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.

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.

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.

Understanding Relative Biological Effectiveness and Clinical Outcome of Prostate Cancer Therapy Using Particle Irradiation: Analysis of Tumor Control Probability With the Modified Microdosimetric Kinetic Model.

PURPOSE: Recent experimental studies and clinical trial results might indicate that-at least for some indications-continued use of the mechanistic model for relative biological effectiveness (RBE) applied at carbon ion therapy facilities in Europe for several decades (LEM-I) may be unwarranted. We present a novel clinical framework for prostate cancer treatment planning and tumor control probability (TCP) prediction based on the modified microdosimetric kinetic model (mMKM) for particle therapy. METHODS AND MATERIALS: Treatment plans of 91 patients with prostate tumors (proton: 46, carbon ions: 45) applying 66 GyRBE [RBE = 1.1 for protons and LEM-I, (α/ß)x = 2.0 Gy, for carbon ions] in 20 fractions were recalculated using mMKM [(α/ß)x = 3.1 Gy]). Based solely on the response data of photon-irradiated patient groups stratified according to risk and usage of androgen deprivation therapy, we derived parameters for an mMKM-based Poisson-TCP model. Subsequently, new carbon and helium ion plans, adhering to prescribed biological dose criteria, were generated. These were systematically compared with the clinical experience of Japanese centers employing an analogous fractionation scheme and existing proton plans. RESULTS: mMKM predictions suggested significant biological dose deviation between the proton and carbon ion arms. Patients irradiated with protons received (3.25 ± 0.08) GyRBEmMKM/Fx, whereas patients treated with carbon ions received(2.51 ± 0.05) GyRBEmMKM/Fx. TCP predictions were (86 ± 3)% for protons and (52 ± 4)% for carbon ions, matching the clinical outcome of 85% and 50%. Newly optimized carbon ion plans, guided by the mMKM/TCP model, effectively replicated clinical data from Japanese centers. Using mMKM, helium ions exhibited similar target coverage as proton and carbon ions and improved rectum and bladder sparing compared with proton. CONCLUSIONS: Our mMKM-based model for prostate cancer treatment planning and TCP prediction was validated against clinical data for proton and carbon ion therapy, and its application was extended to helium ion therapy. Based on the data presented in this work, mMKM seems to be a good candidate for clinical biological calculations in carbon ion therapy for prostate cancer.

Repeat surgery of recurrent glioma for molecularly informed treatment in the age of precision oncology: A risk-benefit analysis.

PURPOSE: Surgery for recurrent glioma provides cytoreduction and tissue for molecularly informed treatment. With mostly heavily pretreated patients involved, it is unclear whether the benefits of repeat surgery outweigh its potential risks. METHODS: Patients receiving surgery for recurrent glioma WHO grade 2-4 with the goal of tissue sampling for targeted therapies were analyzed retrospectively. Complication rates (surgical, neurological) were compared to our institutional glioma surgery cohort. Tissue molecular diagnostic yield, targeted therapies and post-surgical survival rates were analyzed. RESULTS: Between 2017 and 2022, tumor board recommendation for targeted therapy through molecular diagnostics was made for 180 patients. Of these, 70 patients (38%) underwent repeat surgery. IDH-wildtype glioblastoma was diagnosed in 48 patients (69%), followed by IDH-mutant astrocytoma (n = 13; 19%) and oligodendroglioma (n = 9; 13%). Gross total resection (GTR) was achieved in 50 patients (71%). Tissue was processed for next-generation sequencing in 64 cases (91%), and for DNA methylation analysis in 58 cases (83%), while immunohistochemistry for mTOR phosphorylation was performed in 24 cases (34%). Targeted therapy was recommended in 35 (50%) and commenced in 21 (30%) cases. Postoperatively, 7 patients (11%) required revision surgery, compared to 7% (p = 0.519) and 6% (p = 0.359) of our reference cohorts of patients undergoing first and second craniotomy, respectively. Non-resolving neurological deterioration was documented in 6 cases (10% vs. 8%, p = 0.612, after first and 4%, p = 0.519, after second craniotomy). Median survival after repeat surgery was 399 days in all patients and 348 days in GBM patients after repeat GTR. CONCLUSION: Surgery for recurrent glioma provides relevant molecular diagnostic information with a direct consequence for targeted therapy under a reasonable risk of postoperative complications. With satisfactory postoperative survival it can therefore complement a multi-modal glioma therapy approach.

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.