scholarly journals Multicenter, Prospective, Phase II and Biomarker Study of High-Dose Bevacizumab as Induction Therapy in Patients With Neurofibromatosis Type 2 and Progressive Vestibular Schwannoma

2019 ◽  
Vol 37 (35) ◽  
pp. 3446-3454 ◽  
Author(s):  
Scott R. Plotkin ◽  
Dan G. Duda ◽  
Alona Muzikansky ◽  
Jeffrey Allen ◽  
Jaishri Blakeley ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Growth Factor ◽  
Phase Ii ◽  
Standard Dose ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
High Dose ◽  
Radiographic Response ◽  
Bevacizumab Treatment

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.

scholarly journals Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2–Associated Vestibular Schwannomas

2016 ◽  
Vol 34 (14) ◽  
pp. 1669-1675 ◽  
Author(s):  
Jaishri O. Blakeley ◽  
Xiaobu Ye ◽  
Dan G. Duda ◽  
Chris F. Halpin ◽  
Amanda L. Bergner ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Hearing Loss ◽  
Growth Factor ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas ◽  
Vascular Endothelial ◽  
Bevacizumab Treatment ◽  
Endothelial Growth Factor

Purpose Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. Patients and Methods Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. Results Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell–derived factor 1α (P = .037 and .025, respectively). Conclusion Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.

scholarly journals NFB-08. PHASE II STUDY OF AXITINIB IN PATIENTS WITH NEUROFIBROMATOSIS TYPE 2 AND PROGRESSIVE VESTIBULAR SCHWANNOMAS

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii419-iii419
Author(s):  
Sheetal Phadnis ◽  
Mari Hagiwara ◽  
Anna Yaffe ◽  
Carole Mitchell ◽  
Theodore Nicolaides ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Phase Ii Study ◽  
Growth Factor Receptor ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas ◽  
Volumetric Response

Abstract INTRODUCTION Vascular endothelial growth factor receptor (VEGFR), platelet derived growth factor receptor (PDGFR), and c-KIT represent clinically and/or preclinically validated molecular targets in vestibular schwannomas. We conducted a single institution, prospective, open-label, two-stage phase II study (ClinicalTrials.gov identifier NCT02129647) to estimate the response rate to axitinib, an oral multi-receptor tyrosine kinase inhibitor targeting VEGFR, PDGFR and c-KIT, in neurofibromatosis type 2 (NF2) patients with progressive vestibular schwannomas (VS). METHODS NF2 patients older than 5 years with at least one volumetrically measurable, progressive VS were eligible. The primary endpoint was to estimate the objective volumetric response rates to axitinib. Axitinib was given continuously in 28-day cycles for up to of 12 cycles. Response was assessed every 3 months with MRI using 3-D volumetric tumor analysis and audiograms. Volumetric response and progression were defined as ≥20% decrease or increase in VS volume, respectively. RESULTS Twelve eligible patients (ages: 14–56 years) were enrolled on this study. Seven of twelve patients completed 12 cycles (range: 2 to 12 cycles). We observed two imaging and three hearing responses. Best volumetric response was -53.9% after nine months on axitinib. All patients experienced drug-related toxicities, the most common adverse events were diarrhea, hematuria and skin toxicity, not exceeding grade 2 and hypertension, not exceeding grade 3. CONCLUSIONS While axitinib has modest anti-tumor activity in NF2 patients, it is more toxic and appears to be less effective compared to bevacizumab. Based on these findings, further clinical development of axitinib for this indication does not appear warranted.

Bevacizumab for Hearing Preservation in Neurofibromatosis Type 2: Emphasis on Patient-Reported Outcomes and Toxicities

2018 ◽  
Vol 160 (3) ◽  
pp. 526-532 ◽  
Author(s):  
Pavlina Sverak ◽  
Meredith E. Adams ◽  
Stephen J. Haines ◽  
Samuel C. Levine ◽  
David Nascene ◽  
...  
Keyword(s):  
Patient Reported Outcomes ◽  
Tumor Volume ◽  
Neurofibromatosis Type ◽  
Hearing Preservation ◽  
Neurofibromatosis Type 2 ◽  
Hearing Improvement ◽  
Radiographic Response ◽  
Bevacizumab Treatment ◽  
Patient Reported

Objective Bevacizumab for hearing preservation in patients with neurofibromatosis type 2 (NF2) is an emerging practice. We set out to characterize the effectiveness and toxicity of bevacizumab in our patient group. Study Design Case series with chart review. Setting Tertiary referral center. Subjects and Methods Seventeen consecutive patients with NF2 received bevacizumab treatment for vestibular schwannomas, including 2 patients treated to maintain cochlear implant performance. Volumetric analysis of serial magnetic resonance imaging scans was used to evaluate radiographic response, and hearing response was evaluated with serial audiograms. Patient-reported outcomes were also assessed, including subjective hearing improvement, changes in tinnitus, vertigo, headaches, ear pain, and improvement in ability to communicate via telephone. Results A positive radiographic response occurred in 8 of 17 (47%) patients and the median tumor volume change was a tumor decrease of 19%. A positive hearing response was recorded in 5 of 9 (56%) patients. Two patients had a word recognition score improvement over 40%. There was an approximately 40% improvement in patient-reported outcomes. Primary toxicities included hypertension, proteinuria, dysgeusia, and amenorrhea. Conclusion Bevacizumab treatment was followed by hearing improvement in 56% of patients, while decreased tumor volume was noted in 47%. These outcomes agree favorably with prior reported series. There were significant improvements in patient-reported outcomes that have not been described previously.

scholarly journals Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas

2012 ◽  
Vol 14 (9) ◽  
pp. 1163-1170 ◽  
Author(s):  
Matthias A. Karajannis ◽  
Geneviève Legault ◽  
Mari Hagiwara ◽  
Marc S. Ballas ◽  
Krysten Brown ◽  
...  
Keyword(s):  
Phase Ii ◽  
Pediatric Patients ◽  
Phase Ii Trial ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas

Avastin Scintigraphy in Surveillance of Bevacizumab Treatment in a Patient With Neurofibromatosis Type 2

2014 ◽  
Vol 39 (3) ◽  
pp. 277-280 ◽  
Author(s):  
Michelle W.J. Versleijen ◽  
Berit M. Verbist ◽  
Jef J.S. Mulder ◽  
Lioe-Fee de Geus-Oei ◽  
Carla M.L. van Herpen
Keyword(s):  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Bevacizumab Treatment

scholarly journals Age at Onset and Presenting Symptoms of Neurofibromatosis Type 2 as Prognostic Factors for Clinical Course of Vestibular Schwannomas

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2355
Author(s):  
Isabel Gugel ◽  
Florian Grimm ◽  
Julian Zipfel ◽  
Christian Teuber ◽  
Ulrike Ernemann ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Clinical Course ◽  
Age At Onset ◽  
Neurofibromatosis Type ◽  
Neurofibromatosis Type 2 ◽  
Vestibular Schwannomas ◽  
Speech Discrimination ◽  
Predictive Values ◽  
Presenting Symptoms

The presenting symptoms of the tumor suppressor gene syndrome neurofibromatosis type 2 (NF2) are often non-specific and unrelated to the disease hallmark bilateral vestibular schwannomas (VS). However, age at onset and presenting symptoms may have predictive values for the clinical course of VS. In this retrospective single-center study, we addressed this issue by reviewing 106 patients with 194 VS. Presenting symptoms attributable to VS commonly occur in 87% of adults and 31% of children. Age at onset significantly correlates with tumor volumes at presentation (p = 0.034). In addition, age at onset significantly correlates with pure-tone average (p = 0.0001), speech discrimination scores (p = 0.001), age at beginning of hearing loss (p = 0.0001), age at deafness (p = 0.0001), and age at first surgery (p = 0.0001). Patients presenting with VS related symptoms had significantly (p < 0.05) worse hearing values at presentation and after surgery. These patients also exhibited higher growth rates and tumor volumes compared to patients with non-VS related presenting symptoms, but this difference did not reach the significance level of p < 0.05. Due to the late appearance of these symptoms, the time of beginning hearing loss, surgery and deafness is significantly delayed (p < 0.05) compared to patients not presenting with VS. In summary, age at onset and type of presenting symptom provide excellent prognostic parameters for predicting VS- and hearing-related clinical course.

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