Carbon ion radiotherapy of hepatocellular carcinoma provides excellent local control: The prospective phase I PROMETHEUS trial.

Background & Aims: Inoperable hepatocellular carcinoma (HCC) can be treated by stereotactic body radiotherapy. However, carbon ion radiotherapy (CIRT) is more effective for sparing non-tumorous liver. High linear energy transfer could promote therapy efficacy. Japanese and Chinese studies on hypofractionated CIRT have yielded excellent results. Because of different radiobiological models and the different etiological spectrum of HCC, applicability of these results to European cohorts and centers remains questionable. The aim of this prospective study was to assess safety and efficacy and to determine the optimal dose of CIRT with active raster scanning based on the local effect model (LEM) I. Methods: CIRT was performed every other day in four fractions with relative biological effectiveness (RBE)-weighted fraction doses of 8.1-10.5 Gy (total doses 32.4-42.0 Gy [RBE]). Dose escalation was performed in five dose levels with at least three patients each. The primary endpoint was acute toxicity after 4 weeks. Results: Twenty patients received CIRT (median age 74.7 years, n = 16 with liver cirrhosis, Child-Pugh scores [CP] A5 [n = 10], A6 [n = 4], B8 [n = 1], and B9 [n = 1]). Median follow up was 23 months. No dose-limiting toxicities and no toxicities exceeding grade II occurred, except one grade III gamma-glutamyltransferase elevation 12 months after CIRT, synchronous to out-of-field hepatic progression. During 12 months after CIRT, no CP elevation occurred. The highest dose level could be applied safely. No local recurrence developed during follow up. The objective response rate was 80%. Median overall survival was 30.8 months (1/2/3 years: 75%/64%/22%). Median progression-free survival was 20.9 months (1/2/3 years: 59%/43%/43%). Intrahepatic progression outside of the CIRT target volume was the most frequent pattern of progression. Conclusions: CIRT of HCC yields excellent local control without dose-limiting toxicity. Impact and implications: To date, safety and efficacy of carbon ion radiotherapy for hepatocellular carcinoma have only been evaluated prospectively in Japanese and Chinese studies. The optimal dose and fractionation when using the local effect model for radiotherapy planning are unknown. The results are of particular interest for European and American particle therapy centers, but also of relevance for all specialists involved in the treatment and care of patients with hepatocellular carcinoma, as we present the first prospective data on carbon ion radiotherapy in hepatocellular carcinoma outside of Asia. The excellent local control should encourage further use of carbon ion radiotherapy for hepatocellular carcinoma and design of randomized controlled trials. Clinical Trials Registration: The study is registered at ClinicalTrials.gov (NCT01167374).

Patterns of Temporal Lobe Reaction and Radiation Necrosis after Particle Radiotherapy in Patients with Skull Base Chordoma and Chondrosarcoma-A Single-Center Experience.

BACKGROUND: The current study aims to evaluate the occurrence of temporal lobe reactions and identify possible risk factors for patients who underwent particle therapy of the skull base. METHODS: 244 patients treated for skull base chordoma (n = 144) or chondrosarcoma (n = 100) at the Heidelberg Ion Beam Therapy Center (HIT) using a raster scan technique, were analyzed. Follow-up MRI-scans were matched with the initial planning images. Radiogenic reactions were contoured and analyzed based on volume and dose of treatment. RESULTS: 51 patients with chordoma (35.4%) and 30 patients (30%) with chondrosarcoma experienced at least one temporal lobe reaction within the follow-up period (median 49 months for chondrosarcoma, 62 months for chordoma). Age, irradiated volume, and dose values were significant risk factors for the development of temporal lobe reactions with the highest significance for the value of DMax-7 being defined as the dose maximum in the temporal lobe minus the 7cc with the highest dose (p = 0.000000000019; OR 1.087). CONCLUSION: Temporal lobe reactions are a common side effect after particle therapy of the skull base. We were able to develop a multivariate model, which predicted radiation reactions with a specificity of 99% and a sensitivity of 52.2%.

Consensus guide on CT-based prediction of stopping-power ratio using a Hounsfield look-up table for proton therapy.

BACKGROUND AND PURPOSE: Studies have shown large variations in stopping-power ratio (SPR) prediction from computed tomography (CT) across European proton centres. To standardise this process, a step-by-step guide on specifying a Hounsfield look-up table (HLUT) is presented here. MATERIALS AND METHODS: The HLUT specification process is divided into six steps: Phantom setup, CT acquisition, CT number extraction, SPR determination, HLUT specification, and HLUT validation. Appropriate CT phantoms have a head- and body-sized part, with tissue-equivalent inserts in regard to X-ray and proton interactions. CT numbers are extracted from a region-of-interest covering the inner 70% of each insert in-plane and several axial CT slices in scan direction. For optimal HLUT specification, the SPR of phantom inserts is measured in a proton beam and the SPR of tabulated human tissues is computed stoichiometrically at 100 MeV. Including both phantom inserts and tabulated human tissues increases HLUT stability. Piecewise linear regressions are performed between CT numbers and SPRs for four tissue groups (lung, adipose, soft tissue, and bone) and then connected with straight lines. Finally, a thorough but simple validation is performed. RESULTS: The best practices and individual challenges are explained comprehensively for each step. A well-defined strategy for specifying the connection points between the individual line segments of the HLUT is presented. The guide was tested exemplarily on three CT scanners from different vendors, proving its feasibility. CONCLUSION: The presented step-by-step guide for CT-based HLUT specification with recommendations and examples can contribute to reduce inter-centre variations in SPR prediction.

Commissioning of Helium Ion Therapy and the First Patient Treatment With Active Beam Delivery.

PURPOSE: Helium ions offer intermediate physical and biological properties to the clinically used protons and carbon ions. This work presents the commissioning of the first clinical treatment planning system (TPS) for helium ion therapy with active beam delivery to prepare the first patients' treatment at the Heidelberg Ion-Beam Therapy Center (HIT). METHODS AND MATERIALS: Through collaboration between RaySearch Laboratories and HIT, absorbed and relative biological effectiveness (RBE)-weighted calculation methods were integrated for helium ion beam therapy with raster-scanned delivery in the TPS RayStation. At HIT, a modified microdosimetric kinetic biological model was chosen as reference biological model. TPS absorbed dose predictions were compared against measurements with several devices, using phantoms of different complexities, from homogeneous to heterogeneous anthropomorphic phantoms. RBE and RBE-weighted dose predictions of the TPS were verified against calculations with an independent RBE-weighted dose engine. The patient-specific quality assurance of the first treatment at HIT using helium ion beam with raster-scanned delivery is presented considering standard patient-specific measurements in a water phantom and 2 independent dose calculations with a Monte Carlo or an analytical-based engine. RESULTS: TPS predictions were consistent with dosimetric measurements and independent dose engines computations for absorbed and RBE-weighted doses. The mean difference between dose measurements to the TPS calculation was 0.2% for spread-out Bragg peaks in water. Verification of the first patient treatment TPS predictions against independent engines for both absorbed and RBE-weighted doses presents differences within 2% in the target and with a maximum deviation of 3.5% in the investigated critical regions of interest. CONCLUSIONS: Helium ion beam therapy has been successfully commissioned and introduced into clinical use. Through comprehensive validation of the absorbed and RBE-weighted dose predictions of the RayStation TPS, the first clinical TPS for helium ion therapy using raster-scanned delivery was employed to plan the first helium patient treatment at HIT.

Treatment Tolerability and Toxicity of Postoperative Proton Beam Therapy for Gynecologic Malignancies: Results of the Prospective Phase 2 APROVE Trial.

PURPOSE: The APROVE study is a prospective one-arm phase-2 study investigating the safety and treatment tolerability of postoperative proton beam therapy in women with uterine cervical or endometrial cancer. In this analysis, we report the primary study endpoint of safety and treatment tolerability as well as toxicity rates and progression-free survival (PFS). METHODS AND MATERIALS: 25 patients were treated with postoperative proton beam therapy with a total dose of 45 to 50.4 Gy (RBE) in 5 to 6 × 1.8 Gy (RBE) fractions weekly using active raster-scanning intensity modulated proton beam therapy (IMPT). Sequential or simultaneous platinum-based chemotherapy was administered if indicated. The primary endpoint was defined as the lack of any acute ≥grade 3 gastrointestinal (GI) or urogenital (GU) toxicity according to the Common Terminology Criteria for Adverse Events v 4.0 or premature treatment abortion. Secondary endpoints were clinical symptoms and toxicity, quality of life, and PFS. RESULTS: All patients completed IMPT according to the protocol, with a median treatment duration of 43 days (range, 33 to 51 days). No patient developed gastrointestinal or genitourinary toxicity ≥grade 3, and the treatment tolerability rate was 100%. Therefore, the null hypothesis H0: Tolerability Rate ≤80% could be rejected in favor of the alternative hypothesis H1: Tolerability rate >80% using an exact binomial test with a one-sided significance level of α = 10% (one-sided P value P = .0059). The median follow-up time after the end of IMPT was 25.1 months (range, 20.2 to 50.3 months). 18 of 25 (75%) patients completed the study follow-up of 24 months. 7 patients had progressive disease. Kaplan-Meier-estimated mean PFS was 39.9 months (95% confidence interval: 33.37 to 46.5 months). CONCLUSIONS: Postoperative IMPT is a safe treatment option for cervical and endometrial cancer patients, with only low-grade acute and late toxicities. Larger randomized trials are necessary to further assess the potential of IMPT and improve patient selection.

Health-related quality of life and patient-reported symptoms after postoperative proton beam radiotherapy of cervical and endometrial cancer: 2-year results of the prospective phase II APROVE-trial.

INTRODUCTION: The APROVE-trial investigated the tolerability of postoperative proton beam therapy in women with cervical or endometrial cancer. The present analysis evaluated the secondary endpoints of health-related quality of life (HRQOL) and patient-reported symptoms. METHODS: 25 patients were included in this prospective phase-II-trial and treated with postoperative radiotherapy using protons alone or in combination with chemotherapy. To attain general and gynecologic-specific HRQOL measures, the EORTC-QLQ-C30 questionnaires combined with -QLQ-CX24 for cervical and -QLQ-EN24 for endometrial cancer were assessed at baseline, at the end of RT and up to 2 years after radiotherapy. The results were compared to an age-matched norm reference population. Symptoms were assessed using Common Terminology Criteria for Adverse Events (CTCAE) and institutional patient-reported symptoms grading. RESULTS: Scores regarding global health status were markedly impaired at baseline (mean: 58.0 ± 20.1) compared to reference population data, but significantly (p = 0.036) improved and evened out to comparable norm values 2 years after proton therapy (mean: 69.9 ± 19.3). Treatment caused acute and long-term worsening of pain (p = 0.048) and gastrointestinal symptoms (p = 0.016) for women with endometrial cancer, but no higher-grade CTCAE ≥ 3° toxicity was observed. Dosimetric evaluation of rectum, sigmoid, large and small bowel showed no correlation with the reported gastrointestinal symptoms. After 2 years, fatigue had significantly improved (p = 0.030), whereas patients with cervical cancer experienced more often lymphedema (p = 0.017). Scores for endometrial cancer pertaining to sexual activity (p = 0.048) and body image (p = 0.022) had improved post treatment; in the latter this effect persisted after 2 years. CONCLUSION: Proton beam therapy in the adjuvant setting was well tolerated with only low-grade side effects concerning gastrointestinal symptoms, lymphedema and pain. Overall quality of life was impaired at baseline, but patients were able to recover to values comparable to norm population 2 years after proton therapy. Larger studies are needed to confirm whether the benefit of proton therapy translates into a clinical effect. Sexual dysfunction remains an important issue. TRIAL REGISTRATION: The trial was registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT03184350, 09th June 2017).

Optimizing the Patient Positioning Workflow of Patients with Pelvis, Limb, and Chest/Spine Tumors at an Ion-Beam Gantry based on Optical Surface Guidance.

Purpose: Surface-guided radiation therapy (SGRT) has been investigated intensively to ensure correct patient positioning during a radiation therapy course. Although the implementation is well defined for photon-beam facilities, only a few analyses have been published for ion-beam therapy centers. To investigate the accuracy, reliability, and efficiency of SGRT used in ion-beam treatments against the conventional skin marks, a retrospective study of a unique SGRT installation in an ion gantry treatment room was conducted, where the environment is quite different to conventional radiation therapy. Methods and Materials: There were 32 patients, divided into 3 cohorts-pelvis, limb, and chest/spine tumors-and treated with ion-beams. Two patient positioning workflows based on 300 fractions were compared: workflow with skin marks and workflow with SGRT. Position verification was followed by planar kilo voltage imaging. After image matching, 6 degrees of freedom corrections were recorded to assess interfraction positioning errors. In addition, the time required for patient positioning, image matching, and the number of repeated kilo voltage imaging also were gathered. Results: SGRT decreased the translational magnitude shifts significantly (P < .05) by 0.5 ± 1.4 mm for pelvis and 1.9 ± 0.5 mm for limb, whereas for chest/spine, it increased by 0.7 ± 0.3 mm. Rotational corrections were predominantly lowered with SGRT for all cohorts with significant differences in pitch for pelvis (P = .002) and chest/spine (P = .009). The patient positioning time decreased by 18%, 9%, and 15% for pelvis, limb, and chest/spine, respectively, compared with skin marks. By using SGRT, 53% of all studied patients had faster positioning time, and 87.5% had faster matching time. Repositioning and consequent reimaging decreased from about 7% to 2% with a statistically significant difference of .042. Conclusions: The quality of patient positioning before ion-beam treatments has been optimized by using SGRT without additional imaging dose. SGRT clearly reduced inefficiencies in the patient positioning workflow.

Proton and carbon ion beam treatment with active raster scanning method in 147 patients with skull base chordoma at the Heidelberg Ion Beam Therapy Center-a single-center experience.

BACKGROUND: This study aimed to compare the results of irradiation with protons versus irradiation with carbon ions in a raster scan technique in patients with skull base chordomas and to identify risk factors that may compromise treatment results. METHODS: A total of 147 patients (85 men, 62 women) were irradiated with carbon ions (111 patients) or protons (36 patients) with a median dose of 66 Gy (RBE (Relative biological effectiveness); carbon ions) in 4 weeks or 74 Gy (RBE; protons) in 7 weeks at the Heidelberg Ion Beam Therapy Center (HIT) in Heidelberg, Germany. The median follow-up time was 49.3 months. All patients had gross residual disease at the beginning of RT. Compression of the brainstem was present in 38%, contact without compression in 18%, and no contact but less than 3 mm distance in 16%. Local control and overall survival were evaluated using the Kaplan-Meier Method based on scheduled treatment (protons vs. carbon ions) and compared via the log rank test. Subgroup analyses were performed to identify possible prognostic factors. RESULTS: During the follow-up, 41 patients (27.9%) developed a local recurrence. The median follow-up time was 49.3 months (95% CI: 40.8-53.8; reverse Kaplan-Meier median follow-up time 56.3 months, 95% CI: 51.9-60.7). No significant differences between protons and carbon ions were observed regarding LC, OS, or overall toxicity. The 1­year, 3­year, and 5­year LC rates were 97%, 80%, and 61% (protons) and 96%, 80%, and 65% (carbon ions), respectively. The corresponding OS rates were 100%, 92%, and 92% (protons) and 99%, 91%, and 83% (carbon ions). No significant prognostic factors for LC or OS could be determined regarding the whole cohort; however, a significantly improved LC could be observed if the tumor was > 3 mm distant from the brainstem in patients presenting in a primary situation. CONCLUSION: Outcomes of proton and carbon ion treatment of skull base chordomas seem similar regarding tumor control, survival, and toxicity. Close proximity to the brainstem might be a negative prognostic factor, at least in patients presenting in a primary situation.

Particle Therapy in Adult Patients with Pelvic Ewing Sarcoma-Tumor and Treatment Characteristics and Early Clinical Outcomes.

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.

Experimental assessment of inter-centre variation in stopping-power and range prediction in particle therapy.

PURPOSE: Experimental assessment of inter-centre variation and absolute accuracy of stopping-power-ratio (SPR) prediction within 17 particle therapy centres of the European Particle Therapy Network. MATERIAL AND METHODS: A head and body phantom with seventeen tissue-equivalent materials were scanned consecutively at the participating centres using their individual clinical CT scan protocol and translated into SPR with their in-house CT-number-to-SPR conversion. Inter-centre variation and absolute accuracy in SPR prediction were quantified for three tissue groups: lung, soft tissues and bones. The integral effect on range prediction for typical clinical beams traversing different tissues was determined for representative beam paths for the treatment of primary brain tumours as well as lung and prostate cancer. RESULTS: An inter-centre variation in SPR prediction (2σ) of 8.7%, 6.3% and 1.5% relative to water was determined for bone, lung and soft-tissue surrogates in the head setup, respectively. Slightly smaller variations were observed in the body phantom (6.2%, 3.1%, 1.3%). This translated into inter-centre variation of integral range prediction (2σ) of 2.9%, 2.6% and 1.3% for typical beam paths of prostate-, lung- and primary brain-tumour treatments, respectively. The absolute error in range exceeded 2% in every fourth participating centre. The consideration of beam hardening and the execution of an independent HLUT validation had a positive effect, on average. CONCLUSION: The large inter-centre variations in SPR and range prediction justify the currently clinically used margins accounting for range uncertainty, which are of the same magnitude as the inter-centre variation. This study underlines the necessity of higher standardisation in CT-number-to-SPR conversion.

Quality assurance method for monitoring of lateral pencil beam positions in scanned carbon-ion radiotherapy using tracking of secondary ions.

PURPOSE: Ion beam radiotherapy offers enhances dose conformity to the tumor volume while better sparing healthy tissue compared to conventional photon radiotherapy. However, the increased dose gradient also makes it more sensitive to uncertainties. While the most important uncertainty source is the patient itself, the beam delivery is also subject to uncertainties. Most of the proton therapy centers used cyclotrons, which deliver typically a stable beam over time, allowing a continuous extraction of the beam. Carbon-ion beam radiotherapy (CIRT) in contrast uses synchrotrons and requires a larger and energy-dependent extrapolation of the nozzle-measured positions to obtain the lateral beam positions in the isocenter, since the nozzle-to-isocenter distance is larger than for cyclotrons. Hence, the control of lateral pencil beam positions at isocenter in CIRT is more sensitive to uncertainties than in proton radiotherapy. Therefore, an independent monitoring of the actual lateral positions close to the isocenter would be very valuable and provide additional information. However, techniques capable to do so are scarce, and they are limited in precision, accuracy and effectivity. METHODS: The detection of secondary ions (charged nuclear fragments) has previously been exploited for the Bragg peak position of C-ion beams. In our previous work, we investigated for the first time the feasibility of lateral position monitoring of pencil beams in CIRT. However, the reported precision and accuracy were not sufficient for a potential implementation into clinical practice. In this work, it is shown how the performance of the method is improved to the point of clinical relevance. To minimize the observed uncertainties, a mini-tracker based on hybrid silicon pixel detectors was repositioned downstream of an anthropomorphic head phantom. However, the secondary-ion fluence rate in the mini-tracker rises up to 1.5 × 105 ions/s/cm2 , causing strong pile-up of secondary-ion signals. To solve this problem, we performed hardware changes, optimized the detector settings, adjusted the setup geometry and developed new algorithms to resolve ambiguities in the track reconstruction. The performance of the method was studied on two treatment plans delivered with a realistic dose of 3 Gy (RBE) and averaged dose rate of 0.27 Gy/s at the Heidelberg Ion-Beam Therapy Center (HIT) in Germany. The measured lateral positions were compared to reference beam positions obtained either from the beam nozzle or from a multi-wire proportional chamber positioned at the room isocenter. RESULTS: The presented method is capable to simultaneously monitor both lateral pencil beam coordinates over the entire tumor volume during the treatment delivery, using only a 2-cm2 mini-tracker. The effectivity (defined as the fraction of analyzed pencil beams) was 100%. The reached precision of (0.6 to 1.5) mm and accuracy of (0.5 to 1.2) mm are in line with the clinically accepted uncertainty for QA measurements of the lateral pencil beam positions. CONCLUSIONS: It was demonstrated that the performance of the method for a non-invasive lateral position monitoring of pencil beams is sufficient for a potential clinical implementation. The next step is to evaluate the method clinically in a group of patients in a future observational clinical study.

Analytical modeling of depth-dose degradation in heterogeneous lung tissue for intensity-modulated proton therapy planning.

BACKGROUND AND PURPOSE: Proton therapy may be promising for treating non-small-cell lung cancer due to lower doses to the lung and heart, as compared to photon therapy. A reported challenge is degradation, i.e., a smoothing of the depth-dose distribution due to heterogeneous lung tissue. For pencil beams, this causes a distal falloff widening and a peak-to-plateau ratio decrease, not considered in clinical treatment planning systems. MATERIALS AND METHODS: We present a degradation model implemented into an analytical dose calculation, fully integrated into a treatment planning workflow. Degradation effects were investigated on target dose, distal dose falloffs, and mean lung dose for ten patient cases with varying anatomical characteristics. RESULTS: For patients with pronounced range straggling (in our study large tumors, or lesions close to the mediastinum), degradation effects were restricted to a maximum decrease in target coverage (D 95 of the planning target volume) of 1.4%. The median broadening of the distal 80-20% dose falloffs was 0.5 mm at the maximum. For small target volumes deep inside lung tissue, however, the target underdose increased considerably by up to 26%. The mean lung dose was not negatively affected by degradation in any of the investigated cases. CONCLUSION: For most cases, dose degradation due to heterogeneous lung tissue did not yield critical organ at risk overdosing or overall target underdosing. However, for small and deep-seated tumors which can only be reached by penetrating lung tissue, we have seen substantial local underdose, which deserves further investigation, also considering other prevalent sources of uncertainty.

Active-Scanned Protons and Carbon Ions in Cancer Treatment of Patients With Cardiac Implantable Electronic Devices: Experience of a Single Institution.

Background: Ionizing radiation was shown to be able to influence the function of cardiac implantable electronic devices (CIED's) leading to malfunctions with potentially severe consequences. Those effects presumably correlate with beam energy and neutron production. Thus, particle facilities are commonly cautious to treat patients with CIED's with particles, but substantial evidence is lacking. Methods and Materials: In total 31 patients were investigated, who have been treated at the Heidelberg Ion-Beam Therapy Center (HIT) from September 2012 to February 2019 with protons and carbon ions in active-scanning technique. All CIED's were checked after every single irradiation by the department of cardiology. The minimum distance between the CIED and the planning target volume (PTV), the 10% isodose and the single beam in Beam's Eye View (BEV) was analyzed for 12 patients. Results: In total, 31 patients received 32 courses of radiotherapy (RT). Twenty-two received treatment with carbon ion beam and ten with proton beam. The cumulative number of fractions was 582, the cumulative number of documented controls after RT was 504 (87%). Three patients had an implantable cardioverter-defibrillator (ICD) and 28 patients had a pacemaker at the time of treatment. Seven patients had a heart rate of ≤30/min. The majority of patients (69%) were treated for tumors of the head and neck. The median minimum distance between CIED and PTV, 10% isodose and the single beam on BEV was 13.4, 11.6, and 8.3 cm, respectively. There were no registered events associated with the treatment in this evaluation. Conclusion: Treatment of CIED-patients with protons and carbon ions applied with active raster scanning technique was safe without any incidents in our single center experience. Monitoring after almost every fraction provided systematic and extensive data. Further investigations are necessary in order to form reliable guidelines, which should consider different modes of beam application, as active scanning supposedly provides a greater level of safety from malfunctions for patients with CIED undergoing particle irradiation.

High control rates of proton- and carbon-ion-beam treatment with intensity-modulated active raster scanning in 101 patients with skull base chondrosarcoma at the Heidelberg Ion Beam Therapy Center.

BACKGROUND: The current study compares the results of irradiation with protons and irradiation with carbon ions via a raster scan technique in patients with G1 and G2 skull base chondrosarcomas. METHODS: Between 2009 and 2014, a total of 101 patients (40 men and 61 women) with a median age of 44 years (range, 19-77 years) were irradiated with carbon ions (79 patients) or protons (22 patients) via a raster scan technique at the Heidelberg Ion Beam Therapy Center. The median total dose was 60 Gy (relative biological effectiveness [RBE]) at 3 Gy per fraction for carbon ions and 70 Gy (RBE) at 2 Gy per fraction for protons. The median boost planning target volume was 38 cm3 (range, 8-133 cm3 ). Overall survival (OS) and local control (LC) were evaluated with the Kaplan-Meier method. RESULTS: The median follow-up period was 40 months (range, 0.8-78.1 months). At the start of the irradiation, all patients had residual macroscopic tumors. Five patients (5%) developed a local recurrence during the follow-up. The 1-, 2-, and 4-year LC rates were 100%, 100%, and 100%, respectively, for protons and 98.6%, 97.2%, and 90.5%, respectively, for carbon ions. The OS rates during the same periods of time were 100%, 100%, and 100%, respectively, for protons and 100%, 98.5%, and 92.9%, respectively, for carbon ions. An age ≤ 44 years was associated with a trend for a better outcome. No toxicity worse than Common Toxicity Criteria grade 3 was observed after treatment. CONCLUSIONS: No significant difference between carbon ions and protons in the therapy of skull base chondrosarcoma could be detected in these initial retrospective results. Cancer 2018;124:2036-44. © 2018 American Cancer Society.

Inter-centre variability of CT-based stopping-power prediction in particle therapy: Survey-based evaluation.

BACKGROUND AND PURPOSE: Stopping-power ratios (SPRs) are used in particle therapy to calculate particle range in patients. The heuristic CT-to-SPR conversion (Hounsfield Look-Up-Table, HLUT), needed for treatment planning, depends on CT-scan and reconstruction parameters as well as the specific HLUT definition. To assess inter-centre differences in these parameters, we performed a survey-based qualitative evaluation, as a first step towards better standardisation of CT-based SPR derivation. MATERIALS AND METHODS: A questionnaire was sent to twelve particle therapy centres (ten from Europe and two from USA). It asked for details on CT scanners, image acquisition and reconstruction, definition of the HLUT, body-region specific HLUT selection, investigations of beam-hardening and experimental validations of the HLUT. Technological improvements were rated regarding their potential to improve SPR accuracy. RESULTS: Scan parameters and HLUT definition varied widely. Either the stoichiometric method (eight centres) or a tissue-substitute-only HLUT definition (three centres) was used. One centre combined both methods. The number of HLUT line segments varied widely between two and eleven. Nine centres had investigated influence of beam-hardening, often including patient-size dependence. Ten centres had validated their HLUT experimentally, with very different validation schemes. Most centres deemed dual-energy CT promising for improving SPR accuracy. CONCLUSIONS: Large inter-centre variability was found in implementation of CT scans, image reconstruction and especially in specification of the CT-to-SPR conversion. A future standardisation would reduce time-intensive institution-specific efforts and variations in treatment quality. Due to the interdependency of multiple parameters, no conclusion can be drawn on the derived SPR accuracy and its inter-centre variability.

Development of the open-source dose calculation and optimization toolkit matRad.

PURPOSE: We report on the development of the open-source cross-platform radiation treatment planning toolkit matRad and its comparison against validated treatment planning systems. The toolkit enables three-dimensional intensity-modulated radiation therapy treatment planning for photons, scanned protons and scanned carbon ions. METHODS: matRad is entirely written in Matlab and is freely available online. It re-implements well-established algorithms employing a modular and sequential software design to model the entire treatment planning workflow. It comprises core functionalities to import DICOM data, to calculate and optimize dose as well as a graphical user interface for visualization. matRad dose calculation algorithms (for carbon ions this also includes the computation of the relative biological effect) are compared against dose calculation results originating from clinically approved treatment planning systems. RESULTS: We observe three-dimensional γ-analysis pass rates ≥ 99.67% for all three radiation modalities utilizing a distance to agreement of 2 mm and a dose difference criterion of 2%. The computational efficiency of matRad is evaluated in a treatment planning study considering three different treatment scenarios for every radiation modality. For photons, we measure total run times of 145 s-1260 s for dose calculation and fluence optimization combined considering 4-72 beam orientations and 2608-13597 beamlets. For charged particles, we measure total run times of 63 s-993 s for dose calculation and fluence optimization combined considering 9963-45574 pencil beams. Using a CT and dose grid resolution of 0.3 cm3 requires a memory consumption of 1.59 GB-9.07 GB and 0.29 GB-17.94 GB for photons and charged particles, respectively. CONCLUSION: The dosimetric accuracy, computational performance and open-source character of matRad encourages a future application of matRad for both educational and research purposes.

Acute Toxicity and Quality of Life in Patients With Prostate Cancer Treated With Protons or Carbon Ions in a Prospective Randomized Phase II Study--The IPI Trial.

PURPOSE: The purpose of this study was to compare safety and feasibility of proton therapy with that of carbon ion therapy in hypofractionated raster-scanned irradiation of the prostate, in a prospective randomized phase 2 trial. METHODS AND MATERIALS: In this trial, 92 patients with localized prostate cancer were enrolled. Patients were randomized to receive either proton therapy (arm A) or carbon ion therapy (arm B) and treated with a total dose of 66 Gy(relative biological effectiveness [RBE]) administered in 20 fractions (single dose of 3.3 Gy[RBE]). Patients were stratified by the use of antihormone therapy. Primary endpoint was the combined assessment of safety and feasibility. Secondary endpoints were specific toxicities, prostate-specific antigen progression-free survival (PFS), overall survival (OS), and quality of life (QoL). RESULTS: Ninety-one patients completed therapy and have had a median follow-up of 22.3 months. Among acute genitourinary toxicities, grade 1 cystitis rates were 34.1% (39.1% in A; 28.9% in B) and 17.6% grade 2 (21.7% in A; 13.3% in B). Seven patients (8%) required urinary catheterization during treatment due to urinary retention, 5 of whom were in arm A. Regarding acute gastrointestinal toxicities, 2 patients treated with protons developed grade 3 rectal fistulas. Grade 1 radiation proctitis occurred in 12.1% (13.0% in A; 11.1% in B) and grade 2 in 5.5% (8.7% in A; 2.2% in B). No statistically significant differences in toxicity profiles between arms were found. Reduced QoL was evident mainly in fatigue, pain, and urinary symptoms during therapy and 6 weeks thereafter. All European Organization for Research and Treatment of Cancer QLQ-C30 and -PR25 scores improved during follow-up. CONCLUSIONS: Hypofractionated irradiation using either carbon ions or protons results in comparable acute toxicities and QoL parameters. We found that hypofractionated particle irradiation is feasible and may be safe. Due to the occurrence of gel in the rectal wall and the consecutive occurrence of 2 rectal fistulas, we stopped using the insertion of spacer gel. Longer follow-up is necessary for evaluation of PFS and OS. (Ion Prostate Irradiation (IPI); NCT01641185; ClinicalTrials.gov.).

Carbon ion beam treatment in patients with primary and recurrent sacrococcygeal chordoma.

PURPOSE: The purpose of this work was to evaluate the results of high-dose radiation treatment using carbon ion therapy, alone or combined with intensity-modulated radiation treatment (IMRT), in patients with sacral chordoma. MATERIALS AND METHODS: Between 2009 and 2012, 56 patients with sacral chordoma were treated in our center. The tumor was located above S3 in 33 patients and in S3 or below in 23 patients. In all, 41 patients received radiation therapy for the primary tumor, while 15 patients were treated for the recurrent tumor. Toxicity was measured using NCI CTCAE v.4.03. Local control (LC) and overall survival (OS) were evaluated with the Kaplan-Meier method. RESULTS: A total of 23 patients were irradiated with carbon ions in combination with photon IMRT, while 33 received carbon ion therapy only. Forty-three patients had a macroscopic tumor at treatment start with a median tumor size (GTV) of 244 ml (range 5-1188 ml). The median total dose was 66 Gy (range 60-74 Gy; RBE). After a median follow-up time of 25 months, the 2- and 3-year local control probability was 76 % and 53 %, respectively. The overall survival rate was 100 %. Treatment for primary tumor and male patients resulted in significant better local control. No higher toxicity occurred within the follow-up time. CONCLUSION: High-dose photon/carbon ion beam radiation therapy is safe and, especially for primary sacral chordomas, highly effective. A randomized trial is required to evaluate the role of primary definitive hypofractionated particle therapy compared with surgery with or without adjuvant radiotherapy.