Clinical Oncology 26 (2014) 438e445 Contents lists available at ScienceDirect
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Overview
Management of Central Nervous System Tumours in Children N.J. Thorp *, R.E. Taylor y * Clatterbridge y
Cancer Centre, Bebington, Wirral CH63 4JY, UK College of Medicine, Swansea University, UK
Received 30 March 2014; accepted 7 April 2014
Abstract This article reviews current approaches to management of central nervous system tumours of childhood, highlighting aspects particularly pertinent to the paediatric population. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Brain; paediatric; radiotherapy; tumours
Introduction Primary central nervous system tumours are the most frequent solid tumours and the most common cause of cancer-related morbidity and death in childhood (Figure 1). They constitute a heterogeneous group of diseases in terms of histology, biology, clinical course and prognosis. Compared with adult practice, a different spectrum of histological subtypes is seen, reflecting the different stage of development of the nervous system during which tumours arise. Histologically low grade pilocytic astrocytomas are the most frequently occurring, while medulloblastomas are the most common malignant brain tumour. Conversely, high grade astrocytic tumours seen frequently in adults are relatively uncommon in children. In paediatric neurooncology practice significant numbers require the technically challenging technique of craniospinal RT. In common with adult practice an understanding of tumour molecular biology is now in the process of being incorporated into decision making in addition to conventional pathological parameters. However, these molecular biological features frequently differ between adult and paediatric series despite similar appearances on conventional histology.
Author for correspondence: N.J. Thorp, Clatterbridge Cancer Centre, Bebington, Wirral CH63 4JY, UK.
There are important overlaps with adult practice with respect to neurosurgery and imaging. Management of brain tumours in children is highly specialised and should only be carried out by specialist MDT’s in accredited centres. Radiotherapy, normally integrated with surgery and chemotherapy in treatment protocols, continues to play a pivotal role in spite of concerns regarding late effects. Particular challenges for the paediatric clinical oncologist include immobilisation of the young, uncooperative child, psychosocial aspects and the organisation of long term follow up. Modern radiotherapy approaches are evolving to improve the therapeutic ratio including hyperfractionation, IMRT and proton therapy. An improved understanding of molecular biology may enable individualisation of management in the future.
Epidemiology In the UK, the incidence of childhood CNS tumours is reported as 31.4 per million [1]. The cause of most (95%) is not known but there are well recognised risk factors. These include a family history of brain tumour, exposure to ionising radiation (in particular prior therapeutic CNS irradiation) and familial genetic syndromes (for example, neurofibromatosis 1 and 2, tuberous sclerosis, Von Hippel Lindau disease, Li Fraumeni and Gorlin’s syndrome) [2]. CNS tumours are more common in males.
0936-6555/$36.00 Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2014.04.029
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
439
Fig 1. All childhood cancers, average number of new cases, children (0e14), great Britain 2006-2007 (source CRUK http://www. cancerresearchuk.org/cancer-info/cancerstats/childhoodcancer/incidence/).
Pathological Classification Pathological classification is according to the 2007 WHO classification of tumours of the nervous system and is based on histology (Table 1) [3]. Over 90% of CNS tumours originate in the brain. Of these, astrocytomas constitute approximately 43% and these are most frequently low grade lesions. Approximately 19% are embryonal tumours, three quarters of which are medulloblastomas and which are more frequent in younger children. Ten percent of CNS tumours in childhood are ependymomas and choroid plexus tumours with the greatest incidence in very young children [4]. In contrast with the adult setting, high grade gliomas occur relatively infrequently and appear to be biologically distinct from those occurring in adulthood [5]. Molecular profiling of paediatric brain tumours provide opportunities to further enhance understanding of tumour biology. It is anticipated that integration with clinical and histological data in prospective clinical trials may enable further risk stratification and create new opportunities for individualised therapy as well as new therapeutic targets [6].
Clinical Features Presenting symptoms include those of raised intracranial pressure such as morning headache and vomiting, visual disturbance, cranial nerve palsies, ataxia, impairment of motor skills, seizures, endocrine, growth abnormalities and lethargy. Very young children may present with failure to thrive or irritability. As the symptoms of a brain tumour are often non-specific other, more common diagnoses are often explored initially and delayed diagnosis is a well recognised problem internationally [7]. Once a brain tumour is suspected, imaging to confirm the presence of a space occupying lesion should be initiated with minimum delay. Contrast enhanced MRI is the imaging modality of choice
but where this is not readily available a CT scan is acceptable as initial imaging. There is increasing recognition that advanced imaging techniques such as MR spectroscopy, perfusion MRI, functional MRI, diffusion tensor imaging and tractography may assist in diagnosis and in treatment planning [8,9].
Management Management of children with brain tumours requires a well-organised multidisciplinary approach in specialist centres experienced in the management of these diagnoses [10]. In the UK children should only be treated at a Children’s Cancer and Leukaemia Group (CCLG) accredited centre subject to peer review according to the standards outlined in National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance (IOG) [11]. This defines a series of multidisciplinary and multiprofessional standards for management of the patient and family. Recommended standards for radiotherapy centres are also outlined in the CCLG/Royal College of Radiologists (RCR) Paediatric Good Practice Guide [12]. The NICE IOG and CCLG/RCR guidelines recommend that the team caring for a child with a brain tumour should comprise paediatric and clinical oncologists, neurosurgeons, radiologists, endocrinologists, ophthalmologists, neuropathologists and specialist nurses. There should also be ready access to neuropsychologists and clinical psychology, paediatric radiographers, play therapists (or child life specialists), an anaesthetic team and a rehabilitation team including physiotherapy, OT and speech therapy. The aims of treatment should be to maximise tumour control and minimize toxicity (in particular long term effects) through judicious incorporation of the three main modalities of surgery, radiotherapy and chemotherapy into treatment protocols preferably within the context of a clinical trial [13].
440
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
Table 1 2007 WHO classification of tumours of the nervous system Tumour type Astrocytomas and other tumours of glial origin Low grade astrocytomas
High grade astrocytomas
Brain stem gliomas
CNS embryonal tumours Medulloblastoma
CNS Primitive Neuroectodermal tumours (PNET’s) Tumours of the pineal region CNS Atypical teratoid/rhabdoid tumour CNS Germ Cell Tumours Germinomas Teratomas
Non-germinomatous germ cell tumours
Pathologic subtype
Diffuse fibrillary astrocytoma Gemistocytic astrocytoma Oligoastrocytoma Oligodendroglioma Pilocytic astrocytoma Pilomyxoid astrocytoma Pleomorphic xanthoastrocytoma Protoplasmic astrocytoma Subependymal giant cell astrocytoma Anaplastic astrocytoma Anaplastic oligoastrocytoma Anaplastic oligodendroglioma Giant cell glioblastoma Glioblastoma Gliomatosis cerebri Gliosarcoma Diffuse intrinsic pontine glioma Focal or low grade brainstem glioma
Classic Anaplastic Desmoplastic/nodular Large cell Medulloblastoma with extensive nodularity CNS Ganglioneuroblastoma CNS neuroblastoma Ependymoblastoma Medulloepithelioma Pineoblastoma Pineocytoma
Immature teratomas Mature teratomas Teratomas with malignant transformation Choriocarcinoma Embryonal carcinoma Mixed germ cell tumours Yolk sac tumours
Craniopharyngioma Ependymoma Tumours of the choroid plexus
Role of Surgery The first line of management of paediatric brain tumours is generally some form of surgical intervention
[14,15]. The initial aim will depend on the general condition of the child and appearances on imaging. Immediate relief of hydrocephalus through insertion of ventriculoperitoneal shunt or third ventriculostomy may be a priority. This may be in conjunction with a biopsy and/or tumour excision. For some tumours, especially ependymomas, the degree of resection is an important prognostic factor, and the aim is gross total resection. In the case of incomplete resection, review of post-operative imaging should be performed to determine whether complete resection can be achieved by a further (“second look”) procedure [16,17]. Generally, gross total resection is achievable with minimum morbidity for pilocytic astrocytomas of the cerebellum [18]. However, the role of surgery for LGG’s in other sites for example, optic nerve gliomas, is more circumspect. Management is individualized depending on factors such as the age of the child, the degree and rate of visual deficit, any association with NF1 (such that RT is avoided if possible) but there is a recognition that there is a clear role for surgery in diagnosis, tumour control and relief of mass effect [19]. For craniopharyngiomas gross total resection, particularly when there is resulting hypothalamic damage, may result in unacceptable morbidity (visual loss, endocrinopathies and hypothalamic syndrome) and the role of the surgeon may be limited to cyst aspiration and debulking of any solid component where possible [20e22]. Innovative technologies such as navigational guidance, functional mapping and intra-operative MRI are important tools for the modern neurosurgeon ensuring safe, accurate and effective tumour management (Figures 2 and 3).
Role of Chemotherapy Over the past 25 years there has been an increasing recognition of the usefulness of chemotherapy in the management of paediatric brain tumours, in a number of settings (Figure 4). Baby Brain type protocols have been used to defer radiotherapy for as long as possible for children presenting below the age of 3 years with tumours such as ependymomas and medulloblastomas [23,24]. Chemotherapy may be used as an adjunct to surgery and radiotherapy to enable reduction of the radiotherapy dose to the craniospinal axis while maintaining control rates in standard risk medulloblastoma [25e27]. It is also used in metastatic medulloblastoma to improve overall survival [28,29]. It may be used to improve operability of residual disease prior to second look surgery in ependymoma [30]. Chemotherapy is used extensively in low-grade glioma protocols to enable tumour control without recourse to radiotherapy in young children or those with NF1 (who have a high risk of second tumours with radiotherapy) [31]. Recent trials for intracranial germinoma explore the role of chemotherapy in enabling reduction of the radiotherapy fields from craniospinal to whole ventricular and also avoiding irradiating the local tumour boost volume for those who achieve a complete response to chemotherapy [32].
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
441
While radiotherapy was historically the sole modality for intracranial germinoma, (an exquisitely radiosensitive tumour giving cure rates of near 100%), the role of chemotherapy followed by whole ventricular radiotherapy is being tested in clinical trials to avoid the effect on growth of the spinal field [37]. This is a different situation from the rare adult patient with germinoma, where RT alone provides excellent outcomes without the potential sequelae of impaired CNS development.
Radiotherapy Target Volumes and Techniques Immobilisation Generally most children younger than 4e5 years do not possess sufficient comprehension to lie reliably still for radiotherapy, and daily general anaesthetics (GA’s) are necessary. Propofol is the induction anaesthetic agent of choice normally with inhalation maintenance, giving a rapid recovery and a low risk of anaesthesia-related complications [38,39]. Play therapy is invaluable in achieving immobilization in children who have sufficient understanding to co-operate and enables avoidance of GA in “borderline” patients [40]. Hyperfractionated regimes requiring twice daily anaesthetics are particularly demanding for the patient and family as well as the team caring for the child [41]. These children may require PEG feeding to ensure adequate calorific intake. Focal Radiotherapy Fig 2. Theatre set up with intra-operative MRI unit beyond.
Role of Radiotherapy During the second half of the twentieth century, the role of radiotherapy became increasingly limited in the management of children with cancer [33]. This view evolved following the recognition of late effects which can sometimes be devastating, especially in very young children. However, in the twenty first century, with the major technological advances in radiotherapy and better understanding of radiobiological principles, there is greater potential for excellent tumour control with a reduction in the late effects compared with older, ‘traditional’ radiotherapy techniques. Craniospinal radiotherapy followed by a localized boost to the site of disease continues to play an important role in the management of medulloblastoma (both metastatic and non-metastatic) and other CNS embryonal tumours [25e27,34]. Tumour bed radiotherapy (post surgery) is indicated for non-metastatic ependymoma, high grade gliomas and craniopharyngiomas (where there is residual disease) [16,17,22,35]. Radiotherapy is generally the sole treatment modality in diffuse pontine glioma and although survival outcomes remain dismal the majority of children achieve significant symptomatic improvement [36].
CT simulation is employed as standard, with coregistration of planning CT and diagnostic MRI to maximize accurate GTV and CTV definition. 3D conformal radiotherapy, inverse planned IMRT and protons are employed depending on their local availability. Craniospinal The Clinical Target Volume (CTV) for Craniospinal Radiotherapy (CSRT) consists of the entire meninges and subarachnoid space, encompassing the whole brain and spinal cord. It is now standard to treat in the supine position although exact techniques vary from centre to centre [42]. The treatment is CT planned and conventionally consists of two parallel opposed head fields matched to a direct spinal field. Two spinal fields may be necessary for taller patients. Many centres now employ forward-planned intensity modulated radiotherapy (IMRT) which enables reduction of dose inhomogeneities through field-in-field segmentation. Some centres have explored the use of inverse-planned IMRT including tomotherapy or volumetric arc therapy to optimize dose conformity and reduce significant exit dose through the thoracic and abdominal organs [43,44]. Optimal dose distributions may be achieved using protons which avoid the significant exit dose from conventional CSRT and the dose bath from IMRT (Figure 4) [45]. Currently
442
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
Fig 3. MRI scan of a 14 year old boy who presented with a posterior fossa mass. The Axial T2 weighted (a) and sagittal T1 post contrast (b) images demonstrate the enhancing tumour centred over the fourth ventricle (white arrow). There is evidence of a metastatic deposit over the floor of the 3rd ventricle (open arrow). The Apparent Diffusion Coefficient (ADC) map (c) shows evidence of restricted diffusion within the tumour (black arrow) indicative of densely packed cells. Single voxel spectroscopy with an echo time of 144ms (d) demonstrates elevation of Choline (Cho, indicative of cell membrane turnover) and lactate (Lac, indicative of anaerobic glycolysis) relative to creatine (Cr). The cerebral blood volume map (CBV) (e) obtained from dynamic susceptibility contrast (DSC) perfusion imaging demonstrates increased CBV (areas appearing red). These features suggest a high grade tumour and the histopathological assessment was diagnostic of medulloblastoma.
children with medulloblastoma are not referred to proton centres abroad for CSRT. This is because for many patients the time taken for post-operative recovery and subsequent travelling abroad to the USA and the time taken to plan CSRT would preclude the timely commencement of CSRT which should commence if possible no later than four weeks following surgery. There are a number of areas that should receive particular attention. Care should be taken to cover the cribriform plate adequately within the 95% isodose. Exit dose through the mouth (and chin) from the spinal fields should be avoided, by using neck extension and selection of an
appropriate lower border for the head fields. The position of the inferior border should be 1e2 cm below the termination of the thecal sac as visualized on MRI. The spinal CTV must include the spinal cord and nerve roots which may extend more laterally than the vertebral pedicles. Field junctions are moved to avoid clinically significant consequences of overlap on the spinal cord. The CSRT dose depends on diagnosis, stage and, to a lesser extent, the age of the child. For children with standard risk medulloblastoma (non-metastatic and less than 1.5 cm2 of residual disease on a post-operative scan it has been possible with the addition of post-RT adjuvant
Fig 4. Dose distributions for recurrent base of skull meningioma, comparing standard 3D conformal photons (left hand images) with IMRT (right hand images). Note the improved conformity with IMRT, with much less normal tissue receiving a high dose, but with greater volume of normal tissue receiving a low dose of radiation.
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
chemotherapy to reduce the craniospinal dose from 35e36 Gy down to 23.4 Gy in 13 fractions [25e27].
Late Effects of Radiotherapy Late effects are adverse outcomes of treatment for cancer that may manifest months to years after treatment, affect the long-term quality of life of survivors, and are generally irreversible. Although it is important to acknowledge the multifactorial aetiology, with contributions from tumourrelated factors, surgery, chemotherapy and the psychosocial disruption of cancer treatment, radiotherapy remains a major cause [46e48]. Late effects of radiotherapy depend on host factors (such as the age of the child and genetic disposition), the total dose of radiation, the dose per fraction and the dose distribution, and critical structures within the field. The threshold dose for many late effects is in the region of 20Gy. Late effects of central nervous system radiation include neuropsychological sequelae, endocrinopathies, musculoskeletal dysplasia (in particular reduced spinal height), vascular sequelae, cataracts and deafness (especially when given concurrently with cisplatin) and second malignancy. Neurocognitive deficits present a particular challenge. Initially recognised in the late 1960’s in children treated as infants for medulloblastoma, sequelae include functionally significant IQ declines, attention, verbal and short-term memory deficits. These manifest as poor school performance and later problems obtaining paid employment and in more extreme cases an inability to lead an independent existence as an adult. The severity increases with younger age at the time of treatment. Serial neurocognitive testing is helpful to identify deficits as they develop such that appropriate intervention, for example additional support with schooling, may be initiated at an early stage [49]. Most endocrinopathies in children treated for CNS tumours are a direct result of radiation to the hypothalamicpituitary (H-P) axis. They are progressive and irreversible. The most common is growth hormone (GH) deficiency and this effect is dose-dependent [50]. Thus it occurs in about 30% of patients who have received doses of less than 30Gy to the H-P axis but in up to 100% of patients receiving 30e50Gy. Gonadotropin, TSH, ACTH deficiencies also occur with increasing doses above 30Gy. Serial endocrine testing following CNS radiotherapy is mandatory for early diagnosis and hormone replacement therapy [51]. No evidence of any effect of GH administration on tumour proliferation has been demonstrated. Second malignant neoplasms (SMN’s) are a well recognised consequence of successful treatment of all childhood cancers and the incidence is increased significantly by use of radiotherapy [27,52,53]. Registry data for survivors of CNS tumours of childhood suggests a 20 year cumulative incidence of 3.3% and 1.2% respectively for those receiving and not receiving radiotherapy [54]. Meningiomas are the most common second tumour seen following CNS radiotherapy, followed by high grade gliomas. Five-year survivals for SMNs of the CNS range from 57.3e100% for meningiomas to 0e20% for high grade gliomas [54]. Risk is related to
443
dose of radiotherapy (although there is no threshold dose below which SMN’s are not seen), young age and presence of inherited cancer predisposition syndromes such as neurofibromatosis 1 and Li Fraumeni. There is no consensus on the optimum method of screening for SMN’s of the CNS and there is a need for prospective studies to evaluate the benefits of surveillance MRI’s. The modern radiation oncologist may reduce the risk of late effects in a number of ways. Risk adapted strategies may enable a reduction in the total dose for those patients with low risk features [55]. Reduction in the dose per fraction while maintaining the total dose for high risk patients may reduce the late effect profile while maintaining tumour control [29]. The conformity of the dose distribution may be improved with IMRT although there are concerns regarding the potential for an increased risk of second malignancies due to the dose bath and further study in the paediatric population with long term follow up is required.
Long-term Follow up In view of the spectrum of late effects described in childhood CNS tumour survivors, it is mandatory for them to have access to follow up beyond the usual 5 years of active tumour follow up. Most specialist centres host a late effects clinic supported by a multidisciplinary team consisting of oncologists, endocrinologists, specialist nurses, psychologists and other allied health professionals as appropriate. Co-ordination of care and communication across medical groups including between primary and secondary care are extremely important. The point of transition from paediatric to adult services can be challenging and robust mechanisms should be in place to ensure continuity of care [56].
Proton Beam Therapy Protons present a seductive prospect for the paediatric radiation oncologist [57]. The superior dose distributions limit unnecessary irradiation of normal tissues, hence potentially reducing the risk of late effects in children. Current limited capacity and high cost means that there is limited access for most paediatric patients. Low cost, compact solutions may be on the horizon which may make proton therapy affordable and improve access for this patient group. Improved dose distributions are compelling but high quality direct evidence for actual clinical benefit (which will require many years of follow up) is lacking. Evaluation of the clinical benefit of proton therapy relies on comparative dose planning studies and prediction of the reduction in late effects using evidence from historic dose response data for late effects. For example a modeling study has predicted a benefit in terms of reduced neuro-cognitive impact of proton therapy for treating a range of brain tumours [58]. There is currently no high energy proton facility in the UK. There is a low energy cyclotron at Clatterbridge Cancer
444
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
Centre with a very well established and effective eye tumour treatment programme [59]. Acknowledging the general consensus that there is a likely beneficial role for protons in the management of selected paediatric tumours, the NHS funds travel and treatment overseas for patients with selected indications, based on the NHS ethos of equity of access. The indications include a significant proportion of children aged 16 and under, with potentially curable CNS tumours. Although this ambitious programme has presented significant logistical difficulties to the UK paediatric radiotherapy community, it is now an embedded aspect of service provision and has been generally well received by staff and patients alike. Since the inception of the programme in 2008, approximately 350 children have received proton treatment overseas, a significant proportion of whom have had diagnoses of CNS tumours (Dr A Crellin, personal communication). In July 2013, HM Treasury approved the business case for two high energy proton centres in the UK, to be based at University College Hospital, London and the Christie Hospital in Manchester. The anticipated opening date for these centres is 2018. Long term follow up and data collection for all patients treated with protons must be a priority.
Conclusion Since the 1990s paediatric neuro-oncology has evolved into an important multidisciplinary specialty. In particular this has led to a large increase in the understanding of the molecular and pathological classification of histological subtypes and impact of biological factors on outcome, in order to refine stratification of therapy. However, improved outcomes require clinical trials which require international collaboration. There is a pressing need to incorporate assessment of quality of survival into trial reporting in order to help with the difficult balance of benefits and risks of therapies which can be toxic to the developing CNS. There are significant overlaps with adult neuro-oncology, with both similarities and differences, and it is important that these two areas of our speciality continue to collaborate to their mutual benefit [60].
References [1] Parkin DM, Kramarova E, Draper GJ, et al, editors. International incidence of childhood cancer, vol. II. Lyon: IARC; 1998. IARC Scientific Publications no. 144. [2] Ranger A. The epidemiology of paediatric brain cancer d descriptive epidemiology and risk factors. In: Lichtor Terry, editor. Clinical management and evolving novel therapeutic strategies for patients with brain tumors, ISBN 978-953-511058-3; 2013. http://dx.doi.org/10.5772/52427. InTech. [3] Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007 Aug;114(2):97e109. [4] http://www.cancerresearchuk.org/cancer-info/cancerstats/ childhoodcancer/incidence/#brain; 2007 Aug. [5] Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 2010;28(18):3061e3068.
[6] Nageswara RA, Packer RJ. Impact of molecular biology studies on the understanding of brain tumours in childhood. Curr Oncol Rep 2012 Apr;14(2):206e212. [7] Dobrovoijac M, Hengartner H, Bolthauser E, et al. Delay in the diagnosis of paediatric brain tumours. Eur J Pediatr 2002 Dec;161(12):663e667. [8] Borja MJ, Plaza MJ, Altman N, et al. Conventional and advanced MRI features of pediatric intracranial tumors: Supratentorial tumours. Am J Roentgenol 2013 May;200(5):483e503. [9] Borja MJ, Plaza MJ, Altman N, et al. Conventional and advanced MRI features of pediatric intracranial tumors: posterior fossa and suprasellar tumours. Am J Roentgenol 2013 May;200(5):1115e1124. [10] Huang T, Mueller S, Rutkowski MJ, et al. Multidisciplinary care of patients with brain tumours. Surg Oncol Clin N Am 2013 Apr;22(2):161e178. [11] http://www.nice.org.uk/nicemedia/pdf/C&YPManual.pdf; 2013 Apr. [12] http://www.rcr.ac.uk/docs/oncology/pdf/BFCO(12)5_Good_ practice.pdf; 2013 Apr. [13] Pollack I. Multidisciplinary management of childhood brain tumours: a review of outcomes, recent advances, and challenges. J Neurosurg Pediatr 2011 Aug;8(2):135e148. [14] Souweidine MM. The evolving role of surgery in the management of pediatric brain tumours. J Child Neurol 2009 Nov;24(11):1366e1374. [15] Walker DA, Liu J, Keiran M, et al. A multi-disciplinary consensus statement concerning surgical approaches to lowgrade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro Oncol 2013 Apr;15(4):462e468. [16] Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 2009 Mar;10(3):258e266. [17] Merchant TE, Mulhern RK, Krasin MJ, et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 2004;22(15):3156e3162. [18] Gajjar A, Sanford RA, Heideman R, et al. Low grade astrocytoma: a decade of experience at St. Jude Children’s Research Hospital. J Clin Oncol 1997 Aug;15(8):2792e2799. [19] Goodden J, Pizer B, Pettorini B, et al. The role of surgery in optic pathway/hypothalamic gliomas in children. J Neurosurg Pediatr 2014 Jan;13(1):1e12. [20] Elowe-Gruau E, Beltrand R, Pinto G, et al. Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. J Clin Endocrinol Metab 2013 Jun;98(6):2376e2386. [21] Mortini P, Gagliardi F, Boari N, et al. Surgical strategies and modern therapeutic options in the treatment of craniopharyngiomas. Crit Rev Oncol Hematol 2013 Dec;88(3):514e529. [22] Kiehna EN, Merchant TE. Radiation therapy for pediatric craniopharyngioma. Neurosurg Focus 2010;28(4):E10. [23] Grundy RG, Wilne SH, Robinson KJ, et al. Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 2009 Jan;46(1):120e123. [24] Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumours. N Engl J Med 1993 Jun;328(24):1725e1731. [25] Packer RJ, Sutton LN, Elterman R, et al. Outcome for children with medulloblastoma treated with radiation and cisplatin,
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35] [36]
[37]
[38]
[39]
[40]
[41]
CCNU, and vincristine chemotherapy. J Neurosurg 1994 Nov;81(5):690e698. Bailey CC, Gnekow A, Wellek S, et al. Prospective randomized trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 1995 Sep;25(3):166e178. Packer RJ, Zhou T, Holmes E, et al. Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children’s Oncology Group trial A9961. Neuro Oncol 2013 Jan;15(1):97e103. Tarbell N, Friedman H, Polkinghorn WR, et al. High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG9031). J Clin Oncol 2013 Aug;31(23):2936e2941. Gandola L, Massimino M, Cefalo G, et al. Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 2009 Feb;27(4):566e571. Gavin JH, Selch MT, Holmes E, et al. Phase II study of preirradiation chemotherapy for childhood intracranial ependymoma. Children’s Cancer Group Protocol 9942: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2012 Dec 15;59(7):1183e1189. Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997 May;86(5):747e754. Kortmann RD. Current concepts and future strategies in the management of intracranial germinoma. Expert Rev Anticancer Ther 2014 jan;14(1):105e119. Jairam V, Roberts KB, Yu JB. Historical trends in the use of radiation therapy for paediatric cancers: 1973e2008. Int J Radiat Oncol Biol Phys 2013 Mar 1;85(3):e151ee155. € hl J, et al. Role of radioTimmermann B, Kortmann RD, Ku therapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 2002;20(3):842e849. Minturn JE, Fisher MJ. Gliomas in children. Curr Treat Options Neurol 2013 Jun;15(3):316e327. Chassot A, Canale S, Varlat P, et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol 2012 Jan;106(2):399e407. Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 2013 Jun;15(6):788e796. Anghelescu DL, Burgoyne LL, Liu W, et al. Safe anesthesia for radiotherapy in pediatric oncology: St Jude Children’s Research Hospital Experience, 2004e2006. Int J Radiat Oncol Biol Phys 2008 Jun;71(2):491e497. Fortney J, Halperin E, Hertz C, et al. Anesthesia for pediatric external beam radiation therapy. Int J Radiat Oncol Biol Phys 1999 Jun;44(3):587e591. Scott L, Langton F, O’Donoghue J. Minimising the use of sedation/anesthesia in young children receiving radiotherapy through an effective play preparation programme. Eur J Oncol Nurs 2002 Mar;6(1):15e22. Menache L, Eifel PJ, Kennamer DL, et al. Twice-daily anesthesia in infants receiving hyperfractionated irradiation. Int J Radiat Oncol Biol Phys 1990 Mar;18(3):625e629.
445
[42] Parker WA, Freeman CR. A simple technique for craniospinal radiotherapy in the supine position. Radiother Oncol 2006 Feb;78(2):217e222. [43] Lopez Guerra JL, Marrone I, Jaen J, et al. Outcome and toxicity using helical tomotherapy for craniospinal irradiation in pediatric medulloblastoma. Clin Transl Oncol 2014;16:96e101. [44] Bedford JL, Lee YK, Saran FH, et al. Helical volumetric modulated arc therapy for treatment of craniospinal axis. Int J Radiat Biol Phys 2012 Jul;83(3):1047e1054. [45] St Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 2004 Mar;58(3):727e734. [46] Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J Natl Cancer Inst 2009 Jul;101(13):946e958. [47] Turner CD, Rey-Casserly C, Liptak CC, et al. Late effects of therapy for pediatric brain tumour survivors. J Child Neurol 2009 Nov;24(11):1455e1463. [48] Perkins SM, Fei W, Mitra N, et al. Late causes of death in children treated for CNS malignancies. J Neurooncol 2013 Oct;115(1):79e85. [49] Mulhern RK, Merchant TE, Gajjar A, et al. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004 Jul;5(7):399e408. [50] Merchant TE, Gloubeva O, Pritchard DL, et al. Radiation dosevolume effects on growth hormone secretion. Int J Radiat Oncol Biol Phys 2002 April;52(5):1264e1270. [51] Darzy KH, Shalet SM. Hypopituitarism following radiotherapy revisited. Endocr Dev 2009;15:1e24. [52] Meadows AT, Friedman DL, Neglia JP, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study Cohort. J Clin Oncol 2009 May;27(14):2356e2362. [53] Devarahally SR, Severson RK, Chuba P, et al. Second malignant neoplasms after primary central nervous system malignancies of childhood and adolescence. Pediatr Hematol Oncol 2003 Dec;20(8):617e625. [54] Bowers DC, Nathan PC, Constine L, et al. Subsequent neoplasms of the CNS among survivors of childhood cancer: a systemic review. Lancet Oncol 2013 Jul;14(8). [55] Pizer BL, Clifford SC. The potential impact of tumour biology on improved clinical practice for medulloblastoma: progress towards biologically driven clinical trials. Br J Neurosurg 2009 Aug;23(4):364e375. [56] Wallace WHB, Blacklay A, Eiser C, et al. Developing strategies for long term follow up of survivors of childhood cancer. BMJ 2001 Aug;323(7307):271e274. [57] Halperin E. The proton problem. Lancet Oncol 2013 Oct;14(11):1046e1048. [58] Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to ;cognitive function. Pediatr Blood Cancer 2008 Jul;51(1):110e117. [59] Kacperek A. Protontherapy of eye tumours in the UK: a review of treatment at Clatterbridge. Appl Radiat Isot 2009 Mar;67(3):378e386. [60] Taylor RE, Pizer BL, Short S. Promoting collaboration between adult and paediatric groups. Clin Oncol 2008 Nov;20(9):714e716.
Clinical Oncology journal homepage: www.clinicaloncologyonline.net
Overview
Management of Central Nervous System Tumours in Children N.J. Thorp *, R.E. Taylor y * Clatterbridge y
Cancer Centre, Bebington, Wirral CH63 4JY, UK College of Medicine, Swansea University, UK
Received 30 March 2014; accepted 7 April 2014
Abstract This article reviews current approaches to management of central nervous system tumours of childhood, highlighting aspects particularly pertinent to the paediatric population. Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Key words: Brain; paediatric; radiotherapy; tumours
Introduction Primary central nervous system tumours are the most frequent solid tumours and the most common cause of cancer-related morbidity and death in childhood (Figure 1). They constitute a heterogeneous group of diseases in terms of histology, biology, clinical course and prognosis. Compared with adult practice, a different spectrum of histological subtypes is seen, reflecting the different stage of development of the nervous system during which tumours arise. Histologically low grade pilocytic astrocytomas are the most frequently occurring, while medulloblastomas are the most common malignant brain tumour. Conversely, high grade astrocytic tumours seen frequently in adults are relatively uncommon in children. In paediatric neurooncology practice significant numbers require the technically challenging technique of craniospinal RT. In common with adult practice an understanding of tumour molecular biology is now in the process of being incorporated into decision making in addition to conventional pathological parameters. However, these molecular biological features frequently differ between adult and paediatric series despite similar appearances on conventional histology.
Author for correspondence: N.J. Thorp, Clatterbridge Cancer Centre, Bebington, Wirral CH63 4JY, UK.
There are important overlaps with adult practice with respect to neurosurgery and imaging. Management of brain tumours in children is highly specialised and should only be carried out by specialist MDT’s in accredited centres. Radiotherapy, normally integrated with surgery and chemotherapy in treatment protocols, continues to play a pivotal role in spite of concerns regarding late effects. Particular challenges for the paediatric clinical oncologist include immobilisation of the young, uncooperative child, psychosocial aspects and the organisation of long term follow up. Modern radiotherapy approaches are evolving to improve the therapeutic ratio including hyperfractionation, IMRT and proton therapy. An improved understanding of molecular biology may enable individualisation of management in the future.
Epidemiology In the UK, the incidence of childhood CNS tumours is reported as 31.4 per million [1]. The cause of most (95%) is not known but there are well recognised risk factors. These include a family history of brain tumour, exposure to ionising radiation (in particular prior therapeutic CNS irradiation) and familial genetic syndromes (for example, neurofibromatosis 1 and 2, tuberous sclerosis, Von Hippel Lindau disease, Li Fraumeni and Gorlin’s syndrome) [2]. CNS tumours are more common in males.
0936-6555/$36.00 Ó 2014 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.clon.2014.04.029
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
439
Fig 1. All childhood cancers, average number of new cases, children (0e14), great Britain 2006-2007 (source CRUK http://www. cancerresearchuk.org/cancer-info/cancerstats/childhoodcancer/incidence/).
Pathological Classification Pathological classification is according to the 2007 WHO classification of tumours of the nervous system and is based on histology (Table 1) [3]. Over 90% of CNS tumours originate in the brain. Of these, astrocytomas constitute approximately 43% and these are most frequently low grade lesions. Approximately 19% are embryonal tumours, three quarters of which are medulloblastomas and which are more frequent in younger children. Ten percent of CNS tumours in childhood are ependymomas and choroid plexus tumours with the greatest incidence in very young children [4]. In contrast with the adult setting, high grade gliomas occur relatively infrequently and appear to be biologically distinct from those occurring in adulthood [5]. Molecular profiling of paediatric brain tumours provide opportunities to further enhance understanding of tumour biology. It is anticipated that integration with clinical and histological data in prospective clinical trials may enable further risk stratification and create new opportunities for individualised therapy as well as new therapeutic targets [6].
Clinical Features Presenting symptoms include those of raised intracranial pressure such as morning headache and vomiting, visual disturbance, cranial nerve palsies, ataxia, impairment of motor skills, seizures, endocrine, growth abnormalities and lethargy. Very young children may present with failure to thrive or irritability. As the symptoms of a brain tumour are often non-specific other, more common diagnoses are often explored initially and delayed diagnosis is a well recognised problem internationally [7]. Once a brain tumour is suspected, imaging to confirm the presence of a space occupying lesion should be initiated with minimum delay. Contrast enhanced MRI is the imaging modality of choice
but where this is not readily available a CT scan is acceptable as initial imaging. There is increasing recognition that advanced imaging techniques such as MR spectroscopy, perfusion MRI, functional MRI, diffusion tensor imaging and tractography may assist in diagnosis and in treatment planning [8,9].
Management Management of children with brain tumours requires a well-organised multidisciplinary approach in specialist centres experienced in the management of these diagnoses [10]. In the UK children should only be treated at a Children’s Cancer and Leukaemia Group (CCLG) accredited centre subject to peer review according to the standards outlined in National Institute for Health and Care Excellence (NICE) Improving Outcomes Guidance (IOG) [11]. This defines a series of multidisciplinary and multiprofessional standards for management of the patient and family. Recommended standards for radiotherapy centres are also outlined in the CCLG/Royal College of Radiologists (RCR) Paediatric Good Practice Guide [12]. The NICE IOG and CCLG/RCR guidelines recommend that the team caring for a child with a brain tumour should comprise paediatric and clinical oncologists, neurosurgeons, radiologists, endocrinologists, ophthalmologists, neuropathologists and specialist nurses. There should also be ready access to neuropsychologists and clinical psychology, paediatric radiographers, play therapists (or child life specialists), an anaesthetic team and a rehabilitation team including physiotherapy, OT and speech therapy. The aims of treatment should be to maximise tumour control and minimize toxicity (in particular long term effects) through judicious incorporation of the three main modalities of surgery, radiotherapy and chemotherapy into treatment protocols preferably within the context of a clinical trial [13].
440
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
Table 1 2007 WHO classification of tumours of the nervous system Tumour type Astrocytomas and other tumours of glial origin Low grade astrocytomas
High grade astrocytomas
Brain stem gliomas
CNS embryonal tumours Medulloblastoma
CNS Primitive Neuroectodermal tumours (PNET’s) Tumours of the pineal region CNS Atypical teratoid/rhabdoid tumour CNS Germ Cell Tumours Germinomas Teratomas
Non-germinomatous germ cell tumours
Pathologic subtype
Diffuse fibrillary astrocytoma Gemistocytic astrocytoma Oligoastrocytoma Oligodendroglioma Pilocytic astrocytoma Pilomyxoid astrocytoma Pleomorphic xanthoastrocytoma Protoplasmic astrocytoma Subependymal giant cell astrocytoma Anaplastic astrocytoma Anaplastic oligoastrocytoma Anaplastic oligodendroglioma Giant cell glioblastoma Glioblastoma Gliomatosis cerebri Gliosarcoma Diffuse intrinsic pontine glioma Focal or low grade brainstem glioma
Classic Anaplastic Desmoplastic/nodular Large cell Medulloblastoma with extensive nodularity CNS Ganglioneuroblastoma CNS neuroblastoma Ependymoblastoma Medulloepithelioma Pineoblastoma Pineocytoma
Immature teratomas Mature teratomas Teratomas with malignant transformation Choriocarcinoma Embryonal carcinoma Mixed germ cell tumours Yolk sac tumours
Craniopharyngioma Ependymoma Tumours of the choroid plexus
Role of Surgery The first line of management of paediatric brain tumours is generally some form of surgical intervention
[14,15]. The initial aim will depend on the general condition of the child and appearances on imaging. Immediate relief of hydrocephalus through insertion of ventriculoperitoneal shunt or third ventriculostomy may be a priority. This may be in conjunction with a biopsy and/or tumour excision. For some tumours, especially ependymomas, the degree of resection is an important prognostic factor, and the aim is gross total resection. In the case of incomplete resection, review of post-operative imaging should be performed to determine whether complete resection can be achieved by a further (“second look”) procedure [16,17]. Generally, gross total resection is achievable with minimum morbidity for pilocytic astrocytomas of the cerebellum [18]. However, the role of surgery for LGG’s in other sites for example, optic nerve gliomas, is more circumspect. Management is individualized depending on factors such as the age of the child, the degree and rate of visual deficit, any association with NF1 (such that RT is avoided if possible) but there is a recognition that there is a clear role for surgery in diagnosis, tumour control and relief of mass effect [19]. For craniopharyngiomas gross total resection, particularly when there is resulting hypothalamic damage, may result in unacceptable morbidity (visual loss, endocrinopathies and hypothalamic syndrome) and the role of the surgeon may be limited to cyst aspiration and debulking of any solid component where possible [20e22]. Innovative technologies such as navigational guidance, functional mapping and intra-operative MRI are important tools for the modern neurosurgeon ensuring safe, accurate and effective tumour management (Figures 2 and 3).
Role of Chemotherapy Over the past 25 years there has been an increasing recognition of the usefulness of chemotherapy in the management of paediatric brain tumours, in a number of settings (Figure 4). Baby Brain type protocols have been used to defer radiotherapy for as long as possible for children presenting below the age of 3 years with tumours such as ependymomas and medulloblastomas [23,24]. Chemotherapy may be used as an adjunct to surgery and radiotherapy to enable reduction of the radiotherapy dose to the craniospinal axis while maintaining control rates in standard risk medulloblastoma [25e27]. It is also used in metastatic medulloblastoma to improve overall survival [28,29]. It may be used to improve operability of residual disease prior to second look surgery in ependymoma [30]. Chemotherapy is used extensively in low-grade glioma protocols to enable tumour control without recourse to radiotherapy in young children or those with NF1 (who have a high risk of second tumours with radiotherapy) [31]. Recent trials for intracranial germinoma explore the role of chemotherapy in enabling reduction of the radiotherapy fields from craniospinal to whole ventricular and also avoiding irradiating the local tumour boost volume for those who achieve a complete response to chemotherapy [32].
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
441
While radiotherapy was historically the sole modality for intracranial germinoma, (an exquisitely radiosensitive tumour giving cure rates of near 100%), the role of chemotherapy followed by whole ventricular radiotherapy is being tested in clinical trials to avoid the effect on growth of the spinal field [37]. This is a different situation from the rare adult patient with germinoma, where RT alone provides excellent outcomes without the potential sequelae of impaired CNS development.
Radiotherapy Target Volumes and Techniques Immobilisation Generally most children younger than 4e5 years do not possess sufficient comprehension to lie reliably still for radiotherapy, and daily general anaesthetics (GA’s) are necessary. Propofol is the induction anaesthetic agent of choice normally with inhalation maintenance, giving a rapid recovery and a low risk of anaesthesia-related complications [38,39]. Play therapy is invaluable in achieving immobilization in children who have sufficient understanding to co-operate and enables avoidance of GA in “borderline” patients [40]. Hyperfractionated regimes requiring twice daily anaesthetics are particularly demanding for the patient and family as well as the team caring for the child [41]. These children may require PEG feeding to ensure adequate calorific intake. Focal Radiotherapy Fig 2. Theatre set up with intra-operative MRI unit beyond.
Role of Radiotherapy During the second half of the twentieth century, the role of radiotherapy became increasingly limited in the management of children with cancer [33]. This view evolved following the recognition of late effects which can sometimes be devastating, especially in very young children. However, in the twenty first century, with the major technological advances in radiotherapy and better understanding of radiobiological principles, there is greater potential for excellent tumour control with a reduction in the late effects compared with older, ‘traditional’ radiotherapy techniques. Craniospinal radiotherapy followed by a localized boost to the site of disease continues to play an important role in the management of medulloblastoma (both metastatic and non-metastatic) and other CNS embryonal tumours [25e27,34]. Tumour bed radiotherapy (post surgery) is indicated for non-metastatic ependymoma, high grade gliomas and craniopharyngiomas (where there is residual disease) [16,17,22,35]. Radiotherapy is generally the sole treatment modality in diffuse pontine glioma and although survival outcomes remain dismal the majority of children achieve significant symptomatic improvement [36].
CT simulation is employed as standard, with coregistration of planning CT and diagnostic MRI to maximize accurate GTV and CTV definition. 3D conformal radiotherapy, inverse planned IMRT and protons are employed depending on their local availability. Craniospinal The Clinical Target Volume (CTV) for Craniospinal Radiotherapy (CSRT) consists of the entire meninges and subarachnoid space, encompassing the whole brain and spinal cord. It is now standard to treat in the supine position although exact techniques vary from centre to centre [42]. The treatment is CT planned and conventionally consists of two parallel opposed head fields matched to a direct spinal field. Two spinal fields may be necessary for taller patients. Many centres now employ forward-planned intensity modulated radiotherapy (IMRT) which enables reduction of dose inhomogeneities through field-in-field segmentation. Some centres have explored the use of inverse-planned IMRT including tomotherapy or volumetric arc therapy to optimize dose conformity and reduce significant exit dose through the thoracic and abdominal organs [43,44]. Optimal dose distributions may be achieved using protons which avoid the significant exit dose from conventional CSRT and the dose bath from IMRT (Figure 4) [45]. Currently
442
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
Fig 3. MRI scan of a 14 year old boy who presented with a posterior fossa mass. The Axial T2 weighted (a) and sagittal T1 post contrast (b) images demonstrate the enhancing tumour centred over the fourth ventricle (white arrow). There is evidence of a metastatic deposit over the floor of the 3rd ventricle (open arrow). The Apparent Diffusion Coefficient (ADC) map (c) shows evidence of restricted diffusion within the tumour (black arrow) indicative of densely packed cells. Single voxel spectroscopy with an echo time of 144ms (d) demonstrates elevation of Choline (Cho, indicative of cell membrane turnover) and lactate (Lac, indicative of anaerobic glycolysis) relative to creatine (Cr). The cerebral blood volume map (CBV) (e) obtained from dynamic susceptibility contrast (DSC) perfusion imaging demonstrates increased CBV (areas appearing red). These features suggest a high grade tumour and the histopathological assessment was diagnostic of medulloblastoma.
children with medulloblastoma are not referred to proton centres abroad for CSRT. This is because for many patients the time taken for post-operative recovery and subsequent travelling abroad to the USA and the time taken to plan CSRT would preclude the timely commencement of CSRT which should commence if possible no later than four weeks following surgery. There are a number of areas that should receive particular attention. Care should be taken to cover the cribriform plate adequately within the 95% isodose. Exit dose through the mouth (and chin) from the spinal fields should be avoided, by using neck extension and selection of an
appropriate lower border for the head fields. The position of the inferior border should be 1e2 cm below the termination of the thecal sac as visualized on MRI. The spinal CTV must include the spinal cord and nerve roots which may extend more laterally than the vertebral pedicles. Field junctions are moved to avoid clinically significant consequences of overlap on the spinal cord. The CSRT dose depends on diagnosis, stage and, to a lesser extent, the age of the child. For children with standard risk medulloblastoma (non-metastatic and less than 1.5 cm2 of residual disease on a post-operative scan it has been possible with the addition of post-RT adjuvant
Fig 4. Dose distributions for recurrent base of skull meningioma, comparing standard 3D conformal photons (left hand images) with IMRT (right hand images). Note the improved conformity with IMRT, with much less normal tissue receiving a high dose, but with greater volume of normal tissue receiving a low dose of radiation.
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
chemotherapy to reduce the craniospinal dose from 35e36 Gy down to 23.4 Gy in 13 fractions [25e27].
Late Effects of Radiotherapy Late effects are adverse outcomes of treatment for cancer that may manifest months to years after treatment, affect the long-term quality of life of survivors, and are generally irreversible. Although it is important to acknowledge the multifactorial aetiology, with contributions from tumourrelated factors, surgery, chemotherapy and the psychosocial disruption of cancer treatment, radiotherapy remains a major cause [46e48]. Late effects of radiotherapy depend on host factors (such as the age of the child and genetic disposition), the total dose of radiation, the dose per fraction and the dose distribution, and critical structures within the field. The threshold dose for many late effects is in the region of 20Gy. Late effects of central nervous system radiation include neuropsychological sequelae, endocrinopathies, musculoskeletal dysplasia (in particular reduced spinal height), vascular sequelae, cataracts and deafness (especially when given concurrently with cisplatin) and second malignancy. Neurocognitive deficits present a particular challenge. Initially recognised in the late 1960’s in children treated as infants for medulloblastoma, sequelae include functionally significant IQ declines, attention, verbal and short-term memory deficits. These manifest as poor school performance and later problems obtaining paid employment and in more extreme cases an inability to lead an independent existence as an adult. The severity increases with younger age at the time of treatment. Serial neurocognitive testing is helpful to identify deficits as they develop such that appropriate intervention, for example additional support with schooling, may be initiated at an early stage [49]. Most endocrinopathies in children treated for CNS tumours are a direct result of radiation to the hypothalamicpituitary (H-P) axis. They are progressive and irreversible. The most common is growth hormone (GH) deficiency and this effect is dose-dependent [50]. Thus it occurs in about 30% of patients who have received doses of less than 30Gy to the H-P axis but in up to 100% of patients receiving 30e50Gy. Gonadotropin, TSH, ACTH deficiencies also occur with increasing doses above 30Gy. Serial endocrine testing following CNS radiotherapy is mandatory for early diagnosis and hormone replacement therapy [51]. No evidence of any effect of GH administration on tumour proliferation has been demonstrated. Second malignant neoplasms (SMN’s) are a well recognised consequence of successful treatment of all childhood cancers and the incidence is increased significantly by use of radiotherapy [27,52,53]. Registry data for survivors of CNS tumours of childhood suggests a 20 year cumulative incidence of 3.3% and 1.2% respectively for those receiving and not receiving radiotherapy [54]. Meningiomas are the most common second tumour seen following CNS radiotherapy, followed by high grade gliomas. Five-year survivals for SMNs of the CNS range from 57.3e100% for meningiomas to 0e20% for high grade gliomas [54]. Risk is related to
443
dose of radiotherapy (although there is no threshold dose below which SMN’s are not seen), young age and presence of inherited cancer predisposition syndromes such as neurofibromatosis 1 and Li Fraumeni. There is no consensus on the optimum method of screening for SMN’s of the CNS and there is a need for prospective studies to evaluate the benefits of surveillance MRI’s. The modern radiation oncologist may reduce the risk of late effects in a number of ways. Risk adapted strategies may enable a reduction in the total dose for those patients with low risk features [55]. Reduction in the dose per fraction while maintaining the total dose for high risk patients may reduce the late effect profile while maintaining tumour control [29]. The conformity of the dose distribution may be improved with IMRT although there are concerns regarding the potential for an increased risk of second malignancies due to the dose bath and further study in the paediatric population with long term follow up is required.
Long-term Follow up In view of the spectrum of late effects described in childhood CNS tumour survivors, it is mandatory for them to have access to follow up beyond the usual 5 years of active tumour follow up. Most specialist centres host a late effects clinic supported by a multidisciplinary team consisting of oncologists, endocrinologists, specialist nurses, psychologists and other allied health professionals as appropriate. Co-ordination of care and communication across medical groups including between primary and secondary care are extremely important. The point of transition from paediatric to adult services can be challenging and robust mechanisms should be in place to ensure continuity of care [56].
Proton Beam Therapy Protons present a seductive prospect for the paediatric radiation oncologist [57]. The superior dose distributions limit unnecessary irradiation of normal tissues, hence potentially reducing the risk of late effects in children. Current limited capacity and high cost means that there is limited access for most paediatric patients. Low cost, compact solutions may be on the horizon which may make proton therapy affordable and improve access for this patient group. Improved dose distributions are compelling but high quality direct evidence for actual clinical benefit (which will require many years of follow up) is lacking. Evaluation of the clinical benefit of proton therapy relies on comparative dose planning studies and prediction of the reduction in late effects using evidence from historic dose response data for late effects. For example a modeling study has predicted a benefit in terms of reduced neuro-cognitive impact of proton therapy for treating a range of brain tumours [58]. There is currently no high energy proton facility in the UK. There is a low energy cyclotron at Clatterbridge Cancer
444
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
Centre with a very well established and effective eye tumour treatment programme [59]. Acknowledging the general consensus that there is a likely beneficial role for protons in the management of selected paediatric tumours, the NHS funds travel and treatment overseas for patients with selected indications, based on the NHS ethos of equity of access. The indications include a significant proportion of children aged 16 and under, with potentially curable CNS tumours. Although this ambitious programme has presented significant logistical difficulties to the UK paediatric radiotherapy community, it is now an embedded aspect of service provision and has been generally well received by staff and patients alike. Since the inception of the programme in 2008, approximately 350 children have received proton treatment overseas, a significant proportion of whom have had diagnoses of CNS tumours (Dr A Crellin, personal communication). In July 2013, HM Treasury approved the business case for two high energy proton centres in the UK, to be based at University College Hospital, London and the Christie Hospital in Manchester. The anticipated opening date for these centres is 2018. Long term follow up and data collection for all patients treated with protons must be a priority.
Conclusion Since the 1990s paediatric neuro-oncology has evolved into an important multidisciplinary specialty. In particular this has led to a large increase in the understanding of the molecular and pathological classification of histological subtypes and impact of biological factors on outcome, in order to refine stratification of therapy. However, improved outcomes require clinical trials which require international collaboration. There is a pressing need to incorporate assessment of quality of survival into trial reporting in order to help with the difficult balance of benefits and risks of therapies which can be toxic to the developing CNS. There are significant overlaps with adult neuro-oncology, with both similarities and differences, and it is important that these two areas of our speciality continue to collaborate to their mutual benefit [60].
References [1] Parkin DM, Kramarova E, Draper GJ, et al, editors. International incidence of childhood cancer, vol. II. Lyon: IARC; 1998. IARC Scientific Publications no. 144. [2] Ranger A. The epidemiology of paediatric brain cancer d descriptive epidemiology and risk factors. In: Lichtor Terry, editor. Clinical management and evolving novel therapeutic strategies for patients with brain tumors, ISBN 978-953-511058-3; 2013. http://dx.doi.org/10.5772/52427. InTech. [3] Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007 Aug;114(2):97e109. [4] http://www.cancerresearchuk.org/cancer-info/cancerstats/ childhoodcancer/incidence/#brain; 2007 Aug. [5] Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 2010;28(18):3061e3068.
[6] Nageswara RA, Packer RJ. Impact of molecular biology studies on the understanding of brain tumours in childhood. Curr Oncol Rep 2012 Apr;14(2):206e212. [7] Dobrovoijac M, Hengartner H, Bolthauser E, et al. Delay in the diagnosis of paediatric brain tumours. Eur J Pediatr 2002 Dec;161(12):663e667. [8] Borja MJ, Plaza MJ, Altman N, et al. Conventional and advanced MRI features of pediatric intracranial tumors: Supratentorial tumours. Am J Roentgenol 2013 May;200(5):483e503. [9] Borja MJ, Plaza MJ, Altman N, et al. Conventional and advanced MRI features of pediatric intracranial tumors: posterior fossa and suprasellar tumours. Am J Roentgenol 2013 May;200(5):1115e1124. [10] Huang T, Mueller S, Rutkowski MJ, et al. Multidisciplinary care of patients with brain tumours. Surg Oncol Clin N Am 2013 Apr;22(2):161e178. [11] http://www.nice.org.uk/nicemedia/pdf/C&YPManual.pdf; 2013 Apr. [12] http://www.rcr.ac.uk/docs/oncology/pdf/BFCO(12)5_Good_ practice.pdf; 2013 Apr. [13] Pollack I. Multidisciplinary management of childhood brain tumours: a review of outcomes, recent advances, and challenges. J Neurosurg Pediatr 2011 Aug;8(2):135e148. [14] Souweidine MM. The evolving role of surgery in the management of pediatric brain tumours. J Child Neurol 2009 Nov;24(11):1366e1374. [15] Walker DA, Liu J, Keiran M, et al. A multi-disciplinary consensus statement concerning surgical approaches to lowgrade, high-grade astrocytomas and diffuse intrinsic pontine gliomas in childhood (CPN Paris 2011) using the Delphi method. Neuro Oncol 2013 Apr;15(4):462e468. [16] Merchant TE, Li C, Xiong X, et al. Conformal radiotherapy after surgery for paediatric ependymoma: a prospective study. Lancet Oncol 2009 Mar;10(3):258e266. [17] Merchant TE, Mulhern RK, Krasin MJ, et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J Clin Oncol 2004;22(15):3156e3162. [18] Gajjar A, Sanford RA, Heideman R, et al. Low grade astrocytoma: a decade of experience at St. Jude Children’s Research Hospital. J Clin Oncol 1997 Aug;15(8):2792e2799. [19] Goodden J, Pizer B, Pettorini B, et al. The role of surgery in optic pathway/hypothalamic gliomas in children. J Neurosurg Pediatr 2014 Jan;13(1):1e12. [20] Elowe-Gruau E, Beltrand R, Pinto G, et al. Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. J Clin Endocrinol Metab 2013 Jun;98(6):2376e2386. [21] Mortini P, Gagliardi F, Boari N, et al. Surgical strategies and modern therapeutic options in the treatment of craniopharyngiomas. Crit Rev Oncol Hematol 2013 Dec;88(3):514e529. [22] Kiehna EN, Merchant TE. Radiation therapy for pediatric craniopharyngioma. Neurosurg Focus 2010;28(4):E10. [23] Grundy RG, Wilne SH, Robinson KJ, et al. Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 2009 Jan;46(1):120e123. [24] Duffner PK, Horowitz ME, Krischer JP, et al. Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumours. N Engl J Med 1993 Jun;328(24):1725e1731. [25] Packer RJ, Sutton LN, Elterman R, et al. Outcome for children with medulloblastoma treated with radiation and cisplatin,
N.J. Thorp, R.E. Taylor / Clinical Oncology 26 (2014) 438e445
[26]
[27]
[28]
[29]
[30]
[31]
[32]
[33]
[34]
[35] [36]
[37]
[38]
[39]
[40]
[41]
CCNU, and vincristine chemotherapy. J Neurosurg 1994 Nov;81(5):690e698. Bailey CC, Gnekow A, Wellek S, et al. Prospective randomized trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 1995 Sep;25(3):166e178. Packer RJ, Zhou T, Holmes E, et al. Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of Children’s Oncology Group trial A9961. Neuro Oncol 2013 Jan;15(1):97e103. Tarbell N, Friedman H, Polkinghorn WR, et al. High-risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiation therapy (POG9031). J Clin Oncol 2013 Aug;31(23):2936e2941. Gandola L, Massimino M, Cefalo G, et al. Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 2009 Feb;27(4):566e571. Gavin JH, Selch MT, Holmes E, et al. Phase II study of preirradiation chemotherapy for childhood intracranial ependymoma. Children’s Cancer Group Protocol 9942: a report from the Children’s Oncology Group. Pediatr Blood Cancer 2012 Dec 15;59(7):1183e1189. Packer RJ, Ater J, Allen J, et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J Neurosurg 1997 May;86(5):747e754. Kortmann RD. Current concepts and future strategies in the management of intracranial germinoma. Expert Rev Anticancer Ther 2014 jan;14(1):105e119. Jairam V, Roberts KB, Yu JB. Historical trends in the use of radiation therapy for paediatric cancers: 1973e2008. Int J Radiat Oncol Biol Phys 2013 Mar 1;85(3):e151ee155. € hl J, et al. Role of radioTimmermann B, Kortmann RD, Ku therapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 2002;20(3):842e849. Minturn JE, Fisher MJ. Gliomas in children. Curr Treat Options Neurol 2013 Jun;15(3):316e327. Chassot A, Canale S, Varlat P, et al. Radiotherapy with concurrent and adjuvant temozolomide in children with newly diagnosed diffuse intrinsic pontine glioma. J Neurooncol 2012 Jan;106(2):399e407. Calaminus G, Kortmann R, Worch J, et al. SIOP CNS GCT 96: final report of outcome of a prospective, multinational nonrandomized trial for children and adults with intracranial germinoma, comparing craniospinal irradiation alone with chemotherapy followed by focal primary site irradiation for patients with localized disease. Neuro Oncol 2013 Jun;15(6):788e796. Anghelescu DL, Burgoyne LL, Liu W, et al. Safe anesthesia for radiotherapy in pediatric oncology: St Jude Children’s Research Hospital Experience, 2004e2006. Int J Radiat Oncol Biol Phys 2008 Jun;71(2):491e497. Fortney J, Halperin E, Hertz C, et al. Anesthesia for pediatric external beam radiation therapy. Int J Radiat Oncol Biol Phys 1999 Jun;44(3):587e591. Scott L, Langton F, O’Donoghue J. Minimising the use of sedation/anesthesia in young children receiving radiotherapy through an effective play preparation programme. Eur J Oncol Nurs 2002 Mar;6(1):15e22. Menache L, Eifel PJ, Kennamer DL, et al. Twice-daily anesthesia in infants receiving hyperfractionated irradiation. Int J Radiat Oncol Biol Phys 1990 Mar;18(3):625e629.
445
[42] Parker WA, Freeman CR. A simple technique for craniospinal radiotherapy in the supine position. Radiother Oncol 2006 Feb;78(2):217e222. [43] Lopez Guerra JL, Marrone I, Jaen J, et al. Outcome and toxicity using helical tomotherapy for craniospinal irradiation in pediatric medulloblastoma. Clin Transl Oncol 2014;16:96e101. [44] Bedford JL, Lee YK, Saran FH, et al. Helical volumetric modulated arc therapy for treatment of craniospinal axis. Int J Radiat Biol Phys 2012 Jul;83(3):1047e1054. [45] St Clair WH, Adams JA, Bues M, et al. Advantage of protons compared to conventional X-ray or IMRT in the treatment of a pediatric patient with medulloblastoma. Int J Radiat Oncol Biol Phys 2004 Mar;58(3):727e734. [46] Armstrong GT, Liu Q, Yasui Y, et al. Long-term outcomes among adult survivors of childhood central nervous system malignancies in the Childhood Cancer Survivor Study. J Natl Cancer Inst 2009 Jul;101(13):946e958. [47] Turner CD, Rey-Casserly C, Liptak CC, et al. Late effects of therapy for pediatric brain tumour survivors. J Child Neurol 2009 Nov;24(11):1455e1463. [48] Perkins SM, Fei W, Mitra N, et al. Late causes of death in children treated for CNS malignancies. J Neurooncol 2013 Oct;115(1):79e85. [49] Mulhern RK, Merchant TE, Gajjar A, et al. Late neurocognitive sequelae in survivors of brain tumours in childhood. Lancet Oncol 2004 Jul;5(7):399e408. [50] Merchant TE, Gloubeva O, Pritchard DL, et al. Radiation dosevolume effects on growth hormone secretion. Int J Radiat Oncol Biol Phys 2002 April;52(5):1264e1270. [51] Darzy KH, Shalet SM. Hypopituitarism following radiotherapy revisited. Endocr Dev 2009;15:1e24. [52] Meadows AT, Friedman DL, Neglia JP, et al. Second neoplasms in survivors of childhood cancer: findings from the Childhood Cancer Survivor Study Cohort. J Clin Oncol 2009 May;27(14):2356e2362. [53] Devarahally SR, Severson RK, Chuba P, et al. Second malignant neoplasms after primary central nervous system malignancies of childhood and adolescence. Pediatr Hematol Oncol 2003 Dec;20(8):617e625. [54] Bowers DC, Nathan PC, Constine L, et al. Subsequent neoplasms of the CNS among survivors of childhood cancer: a systemic review. Lancet Oncol 2013 Jul;14(8). [55] Pizer BL, Clifford SC. The potential impact of tumour biology on improved clinical practice for medulloblastoma: progress towards biologically driven clinical trials. Br J Neurosurg 2009 Aug;23(4):364e375. [56] Wallace WHB, Blacklay A, Eiser C, et al. Developing strategies for long term follow up of survivors of childhood cancer. BMJ 2001 Aug;323(7307):271e274. [57] Halperin E. The proton problem. Lancet Oncol 2013 Oct;14(11):1046e1048. [58] Merchant TE, Hua CH, Shukla H, et al. Proton versus photon radiotherapy for common pediatric brain tumors: comparison of models of dose characteristics and their relationship to ;cognitive function. Pediatr Blood Cancer 2008 Jul;51(1):110e117. [59] Kacperek A. Protontherapy of eye tumours in the UK: a review of treatment at Clatterbridge. Appl Radiat Isot 2009 Mar;67(3):378e386. [60] Taylor RE, Pizer BL, Short S. Promoting collaboration between adult and paediatric groups. Clin Oncol 2008 Nov;20(9):714e716.
