A pilot study to evaluate the combination of surgery and brachytherapy for local tumor control in young children with perianal rhabdomyosarcoma.

Background: Perianal rhabdomyosarcoma ((P)RMS) are rare and have a poor prognosis. Data in young children are limited and local therapy is not well defined. Combined brachytherapy and surgery is routinely being used for RMS at other sites in children as it provides good oncologic outcomes and allows for organ-sparing surgery. The objective of this study was to evaluate this combination treatment for local tumor control and organ-sparing surgery in young children with (P)RMS. Methods: A retrospective review of the medical records of all children who underwent surgery and brachytherapy for (P)RMS at our institution since 2009 was conducted. Results: Surgery for (P)RMS was performed in 6 patients at a median age of 19 months (range 8-50). Embryonal RMS was diagnosed in 4 patients and alveolar RMS in 2 patients, of which 1 patient had FOXO1 fusion-positive RMS. All patients underwent postoperative high-dose rate (HDR) brachytherapy. Organ-preserving surgery was achieved in 5 of 6 patients (83 %). In 1 patient, the entire sphincter was infiltrated, making organ-preserving resection impossible. 5 of 6 patients (83 %) exhibited an event-free and overall survival at a median follow-up of 26 months (range 8-107). One patient died due to locoregional recurrence. Complications were urethral leakage in 1 patient followed by urethral stenosis and delayed wound healing and vaginal stenosis in another patient. No patient reported fecal incontinence. Conclusions: Combined treatment with surgery and HDR brachytherapy is feasible in very young children with (P)RMS and leads to a favorable oncologic outcome. Preliminary data show a good functional preservation.

Translating the theranostic concept to neuro-oncology: disrupting barriers.

Theranostics integrate molecular imaging and targeted radionuclide therapy for personalised cancer therapy. Theranostic treatments have shown meaningful efficacy in randomised clinical trials and are approved for clinical use in prostate cancer and neuroendocrine tumours. Brain tumours represent an unmet clinical need and theranostics might offer effective treatment options, although specific issues need to be considered for clinical development. In this Policy Review, we discuss opportunities and challenges of developing targeted radionuclide therapies for the treatment of brain tumours including glioma, meningioma, and brain metastasis. The rational choice of molecular treatment targets is highlighted, including the potential relevance of different types of targeted radionuclide therapeutics, and the role of the blood-brain barrier and blood-tumour barrier. Furthermore, we discuss considerations for effective clinical trial design and conduct, as well as logistical and regulatory challenges for implementation of radionuclide therapies into neuro-oncological practice. Rational development will foster successful translation of the theranostic concept to brain tumours.

Targeted RT study: results on early toxicity of targeted therapies and radiotherapy.

PURPOSE/OBJECTIVE: Currently, there are few prospective data on the tolerability of combining targeted therapies (TT) with radiation therapy (RT). The objective of this prospective study was to assess the feasibility and toxicity of pairing RT with concurrent TT in cancer patients. The aim was to enhance the existing evidence base for the simultaneous administration of targeted substances together with radiotherapy. METHODS: Prospective study enrollment was conducted at a single institution between March 1, 2020, and December 31, 2021, for all patients diagnosed with histologically confirmed cancer who underwent external beam radiotherapy in combination with targeted therapy. The study, known as the "targeted RT study," was registered in the German Clinical Trials Register under DRKS00026193. Systematic documentation of the toxicity profiles of different targeted therapies was performed, and the assessment of acute toxicity followed the guidelines of the National Cancer Institute Common Terminology Criteria for Adverse Events Version v5.0. RESULTS: A total of 334 patients underwent 683 radiation therapy series. During the course of RT, 51 different TT substances were concurrently administered. External beam radiotherapy was employed for various anatomical sites. The combination of RT and concurrent TT administration was generally well tolerated, with no instances of severe acute toxicity observed. The most commonly reported toxicity was fatigue, ranging from mild to moderate Common Terminology Criteria for Adverse Events (CTCAE) °I-°III. Other frequently observed toxicities included dermatitis, dyspnea, dysphagia, and dry cough. No toxicity greater than moderate severity was recorded at any point. In only 32 patients (4.7% of evaluated RT series), the concurrent substance administration was discontinued due to side effects. However, these side effects did not exceed mild severity according to CTCAE, suggesting that discontinuation was a precautionary measure. Only one patient receiving Imatinib treatment experienced a severe CTCAE °III side effect, leading to discontinuation of the concurrent substance due to the sudden occurrence of melaena during RT. CONCLUSION: In conclusion, the current study did not demonstrate a significant increase or additional toxicity when combining radiotherapy and concurrent targeted therapy. However, additional research is required to explore the specific toxicity profiles of the various substances that can be utilized in this context. TRIAL REGISTRATION NUMBER: DRKS00026193. Date of registration 12/27/2022 (retrospectively registered).

Tumor board simulation improves interdisciplinary decision-making in medical students.

INTRODUCTION: Training of interdisciplinary clinical reasoning and decision-making skills, essential in daily clinical practice in oncological specialties, are still underrepresented in medical education. Therefore, at LMU University Hospital Munich, we implemented a didactically modified tumor board simulation with experts from five different disciplines (medical oncology, pathology, radiation oncology, radiology, and surgery) presenting patient cases into a one-week course on the basic principles of oncology. In this survey, we examined the self-assessed impact of our course on the interdisciplinary decision-making skills of medical students. METHODS: Between November-December 2023 and January-February 2024, we surveyed two cohorts of medical students in the third year of medical school in our one-week course before and after participating in the tumor board simulation. The objective was to evaluate the self-assessed knowledge in interdisciplinary clinical decision-making, in integrating ethical considerations into clinical reasoning, and in comprehension of various professional viewpoints in interdisciplinary decision-making. Knowledge was assessed using a five-step Likert scale from 1 (no knowledge) to 5 (complete knowledge). RESULTS: The survey was answered by 76 students before and 55 after the simulation, equaling 60-70% of all 100 course participants. Mean knowledge level regarding principles of interdisciplinary clinical decision-making improved significantly in all of the following exemplary aspects: purpose and procedure of tumor boards in clinical practice (from 2.4 ± 1.1 to 4.0 ± 1.0, Spearman's ρ = 0.6, p < 0.001), principles of dealing with ethical challenges in oncology (from 2.4 ± 1.1 to 3.4 ± 1.0, ρ = 0.4, p < 0.001), and principles of shared decision-making in oncology (2.7 ± 1.1 to 3.7 ± 1.0, ρ = 0.4, p < 0.001). Students reported that their skills in clinical decision-making and ability to discuss oncological patient cases from different professional viewpoints improved due to the teaching course. CONCLUSION: By employing our interdisciplinary one-week course and a didactically modified tumor board simulation featuring experts from various oncological disciplines, medical students' comprehension of interdisciplinary clinical decision-making in oncology improved significantly.

Timing of stereotactic radiosurgery within the first-line systemic treatment in non-small cell lung cancer brain metastases: a retrospective single-center cohort study.

Background: Stereotactic radiosurgery/radiotherapy (SRS/SRT) and novel systemic treatments, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), have demonstrated to be effective in managing brain metastases in non-small cell lung cancer (NSCLC). However, the optimal treatment sequence of SRS/SRT and TKI/ICI remains uncertain. This retrospective monocentric analysis addresses this question by comparing the outcomes of patients with NSCLC brain metastases who received upfront SRS/SRT versus those who were initially treated with TKI/ICI. Methods: All patients treated with SRS/SRT and TKI/ICI for NSCLC brain metastases were collected from a clinical database. The patients who received first-line TKI or ICI for the treatment of brain metastases were then selected for further analysis. Within this cohort, a comparative analysis between upfront SRS/SRT and patients initially treated with TKI/ICI was conducted, assessing key parameters such as overall survival (OS), intracranial progression-free survival (iPFS) and treatment-related toxicity. Both OS and iPFS were defined as the time from SRS/SRT to either death or disease progression, respectively. Results: The analysis encompassed 54 patients, of which 34 (63.0%) patients received SRS/SRT and TKI/ICI as their first-line therapy. Of the latter, 17 (50.0%) patients received upfront SRS/SRT and 17 (50.0%) were initially treated with TKI/ICI; 24 (70.6%) received SRS/SRT and ICI, and 10 (29.4%) received SRS/SRT and TKI. The cohorts did not significantly differ in the univariable analyses for the following parameters: sex, age, histology, molecular genetics, disease stage at study treatment, performance status, number of brain metastases, treatment technique, tumor volume, target volume, disease progression, radiation necrosis, dosimetry. While no significant differences were found in terms of iPFS and OS between patients treated with upfront SRS/SRT and patients initially treated with TKI, upfront SRS/SRT demonstrated significantly superior OS when compared to patients initially treated with ICI (median OS not reached vs. 17.5 months; mean 37.8 vs. 23.6 months; P=0.03) with no difference in iPFS. No significant differences in treatment-related toxicity were observed among the cohorts. Conclusions: In this retrospective, single-center cohort study, patients treated with upfront SRS/SRT demonstrated significantly longer OS compared to patients initially treated with ICI in the cohort receiving first-line therapy for brain metastases. However, given the retrospective design and the limited cohort size, definitive conclusions cannot be drawn from these findings. Nevertheless, the results suggest that the timing of SRS/SRT may play an important role in treatment outcomes. Further investigation, preferably through prospective randomized trials, is warranted to provide more conclusive answers to this important question.

Criteria for Re-Irradiation.

BACKGROUND: The treatment options for patients with progressive malignant tumors despite primary radiotherapy are often limited. In selected cases, re-irradiation can be offered. This article concerns the selection criteria and results of re-irradiation for certain types of cancer. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, with particular attention to glioblastoma, head and neck tumors, and prostatic carcinoma. RESULTS: The published studies of re-irradiation are few in number and often of limited methodological quality. For glioblastoma, a randomized controlled trial (RCT) found that adding re-irradiation to treatment with bevacizumab yielded no significant improvement in either median progression-free survival or median overall survival (hazard ratio [HR] 0.73; p = 0.05 and HR 0.98; p = 0.46, respectively). Re-irradiation is a treatment option for locoregional recurrences of head and neck tumors after primary radiotherapy, but it carries a risk of serious side effects. For unresectable recurrences of nasopharyngeal carcinoma, an RCT has shown that hyperfractionated re-irradiation is more effective than normofractionated re-irradiation (overall survival: HR 0.54, p = 0.014). For locally recurrent prostatic carcinoma after radiotherapy, re-irradiation can yield good oncologic outcomes with an acceptable level of urogenital and gastrointestinal side effects (5-year recurrence-free survival: stereotactic body radiation therapy (SBRT), 58%; high dose rate (HDR) brachytherapy, 77%; versus salvage prostatectomy, 72%). RCTs on this topic are lacking. CONCLUSION: Re-irradiation is a treatment option for selected cancer patients. As the available scientific evidence is limited, multidisciplinary collaboration and participatory decision-making are particularly important.

Dose prescription for stereotactic body radiotherapy: general and organ-specific consensus statement from the DEGRO/DGMP Working Group Stereotactic Radiotherapy and Radiosurgery.

PURPOSE AND OBJECTIVE: To develop expert consensus statements on multiparametric dose prescriptions for stereotactic body radiotherapy (SBRT) aligning with ICRU report 91. These statements serve as a foundational step towards harmonizing current SBRT practices and refining dose prescription and documentation requirements for clinical trial designs. MATERIALS AND METHODS: Based on the results of a literature review by the working group, a two-tier Delphi consensus process was conducted among 24 physicians and physics experts from three European countries. The degree of consensus was predefined for overarching (OA) and organ-specific (OS) statements (≥ 80%, 60-79%, < 60% for high, intermediate, and poor consensus, respectively). Post-first round statements were refined in a live discussion for the second round of the Delphi process. RESULTS: Experts consented on a total of 14 OA and 17 OS statements regarding SBRT of primary and secondary lung, liver, pancreatic, adrenal, and kidney tumors regarding dose prescription, target coverage, and organ at risk dose limitations. Degree of consent was ≥ 80% in 79% and 41% of OA and OS statements, respectively, with higher consensus for lung compared to the upper abdomen. In round 2, the degree of consent was ≥ 80 to 100% for OA and 88% in OS statements. No consensus was reached for dose escalation to liver metastases after chemotherapy (47%) or single-fraction SBRT for kidney primaries (13%). In round 2, no statement had 60-79% consensus. CONCLUSION: In 29 of 31 statements a high consensus was achieved after a two-tier Delphi process and one statement (kidney) was clearly refused. The Delphi process was able to achieve a high degree of consensus for SBRT dose prescription. In summary, clear recommendations for both OA and OS could be defined. This contributes significantly to harmonization of SBRT practice and facilitates dose prescription and reporting in clinical trials investigating SBRT.

Re-irradiation treatment regimens for patients with recurrent glioma - Evaluation of the optimal dose and best concurrent therapy.

PURPOSE: Re-irradiation (reRT) is an effective treatment modality for patients with recurrent glioma. Data on dose escalation, the use of simulated integrated boost and concomitant therapy to reRT are still scarce. In this monocentric cohort of n = 223 patients we investigated the influence of reRT dose escalation as well as the concomitant use of bevacizumab (BEV) with regard to post-recurrence survival (PRS) and risk of radionecrosis (RN). PATIENTS AND METHODS: Patients with recurrent glioma treated between July 2008 and August 2022 with reRT with BEV, reRT with temozolomide (TMZ) and reRT without concomitant systemic therapy were retrospectively analyzed. PRS and RN-free survival (RNFS) were calculated for all patients using the Kaplan-Meier estimator. Univariable and multivariable cox regression was performed for PRS and for RNFS. The reRT Risk Score (RRRS) was calculated for all patients. RESULTS: Good, intermediate and poor risk of the RRRS translated into 11 months, 9 months and 7 months of median PRS (univariable: p = 0.008, multivariable: p = 0.013). ReRT was applied with a dose of ≤36 Gy (n = 140) or >36 Gy (n = 83). Concomitant bevacizumab (BEV) therapy was performed in n = 122 and concomitant temozolomide (TMZ) therapy in n = 32 patients. Median PRS was 10 months in patients treated with >36 Gy and 8 months in patients treated with ≤36 Gy (univariable: p = 0.032, multivariable: p = 0.576). Regarding concomitant TMZ therapy, median PRS was 14 months vs. 9 months for patients treated with or without TMZ (univariable: p = 0.041, multivariable: p = 0.019). No statistically significant influence on PRS was seen for concomitant BEV therapy in this series. RN was less frequent for reRT with concomitant BEV, (17/122; 13.9 %) than for reRT without BEV (30/101; 29.7 %). Regarding RNFS, the hazard ratio for reRT with BEV was 0.436 (univariable; p = 0.006) and 0.479 (multivariable; p = 0.023), respectively. ReRT dose did not show statistical significance in regards to RN (univariable: p = 0.073, multivariable: p = 0.404). RNFS was longer for patients receiving concomitant BEV to reRT than for patients treated with reRT only (mean 31.7 vs. 30.9 months, p = 0.004). CONCLUSION: In this cohort, in patients treated with concomitant BEV therapy RN was less frequently detected and in patients treated with concomitant TMZ longer PRS was observed. Based on these results, the best concomitant therapy and the optimal dose should be decided on a patient-by-patient basis.

FET PET-based target volume delineation for the radiotherapy of glioblastoma: A pictorial guide to help overcome methodological pitfalls.

PET is increasingly used for target volume definition in the radiotherapy of glioblastoma, as endorsed by the 2023 ESTRO-EANO guidelines. In view of its growing adoption into clinical practice and upcoming PET-based multi-center trials, this paper aims to assist in overcoming common pitfalls of FET PET-based target delineation in glioblastoma.

Meningioma: International Consortium on Meningiomas consensus review on scientific advances and treatment paradigms for clinicians, researchers, and patients.

Meningiomas are the most common primary intracranial tumors in adults and are increasing in incidence due to the aging population and increased access to neuroimaging. While most exhibit nonmalignant behavior, a subset of meningiomas are biologically aggressive and are associated with treatment resistance, resulting in significant neurologic morbidity and even mortality. In recent years, meaningful advances in our understanding of the biology of these tumors have led to the incorporation of molecular biomarkers into their grading and prognostication. However, unlike other central nervous system (CNS) tumors, a unified molecular taxonomy for meningiomas has not yet been established and remains an overarching goal of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy-Not Official World Health Organization (cIMPACT-NOW) working group. Additionally, clinical equipoise still remains on how specific meningioma cases and patient populations should be optimally managed. To address these existing gaps, members of the International Consortium on Meningiomas including field-leading experts, have prepared this comprehensive consensus narrative review directed toward clinicians, researchers, and patients. Included in this manuscript are detailed overviews of proposed molecular classifications, novel biomarkers, contemporary treatment strategies, trials on systemic therapies, health-related quality-of-life studies, and management strategies for unique meningioma patient populations. In each section, we discuss the current state of knowledge as well as ongoing clinical and research challenges to road map future directions for further investigation.

Online Adaptive MR-Guided Ultrahypofractionated Radiotherapy of Prostate Cancer on a 1.5 T MR-Linac: Clinical Experience and Prospective Evaluation.

The use of hypofractionated radiotherapy in prostate cancer has been increasingly evaluated, whereas accumulated evidence demonstrates comparable oncologic outcomes and toxicity rates compared to normofractionated radiotherapy. In this prospective study, we evaluate all patients with intermediate-risk prostate cancer treated with ultrahypofractionated (UHF) MRI-guided radiotherapy on a 1.5 T MR-Linac within our department and report on workflow and feasibility, as well as physician-recorded and patient-reported longitudinal toxicity. A total of 23 patients with intermediate-risk prostate cancer treated on the 1.5 T MR-Linac with a dose of 42.7 Gy in seven fractions (seven MV step-and-shoot IMRT) were evaluated within the MRL-01 study (NCT04172753). The duration of each treatment step, choice of workflow (adapt to shape-ATS or adapt to position-ATP) and technical and/or patient-sided treatment failure were recorded for each fraction and patient. Acute and late toxicity were scored according to RTOG and CTC V4.0, as well as the use of patient-reported questionnaires. The median follow-up was 12.4 months. All patients completed the planned treatment. The mean duration of a treatment session was 38.2 min. In total, 165 radiotherapy fractions were delivered. ATS was performed in 150 fractions, 5 fractions were delivered using ATP, and 10 fractions were delivered using both ATS and ATP workflows. Severe acute bother (G3+) regarding IPS-score was reported in five patients (23%) at the end of radiotherapy. However, this tended to normalize and no G3+ IPS-score was observed later at any point during follow-up. Furthermore, no other severe genitourinary (GU) or gastrointestinal (GI) acute or late toxicity was observed. One-year biochemical-free recurrence survival was 100%. We report the excellent feasibility of UHF MR-guided radiotherapy for intermediate-risk prostate cancer patients and acceptable toxicity rates in our preliminary study. Randomized controlled studies with long-term follow-up are warranted to detect possible advantages over current state-of-the-art RT techniques.

Dummy run for planning of isotoxic dose-escalated radiation therapy for glioblastoma used in the PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06).

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated. Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD). Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78). Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study. Trial registration: NCT05871021.

Preoperative growth dynamics of untreated glioblastoma: Description of an exponential growth type, correlating factors, and association with postoperative survival.

Background: Little is known about the growth dynamics of untreated glioblastoma and its possible influence on postoperative survival. Our aim was to analyze a possible association of preoperative growth dynamics with postoperative survival. Methods: We performed a retrospective analysis of all adult patients surgically treated for newly diagnosed glioblastoma at our center between 2010 and 2020. By volumetric analysis of data of patients with availability of ≥3 preoperative sequential MRI, a growth pattern was aimed to be identified. Main inclusion criterion for further analysis was the availability of two preoperative MRI scans with a slice thickness of 1 mm, at least 7 days apart. Individual growth rates were calculated. Association with overall survival (OS) was examined by multivariable. Results: Out of 749 patients screened, 13 had ≥3 preoperative MRI, 70 had 2 MRI and met the inclusion criteria. A curve estimation regression model showed the best fit for exponential tumor growth. Median tumor volume doubling time (VDT) was 31 days, median specific growth rate (SGR) was 2.2% growth per day. SGR showed negative correlation with tumor size (rho = -0.59, P < .001). Growth rates were dichotomized according to the median SGR.OS was significantly longer in the group with slow growth (log-rank: P = .010). Slower preoperative growth was independently associated with longer overall survival in a multivariable Cox regression model for patients after tumor resection. Conclusions: Especially small lesions suggestive of glioblastoma showed exponential tumor growth with variable growth rates and a median VDT of 31 days. SGR was significantly associated with OS in patients with tumor resection in our sample.

Intrafractional motion detection for spine SBRT via X-ray imaging using ExacTrac Dynamic.

Purpose: Due to its close vicinity to critical structures, especially the spinal cord, standards for safety for spine stereotactic body radiotherapy (SBRT) should be high. This study was conducted, to evaluate intrafractional motion during spine SBRT for patients without individualized immobilization (e.g., vacuum cushions) using high accuracy patient monitoring via orthogonal X-ray imaging. Methods: Intrafractional X-ray data were collected from 29 patients receiving 79 fractions of spine SBRT. No individualized immobilization devices were used during the treatment. Intrafractional motion was monitored using the ExacTrac Dynamic (ETD) System (Brainlab AG, Munich, Germany). Deviations were detected in six degrees of freedom (6 DOF). Tolerances for repositioning were 0.7 mm for translational and 0.5° for rotational deviations. Patients were repositioned when the tolerance levels were exceeded. Results: Out of the 925 pairs of stereoscopic X-ray images examined, 138 (15 %) showed at least one deviation exceeding the predefined tolerance values. In all 6 DOF together, a total of 191 deviations out of tolerance were recorded. The frequency of deviations exceeding the tolerance levels varied among patients but occurred in all but one patient. Deviations out of tolerance could be seen in all 6 DOF. Maximum translational deviations were 2.6 mm, 2.3 mm and 2.8 mm in the lateral, longitudinal and vertical direction. Maximum rotational deviations were 1.8°, 2.6° and 1.6° for pitch, roll and yaw, respectively. Translational deviations were more frequent than rotational ones, and frequency and magnitude of deviations showed an inverse correlation. Conclusion: Intrafractional motion detection and patient repositioning during spine SBRT using X-ray imaging via the ETD System can lead to improved safety during the application of high BED in critical locations. When using intrafractional imaging with low thresholds for re-positioning individualized immobilization devices (e.g. vacuum cushions) may be omitted.

Repeatability quantification of brain diffusion-weighted imaging for future clinical implementation at a low-field MR-linac.

BACKGROUND: Longitudinal assessments of apparent diffusion coefficients (ADCs) derived from diffusion-weighted imaging (DWI) during intracranial radiotherapy at magnetic resonance imaging-guided linear accelerators (MR-linacs) could enable early response assessment by tracking tumor diffusivity changes. However, DWI pulse sequences are currently unavailable in clinical practice at low-field MR-linacs. Quantifying the in vivo repeatability of ADC measurements is a crucial step towards clinical implementation of DWI sequences but has not yet been reported on for low-field MR-linacs. This study assessed ADC measurement repeatability in a phantom and in vivo at a 0.35 T MR-linac. METHODS: Eleven volunteers and a diffusion phantom were imaged on a 0.35 T MR-linac. Two echo-planar imaging DWI sequence variants, emphasizing high spatial resolution ("highRes") and signal-to-noise ratio ("highSNR"), were investigated. A test-retest study with an intermediate outside-scanner-break was performed to assess repeatability in the phantom and volunteers' brains. Mean ADCs within phantom vials, cerebrospinal fluid (CSF), and four brain tissue regions were compared to literature values. Absolute relative differences of mean ADCs in pre- and post-break scans were calculated for the diffusion phantom, and repeatability coefficients (RC) and relative RC (relRC) with 95% confidence intervals were determined for each region-of-interest (ROI) in volunteers. RESULTS: Both DWI sequence variants demonstrated high repeatability, with absolute relative deviations below 1% for water, dimethyl sulfoxide, and polyethylene glycol in the diffusion phantom. RelRCs were 7% [5%, 12%] (CSF; highRes), 12% [9%, 22%] (CSF; highSNR), 9% [8%, 12%] (brain tissue ROIs; highRes), and 6% [5%, 7%] (brain tissue ROIs; highSNR), respectively. ADCs measured with the highSNR variant were consistent with literature values for volunteers, while smaller mean values were measured for the diffusion phantom. Conversely, the highRes variant underestimated ADCs compared to literature values, indicating systematic deviations. CONCLUSIONS: High repeatability of ADC measurements in a diffusion phantom and volunteers' brains were measured at a low-field MR-linac. The highSNR variant outperformed the highRes variant in accuracy and repeatability, at the expense of an approximately doubled voxel volume. The observed high in vivo repeatability confirms the potential utility of DWI at low-field MR-linacs for early treatment response assessment.

The role of online MR-guided multi-fraction stereotactic ablative radiotherapy in lung tumours.

Background: The aim of this prospective observational study was to evaluate the dosimetry benefits, changes in pulmonary function, and clinical outcome of online adaptive MR-guided SBRT. Methods: From 11/2020-07/2022, 45 consecutive patients with 59 lesions underwent multi-fraction SBRT (3-8 fractions) at our institution. Patients were eligible if they had biopsy-proven NSCLC or lung cancer/metastases diagnosed via clinical imaging. Endpoints were local control (LC) and overall survival (OS). We evaluated PTV/GTV dose coverage, organs at risk exposure, and changes in pulmonary function (PF). Acute toxicity was classified per the National Cancer Institute-Common Terminology Criteria for Adverse Events version 5.0. Results: The median PTV was 14.4 cm3 (range: 3.4 - 96.5 cm3). In total 195/215 (91%) plans were reoptimised. In the reoptimised vs. predicted plans, PTV coverage by the prescribed dose increased in 94.6% of all fractions with a median increase in PTV VPD of 5.6% (range: -1.8 - 44.6%, p < 0.001), increasing the number of fractions with PTV VPD ≥ 95% from 33% to 98%. The PTV D95% and D98% (BED10) increased in 93% and 95% of all fractions with a median increase of 7.7% (p < 0.001) and 10.6% (p < 0.001). The PTV D95% (BED10) increased by a mean of 9.6 Gy (SD: 10.3 Gy, p < 0.001). At a median follow-up of 21.4 months (95% CI: 12.3-27.0 months), 1- and 2-year LC rates were 94.8% (95% CI: 87.6 - 100.0%) and 91.1% (95% CI: 81.3 - 100%); 1- and 2-year OS rates were 85.6% (95% CI: 75.0 - 96.3%) and 67.1 % (95% CI: 50.3 - 83.8%). One grade ≥ 3 toxicity and no significant reduction in short-term PF parameters were recorded. Conclusions: Online adaptive MR-guided SBRT is an effective, safe and generally well tolerated treatment option for lung tumours achieving encouraging local control rates with significantly improved target volume coverage.

Impact of daily plan adaptation on accumulated doses in ultra-hypofractionated magnetic resonance-guided radiation therapy of prostate cancer.

Background and purpose: Ultra-hypofractionated online adaptive magnetic resonance-guided radiotherapy (MRgRT) is promising for prostate cancer. However, the impact of online adaptation on target coverage and organ-at-risk (OAR) sparing at the level of accumulated dose has not yet been reported. Using deformable image registration (DIR)-based accumulation, we compared the delivered adapted dose with the simulated non-adapted dose. Materials and methods: Twenty-three prostate cancer patients treated at two clinics with 0.35 T magnetic resonance-guided linear accelerator (MR-linac) following the same treatment protocol (5 × 7.5 Gy with urethral sparing and daily adaptation) were included. The fraction MR images were deformably registered to the planning MR image. Both non-adapted and adapted fraction doses were accumulated with the corresponding vector fields. Two DIR approaches were implemented. PTV* (planning target volume minus urethra+2mm) D95%, CTV* (clinical target volume minus urethra) D98%, and OARs (urethra+2mm, bladder, and rectum) D0.2cc, were evaluated. Statistical significance was inferred from a two-tailed Wilcoxon signed-rank test (p < 0.05). Results: Normalized to the baseline, the accumulated PTV* D95% increased significantly by 2.7 % ([1.5, 4.3]%) through adaptation, and the CTV* D98% by 1.2 % ([0.1, 1.7]%). For the OARs after adaptation, accumulated bladder D0.2cc decreased by 0.4 % ([-1.2, 0.4]%), urethra+2mmD0.2cc by 0.8 % ([-1.6, -0.1]%), while rectum D0.2cc increased by 2.6 % ([1.2, 4.9]%). For all patients, rectum D0.2cc was still below the clinical constraint. Results of both DIR approaches differed on average by less than 0.2 %. Conclusions: Online adaptation in MRgRT improved target coverage and OARs sparing at the level of accumulated dose.

Stereotactic body radiotherapy for pancreatic cancer - A systematic review of prospective data.

Purpose: This systematic review aims to comprehensively summarize the current prospective evidence regarding Stereotactic Body Radiotherapy (SBRT) in various clinical contexts for pancreatic cancer including its use as neoadjuvant therapy for borderline resectable pancreatic cancer (BRPC), induction therapy for locally advanced pancreatic cancer (LAPC), salvage therapy for isolated local recurrence (ILR), adjuvant therapy after radical resection, and as a palliative treatment. Special attention is given to the application of magnetic resonance-guided radiotherapy (MRgRT). Methods: Following PRISMA guidelines, a systematic review of the Medline database via PubMed was conducted focusing on prospective studies published within the past decade. Data were extracted concerning study characteristics, outcome measures, toxicity profiles, SBRT dosage and fractionation regimens, as well as additional systemic therapies. Results and conclusion: 31 studies with in total 1,571 patients were included in this review encompassing 14 studies for LAPC, 9 for neoadjuvant treatment, 2 for adjuvant treatment, 2 for ILR, with an additional 4 studies evaluating MRgRT. In LAPC, SBRT demonstrates encouraging results, characterized by favorable local control rates. Several studies even report conversion to resectable disease with substantial resection rates reaching 39%. The adoption of MRgRT may provide a solution to the challenge to deliver ablative doses while minimizing severe toxicities. In BRPC, select prospective studies combining preoperative ablative-dose SBRT with modern induction systemic therapies have achieved remarkable resection rates of up to 80%. MRgRT also holds potential in this context. Adjuvant SBRT does not appear to confer relevant advantages over chemotherapy. While prospective data for SBRT in ILR and for palliative pain relief are limited, they corroborate positive findings from retrospective studies.

The Traumatic Inoculation Process Affects TSPO Radioligand Uptake in Experimental Orthotopic Glioblastoma.

BACKGROUND: The translocator protein (TSPO) has been proven to have great potential as a target for the positron emission tomography (PET) imaging of glioblastoma. However, there is an ongoing debate about the potential various sources of the TSPO PET signal. This work investigates the impact of the inoculation-driven immune response on the PET signal in experimental orthotopic glioblastoma. METHODS: Serial [18F]GE-180 and O-(2-[18F]fluoroethyl)-L-tyrosine ([18F]FET) PET scans were performed at day 7/8 and day 14/15 after the inoculation of GL261 mouse glioblastoma cells (n = 24) or saline (sham, n = 6) into the right striatum of immunocompetent C57BL/6 mice. An additional n = 25 sham mice underwent [18F]GE-180 PET and/or autoradiography (ARG) at days 7, 14, 21, 28, 35, 50 and 90 in order to monitor potential reactive processes that were solely related to the inoculation procedure. In vivo imaging results were directly compared to tissue-based analyses including ARG and immunohistochemistry. RESULTS: We found that the inoculation process represents an immunogenic event, which significantly contributes to TSPO radioligand uptake. [18F]GE-180 uptake in GL261-bearing mice surpassed [18F]FET uptake both in the extent and the intensity, e.g., mean target-to-background ratio (TBRmean) in PET at day 7/8: 1.22 for [18F]GE-180 vs. 1.04 for [18F]FET, p < 0.001. Sham mice showed increased [18F]GE-180 uptake at the inoculation channel, which, however, continuously decreased over time (e.g., TBRmean in PET: 1.20 at day 7 vs. 1.09 at day 35, p = 0.04). At the inoculation channel, the percentage of TSPO/IBA1 co-staining decreased, whereas TSPO/GFAP (glial fibrillary acidic protein) co-staining increased over time (p < 0.001). CONCLUSION: We identify the inoculation-driven immune response to be a relevant contributor to the PET signal and add a new aspect to consider for planning PET imaging studies in orthotopic glioblastoma models.