H3 K27-altered diffuse midline glioma (DMG) is a molecularly defined, highly aggressive tumor entity since the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). It has been most extensively characterized in children and adolescents and continues to pose significant challenges to treating physicians due to its growth along the midline structures of the brain and its ability to progress distantly leading to poor prognosis. Clinical and molecular determinants of distant progression and its impact on patient survival particularly in adults have not been thoroughly characterized. This retrospective multicenter cohort study of 52 adult patients with DMG was analyzed for clinical and molecular predictors of distant tumor progression using gene panel sequencing and genome-wide DNA methylation arrays. Distant progression including leptomeningeal disease occurred in 10 out of 52 adult patients (19

Brain metastases occur in approximately 20

Abstract Purpose For patients with large or symptomatic brain metastases (BM), the standard treatment is surgical resection followed by adjuvant radiotherapy to the resection cavity. This prospective, single-arm, open-label phase 2 trial evaluated the safety and efficacy of low-energy X-ray intraoperative radiotherapy (IORT) in patients with resected BM. Methods and Materials Between 2017 and 2022, 35 patients with suspected BM were enrolled. After tumor resection and intraoperative frozen-section confirmation, IORT was delivered using a mobile low-energy X-ray device. A dose of 30 Gy was prescribed to the surface of the resection cavity. The primary endpoint was local control rate (LCR). Secondary endpoints included the incidence of distant intracranial metastases (regional control rate, RCR), overall survival (OS), time to initiation of subsequent systemic therapy, and treatment-related adverse events. Results The median patient age was 64 years (range, 45–85), and 54.3% of patients were male. Lung cancer was the primary tumor in 68.6% of cases. Mean tumor volume was 10.7 cm³ (SD ± 9.5). At study termination, 51.4% of patients were alive. At a mean follow-up of 25.7 months (range, 0.8–64.5 months), the LCR was 94.3% (95% CI, 82.9–98.8%), and the RCR was 57.1% (95% CI, 40.7–72.4%). Median OS was 43.6 months (95% CI, 8.8–78.4%). Leptomeningeal disease outside the irradiated field occurred in 8.6% of patients. Grade 2 or 3 radionecrosis was observed in n = 2 patients, with no identifiable associated risk factors. Overall survival did not differ significantly based on baseline Karnofsky Performance Status (p = 0.056) or development of radionecrosis (any grade, p = 0.214). The mean time to initiation of subsequent systemic therapy was 45.0 days (95% CI, 35.1–54.8). No grade 4 or 5 IORT-related adverse events were observed. Conclusion Intraoperative radiotherapy to the resection cavity achieved excellent local control with a safety profile comparable to postoperative stereotactic radiosurgery.

BACKGROUND:Despite maximal safe resection and chemoradiotherapy, most glioblastomas recur locally. We aimed to evaluate whether additional intraoperative radiotherapy compared with standard of care improves outcomes in patients with newly diagnosed glioblastoma. METHODS:INTRAGO-II was an open-label, multicentre, randomised, controlled, phase 3 trial enrolling patients aged 18-80 years with supratentorial glioblastoma amenable to resection of the contrast enhancing tumour with Karnofsky performance score (KPS) of ≥60%. Patients from 18 centres in Brazil, Canada, China, Germany, Spain, South Korea, and the USA were randomly assigned (1:1) intraoperatively to receive additional kilovoltage intraoperative radiotherapy with 30 Gy (intraoperative radiotherapy group) or surgery alone (standard-of-care group), stratified by age, KPS, and residual tumour. Postoperative treatment consisted of external-beam radiotherapy to 60 Gy with concurrent temozolomide (75 mg/m2), followed by six adjuvant cycles of temozolomide (150-200 mg/m2, days 1-5 every 28 days). The primary endpoint was median progression-free survival in the full-analysis set, confirmed by masked, centralised review. This ongoing study is closed to recruitment and is registered with ClinicalTrials.gov, NCT02685605. FINDINGS:Between Dec 9, 2016, and June 17, 2024, of 411 patients assessed for eligibility, 314 were randomly assigned. The full-analysis set comprised 298 patients (intraoperative radiotherapy, n=161; standard-of-care, n=137), of whom 127 (43%) patients were female and 171 (57%) were male. Data on race and ethnicity were not collected. At a median follow-up of 17·2 months (IQR 10·5-27·1), median progression-free survival was 11·0 months (95% CI 9·2-12·6) in the intraoperative radiotherapy group versus 11·4 months (9·7-13·9) in the standard-of-care group (hazard ratio [HR] 1·1, 95% CI 0·85-1·44; p=0·47). Local recurrence was the predominant pattern of failure in both groups (76 [72%] in the intraoperative radiotherapy group vs 60 [71%] in the standard-of-care group, p=0·87). The most common grade 3-4 adverse events were seizure (21 [13%] in the intraoperative radiotherapy group vs nine [7%] in the standard-of-care group), radiation necrosis (11 [7%] vs three [2%]; p=0·06), thrombocytopenia (seven [4%] vs 11 [8%]), and muscle weakness (12 [7%] vs 19 [14%]). In total, 252 serious adverse events occurred in 105 (65%) patients in the intraoperative radiotherapy group and 142 serious adverse events in 72 (53%) patients in the standard-of-care group. Of these, 65 (26%) events in 40 (38%) patients in the intraoperative radiotherapy group and 27 (19%) events in 19 (26%) patients in the standard-of-care group were considered possibly related to the treatment. Of all grade five adverse events reported, 14 in the intraoperative radiotherapy group (CNS toxicity [n=2], myocardial infarction [n=2], sepsis [n=2], and one each cardiac arrest, fever, lung infection, fracture, postoperative haemorrhage, neoplasm, haematoma, and not otherwise specified death) and six in the standard-of-care group (lung infection [n=2], and one each multiorgan failure, encephalitis, neoplasm, and cystitis) were attributable to specific CTCAE terms. INTERPRETATION:Instant, spatially precise dose escalation with intraoperative radiotherapy added to standard of care did not improve outcomes, questioning the value of further local dose intensification in resectable glioblastoma. FUNDING:Universities of Heidelberg and Bonn, Carl Zeiss Meditec, Deutsche Forschungsgemeinschaft.

Treatment of multiple brain metastases (BM) often involves surgical resection of one lesion combined with stereotactic radiotherapy (SRT) to the resection cavity and unresected BM. Intraoperative radiotherapy (IORT) is an emerging alternative for treating the resection cavity, potentially dosimetric benefits. This study aimed to compare the dosimetry of treating the resection cavity with IORT versus adjuvant SRT when combined with SRT for additional unresected BM. Ten patients with BM who received adjuvant SRT to the resection cavity plus concurrent SRT to additional BM (adjuvant SRT + SRT to BM group) and 4 patients with IORT and SRT to BM were identified. Post-hoc IORT plans were calculated for IORT patients and summed with corresponding SRT plans. Additionally, patients from the adjuvant SRT + SRT to BM group served as templates for IORT simulation and the simulated IORT plans were also summed with the corresponding plans for SRT to residual BM. The simulated IORT cases were then pooled with the actual IORT cases, forming the IORT + SRT to BM group. Brain dose exposure (V12Gy, V18Gy, V20Gy, V24Gy, V25Gy, and V30Gy) and maximum doses (D0.035 cm³) to the brainstem and optic tract were evaluated. The IORT + SRT to BM group showed significantly lower brain dose exposure across all metrics (V12Gy-V30Gy) compared to the adjuvant SRT + SRT to BM group (p < 0.05 for all). Maximum doses to organs at risk were lower in the IORT + SRT to BM group, with mean D0.035 cm³ reduced by 37.7

BACKGROUND/AIM:Stereotactic radiotherapy (SRT), including stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT), is the current standard adjuvant treatment after resection of brain metastases (BM). In the era of immunotherapy and targeted systemic therapies enabling effective extracranial control, achieving durable intracranial outcomes has become increasingly important. Intraoperative radiotherapy (IORT) is an emerging alternative to Gamma Knife-based irradiation. We aimed to assess the clinical outcome of BM resection cavities treated with Gamma Knife SRT (GK-SRT), for retrospective comparison to a cohort treated with IORT. PATIENTS AND METHODS:This retrospective single-center analysis included all patients who received GK-SRT to the resection cavity after complete surgical removal of BM. A total of 41 cavities from 37 patients were evaluated. Local control (LC), distant intracranial control (DIC), and overall survival (OS) were calculated, and the potential influence of whole-brain radiotherapy (WBRT) as part of the adjuvant treatment on OS was analyzed. RESULTS:With a median follow-up of 19.3 months, the 1-year LC was 93.3%. The 1-year DIC was 54.1%, and the median OS was 27.3 months. Median cavity volume was 5.89 cm3; the median interval from surgery to GK-SRT initiation was 24.5 days, and to subsequent systemic treatment 59.0 days. DIC, but not LC, was significantly associated with OS, with better DIC correlating with longer survival. WBRT as part of the adjuvant regimen did not confer a significant survival benefit. CONCLUSION:Adjuvant GK-SRT to the resection cavity is an effective treatment with excellent local control. Nonetheless, challenges remain regarding distant intracranial progression and overall survival.

Purpose Stereotactic radiosurgery (SRS) yields excellent local control in patients with a limited number of brain metastases (BMs), but radiation-induced cerebral edema and radiation necrosis (RN) in particular pose as a dose-limiting late toxicity, with the same holding true after fractionated radiotherapy for glioma. In symptomatic patients, the first-line standard of care includes corticosteroids, which may, however, be counterproductive in the evolving era of immunotherapy. Boswellic acid (BA), available as an over-the-counter dietary supplement, has been suggested as a potential corticosteroid-sparing alternative due to its anti-inflammatory and anti-angiogenic effects. Methods We performed a comprehensive literature search of the MEDLINE, Embase, Scopus, and Cochrane databases, identifying publications reporting on the use of BA during or after brain irradiation in humans. Using the RAMESES framework, relevant data are summarized using a meta-narrative approach. Results Six records (three for edema reduction in large irradiated volumes and three for RN after SRS) were identified, encompassing 130 patients. Roughly half of patients benefited from BA (radiographically or clinically) and about one-third could successfully taper dexamethasone or prevent its long-term intake. Tolerability of BA was favorable, with mild gastrointestinal discomfort being reported most frequently. Current drawbacks include unknown optimal formulation as well as timing and dosing, a considerably large number of required daily capsules, and uncertain interactions with other drugs. Conclusion Overall, the clinical evidence on the use of BA for radiation-induced cerebral edema and RN is lacking and well-designed prospective trials are warranted to further investigate this potential low-cost corticosteroid-sparing option.

PURPOSE:After surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy by enabling superior organ-at-risk preservation, reduction of in-hospital times, and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess the safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). METHODS AND MATERIALS:In a multicentric approach incorporating individual patient data from 6 international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis, leptomeningeal spread, local control, distant brain progression (DBP), and estimated overall survival. RESULTS:In total, 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow-up was 13.2 (range, 1.2-102.4) months, and the median IORT dose was 25 (range, 18-30) Gy prescribed to the applicator surface. There was 1 grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative radiation necrosis rate was observed. The 1-year local control rate was 98.0%, and the 1-year DBP-free survival rate was 60.0%. Median time to DBP was 5.5 (range, 1.0-18.5) months in the subgroup of patients experiencing DBP, and the cumulative leptomeningeal spread rate was 4.9%. The median estimated overall survival was 26 (range, 1.2 to not reached) months with a 1-year survival rate of 74.0%. Early initiation of immunotherapy/TTs was associated with a nonsignificant trend toward improved DBP rate and overall survival. CONCLUSIONS:The combination of ICIs/TTs with IORT for resected BMs does not seem to increase toxicity and yields encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial.

Abstract BACKGROUND Because of demographic changes in highly developed countries, the number of elderly patients requiring surgery for brain metastasis is increasing. However, concerns for risk-benefit ratio, ability to tolerate invasive treatment, and limited healthcare resources may explain why intracranial surgery is often declined in elderly patients. Although prognostic scores have been implemented to predict survival of patients with intracranial metastasis, no evaluation of those scores for the elderly population exist. We aimed to address the lack of data on the accuracy of prognostic scores in this specific population. MATERIAL AND METHODS Patients over the age of 65 who underwent surgery for intracranial metastases between 2015 and 2022 at the Department of Neurosurgery, University Hospital Mannheim (Germany) were retrospectively analysed. The evaluated prognostic scores included the recursive partitioning analysis (RPA) and the disease-specific grade prognostic assessment (ds-GPA). A log-rank analysis was conducted to assess differences in predicted versus observed survival. To further define the different model’s performance metrics, survival was classified into four classes (<6 months, 6-12 months, 12-24 months and < 24 months), and a confusion matrix was generated. The primary endpoint was the accuracy of prediction of survival in elderly patients with surgically treated intracranial metastases. RESULTS A total of 83 patients who underwent surgery for intracranial metastases between 2015 and 2022 were analysed. RPA and ds-GPA scores could be attributed for 83 and 77 patients, respectively. The mean age was 73.2 years. The 0.5-, 1-, 2- and 3-year probabilities of overall survival were 47%, 36%, 24% and 18% in the studied population, respectively. These probabilities were predicted to be 3%, 0%, 0% and 0% by the RPA model and 25%, 6%, 1% and 0% by the ds-GPA model. A statistically significant difference was observed between the predicted and actual survival rates in the studied population (p-value < 0.005). Using the categorised survival and a confusion matrix, the accuracy, recall, precision, and F1-score for the RPA model were 0.41, 0.17 and 0.24, respectively. The recall, precision, and F1 score for the DS-GPA model were 0.39, 0.36 and 0.31, respectively. Conclusion: Our analysis revealed a statistically significant discrepancy between predicted and actual survival in elderly patients with surgically treated intracranial metastases. These findings underscore the critical need for developing updated prognostic scoring systems specifically tailored to this population.

This brief report aimed to show the utility of photon-counting technology alongside standard cranial imaging protocols for visualizing shunt valves in a patient’s cranial computed tomography scan. Photon-counting CT scans with cranial protocols were retrospectively surveyed and four types of shunt valves were encountered: proGAV 2.0®, M.blue®, Codman Certas®, and proSA®. These scans were compared with those obtained from non-photon-counting scanners at different time points for the same patients. The analysis of these findings demonstrated the usefulness of photon-counting technology for the clear and precise visualization of shunt valves without any additional radiation or special reconstruction patterns. The enhanced utility of photon-counting is highlighted by providing superior spatial resolution compared to other CT detectors. This technology facilitates a more accurate characterization of shunt valves and may support the detection of subtle abnormalities and a precise assessment of shunt valves.

Abstract BACKGROUND Fractionated stereotactic radiotherapy to the resection cavity boosts local control of resected brain metastases significantly. However, start of systemic tumor-directed treatment may be protracted and in-hospital times prolonged. Lately, lex-ioRT of BM has been described as a safe and effective one stop-shop treatment modality with a 1-year local control rate of up to 98% while potentially improving patient convenience. Study Design: The LEXIMATE-trial is a multicenter, international, randomized open-label confirmatory trial comparing lex-IORT with FSRT of resected BM. In the experimental arm, INTRABEAM (Carl Zeiss Meditec AG) is used to deliver IORT by application of 50-kV photons at a standard dose of 30 Gy prescribed to the applicator surface. Standard linear accelerator or Gamma Knife based FSRT (3-7 fractions) to the surgical bed is used in the control arm. The primary endpoint is the cumulative incidence of local recurrences (as per RANO-BM) considering death without prior local recurrence as competing event. Inclusion criteria include histologically confirmed BM with indication for resection according to EANO-ESMO/ASCO-SNO-ASTRO guidelines, ≤5 other brain lesions compatible with BM and amenable to radiosurgery and history of solid cancer or CT scan suggestive for localized or metastasized solid cancer (except germ cell tumors, lymphoma, small-cell lung cancer). The resection cavity must be <5cm in size, IORT doses to brainstem or optical tract may not exceed 8 Gy. Study design: Randomized, open-label, non-inferiority. Sample size: 70 patients per group to show a non-inferiority of the experimental therapy compared to the control therapy with a power of approximately 80%. DISCUSSION The best radio-oncologic procedure for resected BM remains under debate. The LEXIMATE-trial offers an opportunity to provide more solid prospective data on effectiveness, safety and patient comfort both for established and new RT techniques.

Abstract BACKGROUND Due to increasing age of the population, the number of elderly patients with brain metastasis accessible for surgery is increasing. The higher risk of peri-procedural complications and a reduced ability to tolerate aggressive treatment are often thought to limit intracranial surgery in older patients. However, little data are available on results of surgical brain metastasis treatment in elderly. In a subset of older patients who underwent surgical removal of brain metastases, we assessed the influence of age on survival and postoperative dependency. MATERIAL AND METHODS This is a retrospective observational study of patients over 65 years of age who underwent surgery for intracranial metastases between 2015 and 2022 at the Department of Neurosurgery, University Hospital Mannheim (Germany). The population was divided into group A (65-74 years old) and group B (75 years or older). The Eastern Cooperative Oncology Group (ECOG) score was used to assess functional status and independence. The primary endpoints were overall survival and the likelihood of remaining independent (ECOG <3) at 6 weeks. A wide range of clinical and radiological baseline factors were analysed. RESULTS 80 patients were included in the analysis. The mean age in the overall cohort was 73.2 years, and 74% of patients had a preoperative ECOG score of 2 or less. 48 patients were included in group A and 32 in group B. The 1-, 2- and 3-year probabilities of overall survival were 31%, 23% and 16% in group A and 38%, 23% and 23% in group B (p-value=0.61). Functional status in the overall cohort remained stable after surgery for most patients (70%), while 17% experienced a decline and 13% an improvement. 42 (88%) and 43 (90%) patients in group A were independent before and after surgery, respectively. 27 (84%) and 26 (81%) patients in group B were independent before and after surgery, respectively. 33 (69%) patients in group A and 19 (59%) patients in group B were independent at follow-up (p=0.65). No significant difference was found between the two groups for independence status preoperatively, postoperatively as well as at follow-up (p-values 0.69, 0.29 and 0.32, respectively). CONCLUSION In our analysis, neither survival nor outcome after surgery for brain metastases showed a correlation with age. Age alone should not be a barrier to intracranial surgery in carefully selected elderly patients with intracranial metastases.

Purpose In the randomized phase III trial CeTeG/NOA-09, temozolomide (TMZ)/lomustine (CCNU) combination therapy was superior to TMZ in newly diagnosed MGMT methylated glioblastoma, albeit reporting more frequent hematotoxicity. Here, we analyze high grade hematotoxicity and its prognostic relevance in the trial population. Methods Descriptive and comparative analysis of hematotoxicity adverse events ≥ grade 3 (HAE) according to the Common Terminology of Clinical Adverse Events, version 4.0 was performed. The association of HAE with survival was assessed in a landmark analysis. Logistic regression analysis was performed to predict HAE during the concomitant phase of chemotherapy. Results HAE occurred in 36.4% and 28.6% of patients under CCNU/TMZ and TMZ treatment, respectively. The median onset of the first HAE was during concomitant chemotherapy (i.e. first CCNU/TMZ course or daily TMZ therapy), and 42.9% of patients with HAE receiving further courses experienced repeat HAE. Median HAE duration was similar between treatment arms (CCNU/TMZ 11.5; TMZ 13 days). Chemotherapy was more often discontinued due to HAE in CCNU/TMZ than in TMZ (19.7 vs. 6.3%, p = 0.036). The occurrence of HAE was not associated with survival differences (p = 0.76). Regression analysis confirmed older age (OR 1.08) and female sex (OR 2.47), but not treatment arm, as predictors of HAE. Conclusion Older age and female sex are associated with higher incidence of HAE. Although occurrence of HAE was not associated with shorter survival, reliable prediction of patients at risk might be beneficial to allow optimal management of therapy and allocation of supportive measures. Trial registration NCT01149109.

Abstract BACKGROUND Brain metastases (BM) are the most common intracranial malignancy. For many years, patients with BM were excluded from clinical trials of systemic cancer therapies based on their presumed bad prognosis, which results in a therapeutic nihilism as soon a BM is diagnosed. With the development of immunotherapies and targeted therapies as systemic cancer therapy, we questioned if there is a difference in intracranial response, regardless of the indicated radiotherapy (RT) for the BM. MATERIAL AND METHODS 67 patients older than 18 years, with multiple BM treated between December 2016 and October 2021, with in total 237 metastases were analyzed. The volume of each metastasis on MRI was calculated at the time of appearance and every 3 months thereafter. The primary outcome was intracranial control according to RANO-BM at 6 months. Because of missing data (MRI at 6 months), 92 metastases had to be excluded, leaving 145 for the analysis. Patients were divided into groups (RT+chemotherapy - CT-group, RT+immunotherapy/targeted therapy - IT/TT-group, RT+chemo-immunotherapy/targeted therapy - CT+IT/TT-group). The second outcome measure was time to progression of metastases; for this outcome 183 metastases could be analyzed. For statistical analysis chi-square test and Tarone-Ware test were performed. RESULTS In the CT-group (n=40)10% (n=4) had a progressive disease (PD), 33% (n=13) had a partial response (PR), 57 % (n=23) complete response (CR), and no one stable disease (SD). In the CT+IT/TT-group (n=28) 14% (n=4) had PD, 11% (n=3) SD, 11% (n=3) PR and 64% (n=18) CR. In the IT/TT-group (n=78) 14% (n=11) had PD, 4% (n=3) SD, 26% (n=20) PR and 56% (n=44) CR. The p values for difference in intracranial control were between CT-group/IT/TT-group 0,81 and between CT-group/CT+IT/TT-group 0,58. Patients in the IT/TT-group had a better outcome if a targetable mutation was present (p=0,005). The median time to progression (days) was 474 ± 30 for the CT-group; 581 ± 50 for the IT/TT- group and 360 ± 35 for the CT+IT/TT-group. Tarone-Ware test showed a trend in the progression distributions between the 3 groups favoring the IT/TT-group p= 0,082. CONCLUSION Intracranial response could be achieved in all analyzed subgroups without statistically significant difference. Against the background of this data, the therapeutic nihilism due to the presumed bad prognosis is not justified. A subgroup analysis of the IT /TT group showed a significantly better outcome for patients who had a matching gene. Patients who received immunotherapy or targeted therapies showed a trend towards later progression than chemotherapy or combination therapy. Larger patient cohorts should be investigated to see if this trend could be confirmed.

Rosette-forming glioneuronal tumors (RGNT) are extremely rare mostly benign tumors of the central nervous system, which are often studied for its histological aspects despite relatively small numbers of clinical especially radiological knowledge.Despite the increasing number of publications on different localizations and treatment protocols, the morphologic and temporal development process of this rare tumor entity is not clear. We were able to coincidentally observe the entire course of the tumor growth of a RGNT on subsequent MRI examinations in a typical case with mild clinical symptoms and no other neurological illnesses, thus possible clinical complications were prevented.

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making.

2031 Background: Brain metastases (BM) occur in about 10-20% of all cancer patients during the course of their disease. The current standard of care for lesions that cause mass effects is neurosurgical resection followed by adjuvant radiotherapy of the resection cavity. We here report efficacy data of the INTRAMET trial (NCT03226483), which tested intraoperative radiation therapy (IORT) using a high-dose, single fraction to the tumor bed. Methods: Patients ≥18 years and Karnofsky (KPS) ≥50 with suspected BM were included. A frozen-section confirmed metastasis and technically applicable IORT were mandatory. Exclusion criteria were surgical or MRI contraindications, meningeal infiltration, or IORT Dmax doses exceeding 8 Gy at risk structures. IORT was performed after tumor resection in the operating room with a mobile low energy X-ray device emitting a spherical radiation field with a sharp dose gradient. A dose of 30Gy was prescribed to the surface of the resection cavity. The primary endpoint was cumulative local control rate (LCR). Secondary endpoints were incidence of other (distant) BM (RCR), overall survival (OS), time to the next systemic treatment and adverse event rates (AE). Results: In total, 35 of the originally 50 planned patients were recruited. After a pre-specified interim analysis, the study was prematurely halted due to good safety and outcomes profiles. 54.3% were men, the mean age was 64 (45-85) years. The mean follow-up was 25.7 (0.8-64.5) month. At the time of this report, 51.4% of patients were alive. 68.6% primary histologies corresponded to lung primaries. The LCR was 94.3% (95% CI 82.9-98.8%) and RCR was 57.1% (95% CI 40.7-72.4%,). 8.6% patients or lesions developed out of field leptomeningeal progression. The mean OS was 37.4 months (95% CI 28.9-46.9). For those patients undergoing salvage whole brain RT (WBRT), the median initiation time was 147 (20-601) days with a significant survival benefit for those not requiring WBRT (p = 0.027). No significant survival differences were identified according to primary histology (p = 0.618), immunotherapy (p = 0.928), seizures at baseline (p = 0.169), KPS (p = 0.056) or radionecrosis appearance (p = 0.214). Mean time to next systemic treatment was 45.0 (95% CI 35.1-54.8) days. No G4-5 AE related to IORT occurred. The overall radionecrosis (RN) rate was 20% (n = 5 G1, n = 1 G2, n = 1 G3). No risk factors could be associated to RN. Post-surgical seizures were present in 28.6% patients, with eloquent localizations as the only predictive factor (p = 0.008). Conclusions: IORT for resected BM yields excellent local control rates and has a toxicity profile similar to those reported in post-operative SRS trials. By easing a prompt initiation of subsequent systemic treatments, IORT might shorten the overall treatment courses of many cancer patients. Clinical trial information: NCT03226483 .

Abstract Background Although glioblastoma (GB) is associated with a devastating prognosis, a small proportion of patients achieve long-term survival rates. We herein present a matched-pair analysis of molecular factors found in long- and short-term survivors (LTS, STS). Methods We performed a cross-institutional analysis of 262 patient records and matched a group of 91 LTS (≥ 3 years) with two groups of STS (STS-1, n = 91; STS-2, n = 80). Matching was performed according to age, Karnofsky Performance Status, initial therapy and adjuvant therapy. Molecular factors were compared between LTS (total of 91 patients) v. STS-1, and LTS (subgroup of 80 patients) v. STS-2. We included glial fibrillary acidic protein (GFAP), O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, isocitrate dehydrogenase 1 (IDH-1); furthermore, the proliferation index was analyzed (Ki-67/MIB-1). Results IDH-1 and decreased Ki-67 were numerically associated with LTS but the difference was only significant compared to STS-1 (n.s. v. STS-2). LTS was associated with MGMT promoter hypermethylation (p = 0.013 and p = 0.022) and GFAP expression (p < 0.001 and p = 0.001). Positivity for both factors combined compared to negativity for one factor occurred more often in the LTS group (p = 0.002 and p = 0.006); negativity for both factors combined did not occur in the LTS group. Conclusion In this retrospective analysis, GFAP expression and MGMT promoter methylation were associated with LTS. Given the hypothesis-generating nature of our study, these observations should be confirmed in prospective clinical trials.