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.

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.

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 radiosurgery for brain metastases from pelvic gynecological malignancies: oncologic outcomes, validation of prognostic scores, and dosimetric evaluation.

INTRODUCTION: Stereotactic radiosurgery is a well-established treatment option in the management of brain metastases. Multiple prognostic scores for prediction of survival following radiotherapy exist, but are not disease-specific or validated for radiosurgery in women with primary pelvic gynecologic malignancies metastatic to the brain. The aim of the present study is to evaluate the feasibility, safety, outcomes, and impact of established prognostic scores. METHODS: We retrospectively identified 52 patients treated with radiotherapy for brain metastases between 2008 and 2021. Stereotactic radiosurgery was utilized in 31 patients for an overall number of 75 lesions; the remaining 21 patients received whole-brain radiotherapy. Kaplan-Meier survival analysis and the log-rank test were used to calculate and compare survival curves and univariate and multivariate Cox regression to assess the influence of cofactors on recurrence, local control, and prognosis. RESULTS: With a median follow-up of 10.7 months, overall survival rates post radiosurgery were 65.3%, 51.3%, and 27.7% for 1, 2, and 5 years, respectively, which were significantly higher than post whole-brain radiotherapy (p=0.049). Five local failures (6.7%) were detected, resulting in 1 and 2 year local cerebral control rates of 97.4% and 94.0%, respectively. Univariate factors for prediction of superior overall survival were high performance status (p=0.030) and application of three prognostic scores, especially the Recursive Partitioning Analysis score (p=0.028). Uni- and multivariate analysis revealed that extracranial progression prior to radiosurgery was significant for inferior overall survival (p<0.0001). Radionecrosis was diagnosed in five women (16%); long-term neurotoxicity was significantly worse after whole-brain radiotherapy compared with radiosurgery (p=0.023). CONCLUSION: Stereotactic radiosurgery for brain metastases from pelvic gynecologic malignancies appears to be safe and well tolerated, achieving promising local cerebral control. Prognostic scores were shown to be transferable and radiosurgery should be recommended as primary intracranial treatment, especially in women with no prior extracranial progression and Recursive Partitioning Analysis class I.

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.

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.

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.

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.

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.

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.

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

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

Upfront and Repeated Stereotactic Radiosurgery in Patients With Brain Metastases From NSCLC.

INTRODUCTION: Approximately 40% of non-small-cell lung cancer (NSCLC) patients develop brain metastases (BM). Stereotactic radiosurgery (SRS) instead of whole-brain radiotherapy (WBRT) is increasingly administered as an upfront treatment to patients with a limited number of BM. We present outcomes and validation of prognostic scores for these patients treated with upfront SRS. METHODS: We retrospectively analyzed 199 patients with a total of 268 SRS courses for 539 brain metastases. Median patient age was 63 years. For larger BM, dose reduction to 18 Gy or hypofractionated SRS in 6 fractions was applied. We analyzed the BMV-, the RPA-, the GPA- and the lung-mol GPA score. Cox proportional hazards models with univariate and multivariate analyses were fitted for overall survival (OS) and intracranial progression-free survival (icPFS). RESULTS: Sixty-four patients died, 7 of them of neurological causes. Thirty eight patients (19,3%) required a salvage WBRT. Median OS was 38, 8 months (IQR: 6-NA). In univariate analysis as well as multivariate analysis, the Karnofsky performance scale index (KPI) ≥90% (P = 0, 012 and P = 0, 041) remained as independent prognostic factor for longer OS. All 4 prognostic scoring indices could be validated for OS assessment (BMV P = 0, 007; RPA P = 0, 026; GPA P = 0, 003; lung-mol GPA P = 0, 05). CONCLUSION: In this large cohort of NSCLC patients with BM treated with upfront and repeated SRS, OS was markedly favourable, in comparison to literature. Upfront SRS is an effective treatment approach in those patients and can decidedly reduce the impact of BM on overall prognosis. Furthermore, the analysed scores are useful prognostic tools for OS prediction.

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.

Oral Sequelae after Head and Neck Radiotherapy: RCT Comparing 3D-Printed Tissue Retraction Devices with Conventional Dental Splints.

OBJECTIVES: To evaluate oral sequelae after head and neck radiotherapy (RT) when using two different types of intraoral appliances. Thermoplastic dental splints (active control) protect against backscattered radiation from dental structures. Semi-individualized, 3D-printed tissue retraction devices (TRDs, study group) additionally spare healthy tissue from irradiation. MATERIALS AND METHODS: A total of 29 patients with head and neck cancer were enrolled in a randomized controlled pilot trial and allocated to receive TRDs (n = 15) or conventional splints (n = 14). Saliva quality and quantity (Saliva-Check, GC), taste perception (Taste strips, Burghart-Messtechnik), and oral disability (JFLS-8, OHIP-14, maximum mouth opening) were recorded before and 3 months after RT start. Radiotherapy target volume, modality, total dose, fractionation, and imaging guidance were case-dependent. To evaluate intra-group developments between baseline and follow-up, nonparametric Wilcoxon tests were performed. Mann-Whitney-U tests were applied for inter-group comparisons. RESULTS: At follow-up, taste perception was unimpaired (median difference in the total score; TRDs: 0, control: 0). No significant changes were found regarding oral disability. Saliva quantity (stimulated flow) was significantly reduced with conventional splints (median -4 mL, p = 0.016), while it decreased insignificantly with TRDs (median -2 mL, p = 0.07). Follow-up was attended by 9/15 study group participants (control 13/14). Inter-group comparisons showed no significant differences but a tendency towards a better outcome for disability and saliva quality in the intervention group. CONCLUSION: Due to the small cohort size and the heterogeneity of the sample, the results must be interpreted with reservation. Further research must confirm the positive trends of TRD application. Negative side-effects of TRD application seem improbable.

To fly or not to fly: Stereotactic MR-guided adaptive radiotherapy effectively treats ultracentral lung tumors with favorable long-term outcomes.

BACKGROUND: Stereotactic radiotherapy of ultracentral lung tumors (ULT) is challenging as it may cause overdoses to sensitive mediastinal organs with severe complications. We aimed to describe long-term outcomes after stereotactic magnetic resonance (MR)-guided online adaptive radiotherapy (SMART) as an innovative treatment of ULT. PATIENTS & METHODS: We analyzed 36 patients that received SMART to 40 tumors between 02/2020 - 08/2021 inside prospective databases. ULT were defined by planning target volume (PTV) overlap with the proximal bronchial tree or esophagus. We calculated Kaplan Meier estimates for overall survival (OS) and progression-free survival (PFS), and competing risk estimates for the incidence of tumor progression and treatment-related toxicities. ULT patients (N = 16) were compared to non-ULT patients (N = 20). RESULTS: Baseline characteristics were similar between ULT and non-ULT, but ULT were larger (median PTV: ULT 54.7 cm3, non-ULT 19.2 cm3). Median follow-up was 23.6 months. ULT and non-ULT showed a similar OS (2-years: ULT 67%, non-ULT 60%, p = 0.7) and PFS (2-years: ULT 37%, non-ULT 34%, p = 0.73). Progressions occurred mainly at distant sites (2-year incidence of distant progression: ULT 63%, non-ULT 61%, p = 0.77), while local tumor control was favorable (2-year incidence of local progression: ULT 7%, non-ULT 0%, p = 0.22). Treatment of ULT led to significantly more toxicities ≥ grade (G) 2 (ULT: 9 (56%), non-ULT: 1 (5%), p = 0.002). Most toxicities were moderate (G2). Two ULT patients developed high-grade toxicities: 1) esophagitis G3 and bronchial bleeding G4 after VEGF treatment, 2) bronchial bleeding G3. Estimated incidence of high-grade toxicities was 19% (3-48%) in ULT, and no treatment-related death occurred. CONCLUSION: Our small series supports SMART as potentially effective treatment of ULT. SMART with careful fractionation could reduce severe complications, but treatment of ULT remains a high-risk procedure and needs careful benefit-risk-assessment.

Clinical outcome following surgical resection and radiotherapy in adult patients with pleomorphic xanthoastrocytoma as defined by DNA methylation profiling.

Background: Molecular brain tumor classification using DNA methylation profiling has revealed that the methylation-class of pleomorphic xanthoastrocytoma (mcPXA) comprised a substantial portion of divergent initial diagnoses, which had been established based on histology alone. This study aimed to characterize the survival outcome in patients with mcPXAs-in light of the diverse selected treatment regimes. Methods: A retrospective cohort of adult mcPXAs were analyzed in regard to their progression-free survival following surgical resection and postoperative radiotherapy. Radiotherapy treatment plans were correlated with follow-up images to characterize the pattern of relapse. Treatment toxicities and molecular tumor characteristics were further analyzed. Results: Divergent initial histological diagnoses were encountered in 40.7%. There was no significant difference in local progression-free (PFS) and overall survival (OS) following gross total or subtotal resection. Postoperative radiotherapy was completed in 81% (22/27) following surgical intervention. Local PFS was 54.4% (95% CI: 35.3-84.0%) and OS was 81.3% (95% CI: 63.8-100%) after 3 years following postoperative radiotherapy. Initial relapses post-radiotherapy were primarily located in the previous tumor location and/or the planning target volume (PTV) (12/13). All patients in our cohort demonstrated the prognostically favorable pTERT-wildtype mcPXA. Conclusion: Our study demonstrated that adult patients with mcPXAs display a worse progression-free survival compared to the reported WHO grade 2 PXAs. Future matched-pair analyses are required with a non-irradiated cohort to elucidate the benefit of postoperative radiotherapy in adult patients with mcPXAs.

Analysis of recurrence probability following radiotherapy in patients with CNS WHO grade 2 meningioma using integrated molecular-morphologic classification.

Background: The current World Health Organization (WHO) classification of brain tumors distinguishes 3 malignancy grades in meningiomas, with increasing risk of recurrence from CNS WHO grades 1 to 3. Radiotherapy is recommended by current EANO guidelines for patients not safely amenable to surgery or after incomplete resection in higher grades. Despite adequately predicting recurrence probability for the majority of CNS WHO grade 2 meningioma patients, a considerable subset of patients demonstrates an unexpectedly early tumor recurrence following radiotherapy. Methods: A retrospective cohort of 44 patients with CNS WHO grade 2 meningiomas were stratified into 3 risk groups (low, intermediate, and high) using an integrated morphological, CNV- and methylation family-based classification. Local progression-free survival (lPFS) following radiotherapy (RT) was analyzed and total dose of radiation was correlated with survival outcome. Radiotherapy treatment plans were correlated with follow-up images to characterize the pattern of relapse. Treatment toxicities were further assessed. Results: Risk stratification of CNS WHO grade 2 meningioma into integrated risk groups demonstrated a significant difference in 3-year lPFS following radiotherapy between the molecular low- and high-risk groups. Recurrence pattern analysis revealed that 87.5 % of initial relapses occurred within the RT planning target volume or resection cavity. Conclusions: Integrated risk scoring can identify CNS WHO grade 2 meningioma patients at risk or relapse and dissemination following radiotherapy. Therapeutic management of CNS WHO grade 2 meningiomas and future clinical trials should be adjusted according to the molecular risk-groups, and not rely on conventional CNS WHO grading alone.

Results of a prospective randomized trial on long-term effectiveness of protons and carbon ions in prostate cancer: LEM I and α/ß = 2 Gy overestimates the RBE.

AIM: To analyze the long-term effectiveness of carbon ions relative to protons in the prospective randomized controlled ion prostate irradiation (IPI) trial. METHODS: Effectiveness via PSA assessment in a randomized study on prostate irradiation with 20x3.3 Gy(RBE) protons versus carbon ions was analyzed in 92 patients. Proton RBE was based on a fixed RBE of 1.1 while the local effect model (LEM) I and an α/ß = 2 Gy was used for carbon ions. The dose in the prostate was recalculated based on the delivered treatment plan using LEM I and LEM IV and different α/ß values. RESULTS: Five-year overall and progression free survival was 98% and 85% with protons and 91% and 50% with carbon ions, respectively, with the latter being unexpectedly low compared to Japanese carbon ion data and rather corresponding to a photon dose <72 Gy in 2 Gy fractions. According to LEM I and the applied α/ß-value of 2 Gy, the applied carbon ion dose in 2 Gy(RBE) fractions (EQD2) was 87.46 Gy(RBE). Recalculations confirmed a strong dependence of RBE-weighted dose on the α/ß ratio as well as on the RBE-model. CONCLUSION: The data demonstrate a significant lower effectiveness of the calculated RBE-weighted dose in the carbon ion as compared to the proton arm. LEM I and an α/ß = 2 Gy overestimates the RBE for carbon ions in prostate cancer treatment. Adjusting the biological dose calculation by using LEM I with α/ß = 4 Gy could be a pragmatic way to safely escalate dose in carbon ion radiotherapy for prostate cancer.

Postoperative Radiotherapy and the Role of Regional Lymph Node Irradiation in Localized Merkel Cell Carcinoma: A Single-Center Retrospective Analysis.

The aim of this study was to analyze the pattern of relapse of patients with Merkel cell carcinoma (MCC) that underwent resection of the primary tumor site and postoperative radiotherapy at the Department of Radiation Oncology of Heidelberg University and to determine the role of the elective radiotherapy of regional lymph nodes with respect to SLNB results. A total of 57 patients were included in the present retrospective analysis. A total of 33 patients had additional lymph node irradiation (LNI); 24 had postoperative radiotherapy of the tumor bed only. Median follow-up was 43 months. Recurrence rate of the total cohort was 22.8%. Most relapses (69%) occurred in the regional nodes. Cumulative infield-tumor recurrence rate was low with 5.3%. Regional recurrence was more frequent in the cohort without LNI with 85.7% versus 37.5% with LNI. These results were similar for patients with negative sentinel lymph node (SLN) only with 80% regional relapses for those without LNI versus 33% with LNI. In conclusion, our data show that regional recurrence is the most frequent site of relapse in stage I-III MCC treated with curative intended postoperative radiotherapy and that elective irradiation of the regional lymph nodes reduces the risk of regional relapse even if the SLN was negative.

Secondary Malignancy Risk Following Proton vs. X-ray Radiotherapy of Thymic Epithelial Tumors: A Comparative Modeling Study of Thoracic Organ-Specific Cancer Risk.

BACKGROUND: Proton beam radiotherapy (PBT) offers physical dose advantages that might reduce the risk for secondary malignancies (SM). The aim of the current study is to calculate the risk for SM after X-ray-based 3D conformal (3DCRT) radiotherapy, intensity-modulated radiotherapy (IMRT), and active pencil beam scanned proton therapy (PBS) in patients treated for thymic malignancies. METHODS: Comparative treatment plans for each of the different treatment modalities were generated for 17 patients. The risk for radiation-induced SM was estimated using two distinct prediction models-the Dasu and the Schneider model. RESULTS: The total and fatal SM risks estimated using the Dasu model demonstrated significant reductions with the use of PBS relative to both 3DCRT and IMRT for all independent thoracic organs analyzed with the exception of the thyroid gland (p ≤ 0.001). SM rates per 10,000 patients per year per Gy evaluated using the Schneider model also resulted in significant reductions with the use of PBS relative to 3DCRT and IMRT for the lungs, breasts, and esophagus (p ≤ 0.001). CONCLUSIONS: PBS achieved superior sparing of relevant OARs compared to 3DCRT and IMRT, leading to a lower risk for radiation-induced SM. PBS should therefore be considered in patients diagnosed with thymic malignancies, particularly young female patients.