Anti-Tumour Treatment Systemic therapy in neurofibromatosis type 2 Stephanie Hui-Su Lim a,⇑ , Simone Ardern-Holmes b,1 , Geoffrey McCowage c,2 , Paul de Souza a,d,3 a Department of Medical Oncology and Ingham Research Institute, Liverpool, NSW, Australia b TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Westmead, NSW, Australia c Oncology Research Unit, The Children’s Hospital at Westmead, Westmead, NSW, Australia d University of Western Sydney, School of Medicine, Molecular Medicine Research Group, NSW, Australia article info Article history: Received 8 May 2014 Accepted 9 May 2014 Keywords: Neurofibromatosis type 2 Signal transduction Tyrosine kinase inhibitors abstract The systemic treatment of patients with neurofibromatosis type 2 associated tumours is challenging, as these patients often have prolonged survival but with the inevitable propensity for their disease to cause symptoms, and no effective therapies other than local treatments such as surgery. Understanding the molecular mechanisms driving NF-2 pathogenesis holds promise for the potential use of targeted ther- apy. Initial studies of agents such as bevacizumab (angiogenesis inhibitor) and lapatinib (epidermal growth factor and ErbB2 inhibitor) have indicated benefit for selected patients. As the biology of NF-2 is dependent on multiple interlinked downstream signalling pathways, targeting multiple pathways may be more effective than single agents. Phase zero trials, adaptive phase II or small multi-arm trials, are likely the way forward in this rare disease. Ideally, well-tolerated targeted therapy would appear to be the most promising approach for patients with NF-2, given the natural history of this disease. Ó 2014 Elsevier Ltd. All rights reserved. Introduction Neurofibromatosis type 2 (NF-2) is an autosomal-dominant, multiple neoplasia syndrome resulting from a mutation in the NF-2 tumour suppressor gene on chromosome 22q12 [1]. It occurs at an estimated incidence of 1:25,000 [2] to 1:33 000 [3] and has a penetrance of nearly 100% by age 60. The course of the disease is usually progressive, though variable, causing significant morbidity associated with deafness, blindness, brain stem compression, gait instability and paralysis. Onset typically occurs while a patient is in their 20s, but more than 40% die by the age of 50. Mean actuarial survival in a series from 1995 was 62 years of age [4]. Other reports state survival ranges between 30 and 50 years of age, however this has likely improved over time given the advances in diagnosis and treatment [5,6]. The distinctive clinical feature is the presence of bilateral vestibular schwannomas. Schwannomas also commonly occur on other cranial nerves, and along with intracranial meningi- omas, often multiple, affect about 50% of patients. Spinal tumours occur in 63–90% of NF-2 patients and are heterogenous, consisting of meningiomas, schwannomas and ependymomas. Posterior subcapsular lens opacities are the most common ocular findings [2,5,7,6]. The clinical diagnostic criteria consist of bilateral vestibular schwannomas, or unilateral vestibular schwannoma and two of the other distinct tumours, or either of these latter two criteria in addition to family history or multiple meningiomas [6]. The development of novel medical therapy is targeted at vestibular schwannomas in the first instance, with recommenda- tions for standardised response criteria in treatment trials developed by an international team of experts in the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) collaboration [8]. Differential diagnosis of NF-2 The neurofibomatosis family of syndromes includes Neurofibro- matosis Type 1 (NF-1), NF-2 and schwannomatosis [5]. NF-1 was clearly established as distinct from NF-2 in 1987 when it was recognised as a different autosomal dominant disorder character- ised by subcutaneous and plexiform neurofibromas, café au lait http://dx.doi.org/10.1016/j.ctrv.2014.05.004 0305-7372/Ó 2014 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Address: Department of Medical Oncology, Ingham Research Institute, 1 Campbell St, Liverpool, NSW 2170, Australia. Tel.: +61 2 9616 4407; fax: +61 2 9616 4499. E-mail addresses: stephanie.lim@sswahs.nsw.gov.au (S.H.-S. Lim), simone. ardernholmes@health.nsw.gov.au (S. Ardern-Holmes), geoff.mccowage@health. nsw.gov.au (G. McCowage), p.desouza@uws.edu.au (P. de Souza). 1 TY Nelson Department of Neurology and Neurosurgery, The Children’s Hospital at Westmead, Corner Hawkesbury Rd and Hainsworth St, Westmead, NSW 2145, Australia. Tel.: +61 2 9845 2551; fax: +61 2 9845 3905. 2 Department of Oncology, The Children’s Hospital at Westmead, Corner Hawkes- bury Rd and Hainsworth St, Westmead, NSW 2145, Australia. Tel.: +61 2 9845 2141; fax: +61 2 9845 2171. 3 Department of Medical Oncology, Liverpool Hospital, Elizabeth St, Liverpool, NSW 2170, Australia. Tel.: +61 2 9616 4407; fax: +61 2 9616 4499. Cancer Treatment Reviews 40 (2014) 857–861 Contents lists available at ScienceDirect Cancer Treatment Reviews journal homepage: www.elsevierhealth.com/journals/ctrv