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Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current Trends in Diagnosis and Management with a Focus on Novel Medical Therapies

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Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current Trends in Diagnosis and Management with a Focus on Novel Medical Therapies Neurofibromatosis Type 1 and Type 2 Associated Tumours: Current trends in Diagnosis and Management with a focus on Novel Medical Therapies Simone Lisa Ardern-Holmes MBChB, MSc, FRACP A thesis submitted in fulfilment of the requirements for the degree of Doctor of Philosophy Faculty of Health Sciences, The University of Sydney February 2018 1 STATEMENT OF ORIGINALITY This is to certify that this submission is my own work and that, to the best of my knowledge, it contains no material previously published or written by another person, or material which to a substantial extent has been accepted for the award of any other degree or diploma of the university or other institute of higher learning, except where due acknowledgement has been made in the text. Simone L. Ardern-Holmes 2 SUMMARY Neurofibromatosis type 1 (NF1) and Neurofibromatosis type 2 (NF2) are distinct single gene disorders, which share a predisposition to formation of benign nervous system tumours due to loss of tumour suppressor function. Since identification of the genes encoding NF1 and NF2 in the early 1990s, significant progress has been made in understanding the biological processes and molecular pathways underlying tumour formation. As a result, identifying safe and effective medical approaches to treating NF1 and NF2-associated tumours has become a focus of clinical research and patient care in recent years. This thesis presents a comprehensive discussion of the complications of NF1 and NF2 and approaches to treatment, with a focus on key tumours in each condition. The significant functional impact of these disorders in children and young adults is illustrated, demonstrating the need for coordinated care from experienced multidisciplinary teams. Response of the first Australian patients offered novel medications under careful prospective monitoring for safety and efficacy, is described. The approach to treatment trials including principles of patient selection, rationale for candidate medication choices, and identification of appropriate outcome measures are outlined. Treatment response is assessed utilizing multiple criteria including radiologic response, functional status and patient reported outcomes. Tumours considered include plexiform neurofibromas in NF1, treated with the protein tyrosine kinase inhibitor imatinib, with limited benefit. In NF2, vestibular schwannomas were treated using the vascular endothelial growth factor inhibitor bevacizumab, showing definite benefit in a proportion of patients. Refinements in the clinical approach to NF-associated tumours are discussed, considering results from this early experience. Optimizing tumour surveillance prior to intervention, identifying the most potent yet tolerable agents for use, determining when medical therapy should be utilized in concert with surgical and other approaches, and establishing ways of stratifying individual risk of disease complications and likelihood of treatment benefit, remain important questions for the future. 3 ACKNOWLEDGEMENTS I have greatly appreciated the support, advice and cooperation of many individuals over time while conducting the research outlined here, and in preparation of this thesis. My sincere thanks and acknowledgements are extended to the following people, in particular: Professor Kathryn North, as my primary supervisor, who established the clinical service for children with neurofibromatoses in 1990 at The Children’s Hospital at Westmead. Her vision to improve the care of Australian patients has been key to evolution of the treatment approaches presented here. My collaborations with experts in the field internationally, were facilitated by relationships established in the NF community by Professor North over many years. I have appreciated her advice in all aspects of the conduct of this research and preparation of the thesis. My associate supervisors, Dr Nigel Clarke for his support and encouragement especially in times of change, Drs Mark Wong and Geoffrey McCowage for their expert oncology advice and patient management, Dr Rachel Skinner for her practical and collegial support in the latter phases of research and thesis preparation. Other oncologists providing dedicated care for patients with complex NF1 and NF2 including Dr Luciano Dalla Pozza (Sydney), Professor Elizabeth Tovey (Sydney), Dr Simon Troon (Perth), Professor Paul De Souza (Sydney), Professor John Simes (Sydney), Dr Michael Slancar (Queensland) (Chapters 4, 8, 9). Radiologists Dr Jane Li, Dr Lavier Gomes and Dr Kristina Prelog, for their assistance with interpretation of neuroimaging, especially in assessment of target and off-target radiologic response to bevacizumab in a single patient (JL, LG, Chapter 9). 4 NFTumormetrics staff for assistance with tumour volumetry, under the direction of Dr Gordon Harris, with special thanks for his pro-active approach to international collaboration (Chapters 4, 8, 9). Members of the medical and surgical communities in Sydney involved in the multidisciplinary care of individuals with complex NF1 and NF2, especially colleagues from the Neurogenetics Clinic, The Children’s Hospital at Westmead, and at other institutions. Dr Gemma Fisher, for assistance with the literature review on NF2 (Chapter 5) including first draft of selected sections of the manuscript, and for support in obtaining ethics approval to evaluate the experience of NF2 in children at our centre (Chapter 6). Dr Fisher also contributed to extraction of data for children with NF2 from clinical notes (Chapter 6). Dr Manoj Kanhangad for assistance with application for ethics approval to evaluate spinal neurofibromas in children with NF1 at The Children’s Hospital at Westmead (Chapter 3). Ms Emma Scanlon (Hearing Australia) for her enthusiastic and accommodating participation in audiology surveillance of NF2 patients from around the country. Ms Rosemary Douglas, Ms Katie O’Brien and others providing audiology services for patients at The Children’s Hospital at Westmead. Ms Natalie Gabrael and Ms Carleen Fernandez for administrative support, including coordinating visits for interstate NF2 patients, and sendaways for volumetric MRI analysis. Dr Federica Barzi and Ms Elizabeth Barnes, for advice on study design and data interpretation. The Children’s Tumour Foundation, Australia for financial support, without which the advances in care for NF1 and NF2 patients described in this thesis 5 would not have been possible. This support funded administrative support for care coordination of complex patients with NF1 and NF2 (2010-2012), acquisition of 3D volumetric imaging data, and a stipend toward my employment during that time. Each and every patient, and family member, whose experiences have enriched my understanding of the presentation and complications of NF1 and NF2, and the potential for resilience in the face of significant medical challenges. I greatly valued the opportunity to contribute in working groups of the REiNS International Collaboration, for development of clinical trials recommendations. Advice from REiNs colleagues on management of complex clinical problems arising in the care of our patients has been appreciated. Finally, and most importantly, I thank my family, particularly my husband Connor, and our two sons Adair and Tierney, with whom I have the greatest pleasure and privilege to share the experience of family life. 6 PRESENTATIONS Ardern-Holmes, S.L., Wong, M, McCowage G, North, K.N. Novel medical treatment approaches to NF1/NF2 associated tumours. ANZCNS Scientific Meeting Sydney, May 2013 (Oral Presentation) Ardern-Holmes S.L., Kellie S. Treatment of the Oncologic Complications of NF1 and NF2. International Neurooncology Society Congress, Auckland NZ, Oct 2011 (Oral Presentation) Ardern-Holmes, S.L., Wong, M., McCowage, G., North, K.N. Avastin (bevacizumab) for target and non-target NF2 tumours: trigeminal and spinal tumours also demonstrate response. (Children’s Tumour Foundation Conference Jackson Hole June 2011, Poster Presentation) PUBLICATIONS Ardern-Holmes S.L. and North K.N. Therapeutics for Childhood Neurofibromatosis. Current Treatment Options in Neurology, 13 (6): 2011. (Chapter 2) Ardern-Holmes S. L., & North, K. N. Treatment for plexiform neurofibromas in patients with NF1. The Lancet Oncology, 2012. Ardern-Holmes S, Fisher, G, North, K. Neurofibromatosis type 2: presentation, major complications and management, with a focus on the pediatric age group. 2016. (Chapter 5) Mautner, V.F., Nguyen, R., Ardern-Holmes, S.L., Kluwe, L., Renard, M., Clarke, N., Denayer, E., Valeyrie-Allanore, L., Wolkenstein, P., Legius, E. Imatinib did not induce regression of plexiform neurofibromas in 7 pediatric NF1 patients. Blood e- letter, January 26, 2011. Lim, S, Ardern-Holmes S, McCowage G and de Souza, P. Systemic therapy in neurofibromatosis type 2. Cancer Treatment Reviews. 40: 857-861, 2014. 7 AUTHOR ATTRIBUTION STATEMENT Chapter 2 of this thesis is modified from the published manuscript [1], as I wrote drafts of the manuscript. Chapter 5 is published as [2], as I co-authored drafts of the manuscript. In addition to the statements above, in cases where I am not the corresponding author of a published item, permission to include the published material has been granted by the corresponding author (eg. Appendices). Dr Simone Ardern-Holmes, 26 February 2017 As supervisor for the candidature upon which this thesis is based, I can confirm that the authorship attribution statements above are correct. Professor Kathryn North, 28th February 2017 [1] Ardern-Holmes, S.L. and K.N. North,
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