Plasma extracellular vesicles in meningioma patients following radiotherapy as liquid biopsy- a prospective explorative biomarker study (ARO 2023-05/AG-NRO-07).

BACKGROUND: While surgical resection remains the primary treatment approach for symptomatic or growing meningiomas, radiotherapy represents an auspicious alternative in patients with meningiomas not safely amenable to surgery. Biopsies are often omitted in light of potential postoperative neurological deficits, resulting in a lack of histological grading and (molecular) risk stratification. In this prospective explorative biomarker study, extracellular vesicles in the bloodstream will be investigated in patients with macroscopic meningiomas to identify a biomarker for molecular risk stratification and disease monitoring. METHODS: In total, 60 patients with meningiomas and an indication of radiotherapy (RT) and macroscopic tumor on the planning MRI will be enrolled. Blood samples will be obtained before the start, during, and after radiotherapy, as well as during clinical follow-up every 6 months. Extracellular vesicles will be isolated from the blood samples, quantified and correlated with the clinical treatment response or progression. Further, nanopore sequencing-based DNA methylation profiles of plasma EV-DNA will be generated for methylation-based meningioma classification. DISCUSSION: This study will explore the dynamic of plasma EVs in meningioma patients under/after radiotherapy, with the objective of identifying potential biomarkers of (early) tumor progression. DNA methylation profiling of plasma EVs in meningioma patients may enable molecular risk stratification, facilitating a molecularly-guided target volume delineation and adjusted dose prescription during RT treatment planning.

Oncologic treatment support via a dedicated mobile app: a prospective feasibility evaluation (OPTIMISE-1).

BACKGROUND: Mobile health (mhealth) is gaining interest, with mobile devices and apps being ever more available among medical facilities and patients. However, in the field of radiation oncology, the medical benefits of mhealth apps are still underexplored. As an additional approach to patient care during radiotherapy, we designed a mobile treatment surveillance app based on patient-reported outcomes. OBJECTIVE: We aimed to examine the feasibility of app-based treatment surveillance in patients undergoing radiotherapy (RT). Alongside technical practicability and acceptance, we assessed patient satisfaction and quality of life during treatment. METHODS: This prospective single-center study was performed at Heidelberg University Hospital between August 2018 and January 2020. During RT we measured patients' quality of life, symptoms, and treatment satisfaction. Respective questionnaires (EORTC QLQ-C30 with diagnosis-specific modules, RAND PSQ-18) were presented to patients via a mobile app running on a designated tablet device. The primary endpoint was determined by the fraction of patients who completed at least 80% of the items. Secondary endpoints were disease-related quality of life and patient satisfaction. RESULTS: A total of 49 cancer patients (14 breast, 13 pelvic, 12 lung, 10 prostate) were eligible for analysis. 79.6% (95% confidence interval: 66.4-88.5%; n = 39) of all patients completed at least 80% of the items received by the mobile app. A mean of 227.5 ± 48.25 questions were answered per patient. Breast cancer patients showed the highest rate of answered questions, with 92.9% (n = 13) completing at least 80% of the items. CONCLUSION: Patients showed high acceptance, with 79.6% (n = 39) completing at least 80% of the given items. The use of a mobile app for reporting symptoms and quality of life during RT is feasible and well accepted by patients. It may allow for resource-efficient, detailed feedback to the medical staff and assist in the assessment of side effects over time.

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.

Severe skin toxicity during whole-brain radiotherapy, targeted therapy, and additional drug intake including St. John's wort skin oil.

BACKGROUND: Metastatic non-small cell lung cancer (NSCLC) often requires a multimodal treatment including chemotherapy, targeted therapy and radiotherapy. In addition to this, many patients take supportive drugs. Since only scarce data on possible interactions between radiotherapy and pharmaceutical or herbal drugs exist, description of clinical cases is of special interest. CASE REPORT: A patient with stage IV NSCLC was treated with docetaxel/ramucirumab followed by radiotherapy for brain and bone metastases while taking several other over-the-counter drugs (OTCs) including topical St. John's wort skin oil. RESULTS: A 63-year-old female patient with stage IV NSCLC presented with 11 asymptomatic brain metastases and a painful osteolytic bone metastasis in the 12th thoracic vertebral body (T12). Four weeks before the start of palliative whole-brain radiotherapy and bone irradiation of T12, she was administered a combination of docetaxel and ramucirumab. At an administered dose of 24 Gy, the patient presented with severe folliculitis capitis, while skin examination over the thoracolumbar spine was unremarkable although skin dose was similar. After thorough questioning, the patient reported using a herbal skin oil that contained St. John's wort for scalp care only, but not for skin care of her back during radiotherapy. After stopping the topical application of the skin oil, folliculitis improved with a course of systemic and topical antibiotics within 10 days, though the healing process was prolonged and included desquamation and hyperpigmentation. CONCLUSION: St. John's wort seems to be a significant radiosensitizer for photon radiotherapy and can cause severe skin toxicity even though the literature lacks data on this interaction. As an OTC, it is easily accessible and often used by oncological patients due to antidepressant and local antimicrobial and pain-relieving effects.

[Perspectives of X-nuclei magnetic resonance imaging in neuro-oncology]. / Perspektiven der X-Kern-Magnetresonanztomographie in der Neuroonkologie.

BACKGROUND: X­nuclei magnetic resonance imaging (MRI) yields a broad spectrum of metabolic and functional imaging techniques with increasing clinical feasibility. OBJECTIVE: Current X­nuclei techniques in (neuro)oncology with emphasis on potential clinical applications of sodium and oxygen MRI are described and discussed. MATERIALS AND METHODS: Review with discussion of state-of-the-art literature on X­nuclei imaging. RESULTS: X­nuclei MRI employs NMR-sensitive nonproton nuclei to enable both anatomical visualization as well as noninvasive imaging and quantification of physiological processes in the human body. At the moment, sodium MRI represents the most common application of X­nuclei MRI because of its comparatively high NMR signal. Moreover, its sensitivity to pathological cellular proliferation renders sodium MRI a good candidate for oncological imaging, yielding additional biochemical information to proton MRI. Oxygen MRI is currently primarily investigational, requiring high technical efforts and costs. However, preliminary results show a huge potential of this technique for metabolic characterization of tumors. CONCLUSIONS: X­nuclei MRI is a rapidly evolving field in metabolic and functional imaging. In coming years, sodium MRI is expected to be increasingly used as an additional clinical tool in oncology to enhance diagnostic accuracy.

Quantitative Dynamic Oxygen 17 MRI at 7.0 T for the Cerebral Oxygen Metabolism in Glioma.

Background Altered metabolism is a characteristic of cancer. Because of a shift in glucose metabolism from oxidative phosphorylation to lactate production for energy generation, malignant tumors are characterized by increased glycolysis followed by lactic acid fermentation, even in the presence of abundant oxygen (the Warburg effect). Purpose To quantitatively investigate dynamic oxygen 17 (17O) MRI in healthy participants and participants with untreated glioma to understand altered cerebral oxygen metabolism in glioma. Materials and Methods In this prospective study conducted from September 2016 to June 2018, individuals with newly diagnosed previously untreated glioma (World Health Organization grade II-IV) and healthy volunteers were included. Dynamic 17O MRI was performed with a 7.0-T whole-body system. 17O2 gas inhalation enabled dynamic measurement of the cerebral metabolic rate of oxygen (CMRO2) consumption. In healthy volunteers and participants with glioma, CMRO2 values in gray matter and white matter volumes were compared by using Wilcoxon signed rank tests. In participants with glioma, the tumor volume and tumor subcompartments were compared with normal-appearing gray matter and white matter by using Friedman test followed by Holm-Sidak post hoc tests. Results Ten participants (mean age, 42 years ± 18 [standard deviation]; nine men) with glioma and three healthy volunteers (mean age, 44 years ± 21; all men) were evaluated. CMRO2 was higher in normal-appearing gray matter compared with white matter in both participants with glioma (2.36 µmol/g/min ± 0.22 vs 0.75 µmol/g/min ± 0.10, respectively) and healthy volunteers (2.38 µmol/g/min ± 0.15 vs 0.63 µmol/g/min ± 0.05, respectively) (P < .001 and P = .03, respectively). In the tumor region, CMRO2 was reduced (high-grade tumor CMRO2, 0.23 µmol/g/min ± 0.07; low-grade tumor CMRO2, 0.39 µmol/g/min ± 0.16; overall CMRO2, 0.34 µmol/g/min ± 0.16) compared with normal-appearing gray matter (P < .001) and normal-appearing white matter (P < .001) in accordance with the Warburg theorem. Conclusion Dynamic oxygen 17 MRI method at 7.0 T as a direct metabolic imaging technique in glioma enabled quantitative visualization of the Warburg effect. A general reduction in oxidative glycolysis was observed in accordance with the Warburg theorem. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Rapalino in this issue.

Early response assessment of glioma patients to definitive chemoradiotherapy using chemical exchange saturation transfer imaging at 7 T.

BACKGROUND: Patients with newly diagnosed inoperable glioma receive chemoradiotherapy (CRT). Standard Response Assessment in Neuro-Oncology (RANO) takes a minimum of 4 weeks after the end of treatment. PURPOSE/HYPOTHESIS: To investigate whether chemical exchange saturation transfer (CEST) MRI enables earlier assessment of response to CRT in glioma patients. STUDY TYPE: Longitudinal prospective study. POPULATION: Twelve brain tumor patients who underwent definitive CRT were included in this study. Three longitudinal CEST MRI measurements were performed for each patient at 7T: first before, second immediately after completion of CRT, and a third measurement as a 6-week follow-up. FIELD STRENGTH/SEQUENCE: Conventional MRI (contrast-enhanced, T2 w and diffusion-weighted imaging) at 3T and T2 w and CEST MRI at 7T was performed for all patients. ASSESSMENT: The mean relaxation-compensated relayed nuclear-Overhauser-effect CEST signal (rNOE) and the mean downfield-rNOE-suppressed amide proton transfer (dns-APT) CEST signal were investigated. Additionally, choline-to-N-acetyl-aspartate ratios (Cho/NAA) were evaluated using single-voxel 1 H-MRS in six of these patients. Performance of obtained contrasts was analyzed in assessing treatment response as classified according to the updated RANO criteria. STATISTICAL TEST: Unpaired Student's t-test. RESULTS: The rNOE signal significantly separated stable and progressive disease directly after the end of therapy (post-treatment normalized to pre-treatment mean ± SD: rNOEresponder = 1.090 ± 0.110, rNOEnon-responder = 0.808 ± 0.155, P = 0.015). In contrast, no significant difference was observed between either group when assessing the normalized dns-APT (dns-APTresponder = 0.953 ± 0.384, dns-APTnon-responder = 0.972 ± 0.477, P = 0.95). In the smaller MRS subcohort, normalized Cho/NAA decreased in therapy responders (Cho/NAAresponder = 0.632 ± 0.007, Cho/NAAnon-responder = 0.946 ± 0.124, P = 0.070). DATA CONCLUSION: rNOE mediated CEST imaging at 7T allowed for discrimination of responders and non-responders immediately after the end of CRT, additionally supported by 1 H-MRS data. This is at least 4 weeks earlier than the standard clinical evaluation according to RANO. Therefore, CEST MRI may enable early response assessment in glioma patients. LEVEL OF EVIDENCE: 1 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019;50:1268-1277.

Chemical exchange saturation transfer (CEST) signal intensity at 7T MRI of WHO IV° gliomas is dependent on the anatomic location.

BACKGROUND: Chemical exchange saturation transfer (CEST) is a novel MRI technique applied to brain tumor patients. PURPOSE: To investigate the anatomic location dependence of CEST MRI obtained at 7T and histopathological/molecular parameters in WHO IV° glioma patients. STUDY TYPE: Analytic prospective study. POPULATION: Twenty-one patients with newly diagnosed WHO IV° gliomas were studied prior to surgery; 11 healthy volunteers were investigated. FIELD STRENGTH/SEQUENCE: Conventional MRI (contrast-enhanced, T2 w and diffusion-weighted imaging) at 3T and T2 w and CEST MRI at 7T was performed for patients and both patients and volunteers. ASSESSMENT: Mean CEST signal intensities (nuclear-Overhauser-enhancement [NOE], amide-proton-transfer [APT], downfield NOE-suppressed APT [dns-APT]), ADC values, and histopathological/molecular parameters were evaluated with regard to hemisphere location and contact with the subventricular zone. CEST signal intensities of cerebral tissue of healthy volunteers were evaluated with regard to hemisphere discrimination. STATISTICAL TESTS: Spearman correlation, Mann-Whitney U-test, Wilcoxon signed-rank-test, Fisher's exact test, and area under the receiver operating curve. RESULTS: Maximum APT and dns-APT signal intensities were significantly different in right vs. left hemisphere gliomas (P = 0.037 and P = 0.007), but not in right vs. left hemisphere cerebral tissue of healthy subjects (P = 0.062-0.859). Mean ADC values were significantly decreased in right vs. left hemisphere gliomas (P = 0.044). Mean NOE signal intensity did not differ significantly between gliomas of either hemisphere (P = 0.820), but in case of subventricular zone contact (P = 0.047). A significant correlation was observed between APT and dns-APT and ADC signal intensities (rs = -0.627, P = 0.004 and rs = -0.534, P = 0.019), but not between NOE and ADC (rs = -0.341, P = 0.154). Histopathological/molecular parameters were not significantly different concerning the tumor location (P = 0.104-1.000, P = 0.286-0.696). DATA CONCLUSION: APT, dns-APT, and ADC were inversely correlated and depended on the gliomas' hemisphere location. NOE showed significant dependence on subventricular zone contact. Location dependency of APT- and NOE-mediated CEST effects should be considered in clinical investigations of CEST MRI. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019;49:777-785.

Relaxation-compensated amide proton transfer (APT) MRI signal intensity is associated with survival and progression in high-grade glioma patients.

OBJECTIVES: The purpose of this study was to investigate the association of relaxation-compensated chemical exchange saturation transfer (CEST) MRI with overall survival (OS) and progression-free survival (PFS) in newly diagnosed high-grade glioma (HGG) patients. METHODS: Twenty-six patients with newly diagnosed high-grade glioma (WHO grades III-IV) were included in this prospective IRB-approved study. CEST MRI was performed on a 7.0-T whole-body scanner. Association of patient OS/PFS with relaxation-compensated CEST MRI (amide proton transfer (APT), relayed nuclear Overhauser effect (rNOE)/NOE, downfield-rNOE-suppressed APT (dns-APT)) and diffusion-weighted imaging (apparent diffusion coefficient) were assessed using the univariate Cox proportional hazards regression model. Hazard ratios (HRs) and corresponding 95% confidence intervals were calculated. Furthermore, OS/PFS association with clinical parameters (age, gender, O6-methylguanine-DNA methyltransferase (MGMT) promotor methylation status, and therapy: biopsy + radio-chemotherapy vs. debulking surgery + radio-chemotherapy) were tested accordingly. RESULTS: Relaxation-compensated APT MRI was significantly correlated with patient OS (HR = 3.15, p = 0.02) and PFS (HR = 1.83, p = 0.009). The strongest association with PFS was found for the dns-APT metric (HR = 2.61, p = 0.002). These results still stand for the relaxation-compensated APT contrasts in a homogenous subcohort of n = 22 glioblastoma patients with isocitrate dehydrogenase (IDH) wild-type status. Among the tested clinical parameters, patient age (HR = 1.1, p = 0.001) and therapy (HR = 3.68, p = 0.026) were significant for OS; age additionally for PFS (HR = 1.04, p = 0.048). CONCLUSION: Relaxation-compensated APT MRI signal intensity is associated with overall survival and progression-free survival in newly diagnosed, previously untreated glioma patients and may, therefore, help to customize treatment and response monitoring in the future. KEY POINTS: • Amide proton transfer (APT) MRI signal intensity is associated with overall survival and progression in glioma patients. • Relaxation compensation enhances the information value of APT MRI in tumors. • Chemical exchange saturation transfer (CEST) MRI may serve as a non-invasive biomarker to predict prognosis and customize treatment.

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.

Radiation-Induced Cerebral Contrast Enhancements Strongly Share Ischemic Stroke Risk Factors.

PURPOSE: Radiation-induced cerebral contrast enhancements (RICE) are frequent after photon and particularly proton radiation therapy and are associated with a significant risk for neurologic morbidity. Nevertheless, risk factors are poorly understood. A more robust understanding of RICE risk factors is crucial to improve management and offer adaptive therapy at the outset and during follow-up. METHODS AND MATERIALS: We analyzed the comorbidities in detail of 190 consecutive adult patients treated at a single European national comprehensive cancer center with proton radiation therapy (54 Gy relative biological effectiveness) for LGG from 2010 to 2020 who were followed with serial clinical examinations and magnetic resonance imaging for a median 5.6 years. RESULTS: Classical vascular risk factors including age (≥50 vs <50 years: 1.6-fold; P = .0024), hypertension (2.7-fold; P = .00012), and diabetes (11.7-fold; P = .0066) were observed more frequently in the cohort that developed RICE. Dyslipidemia (2.1-fold), being overweight (2.0-fold), and smoking (2.6-fold), as well as history of previous stroke (1.7-fold), were also more frequently observed in the RICE cohort, although these factors did not reach the threshold for significance. Multivariable regression modeling supported the influence of age (P = .05), arterial hypertension (P = .01), and potentially male sex (P = .02), diabetes (P = .0008), and smoking (P = .001) on RICE occurrence over time, independent of each other and further vascular risk factors. If RICE occurred, bevacizumab treatment was 2-fold more frequently needed in the cohort with vascular risk factors, but RICE long-term prognosis did not differ between the RICE subcohorts with and without vascular risk factors. CONCLUSIONS: This is the first report in the literature demonstrating that RICE strongly shares vascular risk factors with ischemic stroke, which further enhances the nebulous understanding of the multifactorial pathophysiology of RICE. Classical vascular risk factors, especially age, hypertension, and diabetes, clearly correlated independently with RICE risk. Risk-adapted screening and management for RICE can be directly derived from these data to assist in clinical management.

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.

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.

[Cancer of unknown primary (CUP)-single-site, oligometastatic, and in the head and neck region]. / Cancer of unknown primary (CUP) ­ lokal begrenzt, oligometastatisch und im Kopf-Hals-Bereich.

INTRODUCTION: About 20% of all cancer of unknown primary (CUP) cases can be classified into favorable subgroups, which are defined by either obvious analogies to certain cancers with a known primary or amenability to local ablative treatment. In the updated European Society for Medical Oncology (ESMO) guidelines for diagnosis and treatment of CUP, the definition of favorable subgroups has been revised according to the latest scientific findings. In particular, the definition and treatment of oligometastatic CUP have undergone considerable changes in recent years. Thus, we delineate the current diagnostic and therapeutic standards for the two favorable CUP subtypes single-site/oligometastatic and head/neck CUP. METHODS: The classification, diagnostic workup, and treatment of single-site and oligometastatic CUP are summarized based on the current ESMO and American Society of Clinical Oncology (ASCO) guidelines together with a literature review. CONCLUSIONS: Single-site and oligometastatic CUP is defined by the presence of a maximum of five metastases that are amenable to local ablative treatment. Median overall survival is favorable and exceeds 4 years after local ablation of all detectable metastases. Lymph node metastases in the head and neck region represent a frequent scenario of single-site CUP. They usually originate from human papillomavirus (HPV)-associated squamous cell carcinoma in the oropharynx. Diagnostic workup comprises computed tomography (CT), magnetic resonance imaging (MRI) if necessary, and fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), followed by panendoscopy and biopsies of suspicious mucosal sites. Neck dissection, potentially followed by adjuvant radiotherapy, and definitive radiotherapy represent equally effective oncological treatment options with respect to a favorable prognosis.

Tumor treating fields as novel combination partner in the multimodal treatment of head and neck cancer.

BACKGROUND: We aimed to demonstrate the effects of tumor treating fields (TTFields) in head and neck squamous cell carcinoma (HNSCC) cells when combined with radiotherapy (RT) and chemotherapy. METHODS: Two human HNSCC cell lines (Cal27, FaDu) received five different treatments: TTFields, RT +/- TTFields and RT + simultaneous cisplatin +/- TTFields. Effects were quantified using clonogenic assays and flow cytometric analyses of DAPI, caspase-3 activation and γH2AX foci. RESULTS: Treatment with RT + TTFields decreased the clonogenic survival as strong as treatment with RT + simultaneous cisplatin. The triple combination of RT + simultaneous cisplatin + TTFields even further decreased the clonogenic survival. Accordingly, combination of TTFields with RT or RT + simultaneous cisplatin increased cellular apoptosis and DNA double-strand breaks. CONCLUSION: TTFields therapy seems a promising combination partner in the multimodal treatment of locally advanced HNSCC. It could be used to intensify chemoradiotherapy or as alternative to chemotherapy.

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.

Stereotactic magnetic resonance-guided online adaptive radiotherapy of adrenal metastases combines high ablative doses with optimized sparing of organs at risk.

Purpose/Objective: To evaluate the potential of stereotactic magnetic resonance-guided online adaptive radiotherapy (SMART) to fulfill dose recommendations for stereotactic body radiotherapy (SBRT) of adrenal metastases and spare organs at risk (OAR). Materials and methods: In this subgroup analysis of a prospective registry trial, 22 patients with adrenal metastases were treated on a 0.35 T MR-Linac in 5-12 fractions with fraction doses of 4-10 Gy. Baseline plans were re-calculated to the anatomy of the day. These predicted plans were reoptimized to generate adapted plans. Baseline, predicted and adapted plans were compared with regard to PTV objectives, OAR constraints and published dose recommendations. Results: The cohort comprised patients with large GTV (median 36.0 cc) and PTV (median 66.6 cc) and predominantly left-sided metastases. 179 of 181 fractions (98.9 %) were adapted because of PTV and/or OAR violations. Predicted plans frequently violated PTV coverage (99.4 %) and adjacent OAR constraints (bowel: 32.9 %, stomach: 32.8 %, duodenum: 10.4 %, kidneys: 10.8 %). In the predicted plans, the volume exposed to the maximum dose was exceeded up to 16-fold in the duodenum and up to 96-fold in the spinal cord. Adapted plans significantly reduced OAR violations by 96.4 % for the bowel, 98.5 % for the stomach, 85.6 % for the duodenum and 83.3 % for the kidneys. Plan adaptation improved PTV coverage from 82.7 ± 8.1 % to 90.6 ± 4.9 % (p < 0.001). Furthermore, recently established target volume thresholds could easily be fulfilled with SMART. No toxicities > grade II occurred. Conclusion: SMART fulfills established GTV and PTV dose recommendations while simultaneously sparing organs at risk even in a challenging cohort.