Progressive Vestibular Schwannomas Research Articles

Repeat stereotactic radiosurgery for progressive vestibular schwannomas after primary gamma knife radiosurgery

PurposeLimited data provides guidance on the management of vestibular schwannomas (VSs) that have progressed despite primary Gamma Knife radiosurgery (GKRS). The present article reports our long-term experience after repeat GKRS for VS with sustained progression after solely primary GKRS management.MethodsA retrospective review of 1997 patients managed between 1987 and 2023 was conducted. Eighteen patients had sustained tumor progression after primary GKRS and underwent repeat GKRS. The median repeat GKRS margin dose was 11 Gy (IQR: 11–12), the median tumor volume was 2.0 cc (IQR: 1.3–6.3), and the median cochlear dose in patients with preserved hearing was 3.9 Gy (IQR: 3-4.1). The median time between initial and repeat GKRS was 65 months (IQR: 38–118).ResultsThe median follow-up was 70 months (IQR: 23–101). After repeat GKRS, two patients had further tumor progression at 4 and 21 months and required partial resection of their tumors. The 10-year actuarial tumor control rate after repeat GKRS was 88%. Facial nerve function was preserved in 13 patients who had House-Brackmann grade 1 or 2 function at the time of repeat GKRS. Two patients with serviceable hearing preservation (Gardner-Robertson grade 1 or 2) at repeat GKRS retained that function afterwards. In patients with tinnitus, vestibular dysfunction, and trigeminal neuropathy, symptoms remained stable or improved for 16/16 patients, 12/15 patients, and 10/12 patients, respectively. One patient developed facial twitching in the absence of tumor growth 21 months after repeat GKRS.ConclusionsRepeat GKRS effectively controlled tumor growth and preserved cranial nerve outcomes in most patients whose VS had sustained progression after initial primary radiosurgery.

Imaging as an early biomarker to predict sensitivity to everolimus for progressive NF2-related vestibular schwannoma

PurposeNF2-related schwannomatosis (NF2) is characterized by bilateral vestibular schwannomas (VS) often causing hearing and neurologic deficits, with currently no FDA-approved drug treatment. Pre-clinical studies highlighted the potential of mTORC1 inhibition in delaying schwannoma progression. We conducted a prospective open-label, phase II study of everolimus for progressive VS in NF2 patients and investigated imaging as a potential biomarker predicting effects on growth trajectory.MethodsThe trial enrolled 12 NF2 patients with progressive VS. Participants received oral everolimus daily for 52 weeks. Brain imaging was obtained quarterly. As primary endpoint, radiographic response (RR) was defined as ≥ 20% decrease in target VS volume. Secondary endpoints included other tumors RR, hearing outcomes, drug safety and quality of life (QOL).ResultsEight participants completed the trial and four discontinued the drug early due to significant volumetric VS progression. After 52 weeks of treatment, the median annual VS growth rate decreased from 77.2% at baseline to 29.4%. There was no VS RR and 3 of 8 (37.5%) participants had stable disease. Decreased or unchanged VS volume after 3 months of treatment was predictive of stabilization at 12 months. Seven of eight participants had stable hearing during treatment except one with a decline in word recognition score. Ten of twelve participants reported only minimal changes to their QOL scores.ConclusionsVolumetric imaging at 3 months can serve as an early biomarker to predict long-term sensitivity to everolimus treatment. Everolimus may represent a safe treatment option to decrease the growth of NF2-related VS in patients who have stable hearing and neurological condition. TRN: NCT01345136 (April 29, 2011).

Repeat Surgery for Vestibular Schwannomas: An Institutional Case Series.

Introduction Vestibular schwannomas (VSs) are treated with microsurgery and/or radiosurgery. Repeat resection is rare, and few studies have reported postoperative outcomes. The objective of this study was to describe clinical characteristics and outcomes in patients undergoing repeat surgery for VS. Methods All adult (≥ 18 years) patients undergoing VS resection between 2003 and 2022 at our institution were retrospectively reviewed to identify patients who underwent repeat surgery of an ipsilateral VS following prior gross-total (GTR) or subtotal resection. Patient, radiographic, and clinical characteristics were reviewed. Primary outcomes were postoperative tumor volume, extent of resection, postoperative cranial nerve deficits, and time to further tumor progression. Results Of 102 patients undergoing VS resection, 6 (5.9%) had undergone repeat surgery. Median (range) follow-up was 20 (5-117) months. Three patients were female. Median age was 56 (36-60) years. Median pre- and postoperative tumor volumes were 8.2 (1.8-28.2) cm 3 and 0.4 (0-3.8) cm 3 . GTR was achieved in two patients. Four patients had higher House-Brackmann scores at last follow-up, but none had tumor progression. Conclusion In this small cohort of patients, repeat resection of recurrent or progressive VS can effectively reduce tumor volume with acceptable perioperative outcomes.

The Course of Hearing Loss in Patients With a Progressive Vestibular Schwannoma.

This study evaluates the natural course of hearing loss (HL) prior to treatment in patients with progressive tumors and an indication for active intervention. Evaluating this patient group specifically can put hearing outcomes after vestibular schwannoma therapy into an adequate context. Retrospective cohort study. Tertiary referral center. Inclusion criteria comprised unilateral vestibular schwannomas prior to active treatment, with ≥2 mm extracanalicular (EC) tumor growth and ≥2 audiograms. We performed a comprehensive assessment of hearing using multiple outcome parameters including (the annual decrease in) pure-tone averages (PTAs; an average of 0.5, 1, 2, and 3 kHz). Predictors for HL were evaluated (patient age, tumor size/progression, follow-up duration, baseline hearing). At presentation, 86% of patients suffered from sensorineural HL on the affected side (≥20 dB PTA) with a median of 39 dB (interquartile rate [IQR]: 27-51 dB). The median follow-up duration was 21 months (IQR: 13-34 months), after which 58% (187/322) of patients experienced progressive HL (≥10 dB), with a median increase of 6.4 dB/year. At the last follow-up, the median PTA was 56 dB (IQR: 37-73). Median speech discrimination scores deteriorated from 90% (IQR: 70%-100%) to 65% (IQR: 35%-100%). Tumor progression (maximal EC diameter) was significantly correlated to the progression of sensorineural HL, corrected for follow-up (F(2,228) = 10.4, p < .001, R2 = 8%). The majority of patients (58%) with radiologically confirmed progressive vestibular schwannomas experience progressive sensorineural HL during observation. Tumor progression rate, ECtumor extension, and longer follow-up are factors associated with more sensorineural HL.

Vestibular Schwannoma Hypofractionated Stereotactic Radiation Therapy in Five Fractions

AimTo retrospectively analyse the long-term results of hypofractionated stereotactic radiation therapy (HSRT) applied in five fractions for vestibular schwannomas. Materials and methodsOne hundred and thirty-four patients with vestibular schwannomas underwent medical treatment of HSRT. The median follow-up time interval was 54 months (range 6–121 months). All patients had a prescribed dose of 22 Gy in five fractions to D90. Restaging was carried out by thin-slice contrast-enhanced T1 magnetic resonance imaging. Progression was defined as 2 mm post-treatment tumour enlargement. Progression or death for any reason was counted as an event in progression-free survival rates. Acute toxicity was defined as adverse events occurring within 3 months of HSRT; long-term toxicity was defined as such events occurring after 3 months. ResultsIn 74/128 patients who had >6 months of follow-up (54%), the HSRT resulted in a partial or a complete response. The mean time interval for response in 50% of these was 4 years, whereas in 49 patients (38%) vestibular schwannomas failed to show any response, resulting in stable disease. Five of 128 patients (4%) showed marked progressive vestibular schwannomas after treatment in the first 3 years; two of them received conventionally fractionated radiation therapy. Local control at 3, 5 and 7 years was 96%, 95% and 94%, respectively. Seven were lost to follow-up. The median planning target volume was 2.1 ml (range 0.78–8.66). The 3- and 5-year progression-free survival rates were 95% and 94%, respectively. Seven patients reported a marked deterioration in hearing ability. Post-radiation therapy magnetic resonance imaging showed variability in oedema collection, but no patient suffered from radio-necrosis. Grade 2 temporary facial nerve disorders were observed in 10 patients (8%) 3–6 months after HSRT. ConclusionDelivering HSRT in five fractions for vestibular schwannoma appears safe and efficient, combining both efficiency and short treatment time while optimising neurological function preservation.

Phase II trial of icotinib in adult patients with neurofibromatosis type 2 and progressive vestibular schwannoma.

Neurofibromatosis type 2 (NF2) is a rare autosomal dominant syndrome associated primarily with bilateral vestibular schwannomas (VSs). Conventional surgical or radiosurgical treatments for VS in NF2 usually result in high risks of hearing loss and facial nerve impairment, while there is no validated medical option to date. This single-institution phase II study evaluated the efficacy and safety of icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, in patients with NF2 and progressive VS. Icotinib was administered daily at 375 mg orally in a continuous 28-day course for up to 12 courses. The primary endpoint of the study was radiographic response assessed by brain MRI using 3D volumetric tumor analysis and defined as a ≥ 20% decrease in VS volume. Hearing function was evaluated as a secondary endpoint, with response defined as a statistically significant increase in word recognition scores. Ten eligible patients with a mean age of 23.8 years were enrolled. One patient (10%) with bilateral tumors experienced an objective radiographic response (-23.58% and -22.01%). Three (43%) of 7 patients met the hearing response criteria. At 12 months, the estimated progression-free survival was 82.0% (95% CI 42.3%-95.5%) for volumetric progression and 69.2% (95% CI 37.3%-87.2%) for hearing progression. Common mild to moderate adverse events included rash (90%), diarrhea (50%), myalgia (20%), and nausea/gastrointestinal pain (20%). Icotinib carries minor toxicity and is associated with radiographic and hearing responses in patients with NF2 and progressive VS.

Outcome after Radiotherapy for Vestibular Schwannomas (VS)-Differences in Tumor Control, Symptoms and Quality of Life after Radiotherapy with Photon versus Proton Therapy.

Simple SummaryThe standard of care for radiotherapy of symptomatic or progressive vestibular schwannomas (VS) is photon beam single-dose radiosurgery (applying 1 × 12 Gy) or (hypo)fractionated radiotherapy (applying 3 × 6 Gy up to 32 × 1.8 Gy). Only few centers also enable irradiation with protons. Proton therapy offers unique physical properties whereby healthy tissue around the tumor can be protected although a very high dose is applied to the target lesion. In patients with benign brain tumors such as vestibular schwannomas reduction of treatment-related side effects is very important. Few data comparing photon vs. proton beam radiotherapy for patients with VS are available. Thus, a detailed evaluation of differences in tumor control, symptoms and quality of life in patients with VS after photon beam vs. proton beam radiotherapy is needed.Background: To evaluate differences in local tumor control (LC), symptoms and quality of life (QOL) of 261 patients with VS after stereotactic radiosurgery/hypofractionated stereotactic radiotherapy (SRS/HFSRT) vs. fractionated radiotherapy (FRT) vs. fractionated proton therapy (FPT) were studied. Methods: For SRS/HFSRT (n = 149), the median fraction dose applied was 12 Gy. For FRT (n = 87) and FPT (n = 25), the median cumulative doses applied were 57.6 Gy and 54 Gy (RBE), respectively. FRT and FPT used single median doses of 1.8 Gy/Gy (RBE). Median follow-up was 38 months. We investigated dosimetry for organs at risk and analyzed toxicity and QOL by sending out a questionnaire. Results: LC was 99.5% at 12 months after RT with no statistical difference between treatment groups (p = 0.19). LC was significantly lower in NF2 patients (p = 0.004) and in patients with higher tumor extension grade (p = 0.039). The hearing preservation rate was 97% at 12 months after RT with no statistical difference between treatment groups (p = 0.31). Facial and trigeminal nerve affection after RT occurred as mild symptoms with highest toxicity rate in FPT patients. Conclusion: SRS/HFSRT, FRT and FPT for VS show similar overall clinical and functional outcomes. Cranial nerve impairment rates vary, potentially due to selection bias with larger VS in the FRT and FPT group.

The Effect of Bevacizumab on Vestibular Schwannoma Related to Neurofibromatosis Type 2

Abstract Introduction: We describe an Australian experience of infusional bevacizumab for vestibular schwannoma (VS) in neurofibromatosis type 2 patients, with specific focus on 3-dimensional tumour volume and audiometry. Method: Data was pooled from patients with symptomatic or progressive VS from 2009 to April 2018. Tumours were assessed as total volume per patient. Bevacizumab infusions were administered every 2-4 weeks. 3-D volumetric response (cm3) was determined through serial magnetic resonance imaging, at baseline and at 3-6-month intervals, until cessation of infusions following progression or prior to surgery. Volumetric response was defined as a reduction of volume ³ 20%, from baseline. Patients underwent interval pure tone audiometry. A decrease in the average pure tone analyses by 10dB indicated response. Results: Twenty-one VS tumours were identified in eleven patients. Median age was 26 (range 13 – 67yr). Average baseline tumour volume was 14.17cm3 (range 1.45cm3 - 38.51cm3). Tumour volume reduction &gt;20% was shown in 7/11 patients (64%), indicating partial response, 2/11 (18%) patients showed stable disease, and 2/11 (18%) progressed. Average percentage tumour volume change was +4.45% from baseline (range -57% to 241%). 16 individual ears were tested, 3/16 (19%) of ears showed an average decibel reduction of 10dB or more, indicating response (average change 2.5dB, range -36dB to 81dB). 10/16 (63%) showed stable hearing, and 3/16 (19%) showed hearing deterioration. Conclusion: Bevacizumab is a useful agent for reducing tumour volume and improving hearing losses due to vestibular schwannoma in neurofibromatosis type 2 patients. These results reflect results described from the United Kingdom and United States.

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

INTRODUCTIONVascular 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).METHODSNF2 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.RESULTSTwelve 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.CONCLUSIONSWhile 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.

CTNI-10. MAINTENANCE CHEMOTHERAPY USING BEVACIZUMAB FOR NEUROFIBROMATOSIS 2 PATIENTS WITH HEARING LOSS AND PROGRESSIVE VESTIBULAR SCHWANNOMAS: AN NF CLINICAL TRIALS CONSORTIUM STUDY (NF104)

Abstract BACKGROUND Bevacizumab treatment at 2.5–5 mg/kg/week is associated with hearing improvement and tumor shrinkage in about 40% of patients with neurofibromatosis 2 (NF2) and progressive vestibular schwannomas (VS). Treatment-emergent hypertension and proteinuria are common with prolonged treatment, and data supporting strategies to maintain hearing and minimize toxicity are lacking. METHODS We conducted a multicenter, phase II, open-label study of bevacizumab for subjects (≥6 years old) with NF2, hearing loss, and progressive VS. After 6 months of induction therapy (10 mg/kg every 2 weeks), subjects received low dose bevacizumab at 5 mg/kg every 3 weeks during maintenance therapy (18 months). Hearing decline was defined as a significant decrease in word recognition score below baseline. Progressive disease was defined as ≥20% increase in tumor volume from baseline. RESULTS Twenty of 22 subjects (median age=23 years) were treated with maintenance bevacizumab. The proportion of subjects free from hearing decline at 6, 12, and 18 months was 88%, 94%, and 85%, respectively; the proportion free from tumor progression at 6, 12, and 18 months from baseline was 88%, 94%, and 85%, respectively. Three subjects (15%) experienced hearing loss during maintenance and required dose escalation. Maintenance chemotherapy with bevacizumab was well tolerated: 1 subject discontinued due to perirectal abscess and 2 discontinued by choice. Grade 3 hypertension occurred in 2 subjects (10%). Adverse events of interest included hypertension (55%), proteinuria (20%), and irregular menstruation (6/13, 46%). CONCLUSIONS Maintenance chemotherapy with bevacizumab at 5 mg/kg every 3 weeks is associated with prolonged hearing and tumor stability that surpasses historical controls. A minority of subjects require dose escalation during low dose bevacizumab treatment.

Progressive Vestibular Schwannoma following Subtotal or Near-Total Resection: Dose-Escalated versus Standard-Dose Salvage Stereotactic Radiosurgery.

Objective Local failure of incompletely resected vestibular schwannoma (VS) following salvage stereotactic radiosurgery (SRS) using standard doses of 12 to 13 Gy is common. We hypothesized that dose-escalated SRS, corrected for biologically effective dose, would have superior local control of high-grade VS progressing after subtotal or near-total resection compared with standard-dose SRS. Design Retrospective cohort study. Setting Tertiary academic referral center. Participants Adult patients treated with linear accelerator-based SRS for progressive VS following subtotal or near-total resection. Main Outcome Measures Dose-escalated SRS was defined by a biologically effective dose exceeding a single-fraction 13-Gy regimen. Study outcomes were local control and neurologic sequelae of SRS. Binary logistic regression was used to evaluate predictors of study outcomes. Results A total of 18 patients with progressive disease following subtotal (71%) and near-total (39%) resection of Koos grade IV disease (94%) were enrolled. Of the 18 patients, 7 were treated with dose-escalated SRS and 11 with standard-dose SRS. Over a median follow-up of 32 months after SRS, local control was 100% in the dose-escalated cohort and 91% in the standard-dose cohort ( p = 0.95). Neurologic sequelae occurred in 28% of patients, including 60% of dose-escalated cohort and 40% of the standard-dose cohort ( p = 0.12), although permanent neurologic sequelae were low at 6%. Conclusions Dose-escalated SRS has similar local control of recurrent VS following progression after subtotal or near-total resection and does not appear to have higher neurologic sequalae. Larger studies are needed.

Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

Phase 2 Clinical Trial of Crizotinib for Children and Adults With Neurofibromatosis Type 2 and Progressive Vestibular Schwannomas

Preliminary report of a multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: An NF Clinical Trials Consortium study.

2056Background: Profound hearing loss is common in patients with neurofibromatosis 2 (NF2) and vestibular schwannomas (VS). Bevacizumab treatment at 7.5 mg/kg every 3 weeks has been associated with...

Multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: an NF Clinical Trials Consortium study (S23.004)

Multicenter, phase 2 study of bevacizumab in children and adults with neurofibromatosis 2 and progressive vestibular schwannomas: an NF Clinical Trials Consortium study (S23.004)

Targeting the cMET pathway augments radiation response without adverse effect on hearing in NF2 schwannoma models

Neurofibromatosis type II (NF2) is a disease that needs new solutions. Vestibular schwannoma (VS) growth causes progressive hearing loss, and the standard treatment, including surgery and radiotherapy, can further damage the nerve. There is an urgent need to identify an adjunct therapy that, by enhancing the efficacy of radiation, can help lower the radiation dose and preserve hearing. The mechanisms underlying deafness in NF2 are still unclear. One of the major limitations in studying tumor-induced hearing loss is the lack of mouse models that allow hearing testing. Here, we developed a cerebellopontine angle (CPA) schwannoma model that faithfully recapitulates the tumor-induced hearing loss. Using this model, we discovered that cMET blockade by crizotinib (CRZ) enhanced schwannoma radiosensitivity by enhancing DNA damage, and CRZ treatment combined with low-dose radiation was as effective as high-dose radiation. CRZ treatment had no adverse effect on hearing; however, it did not affect tumor-induced hearing loss, presumably because cMET blockade did not change tumor hepatocyte growth factor (HGF) levels. This cMET gene knockdown study independently confirmed the role of the cMET pathway in mediating the effect of CRZ. Furthermore, we evaluated the translational potential of cMET blockade in human schwannomas. We found that human NF2-associated and sporadic VSs showed significantly elevated HGF expression and cMET activation compared with normal nerves, which correlated with tumor growth and cyst formation. Using organoid brain slice culture, cMET blockade inhibited the growth of patient-derived schwannomas. Our findings provide the rationale and necessary data for the clinical translation of combined cMET blockade with radiation therapy in patients with NF2.

Medical treatment in neurofibromatosis type 2. Review of the literature and presentation of clinical reports

The understanding of the molecular pathways underlying tumor development in neurofibromatosis type 2 (NF2) is increasing. Thus, repositioning drugs, drug therapies that are already clinically available for various cancers, appear potentially promising for NF2 patients. Based on preclinical data from in vitro or animal models, five different treatments have been proposed for selected NF2 cases. Evaluation of bevacizumab, a monoclonal antibody against VEGF has mainly been reported in retrospective studies; it has been reported to induce hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas (VS). In our experience with 16 patients, bevacizumab is associated with an increase of median time to tumor progression of VS from 5.6 months before bevacizumab onset, to more than 29.3 months. The need for intravenous injections and long term adverse events (hypertension, proteinuria, hemorrhage) are the main drawbacks. Lapatinib seemed promising in a single phase II trial with a volumetric response observed in 4/17 patients and a hearing response in 4/13, but is not currently used in clinical practice. Erlotinib has not been associated with radiographic or hearing responses in a phase II trial. Everolimus has been evaluated in 3 phase II trials. Everolimus did not induced tumor shrinkage, but seems to be able to increase time to tumor progression in selected cases. Currently, bevacizumab is the only drug proposed to selected NF2 patients.

A Matched Cohort Comparison of Facial Nerve Outcomes in Salvage Surgery after Stereotactic Radiosurgery for Progressive Vestibular Schwannomas Compared with Microsurgery Alone

A Matched Cohort Comparison of Facial Nerve Outcomes in Salvage Surgery after Stereotactic Radiosurgery for Progressive Vestibular Schwannomas Compared with Microsurgery Alone

MNGO-17EFFECTS OF LAPATINIB ON MENINGIOMAS IN ADULTS WITH NEUROFIBROMATOSIS TYPE 2 (NF2)

BACKGROUND: EGFR and ErbB2 are overexpressed schwannomas and meningiomas. Preclinical and clinical data indicate that lapatinib, an EGFR/ErbB2 inhibitor, has antitumor activity against schwannomas. METHODS: We conducted a single institution, retrospective review of patients with NF2 and progressive vestibular schwannomas treated on a Phase II clinical trial with lapatinib (NCT00973739). We included patients with at least one volumetrically measurable meningioma (>0.5cm3) who received at least five 28-day courses of therapy. Lapatinib was administered in continuous 4-week courses receiving standard adult doses (1,500mg once daily). Meningioma response was assessed using 3-dimensional MRI volumetrics. Progressive meningioma growth and response were defined as +20%/-20%-change from baseline in tumor volume, respectively. Off-treatment defined as any period >5 months without lapatinib. RESULTS: Eight patients (ages: 20-58 years) who met criteria had 17 evaluable meningiomas with a combined volume of 61.35cc baseline, 61.17cc during treatment, and 108.86cc (+77.44%-change) off-treatment. Tumor volume differences were significant (p = 0.0033) using a two-sided Wilcoxon-Signed-Rank test. Median time on-therapy: 15 months and off-therapy: 14 months (both ranged 5-29 months). We calculated a median and mean annual growth rate off-treatment: 10.42% and 20.05%, respectively. The best response to therapy was -26.1% after 23 months on lapatinib. Two of 17 tumors grew >20% on-treatment while 9 of 17 grew >20% off-treatment. CONCLUSIONS: These data suggest that lapatinib has modest growth-inhibitory effects on meningiomas in NF2 patients. Prospective studies of lapatinib for NF2 patients with progressive meningiomas may be warranted.

Bevacizumab treatment for symptomatic spinal ependymomas in neurofibromatosis type 2.

Neurofibromatosis type 2 (NF2) is a tumor suppressor syndrome associated with vestibular schwannomas, meningiomas, and spinal ependymomas. There have been anecdotal reports of radiographic response of spinal ependymomas in NF2 patients being treated for progressive vestibular schwannomas with bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF). The aim of this study was to review the clinical effects of bevacizumab treatment for symptomatic, NF2-associated ependymomas We conducted a retrospective review of all patients with NF2 treated with bevacizumab for symptomatic ependymoma at three NF2 specialty centers. Tumor size was evaluated by linear measurements; radiographic response was defined as >20% reduction in tumor size. We also performed immunohistochemical evaluation of NF2-associated symptomatic ependymomas from five patients, including two from this clinical series. Eight patients with NF2 and symptomatic ependymoma were treated with bevacizumab. All patients had subjective clinical improvement with bevacizumab, although only five of eight patients evaluated had radiographic response. All tumors expressed VEGF-R2. Four of five evaluated ependymomas expressed VEGF-R1; one without VEGF-R1 expression was from a patient who showed clinical but not radiographic response. Treatment using bevacizumab improved symptoms related to NF2-associated ependymomas, often without concurrent radiographic response. This treatment effect may be related to VEGF-R1 expression in NF2-associated ependymoma.

Bevacizumab decreases vestibular schwannomas growth rate in children and teenagers with neurofibromatosis type 2.

Vestibular schwannoma (VS) growth in neurofibromatosis type 2 (NF2) can be responsible for brainstem compression and hearing loss. Surgical removal remains the standard therapy despite potential morbidity. Previous studies suggested that the inhibition of the VEGF-pathway with bevacizumab could result in hearing improvement, reduction of the tumor volume or both in adults. We retrospectively describe the French experience of bevacizumab treatment delivered for progressive VS in pediatric NF2 patients. Patients received Bevacizumab 5 or 10mg/kg every 2weeks according to the physician's choice. Follow-up included clinical assessment, audiometry and volumetric MRI every 3-6months. Seven patients harboring 11 VS were included. The median age at inclusion was 15years (11.4-18.8), and the median treatment duration was 11.3months (3.2-55.6). At baseline, the median tumor volume was 1.2cm(3) (0.52-13.5) and the median word recognition score was 90% (0-100). We observed one major response, two minor responses and a decrease in the rate of tumor growth for the 4 other patients. The median annual growth rate before treatment was significantly higher than after 1year of treatment (138 vs. 36%, n=5, p=0.043). We noted one hearing improvement over the course of 1year under treatment (hearing response rate was 14%). Overall, the treatment was well tolerated. Our study supports that bevacizumab is an attractive therapeutic option for pediatric NF2 patients with growing VS. Thorough multidisciplinary evaluation is necessary to identify the best candidates prior to treatment. It is likely that a better functional outcome would be expected if targeted therapies were discussed early in the management of the disease.