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).

Efficacy and toxicity of photon, proton, and carbon ion radiotherapy in the treatment of intracranial solitary fibrous tumor/hemangiopericytoma.

BACKGROUND: Solitary fibrous tumors (SFT) of the central nervous system are rare and treatment options are not well established. The aim of this study was to evaluate the clinical outcomes of radiotherapy (RT) and re-radiotherapy (re-RT) for de novo intracranial SFT and recurrent intracranial SFT. METHODS: This retrospective study analyzed efficacy and toxicity of different RT modalities in patients who received radiotherapy (RT) for intracranial SFT at Heidelberg University Hospital between 2000 and 2020 following initial surgery after de novo diagnosis ("primary group"). We further analyzed the patients of this cohort who suffered from tumor recurrence and received re-RT at our institution ("re-irradiation (re-RT) group"). Median follow-up period was 54.0 months (0-282) in the primary group and 20.5 months (0-72) in the re-RT group. RT modalities included 3D-conformal RT (3D-CRT), intensity-modulated RT (IMRT), stereotactic radiosurgery (SRS), proton RT, and carbon-ion RT (C12-RT). Response rates were analyzed according to RECIST 1.1 criteria. RESULTS: While the primary group consisted of 34 patients (f: 16; m:18), the re-RT group included 12 patients (f: 9; m: 3). Overall response rate (ORR) for the primary group was 38.3% (N = 11), with 32.4% (N = 11) complete remissions (CR) and 5.9% (N = 2) partial remissions (PR). Stable disease (SD) was confirmed in 5.9% (N = 2), while 41.2% (N = 14) experienced progressive disease (PD). 14% (N = 5) were lost to follow up. The re-RT group had 25.0% CR and 17.0% PR with 58.0% PD. The 1-, 3-, and 5-year progression-free survival rates were 100%, 96%, and 86%, respectively, in the primary group, and 81%, 14%, and 14%, respectively, in the re-RT group. Particle irradiation (N = 11) was associated with a lower likelihood of developing a recurrence in the primary setting than photon therapy (N = 18) (OR = 0.038; p = 0.002), as well as doses ≥ 60.0 Gy (N = 15) versus < 60.0 Gy (N = 14) (OR = 0.145; p = 0.027). Risk for tumor recurrence was higher for women than for men (OR = 8.07; p = 0.014) with men having a median PFS of 136.3 months, compared to women with 66.2 months. CONCLUSION: The data suggests RT as an effective treatment option for intracranial SFT, with high LPFS and PFS rates. Radiation doses ≥ 60 Gy could be associated with lower tumor recurrence. Particle therapy may be associated with a lower risk of recurrence in the primary setting, likely due to the feasibility of higher RT-dose application.

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%.

Efficacy and toxicity of bimodal radiotherapy in WHO grade 2 meningiomas following subtotal resection with carbon ion boost: Prospective phase 2 MARCIE trial.

BACKGROUND: Novel radiotherapeutic modalities using carbon ions provide an increased relative biological effectiveness (RBE) compared to photons, delivering a higher biological dose while reducing radiation exposure for adjacent organs. This prospective phase 2 trial investigated bimodal radiotherapy using photons with carbon-ion (C12)-boost in patients with WHO grade 2 meningiomas following subtotal resection (Simpson grade 4 or 5). METHODS: A total of 33 patients were enrolled from July 2012 until July 2020. The study treatment comprised a C12-boost (18 Gy [RBE] in 6 fractions) applied to the macroscopic tumor in combination with photon radiotherapy (50 Gy in 25 fractions). The primary endpoint was the 3-year progression-free survival (PFS), and the secondary endpoints included overall survival, safety and treatment toxicities. RESULTS: With a median follow-up of 42 months, the 3-year estimates of PFS, local PFS and overall survival were 80.3%, 86.7%, and 89.8%, respectively. Radiation-induced contrast enhancement (RICE) was encountered in 45%, particularly in patients with periventricularly located meningiomas. Patients exhibiting RICE were mostly either asymptomatic (40%) or presented immediate neurological and radiological improvement (47%) after the administration of corticosteroids or bevacizumab in case of radiation necrosis (3/33). Treatment-associated complications occurred in 1 patient with radiation necrosis who died due to postoperative complications after resection of radiation necrosis. The study was prematurely terminated after recruiting 33 of the planned 40 patients. CONCLUSIONS: Our study demonstrates a bimodal approach utilizing photons with C12-boost may achieve a superior local PFS to conventional photon RT, but must be balanced against the potential risks of toxicities.

Carbon Ion Radiotherapy: An Evidence-Based Review and Summary Recommendations of Clinical Outcomes for Skull-Base Chordomas and Chondrosarcomas.

Skull-base chordoma and chondrosarcoma are rare radioresistant tumors treated with surgical resection and/or radiotherapy. Because of the established dosimetric and biological benefits of heavy particle therapy, we performed a systematic and evidence-based review of the clinical outcomes of patients with skull-base chordoma and chondrosarcoma treated with carbon ion radiotherapy (CIRT). A literature review was performed using a MEDLINE search of all articles to date. We identified 227 studies as appropriate for review, and 24 were ultimately included. The published data illustrate that CIRT provides benchmark disease control outcomes for skull-base chordoma and chondrosarcoma, respectively, with acceptable toxicity. CIRT is an advanced treatment technique that may provide not only dosimetric benefits over conventional photon therapy but also biologic intensification to overcome mechanisms of radioresistance. Ongoing research is needed to define the magnitude of benefit, patient selection, and cost-effectiveness of CIRT compared to other forms of radiotherapy.

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.

Long-term quality of life after resection of retroperitoneal soft tissue sarcoma.

INTRODUCTION: Retroperitoneal soft tissue sarcoma (RPS) is characterized by high recurrence rates. Since complete tumor resection, often necessitating multivisceral resection, enables long-term survival in both primary and recurrent disease, health related quality of life (QoL) after RPS resection has attracted increasing interest. However, data regarding this topic is limited. Here, we multidimensionally assessed long-term QoL after RPS resection. METHODS: Five previously validated (1. EORTC QLQ-C30, 2. WEMWBS, 3. FoP-Q-SF, 4. PC-PTSD, 5. Pro-CTCAE) were sent to patients having undergone resection of primary, recurrent and metastasized RPS at Heidelberg University Hospital between 10/2001 and 12/2020. Multivariable linear regression models were used to test associations between clinical/demographic variables and patient reported outcomes (PROs). RESULTS: Questionnaires were answered by 127 patients (71% response rate). The median interval between RPS diagnosis and assessment of PROs was 80 months. The overall Global Health score was 64.1 and comparable to the general German population. RPS patients reported deficits regarding emotional and social functioning, whereas physical limitations were less pronounced. Besides diarrhea, abdominal symptoms were comparable to the overall population. Tumor recurrences, the number of surgeries, multivisceral resections or postoperative complications did not significantly affect long-term QoL ratings. CONCLUSION: RPS patients rate their QoL relatively high, even after multiple and multivisceral resections. Psychosocial well-being should be monitored in follow-up sessions to offer tailored support if necessary, thus improving postoperative care.

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.

Pragmatic, Prospective Comparative Effectiveness Trial of Carbon Ion Therapy, Surgery, and Proton Therapy for the Management of Pelvic Sarcomas (Soft Tissue/Bone) Involving the Bone: The PROSPER Study Rationale and Design.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

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

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

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

PURPOSE: To report dosimetric characteristics and early clinical outcomes in patients with pelvic Ewing sarcoma undergoing particle therapy. METHODS: Patients ≥ 18 years old with pelvic Ewing sarcoma treated in adjuvant or definitive settings were considered for this retrospective analysis. Proton therapy was carried out with 45-60 Gy (RBE) (1.5-2 Gy (RBE) per fraction) and carbon ion therapy for recurrent disease with 51 Gy (RBE) (3 Gy (RBE) per fraction). Local control (LC), disease control (DC) and overall survival (OS) were calculated using the Kaplan-Meier method. RESULTS: For our sample, 21 patients were available, 18 of whom were treated for primary, 3 for locally recurrent and 16 for inoperable disease. The median CTV and PTV were 1215 cm3 and 1630 cm3. Median Dmean values for the PTV, bladder and rectum and median V40 Gy for the bowel for patients undergoing proton therapy were 56 Gy (RBE), 0.6 Gy (RBE), 9 Gy (RBE) and 15 cm3, respectively. At the end of particle therapy, G 1-2 skin reactions (n = 16/21) and fatigue (n = 9/21) were the main reported symptoms. After a median follow-up of 21 months, the 2-year LC, DC and OS were 76%, 56% and 86%, respectively. CONCLUSIONS: Particle therapy in adult pelvic Ewing sarcoma is feasible and provides excellent dosimetric results. First clinical outcomes are promising; however, further long-term follow-up is needed.

Radiotherapy with Helium Ions Has the Potential to Improve Both Endocrine and Neurocognitive Outcome in Pediatric Patients with Ependymoma.

Ependymomas are the third most-frequent pediatric brain tumors. To prevent local recurrence, the resection site should be irradiated. Compared to photon radiation treatment, proton therapy often achieves even better results regarding target coverage and organ-sparing. Due to their physical properties, helium ions could further reduce side effects, providing better protection of healthy tissue despite similar target coverage. In our in silico study, 15 pediatric ependymoma patients were considered. All patients underwent adjuvant radiotherapeutic treatment with active-scanned protons at Heidelberg Ion Beam Therapy Center (HIT). Both helium ion and highly conformal IMRT plans were calculated to evaluate the potential dosimetric advantage of ion beam therapy compared to the current state-of-the-art photon-based treatments. To estimate the potential clinical benefit of helium ions, normal tissue complication probabilities (NTCP) were calculated. Target coverage was comparable in all three modalities. As expected, the integral dose absorbed by healthy brain tissue could be significantly reduced with protons by up to -48% vs. IMRT. Even compared to actively scanned protons, relative dose reductions for critical neuronal structures of up to another -39% were achieved when using helium ions. The dose distribution of helium ions is significantly superior when compared to proton therapy and IMRT due to the improved sparing of OAR. In fact, previous studies could clearly demonstrate that the dosimetric advantage of protons translates into a measurable clinical benefit for pediatric patients with brain tumors. Given the dose-response relationship of critical organs at risk combined with NTCP calculation, the results of our study provide a strong rationale that the use of helium ions has the potential to even further reduce the risk for treatment related sequelae.

Inoperable or incompletely resected craniofacial osteosarcoma treated by particle radiotherapy.

Background: To report survival of craniofacial osteosarcoma patients treated by particle radiotherapy. Methods: Between January 2010 and December 2021, 51 patients with primary (N = 35) or recurrent (N = 16) inoperable or incompletely resected craniofacial osteosarcoma were treated. In most cases, intracranial infiltration (59%) and macroscopic tumor on MRI/CT (75%) were present. Thirteen had a secondary osteosarcoma (25%). Treatment concepts included combined ion beam radiotherapy (CIBRT, N = 18), protons only (N = 3), carbon ions only (N = 12), IMRT with a carbon ion boost (N = 5), and carbon ion re-irradiation (N = 13). Eighty percent (N = 41) received additionally chemotherapy, most frequently EURAMOS-1 (47%) or EURO-B.O.S.S. (18%). Results: The median age was 38, and all patients finished treatment predominantly as outpatients (N = 44). Information on overall survival was available for N = 49 patients. The median follow-up of the survivors was 55 months. For the whole cohort 1-, 2-, 3-, and 5-year overall survival (OS) was 82.8%, 60.4%, 55.2%, and 51.7%, respectively. Those treated by CIBRT (N = 17) demonstrated a superior OS with 92.9% after 1 and 2 years and 83.6% after 3 and 5 years. The median clinical target volume (CTV) was 192.7 and 95.2 cc for the primary and boost plan, respectively. CIBRT, primary diagnosis, age ≤40a, and no macroscopic residual tumor were associated with improved survival in univariate analysis (p = 0.006, p = 0.004, p = 0.002, p = 0.026, respectively), while any foregoing resection compared to biopsy was not identified as a prognostic factor. CIBRT and no macroscopic residual tumor were confirmed as independent predictors of OS on multivariate analysis (HR = 0.107, 95% CI = [0.014, 0.797], p = 0.029 and HR = 0.130, 95% CI = [0.023, 0.724], p = 0.020, respectively). No acute toxicity > grade III was observed. Conclusion: CIBRT shows promising results for patients with inoperable or incompletely resected craniofacial osteosarcoma.

The Patient's Perspective on Proton Radiotherapy of Skull Base Meningioma: A Retrospective Cross-Sectional Survey.

Background: Radiotherapy plays an important role in the management of skull base meningioma. The aim of the study was to investigate patient-reported outcomes. Methods: A questionnaire of 20 items was sent to 192 patients with meningioma of the skull base who have been treated with proton therapy at a single institution. The survey included dichotomous, scaling, and open questions about symptoms, social distancing, rehabilitation, work, reintegration, limitations in recreational activities, as well as daily life activities and correlating diagnoses. Additionally, symptoms were reported retrospectively by the patients at different time points. In total, 128 patients (66.7%) responded. The median age at the time of RT was 55 years (range: 28-91); the majority were female (79%). The median time between the treatment of meningioma and the survey was 38.5 months (range: 7-100). Results: The most common initial symptoms were visual impairment (N=54, 42.2%), dizziness (N=38, 29.7%), and double vision (N=32, 25%). The most limiting symptom in daily life at the time of the survey was fatigue (N=31, 24.2%); a significant proportion of patients reported depression as associated with diagnosis (31.3%). Only 53% of patients reported occupational activity before treatment, this number did not increase with time. Only N= 40 (31.3%) and N=35 (27.3%) patients reported no limitations in daily household chores or recreational activities by the disease and treatment. The course of cognitive function after treatment showed a temporary deterioration with subsequent improvement. Except for the improvement in emotional functioning, most domains showed a temporary deterioration during radiotherapy, still, the values reached after 6 months differed weekly or moderately from the initial values. Conclusion: Besides neurological deficits, patients with skull base meningioma experience a variety of unspecific symptoms, which can be most limiting in daily life. Even successful treatment does not necessarily translate into the alleviation of those symptoms. A greater focus on the characterization of those symptom complexes is necessary. Greater focus on functional structures such as the hippocampus might improve the results. Due to the retrospective character, this study is hypothesis-generating.

Specific Targeting of Antiapoptotic Bcl-2 Proteins as a Radiosensitizing Approach in Solid Tumors.

Avoidance of therapy-induced apoptosis is a hallmark of acquired resistance towards radiotherapy. Thus, breaking resistance still challenges modern cancer therapy. The Bcl-2 protein family is known for its regulatory role in apoptosis signaling, making Bcl-2, Mcl-1 and Bcl-xL promising targets. This study evaluates the effects of highly specific inhibitors for Bcl-xL (WEHI-539), Bcl-2 (ABT-199) and Mcl-1 (S63845) as radiosensitizers. Covering a broad spectrum of solid tumors, Non-Small-Cell Lung Cancer (NSCLC), Head and Neck Squamous Cell Carcinoma (HNSCC) and synovial sarcoma cell lines were exposed to fractionated radiation as standard therapy with or without Bcl-2 protein inhibition. Protein expression was detected by Western blot and cell death was assessed by flow cytometry measuring apoptosis. In contrast to NSCLC, a high level of Bcl-xL and its upregulation during radiotherapy indicated radioresistance in HNSCC and synovial sarcoma. Radioresistant cell lines across all entities benefited synergistically from combined therapy with Bcl-xL inhibition and fractionated radiation. In NSCLC cell lines, Mcl-1 inhibition significantly augmented radiotherapy independent of the expression level. Our data suggest that among antiapoptotic Bcl-2 proteins, targeting Bcl-xL may break resistance to radiation in HNSCC, synovial sarcoma and NSCLC in vitro. In NSCLC, Mcl-1 might be a promising target that needs further investigation.

Radiation induced contrast enhancement after proton beam therapy in patients with low grade glioma - How safe are protons?

PURPOSE: The optimal treatment strategy for low-grade glioma (LGG) is still a matter of controversy. Considering that the prognosis is typically favorable, the prevention of late sequelae is of particular importance. Proton beam therapy (PRT) has the potential to further reduce the burden of treatment related side effects. We set out to evaluate the clinical outcome of proton irradiation with a particular focus on morphologic features on magnetic resonance imaging (MRI). METHODS: We assessed prospectively 110 patients who received radiotherapy with protons for histologically proven LGG. Clinical and radiological information were analyzed resulting in more than 1200 available MRI examinations with a median follow-up of 39 months. Newly diagnosed contrast-enhancing lesions on MRI were delineated and correlated with parameters of the corresponding treatment plan. A voxel-based dose-matched paired analysis of the linear energy transfer (LET) inside vs outside lesions was performed. RESULTS: Proton beam irradiation of patients with low-grade glioma results in overall survival (OS) of 90% after seven years. Median progression free survival had not yet been reached with surviving fraction of 54% after seven years. The incidence of temporary or clinically silent radiation induced contrast enhancement was significantly higher than previously assumed, however, symptomatic radiation necrosis was only detected in one patient. These radiation-induced contrast-enhancing lesions were almost exclusively seen at the distal beam end of the proton beam. In 22 out of 23 patients, the average LET of voxels inside contrast-enhancing lesions was significantly increased, compared to dose-matched voxels outside the lesions. CONCLUSION: Symptomatic radiation necrosis following PRT was as rare as conventional photon-based treatment series suggest. However, the increased incidence of asymptomatic radiation-induced brain injuries with an increased average LET observed in this cohort provides strong clinical evidence to support the hypothesis that the relative biological effectiveness of protons is variable and different to the fixed factor of 1.1 currently used worldwide.

Recommendations regarding cardiac stereotactic body radiotherapy for treatment refractory ventricular tachycardia.

BACKGROUND: Ventricular tachycardia (VT) is a potentially lethal complication of structural heart disease. Despite optimal management, a subgroup of patients continue to suffer from recurrent VT. Recently, cardiac stereotactic body radiotherapy (CSBRT) has been introduced as a treatment option in patients with VT refractory to antiarrhythmic drugs and catheter ablation. OBJECTIVE: The purpose of this study was to establish an expert consensus regarding the conduct and use of CSBRT for refractory VT. METHODS: We conducted a modified Delphi process. Thirteen experts from institutions from Germany and Switzerland participated in the modified Delphi process. Statements regarding the following topics were generated: treatment setting, institutional expertise and technical requirements, patient selection, target volume definition, and monitoring during and after CSBRT. Agreement was rated on a 5-point Likert scale. The strength of agreement was classified as strong agreement (≥80%), moderate agreement (≥66%) or no agreement (<66%). RESULTS: There was strong agreement regarding the experimental status of the procedure and the preference for treatment in clinical trials. CSBRT should be conducted at specialized centers with a strong expertise in the management of patients with ventricular arrhythmias and in stereotactic body radiotherapy for moving targets. CSBRT should be restricted to patients with refractory VT with optimal antiarrhythmic medication who underwent prior catheter ablation or have contraindications. Target volume delineation for CSBRT is complex. Therefore, interdisciplinary processes that should include cardiology/electrophysiology and radiation oncology as well as medical physics, radiology, and nuclear medicine are needed. Optimal follow-up is required. CONCLUSION: Prospective trials and pooled registries are needed to gain further insight into this promising treatment option for patients with refractory VT.

Magnetic Resonance-Guided Stereotactic Body Radiotherapy of Liver Tumors: Initial Clinical Experience and Patient-Reported Outcomes.

PURPOSE/OBJECTIVE: Stereotactic body radiation therapy (SBRT) has emerged as a valid treatment alternative for non-resectable liver metastases or hepatocellular carcinomas (HCC). Magnetic resonance (MR) guided SBRT has a high potential of further improving treatment quality, allowing for higher, tumoricidal irradiation doses whilst simultaneously sparing organs at risk. However, data on treatment outcome and patient acceptance is still limited. MATERIAL/METHODS: We performed a subgroup analysis of an ongoing prospective observational study comprising patients with liver metastases or HCC. Patients were treated with ablative MR-guided SBRT at the MRIdian Linac in the Department of Radiation Oncology at Heidelberg University Hospital between January 2019 and February 2020. Local control (LC) and overall survival (OS) analysis was performed using the Kaplan-Meier method. An in-house designed patient-reported outcome questionnaire was used to measure patients' experience with the MR-Linac treatment. Toxicity was evaluated using the Common Terminology Criteria for Adverse Events (CTCAE v. 5.0). RESULTS: Twenty patients (with n = 18 metastases; n = 2 HCC) received MR-guided SBRT for in total 26 malignant liver lesions. Median biologically effective dose (BED at α/ß = 10) was 105.0 Gy (range: 67.2-112.5 Gy) and median planning target volume was 57.20 ml (range: 17.4-445.0 ml). Median treatment time was 39.0 min (range: 26.0-67.0 min). At 1-year, LC was 88.1% and OS was 84.0%. Grade I° gastrointestinal toxicity °occurred in 30.0% and grade II° in 5.0% of the patients with no grade III° or higher toxicity. Overall treatment experience was rated positively, with items scoring MR-Linac staff's performance and items concerning the breath hold process being among the top positively rated elements. Worst scored items were treatment duration, positioning and low temperature. CONCLUSION: MR-guided SBRT of liver tumors is a well-tolerated and well-accepted treatment modality. Initial results are promising with excellent local control and only mildest toxicity. However, prospective studies are warranted to truly assess the potential of MR-guided liver SBRT and to identify which patients profit most from this new versatile technology.

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.