Dataset Information

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma.

ABSTRACT:

Background

Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS).

Methods

Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants were monitored for changes in hearing, tumor size, and quality of life (QOL), and for adverse events. Hearing loss was defined as a statistically significant decline in word recognition score (WRS) or pure-tone average compared to the study baseline; tumor growth was defined as >20% increase in volume compared to baseline.

Results

Twenty participants with NF2-SWN (median age 23.5 years; range, 12.5-62.5 years) with hearing loss in the target ear (median WRS 70%, range 2%-94%) received maintenance bevacizumab. Freedom from hearing loss in the target ear was 95% after 48 weeks, 89% after 72 weeks, and 70% after 98 weeks. Freedom from tumor growth in the target VS was 94% after 48 weeks, 89% after 72 weeks, and 89% after 98 weeks. NF2-related QOL remained stable for 98 weeks whereas tinnitus-related distress decreased. Maintenance bevacizumab was well tolerated, with 3 participants (15%) discontinuing treatment due to adverse events.

Conclusions

Maintenance bevacizumab (5 mg/kg every 3 weeks) is associated with high rates of hearing and tumor stability during 18 months of follow-up. No new unexpected adverse events related to bevacizumab were identified in this population.

SUBMITTER: Plotkin SR

PROVIDER: S-EPMC10398799 | biostudies-literature | 2023 Aug

REPOSITORIES: biostudies-literature

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Publications

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma.

Plotkin Scott R SR Allen Jeffrey J Dhall Girish G Campian Jian L JL Clapp D Wade DW Fisher Michael J MJ Jain Rakesh K RK Tonsgard James J Ullrich Nicole J NJ Thomas Coretta C Edwards Lloyd J LJ Korf Bruce B Packer Roger R Karajannis Matthias A MA Blakeley Jaishri O JO

Neuro-oncology 20230801 8

<h4>Background</h4>Prospective data on maintenance therapy with bevacizumab for persons with NF2-related schwannomatosis (NF2-SWN) is lacking. In this prospective multicenter phase II study, we evaluated the efficacy, safety, and tolerability of bevacizumab for maintenance therapy in children and adults with NF2-SWN and hearing loss due to vestibular schwannomas (VS).<h4>Methods</h4>Following induction therapy, participants received bevacizumab 5 mg/kg every 3 weeks for 18 months. Participants w ...[more]

PMID: 37010875

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Project description:Bilateral vestibular schwannoma is the hallmark of NF2-related schwannomatosis, a rare tumour predisposition syndrome associated with a lifetime of surgical interventions, radiotherapy and off-label use of the anti-angiogenic drug bevacizumab. Unilateral vestibular schwannoma develops sporadically in non-NF2-related schwannomatosis patients for which there are no drug treatment options available. Tumour-infiltrating immune cells such as macrophages and T-cells correlate with increased vestibular schwannoma growth, which is suggested to be similar in sporadic and NF2-related schwannomatosis tumours. However, differences between NF2-related schwannomatosis and the more common sporadic disease include NF2-related schwannomatosis patients presenting an increased number of tumours, multiple tumour types and younger age at diagnosis. A comparison of the tumour microenvironment in sporadic and NF2-related schwannomatosis tumours is therefore required to underpin the development of immunotherapeutic targets, identify the possibility of extrapolating ex vivo data from sporadic vestibular schwannoma to NF2-related schwannomatosis and help inform clinical trial design with the feasibility of co-recruiting sporadic and NF2-related schwannomatosis patients. This study drew together bulk transcriptomic data from three published Affymetrix microarray datasets to compare the gene expression profiles of sporadic and NF2-related schwannomatosis vestibular schwannoma and subsequently deconvolved to predict the abundances of distinct tumour immune microenvironment populations. Data were validated using quantitative PCR and Hyperion imaging mass cytometry. Comparative bioinformatic analyses revealed close similarities in NF2-related schwannomatosis and sporadic vestibular schwannoma tumours across the three datasets. Significant inflammatory markers and signalling pathways were closely matched in NF2-related schwannomatosis and sporadic vestibular schwannoma, relating to the proliferation of macrophages, angiogenesis and inflammation. Bulk transcriptomic and imaging mass cytometry data identified macrophages as the most abundant immune population in vestibular schwannoma, comprising one-third of the cell mass in both NF2-related schwannomatosis and sporadic tumours. Importantly, there were no robust significant differences in signalling pathways, gene expression, cell type abundance or imaging mass cytometry staining between NF2-related schwannomatosis and sporadic vestibular schwannoma. These data indicate strong similarities in the tumour immune microenvironment of NF2-related schwannomatosis and sporadic vestibular schwannoma.

Project description:PURPOSE:Bevacizumab treatment at 7.5 mg/kg every 3 weeks results in improved hearing in approximately 35%-40% of patients with neurofibromatosis type 2 (NF2) and progressive vestibular schwannomas (VSs). However, the optimal dose is unknown. In this multicenter phase II and biomarker study, we evaluated the efficacy and safety of high-dose bevacizumab in pediatric and adult patients with NF2 with progressive VS. PATIENTS AND METHODS:Bevacizumab was given for 6 months at 10 mg/kg every 2 weeks, followed by 18 months at 5 mg/kg every 3 weeks. The primary end point was hearing response defined by word recognition score (WRS) at 6 months. Secondary end points included toxicity, radiographic response, quality of life (QOL), and plasma biomarkers. RESULTS:Twenty-two participants with NF2 (median age, 23 years) with progressive hearing loss in the target ear (median baseline WRS, 53%) were enrolled. Nine (41%) of 22 participants achieved a hearing response at 6 months (1 of 7 children and 8 of 15 adults; P = .08). Radiographic response was seen in 7 (32%) of 22 patients with VS at 6 months (7 of 15 adults and 0 of 7 children; P = .05). Common mild to moderate adverse events included hypertension, fatigue, headache, and irregular menstruation. Improvement in NF2-related QOL and reduction in tinnitus-related distress were reported in 30% and 60% of participants, respectively. Paradoxically, high-dose bevacizumab treatment was not associated with a significant decrease in free vascular endothelial growth factor but was associated with increased carbonic anhydrase IX, hepatocyte growth factor, placental growth factor, stromal cell-derived factor 1α, and basic fibroblast growth factor concentrations in plasma. CONCLUSION:High-dose bevacizumab seems to be no more effective than standard-dose bevacizumab for treatment of patients with NF2 with hearing loss. In contrast to adults, pediatric participants did not experience tumor shrinkage. However, adult and pediatric participants reported similar improvement in QOL during induction. Novel approaches using bevacizumab should be considered for children with NF2.

Project description:Background/objectivesNF2-related schwannomatosis (NF2) is a tumor predisposition syndrome that typically presents with bilateral vestibular schwannomas, together with other intracranial and spinal schwannomas, meningiomas, and/or ependymomas. Bevacizumab, a VEGF inhibitor, has the potential to decrease schwannoma volume and improve hearing in adults, but the literature on the effects in children is sparse. This narrative review aims to evaluate the use of bevacizumab in pediatric NF2 patients, focusing on hearing, tumor progression, and toxicity.MethodsA literature review was conducted following PRISMA guidelines. Articles were searched in PubMed, Embase, Web of Science, Cochrane Library, Emcare, and Academic Search Premier on 18 July 2024. Inclusion criteria were patients ≤ 18 years, diagnosed with NF2 and treated with bevacizumab. Two authors independently assessed the quality of the evidence and extracted relevant data from the included articles.ResultsSeventeen articles including 62 pediatric NF2 patients met the inclusion criteria. Studies varied widely in treatment regimens and outcome parameters. Tumor regression was reported in 6/56 patients (11%) and 38/56 (68%) remained stable. Hearing improved in 15/45 patients (33%) and did not further deteriorate in 27/45 (60%). An improvement in other symptoms was seen in 6/29 patients (28%). Toxicity was reported in five studies, documenting 13 adverse events in 28 patients ranging from grade 1 to grade 3. Treatment was discontinued in both patients who experienced grade 3 toxicity.ConclusionsBevacizumab seems to be a viable treatment option for pediatric NF2 patients. Tumor regression or stabilization is achieved in the majority of patients (77%). Moreover, a considerable number of pediatric patients experience hearing stabilization or improvement (93%). Bevacizumab appears to be relatively well tolerated, offering a non-invasive therapeutic option for children with NF2 suffering from progressive vestibular schwannomas and hearing loss.

Project description:To compare 1D (linear) tumor volume calculations and classification systems with 3D-segmented volumetric analysis (SVA), focusing specifically on their effectiveness in the evaluation and management of NF2-associated vestibular schwannomas (VS). VS were clinically followed every 6 months with cranial, thin-sliced (< 3 mm) MRI. We retrospectively reviewed and used T1-weighted post-contrast enhanced (gadolinium) images for both SVA and linear measurements. 3D-SVA was performed manually or combined with semiautomated segmentation by using axial planes. The maximum linear dimensions (MLD) were determined in three dimensions (anteroposterior, transverse, and craniocaudal planes) using axial and coronal planes. The MLD was cubed (MLD3), and orthogonal analysis (OA) was derived to establish comparability with the SVA. The Hannover and Koos classification was used to depict the size ratio in each MRI and tumor. A linear regression model was performed to compare 1D/classification systems to SVA, and the percentage deviation change of MLD3 and OA to SVA was established using a one-way multivariate variance analysis. 2586 SVA and 10344 linear measurements were performed in a cohort of 149 NF2 patients and 292 associated VS. All measurement techniques (MLD3, OA, KOOS, and Hannover) significantly (and strongly, r2 > 0.5) correlated with SVA (p < 0.001). The OA showed an even stronger positive correlation than the MLD3 to SVA. Smaller classified tumors (T1/T2, K1/K2) exhibited a low-moderate positive correlation (r2 = 0.23-0.44) compared to medium-sized (T3, K2/3) and large tumors (T4, K4; r2 = 0.54-0.76). Pre- and postoperative MLD3 and OA statistically significantly predict SVA (p < 0.001), but the postoperative correlation was weaker, particularly for MLD3 to SVA values. All analyses showed a large scatter range. In the percentage deviation analysis of MLD3 and OA from SVA, small tumors (K1/K2, T1/T2) were overestimated. Compared to the SVA, the MLD3 and especially the OA are a time-saving alternative for monitoring the tumor volume of NF2-associated VS. However, the scatter range in small/surgically reduced tumors is enormous. For this reason, they are not recommended for monitoring off-label therapy with Bevacizumab or for treatment decisions depending on a precise assessment of tumor volume and growth. Developing deep learning-based volume determinations in the future is essential to reduce SVA's time intensity.

Project description:Background: Neurofibromatosis type 2 (NF2) is a rare genetic syndrome that predisposes individuals to develop bilateral vestibular schwannomas (VSs) causing a high risk of life-threatening neurological complications. Traditional treatment options for NF2-associated VS usually cause neurological damage, and to date, there are no FDA-approved pharmacotherapies for NF2. The aim of this study was to evaluate the antitumor efficacy of Qu-Du-San-Jie (QDSJ) decoction, a traditional Chinese medicine formula, on NF2-associated VS and to investigate the potential underlying mechanisms. Methods: Ultra high-performance liquid chromatography-mass spectroscopy (UHPLC-MS) analysis was performed to identify the components of QDSJ and their targets. To determine the relationships between the putative targets of QDSJ and the differential genes of NF2-associated VS, the drug-disease crossover genes were screened using the UHPLC-MS data combined with our previous gene expression profiling data. The differentially expressed genes were imported into the STRING database to generate a PPI network. Differentially expressed gene targets and pathways were identified using GO and KEGG pathway enrichment analyses. The in vitro and in vivo drug efficacy of QDSJ decoction was tested using a patient-derived schwannoma cell line and a patient-derived xenograft mouse model, respectively. H&E staining, immunochemistry, and immunofluorescence staining were used to evaluate the cell proliferation and tumor vessels. Results: A total of 133 compounds were identified in QDSJ decoction using UHPLC-MS analysis. Network pharmacology showed that the regulation of necroptosis, apoptosis, cell cycle, angiogenesis, adherens junction, and neuroactive ligand-receptor interaction could be associated with the efficacy of QDSJ in treating NF2-associated VS. Treatment with QDSJ induced necrotic cell death and apoptosis of schwannoma cells in vitro and suppressed the tumor growth in vivo. Histopathological analysis revealed areas of cell necrosis and enlarged tumor blood vessels in the QDSJ-treated tumors. The numbers of cells positive for Cyclin D1 and Ki-67 were significantly reduced in QDSJ-treated tumors compared to control tumors. Immunofluorescence staining of CD31 and αSMA showed a decreased number and density of tumor vessels and normalized vessel structure in QDSJ-treated tumors. Conclusion: Our study demonstrates that QDSJ decoction shows significant antitumor activity against NF2-associated schwannoma and is a possible candidate for future clinical trials.

Dataset Information

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma.

Background

Methods

Results

Conclusions

Publications

Multicenter, prospective, phase II study of maintenance bevacizumab for children and adults with NF2-related schwannomatosis and progressive vestibular schwannoma.

Similar Datasets

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