Analysis of safety and efficacy of proton radiotherapy for IDH-mutated glioma WHO grade 2 and 3.

PURPOSE: Proton beam radiotherapy (PRT) has been demonstrated to improve neurocognitive sequelae particularly. Nevertheless, following PRT, increased rates of radiation-induced contrast enhancements (RICE) are feared. How safe and effective is PRT for IDH-mutated glioma WHO grade 2 and 3? METHODS: We analyzed 194 patients diagnosed with IDH-mutated WHO grade 2 (n = 128) and WHO grade 3 (n = 66) glioma who were treated with PRT from 2010 to 2020. Serial clinical and imaging follow-up was performed for a median of 5.1 years. RESULTS: For WHO grade 2, 61% were astrocytoma and 39% oligodendroglioma while for WHO grade 3, 55% were astrocytoma and 45% oligodendroglioma. Median dose for IDH-mutated glioma was 54 Gy(RBE) [range 50.4-60 Gy(RBE)] for WHO grade 2 and 60 Gy(RBE) [range 54-60 Gy(RBE)] for WHO grade 3. Five year overall survival was 85% in patients with WHO grade 2 and 67% in patients with WHO grade 3 tumors. Overall RICE risk was 25%, being higher in patients with WHO grade 2 (29%) versus in patients with WHO grade 3 (17%, p = 0.13). RICE risk increased independent of tumor characteristics with older age (p = 0.017). Overall RICE was symptomatic in 31% of patients with corresponding CTCAE grades as follows: 80% grade 1, 7% grade 2, 13% grade 3, and 0% grade 3 + . Overall need for RICE-directed therapy was 35%. CONCLUSION: These data demonstrate the effectiveness of PRT for IDH-mutated glioma WHO grade 2 and 3. The RICE risk differs with WHO grading and is higher in older patients with IDH-mutated Glioma WHO grade 2 and 3.

Stereotactic body radiotherapy of lymph node metastases under MR-guidance: First clinical results and patient-reported outcomes.

OBJECTIVE: Stereotactic body radiotherapy (SBRT) is a noninvasive treatment option for lymph node metastases (LNM). Magnetic resonance (MR)-guidance offers superior tissue contrast and enables treatment of targets in close vicinity to radiosensitive organs at risk (OAR). However, literature on MR-guided SBRT of LNM is scarce with no report on outcome parameters. MATERIALS AND METHODS: We report a subgroup analysis of a prospective observational study comprising patients with LNM. Patients received MR-guided SBRT at our MRIdian Linac (ViewRay Inc., Mountain View, CA, USA) between January 2019 and February 2020. Local control (LC), progression-free survival (PFS) and overall survival (OS) analysis were performed using the Kaplan-Meier method with log rank test to test for significance (p < 0.05). Our patient-reported outcome questionnaire was utilized to evaluate patients' perspective. The CTCAE (Common Terminology Criteria for Adverse Events) v. 5.0 was used to describe toxicity. RESULTS: Twenty-nine patients (72.4% with prostate cancer; 51.7% with no distant metastases) received MR-guided SBRT for in total 39 LNM. Median dose was 27 Gy in three fractions, prescribed to the 80% isodose. At 1­year, estimated LC, PFS and OS were 92.6, 67.4 and 100.0%. Compared to baseline, six patients (20.7%) developed new grade I toxicities (mainly fatigue). One grade II toxicity occurred (fatigue), with no adverse event grade ≥III. Overall treatment experience was rated particularly positive, while the technically required low room temperature still represents the greatest obstacle in the pursuit of the ideal patient acceptance. CONCLUSION: MR-guided SBRT of LNM was demonstrated to be a well-accepted treatment modality with excellent preliminary results. Future studies should evaluate the clinical superiority to conventional SBRT.

MR-guided radiotherapy of moving targets.

INTRODUCTION: Hybrid magnetic resonance (MR) linear accelerators (MR-Linacs) for radiotherapy allow for the visualization and tracking of moving target volumes during the entire treatment. This makes gated treatments possible, decreasing the irradiated volumes and thus sparing healthy tissue from unnecessary radiation dose. Conventionally, tumors that are subject to respiration motion are treated by irradiating the entire area of potential target presence (internal target volume, ITV). This study presents three patient cases (lung, adrenal gland, and liver tumors) treated with gated MR-guided radiotherapy and compares the treatment plans retrospectively with conventional ITV plans. MATERIALS AND METHODS: The gross tumor volume was delineated on MR and computed tomography (CT) images of the patients, and MR-Linac treatment plans were generated using additional clinical and planning target volume margins. The motion of the gross tumor volume was evaluated on two-dimensional cine-MRI images during the entire MR-Linac treatment. Based on the motion analysis, standard ITV-based plans were retrospectively created and compared by means of irradiated target volumes and dose-volume parameters. RESULTS: For the MR-Linac plans, the irradiated treatment volumes were reduced by an average of 62% across the three cases, and for one case the ITV-based target volume would have overlapped with a critical organ. Target volume coverage was much better and the lung and adrenal MR-Linac plans revealed superior sparing of the organs at risks thanks to gated treatments. CONCLUSION: Dosimetrically beneficial treatment plans with promising clinical outcomes can be applied when using gated MR-guided radiotherapy. Future studies will reveal which patients will benefit most from this technique. To utilize the full potential of online adaptive, individualized MR-guided therapy, the close collaboration of radio-oncology and radiology is needed.

How Precise Are Preinterventional Measurements Using Centerline Analysis Applications? Objective Ground Truth Evaluation Reveals Software-Specific Centerline Characteristics.

PURPOSE: To evaluate different centerline analysis applications using objective ground truth from realistic aortic aneurysm phantoms with precisely defined geometry and centerlines to overcome the lack of unknown true dimensions in previously published in vivo validation studies. METHODS: Three aortic phantoms were created using computer-aided design (CAD) software and a 3-dimensional (3D) printer. Computed tomography angiograms (CTAs) of phantoms and 3 patients were analyzed with 3 clinically approved and 1 research software application. The 3D centerline coordinates, intraluminal diameters, and lengths were validated against CAD ground truth using a dedicated evaluation software platform. RESULTS: The 3D centerline position mean error ranged from 0.7±0.8 to 2.9±2.5 mm between tested applications. All applications calculated centerlines significantly different from ground truth. Diameter mean errors varied from 0.5±1.2 to 1.1±1.0 mm among 3 applications, but exceeded 8.0±11.0 mm with one application due to an unsteady distortion of luminal dimensions along the centerline. All tested commercially available software tools systematically underestimated centerline total lengths by -4.6±0.9 mm to -10.4±4.3 mm (maximum error -14.6 mm). Applications with the highest 3D centerline accuracy yielded the most precise diameter and length measurements. CONCLUSION: One clinically approved application did not provide reproducible centerline-based analysis results, while another approved application showed length errors that might influence stent-graft choice and procedure success. The variety and specific characteristics of endovascular aneurysm repair planning software tools require scientific evaluation and user awareness.

Incidence and Risk Assessment of Capsular Contracture in Breast Cancer Patients following Post-Mastectomy Radiotherapy and Implant-Based Reconstruction.

Our study aims to identify the risk factors and dosimetry characteristics associated with capsular contracture. METHODS: We retrospectively analyzed 118 women with breast cancer who underwent PMRT following an IBR between 2010 and 2022. Patients were treated with PMRT of 50.0-50.4 Gy in 25-28 fractions. Capsular contracture was categorized according to the Baker Classification for Reconstructed Breasts. RESULTS: After a median follow-up of 22 months, the incidence of clinically relevant capsular contracture (Baker III-IV) was 22.9%. Overall, capsular contracture (Baker I-IV) occurred in 56 patients (47.5%) after a median of 9 months after PMRT. The rate of reconstruction failure/implant loss was 25.4%. In the univariate analysis, postoperative complications (prolonged pain, prolonged wound healing, seroma and swelling) and regional nodal involvement were associated with higher rates of capsular contracture (p = 0.017, OR: 2.5, 95% CI: 1.2-5.3 and p = 0.031, respectively). None of the analyzed dosimetric factors or the implant position were associated with a higher risk for capsular contracture. CONCLUSION: Postoperative complications and regional nodal involvement were associated with an increased risk of capsular contracture following breast reconstruction and PMRT, while none of the analyzed dosimetric factors were linked to a higher incidence. Additional studies are needed to identify further potential risk factors.

Dosimetric benefit of online treatment plan adaptation in stereotactic ultrahypofractionated MR-guided radiotherapy for localized prostate cancer.

Background: Apart from superior soft tissue contrast, MR-guided stereotactic body radiation therapy (SBRT) offers the chance for daily online plan adaptation. This study reports on the comparison of dose parameters before and after online plan adaptation in MR-guided SBRT of localized prostate cancer. Materials and methods: 32 consecutive patients treated with ultrahypofractionated SBRT for localized prostate cancer within the prospective SMILE trial underwent a planning process for MR-guided radiotherapy with 37.5 Gy applied in 5 fractions. A base plan, derived from MRI simulation at an MRIdian Linac, was registered to daily MRI scans (predicted plan). Following target and OAR recontouring, the plan was reoptimized based on the daily anatomy (adapted plan). CTV and PTV coverage and doses at OAR were compared between predicted and adapted plans using linear mixed regression models. Results: In 152 out of 160 fractions (95%), an adapted radiation plan was delivered. Mean CTV and PTV coverage increased by 1.4% and 4.5% after adaptation. 18% vs. 95% of the plans had a PTV coverage ≥95% before and after online adaptation, respectively. 78% vs. 100% of the plans had a CTV coverage ≥98% before and after online adaptation, respectively. The D0.2cc for both bladder and rectum were <38.5 Gy in 93% vs. 100% before and after online adaptation. The constraint at the urethra with a dose of <37.5 Gy was achieved in 59% vs. 93% before and after online adaptation. Conclusion: Online adaptive plan adaptation improves target volume coverage and reduces doses to OAR in MR-guided SBRT of localized prostate cancer. Online plan adaptation could potentially further reduce acute and long-term side effects and improve local failure rates in MR-guided SBRT of localized prostate cancer.

Intrafraction organ movement in adaptive MR-guided radiotherapy of abdominal lesions - dosimetric impact and how to detect its extent in advance.

INTRODUCTION: Magnetic resonance guided radiotherapy (MRgRT) allows daily adaptation of treatment plans to compensate for positional changes of target volumes and organs at risk (OARs). However, current adaptation times are relatively long and organ movement occurring during the adaptation process might offset the benefit gained by adaptation. The aim of this study was to evaluate the dosimetric impact of these intrafractional changes. Additionally, a method to predict the extent of organ movement before the first treatment was evaluated in order to have the possibility to compensate for them, for example by adding additional margins to OARs. MATERIALS & METHODS: Twenty patients receiving adaptive MRgRT for treatment of abdominal lesions were retrospectively analyzed. Magnetic resonance (MR) images acquired at the start of adaptation and immediately before irradiation were used to calculate adapted and pre-irradiation dose in OARs directly next to the planning target volume. The extent of organ movement was determined on MR images acquired during simulation sessions and adaptive treatments, and their agreement was evaluated. Correlation between the magnitude of organ movement during simulation and the duration of simulation session was analyzed in order to assess whether organ movement might be relevant even if the adaptation process could be accelerated in the future. RESULTS: A significant increase in dose constraint violations was observed from adapted (6.9%) to pre-irradiation (30.2%) dose distributions. Overall, OAR dose increased significantly by 4.3% due to intrafractional organ movement. Median changes in organ position of 7.5 mm (range 1.5-10.5 mm) were detected within a median time of 17.1 min (range 1.6-28.7 min). Good agreement was found between the range of organ movement during simulation and adaptation (66.8%), especially if simulation sessions were longer and multiple MR images were acquired. No correlation was determined between duration of simulation sessions and magnitude of organ movement. CONCLUSION: Intrafractional organ movement can impact dose distributions and lead to violations of OAR tolerance doses, which impairs the benefit of daily on-table plan adaptation. By application of simulation images, the extent of intrafractional organ movement can be predicted, which possibly allows to compensate for them.

Segmentation of 71 Anatomical Structures Necessary for the Evaluation of Guideline-Conforming Clinical Target Volumes in Head and Neck Cancers.

The delineation of the clinical target volumes (CTVs) for radiation therapy is time-consuming, requires intensive training and shows high inter-observer variability. Supervised deep-learning methods depend heavily on consistent training data; thus, State-of-the-Art research focuses on making CTV labels more homogeneous and strictly bounding them to current standards. International consensus expert guidelines standardize CTV delineation by conditioning the extension of the clinical target volume on the surrounding anatomical structures. Training strategies that directly follow the construction rules given in the expert guidelines or the possibility of quantifying the conformance of manually drawn contours to the guidelines are still missing. Seventy-one anatomical structures that are relevant to CTV delineation in head- and neck-cancer patients, according to the expert guidelines, were segmented on 104 computed tomography scans, to assess the possibility of automating their segmentation by State-of-the-Art deep learning methods. All 71 anatomical structures were subdivided into three subsets of non-overlapping structures, and a 3D nnU-Net model with five-fold cross-validation was trained for each subset, to automatically segment the structures on planning computed tomography scans. We report the DICE, Hausdorff distance and surface DICE for 71 + 5 anatomical structures, for most of which no previous segmentation accuracies have been reported. For those structures for which prediction values have been reported, our segmentation accuracy matched or exceeded the reported values. The predictions from our models were always better than those predicted by the TotalSegmentator. The sDICE with 2 mm margin was larger than 80% for almost all the structures. Individual structures with decreased segmentation accuracy are analyzed and discussed with respect to their impact on the CTV delineation following the expert guidelines. No deviation is expected to affect the rule-based automation of the CTV delineation.

Clinical Outcomes of Online Adaptive Magnetic Resonance-Guided Stereotactic Body Radiotherapy of Adrenal Metastases from a Single Institution.

(1) Background: Recent publications foster stereotactic body radiotherapy (SBRT) in patients with adrenal oligometastases or oligoprogression. However, local control (LC) after non-adaptive SBRT shows the potential for improvement. Online adaptive MR-guided SBRT (MRgSBRT) improves tumor coverage and organ-at-risk (OAR) sparing. Long-term results of adaptive MRgSBRT are still sparse. (2) Methods: Adaptive MRgSBRT was performed on a 0.35 T MR-Linac. LC, overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and toxicity were assessed. (3) Results: 35 patients with 40 adrenal metastases were analyzed. The median gross tumor volume was 30.6 cc. The most common regimen was 10 fractions at 5 Gy. The median biologically effective dose (BED10) was 75.0 Gy. Plan adaptation was performed in 98% of all fractions. The median follow-up was 7.9 months. One local failure occurred after 16.6 months, resulting in estimated LC rates of 100% at one year and 90% at two years. ORR was 67.5%. The median OS was 22.4 months, and the median PFS was 5.1 months. No toxicity > CTCAE grade 2 occurred. (4) Conclusions: LC and ORR after adrenal adaptive MRgSBRT were excellent, even in a cohort with comparably large metastases. A BED10 of 75 Gy seems sufficient for improved LC in comparison to non-adaptive SBRT.

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.

Clinical Workflow of Cone Beam Computer Tomography-Based Daily Online Adaptive Radiotherapy with Offline Magnetic Resonance Guidance: The Modular Adaptive Radiotherapy System (MARS).

PURPOSE: The Ethos (Varian Medical Systems) radiotherapy device combines semi-automated anatomy detection and plan generation for cone beam computer tomography (CBCT)-based daily online adaptive radiotherapy (oART). However, CBCT offers less soft tissue contrast than magnetic resonance imaging (MRI). This work aims to present the clinical workflow of CBCT-based oART with shuttle-based offline MR guidance. METHODS: From February to November 2023, 31 patients underwent radiotherapy on the Ethos (Varian, Palo Alto, CA, USA) system with machine learning (ML)-supported daily oART. Moreover, patients received weekly MRI in treatment position, which was utilized for daily plan adaptation, via a shuttle-based system. Initial and adapted treatment plans were generated using the Ethos treatment planning system. Patient clinical data, fractional session times (MRI + shuttle transport + positioning, adaptation, QA, RT delivery) and plan selection were assessed for all fractions in all patients. RESULTS: In total, 737 oART fractions were applied and 118 MRIs for offline MR guidance were acquired. Primary sites of tumors were prostate (n = 16), lung (n = 7), cervix (n = 5), bladder (n = 1) and endometrium (n = 2). The treatment was completed in all patients. The median MRI acquisition time including shuttle transport and positioning to initiation of the Ethos adaptive session was 53.6 min (IQR 46.5-63.4). The median total treatment time without MRI was 30.7 min (IQR 24.7-39.2). Separately, median adaptation, plan QA and RT times were 24.3 min (IQR 18.6-32.2), 0.4 min (IQR 0.3-1,0) and 5.3 min (IQR 4.5-6.7), respectively. The adapted plan was chosen over the scheduled plan in 97.7% of cases. CONCLUSION: This study describes the first workflow to date of a CBCT-based oART combined with a shuttle-based offline approach for MR guidance. The oART duration times reported resemble the range shown by previous publications for first clinical experiences with the Ethos system.

Daily AI-Based Treatment Adaptation under Weekly Offline MR Guidance in Chemoradiotherapy for Cervical Cancer 1: The AIM-C1 Trial.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45-50.4 Gy in 25-28 fractions with 55.0-58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

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).

Preoperative Dose-Escalated Intensity-Modulated Radiotherapy (IMRT) and Intraoperative Radiation Therapy (IORT) in Patients with Retroperitoneal Soft-Tissue Sarcoma: Final Results of a Clinical Phase I/II Trial.

BACKGROUND: To report the final results of a prospective, one-armed, single-center phase I/II trial (NCT01566123). METHODS: Between 2007 and 2017, 37 patients with primary or recurrent (N = 6) retroperitoneal sarcomas were enrolled. Treatment included preoperative IMRT of 45-50 Gy with a simultaneous integrated boost of 50-56 Gy, surgery and IORT. The primary endpoint was local control (LC) at 5 years. The most common histology was dedifferentiated liposarcoma (51%), followed by leiomyosarcoma (24%) and well-differentiated liposarcoma (14%). The majority of lesions were high-grade (FNCLCC G1: 30%, G2: 38%, G3: 27%, two missing). Five patients were excluded from LC analysis per protocol. RESULTS: The minimum follow-up of the survivors was 62 months (median: 109; maximum 162). IORT was performed for 27 patients. Thirty-five patients underwent gross total resection; the pathological resection margin was mostly R+ (80%) and, less often, R0 (20%). We observed 10 local recurrences. The 5-year LC of the whole cohort was 59.6%. Eleven patients received a dose > 50 Gy plus IORT boost; LC was 64.8%; the difference, however, was not significant (p = 0.588). Of 37 patients, 15 were alive and 22 deceased at the time of final analysis. The 5-year OS was 59.5% (68.8% per protocol). CONCLUSIONS: The primary endpoint of a 5-year LC of 70% was not met. This might be explained by the inclusion of recurrent disease and the high rate of G3 lesions and leiomyosarcoma, which have been shown to profit less from radiotherapy. Stratification by grading and histology should be considered for future studies.

Biofidelic image registration for head and neck region utilizing an in-silico articulated skeleton as a transformation model.

Objective.We propose an integration scheme for a biomechanical motion model into a deformable image registration. We demonstrate its accuracy and reproducibility for adaptive radiation therapy in the head and neck region.Approach. The novel registration scheme for the bony structures in the head and neck regions is based on a previously developed articulated kinematic skeleton model. The realized iterative single-bone optimization process directly triggers posture changes of the articulated skeleton, exchanging the transformation model within the deformable image registration process. Accuracy in terms of target registration errors in the bones is evaluated for 18 vector fields of three patients between each planning CT and six fraction CT scans distributed along the treatment course.Main results. The median of target registration error distribution of the landmark pairs is 1.4 ± 0.3 mm. This is sufficient accuracy for adaptive radiation therapy. The registration performs equally well for all three patients and no degradation of the registration accuracy can be observed throughout the treatment.Significance. Deformable image registration, despite its known residual uncertainties, is until now the tool of choice towards online re-planning automation. By introducing a biofidelic motion model into the optimization, we provide a viable way towards an in-build quality assurance.

Proton Therapy for Advanced Juvenile Nasopharyngeal Angiofibroma.

PURPOSE: To provide the first report on proton radiotherapy (PRT) in the management of advanced nasopharyngeal angiofibroma (JNA) and evaluate potential benefits compared to conformal photon therapy (XRT). METHODS: We retrospectively reviewed 10 consecutive patients undergoing PRT for advanced JNA in a definitive or postoperative setting with a relative biological effectiveness weighted dose of 45 Gy in 25 fractions between 2012 and 2022 at the Heidelberg Ion Beam Therapy Center. Furthermore, dosimetric comparisons and risk estimations for short- and long-term radiation-induced complications between PRT plans and helical XRT plans were conducted. RESULTS: PRT was well tolerated, with only low-grade acute toxicities (CTCAE I-II) being reported. The local control rate was 100% after a median follow-up of 27.0 (interquartile range 13.3-58.0) months. PRT resulted in considerable tumor shrinkage, leading to complete remission in five patients and bearing the potential to provide partial or complete symptom relief. Favorable dosimetric outcomes in critical brain substructures by the use of PRT translated into reduced estimated risks for neurocognitive impairment and radiation-induced CNS malignancies compared to XRT. CONCLUSIONS: PRT is an effective treatment option for advanced JNA with minimal acute morbidity and the potential for reduced radiation-induced long-term complications.

Management of initial and recurrent radiation-induced contrast enhancements following radiotherapy for brain metastases: Clinical and radiological impact of bevacizumab and corticosteroids.

Purpose: The appearance of radiation-induced contrast enhancements (RICE) after radiotherapy for brain metastases can go along with severe neurological impairments. The aim of our analysis was to evaluate radiological changes, the course and recurrence of RICE and identify associated prognostic factors. Methods: We retrospectively identified patients diagnosed with brain metastases, who were treated with radiotherapy and subsequently developed RICE. Patient demographic and clinical data, radiation-, cancer-, and RICE-treatment, radiological results, and oncological outcomes were reviewed in detail. Results: A total of 95 patients with a median follow-up of 28.8 months were identified. RICE appeared after a median time of 8.0 months after first radiotherapy and 6.4 months after re-irradiation. Bevacizumab in combination with corticosteroids achieved an improvement of clinical symptoms and imaging features in 65.9% and 75.6% of cases, respectively, both significantly superior compared to treatment with corticosteroids only, and further significantly prolonged RICE-progression-free survival to a median of 5.6 months. Recurrence of RICE after initially improved or stable imaging occurred in 63.1% of cases, significantly more often in patients after re-irradiation and was associated with high mortality of 36.6% after the diagnosis of flare-up. Response of recurrence significantly depended on the applied treatment and multiple courses of bevacizumab achieved good response. Conclusion: Our results suggest that bevacizumab in combination with corticosteroids is superior in achieving short-term imaging and symptom improvement of RICE and prolongs the progression-free time compared to corticosteroids alone. Long-term RICE flare-up rates after bevacizumab discontinuation are high, but repeated treatments achieved effective symptomatic control.

Long-Term Clinical Results of MR-Guided Stereotactic Body Radiotherapy of Liver Metastases.

(1) Background: Magnetic-resonance (MR)-guided stereotactic body radiotherapy (SBRT) allows for ablative, non-invasive treatment of liver metastases. However, long-term clinical outcome data are missing. (2) Methods: Patients received MR-guided SBRT with a MRIdian Linac between January 2019 and October 2021 and were part of an ongoing prospective observational registry. Local hepatic control (LHC), distant hepatic control (DHC), progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method. Toxicity was documented according to CTCAE (v.5.0). (3) Results: Forty patients were treated for a total of 54 liver metastases (56% with online plan adaptation). Median prescribed dose was 50 Gy in five fractions equal to a biologically effective dose (BED) (alpha/beta = 10 Gy) of 100 Gy. At 1 and 2 years, LHC was 98% and 75%, DHC was 34% and 15%, PFS was 21% and 5% and OS was 83% and 57%. Two-year LHC was higher in case of BED > 100 Gy (100% vs. 57%; log-rank p = 0.04). Acute grade 1 and 2 toxicity (mostly nausea) occurred in 26% and 7% of the patients, with no grade ≥ 3 event. (4) Conclusions: To our knowledge, this is the largest cohort of MR-guided liver SBRT. Long-term local control was promising and underscores the aim of achieving >100 Gy BED. Nonetheless, distant tumor control remains challenging.

Comparison of different dose accumulation strategies to estimate organ doses after stereotactic magnetic resonance-guided adaptive radiotherapy.

INTRODUCTION: Re-irradiation is frequently performed in the era of precision oncology, but previous doses to organs-at-risk (OAR) must be assessed to avoid cumulative overdoses. Stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) enables highly precise ablation of tumors close to OAR. However, OAR doses may change considerably during adaptive treatment, which complicates potential re-irradiation. We aimed to compare the baseline plan with different dose accumulation techniques to inform re-irradiation. PATIENTS & METHODS: We analyzed 18 patients who received SMART to lung or liver tumors inside prospective databases. Cumulative doses were calculated inside the planning target volumes (PTV) and OAR for the adapted plans and theoretical non-adapted plans via (1) cumulative dose volume histograms (DVH sum plan) and (2) deformable image registration (DIR)-based dose accumulation to planning images (DIR sum plan). We compared cumulative dose parameters between the baseline plan, DVH sum plan and DIR sum plan using equivalent doses in 2 Gy fractions (EQD2). RESULTS: Individual patients presented relevant increases of near-maximum doses inside the proximal bronchial tree, spinal cord, heart and gastrointestinal OAR when comparing adaptive treatment to the baseline plans. The spinal cord near-maximum doses were significantly increased in the liver patients (D2% median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.4 Gy, p = 0.04; D0.1 cm³ median: baseline 6.1 Gy, DIR sum 8.1 Gy, DVH sum 8.5 Gy, p = 0.04). Three OAR overdoses occurred during adaptive treatment (DIR sum: 1, DVH sum: 2), and four more intense OAR overdoses would have occurred during non-adaptive treatment (DIR sum: 4, DVH sum: 3). Adaptive treatment maintained similar PTV coverages to the baseline plans, while non-adaptive treatment yielded significantly worse PTV coverages in the lung (D95% median: baseline 86.4 Gy, DIR sum 82.4 Gy, DVH sum 82.2 Gy, p = 0.006) and liver patients (D95% median: baseline 87.4 Gy, DIR sum 82.1 Gy, DVH sum 81.1 Gy, p = 0.04). CONCLUSION: OAR doses can increase during SMART, so that re-irradiation should be planned based on dose accumulations of the adapted plans instead of the baseline plan. Cumulative dose volume histograms represent a simple and conservative dose accumulation strategy.

Palliative Radiotherapy for Symptomatic Locally Advanced Breast Cancer.

Objective: Women with locally advanced breast cancer (LABC) or inoperable local recurrence often suffer from a significantly reduced quality of life (QOL) due to local tumor-associated pain, bleeding, exulceration, or malodorous discharge. We aimed to further investigate the benefit of radiotherapy (RT) for symptom relief while weighing the side-effects. Materials and methods: Patients who received symptom-oriented RT for palliative therapy of their LABC or local recurrence in the Department of Radiation Oncology at Heidelberg University Hospital between 2012 and 2021 were recorded. Clinical, pathological, and therapeutic data were collected and the oncological and symptomatic responses as well as therapy-associated toxicities were analyzed. Results: We retrospectively identified 26 consecutive women who received palliative RT with a median total dose of 39 Gy or single dose of 3 Gy in 13 fractions due to (impending) exulceration, pain, local hemorrhage, and/or vascular or plexus compression. With a median follow-up of 6.5 months after initiation of RT, overall survival at 6 and 12 months was 60.0% and 31.7%, and local control was 75.0% and 47.6%, respectively. Radiation had to be discontinued in 4 patients due to oncological clinical deterioration or death. When completed as initially planned, symptom improvement was achieved in 95% and WHO level reduction of analgesics in 28.6% of patients. In 36% (16%) of patients, local RT had already been indicated >3 months (>6 months) before the actual start of RT, but was delayed or not initiated among others in favor of drug alternatives or systemic therapies. RT-associated toxicities included only low-grade side-effects (CTCAE I°-II°) with predominantly skin erythema and fatigue even in the context of re-RT. Conclusion: Palliative RT in symptomatic LABC or locoregional recurrence is an effective treatment option for controlling local symptoms with only mild toxicity. It may thus improve QOL and should be considered early in palliative patient care management.