Heidelberg Ion Therapy Center Research Articles

The potential of mixed carbon-helium beams for online treatment verification: a simulation and treatment planning study.

Recently, a new and promising approach for range verification was proposed. This method requires the use of two different ion species. Due to their equal magnetic rigidity, fully ionized carbon and helium ions can be simultaneously accelerated in accelerators like synchrotrons. At sufficiently high treatment energies, helium ions can exit the patient distally, reaching approximately three times the range
of carbon ions at an equal energy per nucleon. Therefore, the proposal involves adding a small helium fluence to the carbon ion beam and utilizing helium as an online range probe during radiation therapy. This work aims to develop a software framework for treatment planning and motion verification in range-guided radiation therapy using mixed carbon-helium beams. The developed framework is
based on the open-source treatment planning toolkit matRad. Dose distributions and helium radiographs were simulated using the open-source Monte Carlo package TOPAS. Beam delivery system parameters were obtained from the Heidelberg Ion Therapy Center, and imaging detectors along with reconstruction were facilitated by ProtonVDA. Methods for reconstructing the most likely patient positioning error scenarios and the motion phase of 4DCT are presented for prostate and lung cancer sites. The developed framework provides the capability to calculate and optimize treatment plans for mixed carbon-helium ion therapy. It can simulate the treatment process and generate helium radiographs for simulated patient geometry, including small beam views. Furthermore, motion reconstruction based on these radiographs seems possible with preliminary validation. The developed framework can be applied for further experimental work with the promising mixed carbon-helium ion implementation of range-guided radiotherapy. It offers opportunities for adaptation in particle therapy, improving dose accumulation, and enabling patient anatomy reconstruction during radiotherapy.&#xD.

Carbon-ion radiotherapy (CIRT) as treatment of pancreatic cancer at HIT: initial radiation plan analysis of the prospective phase II PACK-study

PurposeTo analyze the dose objectives and constraints applied at the prospective phase II PACK-study at Heidelberg ion therapy center (HIT) for different radiobiological models. MethodsTreatment plans of 14 patients from the PACK-study were analyzed and recomputed in terms of physical, biological dose and dose-averaged linear energy transfer (LETd). Both LEM-I (local effect model 1) and the adapted NIRS-MKM (microdosimetric kinetic model), were used for relative biological effectiveness (RBE)-weighted dose calculations (DBio|HIT and DBio|NIRS). A new constraint to the gastrointestinal (GI) tract was derived from the National Institute of Radiological Science (NIRS) clinical experience and considered for plan reoptimization (DBio|NIRS-const_48Gy and DBio|NIRS-const_50.4Gy). The Lyman-Kutcher-Burman (LKB) model of Normal Tissue Complication Probability (NTCP) for GI toxicity endpoints was computed. Furthermore, the computed LETd distribution was evaluated and correlated with Local Control (LC). ResultsOnly two patients showed a LETd98% in the GTV greater than 44 keV/μm. A HIT-dose constraint to the GI of D2cm3=48.6GyRBEHIT was derived from the NIRS experience, in alternative to the standard at HIT Dmax = 45.6 GyRBEHIT. In comparison with the original DBio|HIT,DBio|NIRS-const_48GyandDBio|NIRS-const_50.4Gy resulted in an increase in the ITV’s D98% of 8.7% and 11.3%. The NTCP calculation resulted in a probability for gastrointestinal bleeding of 4.5%, 12.3% and 13.0%, for DBio|NIRS, DBio|NIRS-const_48Gy and DBio|NIRS-const_50.4Gy, respectively. ConclusionThe results indicate that the current standards applied at HIT for CIRT closely align with the Japanese experience. However, to enhance tumor coverage, a more relaxed constraint on the GI tract may be considered. As the PACK-trial progresses, further analyses of various clinical endpoints are anticipated.

Differential response of esophageal cancer cells to particle irradiation

BackgroundRadiation therapy is a mainstay in the treatment of esophageal cancer (EC) patients, and photon radiotherapy has proved beneficial both in the neoadjuvant and the definitive setting. However, regarding the still poor prognosis of many EC patients, particle radiation employing a higher biological effectiveness may help to further improve patient outcomes. However, the influence of clinically available particle radiation on EC cells remains largely unknown.MethodsPatient-derived esophageal adenocarcinoma and squamous cell cancer lines were treated with photon and particle irradiation using clinically available proton (1H), carbon (12C) or oxygen (16O) beams at the Heidelberg Ion Therapy Center. Histology-dependent clonogenic survival was calculated for increasing physical radiation doses, and resulting relative biological effectiveness (RBE) was calculated for each radiation modality. Cell cycle effects caused by photon and particle radiation were assessed, and radiation-induced apoptosis was measured in adenocarcinoma and squamous cell EC samples by activated caspase-3 and sub-G1 populations. Repair kinetics of DNA double strand breaks induced by photon and particle radiation were investigated.ResultsWhile both adenocarcinoma EC cell lines demonstrated increasing sensitivities for 1H, 12C and 16O radiation, the two squamous cell carcinoma lines exhibited a more heterogeneous response to photon and particle treatment; average RBE values were calculated as 1.15 for 1H, 2.3 for 12C and 2.5 for 16O irradiation. After particle irradiation, squamous cell EC samples reacted with an increased and prolonged block in G2 phase of the cell cycle compared to adenocarcinoma cells. Particle radiation resulted in an incomplete repair of radiation-induced DNA double strand breaks in both adenocarcinoma and squamous cell carcinoma samples, with the levels of initial strand break induction correlating well with the individual cellular survival after photon and particle radiation. Similarly, EC samples demonstrated heterogeneous levels of radiation-induced apoptosis that also corresponded to the observed cellular survival of individual cell lines.ConclusionsEsophageal cancer cells exhibit differential responses to irradiation with photons and 1H, 12C and 16O particles that were independent of tumor histology. Therefore, yet unknown molecular markers beyond histology may help to establish which esophageal cancer patients benefit from the biological effects of particle treatment.

Clinical outcome after particle therapy for meningiomas of the skull base: toxicity and local control in patients treated with active rasterscanning

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

Early treatment response of a rare papillary tumor of the pineal region after primary proton-beam therapy using the raster-scanning technique at HIT.

Pineocytomas are rare intracranial tumors occurring in the pineal gland region. The curative therapy of choice is gross total resection, which cannot be performed in all patients because of the frequent eloquent location of these tumors. Percutaneous fractionated radiotherapy is an alternative treatment approach that may result in high local control rates. Nevertheless, our knowledge of this tumor entity is limited and based on retrospective case series only. We present a patient with a papillary tumor of the pineal region who was treated with highly conformal proton-beam therapy at the Heidelberg Ion Therapy Center (HIT) using the raster-scanning technique.

Oncogene addiction and radiation oncology: effect of radiotherapy with photons and carbon ions in ALK-EML4 translocated NSCLC

BackgroundPatients with Echinoderm microtubule-associated protein-like 4 (EML4)-anaplastic lymphoma kinase (ALK) positive lung cancer are sensitive to ALK-kinase inhibitors. TAE684 is a potent second generation ALK inhibitor that overcomes Crizotinib resistance. Radiotherapy is an integral therapeutic component of locally advanced lung cancer. Therefore, we sought to investigate the effects of combined radiotherapy and ALK-inhibition via TAE684 in ALK-positive vs. wild type lung cancer cells.MethodsHuman non-small cell lung cancer (NSCLC) cell lines harboring wild-type ALK (A549), EML4-ALK translocation (H3122) and murine Lewis Lung Cancer (LLC) cells were investigated. Cells were irradiated with 1–4 Gy X-Rays (320 keV) and carbon ions (Spread-out Bragg Peak, SOBP (245.4–257.0 MeV/u)) at Heidelberg Ion Therapy center. TAE684 was administered at the dose range 0–100 nM. Clonogenic survival, proliferation and apoptosis via caspase 3/7 expression level were assessed in all three cell lines using time-lapse live microscopy.ResultsTAE684 inhibited the proliferation of H3122 cells in a dose-dependent manner with a half maximal inhibitory concentration (IC50) of ~ 8.2 nM. However, A549 and LLC cells were relatively resistant to TAE684 and IC50 was not reached at concentrations tested (up to 100 nM) in proliferation assay. The antiproliferative effect of TAE684 was augmented by radiotherapy in H3122 cells. TAE684 significantly sensitized H3122 cells to particle therapy with carbon ions (sensitizer enhancement ratio ~1.61, p < 0.05). Caspase 3/7 activity was evidently enhanced after combination therapy in H3122 cells.ConclusionsThis is the first report demonstrating synergistic effects of combined TAE684 and radiotherapy in EML4-ALK positive lung cancer cells. In addition to conventional photon radiotherapy, ALK-inhibition also enhanced the effects of particle irradiation using carbon ions. Our data indicate beneficial effects of combined ALK-inhibition and radiotherapy in treatment of this distinct subpopulation of NSCLC that warrant further evaluation.

Optimization of Monte Carlo particle transport parameters and validation of a novel high throughput experimental setup to measure the biological effects of particle beams.

Accurate modeling of the relative biological effectiveness (RBE) of particle beams requires increased systematic invitro studies with human cell lines with care towards minimizing uncertainties in biologic assays as well as physical parameters. In this study, we describe a novel high-throughput experimental setup and an optimized parameterization of the Monte Carlo (MC) simulation technique that is universally applicable for accurate determination of RBE of clinical ion beams. Clonogenic cell-survival measurements on a human lung cancer cell line (H460) are presented using proton irradiation. Experiments were performed at the Heidelberg Ion Therapy Center (HIT) with support from the Deutsches Krebsforschungszentrum (DKFZ) in Heidelberg, Germany using a mono-energetic horizontal proton beam. A custom-made variable range selector was designed for the horizontal beam line using the Geant4 MC toolkit. This unique setup enabled a high-throughput clonogenic assay investigation of multiple, well defined dose and linear energy transfer (LETs) per irradiation for human lung cancer cells (H460) cultured in a 96-well plate. Sensitivity studies based on application of different physics lists in conjunction with different electromagnetic constructors and production threshold values to the MC simulations were undertaken for accurate assessment of the calculated dose and the dose-averaged LET (LETd ). These studies were extended to helium and carbon ion beams. Sensitivity analysis of the MC parameterization revealed substantial dependence of the dose and LETd values on both the choice of physics list and the production threshold values. While the dose and LETd calculations using FTFP_BERT_LIV, FTFP_BERT_EMZ, FTFP_BERT_PEN and QGSP_BIC_EMY physics lists agree well with each other for all three ions, they show large differences when compared to the FTFP_BERT physics list with the default electromagnetic constructor. For carbon ions, the dose corresponding to the largest LETd value is observed to differ by as much as 78% between FTFP_BERT and FTFP_BERT_LIV. Furthermore, between the production threshold of 700μm and 5μm, proton dose varies by as much as 19% corresponding to the largest LETd value sampled in the current investigation. Based on the sensitivity studies, the FTFP_BERT physics list with the low energy Livermore electromagnetic constructor and a production threshold of 5μm was employed for determining accurate dose and LETd . The optimized MC parameterization results in a different LETd dependence of the RBE curve for 10% SF of the H460 cell line irradiated with proton beam when compared with the results from a previous study using the same cell line. When the MC parameters are kept consistent between the studies, the proton RBE results agree well with each other within the experimental uncertainties. A custom high-throughput, high-accuracy experimental design for accurate invitro cell survival measurements was employed at a horizontal beam line. High sensitivity of the physics-based optimization establishes the importance of accurate MC parameterization and hence the conditioning of the MC system on a case-by-case basis. The proton RBE results from current investigations are observed to agree with a previous measurement made under different experimental conditions. This establishes the consistency of our experimental findings across different experiments and institutions.

4A. Helium ions at the Heidelberg Ion Therapy Center: From measurements to Monte-Carlo Treatment Planning

Introduction At the Heidelberg Ion beam Therapy Center (HIT), besides the clinically used protons and carbon ions, helium ions are available for research purposes. Despite the discontinuation of their use after the end of the clinical experience at the Berkeley National Laboratory in 1992, several Monte Carlo- (MC) [1] , analytical- [2] or experimental-based studies [3] show that helium ions may be good candidates for further particle therapy improvement. We present in this work the experimental validation of the MC FLUKA code [4] , [5] predictions and the first steps of the physical validation of a research MC treatment planning tool (MCTP) [6] for helium ions at HIT. Methods Laterally integrated depth-dose distributions (DDD) of pencil-like helium beams have been measured using a water column, for 10 different energies in the therapeutic range. Lateral dose profiles were investigated at several depths in water, at low, middle and high beam energies. The measurements have been performed in a water tank coupled with 24 motor-driven PinPoint ionization chambers and by delivering a vertically scanned beam. Results were compared to MC-FLUKA dose predictions using the HIT beamline geometry and optimized input parameters (water ionization potential, momentum spread). Physically-optimized spread-out Bragg peaks (SOBPs) of several sizes (3 × 3 × 3 and 6 × 6 × 6 cm3 were planned with the MCTP, using the previously experimentally-validated MC input parameters, at different depths (5, 12.5, 20 cm). A biologically-optimized SOBP was also planned by integrating a data-driven biological model to the MCTP [7] , [8] . Depth and lateral dose distributions of these plans were verified in the previously described water phantom. MCTP was used for the dose calculation of a meningioma case using helium ions and was compared to protons in term of dose volume histogram (DVH). Results DDD measurements and MC calculations show good agreements with weighted dose differences from 0.5% to 2.3% and range differences Physically- and biologically-optimized simulated SOBPs show good agreements with measurements with dose differences below 3% for both depth and lateral dose profiles. The homogeneity inside the physically-optimized SOBPs is below 5%. For the clinical case, the DVH analysis shows advantages of helium ions compared to protons, including a sharper slope (better homogeneity) for the target and a better sparing of the organ at risk. Conclusion The satisfactory results between MC-FLUKA predictions and MCTP-optimized plans against measurements suggest that the FLUKA code, and its research MCTP extension, offer a promising research engine for further investigations and planning studies comparisons between helium ions and the clinically used protons and carbon ions towards eventual clinical deployment. Acknowledgement We acknowledge funding from DFG (KFO Schwerionentherapie 214). Download : Download high-res image (180KB) Download : Download full-size image

Range assignment of protons in 18-oxygenated dosimetry gel using MR-PET imaging

Introduction When treating patients in radiation therapy with heavy ions the produced radioactivity can be used to determine particle ranges and/or the agreement with the target volume to be irradiated using positron emission tomography (PET). We present a method that combines dosimetry and PET data to verify proton ranges using phantom measurements. Purpose Qualitative methods for the determination of proton energy range using a combination of polymer gel dosimetry and PET. Materials and methods Polymer dosimetry-gel (PAGAT) was used to produce a radiation-induced polymerization which can be measured by magnetic resonance imaging (MRI). An additional enhancement of 21.75% of dosimetry-gel with oxigen-18 produces fluorine-18 by means of nuclear reaction with proton irradiation at the Heidelberg Ion-Therapy -Center (HIT) which can be measured with PET. The structure was tested for different kinds of beam applications: (i) pencil beam, (ii) pencil beam scanning and (iii) spread-out Bragg peak. Combined measurements were carried out on a MR/PET hybrid imaging device at the DKFZ. Results MRI analysis and calculations showed good compliance with respect to beam shape and energy range. The location of dose enhancement could be verified with PET. Due to the low resolution, however, no precise statements about the beam shapes and ranges could be made. Conclusion Oxygen-18 enriched PAGAT gels can be used to combine standard dosimetry gel evaluation and PET measurements. They showed a significant F-18 increase at the high dose area of MRI data. Improvements in the detection of beam shape and range can be realized using a small animal PET and/or by increasing the Oxyen-18 concentration.

SU‐F‐T‐184: 3D Range‐Modulator for Scanned Particle Therapy: Development, Monte Carlo Simulations and Measurements

Purpose:Active raster scanning in particle therapy results in highly conformal dose distributions. Treatment time, however, is relatively high due to the large number of different iso‐energy layers used. By using only one energy and the so called 3D range‐modulator irradiation times of a few seconds only can be achieved, thus making delivery of homogeneous dose to moving targets (e.g. lung cancer) more reliable.Methods:A 3D range‐modulator consisting of many pins with base area of 2.25 mm2 and different lengths was developed and manufactured with rapid prototyping technique. The form of the 3D range‐modulator was optimised for a spherical target volume with 5 cm diameter placed at 25 cm in a water phantom. Monte Carlo simulations using the FLUKA package were carried out to evaluate the modulating effect of the 3D range‐modulator and simulate the resulting dose distribution. The fine and complicated contour form of the 3D range‐modulator was taken into account by a specially programmed user routine. Additionally FLUKA was extended with the capability of intensity modulated scanning. To verify the simulation results dose measurements were carried out at the Heidelberg Ion Therapy Center (HIT) with a 400.41 MeV 12C beam.Results:The high resolution measurements show that the 3D range‐modulator is capable of producing homogeneous 3D conformal dose distributions, simultaneously reducing significantly irradiation time. Measured dose is in very good agreement with the previously conducted FLUKA simulations, where slight differences were traced back to minor manufacturing deviations from the perfect optimised form.Conclusion:Combined with the advantages of very short treatment time the 3D range‐modulator could be an alternative to treat small to medium sized tumours (e.g. lung metastasis) with the same conformity as full raster‐scanning treatment. Further simulations and measurements of more complex cases will be conducted to investigate the full potential of the 3D range‐modulator.

Phase Space Generation for Proton and Carbon Ion Beams for External Users' Applications at the Heidelberg Ion Therapy Center.

In the field of radiation therapy, accurate and robust dose calculation is required. For this purpose, precise modeling of the irradiation system and reliable computational platforms are needed. At the Heidelberg Ion Therapy Center (HIT), the beamline has been already modeled in the FLUKA Monte Carlo (MC) code. However, this model was kept confidential for disclosure reasons and was not available for any external team. The main goal of this study was to create efficiently phase space (PS) files for proton and carbon ion beams, for all energies and foci available at HIT. PSs are representing the characteristics of each particle recorded (charge, mass, energy, coordinates, direction cosines, generation) at a certain position along the beam path. In order to achieve this goal, keeping a reasonable data size but maintaining the requested accuracy for the calculation, we developed a new approach of beam PS generation with the MC code FLUKA. The generated PSs were obtained using an infinitely narrow beam and recording the desired quantities after the last element of the beamline, with a discrimination of primaries or secondaries. In this way, a unique PS can be used for each energy to accommodate the different foci by combining the narrow-beam scenario with a random sampling of its theoretical Gaussian beam in vacuum. PS can also reproduce the different patterns from the delivery system, when properly combined with the beam scanning information. MC simulations using PS have been compared to simulations, including the full beamline geometry and have been found in very good agreement for several cases (depth dose distributions, lateral dose profiles), with relative dose differences below 0.5%. This approach has also been compared with measured data of ion beams with different energies and foci, resulting in a very satisfactory agreement. Hence, the proposed approach was able to fulfill the different requirements and has demonstrated its capability for application to clinical treatment fields. It also offers a powerful tool to perform investigations on the contribution of primary and secondary particles produced in the beamline. These PSs are already made available to external teams upon request, to support interpretation of their measurements.

Treatment tolerance of particle therapy in pediatric patients

Curative treatment of pediatric cancer not only focuses on long-term survival, but also on reducing treatment-related side effects. Advantages of particle therapy are mainly due to their physical ability of significantly reducing integral dose.Methods. Between January 2009 and December 2012, we treated 83 pediatric patients (aged 21 and younger) at the Heidelberg Ion Therapy Center at University Hospital of Heidelberg (HIT). In total 56 patients (67%) received proton irradiation, while 25 (30%) patients were treated with carbon ions (C12). Two patients received both treatments (3%). Treatment toxicity was analyzed retrospectively and documented according to the CTCAE/RTOG classification. In a second step, treatment toxicity from ion therapy was analyzed in comparison to treatment toxicity during photon irradiation of a comparable historical group of 19 pediatric patients.Results. In all patients, particle therapy was tolerated well (median follow-up time 3.7 months), children (20 patients) with at least two follow-up visits showed a median follow-up time of 10.2 months. During the first two months patients mainly suffered from radiogenic skin reaction (63%), mucositis (30%), headache and dizziness (35%) as well as nausea and vomiting (13%). Severe toxicity reaction (grade II–IV) was only seen in patients who had intensive simultaneous chemotherapy or who had undergone several operations in the irradiated area before radiotherapy (18%). Treatment toxicity during ion therapy was comparable to treatment toxicity from photon irradiation of a historical group.Conclusions. In comparison to conventional therapy, patients with particle therapy do not suffer from increased acute treatment-related toxicity during the first months. More experience with particle therapy will be needed during the next years to help to thoroughly evaluate the high potential of ion therapy.

WE‐D‐BRF‐04: Experimental Investigations On Ion Radiography with Beam Scanning Using a Range Telescope

Purpose:Ion beams exhibit a finite range and an inverted depth‐dose profile, the Bragg peak. These favorable properties allow superior tumordose conformality, but introduce sensitivity to range uncertainties. Hence, imaging techniques play an increasingly important role to support the treatment planning and the in‐vivo monitoring of the actual ion beam treatment.Methods:This work presents the experimental investigations carried out to address the feasibility of ion transmission imaging at the Heidelberg Ion Therapy center using an active raster scanning beam delivery system and a prototype range telescope set‐up based on a stack of 61 parallel‐plate ionization chambers (PPIC) interleaved with 3 mm absorber plates of PMMA.Results:An extensive characterization of the set‐up in terms of beam parameters and settings of the read‐out electronics was performed and results will be presented. A data processing method to increase the range resolution (MIRR) of the PPIC stack was developed. In this approach, the position of the maximum of the Bragg curve is deduced from the ratio of measured signals in adjacent PPIC channels. MIRR evaluation is based on Bragg curves obtained from Monte Carlo simulations and validated with experimental data acquired with the PPIC stack using ion beams. MIRR was applied to the carbon ion radiography of an anthropomorphic Alderson head phantom yielding a resolution of 0.8 mm water equivalent thickness (WET) compared to the nominal value of 3.495 mm WET given by the thickness of the absorber slabs in the PPIC stack. An absolute comparison of the Alderson phantom carbon ion transmitted image with an X‐ray digitally reconstructed radiography, both converted into WET, will also be shown.Conclusion:The obtained results are very promising and motivate further developments of the system towards an eventual clinical use. This work is supported by the German Research Foundation and the German Academic Exchange Service.This work is supported by the German Research Foundation (DFG) and the German Academic Exchange Service (DAAD).

Experimental investigations on carbon ion scanning radiography using a range telescope

Ion beams offer an excellent tumor-dose conformality due to their inverted depth-dose profile and finite range in tissue, the Bragg peak (BP). However, they introduce sensitivity to range uncertainties. Imaging techniques play an increasingly important role in ion beam therapy to support precise diagnosis and identification of the target volume at the planning stage as well as to ensure the correspondence between the planning and treatment situation at the actual irradiation. For the purpose of improved treatment quality, ion-based radiographic images could be acquired at the treatment site before or during treatment and be employed to monitor the patient positioning and to check the patient-specific ion range. This work presents the initial experimental investigations carried out to address the feasibility of carbon ion radiography at the Heidelberg ion therapy center using a prototype range telescope set-up and an active raster scanning ion beam delivery system. Bragg curves are measured with a stack of ionization chambers (IC) synchronously to the beam delivery. The position of the BP is extracted from the data by locating the channel of maximum current signal for each delivered beam. Each BP is associated to the lateral and vertical positions of the scanned raster point extrapolated from the beam monitor system to build up a radiography. The radiographic images are converted into water equivalent thickness (WET) based on two calibrations of the detector. Radiographies of two phantoms of different complexities are reconstructed and their image quality is analyzed. A novel method proposed to increase the nominal range resolution of the IC stack is applied to the carbon ion radiography of an Alderson head phantom. Moreover, an x-ray digitally reconstructed radiography of the same anthropomorphic head phantom is converted in WET through the clinically used ion range calibration curve and compared with the carbon ion radiography based on a γ-index approach, yielding a good correspondence in terms of absolute WET within ±3%, 3 mm distance-to-agreement and, 87% passing ratio. Imaging artifacts at interfaces within the irradiated phantom due to the finite size of the beam, resulting in multiple maxima, are addressed. Overall, this work demonstrates the feasibility of the prototype range telescope to acquire ion-based transmission imaging with a resolution of up to 0.8 mm WET.

Proton and carbon ion radiotherapy for primary brain tumors and tumors of the skull base

To analyze clinical concepts, toxicity and treatment outcome in patients with brain and skull base tumors treated with photons and particle therapy. Material and methods. In total 260 patients with brain tumors and tumors of the skull base were treated at the Heidelberg Ion Therapy Center (HIT). Patients enrolled in and randomized within prospective clinical trials as well as bony or soft tissue tumors are not included in this analysis. Treatment was delivered as protons, carbon ions, or combinations of photons and a carbon ion boost. All patients are included in a tight follow-up program. The median follow-up time is 12 months (range 2–39 months). Results. Main histologies included meningioma (n = 107) for skull base lesions, pituitary adenomas (n = 14), low-grade gliomas (n = 51) as well as high-grade gliomas (n = 55) for brain tumors. In all patients treatment could be completed without any unexpected severe toxicities. No side effects > CTC Grade III were observed. To date, no severe late toxicities were observed, however, for endpoints such as secondary malignancies or neurocognitive side effects follow-up time still remains too short. Local recurrences were mainly seen in the group of high-grade gliomas or atypical meningiomas; for benign skull base meningiomas, to date, no recurrences were observed during follow-up. Conclusion. The specific benefit of particle therapy will potentially reduce the risk of secondary malignancies as well as improve neurocognitive outcome and quality of life (QOL); thus, longer follow-up will be necessary to confirm these endpoints. Indication-specific trials on meningiomas and gliomas are underway to elucidate the role of protons and carbon ions in these indications.

In vitro evaluation of photon and raster-scanned carbon ion radiotherapy in combination with gemcitabine in pancreatic cancer cell lines

Background: Pancreatic cancer is the fourth leading cause of cancer deaths, being responsible for 6% of all cancer-related deaths. Conventional radiotherapy with or without additional chemotherapy has been applied in the past in the context of neoadjuvant or adjuvant therapy concepts with only modest results, however new radiation modalities, such as particle therapy with promising physical and biological characteristics, present an alternative treatment option for patients with pancreatic cancer. Up until now the raster scanning technique employed at our institution for the application of carbon ions has been unique, and no radiobiological data using pancreatic cancer cells has been available yet. The aim of this study was to evaluate cytotoxic effects that can be achieved by treating pancreatic cancer cell lines with combinations of X-rays and gemcitabine, or alternatively with carbon ion irradiation and gemcitabine, respectively. Materials and Methods: Human pancreatic cancer cell lines AsPC-1, BxPC-3 and Panc-1 were irradiated with photons and carbon ions at various doses and treated with gemcitabine. Photon irradiation was applied with a biological cabin X-ray irradiator, and carbon ion irradiation was applied with an extended Bragg peak (linear energy transfer (LET) 103 keV/μm) using the raster scanning technique at the Heidelberg Ion Therapy Center (HIT). Responsiveness of pancreatic cancer cells to the treatment was measured by clonogenic survival. Clonogenic survival curves were then compared to predicted curves that were calculated employing the local effect model (LEM). Results: Cell survival curves were calculated from the surviving fractions of each combination experiment and compared to a drug control that was only irradiated with X-rays or carbon ions, without application of gemcitabine. In terms of cytotoxicity, additive effects were achieved for the cell lines Panc-1 and BxPC-3, and a slight radiosensitizing effect was observed for AsPC-1. Relative biological effectiveness (RBE) of carbon ion irradiation ranged from 1.5–4.5 depending on survival level and dose. Sensitizer enhancement ratio (SER) values calculated at 10% cell survival ranged from 1.24–1.66, depending on cell line, gemcitabine dose and irradiation modality. Experimentally ascertained survival curves matched those predicted by LEM-calculation. Conclusion: Our experiments have shown a combined treatment of irradiation and chemotherapy with gemcitabine to be a good means of achieving additive cytotoxic effects on pancreatic cancer cell lines. The data generated in this study will serve as radiobiological basis for further preclinical and clinical studies.

Treatment of pediatric patients and young adults with particle therapy at the Heidelberg Ion Therapy Center (HIT): establishment of workflow and initial clinical data

BackgroundTo report on establishment of workflow and clinical results of particle therapy at the Heidelberg Ion Therapy Center.Materials and methodsWe treated 36 pediatric patients (aged 21 or younger) with particle therapy at HIT. Median age was 12 years (range 2-21 years), five patients (14%) were younger than 5 years of age. Indications included pilocytic astrocytoma, parameningeal and orbital rhabdomyosarcoma, skull base and cervical chordoma, osteosarcoma and adenoid-cystic carcinoma (ACC), as well as one patient with an angiofibroma of the nasopharynx. For the treatment of small children, an anesthesia unit at HIT was established in cooperation with the Department of Anesthesiology.ResultsTreatment concepts depended on tumor type, staging, age of the patient, as well as availability of specific study protocols. In all patients, particle radiotherapy was well tolerated and no interruptions due to toxicity had to be undertaken. During follow-up, only mild toxicites were observed. Only one patient died of tumor progression: Carbon ion radiotherapy was performed as an individual treatment approach in a child with a skull base recurrence of the previously irradiated rhabdomyosarcoma. Besides this patient, tumor recurrence was observed in two additional patients.ConclusionClinical protocols have been generated to evaluate the real potential of particle therapy, also with respect to carbon ions in distinct pediatric patient populations. The strong cooperation between the pediatric department and the department of radiation oncology enable an interdisciplinary treatment and stream-lined workflow and acceptance of the treatment for the patients and their parents.

Early Treatment Response of a Rare Papillary Tumor of the Pineal Region after Primary Proton-Beam Therapy using the Raster-Scanning Technique at HIT

Pineocytomas are rare intracranial tumors occurring in the pineal gland region. The curative therapy of choice is gross total resection, which cannot be performed in all patients because of the frequent eloquent location of these tumors. Percutaneous fractionated radiotherapy is an alternative treatment approach that may result in high local control rates. Nevertheless, our knowledge of this tumor entity is limited and based on retrospective case series only. We present a patient with a papillary tumor of the pineal region who was treated with highly conformal proton-beam therapy at the Heidelberg Ion Therapy Center (HIT) using the raster-scanning technique.

Proton and carbon ion radiotherapy for primary brain tumors delivered with active raster scanning at the Heidelberg Ion Therapy Center (HIT): early treatment results and study concepts

BackgroundParticle irradiation was established at the University of Heidelberg 2 years ago. To date, more than 400 patients have been treated including patients with primary brain tumors. In malignant glioma (WHO IV) patients, two clinical trials have been set up-one investigating the benefit of a carbon ion (18 GyE) vs. a proton boost (10 GyE) in addition to photon radiotherapy (50 Gy), the other one investigating reirradiation with escalating total dose schedules starting at 30 GyE. In atypical meningioma patients (WHO °II), a carbon ion boost of 18 GyE is applied to macroscopic tumor residues following previous photon irradiation with 50 Gy.This study was set up in order to investigate toxicity and response after proton and carbon ion therapy for gliomas and meningiomas.Methods33 patients with gliomas (n = 26) and meningiomas (n = 7) were treated with carbon ion (n = 26) and proton (n = 7) radiotherapy. In 22 patients, particle irradiation was combined with photon therapy. Temozolomide-based chemotherapy was combined with particle therapy in 17 patients with gliomas. Particle therapy as reirradiation was conducted in 7 patients. Target volume definition was based upon CT, MRI and PET imaging. Response was assessed by MRI examinations, and progression was diagnosed according to the Macdonald criteria. Toxicity was classified according to CTCAE v4.0.ResultsTreatment was completed and tolerated well in all patients. Toxicity was moderate and included fatigue (24.2%), intermittent cranial nerve symptoms (6%) and single episodes of seizures (6%). At first and second follow-up examinations, mean maximum tumor diameters had slightly decreased from 29.7 mm to 27.1 mm and 24.9 mm respectively. Nine glioma patients suffered from tumor relapse, among these 5 with infield relapses, causing death in 8 patients. There was no progression in any meningioma patient.ConclusionsParticle radiotherapy is safe and feasible in patients with primary brain tumors. It is associated with little toxicity. A positive response of both gliomas and meningiomas, which is suggested in these preliminary data, must be evaluated in further clinical trials.

A review of ion sources for medical accelerators (invited)

There are two major medical applications of ion accelerators. One is a production of short-lived isotopes for radionuclide imaging with positron emission tomography and single photon emission computer tomography. Generally, a combination of a source for negative ions (usually H- and/or D-) and a cyclotron is used; this system is well established and distributed over the world. Other important medical application is charged-particle radiotherapy, where the accelerated ion beam itself is being used for patient treatment. Two distinctly different methods are being applied: either with protons or with heavy-ions (mostly carbon ions). Proton radiotherapy for deep-seated tumors has become widespread since the 1990s. The energy and intensity are typically over 200 MeV and several 10(10) pps, respectively. Cyclotrons as well as synchrotrons are utilized. The ion source for the cyclotron is generally similar to the type for production of radioisotopes. For a synchrotron, one applies a positive ion source in combination with an injector linac. Carbon ion radiotherapy awakens a worldwide interest. About 6000 cancer patients have already been treated with carbon beams from the Heavy Ion Medical Accelerator in Chiba at the National Institute of Radiological Sciences in Japan. These clinical results have clearly verified the advantages of carbon ions. Heidelberg Ion Therapy Center and Gunma University Heavy Ion Medical Center have been successfully launched. Several new facilities are under commissioning or construction. The beam energy is adjusted to the depth of tumors. It is usually between 140 and 430 MeV∕u. Although the beam intensity depends on the irradiation method, it is typically several 10(8) or 10(9) pps. Synchrotrons are only utilized for carbon ion radiotherapy. An ECR ion source supplies multi-charged carbon ions for this requirement. Some other medical applications with ion beams attract developer's interests. For example, the several types of accelerators are under development for the boron neutron capture therapy. This treatment is conventionally demonstrated by a nuclear reactor, but it is strongly expected to replace the reactor by the accelerator. We report status of ion source for medical application and such scope for further developments.