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%.

Intensity-modulated radiotherapy for the management of primary and recurrent chordomas: a retrospective long-term follow-up study.

Background: Chordomas have a high risk of recurrence. Radiotherapy (RT) is required as adjuvant therapy after resection. Sufficient radiation doses for local control (LC) can be achieved using either particle therapy, if this technology is available and feasible, or intensity-modulated radiotherapy. Materials and methods: 57 patients (age, 11.8-81.6 years) with chordomas of the skull base, spine and pelvis who received photon radiotherapy between 1995 and 2017 were enrolled in the study. Patients were treated at the time of initial diagnosis (68.4%) or during recurrence (31.6%). 44 patients received adjuvant radiotherapy and 13 received definitive radiotherapy. The median total dose to the physical target volume was 70 Gy equivalent dose in 2 Gy fractions (EQD2) (range: 54.7-82.5) in 22-36 fractions. Results: LC was 76.4%, 58.4%, 46.7% and 39.9% and overall survival (OS) was 98.3%, 89%, 76.9% and 47.9% after 1, 3, 5 and 10 years, respectively, with a median follow-up period of 6.5 years (range, 0.5-24.3 years). Age, dose and treatment concept (post-operative or definitive) were significant prognostic factors for OS. Primary treatment, macroscopic tumour at RT and size of the irradiated volume were statistically significant prognostic factors for LC. Conclusion: Photon treatment is a safe and effective treatment for chordomas if no particle therapy is available. The best results can be achieved against primary tumours if the application of curative doses is possible due to organs at risk in direct proximity. We recommend high-dose radiotherapy, regardless of the resection status, as part of the initial treatment of chordoma, using the high conformal radiation technique if particle therapy is not feasible.

Geriatric Radiation Oncology: What We Know and What Can We Do Better?

Elderly patients represent a growing subgroup of cancer patients for whom the role of radiation therapy is poorly defined. Older patients are still clearly underrepresented in clinical trials, resulting in very limited high-level evidence. Moreover, elderly patients are less likely to receive radiation therapy in similar clinical scenarios compared to younger patients. However, there is no clear evidence for a generally reduced radiation tolerance with increasing age. Modern radiation techniques have clearly reduced acute and late side effects, thus extending the boundaries of the possible regarding treatment intensity in elderly or frail patients. Hypofractionated regimens have further decreased the socioeconomic burden of radiation treatments by reducing the overall treatment time. The current review aims at summarizing the existing data for the use of radiation therapy or chemoradiation in elderly patients focusing on the main cancer types. It provides an overview of treatment tolerability and outcomes with current standard radiation therapy regimens, including possible predictive factors in the elderly population. Strategies for patient selection for standard or tailored radiation therapy approaches based on age, performance score or comorbidity, including the use of prediction tests or geriatric assessments, are discussed. Current and future possibilities for improvements of routine care and creation of high-level evidence in elderly patients receiving radiation therapy are highlighted.

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.

The role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma.

BACKGROUND: To investigate the role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma; final analysis of a one-armed, single center phase I/II trial. METHODS: Between August 2011 until September 2018, 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) inoperable pelvic (70%) or craniofacial (30%) osteosarcoma were treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) and followed until May 2019. A Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed before CIBRT in search for a prognostic factor. The primary endpoint was toxicity. Secondary endpoints included treatment response, global, local and distant progression free survival (PFS, LPFS and DPFS) and overall (OS), among others. RESULTS: The median age was 20; all patients finished treatment per protocol. LPFS, DPFS, PFS and OS were 73%, 74%, 60% and 75% after one year and 55%, 65% 65.3%, 45% and 68% after two years, respectively. The median clinical target volume (CTV) was 1042 cc and 415 cc for the primary and boost plan, respectively. Craniofacial localization, lower uptake of FDG in PET/CT and boost plan CTV ≤ median were associated with improved overall survival (p = 0.039, p = 0.016 and p = 0.0043, respectively). No acute toxicities > grade III were observed. We observed one case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss. CONCLUSION: CIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma.

High-dose carbon-ion based radiotherapy of primary and recurrent sacrococcygeal chordomas: long-term clinical results of a single particle therapy center.

BACKGROUND: This study aimed to analyze the oncological long-term results and late toxicity of carbon ion-based radiotherapy (RT) of patients with sacral chordoma and to identify potential prognostic factors for local control (LC) and overall survival (OS). METHODS: A total of 68 patients with sacral chordoma treated at the Heidelberg Ion Beam Therapy Center were included in this study. Of these 52 patients (77%) received a primary RT and 16 patients (23%) received a RT in a recurrent situation. All patients were treated with carbon ion RT (CIRT), either in combination with photons (n = 22; 32%) or as a monotherapy (n = 46; 68%), with a median radiation dose of 66 Gy RBE (range 60-74 Gy). In 40 patients (59%), RT was performed in the postoperative situation. Postoperative care included regular MRI scans. Local progression was defined as an enlargement of the maximum tumor diameter by 10% or a new tumor growth within the planning target volume (PTV). LC and OS were determined using the Kaplan-Meier method. Furthermore, the relevance of various prognostic factors for LC and OS was assessed by univariate and multivariate analysis. RESULTS: The median follow-up period was 60 months (range 1.3-97.4 months). The 5-year rates for LC, progression-free survival, metastasis-free survival and OS were 53, 53, 52 and 74%, respectively. Local recurrence was observed in 31 patients (46%), occurring after a median follow-up time of 25 months (range 2.5-73.1 months). Only 10% of local recurrences occurred later than 5 years after RT. Statistical analysis showed that RT in the relapse situation corresponded to inferior LC rates compared to the primary situation, while other factors such as the GTV, radiation dose (EQD2) and treatment approach (CIRT alone vs. CIRT combined with photons) were insignificant. For OS after RT, patient age and PTV size proved to be significant predictors. The incidence of late toxicity ≥ III° according to CTCAE v5.0 was 21%. Sacral insufficiency fractures occurred in 49% of patients (maximum III°: 16%) and were thus by far the most frequent late side effect in our analysis. Radiogenic damage to the peripheral nerves, intestinal tract and skin was observed in only 9% (≥ III°: 5%), 3% (all II°) and 9% (all I°) of patients. CONCLUSION: Our analysis showed only moderate long-term LC rates after carbon ion-based RT, with sacral chordomas having a particularly poor prognosis in the recurrent situation. Therefore, future studies should evaluate the safety and effectiveness of further dose escalation and hypofractionation of RT in sacral chordoma and weight potential benefits of dose escalation against side effects.

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.

Results of a combination treatment with intensity modulated radiotherapy and active raster-scanning carbon ion boost for adenoid cystic carcinoma of the minor salivary glands of the nasopharynx.

OBJECTIVES: We aimed to present the first clinical results for adenoid cystic carcinoma (ACC) of the nasopharynx after primary radiotherapy (RT) with the focus on local control (LC) and patterns of recurrence. MATERIALS AND METHODS: We retrospectively analyzed 59 patients with ACC of the nasopharynx, who were treated with bimodal radiotherapy (RT) consisting of intensity modulated radiotherapy and carbon ion boost at the Heidelberg Ion-Beam Therapy Center between 2009 and 2018. The patients had predominantly inoperable (n = 42, 72%) or incompletely resected (n = 17, 29%) tumors. Kaplan-Meier estimates and the log-rank (Mantel-Cox) test were used for univariate and multivariate analyses. RESULTS: The median follow-up was 32 months. At last follow-up, 67% of the patients were still alive (n = 39/58), of whom 74% were free of progression (n = 29/39). The 2-year LC, distant progression-free survival (DPFS) and overall survival (OS) were 83%, 81%, 87% and the estimated 5-year LC, DPFS and OS were 49%, 54%, 69%, respectively. LC was significantly inferior in patients with large tumor volumes (gross tumor volume, GTV > 100 cc, p = 0.020) and T4 tumors (p = 0.021). The majority of the recurrences occurred at the margin, where critical structures were spared (n = 11/19, 58%). Overall, grade 3 toxicity was moderate with 12% acute and 8% late side effects. CONCLUSION: Bimodal RT including active raster-scanning carbon ion boost for nasopharyngeal ACC resulted in adequate LC and OS rates with moderate toxicity. T4 stage, large tumor volume and the necessary dose sparing in critical structures, i.e. optic nerves, brain stem and orbit, negatively affected LC.

Accelerated Hypofractionated Active Raster-Scanned Carbon Ion Radiotherapy (CIRT) for Laryngeal Malignancies: Feasibility and Safety.

(1) Background: The authors present the first results of active raster-scanned carbon ion radiotherapy (CIRT) for radioresistant laryngeal malignancies regarding efficacy and toxicity. (2) Methods: 15 patients with laryngeal adenoid cystic carcinoma (ACC; n = 8; 53.3%) or chondrosarcoma (CS; n = 7; 46.7%) who underwent radiotherapy with carbon ions (C12) at the Heidelberg Ion Beam Therapy Center (HIT) between 2013 and 2018 were identified retrospectively and analyzed for local control (LC), overall survival (OS), and distant progression-free survival using the Kaplan⁻Meier method. CIRT was applied either alone (n = 7, 46.7%) or in combination with intensity modulated radiotherapy (IMRT) (n = 8, 53.3%). The toxicity was assessed according to the Common Toxicity Terminology Criteria for Adverse Events (CTCAE) v4.03. (3). Results: the median follow-up was 24 months (range 5⁻61 months). Overall, the therapy was tolerated very well. No grade >3 acute and chronic toxicity could be identified. The most reported acute grade 3 side effects were acute dysphagia (n = 2; 13%) and acute odynophagia (n = 3; 20%), making supportive nutrition via gastric tube (n = 2; 13.3%) and via high caloric drinks (n = 1; 6.7%) necessary due to swallowing problems (n = 4; 27%). Overall, chronic grade 3 toxicity in the form of chronic hoarseness occurred in 7% of the patients (n = 1; 7%). At the last follow-up, all the patients were alive. No local or locoregional recurrence could be identified. Only one patient with laryngeal ACC developed lung metastases three years after the first diagnosis. (4) Conclusions: the accelerated hypofractionated active raster-scanned carbon ion radiotherapy for radioresistant laryngeal malignancies is feasible in practice with excellent local control rates and moderate acute and late toxicity. Further follow-ups are necessary to evaluate the long-term clinical outcome.

Sacral insufficiency fractures after high-dose carbon-ion based radiotherapy of sacral chordomas.

BACKGROUND: This study aimed to analyse the frequency and clinical relevance of sacral insufficiency fractures (SIFs) after high-dose carbon-ion based irradiation of sacral chordomas. METHODS: A total of 56 patients were included in this retrospective study. Twenty one patients (37%) were treated with definitive radiotherapy (RT), and 35 patients (63%) received postoperative RT using carbon ions, either in combination with photons or as single-modality treatment (median radiation dose 66 Gy RBE, range 60-74 Gy). Follow-up examinations including MRI of the pelvis were performed at 3-monthly intervals in the first year and consecutively at 6-monthly intervals. Median follow-up was 35.5 months (range 2-83). RESULTS: SIFs were diagnosed in 29 patients (52%) after a median follow-up of 11 months (range 1-62 months). Most sacral fractures (79%) occurred within 2 years after RT. For the overall study population, the fracture-free survival probability amounted to values of 0.68 (95% CI, 0.53-0.79) after 1 year, 0.46 (95% CI, 0.31-0.60) after 2 years, and 0.31 (95% CI, 0.16-0.47) after 5 years. Statistical analysis showed no significant difference regarding the fracture rates between patients who received an operation and postoperative RT and patients treated with definitive RT. About one third of the patients with SIFs (34%; 10 of 29 patients) had associated clinical symptoms, most notably pain. All patients with symptomatic fractures required strong analgesics and often intensive pain management. CONCLUSIONS: Sacral fractures after high-dose carbon ion-based RT of sacral chordomas were shown to be a considerable radiogenic late effect, affecting about half of the treated patients. However, only one third of these fractures were clinically symptomatic requiring regular medical care and pain therapy. Further hazard factor analysis in the future with larger patient numbers will possibly enable the identification of high-risk patients for developing SIFs with the ultimate goal to prevent symptomatic fractures.

3D-Printed masks as a new approach for immobilization in radiotherapy - a study of positioning accuracy.

We developed a new approach to produce individual immobilization devices for the head based on MRI data and 3D printing technologies. The purpose of this study was to determine positioning accuracy with healthy volunteers. 3D MRI data of the head were acquired for 8 volunteers. In-house developed software processed the image data to generate a surface mesh model of the immobilization mask. After adding an interface for the couch, the fixation setup was materialized using a 3D printer with acrylonitrile butadiene styrene (ABS). Repeated MRI datasets (n=10) were acquired for all volunteers wearing their masks thus simulating a setup for multiple fractions. Using automatic image-to-image registration, displacements of the head were calculated relative to the first dataset (6 degrees of freedom). The production process has been described in detail. The absolute lateral (x), vertical (y) and longitudinal (z) translations ranged between -0.7 and 0.5 mm, -1.8 and 1.4 mm, and -1.6 and 2.4 mm, respectively. The absolute rotations for pitch (x), yaw (y) and roll (z) ranged between -0.9 and 0.8°, -0.5 and 1.1°, and -0.6 and 0.8°, respectively. The mean 3D displacement was 0.9 mm with a standard deviation (SD) of the systematic and random error of 0.2 mm and 0.5 mm, respectively. In conclusion, an almost entirely automated production process of 3D printed immobilization masks for the head derived from MRI data was established. A high level of setup accuracy was demonstrated in a volunteer cohort. Future research will have to focus on workflow optimization and clinical evaluation.

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.

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.