survival rates at moderate toxicity. Margin status did not correlate with LC in T4 tumors, extensive and potentially mutilating surgical procedures may have to be re-evaluated. RECIST assessment did not correlate with either LC or survival rates; potentially more meaningful radiological parameters need to be developed.

Purpose The aim of this study was to estimate normal tissue complication probability (NTCP) parameters for late rectal complications after carbon ion radiotherapy (C-ion RT) for prostate cancer. Methods and materials A total of 163 patients were used to derive NTCP parameters. These patients were treated with relative biological effectiveness (RBE)-weighted dose ranging from 57.6Gy (RBE) up to 72Gy (RBE) and included in dose escalation trials. The Lyman–Kutcher–Burman (LKB) model was used and the model parameters were fit to the relation between dose and complication observed after C-ion RT. Results The resulting NTCP parameters were the volume effect parameter; n =0.035 (95% CI: 0.024–0.047), the steepness of the NTCP curve; m =0.10 (0.084–0.13), the tolerance dose associated with 50% probability of complication; TD 50 =63.6Gy (RBE) (61.8–65.4Gy (RBE)) for Grade⩾1, n =0.012 (0.0050–0.023), m =0.046 (0.033–0.062), TD 50 =69.1Gy (RBE) (67.6–70.9Gy (RBE)) for Grade⩾2. Conclusion A new set of rectal NTCP parameters in C-ion RT was determined. The rather small n values suggest that the rectum was consistent with being strictly serial organ. The new derived parameter values facilitate estimation of rectal NTCP in C-ion RT.

Background and purpose The aim of this study was to retrospectively analyse the outcomes of cases of adenoid cystic carcinomas (ACCs) of the head and neck that were treated at a single institution with particle therapy consisting of either protons or carbon ions. Methods and materials Between February 2002 and March 2012, 80 patients were treated with proton therapy (PT) or carbon ion therapy (CIT) alone. PT and CIT were employed in 40 (50%) patients each, and more than half of the patients received 65.0 GyE in 26 fractions ( n =47, 59%). Results The median duration of follow-up was 38months (range, 6–115months). For all patients, the 5-year for overall survival (OS) rate, progression-free survival (PFS) rate, and local control (LC) rate were 63%, 39%, and 75%, respectively. No significant differences between PT and CIT were observed. The 5-year LC rates for T4 and inoperable cases were 66% and 68%, respectively. Twenty-one patients (26%) experienced grade 3 or greater late toxicities, including three patients who developed grade 5 bleeding from nasopharyngeal ulcers. Conclusions Particle radiotherapy for ACC achieves favourable LC, and its efficacy in inoperable or T4 cases is promising. There were no significant differences between PT and CIT in terms of OS, PFS and LC.

Purpose Biological models to estimate the relative biological effectiveness (RBE) or the equivalent dose in 2 Gy fractions (EQD2) are needed for treatment planning and plan evaluation in carbon ion therapy. We present a model-independent, Monte Carlo based sensitivity analysis (SA) approach to quantify the impact of different uncertainties on the biological models. Methods and materials The Monte Carlo based SA is used for the evaluation of variations in biological parameters. The key property of this SA is the high number of simulation runs, each with randomized input parameters, allowing for a statistical variance-based ranking of the input variations. The potential of this SA is shown in a simplified one-dimensional treatment plan optimization. Physical properties of carbon ion beams (e.g. fragmentation) are simulated using the Monte Carlo code FLUKA. To estimate biological effects of ion beams compared to X-rays, we use the Local Effect Model (LEM) in the framework of the linear-quadratic (LQ) model. Currently, only uncertainties in the output of the biological models are taken into account. Results/conclusions The presented SA is suitable for evaluation of the impact of variations in biological parameters. Major advantages are the possibility to access and display the sensitivity of the evaluated quantity on several parameter variations at the same time. Main challenges for later use in three-dimensional treatment plan evaluation are computational time and memory usage. The presented SA can be performed with any analytical or numerical function and hence be applied to any biological model used in carbon ion therapy.

Purpose To compare photons, protons and carbon ions and their combinations for treatment of atypical and anaplastical skull base meningioma. Material and methods Two planning target volumes (PTV initial /PTV boost ) were delineated for 10 patients (prescribed doses 50Gy(RBE) and 10Gy(RBE)). Plans for intensity modulated photon (IMXT), proton (IMPT) and carbon ion therapy ( 12 C) were generated assuming a non-gantry scenario for particles. The following combinations were compared: IMXT+IMXT/IMPT/ 12 C; IMPT+IMPT/ 12 C; and 12 C+ 12 C. Plan quality was evaluated by target conformity and homogeneity (CI, HI), V 95% , D 2% and D 50% and dose-volume-histogram (DVH) parameters for organs-at-risk (OAR). If dose escalation was possible, it was performed until OAR tolerance levels were reached. Results CI was worst for IMXT. HI 12 C was significantly better than for IMXT. For all treatment options dose escalation above 60Gy(RBE) was possible for four patients, but impossible for six patients. Compared to IMXT+IMXT, ion beam therapy showed an improved sparing for most OARs, e.g. using protons and carbon ions D 50% was reduced by more than 50% for the ipsilateral eye and the brainstem. Conclusion Highly conformal IMPT and 12 C plans could be generated with a non-gantry scenario. Improved OAR sparing favors both sole 12 C and/or IMPT plans.

Background and purpose To evaluate the outcome of malignant salivary gland tumours treated with neutron therapy to assess the potential for other high linear energy transfer (LET) beams. Materials and methods Neutrons at iThemba LABS are produced by the reaction of 66 MeV protons on a beryllium target. A median dose 20.4 Gy, in 12 fractions in 4 weeks or 15 fractions in 5 weeks, was given to 335 patients with 176 irresectable, 104 macroscopically residual and 55 unresected tumours. Results Locoregional control was 60.6% at 5 years and 39.1% at 10 years and DSS was 66.8% and 53.7% at 5 and 10 years respectively. In the univariate analysis T4, >4 cm, high grade, squamous carcinoma, unresected and irresectable tumours, and positive nodes were significantly worse for LRC. In the multivariate analysis tumours >6 cm, squamous carcinoma, irresectable tumours and nodes were significantly worse for LRC. Tumours >6 cm, high grade, squamous carcinoma and nodes were significantly worse for DSS. Neither LRC nor DSS was influenced by age, sex, site, dose, fractionation or for initial or recurrent disease. Conclusions Neutron therapy appears to be the treatment of choice for macroscopically incompletely excised and irresectable salivary gland tumours with improved survival rates. Further improvement may be achieved with other high LET modalities with a superior dose profile, such as carbon ions.

Introduction Although many reports have shown the safety and efficacy of stereotactic body radiotherapy (SBRT) for T1N0M0 non–small-cell lung cancer (NSCLC), it is rather difficult to treat T2N0M0 NSCLC, especially T2b (>5 cm) tumor, with SBRT. Our hypothesis was that particle therapy might be superior to SBRT in T2 patients. We evaluated the clinical outcome of particle therapy for T2a/bN0M0 NSCLC staged according to the 7th edition of the International Union Against Cancer (UICC) tumor, node, metastasis classification. Methods From April 2003 to December 2009, 70 histologically confirmed patients were treated with proton ( n = 43) or carbon-ion ( n = 27) therapy according to institutional protocols. Forty-seven patients had a T2a tumor and 23 had a T2b tumor. The total dose and fraction (fr) number were 60 (Gray equivalent) GyE/10 fr in 20 patients, 52.8 GyE/4 fr in 16, 66 GyE/10 fr in 16, 80 GyE/20 fr in 14, and other in four patients, respectively. Toxicities were scored according to the Common Terminology Criteria for Adverse Events, Version 4.0. Results The median follow-up period for living patients was 51 months (range, 24–103). For all 70 patients, the 4-year overall survival, local control, and progression-free survival rates were 58% (T2a, 53%; T2b, 67%), 75% (T2a, 70%; T2b, 84%), and 46% (T2a, 43%; T2b, 52%), respectively, with no significant differences between the two groups. The 4-year regional recurrence rate was 17%. Grade 3 pulmonary toxicity was observed in only two patients. Conclusion Particle therapy is well tolerated and effective for T2a/bN0M0 NSCLC. To further improve treatment outcome, adjuvant chemotherapy seems a reasonable option, whenever possible.

International audience; The aim of this work was to study the influence of Geant4 parameters on dose distribution and computational time for simulations of carbon ion therapy. The study was done using Geant4 version 9.0. The dose distribution in water for incident monoenergetic carbon ion beams of 300 MeV/u were compared for different values of secondary particle production threshold and different step limits. Variations of depth dose of about 2 mm were observed in some cases, which induced a 30% variation of dose deposit in the Bragg peak region. Other tests were done using Geant4 version 9.2 to verify the results from this study. The two versions provided converging results and led to the same conclusions.

This paper reviews current thinking about the epidemiology, investigation, treatment and outcome of chondrosarcoma, including the role of PET-CT. It also looks at current controversies about management and specific difficulties with pelvic location. New hopes for treatment such bisphosphonates, COX-2 inhibitors and carbon ion therapy and the latest genetic studies are reviewed.

Carbon ion therapy is an innovative radiation therapy. It has been first proposed in the forties by Robert Wilson, however the first dedicated centres for human care have been build up only recently in Japan and Germany. The interest of carbon ion is twofold: 1) the very sharp targeting of the tumour with the so called spread out Bragg peak that delivers most of the beam energy in the tumour and nothing beyond it, sparing very efficiently the healthy tissues; 2) the higher relative biological efficiency compared to X rays or protons, able to kill radioresistant tumour cells. Both properties make carbon ions the elective therapy for non resectable radioresistant tumours loco-regionally threatening. The technical and clinical experience accumulated during the recent decades is summarized in this paper along with a detailed presentation of the elective indications. A short comparison between conventional radiotherapy and hadrontherapy is proposed for the indications which are considered as priority for carbon ions.

A number of aspects of radiotherapy using protons and ions such as carbon and neon are discussed, focusing less on the oft-enumerated advantages or potential advantages of these particles as on those aspects which are, or may be, problematic. First, for protons and so-called heavy ions separately, the potential advantages and disadvantages of the particles, on physical and radiobiological grounds, are reviewed and some outstanding problems, both technical and scientific, are enumerated. Then, mention is made of the danger that financial pressures can lead to suboptimal medical care of patients. Finally, the issue of clinical trials, and especially randomized clinical trials, is addressed. On the one hand, very few randomized trials have been reported. On the other hand, there is a widespread desire to see trials of charged particle therapy undertaken. The ethical considerations are briefly reviewed and it is concluded that they pose strong limitations on the types of trials which can be undertaken. Nevertheless, some clinical trials would certainly be appropriate and desirable and a number are suggested, under the categories of retrospective non-randomized clinical trials, prospective non-randomized clinical trials, and prospective-randomized clinical trials.

Carbon ion radiotherapy has been conducted since 1994 at National Institute of Radiological Sciences, Japan, with beams from Heavy Ion Medical Accelerator in Chiba. Accumulated number of patients treated will become more than 5,000 by the end of this year. The tumor sites with more than 200 treated patients include Prostate, Lung, Head and Neck, Bone and Soft Tissue, and Liver. The experience of 15 years can be summarized as that carbon ion therapy has established efficacy in treatment of tumors, especially so-called ‘radio-resistant’ ones and including ‘inoperable’ cases. Reduction of fractionation, and thus treatment period, is another important achievement which can benefit patients in many ways. Recent development of the therapeutic system in order to advance more efficient and patient-friendly treatments will be presented also.

Hadrontherapy is an advanced technique of cancer radiation therapy which instead of X-rays employs beams of charged hadrons, protons and carbon ions in particular. Due to their physical and radio-biological properties, they allow to obtain a highly conformal treatment, sparing at best the surrounding healthy tissues. From being practised only in nuclear and particle physics laboratories, hadrontherapy is becoming today a clinical reality. By now about 45 ′ 000 patients have been treated worldwide with proton beams and several hospital based centres are either running or under construction. Carbon ions are characterized by a larger biological effectiveness than X-rays and protons and they are particularly suited to treat radio-resistant tumours. Carbon ion therapy is developing in the world and two hospital based centers are under construction in Europe. A large diffusion of hadrontherapy is foreseen in the near future but a much larger diffusion, possibly comparable with conventional X-ray radiation therapy, will be achieved only if much compact and cheap accelerators and dose delivery systems will be conceived and constructed. In this paper the present status of hadrontherapy and some innovative ideas for the future are summarized.

Summary Background: The planned MedAustron hadron therapy facility is designed to compare proton and carbon ion beam therapy under the same technical conditions. For the calculation of the number of potential patients for hadron therapy so far, only epidemiological estimations on cancer incidence are available without inclusion of the percentage of patients routinely referred to conventional radiotherapy Materials and Methods: Nationwide prospective survey to collect disease and treatment related data on patients receiving conventional radiotherapy at all 12 treatment facilities. Epidemiological cancer incidence (Statistic Austria 1999) were correlated with the number of patients receiving conventional radiotherapy. Based on published clinical and experimental results on proton and carbon ion therapy, a calculation of patient's subgroups suitable for hadron therapy was performed at five European University hospitals involved in the HICAT, CNAO, ETOILE and MEDAustron project. Using the mean values of the University specific percentages per tumour site, the number of potential patients was estimated. Results: In Austria, a total of 3783 patients started radiotherapy during the study period of 3 months resulting in an approximated number of 15132 patients per year. The number of potential patients was estimated to 2044 per year, representing 5.6% of all newly diagnosed cancer patients and 13.5% of all irradiated cancer patients. Conclusion: There is a clear place for a hadron therapy facility in Austria, based on pattern of care in radiotherapy, cancer incidence and indications.

Clinical results obtained with hadrontherapy have been extremely positive for various tumours, with percentages of local control and survival higher than those ascribed to conventional radiotherapy. Most clinical data obtained with charged particles are related to protontherapy but the implementation of carbon ion therapy has demonstrated to be of great interest in the last decade. These results, accompanied by the new performances in accelerator technology and calculation systems of the delivered doses, have determined over the past years an increased interest for the development of hadrontherapy, with the construction of new centres provided with equipment entirely dedicated to clinical activity (LLUMC, Loma Linda and NPTC, Boston in USA, HIMAC-NIRS, Chiba, PROBEAT, Tsukuba, and Hyogo Beam Medical Centres in Japan). A revision of the clinical indications specifically focused on ion therapy is presented as well as the results obtained in the different centres. With hadrontherapy, it is finally possible to increase the spectrum of treatments allowing preserving the organ and its functionality, with positive impacts from a social and economic point of view.

Since December 1997, patients are treated with carbon ions at GSI (Gesellschaft fur Schwerionenforschung). Dose delivery is performed with the intensity-controlled raster-scanning technique, which allows a highly conformal treatment of the tumor. To meet the special requirements of dosimetry with heavy ion beams, new dosimetric measurement techniques were developed and introduced into clinical application by the DKFZ (Deutsches Krebsforschungszentrum). The techniques comprise calibration of the irradiation monitor, checks of lateral and depth dose profiles, as well as verification of the beam delivery for complex three-dimensional dose distributions. The developed dosimetric methods are now integral part of clinical application and enable safe treatment with carbon ion therapy.

Summary On April 1, 2001, the Hyogo Ion Beam Medical Center (HIBMC) was opened as the first facility in the world to provide ion beam therapy using 2 types of beams, protons and carbon-ions. We will introduce the HIBMC, and report the results of the clinical study and general practice.