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

Abstract

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.

Bevacizumab for NF2‐associated vestibular schwannomas of childhood and adolescence

“…6,7 To this effect, bevacizumab has been described in numerous adult studies to be an effective therapy to ameliorate both hearing loss and radiological progression of NF2-related vestibular schwannomas, but pediatric data are lacking. [7][8][9][10][11] To address this, we assess a retrospective international cohort of pediatric patients with NF2-associated vestibular schwannomas treated with bevacizumab. Our results suggest that responses may not be as robust as observed in adults, and longer duration of therapy may be necessary.…”

“…Previous studies have suggested that inhibition of the VEGF pathway, using the monoclonal antibody bevacizumab, could result in hearing improvement, reduction of the tumor volume, or both 6,7 . To this effect, bevacizumab has been described in numerous adult studies to be an effective therapy to ameliorate both hearing loss and radiological progression of NF2‐related vestibular schwannomas, but pediatric data are lacking 7‐11 . To address this, we assess a retrospective international cohort of pediatric patients with NF2‐associated vestibular schwannomas treated with bevacizumab.…”

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

“…Available and well-investigated treatment options are limited to surgery with variable degrees of resection extents [ 5 , 27 ], long-term systemic treatment with bevacizumab [ 9 , 28 , 29 ] and radiation [ 30 ] but the responses are heterogeneous and can be associated with side-effects and complications. Radical total tumor removal carries a high risk of surgically induced deafness as we could show that hearing preservation is dependent on the extent of resection [ 27 ].…”

Rare Primary Central Nervous System Tumors in Adults: An Overview

“…Surgery is recommended in case of symptomatic or growing tumors and GTR can be reached in most cases. Radiotherapy should be used with caution and only when absolutely necessary, especially in hereditary diseases; indeed, in these patients the use of radiation therapy could increase the risk of a malignant tumor in the radiation field ( 107 ) Bevacizumab, an antiangiogenic drug, could also be beneficial in spinal cord lesions due to its promising activity in neurofibromatosis type 2-associated vestibular schwannomas ( 108 ); moreover, lapatinib and nilotinib in combination with radiotherapy demonstrated some benefit in a preclinical model of NF2 associated peripheral schwannoma ( 109 ).…”