Radiobiology of vestibular schwannomas: mechanisms of radioresistance and potential targets for therapeutic sensitization

2009 ◽  
Vol 27 (6) ◽  
pp. E2 ◽  
Author(s):  
Andrea H. Yeung ◽  
Michael E. Sughrue ◽  
Ari J. Kane ◽  
Tarik Tihan ◽  
Steven W. Cheung ◽  
...  
Keyword(s):  
Radiation Treatment ◽  
Molecular Level ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Tumor Control ◽  
Side Effect Profile ◽  
Novel Therapies ◽  
Microsurgical Resection ◽  
Selection For ◽  
Cranial Nerve Viii

Vestibular schwannomas (VS) are benign tumors arising from the Schwann cells of cranial nerve VIII. Historically the prevailing therapy for patients with VS has been microsurgical resection. More recently, stereotactic radiosurgery (SRS) and fractionated stereotactic radiotherapy have gained acceptance as effective alternatives. Although the side effect profile and rates of tumor control appear to be favorable for SRS, there is a subset of radioresistant tumors that continue to progress despite properly administered radiation treatment. In this review, the authors summarize what is known about the mechanism of radioresistance in VS at the clinical and molecular level. An improved understanding of the radiobiological behavior of VS may help guide appropriate patient selection for SRS and potentially aid in the design of novel therapies to treat radioresistant tumors.

scholarly journals Understanding the Radiobiology of Vestibular Schwannomas to Overcome Radiation Resistance

Cancers ◽  
2021 ◽  
Vol 13 (18) ◽  
pp. 4575
Author(s):  
Torin P. Thielhelm ◽  
Stefania Goncalves ◽  
Scott M. Welford ◽  
Eric A. Mellon ◽  
Erin R. Cohen ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Current Knowledge ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Intracranial Tumors ◽  
Treatment Protocols ◽  
Cycle Arrest ◽  
Microsurgical Resection ◽  
Cranial Nerve Viii ◽  
Key Events

Vestibular schwannomas (VS) are benign tumors arising from cranial nerve VIII that account for 8–10% of all intracranial tumors and are the most common tumors of the cerebellopontine angle. These tumors are typically managed with observation, radiation therapy, or microsurgical resection. Of the VS that are irradiated, there is a subset of tumors that are radioresistant and continue to grow; the mechanisms behind this phenomenon are not fully understood. In this review, the authors summarize how radiation causes cellular and DNA injury that can activate (1) checkpoints in the cell cycle to initiate cell cycle arrest and DNA repair and (2) key events that lead to cell death. In addition, we discuss the current knowledge of VS radiobiology and how it may contribute to clinical outcomes. A better understanding of VS radiobiology can help optimize existing treatment protocols and lead to new therapies to overcome radioresistance.

The molecular biology and novel treatments of vestibular schwannomas

2011 ◽  
Vol 115 (5) ◽  
pp. 906-914 ◽  
Author(s):  
Brendan Fong ◽  
Garni Barkhoudarian ◽  
Patrick Pezeshkian ◽  
Andrew T. Parsa ◽  
Quinton Gopen ◽  
...  
Keyword(s):  
Molecular Biology ◽  
Vestibular Schwannoma ◽  
Cranial Nerve ◽  
Molecular Mechanisms ◽  
Tumor Burden ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Novel Therapies ◽  
Phase Ii Trials

Vestibular schwannomas are histopathologically benign tumors arising from the Schwann cell sheath surrounding the vestibular branch of cranial nerve VIII and are related to the NF2 gene and its product merlin. Merlin acts as a tumor suppressor and as a mediator of contact inhibition. Thus, deficiencies in both NF2 genes lead to vestibular schwannoma development. Recently, there have been major advances in our knowledge of the molecular biology of vestibular schwannomas as well as the development of novel therapies for its treatment. In this article the authors comprehensively review the recent advances in the molecular biology and characterization of vestibular schwannomas as well as the development of modern treatments for vestibular schwannoma. For instance, merlin is involved with a number of receptors including the CD44 receptor, EGFR, and signaling pathways, such as the Ras/raf pathway and the canonical Wnt pathway. Recently, merlin was also shown to interact in the nucleus with E3 ubiquitin ligase CRL4DCAF1. A greater understanding of the molecular mechanisms behind vestibular schwannoma tumorigenesis has begun to yield novel therapies. Some authors have shown that Avastin induces regression of progressive schwannomas by over 40% and improves hearing. An inhibitor of VEGF synthesis, PTC299, is currently in Phase II trials as a potential agent to treat vestibular schwannoma. Furthermore, in vitro studies have shown that trastuzumab (an ERBB2 inhibitor) reduces vestibular schwannoma cell proliferation. With further research it may be possible to significantly reduce morbidity and mortality rates by decreasing tumor burden, tumor volume, hearing loss, and cranial nerve deficits seen in vestibular schwannomas.

scholarly journals Evolution in Surgical Treatment of Vestibular Schwannomas

2021 ◽  
Author(s):  
Marcos Tatagiba ◽  
Florian H. Ebner ◽  
Taishi Nakamura ◽  
Georgios Naros
Keyword(s):  
Surgical Treatment ◽  
Cranial Nerve ◽  
Radiation Treatment ◽  
Tumor Resection ◽  
Vestibular Schwannomas ◽  
Tumor Control ◽  
Consecutive Series ◽  
Additional Tool ◽  
Neuroprotective Strategy

Abstract Purpose of Review Management of vestibular schwannomas (VSs) is multimodal and include watchful observation, radiation treatment, and surgery. Over the past decades, a shift in treatment strategy toward radiation treatment has gradually displaced surgery from the main treatment option for VS. In recent years, however, surgery has been further refined by developments of microsurgical and endoscopic techniques and advances in intraoperative application of neuroprotective drugs. This article presents outcomes of modern surgical treatment of VS in the era of radiosurgery and reviews recent published advancements relevant to VS management. Recent Findings Following VS surgery, excellent tumor resection rates and cranial nerve outcomes were achieved in a consecutive series of 572 adult patients with mean postoperative follow up of 4 years. Innovations in surgical technique include endoscopic technique as additional tool to microsurgery, exploration of semi-sitting position for large tumors, and intraoperative use of vasoactive agents as neuroprotective strategy. Summary Despite great developments in radiation treatment of VS, surgery remains the key solution for the majority of the cases in order to achieve cure of the disease, long-term tumor control, and preservation of cranial nerve function at long-term.

Molecular biology of familial and sporadic vestibular schwannomas: implications for novel therapeutics

2011 ◽  
Vol 114 (2) ◽  
pp. 359-366 ◽  
Author(s):  
Michael E. Sughrue ◽  
Andrea H. Yeung ◽  
Martin J. Rutkowski ◽  
Steven W. Cheung ◽  
Andrew T. Parsa
Keyword(s):  
Molecular Biology ◽  
Cranial Nerve ◽  
Single Gene ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Genetic Mutations ◽  
Chromosome 22 ◽  
Novel Therapeutics ◽  
Broad Variety ◽  
Cranial Nerve Viii

Vestibular schwannomas (VSs) are benign tumors arising from the sheath of cranial nerve VIII. The pathogenesis underlying most familial and sporadic VSs has been linked to a mutation in a single gene, the neurofibromin 2 (NF2) gene located on chromosome 22, band q11–13.1. In this review, the authors summarized what is known about the epidemiology of NF2 mutations and patients with VSs. The authors also discuss the function of the NF2 gene product, merlin, and describe the known and hypothetical effects of genetic mutations that lead to merlin dysfunction on a broad variety of cellular and histological end points. A better understanding of the molecular pathobiology of VSs may lead to novel therapeutics to augment current modalities of treatment while minimizing morbidity.

scholarly journals Repeat stereotactic radiosurgery for progressive vestibular schwannomas after previous radiosurgery: a systematic review and meta-analysis

2021 ◽  
Author(s):  
Anne Balossier ◽  
Jean Régis ◽  
Nicolas Reyns ◽  
Pierre-Hugues Roche ◽  
Roy Thomas Daniel ◽  
...  
Keyword(s):  
Systematic Review ◽  
Hearing Loss ◽  
Facial Nerve ◽  
Stereotactic Radiosurgery ◽  
Cranial Nerve ◽  
Meta Analysis ◽  
Cranial Nerves ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Tumor Control

AbstractVestibular schwannomas (VS) are slow-growing intracranial extraaxial benign tumors, developing from the vestibular part of the eight cranial nerves. Stereotactic radiosurgery (SRS) has now a long-term scientific track record as first intention treatment for small- to medium-sized VS. Though its success rate is very high, SRS for VS might fail to control tumor growth in some cases. However, the literature on repeat SRS after previously failed SRS remains scarce and reported in a low number of series with a limited number of cases. Here, we aimed at performing a systematic review and meta-analysis of the literature on repeat SRS for VS. Using PRISMA guidelines, we reviewed manuscripts published between January 1990 and October 2020 and referenced in PubMed. Tumor control and cranial nerve outcomes were evaluated with separate meta-analyses. Eight studies comprising 194 patients were included. The overall rate of patients treated in repeat SRS series as per overall series with first SRS was 2.2% (range 1.2–3.2%, p < 0.001). The mean time between first and second SRS was 50.7 months (median 51, range 44–64). The median marginal dose prescribed at first SRS was 12 Gy (range 8–24) and at second SRS was 12 Gy (range 9.8–19). After repeat SRS, tumor stability was reported in 61/194 patients, i.e., a rate of 29.6% (range 20.2–39%, I2 = 49.1%, p < 0.001). Tumor decrease was reported in 83/194 patients, i.e., a rate of 54.4% (range 33.7–75.1%, I2 = 89.1%, p < 0.001). Tumor progression was reported in 50/188 patients, i.e., a rate of 16.1% (range 2.5–29.7%, I2 = 87.1%, p = 0.02), rarely managed surgically. New trigeminal numbness was reported in 27/170 patients, i.e., a rate of 9.9% (range 1.4–18.3%, p < 0.02). New facial nerve palsy of worsened of previous was reported in 8/183 patients, i.e., a rate of 4.3% (range 1.4–7.2%, p = 0.004). Hearing loss was reported in 12/22 patients, i.e., a rate of 54.3% (range 24.8–83.8%, I2 = 70.7%, p < 0.001). Repeat SRS after previously failed SRS for VS is associated with high tumor control rates. Cranial nerve outcomes remain favorable, particularly for facial nerve. The rate of hearing loss appears similar to the one related to first SRS.

Microsurgical Resection of Vestibular Schwannomas, Presentation of Cases in 3D: 3-Dimensional Operative Video

2019 ◽  
Vol 19 (1) ◽  
pp. E61-E62
Author(s):  
Alvaro Campero ◽  
Matias Baldoncini
Keyword(s):  
Facial Nerve ◽  
Cochlear Nerve ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
3 Dimensional ◽  
Microsurgical Resection ◽  
Magnetic Resonance Imaging Mri ◽  
The Right ◽  
Functional Preservation

Abstract Vestibular schwannomas are the most common benign tumors of the pontocerebellar angle,1,2 their microsurgical complexity is related to their size and neurovascular relationships. The purpose of this work is to analyze the clinical, anatomic characteristics, microsurgical treatment, and the postoperative results according to the Hannover gradual scale in 4 patients with vestibular schwannomas. The 4 patients gave their consent to the procedure and all consented to the use of their surgical videos, preoperative and postoperative studies, and postoperative pictures. Case 1: A 39-yr-old woman, with left ear hearing loss. Magnetic resonance imaging (MRI) showed small Intracanalicular schwannoma (T1 classification by Hannover). Microsurgery was performed and resection through a retrosigmoid approach2,3 with anatomic and functional preservation of the facial and cochlear nerve. Case 2: A 40-yr-old woman, with left ear hypoacusia. MRI showed an extrameatal schwannoma reaching the brainstem (T3b Hannover classification). The complete re-section through retrosigmoid approach were performed. Case 3: A 69-yr-old woman, without hearing in the right ear. RM: Medium schwannoma (T4a classification of Hannover). Microsurgery was performed with anatomic and functional preservation of the facial nerve.4-6 Case 4: A 32-yr-old woman, without hearing in the left ear. In addition, cerebellar syndrome and headache. RM: Large schwannoma (T4b classification of Hannover). Sur-gery was performed, anatomic preservation of the facial nerve, with moderate paresis in the postoperative period. Microsurgical resection with functional preservation of the facial and cochlear nerve is the main objective7 when addressing this pathology.

Stereotactic radiosurgery versus stereotactic radiotherapy for patients with vestibular schwannoma: a Leksell Gamma Knife Society 2000 debate

2000 ◽  
Vol 93 (supplement_3) ◽  
pp. 90-92 ◽  
Author(s):  
Mark E. Linskey
Keyword(s):  
Gamma Knife ◽  
Stereotactic Radiotherapy ◽  
Three Dimensional ◽  
Late Recurrence ◽  
Vestibular Schwannomas ◽  
Tumor Control ◽  
Complication Rates ◽  
Content Type ◽  
Single Fraction ◽  
Fine Print

✓ By definition, the term “radiosurgery” refers to the delivery of a therapeutic radiation dose in a single fraction, not simply the use of stereotaxy. Multiple-fraction delivery is better termed “stereotactic radiotherapy.” There are compelling radiobiological principles supporting the biological superiority of single-fraction radiation for achieving an optimal therapeutic response for the slowly proliferating, late-responding, tissue of a schwannoma. It is axiomatic that complication avoidance requires precise three-dimensional conformality between treatment and tumor volumes. This degree of conformality can only be achieved through complex multiisocenter planning. Alternative radiosurgery devices are generally limited to delivering one to four isocenters in a single treatment session. Although they can reproduce dose plans similar in conformality to early gamma knife dose plans by using a similar number of isocenters, they cannot reproduce the conformality of modern gamma knife plans based on magnetic resonance image—targeted localization and five to 30 isocenters. A disturbing trend is developing in which institutions without nongamma knife radiosurgery (GKS) centers are championing and/or shifting to hypofractionated stereotactic radiotherapy for vestibular schwannomas. This trend appears to be driven by a desire to reduce complication rates to compete with modern GKS results by using complex multiisocenter planning. Aggressive advertising and marketing from some of these centers even paradoxically suggests biological superiority of hypofractionation approaches over single-dose radiosurgery for vestibular schwannomas. At the same time these centers continue to use the term radiosurgery to describe their hypofractionated radiotherapy approach in an apparent effort to benefit from a GKS “halo effect.” It must be reemphasized that as neurosurgeons our primary duty is to achieve permanent tumor control for our patients and not to eliminate complications at the expense of potential late recurrence. The answer to minimizing complications while maintaining maximum tumor control is improved conformality of radiosurgery dose planning and not resorting to homeopathic radiosurgery doses or hypofractionation radiotherapy schemes.

Radiotherapy for Brain Tumors: Current Practice and Future Directions

2020 ◽  
Vol 16 (3) ◽  
pp. 182-195
Author(s):  
Sarah Baker ◽  
Natalie Logie ◽  
Kim Paulson ◽  
Adele Duimering ◽  
Albert Murtha
Keyword(s):  
Brain Tumors ◽  
Treatment Strategies ◽  
Brain Parenchyma ◽  
Benign Tumors ◽  
Tumor Control ◽  
Normal Brain ◽  
Neurocognitive Deficits ◽  
Close Proximity ◽  
Recent Developments ◽  
High Level

Radiotherapy is an important component of the treatment for primary and metastatic brain tumors. Due to the close proximity of critical structures and normal brain parenchyma, Central Nervous System (CNS) radiotherapy is associated with adverse effects such as neurocognitive deficits, which must be weighed against the benefit of improved tumor control. Advanced radiotherapy technology may help to mitigate toxicity risks, although there is a paucity of high-level evidence to support its use. Recent advances have been made in the treatment for gliomas, meningiomas, benign tumors, and metastases, although outcomes remain poor for many high grade tumors. This review highlights recent developments in CNS radiotherapy, discusses common treatment toxicities, critically reviews advanced radiotherapy technologies, and highlights promising treatment strategies to improve clinical outcomes in the future.

scholarly journals Biologically effective dose correlates with linear tumor volume changes after upfront single-fraction stereotactic radiosurgery for vestibular schwannomas

2021 ◽  
Author(s):  
Constantin Tuleasca ◽  
Mohamed Faouzi ◽  
Philippe Maeder ◽  
Raphael Maire ◽  
Jonathan Knisely ◽  
...  
Keyword(s):  
Standard Deviation ◽  
Effective Dose ◽  
Stereotactic Radiosurgery ◽  
Tumor Volume ◽  
Vestibular Schwannomas ◽  
Benign Tumors ◽  
Biologically Effective Dose ◽  
Volume Changes ◽  
Single Fraction

AbstractVestibular schwannomas (VSs) are benign, slow-growing tumors. Management options include observation, surgery, and radiation. In this retrospective trial, we aimed at evaluating whether biologically effective dose (BED) plays a role in tumor volume changes after single-fraction first intention stereotactic radiosurgery (SRS) for VS. We compiled a single-institution experience (n = 159, Lausanne University Hospital, Switzerland). The indication for SRS was decided after multidisciplinary discussion. Only cases with minimum 3 years follow-up were included. The Koos grading, a reliable method for tumor classification was used. Radiosurgery was performed using Gamma Knife (GK) and a uniform marginal prescription dose of 12 Gy. Mean BED was 66.3 Gy (standard deviation 3.8, range 54.1–73.9). The mean follow-up period was 5.1 years (standard deviation 1.7, range 3–9.2). The primary outcome was changes in 3D volumes after SRS as function of BED and of integral dose received by the VS. Random-effect linear regression model showed that tumor volume significantly and linearly decreased over time with higher BED (p < 0.0001). Changes in tumor volume were also significantly associated with age, sex, number of isocenters, gradient index, and Koos grade. However, the effect of BED on tumor volume change was moderated by time after SRS and Koos grade. Lower integral doses received by the VSs were inversely correlated with BED in relationship with tumor volume changes (p < 0.0001). Six (3.4%) patients needed further intervention. For patients having uniformly received the same marginal dose prescription, higher BED linearly and significantly correlated with tumor volume changes after SRS for VSs. BED could represent a potential new treatment paradigm for patients with benign tumors, such as VSs, for attaining a desired radiobiological effect. This could further increase the efficacy and decrease the toxicity of SRS not only in benign tumors but also in other SRS indications.

scholarly journals Advanced Imaging Techniques for Radiotherapy Planning of Gliomas

Cancers ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1063
Author(s):  
Antonella Castellano ◽  
Michele Bailo ◽  
Francesco Cicone ◽  
Luciano Carideo ◽  
Natale Quartuccio ◽  
...  
Keyword(s):  
Radiation Treatment ◽  
Imaging Modality ◽  
Imaging Techniques ◽  
Clinical Results ◽  
Target Volume ◽  
Radiotherapy Planning ◽  
Tumor Control ◽  
Current Standard ◽  
Volume Delineation ◽  
Hemodynamic Information

The accuracy of target delineation in radiation treatment (RT) planning of cerebral gliomas is crucial to achieve high tumor control, while minimizing treatment-related toxicity. Conventional magnetic resonance imaging (MRI), including contrast-enhanced T1-weighted and fluid-attenuated inversion recovery (FLAIR) sequences, represents the current standard imaging modality for target volume delineation of gliomas. However, conventional sequences have limited capability to discriminate treatment-related changes from viable tumors, owing to the low specificity of increased blood-brain barrier permeability and peritumoral edema. Advanced physiology-based MRI techniques, such as MR spectroscopy, diffusion MRI and perfusion MRI, have been developed for the biological characterization of gliomas and may circumvent these limitations, providing additional metabolic, structural, and hemodynamic information for treatment planning and monitoring. Radionuclide imaging techniques, such as positron emission tomography (PET) with amino acid radiopharmaceuticals, are also increasingly used in the workup of primary brain tumors, and their integration in RT planning is being evaluated in specialized centers. This review focuses on the basic principles and clinical results of advanced MRI and PET imaging techniques that have promise as a complement to RT planning of gliomas.

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