Clinical Oncology xxx (2014) 1e3 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Editorial
Developments in the Management of Central Nervous System Tumours N.G. Burnet University of Cambridge Department of Oncology, Cambridge Biomedical Campus, Addenbrooke’s Hospital, Cambridge, UK Received 7 April 2014; accepted 11 April 2014
This special issue of Clinical Oncology is devoted to some of the recent significant developments in neuro-oncology. Developments in imaging and pathology seem set to change standard management paradigms in the next few years, by allowing greater individualisation of treatment; surgical developments are improving resection in patients with glioma; radiotherapy can now deliver better dose distributions; and chemotherapy developments are gathering momentum. Particular challenges exist at the extremes of age, and treatment approaches need to be designed differently, and better, in these groups. Imaging is a key component of diagnosis, treatment planning and follow-up for patients with central nervous system (CNS) tumours of all types. Whitfield et al. [1] discuss novel imaging techniques that have the potential to influence radiotherapy planning. Improvement in the definition of tumour extent, particularly using magnetic resonance imaging and positron emission tomography imaging, would be welcome. What is particularly interesting is that newer methods, particularly using magnetic resonance imaging, are now beginning to show surrogates of tumour invasion, such as disruption of white matter tracts. Together with imaging to show potential routes of invasion, this might allow the selection of individualised clinical target volume margins in different directions around the gross tumour or tumour cavity, with anisotropic expansion reflecting risk of recurrence. This type of approach might also be used to triage patients into different management programmes. Surgical developments for patients with glioma [2] include the use of image guidance based on fluorescent molecules such as 5-aminolevulinic acid (5-ALA), for
Author for correspondence: N.G. Burnet, University of Cambridge Department of Oncology, Box 193 e R4, Cambridge Biomedical Campus, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK. Tel: þ441223-336800; Fax: þ44-1223-763120. E-mail addresses: [email protected], [email protected]
patients with glioblastoma (GBM). This technique allows the surgeon to safely resect much more GBM tissue than has been possible before. Debulking surgery can alleviate symptoms, reduce the need for steroids and facilitate radioand chemotherapy. There is emerging evidence [2] that more complete resection of GBM, enhanced by the use of 5ALA, translates into improved survival [3], although further evidence is certainly warranted [4]. Although surgery alone cannot cure GBM, better surgical techniques, leaving a smaller tumour burden, should synergise with radio- and chemotherapy developments. Pathologically, gliomas have been classified by conventional histology for over a century, but the area of molecular diagnostics is now moving rapidly [5]. Although only a few single markers have been shown to have diagnostic, prognostic or predictive value, these have begun to be used clinically. These include the presence of the isocitrate dehydrogenase 1 (IDH1) mutation, which occurs in most lowgrade and many secondary GBMs, and whose presence predicts better survival. The presence of MGMT methylation (i.e. O6-methylguanine DNA methyltransferase promoter methylation) is predictive of the response to alkylating agent chemotherapy, including temozolomide. Thus, developments in molecular diagnostics for glial tumours are beginning to provide opportunities for some individualisation of treatment. The key developments in radiotherapy have been intensity-modulated radiotherapy (IMRT) and imageguided radiotherapy (IGRT), which offer significant opportunities to improve outcome for our patients: IMRT allows better target coverage and lower organ at risk doses than conformal therapy. It also facilitates treatment with inhomogeneous doses, including simultaneous integrated boosts and dose avoidance to organs at risk [6]. Image guidance improves the accuracy of dose delivery, and in some carefully controlled situations the possibility of reducing planning target volume margins. IMRT and IGRT can provide an advantage for patients with the complete
0936-6555/$36.00 Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists. http://dx.doi.org/10.1016/j.clon.2014.04.028
Please cite this article in press as: Burnet NG, , Developments in the Management of Central Nervous System Tumours, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.04.028
2
N.G. Burnet / Clinical Oncology xxx (2014) 1e3
spectrum of diseases, from the most malignant GBM to less malignant or benign tumours, and they can be useful for children too. These technologies should be regarded as standard for many of the tumours we treat. Within CNS practice there has perhaps been a tendency not to apply the latest technology, perhaps in part because of the poor prognosis of many GBM patients. However, surgical and chemotherapy developments in the management of GBM have shown significant improvements in outcome in suitable patients. There is every reason to suppose that the addition of new targeted drugs will further improve this [7,8]. In this context of incremental improvement in surgical and medical therapies, it is essential that radiation oncologists work to improve and optimise radiotherapy, using IMRT, IGRT and other technologies, to provide the best possible outcomes for all of our patients. A challenging issue is that of radiotherapy retreatment of CNS tumours [9]. The first challenge is to select patients appropriately. Most clinicians might agree that young, fit patients with tiny recurrences in originally small, relatively non-infiltrative tumours, and with a long disease-free interval might be considered from retreatment, but this group is extremely small. The second question is how to calculate a safe dose fractionation schedule, and a review of published data and worked examples are presented to give practical help [9]. Radiotherapy retreatment is relatively under-used and there is more to do to optimise this aspect of treatment. The advantage from adding temozolomide chemotherapy to surgery and radiotherapy for GBM [10], first published in 2005, is well known, and can deliver the same improvement in survival in routine clinical practice [3,11]. Although the three drug PCV [procarbazine, CCNU (lomustine), vincristine] schedule has efficacy, the value of the procarbazine and vincristine has begun to be questioned [7], and evidence is emerging for the use of single-agent lomustine (CCNU). Newer targeted agents are beginning to suggest value, at least in combination with conventional alkylating agents. There is considerable scope for testing newer drugs in GBM and increasing interest in making intelligent selection for targeted agents. The development of the CTRad/Cancer Research UK Radiotherapy Drug Combinations Consortium [12] is a demonstration that both the clinical research community and funders are taking seriously the combination of drugs with radiation in general. Neuro-oncology contains particular challenges for the treatment of patients at the extremes of age. There is a prevalent opinion that older general oncology patients are under-treated [13] and that this represents inequitable access to cancer care. On the other hand, general oncology patients receiving chemotherapy close to the end of life have a higher chance of undergoing mechanical ventilation or cardiopulmonary resuscitation, are less likely to die in their preferred location and less likely to be referred to a hospice, outcomes that are associated with a poorer quality of life without much evidence of benefit [14]. These issues apply especially to elderly glioma patients, and there is debate as to whether treatment intensity should be reduced
or not, and if so, by how much [15]. Rampling and Erridge [15] recommend that elderly patients with GBM who have good performance status (KPS > 70) should be managed actively; surgical resection should be considered; and MGMT promoter methylation status (as a predictor of chemotherapy response) should be routinely estimated to guide management. For methylated patients, chemotherapy or hypofractionated radiotherapy are both reasonable options, but high-dose radiotherapy should be avoided. For unmethylated patients, chemotherapy is not warranted. Data suggesting that the combination of chemotherapy with radiotherapy may be advantageous are not yet mature [15] and some suggest the opposite [16]. It is clear that older patients require specific treatment approaches, with quality of life as a clear focus, as well as survival. In the paediatric group, where there are important differences from adult neuro-oncology [17], there has been considerable evolution in treatment, partly based on improvements in the molecular classification of tumours. In the UK, the multidisciplinary management of children with brain tumours is well organised in specialist centres. International collaboration has been a feature in paediatric oncology for many years, and has allowed progress, even with relatively rare tumours. The quality of survivorship, including late effects of radiotherapy, is a key consideration for paediatric oncology. Although radiotherapy is a major cause of late toxicities, the tumour, surgery, chemotherapy, and psychosocial disruption all play a part too. Growth impairment, neurocognitive deficits, endocrinopathies and second malignant neoplasms are particular issues. IMRT improves the conformation of the high dose to the target, compared with conformal radiotherapy, but concerns remain about the increased volume receiving low dose. Further work is required, including long-term follow-up in relation to risk of second malignant neoplasms. Proton beam therapy offers a particular value for paediatric patients by reducing the dose in the exit path virtually to zero. This clear dosimetry advantage played a major part in the establishment of the Proton Oversees Programme in 2008, under which many children and some adult patients with selected indications can have proton beam therapy abroad, funded and supported by the National Health Service [18]. Many patients have been treated successfully, and the process has been widely embraced by the paediatric radiotherapy community in particular. Two centres will be built in the UK (at the Christie in Manchester and UCLH in London), and it is anticipated that patients will be treated in 2018. This will be a key area for clinical development and research, and will benefit from engagement across the whole community. There are other important developments in neurooncology, not addressed here, including stereotactic radiosurgery [19]. Stereotactic radiosurgery represents an important mode of radiotherapy, and many patients have been treated successfully over a long period. Its exact role in relation to fractionated stereotactic radiotherapy remains to be established and technical aspects warrant further study. The developments described in the following papers suggest that interesting times are coming to neuro-oncology.
Please cite this article in press as: Burnet NG, , Developments in the Management of Central Nervous System Tumours, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.04.028
N.G. Burnet / Clinical Oncology xxx (2014) 1e3
We are on the brink of major changes in management, with a degree of personalised care becoming possible, that has never been dreamt of before. The evaluation of these, and the potential to deliver an improved outlook for our patients, should make the next few years genuinely exciting.
References [1] Whitfield GA, Kennedy SR, Djoukhadar IK, Jackson A. Imaging and target volume delineation in glioma. Clin Oncol 2014;26, in this issue. [2] Watts C, Price SJ, Santarius T. Current concepts in the surgical management of glioma patients. Clin Oncol 2014;26, in this issue. [3] Slotty PJ, Siantidis B, Beez T, Steiger HJ, Sabel M. The impact of improved treatment strategies on overall survival in glioblastoma patients. Acta Neurochir (Wien) 2013;155(6): 959e963. [4] Barone DG, Lawrie TA, Hart MG. Image guided surgery for the resection of brain tumours. Cochrane Database Syst Rev 2014;1:CD009685. [5] Collins VP. Pathology of gliomas and developments in molecular testing. Clin Oncol 2014;26, in this issue. [6] Burnet NG, Jena R, Burton KE, et al. Clinical and practical considerations for the use of intensity-modulated radiotherapy and image guidance in neuro-oncology. Clin Oncol 2014;26, in this issue. [7] Ajaz M, Jefferies S, Brazil L, Chalmers A. Current and investigational drug strategies for glioblastoma multiforme. Clin Oncol 2014;26, in this issue. [8] Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 2011;11(4):239e253. [9] Jones B, Grant W. Retreatment of central nervous system tumours. Clin Oncol 2014;26, in this issue.
3
[10] Stupp R, Hegi ME, Mason WP, et al, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10(5):459e466. [11] Guilfoyle MR, Weerakkody RA, Oswal A, et al. Implementation of neuro-oncology service reconfiguration in accordance with NICE guidance provides enhanced clinical care for patients with glioblastoma multiforme. Br J Cancer 2011;104(12): 1810e1815. [12] CTRad Radiotherapy-Drug Combinations Consortium. Available at: http://www2.ncri.org.uk/ctrad/documents/ctrad_ bulletin_2013-05_final.pdf. [13] Lawler M, Selby P, Aapro MS, Duffy S. Ageism in cancer care. Br Med J 2014;348:g1614. [14] Rabow MW. Chemotherapy near the end of life. Br Med J 2014;348:g1529. [15] Rampling R, Erridge S. Management of central nervous system tumours at the extremes of life d the elderly. Clin Oncol 2014;26, in this issue. [16] Cao JQ, Fisher BJ, Bauman GS, Megyesi JF, Watling CJ, Macdonald DR. Hypofractionated radiotherapy with or without concurrent temozolomide in elderly patients with glioblastoma multiforme: a review of ten-year single institutional experience. J Neurooncol 2012;107(2):395e405. [17] Thorp NJ, Taylor RE. Management of central nervous system tumours in children. Clin Oncol 2014;26, in this issue. [18] Proton Oversees Programme. Available at: http://www. specialisedservices.nhs.uk/info/proton-beam-therapy. [19] Short S, Tobias J. Radiosurgery for brain tumours. Br Med J 2010;340:c3247.
Please cite this article in press as: Burnet NG, , Developments in the Management of Central Nervous System Tumours, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.04.028
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Editorial
Developments in the Management of Central Nervous System Tumours N.G. Burnet University of Cambridge Department of Oncology, Cambridge Biomedical Campus, Addenbrooke’s Hospital, Cambridge, UK Received 7 April 2014; accepted 11 April 2014
This special issue of Clinical Oncology is devoted to some of the recent significant developments in neuro-oncology. Developments in imaging and pathology seem set to change standard management paradigms in the next few years, by allowing greater individualisation of treatment; surgical developments are improving resection in patients with glioma; radiotherapy can now deliver better dose distributions; and chemotherapy developments are gathering momentum. Particular challenges exist at the extremes of age, and treatment approaches need to be designed differently, and better, in these groups. Imaging is a key component of diagnosis, treatment planning and follow-up for patients with central nervous system (CNS) tumours of all types. Whitfield et al. [1] discuss novel imaging techniques that have the potential to influence radiotherapy planning. Improvement in the definition of tumour extent, particularly using magnetic resonance imaging and positron emission tomography imaging, would be welcome. What is particularly interesting is that newer methods, particularly using magnetic resonance imaging, are now beginning to show surrogates of tumour invasion, such as disruption of white matter tracts. Together with imaging to show potential routes of invasion, this might allow the selection of individualised clinical target volume margins in different directions around the gross tumour or tumour cavity, with anisotropic expansion reflecting risk of recurrence. This type of approach might also be used to triage patients into different management programmes. Surgical developments for patients with glioma [2] include the use of image guidance based on fluorescent molecules such as 5-aminolevulinic acid (5-ALA), for
Author for correspondence: N.G. Burnet, University of Cambridge Department of Oncology, Box 193 e R4, Cambridge Biomedical Campus, Addenbrooke’s Hospital, Hills Road, Cambridge CB2 0QQ, UK. Tel: þ441223-336800; Fax: þ44-1223-763120. E-mail addresses: [email protected], [email protected]
patients with glioblastoma (GBM). This technique allows the surgeon to safely resect much more GBM tissue than has been possible before. Debulking surgery can alleviate symptoms, reduce the need for steroids and facilitate radioand chemotherapy. There is emerging evidence [2] that more complete resection of GBM, enhanced by the use of 5ALA, translates into improved survival [3], although further evidence is certainly warranted [4]. Although surgery alone cannot cure GBM, better surgical techniques, leaving a smaller tumour burden, should synergise with radio- and chemotherapy developments. Pathologically, gliomas have been classified by conventional histology for over a century, but the area of molecular diagnostics is now moving rapidly [5]. Although only a few single markers have been shown to have diagnostic, prognostic or predictive value, these have begun to be used clinically. These include the presence of the isocitrate dehydrogenase 1 (IDH1) mutation, which occurs in most lowgrade and many secondary GBMs, and whose presence predicts better survival. The presence of MGMT methylation (i.e. O6-methylguanine DNA methyltransferase promoter methylation) is predictive of the response to alkylating agent chemotherapy, including temozolomide. Thus, developments in molecular diagnostics for glial tumours are beginning to provide opportunities for some individualisation of treatment. The key developments in radiotherapy have been intensity-modulated radiotherapy (IMRT) and imageguided radiotherapy (IGRT), which offer significant opportunities to improve outcome for our patients: IMRT allows better target coverage and lower organ at risk doses than conformal therapy. It also facilitates treatment with inhomogeneous doses, including simultaneous integrated boosts and dose avoidance to organs at risk [6]. Image guidance improves the accuracy of dose delivery, and in some carefully controlled situations the possibility of reducing planning target volume margins. IMRT and IGRT can provide an advantage for patients with the complete
0936-6555/$36.00 Ó 2014 Published by Elsevier Ltd on behalf of The Royal College of Radiologists. http://dx.doi.org/10.1016/j.clon.2014.04.028
Please cite this article in press as: Burnet NG, , Developments in the Management of Central Nervous System Tumours, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.04.028
2
N.G. Burnet / Clinical Oncology xxx (2014) 1e3
spectrum of diseases, from the most malignant GBM to less malignant or benign tumours, and they can be useful for children too. These technologies should be regarded as standard for many of the tumours we treat. Within CNS practice there has perhaps been a tendency not to apply the latest technology, perhaps in part because of the poor prognosis of many GBM patients. However, surgical and chemotherapy developments in the management of GBM have shown significant improvements in outcome in suitable patients. There is every reason to suppose that the addition of new targeted drugs will further improve this [7,8]. In this context of incremental improvement in surgical and medical therapies, it is essential that radiation oncologists work to improve and optimise radiotherapy, using IMRT, IGRT and other technologies, to provide the best possible outcomes for all of our patients. A challenging issue is that of radiotherapy retreatment of CNS tumours [9]. The first challenge is to select patients appropriately. Most clinicians might agree that young, fit patients with tiny recurrences in originally small, relatively non-infiltrative tumours, and with a long disease-free interval might be considered from retreatment, but this group is extremely small. The second question is how to calculate a safe dose fractionation schedule, and a review of published data and worked examples are presented to give practical help [9]. Radiotherapy retreatment is relatively under-used and there is more to do to optimise this aspect of treatment. The advantage from adding temozolomide chemotherapy to surgery and radiotherapy for GBM [10], first published in 2005, is well known, and can deliver the same improvement in survival in routine clinical practice [3,11]. Although the three drug PCV [procarbazine, CCNU (lomustine), vincristine] schedule has efficacy, the value of the procarbazine and vincristine has begun to be questioned [7], and evidence is emerging for the use of single-agent lomustine (CCNU). Newer targeted agents are beginning to suggest value, at least in combination with conventional alkylating agents. There is considerable scope for testing newer drugs in GBM and increasing interest in making intelligent selection for targeted agents. The development of the CTRad/Cancer Research UK Radiotherapy Drug Combinations Consortium [12] is a demonstration that both the clinical research community and funders are taking seriously the combination of drugs with radiation in general. Neuro-oncology contains particular challenges for the treatment of patients at the extremes of age. There is a prevalent opinion that older general oncology patients are under-treated [13] and that this represents inequitable access to cancer care. On the other hand, general oncology patients receiving chemotherapy close to the end of life have a higher chance of undergoing mechanical ventilation or cardiopulmonary resuscitation, are less likely to die in their preferred location and less likely to be referred to a hospice, outcomes that are associated with a poorer quality of life without much evidence of benefit [14]. These issues apply especially to elderly glioma patients, and there is debate as to whether treatment intensity should be reduced
or not, and if so, by how much [15]. Rampling and Erridge [15] recommend that elderly patients with GBM who have good performance status (KPS > 70) should be managed actively; surgical resection should be considered; and MGMT promoter methylation status (as a predictor of chemotherapy response) should be routinely estimated to guide management. For methylated patients, chemotherapy or hypofractionated radiotherapy are both reasonable options, but high-dose radiotherapy should be avoided. For unmethylated patients, chemotherapy is not warranted. Data suggesting that the combination of chemotherapy with radiotherapy may be advantageous are not yet mature [15] and some suggest the opposite [16]. It is clear that older patients require specific treatment approaches, with quality of life as a clear focus, as well as survival. In the paediatric group, where there are important differences from adult neuro-oncology [17], there has been considerable evolution in treatment, partly based on improvements in the molecular classification of tumours. In the UK, the multidisciplinary management of children with brain tumours is well organised in specialist centres. International collaboration has been a feature in paediatric oncology for many years, and has allowed progress, even with relatively rare tumours. The quality of survivorship, including late effects of radiotherapy, is a key consideration for paediatric oncology. Although radiotherapy is a major cause of late toxicities, the tumour, surgery, chemotherapy, and psychosocial disruption all play a part too. Growth impairment, neurocognitive deficits, endocrinopathies and second malignant neoplasms are particular issues. IMRT improves the conformation of the high dose to the target, compared with conformal radiotherapy, but concerns remain about the increased volume receiving low dose. Further work is required, including long-term follow-up in relation to risk of second malignant neoplasms. Proton beam therapy offers a particular value for paediatric patients by reducing the dose in the exit path virtually to zero. This clear dosimetry advantage played a major part in the establishment of the Proton Oversees Programme in 2008, under which many children and some adult patients with selected indications can have proton beam therapy abroad, funded and supported by the National Health Service [18]. Many patients have been treated successfully, and the process has been widely embraced by the paediatric radiotherapy community in particular. Two centres will be built in the UK (at the Christie in Manchester and UCLH in London), and it is anticipated that patients will be treated in 2018. This will be a key area for clinical development and research, and will benefit from engagement across the whole community. There are other important developments in neurooncology, not addressed here, including stereotactic radiosurgery [19]. Stereotactic radiosurgery represents an important mode of radiotherapy, and many patients have been treated successfully over a long period. Its exact role in relation to fractionated stereotactic radiotherapy remains to be established and technical aspects warrant further study. The developments described in the following papers suggest that interesting times are coming to neuro-oncology.
Please cite this article in press as: Burnet NG, , Developments in the Management of Central Nervous System Tumours, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.04.028
N.G. Burnet / Clinical Oncology xxx (2014) 1e3
We are on the brink of major changes in management, with a degree of personalised care becoming possible, that has never been dreamt of before. The evaluation of these, and the potential to deliver an improved outlook for our patients, should make the next few years genuinely exciting.
References [1] Whitfield GA, Kennedy SR, Djoukhadar IK, Jackson A. Imaging and target volume delineation in glioma. Clin Oncol 2014;26, in this issue. [2] Watts C, Price SJ, Santarius T. Current concepts in the surgical management of glioma patients. Clin Oncol 2014;26, in this issue. [3] Slotty PJ, Siantidis B, Beez T, Steiger HJ, Sabel M. The impact of improved treatment strategies on overall survival in glioblastoma patients. Acta Neurochir (Wien) 2013;155(6): 959e963. [4] Barone DG, Lawrie TA, Hart MG. Image guided surgery for the resection of brain tumours. Cochrane Database Syst Rev 2014;1:CD009685. [5] Collins VP. Pathology of gliomas and developments in molecular testing. Clin Oncol 2014;26, in this issue. [6] Burnet NG, Jena R, Burton KE, et al. Clinical and practical considerations for the use of intensity-modulated radiotherapy and image guidance in neuro-oncology. Clin Oncol 2014;26, in this issue. [7] Ajaz M, Jefferies S, Brazil L, Chalmers A. Current and investigational drug strategies for glioblastoma multiforme. Clin Oncol 2014;26, in this issue. [8] Begg AC, Stewart FA, Vens C. Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 2011;11(4):239e253. [9] Jones B, Grant W. Retreatment of central nervous system tumours. Clin Oncol 2014;26, in this issue.
3
[10] Stupp R, Hegi ME, Mason WP, et al, European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups; National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 2009;10(5):459e466. [11] Guilfoyle MR, Weerakkody RA, Oswal A, et al. Implementation of neuro-oncology service reconfiguration in accordance with NICE guidance provides enhanced clinical care for patients with glioblastoma multiforme. Br J Cancer 2011;104(12): 1810e1815. [12] CTRad Radiotherapy-Drug Combinations Consortium. Available at: http://www2.ncri.org.uk/ctrad/documents/ctrad_ bulletin_2013-05_final.pdf. [13] Lawler M, Selby P, Aapro MS, Duffy S. Ageism in cancer care. Br Med J 2014;348:g1614. [14] Rabow MW. Chemotherapy near the end of life. Br Med J 2014;348:g1529. [15] Rampling R, Erridge S. Management of central nervous system tumours at the extremes of life d the elderly. Clin Oncol 2014;26, in this issue. [16] Cao JQ, Fisher BJ, Bauman GS, Megyesi JF, Watling CJ, Macdonald DR. Hypofractionated radiotherapy with or without concurrent temozolomide in elderly patients with glioblastoma multiforme: a review of ten-year single institutional experience. J Neurooncol 2012;107(2):395e405. [17] Thorp NJ, Taylor RE. Management of central nervous system tumours in children. Clin Oncol 2014;26, in this issue. [18] Proton Oversees Programme. Available at: http://www. specialisedservices.nhs.uk/info/proton-beam-therapy. [19] Short S, Tobias J. Radiosurgery for brain tumours. Br Med J 2010;340:c3247.
Please cite this article in press as: Burnet NG, , Developments in the Management of Central Nervous System Tumours, Clinical Oncology (2014), http://dx.doi.org/10.1016/j.clon.2014.04.028
