Schulder, Michael

OBJECTIVE The aim of this study was to evaluate freedom from tumor progression and clinical outcomes in older adults with small- to medium-sized vestibular schwannoma (VS) managed by observation versus stereotactic radiosurgery (SRS) to better inform optimal management in this patient population. METHODS In this international multicenter study, patients aged ≥ 60 years with Koos grade I or II VS managed by observation or SRS were retrospectively reviewed. Propensity score matching was conducted using patient characteristics, tumor size, and hearing assessments. Outcome measures of freedom from tumor progression, serviceable hearing preservation (SHP), and neurological function (tinnitus, vestibulopathy, House-Brackmann grade, and trigeminal nerve function) were assessed for both groups. RESULTS The observation and SRS groups each comprised 51 matched patients (median age 68 years for both). Ipsilateral serviceable hearing was observed at presentation for 35 patients in each group. The median follow-up duration was 39 months in the observation group versus 27 months in the SRS group (p = 0.5). Tumor progression was significantly lower with SRS than with observation (2% vs 52.9%, p < 0.001). The rate of 5-year freedom from tumor progression was 100% in the SRS group versus 43% (95% CI 29%–64%) in the observation group. The rate of 10-year freedom from tumor progression was 90% (95% CI 73%–100%) in the SRS group versus 20% (95% CI 8.5%–49%) in the observation group. At the last follow-up, hearing loss occurred in 42.9% of the observation group and 51.4% of those who underwent SRS (p = 0.5). The 3-year SHP rate was 68% (95% CI 53%–88%) versus 65% (95% CI 49%–85%) (p = 0.8), and the 5-year SHP rate was 53% in both groups (95% CI 36%–78% in the observation group and 95% CI 35%–79% in the SRS group, p = 0.8). The composite endpoint of tumor progression and/or worsened neurological outcome, including hearing loss, tinnitus, vestibulopathy, facial nerve dysfunction (House-Brackmann grade), or trigeminal dysfunction, demonstrated a significantly lower rate in the SRS group (17.6%) compared with the observation group (66.7%) (p < 0.001). CONCLUSIONS SRS in older patients for management of Koos grade I or II VS resulted in significantly superior rates of freedom from tumor progression, comparable hearing preservation rates, and significantly higher rates of favorable overall radiographic and neurological outcomes than observation alone. Compared with observation, SRS might be the preferred management option in this patient population.

Background Psychiatric disorders are increasingly contributing to global disability. Despite advances in conservative management, the prevalence of treatment-resistant cases remains high. Meanwhile, neurosurgery for psychiatric disorders (NPD) remains underused, largely due to strict regulations and historical concerns, particularly those related to neuropsychological side effects (NPSE). Objective To address this issue, we conducted a systematic review with meta-analysis to compare NPSE associated with radiofrequency ablative NPD to those observed in neuro-oncological, neurovascular and epilepsy surgeries. Methods PubMed, Embase and LILACS databases were searched in April 2024 for articles published in English/Spanish from 1990 to 2022, following Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Results A total of 48 articles with 2678 participants were included. The frequency of transient and permanent NPSE in the NPD group ranged from 0.94% to 11.50% and 0.94% to 2.03%, respectively, comparable to the other surgical groups (epilepsy: 0.31–11.70%; vascular: 0.52–22.90%; oncology: 0.94–17.60% for transient NPSE; epilepsy: 0.31–12%; vascular: 0.40–1.96% and oncology: 0.84–1.48% for permanent NPSE). Regarding permanent NPSE, arguably the most critical consideration, the NPD group showed better outcomes in memory, language and social cognition than the epilepsy group, but worse outcomes in executive and perceptual-motor functions. Compared with the vascular group, the NPD group had better executive function but worse complex attention. Finally, the NPD group had fewer permanent deficits than the oncology group in executive function, complex attention and perceptual-motor domains, although language performance was lower. Conclusions Contemporary NPD apparently carries a similar risk of NPSE as other conventional neurosurgical procedures, challenging misconceptions and this unjustified barrier to its broader use.

Abstract BACKGROUND Ovarian cancer rarely metastasises to the brain, thus studies reporting the outcomes of affected patients are lacking. Stereotactic radiosurgery (SRS) is now the mainstay of management for patients with brain metastases (BM) from most primary sites, but little evidence of its efficacy in ovarian cancer is available. The current study was undertaken to provide guidance for SRS management using pooled data from multiple institutions. MATERIAL AND METHODS Centers participating in the IRRF (International Radiosurgery Research Foundation) were asked to provide outcome data for patients who had SRS for ovarian cancer brain metastases between 2020 and 2024 and at least one clinical and imaging follow-up after the procedure. Primary endpoints included survival from SRS, local tumor response according to RANO-BM criteria and occurrence of adverse radiation effects (ARE). Cox regression analyses were performed to identify variables impact each endpoint. RESULTS 128 patients had SRS for a total of 532 BM treated. Epithelial histology was the most common (91%). Median age at SRS was 62 years (IQR 56-70). Median KPS was 80% (IQR 80-90%) and 71.9% of patients had neurological symptoms at presentation. Other active systemic metastases were present in 41.4%. The median number of treated BM was 2 (IQR1-3) and the median cumulative treatment volume was 6 cc (IQR 2-12.9). The median margin dose was 18 Gy (IQR 16-20). At last follow-up, 19.5% of patients were still alive. The median overall survival (OS) after SRS was 27 months, and 6-, 12- and 24-month OS was 83.8%, 74.2% and 52.2%, respectively. Multivariate analyses revealed that increasing age at SRS (HR 1.02, p=0.05), active systemic metastases (HR 2, p=0.005) and increasing number of brain metastases (HR 1.05, p=0.04) were associated with worse survival, while repeating SRS (HR 0.4, p=0.002) led to improved survival. Local failure occurred in 12.8% of treated BM. Actuarial progression-free survival (PFS) at 6, 12 and 24 months was 92.3%, 86.6% and 70.3%, respectively. Only prior WBRT (HR 4.36, p=0.03) led to worse local control on multivariate analyses. New remote BM appeared in 49.5% of patients and 14.5% suffered from leptomeningeal dissemination. ARE were seen in 12.1% of BM but were symptomatic in only 3.2%. On multivariate analyses, prior SRS (HR 3.13, p=0.002) was associated with increased risk of ARE. CONCLUSION Ovarian cancer brain metastases can be safely and effectively managed with SRS as the primary treatment modality in most patients.

BACKGROUND AND OBJECTIVES: The therapeutic approach for small- and medium-sized vestibular schwannoma (VS) with normal hearing function remains controversial, with limited comparative data regarding hearing outcomes after stereotactic radiosurgery (SRS) or observation (OBS). We evaluated the serviceable hearing preservation, loss of American Academy of Otolaryngology-Head and Neck Surgery class A hearing, and tumor control (TC) across individuals with Koos grade I and II VSs and normal hearing at presentation who underwent SRS or OBS. METHODS: In this multicenter international study, we retrospectively analyzed the hearing, radiological, and neurological outcomes of patients who underwent SRS (SRS group) or OBS (OBS group). The cohorts were matched using propensity scores based on age, sex, tumor volume, pure-tone average, and speech discrimination score at a 1:1 ratio without replacement. RESULTS: After matching, each group comprised 57 patients. The median follow-up was 49 and 37 months for the SRS and the OBS groups, respectively ( P = .3). The 5- and 9-year serviceable hearing preservation rates in the SRS group were 76.2% and 42.4% vs 56.1% and 16.8% in the OBS group ( P = .17). Class A preservation occurred in 57.9% (33/57) of the SRS and 52.6% (30/57) of the OBS cohorts ( P = .70). Regarding the TC rates, SRS was associated with significantly higher TC rates ( P < .0001). CONCLUSION: We found that SRS is significantly superior regarding TC and provided noninferior hearing outcomes compared with OBS in VS patients with American Academy of Otolaryngology-Head and Neck Surgery class A hearing at presentation. Therefore, we suggest performing SRS in individuals with VS and normal hearing function.

BACKGROUND AND OBJECTIVES: Gynecological cancers represent 10% to 15% of cancers in women, but brain metastases (BM) are uncommon, with limited evidence regarding their management. This study investigates the role of stereotactic radiosurgery (SRS) for BM from primary gynecological cancers. METHODS: Institutions of the International Radiosurgery Research Foundation participated in this study. Inclusion criteria required histological diagnosis of epithelial ovarian, cervical, or endometrial cancer, SRS between 2000 and 2020, and at least 1 imaging or clinical follow-up. RESULTS: A total of 276 patients having SRS for 977 BM were included. Median age at SRS was 62 years (IQR, 55-70). Primary cancer origin was ovarian in 128 (46%), cervical in 43 (16%), and endometrial in 105 patients (38%). Median Karnofsky Performance Scale was 80%, and systemic disease was active in 124 (45%) of patients. A median of 1 metastasis was treated (IQR, 1-3) per patient. Median individual metastasis volume was 0.27 cc (IQR, 0.05-1.59 cc). The majority (91%) received single-fraction SRS, using a median margin dose of 18 Gy (IQR, 16-20 Gy). Actuarial overall survival was 77%, 65%, and 44% at 6, 12, and 24 months, respectively. Predictors of worsened survival included older age, cervical and endometrial primary, previous whole-brain radiation therapy (WBRT), active systemic disease, worsened Karnofsky Performance Scale, absence of subsequent surgery, and increasing number of BM. Actuarial local control was 94% at 6 months, 89% at 12 months, and 78% at 24 months. Previous SRS or WBRT, tumor bed treatment, and cervical histology increased the risk of local failure. New remote BM and leptomeningeal dissemination occurred in 44% and 11% of patients, respectively. Adverse radiation effects (ARE) occurred in 13% of cases but were symptomatic in only 3%. Previous WBRT or SRS and increased tumor diameter increased the risk of ARE. CONCLUSION: SRS is an effective management for BM from gynecological cancers with low risks of symptomatic ARE.

Abstract Standard of care (SOC) for ndGBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. IGV-001 is an autologous biologic-device combination immunotherapy for the treatment of ndGBM that consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA, irradiated and administered via biodiffusion chambers implanted in the abdomen. In a phase 1b study, IGV-001 was well tolerated without unexpected adverse events in subjects with ndGBM. Multiple efficacy signals were observed, including significant improvements in progression-free survival (PFS), overall survival (OS), radiographic evidence of tumor response, and changes in immune response biomarkers. Here, we present early safety data from the phase 2b randomized, multicenter, double-blind, placebo-controlled study (NCT04485949) designed to assess efficacy and safety of IGV-001 in subjects with ndGBM across 20 sites in the United States. After surgical resection, subjects were randomized 2:1 and treated with IGV-001 or placebo followed by SOC. The primary outcome is PFS, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include OS, defined as the time from randomization to death due to any cause, and safety. As of May 22, 2024, 99 subjects were randomized and 95 implanted with IGV-001 or placebo plus SOC. A total of 39/45 (86.7%) subjects had sufficient follow-up time after initiated treatment with concurrent radiation and temozolomide. Nine of 72 randomized (12.5%) discontinued treatment, including 7 who stopped during the SOC treatment period. None ceased treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized subjects discontinued the study after randomization. A review of blinded safety data did not show any emerging risk and supports no change to the benefit-risk profile of IGV-001 versus placebo. Updated data will be presented.

BACKGROUND AND OBJECTIVE: This investigation evaluates the safety and efficacy of stereotactic radiosurgery (SRS) vs observation for Koos grade I vestibular schwannomas (VS). METHODS: In a multicenter study, we retrospectively analyzed data of patients with Koos grade I VS who underwent SRS (SRS group) or were observed (observation group). Propensity score matching was used to equilibrate demographics, tumor size, and audiometric data across groups. The outcome analyzed included tumor control, preservation of serviceable hearing, and neurological function. RESULTS: The study matched 142 patients, providing a median follow-up period of 36 months. SRS significantly enhanced tumor control compared with observation, with a 100% control rate at both 5- and 8-year marks in the SRS group vs 48.6% and 29.5% in the observation group at the same time intervals, respectively ( P < .001). Preservation of serviceable hearing outcomes between groups showed no significant difference at 5 and 8 years, ensuring a comparable quality of auditory function (SRS 70.1% vs observation 53.4% at 5 years; P = .33). Furthermore, SRS was associated with a reduced likelihood of tinnitus (odds ratio [OR] = 0.46, P = .04), vestibular dysfunction (OR = 0.17, P = .002), and overall cranial nerve dysfunction (OR = 0.49, P = .03) at last follow-up. CONCLUSION: SRS management of patients with Koos grade I VS was associated with superior tumor control and reduced odds for cranial nerve dysfunction, while not compromising hearing preservation compared with observation. These findings support the safety and efficacy of SRS as a primary care approach for this patient population.

BACKGROUND AND OBJECTIVES: This study assessed the efficacy and safety of stereotactic radiosurgery (SRS) in comparison with watchful waiting for managing Koos grade II vestibular schwannomas (VS). METHODS: A retrospective, multicentric analysis was conducted, focusing on patients with Koos grade II VS who either received SRS (SRS group) or were observed (observation group). To ensure comparability between groups, propensity score matching was used, including factors such as demographic characteristics, tumor dimensions, and hearing assessments. The primary end points examined were tumor control, maintenance of serviceable hearing, and neurological outcomes. RESULTS: A total of 92 patients were equally matched across both cohorts, with a median follow-up of 37 months for the SRS group and 27.5 months for those observed. The SRS cohort exhibited superior tumor control over observation across 3, 5, and 8 years, achieving a 100% control rate vs 47.9%, 40.1%, and 34.3% for the observation group at these time intervals, respectively ( P < .001). Serviceable hearing preservation rates were comparable between the 2 groups throughout 3, 5, and 7 years (72.9% for SRS vs 65.4% for observation at 3 years; P = .86). Moreover, SRS management correlated with a lower incidence of vestibular symptoms (odds ratio = 0.11, P = .002), with no significant disparity in the deterioration of cranial nerve (CN) V or CN VII functions. Notably, the likelihood of experiencing any CN impairment was significantly diminished in the SRS cohort (odds ratio = 0.47, P = .04). CONCLUSION: For patients with Koos grade II VS, SRS offers superior tumor control rate and a lower risk of CN dysfunction without sacrificing hearing preservation.

Abstract BACKGROUND Glioblastoma (GBM) is the most common primary brain malignancy in adults. Standard of care (SOC) for suspected GBM begins with maximal safe resection followed by adjuvant radiotherapy and temozolomide, and maintenance temozolomide. Imvax has utilized its Goldspire™ platform to create IGV-001, an autologous biologic-device combination product for the treatment of newly diagnosed GBM (ndGBM). IGV-001 consists of autologous GBM tumor cells and an antisense oligonucleotide against IGF-1R mRNA (IMV-001), irradiated and administered via biodiffusion chambers implanted in the abdomen. Together, these components stimulate immunogenic cell death and antigen release. In a phase 1b study in patients with ndGBM, IGV-001 was well tolerated without unexpected adverse events. Multiple efficacy signals were also observed, including significant improvements in progression-free survival, overall survival, radiographic evidence of tumor response, and changes in immune response biomarkers. A phase 2b randomized, multicenter, double-blind, placebo-controlled study to assess the safety and efficacy of IGV-001 in patients with ndGBM (ClinicalTrials.gov identifier: NCT04485949) is ongoing. Here, we present the first safety data from the study. MATERIAL AND METHODS After surgical resection, patients are treated with IGV-001 or placebo followed by SOC. The study will enroll approximately 93 patients at 20 sites in the United States, with a 2:1 randomization favoring IGV-001. The primary outcome is progression-free survival, defined as the time from randomization to first progression, as determined by blinded central radiology review, or death. Secondary outcomes include overall survival, defined as the time from randomization to death due to any cause, and safety. RESULTS As of February 2, 2024, a total of 72 patients have been randomized and 69 have been implanted with IGV-001 or placebo plus SOC. The median age was 60.0 years (range, 24-70 years). Most randomized patients (76.4%) were 51-70 years of age, and the male:female ratio was 2.27. A total of 39/45 (86.7%) patients with enough follow-up time, initiated treatment with concurrent radiation and temozolomide. A total of 9/72 (12.5%) randomized patients discontinued treatment, including 7 patients who discontinued during the SOC treatment period. No patients discontinued treatment for adverse events, protocol deviations, or death. A total of 11/72 (15.3%) randomized patients discontinued the study after randomization. CONCLUSION To date, the review of blinded safety data did not show any emerging risk and supports that there is no change to the benefit-risk profile of treatment with IGV-001 versus placebo. The data will be updated before presentation.