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.

Consolidative mediastinal irradiation of malignant lymphoma using active scanning proton beams: clinical outcome and dosimetric comparison.

PURPOSE: Current research approaches in lymphoma focus on reduction of therapy-associated long-term side effects. Especially in mediastinal lymphoma, proton beam radiotherapy (PT) may be a promising approach for reducing the dose to organs at risk (OAR). PATIENTS: In total, 20 patients were irradiated with active scanning PT at Heidelberg Ion Beam Therapy Center (HIT) between September 2014 and February 2017. For comparative analysis, additional photon irradiation plans with helical intensity-modulated radiotherapy (IMRT) were calculated and quantitative and qualitative dose evaluations were made for both treatment modalities. Toxicity and survival outcomes were evaluated. RESULTS: Clinical target volume coverage was comparable in both treatment modalities and did not significantly differ between IMRT and PT. Nevertheless, PT showed superiority regarding the homogeneity index (HIPT = 1.041 vs. HIIMRT = 1.075, p < 0.001). For all OAR, PT showed significantly higher dose reductions compared with IMRT. In particular, the dose to the heart was reduced in PT (absolute dose reduction of Dmean of 3.3 Gy [all patients] and 4.2 Gy [patients with pericardial involvement]). Likewise, the subgroup analysis of female patients, who were expected to receive higher doses to the breast, showed a higher dose reduction in Dmean of 1.2 Gy (right side) and 2.2 Gy (left side). After a median follow-up of 32 months (range 21-48 months), local and distant progression free survival (LPFS and DPFS) were 95.5% and 95.0%, respectively. Radiotherapy was tolerated well with only mild (grade 1-2) radiation-induced acute and chronic side effects. CONCLUSION: A significant reduction in the dose to the surrounding OAR was achieved with PT compared with photon irradiation, without compromising target volume coverage. Dosimetric advantages may have the potential to translate into a reduction of long-term radiation-induced toxicity in young patients with malignant lymphoma of the mediastinum.

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.

Dosimetric comparison of advanced radiotherapy approaches using photon techniques and particle therapy in the postoperative management of thymoma.

BACKGROUND: The purpose of this study was to compare dosimetric differences related to target volume and organs-at-risk (OAR) using 3D-conformal radiotherapy (3DCRT), volumetric modulated arc therapy (VMAT), TomoTherapy (Tomo), proton radiotherapy (PRT), and carbon ion radiotherapy (CIRT) as part of postoperative thymoma irradiation. MATERIAL AND METHODS: This single-institutional analysis included 10 consecutive patients treated with adjuvant radiotherapy between December 2013 and September 2016. CT-datasets and respective RT-structures were anonymized and plans for all investigated RT modalities (3DCRT, VMAT, Tomo, PRT, CIRT) were optimized for a total dose of 50 Gy in 25 fractions. Comparisons between target volume and OAR dosimetric parameters were performed using the Wilcoxon rank-sum test. RESULTS: The best target volume coverage (mean PTV V95% for all patients) was observed for Tomo (97.9%), PRT (97.6%), and CIRT (96.6%) followed by VMAT (85.4%) and 3DCRT (74.7%). PRT and CIRT both significantly reduced mean doses to the lungs, breasts, heart, and esophagus, as well as the spinal cord maximum dose compared with photon modalities. Among photon-based techniques, VMAT showed improved OAR sparing over 3DCRT. Tomo was associated with considerable low-dose exposure to the lungs, breasts, and heart. CONCLUSIONS: Particle radiotherapy (PRT, CIRT) showed superior OAR sparing and optimal target volume coverage. The observed dosimetric advantages are expected to reduce toxicity rates. However, their clinical impact must be investigated prospectively.

Combined intensity-modulated radiotherapy plus raster-scanned carbon ion boost for advanced adenoid cystic carcinoma of the head and neck results in superior locoregional control and overall survival.

BACKGROUND: Local control in patients with adenoid cystic carcinoma (ACC) of the head and neck remains a challenge because of the relative radioresistance of these tumors. This prospective carbon ion pilot project was designed to evaluate the efficacy and toxicity of intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost (C12 therapy). The authors present the first analysis of long-term outcomes of raster-scanned C12 therapy compared with modern photon techniques. METHODS: Patients with inoperable or subtotally resected ACC received C12 therapy within the pilot project. Whenever C12 was not available, patients were offered IMRT or fractionated stereotactic radiotherapy (FSRT). Patients received either C12 therapy at a C12 dose of 3 Gray equivalents (GyE) per fraction up to 18 GyE followed by 54 Gray (Gy) of IMRT or IMRT up to a median total dose of 66 Gy. Toxicity was evaluated according to version 3 of the Common Toxicity Terminology for Adverse Events. Locoregional control (LC), progression-free survival (PFS), and overall survival (OS) were analyzed using the Kaplan-Meier method. RESULTS: Fifty-eight patients received C12 therapy, and 37 received photons (IMRT or FSRT). The median follow-up was 74 months in the C12 group and 63 months in the photon group. Overall, 90% of patients in the C12 group and 94% of those in the photon group had T4 tumors; and the most common disease sites were paranasal sinus, parotid with skull base invasion, and nasopharynx. LC, PFS, and OS at 5 years were significantly higher in the C12 group (59.6%, 48.4%, 76.5%, respectively) compared with the photon group (39.9%, 27%, and 58.7%, respectively). There was no significant difference between patients who had subtotally resected and inoperable ACC. CONCLUSIONS: C12 therapy resulted in superior LC, PFS, and OS without a significant difference between patients with inoperable and partially resected ACC. Extensive and morbid resections in patients with advanced ACC may need to be reconsidered. The most common site of locoregional recurrence remains in field, and further C12 dose escalation should be evaluated.

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.

Highly effective treatment of skull base chordoma with carbon ion irradiation using a raster scan technique in 155 patients: first long-term results.

BACKGROUND: The current study was conducted to evaluate the long-term results of irradiation with carbon ions in a raster scanning technique in patients with skull base chordomas. METHODS: Between 1998 and 2008, a total of 155 patients (76 men and 79 women) with a median age of 48 years (range, 15 years-85 years) were irradiated with carbon ions using a raster scan technique. The irradiation was performed at the Society for Heavy Ion Research in Darmstadt, Germany. The median total dose was 60 gray (relative biological effectiveness) at 3 gray (relative biological effectiveness) per fraction. The median boost planning target volume was 70 mL (range, 2 mL-294 mL). Local control (LC) and overall survival (OS) were evaluated using the Kaplan-Meier method, whereas long-term toxicity was evaluated via questionnaires. RESULTS: The median follow-up was 72 months (range, 12 months-165 months). All patients had residual macroscopic tumors at the initiation of radiotherapy. The authors observed 55 local recurrences during follow-up, as well as systemic disease progression in 4 patients. The resulting 3-year, 5-year, and 10-year LC rates were 82%, 72%, and 54%, respectively, whereas the 3-year, 5-year, and 10-year OS rates were 95%, 85%, and 75%, respectively. Age <48 years and a boost volume >75 mL were associated with a significantly improved LC and OS. Primary treatment resulted in a significantly better OS probability. No higher late toxicity could be detected after carbon ion treatment. CONCLUSIONS: Carbon ion therapy appears to be a safe and effective treatment for patients with skull base chordoma, resulting in high LC and OS rates.

High control rate in patients with chondrosarcoma of the skull base after carbon ion therapy: first report of long-term results.

BACKGROUND: The current study was performed to evaluate the safety and effectiveness of irradiation with carbon ions using raster scanning as well as prognostic factors in patients with skull base chondrosarcomas. METHODS: Between 1998 and 2008, 79 patients with chondrosarcoma of the skull base were treated using carbon ions in raster scanning. The applied median total dose was 60 gray equivalent (GyE) at 3 GyE per fraction. Local control and overall survival (OS) were evaluated using the Kaplan-Meier method. Long-term toxicity was quantitatively assessed using questionnaires. RESULTS: The median follow-up after irradiation was 91 months (range, 3 months-175 months). Within the follow-up, 10 patients developed local disease recurrence. The 3-year, 5-year, and 10-year local control rates were 95.9%, 88%, and 88%, respectively; the corresponding OS rates were 96.1%, 96.1%, and 78.9%, respectively. With a median follow-up of 110 months after first diagnosis, the corresponding 3-year, 5-year, and 10-year OS rates were 97.5%, 97.5%, and 91.5%, respectively. Age ≤ 45 years and boost volume ≤ 55 mL were associated with significantly better local control rates. We observed a clinically relevant improvement in cranial nerve deficits 7 to 10 years after treatment (range, 45.5%-53.3%) compared with the baseline (73.4%). During follow-up, none of the patients in the current study developed a secondary malignancy. CONCLUSIONS: Carbon ion therapy is a safe and effective treatment in patients with chondrosarcoma of the skull base. For further evaluation, a prospective randomized phase 3 trial comparing protons versus carbon ions has been recruiting patients with low-grade and intermediate-grade chondrosarcoma of the skull base since 2009.

Development and validation of MonteRay, a fast Monte Carlo dose engine for carbon ion beam radiotherapy.

BACKGROUND: Monte Carlo (MC) simulations are considered the gold-standard for accuracy in radiotherapy dose calculation; so far however, no commercial treatment planning system (TPS) provides a fast MC for supporting clinical practice in carbon ion therapy. PURPOSE: To extend and validate the in-house developed fast MC dose engine MonteRay for carbon ion therapy, including physical and biological dose calculation. METHODS: MonteRay is a CPU MC dose calculation engine written in C++ that is capable of simulating therapeutic proton, helium and carbon ion beams. In this work, development steps taken to include carbon ions in MonteRay are presented. Dose distributions computed with MonteRay are evaluated using a comprehensive validation dataset, including various measurements (pristine Bragg peaks, spread out Bragg peaks in water and behind an anthropomorphic phantom) and simulations of a patient plan. The latter includes both physical and biological dose comparisons. Runtimes of MonteRay were evaluated against those of FLUKA MC on a standard benchmark problem. RESULTS: Dosimetric comparisons between MonteRay and measurements demonstrated good agreement. In terms of pristine Bragg peaks, mean errors between simulated and measured integral depth dose distributions were between -2.3% and +2.7%. Comparing SOBPs at 5, 12.5 and 20 cm depth, mean absolute relative dose differences were 0.9%, 0.7% and 1.6% respectively. Comparison against measurements behind an anthropomorphic head phantom revealed mean absolute dose differences of 1.2 % ± 1.1 % $1.2\% \pm 1.1\;\%$ with global 3%/3 mm 3D-γ passing rates of 99.3%, comparable to those previously reached with FLUKA (98.9%). Comparisons against dose predictions computed with the clinical treatment planning tool RayStation 11B for a meningioma patient plan revealed excellent local 1%/1 mm 3D-γ passing rates of 98% for physical and 94% for biological dose. In terms of runtime, MonteRay achieved speedups against reference FLUKA simulations ranging from 14× to 72×, depending on the beam's energy and the step size chosen. CONCLUSIONS: Validations against clinical dosimetric measurements in homogeneous and heterogeneous scenarios and clinical TPS calculations have proven the validity of the physical models implemented in MonteRay. To conclude, MonteRay is viable as a fast secondary MC engine for supporting clinical practice in proton, helium and carbon ion radiotherapy.

Ultra-High Dose Rate Helium Ion Beams: First In Vivo Evidence for Neuroprotective FLASH Effect.

Purpose: To investigate ultra-high-dose rate helium ion irradiation and its potential FLASH sparing effect with the endpoint acute brain injury in preclinical in vivo settings. Material and methods: Raster-scanned helium ion beams were administered to explore and compare the impact of dose rate variations between standard dose rate (SDR at 0.2 Gy/s) and FLASH (at 141 Gy/s) radiotherapy (RT). Irradiation-induced brain injury was investigated in healthy C57BL/6 mice via DNA damage response kinetic studies using nuclear γH2AX as a surrogate for double-strand breaks (DSB). The integrity of the neurovascular and immune compartments was assessed via CD31+ microvascular density and microglia/macrophages activation. Iba1+ ramified and CD68+ phagocytic microglia/macrophages were quantified, together with the expression of inducible nitric oxide synthetase (iNOS). Results: Helium FLASH RT significantly prevented acute brain tissue injury compared with SDR. This was demonstrated by reduced levels of DSB and structural preservation of the neurovascular endothelium after FLASH RT. Moreover, FLASH RT exhibited reduced activation of neuroinflammatory signals compared with SDR, as detected by quantification of CD68+ iNOS+ microglia/macrophages. Conclusion: To our knowledge, this is the first report on the FLASH-sparing neuroprotective effect of raster scanning helium ion radiotherapy in vivo.

Understanding Relative Biological Effectiveness and Clinical Outcome of Prostate Cancer Therapy Using Particle Irradiation: Analysis of Tumor Control Probability With the Modified Microdosimetric Kinetic Model.

PURPOSE: Recent experimental studies and clinical trial results might indicate that-at least for some indications-continued use of the mechanistic model for relative biological effectiveness (RBE) applied at carbon ion therapy facilities in Europe for several decades (LEM-I) may be unwarranted. We present a novel clinical framework for prostate cancer treatment planning and tumor control probability (TCP) prediction based on the modified microdosimetric kinetic model (mMKM) for particle therapy. METHODS AND MATERIALS: Treatment plans of 91 patients with prostate tumors (proton: 46, carbon ions: 45) applying 66 GyRBE [RBE = 1.1 for protons and LEM-I, (α/ß)x = 2.0 Gy, for carbon ions] in 20 fractions were recalculated using mMKM [(α/ß)x = 3.1 Gy]). Based solely on the response data of photon-irradiated patient groups stratified according to risk and usage of androgen deprivation therapy, we derived parameters for an mMKM-based Poisson-TCP model. Subsequently, new carbon and helium ion plans, adhering to prescribed biological dose criteria, were generated. These were systematically compared with the clinical experience of Japanese centers employing an analogous fractionation scheme and existing proton plans. RESULTS: mMKM predictions suggested significant biological dose deviation between the proton and carbon ion arms. Patients irradiated with protons received (3.25 ± 0.08) GyRBEmMKM/Fx, whereas patients treated with carbon ions received(2.51 ± 0.05) GyRBEmMKM/Fx. TCP predictions were (86 ± 3)% for protons and (52 ± 4)% for carbon ions, matching the clinical outcome of 85% and 50%. Newly optimized carbon ion plans, guided by the mMKM/TCP model, effectively replicated clinical data from Japanese centers. Using mMKM, helium ions exhibited similar target coverage as proton and carbon ions and improved rectum and bladder sparing compared with proton. CONCLUSIONS: Our mMKM-based model for prostate cancer treatment planning and TCP prediction was validated against clinical data for proton and carbon ion therapy, and its application was extended to helium ion therapy. Based on the data presented in this work, mMKM seems to be a good candidate for clinical biological calculations in carbon ion therapy for prostate cancer.

Exploring Helium Ions' Potential for Post-Mastectomy Left-Sided Breast Cancer Radiotherapy.

Proton therapy presents a promising modality for treating left-sided breast cancer due to its unique dose distribution. Helium ions provide increased conformality thanks to a reduced lateral scattering. Consequently, the potential clinical benefit of both techniques was explored. An explorative treatment planning study involving ten patients, previously treated with VMAT (Volumetric Modulated Arc Therapy) for 50 Gy in 25 fractions for locally advanced, node-positive breast cancer, was carried out using proton pencil beam therapy with a fixed relative biological effectiveness (RBE) of 1.1 and helium therapy with a variable RBE described by the mMKM (modified microdosimetric kinetic model). Results indicated that target coverage was improved with particle therapy for both the clinical target volume and especially the internal mammary lymph nodes compared to VMAT. Median dose value analysis revealed that proton and helium plans provided lower dose on the left anterior descending artery (LAD), heart, lungs and right breast than VMAT. Notably, helium therapy exhibited improved ipsilateral lung sparing over protons. Employing NTCP models as available in the literature, helium therapy showed a lower probability of grade ≤ 2 radiation pneumonitis (22% for photons, 5% for protons and 2% for helium ions), while both proton and helium ions reduce the probability of major coronary events with respect to VMAT.

Robustness of carbon-ion radiotherapy against DNA damage repair associated radiosensitivity variation based on a biophysical model.

BACKGROUND: Interpatient variation of tumor radiosensitivity is rarely considered during the treatment planning process despite its known significance for the therapeutic outcome. PURPOSE: To apply our mechanistic biophysical model to investigate the biological robustness of carbon ion radiotherapy (CIRT) against DNA damage repair interference (DDRi) associated patient-to-patient variability in radiosensitivity and its potential clinical advantages against conventional radiotherapy approaches. METHODS AND MATERIALS: The "UNIfied and VERSatile bio response Engine" (UNIVERSE) was extended by carbon ions and its predictions were compared to a panel of in vitro and in vivo data including various endpoints and DDRi settings within clinically relevant dose and linear energy transfer (LET) ranges. The implications of UNIVERSE predictions were then assessed in a clinical patient scenario considering DDRi variance. RESULTS: UNIVERSE tests well against the applied benchmarks. While in vitro survival curves were predicted with an R2 > 0.92, deviations from in vivo RBE data were less than 5.6% The conducted paradigmatic patient plan study implies a markedly reduced significance of DDRi based radiosensitivity variability in CIRT (13% change of D 50 ${{D}_{50}}$ in target) compared to conventional radiotherapy (62%) and that boosting the LET within the target further amplifies this robustness of CIRT (8%). In the case of heightened tumor radiosensitivity, a dose de-escalation strategy for photons allows a reduction of the maximum effective dose within the normal tissue (NT) from a D 2 ${{D}_2}$ of 2.65 to 1.64 Gy, which lies below the level found for CIRT ( D 2 ${{D}_2}$  = 2.41 Gy) for the analyzed plan and parameters. However, even after de-escalation, the integral effective dose in the NT is found to be substantially higher for conventional radiotherapy in comparison to CIRT ( D m e a n ${{D}_{mean}}$ of 0.75, 0.46, and 0.24 Gy for the conventional plan, its de-escalation and CIRT, respectively). CONCLUSIONS: The framework offers adequate predictions of in vitro and in vivo radiation effects of CIRT while allowing the consideration of DRRi based solely on parameters derived from photon data. The results of the patient planning study underline the potential of CIRT to minimize important sources of interpatient divergence in therapy outcome, especially when combined with techniques that allow to maximize the LET within the tumor. Despite the potential of de-escalation strategies for conventional radiotherapy to reduce the maximum effective dose in the NT, CIRT appears to remain a more favorable option due to its ability to reduce the integral effective dose within the NT.

Combined Photon and Carbon Ion Radiation Therapy for Sinonasal Malignancies: Results of the HIT-SNT Prospective Phase 2 Trial.

PURPOSE: Radiation treatment of sinonasal malignancies is a challenging task due to proximity to critical structures of the head and neck and skull base. Local tumor control is highly dose-dependent, but dose application is limited due to accompanying toxicity and dose constraints. To evaluate the toxicity and efficacy of combined radiation treatment with intensity-modulated radiation therapy (IMRT) and carbon ion boost, we conducted a prospective phase 2 IMRT-Heidelberg Ion-Beam Therapy Sinonasal Tumors (HIT-SNT) trial. METHODS AND MATERIALS: Between 2011 and 2019, we treated 35 patients with histologically proven, incompletely resected or inoperable adeno- (51%) or squamous cell carcinoma (49%) of the paranasal sinuses with combined IMRT (50 Gy) and carbon ion boost (24 Gy relative biologic effectiveness) to a total dose of 74 Gy. RESULTS: Acute mucositis Common Terminology Criteria for Adverse Events (CTCAE) grade 3 occurred in 12% of patients (n = 4) and was accompanied by odynophagia CTCAE grade 3. Except for 1 case of grade 3 weight loss, no other acute high-grade toxicity (grade 3-4) was observed. In a small patient cohort of 15 patients eligible for long-term follow-up we have seen no high-grade (grade ≥3) long-term side effects 2 years after radiation therapy. None of these patients suffered from therapy-associated vision or hearing loss. Secondary endpoints were 2-year overall survival, 2-year local progression-free survival, 2-year progression-free survival, and 2-year metastases-free survival with 79.4%, 61.8%, 61.8%, and 64.8%, respectively. CONCLUSIONS: To our knowledge, this is the first prospective data on toxicity and outcome of bimodal radiation therapy for the rare entity of sinonasal malignancies. Our study shows a low rate of CTCAE-reported acute toxicity with reasonable tumor control and survival rates after bimodal radiation therapy, which therefore remains a therapy approach to be further evaluated.

Helium Ion Therapy for Advanced Juvenile Nasopharyngeal Angiofibroma.

Helium ion therapy (HRT) is a promising modality for the treatment of pediatric tumors and those located close to critical structures due to the favorable biophysical properties of helium ions. This in silico study aimed to explore the potential benefits of HRT in advanced juvenile nasopharyngeal angiofibroma (JNA) compared to proton therapy (PRT). We assessed 11 consecutive patients previously treated with PRT for JNA in a definitive or postoperative setting with a relative biological effectiveness (RBE) weighted dose of 45 Gy (RBE) in 25 fractions at the Heidelberg Ion-Beam Therapy Center. HRT plans were designed retrospectively for dosimetric comparisons and risk assessments of radiation-induced complications. HRT led to enhanced target coverage in all patients, along with sparing of critical organs at risk, including a reduction in the brain integral dose by approximately 27%. In terms of estimated risks of radiation-induced complications, HRT led to a reduction in ocular toxicity, cataract development, xerostomia, tinnitus, alopecia and delayed recall. Similarly, HRT led to reduced estimated risks of radiation-induced secondary neoplasms, with a mean excess absolute risk reduction of approximately 30% for secondary CNS malignancies. HRT is a promising modality for advanced JNA, with the potential for enhanced sparing of healthy tissue and thus reduced radiation-induced acute and long-term complications.

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%.

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).

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

UNLABELLED: 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.

Development and benchmarking of the first fast Monte Carlo engine for helium ion beam dose calculation: MonteRay.

BACKGROUND: Monte Carlo (MC) simulations are considered the gold-standard for accuracy in radiotherapy dose calculation; however, general purpose MC engines are computationally demanding and require long runtimes. For this reason, several groups have recently developed fast MC systems dedicated mainly to photon and proton external beam therapy, affording both speed and accuracy. PURPOSE: To support research and clinical activities at the Heidelberg Ion-beam Therapy Center (HIT) with actively scanned helium ion beams, this work presents MonteRay, the first fast MC dose calculation engine for helium ion therapy. METHODS: MonteRay is a CPU MC dose calculation engine written in C++, capable of simulating therapeutic proton and helium ion beams. In this work, development steps taken to include helium ion beams in MonteRay are presented. A detailed description of the newly implemented physics models for helium ions, for example, for multiple coulomb scattering and inelastic nuclear interactions, is provided. MonteRay dose computations of helium ion beams are evaluated using a comprehensive validation dataset, including measurements of spread-out Bragg peaks (SOBPs) with varying penetration depths/field sizes, measurements with an anthropomorphic phantom and FLUKA simulations of a patient plan. Improvement in computational speed is demonstrated in comparison against reference FLUKA simulations. RESULTS: Dosimetric comparisons between MonteRay and measurements demonstrated good agreement. Comparing SOBPs at 5, 12.5, and 20 cm depth, mean absolute percent dose differences were 0.7%, 0.7%, and 1.4%, respectively. Comparison against measurements behind an anthropomorphic head phantom revealed mean absolute dose differences of about 1.2% (FLUKA: 1.5%) with per voxel errors ranging from -4.5% to 4.1% (FLUKA: -6% to 3%). Computed global 3%/3 mm 3D-gamma passing rates of ∼99% were achieved, exceeding those previously reported for an analytical dose engine. Comparisons against FLUKA simulations for a patient plan revealed local 2%/2 mm 3D-gamma passing rates of 98%. Compared to FLUKA in voxelized geometries, MonteRay saw run-time reductions ranging from 20× to 60×, depending on the beam's energy. CONCLUSIONS: MonteRay, the first fast MC engine dedicated to helium ion therapy, has been successfully developed with a focus on both speed and accuracy. Validations against dosimetric measurements in homogeneous and heterogeneous scenarios and FLUKA MC calculations have proven the validity of the physical models implemented. Timing comparisons have shown significant speedups between 20 and 60 when compared to FLUKA, making MonteRay viable for clinical routine. MonteRay will support research and clinical practice at HIT, for example, TPS development, validation and treatment design for upcoming clinical trials for raster-scanned helium ion therapy.

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

PURPOSE: To analyze the dose objectives and constraints applied at the prospective phase II PACK-study at Heidelberg ion therapy center (HIT) for different radiobiological models. METHODS: Treatment 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). RESULTS: Only two patients showed a LETd98% in the GTV greater than 44 keV/µm. A HIT-dose constraint to the GI of [Formula: see text] 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. CONCLUSION: The 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.