Journal of Medical Imaging and Radiation Oncology 59 (2015) 379–385
RADIATION O N C O LO GY —O R I G I N A L A RTICLE
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Clinical equipoise: Protons and the child with craniopharyngioma Ruth Conroy,1 Lavier Gomes,2 Catherine Owen,1 Jeffrey Buchsbaum3,4 and Verity Ahern1 1 Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia 2 Medical Imaging, Westmead Hospital, Sydney, New South Wales, Australia 3 Departments of Radiation Oncology, Paediatrics, and Neurological Surgery, Indiana University College of Arts and Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA 4 Department of Physics, IU Proton Therapy Center, Riley Hospital for Children, Indiana University Hospital, Bloomington, Indiana, USA
R Conroy MBBS, FRCR; L Gomes MBBS; C Owen BSc (med Sci); J Buchsbaum MD, PhD, AM; V Ahern MBBS, FRANZCR. Correspondence Dr Verity Ahern, Crown Princess Mary Cancer Centre, Westmead Hospital, PO Box 533, Wentworthville, NSW 2145, Australia. Email: [email protected] Conflict of interest: No author declares any conflict of interest. Submitted 24 March 2014; accepted 8 October 2014. doi:10.1111/1754-9485.12264
Abstract Introduction: Childhood craniopharyngioma is a complex condition to manage. Survival figures are high but the potential for long-term morbidity is great. There is much debate regarding the best management for these tumours with increasing interest in the use of proton beam therapy. We have therefore reviewed our radiotherapy (RT) practice at Westmead Hospital and the literature regarding the use of protons for these children. Methods: Three children have received fractionated stereotactic RT for craniopharyngioma at Westmead Hospital since 2007. Each RT plan was reviewed and additional organs at risk were contoured to enable comparison with published proton data. Results: Planning target volume coverage was similar with all modalities: with the conformity index ranging from 0.70 to 0.78 in our patients compared with 0.50–0.84 in the published data. RT dose to temporal lobes, hippocampi and whole brain was also similar with protons and photons. Proton beam therapy may give lower dose to the Circle of Willis than stereotactic RT. Conclusion: Currently there is no clear evidence that proton beam therapy will improve survival or reduce morbidity for children with craniopharyngioma. However, proton therapy has the potential to reduce RT dose to the Circle of Willis, which may reduce the risk of future cerebrovascular complications. We propose that more resources should be allocated to ensuring these patients are managed by experienced multidisciplinary teams through the continuum from diagnosis to long-term follow-up. Key words: children; craniopharyngioma; protons; sequelae; stereotactic radiotherapy.
Introduction There are around 141 cases of tumours of the central nervous system (CNS) in children diagnosed each year in Australia,1 with craniopharyngiomas (CP) expected to account for around 10 cases.2 Although benign there is often significant morbidity present even prior to any treatment3,4 due to the tumour’s proximity to vital structures such as the pituitary gland, hypothalamus, optic chiasm and Circle of Willis. With expected five years survival of over 80%5,6 minimising long-term morbidity for these patients is important.
© 2014 The Royal Australian and New Zealand College of Radiologists
There continues to be much debate regarding the optimal treatment strategy for childhood craniopharyngioma.5–10 Over the past three decades there has been increasing use of radiation and with new radiation techniques emerging this has only increased the complexity of treatment options for these children. With increasing use of protons in the UK7 and US8 there is debate whether paediatric patients from Australia should also be receiving this treatment. The drivers of increased use of protons are complex and may reflect the implementation of referral guidelines (UK) as well as availability (US). This study reviews the radiotherapy management of the
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last three childhood CP cases treated at Westmead Hospital and reviews the literature surrounding proton use in these patients to inform further national discussion regarding best radiotherapy management of these children.
Methods We reviewed the case notes and radiotherapy plans for all three children who have received radiation for treatment of craniopharyngioma at Westmead Hospital since 2007. Two of the children were planned using BrainLAB iPlan RT Dose 4.1 (BrainLAB, Munich, Germany), and we added contours for organs at risk (OAR) that had not been contoured previously. The following OAR were contoured: hippocampi, temporal lobes, internal carotid artery, middle cerebral artery, supratentorial brain, infratentorial brain and whole brain. All contours were reviewed by a consultant neuroradiologist. As one child had been planned on an older version of BrainLab, we transferred the imaging and re-contoured the gross tumour volume (GTV) and the planning target volume (PTV) using the original plan as a guide to create a new plan. Each child had a radiotherapy planning CT performed at Westmead Hospital (axial 2.5-mm slices); these were then fused with post-operative diagnostic T1 and T2 MRI images – for two patients these were from external sources with 6-mm slice thickness. GTV was contoured using MRI and 3-mm margin added for PTV. All were treated on Varian Clinac® 6EX (Varian Medical Systems, Palo Alto, CA, USA). One child underwent progress MRI during therapy because of a cystic component causing concern for possible change in GTV but did not require re-plan. The prescribed dosage was 50.4 Gy delivered at 1.8 Gy per fraction, five days a week, for a total of five and a half weeks. Approval for this review was granted by the Western Sydney Local Health District Human Research Ethics Committee.
Results Patient characteristics Patient 1 was initially diagnosed before age 2 and underwent surgery, which was felt to have achieved a radical resection. The infant subsequently developed a large subdural cerebrospinal fluid collection and required a subdural peritoneal shunt. Around six months later the infant was noted to be irritable and holding the head. Imaging revealed tumour recurrence. Further surgery was undertaken to reduce tumour bulk despite predicting there would be residual disease post-operatively. Fractionated stereotactic conformal radiotherapy (FSRT) under daily general anaesthesia was therefore recommended and delivered. Due to the reconstructed coronal images from a volumetric data set it was not possible to confidently contour the hippocampi for this child.
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Patient 2 initially had a gross resection with residual cyst wall on imaging. Five and a half years later the patient experienced a sudden decline in vision and imaging confirmed an increase in size of the cystic suprasellar craniopharyngioma associated with a mass effect on the optic chiasm and optic nerves with splaying of the circle of Willis. Surgery to evacuate the cyst was performed along with insertion of a Rickham reservoir. Intensity-modulated stereotactic radiotherapy (IMSRT) was delivered following this surgery. The patient was over 10 years of age at the time of radiotherapy. Patient 3 was diagnosed after a two-month history of headaches and vomiting. Imaging revealed a very large supra sellar mass lesion extending into the third ventricle and causing secondary obstructive hydrocephalus. Eight months after surgery, imaging confirmed two small areas of cyst recurrence, and the child, who was under seven years old, was referred for radiotherapy, delivered as IMSRT. All three were pan-hypopituitary post-initial surgery and had some degree of visual impairment. All three children remain alive without further tumour recurrence or new complication between two and six years after completion of radiotherapy.
Radiotherapy dose comparisons The PTVs for the patients were 10.52 cm3, 12.81 cm3 and 23.27 cm3. Tables 1 and 2 summarise and compare the results of our three patients with those of two key proton publications.9,10 There is no proton planning system in operation in Australia as yet. We approached colleagues at two different proton facilities in the US to collaborate with us for this study. One considered the exercise unrewarding given existing publications.9,10 We sent a CD with image and structure sets for all three patients to the other (A/Professor Jeffrey Buchsbaum). However, we were not able to export the plan dose files with the treatment plans because no licence to do so was purchased with our iPlan license. No dose proton/photon plan comparison could be made despite considerable effort on our colleague’s behalf. Figure 1 displays dose-wash for patient 1. It is important to note the dramatic difference in appearance depending on dose range applied, and this is particularly relevant when comparing treatment plans between publications.
Discussion PTV coverage with fractionated stereotactic radiotherapy for our three patients was as good as that achieved with intensity modulate proton therapy (IMPT) and superior to that achieved with three dimensional proton therapy (3D-PRT) when compared with publications by Beltran and Boehling.9,10 The dose to the temporal lobes and hippocampi was similar to that achieved with protons.
© 2014 The Royal Australian and New Zealand College of Radiologists
Protons and childhood craniopharyngioma
Table 1. Comparison of stereotactic plans to previously published work by Beltran et al.9 (Reprinted from the International Journal of Radiation Oncology*Biology*Physics, 82/2, Beltran C, Roca M, Merchant TE; On the Benefits and Risks of Proton Therapy in Pediatric Craniopharyngioma, e281–e287, Copyright (2012), with permission from Elsevier) Westmead patients
PTV Conformity Index Right Temporal Lobe D50 (Gy) Left Temporal Lobe D50 (Gy) Right Hippocampus D50 (Gy) Left Hippocampus D50 (Gy) Whole Brain D50 (Gy)
Beltran et al.
1
2
3
IMRT
DSP
IMPT
0.73
0.70
0.78
0.71 ± 0.04
0.50 ± 0.04
0.84 ± 0.04
5.75
10.46
10.92
8.51 ± 3.79
8.17 ± 4.37
5.92 ± 3.03
5.75 NA NA 1.61
9.31 1.61 17.12 1.49
10.70 12.23 11.90 3.71
7.25 ± 2.70 19.29 ± 10.96 17.97 ± 8.42 12.22 ± 2.56
7.45 ± 3.69 19.17 ± 13.46 18.44 ± 12.18 9.48 ± 2.26
5.17 ± 2.62 13.87 ± 11.04 11.99 ± 8.80 7.58 ± 1.90
Conformity Index (the reference isodose was 95%), TVRI/TV × TVRI/VRI; TVRI, PTV volume for reference isodose. D50, dose to 50% of structure; DSP, double-scatter proton; IMPT, intensity-modulated proton therapy; IMRT, intensity-modulated radiation therapy; TV, target volume; VRI, total volume for reference isodose.
Dose to the whole brain was significantly lower than that from the published proton data when comparing D50 but very similar when comparing mean and maximum doses. However, the mean dose to the Circle of Willis for our patients compared poorly even with the published IMRT plans. This may reflect variation in tumour size and therefore volume to be irradiated. Smee et al. treated a
median volume of 3.55-cm311 for 41 patients (12 children), while Beltran et al.9 treated a PTV range from 28.8 to 112.2 cm3 in 14 children and our PTV volumes ranged from 10.52 to 23.27 cm3. It is difficult to compare results between studies because contouring of OAR will also vary and which OAR and dose-volume should be prioritised is not defined. We
Table 2. Comparison of stereotactic plans to previously published work by Boehling et al.10 (Reprinted from the International Journal of Radiation Oncology*Biology*Physics, 82/2, Boehling NS, Grosshans DR, Bluett JB, Palmer MT, Song X, Amos RA, Sahoo N, Meyer JJ, Mahajan A, Woo SY; 643–652, Copyright (2012), with permission from Elsevier) Westmead Patients
PTV Hippocampus MCA Internal Carotid Arteries Infratentorial Brain Supratentorial Brain Brainstem Whole Brain-PTV
CN 95% DMean DMax DMean DMax DMean DMax DMean DMax DMean DMax DMean DMax DMean DMax
Boehling et al.
1
2
3
IMRT
3D-PRT
IMPT
0.73
0.70 10.79 38.68 38.16 54.77 37.61 54.21 4.74 22.63 5.45 54.94 17.87 51.56 5.24 54.27
0.78 13.28 38.76 36.0 52.48 42.93 52.06 4.25 24.43 7.49 53.36 30.21 52.29 7.1 53.35
0.76 ± 0.07 10.6 ± 6.6 46.4 ± 12.9 15.8 ± 3.9 52.3 ± 2.9 21.0 ± 5.4 54.4 ± 0.8 8.0 ± 3.6 53.5 ± 5.6 8.7 ± 3.5 56.0 ± 0.8 25.2 ± 10.7 52.7 ± 6.3 7.6 ± 2.7 54.7 ± 1.1
0.56 ± 0.08 9.6 ± 6.5 46.0 ± 10.9 17.3 ± 4.4 52.6 ± 1.6 15.2 ± 5.5 53.9 ± 0.7 2.8 ± 1.8 52.7 ± 3.6 7.9 ± 2.8 55.4 ± 1.3 17.9 ± 10.1 52.8 ± 3.3 6.4 ± 2.0 54.5 ± 1.0
0.73 ± 0.05 7.6 ± 5.3 45.8 ± 9.6 10.6 ± 1.6 51.4 ± 2.3 13.0 ± 5.0 53.6 ± 0.8 3.9 ± 2.3 52.7 ± 4.2 7.0 ± 2.6 55.2 ± 1.4 21.0 ± 10.0 52.2 ± 4.2 5.6 ± 1.8 54.7 ± 1.6
33.39 52.84 34.43 53.15 4.4 25.77 5.93 54.02 22.82 51.95 5.62 53.96
Dmean and Dmax units are presented in Gray. 3D-PRT, three-dimensional conformal proton radiotherapy; CN95% (conformation number for 95% of prescription dose), TVRI/TV x TVRI/VRI; TVRI, PTV volume for reference isodose; IMRT, intensity-modulated radiotherapy; Dmax, maximum dose to OAR indicated; Dmean, mean dose to OAR indicated; MCA, middle cerebral arteries; TV, target volume; VRI, total volume for reference isodose.
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Fig. 1. Images displaying dose wash for patient 1. On the left the dose range is 30%–107% and on the right is 5%–107%.
were unable to create proton plans for our three patients as no proton treatment planning system is operational in Australia, and we were unable to export the dose files for our patients to allow an overseas centre to do this on our behalf. We have reviewed the literature regarding long-term consequences of childhood craniopharyngioma to determine the relevant OAR and the impact radiotherapy has on these.
Long-term consequences of childhood CP Endocrine More than three quarters of long-term survivors of paediatric craniopharyngioma require some form of hormone replacement.12–14 Much of the deficit relates to the position of the tumour itself and is present before any treatment is directed to the tumour. There is debate whether treatment modality also has an effect. Some series report no association with treatment modality.6 Yet others have found a significantly higher number of patients developed diabetes insipidus and hypopituitarism post gross total resection (GTR) compared with sub-total resection (STR) or STR + radiotherapy.15 Others have suggested that use of FSRT following limited resection or biopsy may be able to reduce endocrine deficit.16 Delaying radiotherapy for as long as possible is a relevant strategy in children with CP who maintain endocrine function after initial resection. Whenever external radiation is delivered, the pituitary gland and hypothalamus are almost certainly contained within the high dose region, so protons will offer no endocrine advantage. Knowing when to initiate treat-
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ment for endocrine disturbances can be complex and relies on clear communication between patient, carer and multiple specialists (neurosurgeon, paediatrician, radiation oncologist, endocrinologist, general practitioner).17 Dedicated follow-up clinics for these patients are essential.
Neurocognitive/IQ A large, prospective study from St Jude of 120 children and young patients with primary brain tumours found that a diagnosis of childhood craniopharyngioma on its own, irrespective of treatment, impacts on attention and schooling.18 There is evidence from the laboratory19,20 and increasingly from clinical practice21,22 that certain areas of the brain, namely those containing neuronal stem cells (NSCs) that are critical for learning and memory, are very sensitive to radiation and are responsible for the long-term cognitive impairment seen post-radiation. NSCs are found in the subgranular zone of the hippocampal dentate gyrus.20 At present there is little data to suggest a hippocampal radiation dose at which clinically detectable differences are seen, although as low dose as achievable is appropriate with incorporation of this structure as an OAR. We achieved as good hippocampal sparing with the stereotactic photon plans for our three patients as with published proton plans, and there is potential for further improvement if hippocampal sparing is prioritised in the planning process. The St Jude experience of childhood craniopharyngioma demonstrated that while all patients experienced some decline in full-scale IQ (FSIQ) it was not clinically
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Protons and childhood craniopharyngioma
significant for those treated with STR + radiotherapy, but those treated by GTR had a worse decline in FSIQ and performance IQ scores.12 They also demonstrated that those who relapsed post-surgery had a significantly worse FSIQ. In another of the few prospective series that have been published, the volume of total brain, supratentorial brain or left temporal lobe receiving >45 Gy had a significant impact on longitudinal IQ.23 Much of the work looking at reduction in IQ following treatment for craniopharyngioma in children is retrospective. Though not specific to CP, Jalali et al. found that >43.2 Gy to >13% of the left temporal lobe correlated to a significant (>10%) drop in FSIQ.24 Others have also demonstrated that large areas receiving >30 or >50 Gy result in worse outcomes.25 Work looking at modelling radiotherapy dose characteristics and their relationship to cognitive function has suggested that a reduction in the lower-dose volumes or mean dose would have long-term clinical advantages for children with CP and that protons were able to moderately reduce the intermediate volume and substantially reduce the low dose volume.26 However, this study was comparing protons to 3D-conformal radiotherapy with a 1.3–1.5-cm expansion from GTV-PTV. Smaller margins (5 mm GTV-PTV)27 do not impact on loco-regional recurrence and will result in a reduced mean brain dose as will attention to photon technique. Other modelling studies have suggested that reducing mean dose to whole brain will reduce IQ loss.28 Our results suggest that protons are not superior in this respect as the mean brain dose was no different.
Vascular Long-term survivors treated with cranial or cervical radiation have an increased risk of stroke.29 Cerebrovascular complications may relate to compression by the tumour30 and exist prior to any treatment. Liu et al. 31 identified some type of vasculopathy in six out of twenty evaluable patients but were unable to demonstrate any relation between stroke and radiotherapy dose in survivors of childhood CP, though there was little variation in doses received in their patient cohort. Ullrich et al. suggested a 1-Gy increase in dose to the optic chiasm leads to a 7% increased risk of Moyamoya.30 Protons may reduce the dose to the vessels10 and potentially reduce the risk of cerebrovascular complications for these patients; though there is no data to support this currently. What does appear clear is that the risk of stroke is further increased by well-known atherosclerotic risk factors, for example, hypertension.32 Up to 50% of children with CP are obese and have multiple endocrine deficiencies,5 which contribute to their risk of cerebrovascular complications. Attention to modifying these risks through careful follow-up may well be more important than adopting new radiotherapy technologies.
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Second malignancies In the largest reported craniopharyngioma series to date with 173 patients (77 under age of 16 at time of radiotherapy) from The Marsden there have been no documented second malignancies despite a median follow-up of 12 years.4 Other series have reported various second tumours11,13–15 Modelling suggests that the use of protons rather than photons can reduce the second cancer risk,33 but this has not yet been demonstrated in clinical practice, with current reviews only demonstrating that protons do not appear to increase the risk for second malignancy without proof that they actually avoid or reduce it.34,35
Quality of life (QoL) There are many factors associated with a negative impact on QoL in childhood survivors of CP. In a recent review from the UK, prognostic factors that correlate with a higher risk of postoperative long-term morbidity, poor functional outcomes and QoL were identified as: the degree of hypothalamic involvement; patient age 4 cm; a retrochiasmatic location; hydrocephalus at diagnosis and multiple surgical procedures.36 In a recent German review: younger age, pre-operative functional impairment, large tumour size, hypothalamic or 3rd ventricle involvement, surgery alone and multiple surgeries were associated with worse QOL.3 In a large series of 102 survivors of childhood CP Müller also demonstrated that on multivariate analysis, only hypothalamic involvement, tumour relapse, progression, baseline Fertigkeitenskala Münster–Heidelberg score (measures the functional capability for daily life actions), and time between diagnosis and baseline evaluation had independent impact on QoL. Hypothalamic involvement, tumour progression, and relapse had long-term QoL affects – most notably, severe obesity.37 Despite the presumed reduced radiotherapy dose to OARs from protons there has yet to be any data demonstrating an improved QoL. One small series of children treated with surgery and protons that has been published demonstrates reduced QoL for these children.38 Factors that may improve QoL include: the neurosurgical experience,39 fewer surgeries,36 extent of surgery40 and timing of radiotherapy.41 These are all factors that could potentially be improved by cases being reviewed by an experienced multidisciplinary team (MDT) and the creation of a national registry.
Conclusion There remains controversy regarding the best management of children with craniopharyngioma. These children are at high risk for significant morbidity related to the tumour and its treatment. From our review we conclude that radiotherapy is only one of the factors contributing
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to the long-term morbidity of these patients and that the potential gains in reduced dose to OAR from proton beam therapy may not translate into significant clinical benefit. These children need to be treated by an experienced MDT to ensure that rigorous baseline endocrine, ophthalmological and neurocognitive testing can be carried out prior to any treatment (when possible). They then require careful follow-up into adulthood to reduce morbidity by detecting problems and offering appropriate intervention earlier.
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26. Merchant TE, Hua C, Shukla H, Ying X, Nill S, Oelfke U. Proton versus photon radiotherapy for common pediatric brain tumours: comparison of models of dose characteristics and their relationship to cognitive function. Pediatr Blood Cancer 2008; 51: 110–17. 27. Minniti G, Saran F, Traishe D et al. Fractionated stereotactic conformal radiotherapy following conservative surgery in the control of craniopharyngiomas. Radiother Oncol 2007; 82: 90–5. 28. Merchant TE, Kiehna EN, Li C et al. Modeling radiation dosimetry to predict cognitive outcomes in pediatric patients with CNS embryonal tumours including medulloblastoma. Int J Radiat Oncol Biol Phys 2006; 65: 210–21. 29. Mueller S, Sear K, Hills NK et al. Risk of first and recurrent stroke in childhood cancer survivors treated with cranial and cervical radiation therapy. Int J Radiat Oncol Biol Phys 2013; 86: 643–8. 30. Ullrich NJ, Robertson R, Kinnamon MS et al. Moyomoya following cranial irradiation for primary brain tumours in children. Neurology 2007; 68: 932–8. 31. Liu AK, Bagrosky B, Fenton LZ et al. Vascular abnormalities in pediatric craniopharyngioma patients treated with radiation therapy. Pediatr Blood Cancer 2009; 52: 227–30. 32. Mueller S, Fullerton HJ, Stratton K et al. Radiation, atherosclerotic risk factors, and stroke risk in survivors of pediatric cancer: a report from the childhood cancer survivor study. Int J Radiat Oncol Biol Phys 2013; 86: 649–55. 33. Miralbell R, Lomax A, Cella L, Schneider U. Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the
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Clinical equipoise: Protons and the child with craniopharyngioma Ruth Conroy,1 Lavier Gomes,2 Catherine Owen,1 Jeffrey Buchsbaum3,4 and Verity Ahern1 1 Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia 2 Medical Imaging, Westmead Hospital, Sydney, New South Wales, Australia 3 Departments of Radiation Oncology, Paediatrics, and Neurological Surgery, Indiana University College of Arts and Sciences, Indiana University School of Medicine, Bloomington, Indiana, USA 4 Department of Physics, IU Proton Therapy Center, Riley Hospital for Children, Indiana University Hospital, Bloomington, Indiana, USA
R Conroy MBBS, FRCR; L Gomes MBBS; C Owen BSc (med Sci); J Buchsbaum MD, PhD, AM; V Ahern MBBS, FRANZCR. Correspondence Dr Verity Ahern, Crown Princess Mary Cancer Centre, Westmead Hospital, PO Box 533, Wentworthville, NSW 2145, Australia. Email: [email protected] Conflict of interest: No author declares any conflict of interest. Submitted 24 March 2014; accepted 8 October 2014. doi:10.1111/1754-9485.12264
Abstract Introduction: Childhood craniopharyngioma is a complex condition to manage. Survival figures are high but the potential for long-term morbidity is great. There is much debate regarding the best management for these tumours with increasing interest in the use of proton beam therapy. We have therefore reviewed our radiotherapy (RT) practice at Westmead Hospital and the literature regarding the use of protons for these children. Methods: Three children have received fractionated stereotactic RT for craniopharyngioma at Westmead Hospital since 2007. Each RT plan was reviewed and additional organs at risk were contoured to enable comparison with published proton data. Results: Planning target volume coverage was similar with all modalities: with the conformity index ranging from 0.70 to 0.78 in our patients compared with 0.50–0.84 in the published data. RT dose to temporal lobes, hippocampi and whole brain was also similar with protons and photons. Proton beam therapy may give lower dose to the Circle of Willis than stereotactic RT. Conclusion: Currently there is no clear evidence that proton beam therapy will improve survival or reduce morbidity for children with craniopharyngioma. However, proton therapy has the potential to reduce RT dose to the Circle of Willis, which may reduce the risk of future cerebrovascular complications. We propose that more resources should be allocated to ensuring these patients are managed by experienced multidisciplinary teams through the continuum from diagnosis to long-term follow-up. Key words: children; craniopharyngioma; protons; sequelae; stereotactic radiotherapy.
Introduction There are around 141 cases of tumours of the central nervous system (CNS) in children diagnosed each year in Australia,1 with craniopharyngiomas (CP) expected to account for around 10 cases.2 Although benign there is often significant morbidity present even prior to any treatment3,4 due to the tumour’s proximity to vital structures such as the pituitary gland, hypothalamus, optic chiasm and Circle of Willis. With expected five years survival of over 80%5,6 minimising long-term morbidity for these patients is important.
© 2014 The Royal Australian and New Zealand College of Radiologists
There continues to be much debate regarding the optimal treatment strategy for childhood craniopharyngioma.5–10 Over the past three decades there has been increasing use of radiation and with new radiation techniques emerging this has only increased the complexity of treatment options for these children. With increasing use of protons in the UK7 and US8 there is debate whether paediatric patients from Australia should also be receiving this treatment. The drivers of increased use of protons are complex and may reflect the implementation of referral guidelines (UK) as well as availability (US). This study reviews the radiotherapy management of the
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last three childhood CP cases treated at Westmead Hospital and reviews the literature surrounding proton use in these patients to inform further national discussion regarding best radiotherapy management of these children.
Methods We reviewed the case notes and radiotherapy plans for all three children who have received radiation for treatment of craniopharyngioma at Westmead Hospital since 2007. Two of the children were planned using BrainLAB iPlan RT Dose 4.1 (BrainLAB, Munich, Germany), and we added contours for organs at risk (OAR) that had not been contoured previously. The following OAR were contoured: hippocampi, temporal lobes, internal carotid artery, middle cerebral artery, supratentorial brain, infratentorial brain and whole brain. All contours were reviewed by a consultant neuroradiologist. As one child had been planned on an older version of BrainLab, we transferred the imaging and re-contoured the gross tumour volume (GTV) and the planning target volume (PTV) using the original plan as a guide to create a new plan. Each child had a radiotherapy planning CT performed at Westmead Hospital (axial 2.5-mm slices); these were then fused with post-operative diagnostic T1 and T2 MRI images – for two patients these were from external sources with 6-mm slice thickness. GTV was contoured using MRI and 3-mm margin added for PTV. All were treated on Varian Clinac® 6EX (Varian Medical Systems, Palo Alto, CA, USA). One child underwent progress MRI during therapy because of a cystic component causing concern for possible change in GTV but did not require re-plan. The prescribed dosage was 50.4 Gy delivered at 1.8 Gy per fraction, five days a week, for a total of five and a half weeks. Approval for this review was granted by the Western Sydney Local Health District Human Research Ethics Committee.
Results Patient characteristics Patient 1 was initially diagnosed before age 2 and underwent surgery, which was felt to have achieved a radical resection. The infant subsequently developed a large subdural cerebrospinal fluid collection and required a subdural peritoneal shunt. Around six months later the infant was noted to be irritable and holding the head. Imaging revealed tumour recurrence. Further surgery was undertaken to reduce tumour bulk despite predicting there would be residual disease post-operatively. Fractionated stereotactic conformal radiotherapy (FSRT) under daily general anaesthesia was therefore recommended and delivered. Due to the reconstructed coronal images from a volumetric data set it was not possible to confidently contour the hippocampi for this child.
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Patient 2 initially had a gross resection with residual cyst wall on imaging. Five and a half years later the patient experienced a sudden decline in vision and imaging confirmed an increase in size of the cystic suprasellar craniopharyngioma associated with a mass effect on the optic chiasm and optic nerves with splaying of the circle of Willis. Surgery to evacuate the cyst was performed along with insertion of a Rickham reservoir. Intensity-modulated stereotactic radiotherapy (IMSRT) was delivered following this surgery. The patient was over 10 years of age at the time of radiotherapy. Patient 3 was diagnosed after a two-month history of headaches and vomiting. Imaging revealed a very large supra sellar mass lesion extending into the third ventricle and causing secondary obstructive hydrocephalus. Eight months after surgery, imaging confirmed two small areas of cyst recurrence, and the child, who was under seven years old, was referred for radiotherapy, delivered as IMSRT. All three were pan-hypopituitary post-initial surgery and had some degree of visual impairment. All three children remain alive without further tumour recurrence or new complication between two and six years after completion of radiotherapy.
Radiotherapy dose comparisons The PTVs for the patients were 10.52 cm3, 12.81 cm3 and 23.27 cm3. Tables 1 and 2 summarise and compare the results of our three patients with those of two key proton publications.9,10 There is no proton planning system in operation in Australia as yet. We approached colleagues at two different proton facilities in the US to collaborate with us for this study. One considered the exercise unrewarding given existing publications.9,10 We sent a CD with image and structure sets for all three patients to the other (A/Professor Jeffrey Buchsbaum). However, we were not able to export the plan dose files with the treatment plans because no licence to do so was purchased with our iPlan license. No dose proton/photon plan comparison could be made despite considerable effort on our colleague’s behalf. Figure 1 displays dose-wash for patient 1. It is important to note the dramatic difference in appearance depending on dose range applied, and this is particularly relevant when comparing treatment plans between publications.
Discussion PTV coverage with fractionated stereotactic radiotherapy for our three patients was as good as that achieved with intensity modulate proton therapy (IMPT) and superior to that achieved with three dimensional proton therapy (3D-PRT) when compared with publications by Beltran and Boehling.9,10 The dose to the temporal lobes and hippocampi was similar to that achieved with protons.
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Table 1. Comparison of stereotactic plans to previously published work by Beltran et al.9 (Reprinted from the International Journal of Radiation Oncology*Biology*Physics, 82/2, Beltran C, Roca M, Merchant TE; On the Benefits and Risks of Proton Therapy in Pediatric Craniopharyngioma, e281–e287, Copyright (2012), with permission from Elsevier) Westmead patients
PTV Conformity Index Right Temporal Lobe D50 (Gy) Left Temporal Lobe D50 (Gy) Right Hippocampus D50 (Gy) Left Hippocampus D50 (Gy) Whole Brain D50 (Gy)
Beltran et al.
1
2
3
IMRT
DSP
IMPT
0.73
0.70
0.78
0.71 ± 0.04
0.50 ± 0.04
0.84 ± 0.04
5.75
10.46
10.92
8.51 ± 3.79
8.17 ± 4.37
5.92 ± 3.03
5.75 NA NA 1.61
9.31 1.61 17.12 1.49
10.70 12.23 11.90 3.71
7.25 ± 2.70 19.29 ± 10.96 17.97 ± 8.42 12.22 ± 2.56
7.45 ± 3.69 19.17 ± 13.46 18.44 ± 12.18 9.48 ± 2.26
5.17 ± 2.62 13.87 ± 11.04 11.99 ± 8.80 7.58 ± 1.90
Conformity Index (the reference isodose was 95%), TVRI/TV × TVRI/VRI; TVRI, PTV volume for reference isodose. D50, dose to 50% of structure; DSP, double-scatter proton; IMPT, intensity-modulated proton therapy; IMRT, intensity-modulated radiation therapy; TV, target volume; VRI, total volume for reference isodose.
Dose to the whole brain was significantly lower than that from the published proton data when comparing D50 but very similar when comparing mean and maximum doses. However, the mean dose to the Circle of Willis for our patients compared poorly even with the published IMRT plans. This may reflect variation in tumour size and therefore volume to be irradiated. Smee et al. treated a
median volume of 3.55-cm311 for 41 patients (12 children), while Beltran et al.9 treated a PTV range from 28.8 to 112.2 cm3 in 14 children and our PTV volumes ranged from 10.52 to 23.27 cm3. It is difficult to compare results between studies because contouring of OAR will also vary and which OAR and dose-volume should be prioritised is not defined. We
Table 2. Comparison of stereotactic plans to previously published work by Boehling et al.10 (Reprinted from the International Journal of Radiation Oncology*Biology*Physics, 82/2, Boehling NS, Grosshans DR, Bluett JB, Palmer MT, Song X, Amos RA, Sahoo N, Meyer JJ, Mahajan A, Woo SY; 643–652, Copyright (2012), with permission from Elsevier) Westmead Patients
PTV Hippocampus MCA Internal Carotid Arteries Infratentorial Brain Supratentorial Brain Brainstem Whole Brain-PTV
CN 95% DMean DMax DMean DMax DMean DMax DMean DMax DMean DMax DMean DMax DMean DMax
Boehling et al.
1
2
3
IMRT
3D-PRT
IMPT
0.73
0.70 10.79 38.68 38.16 54.77 37.61 54.21 4.74 22.63 5.45 54.94 17.87 51.56 5.24 54.27
0.78 13.28 38.76 36.0 52.48 42.93 52.06 4.25 24.43 7.49 53.36 30.21 52.29 7.1 53.35
0.76 ± 0.07 10.6 ± 6.6 46.4 ± 12.9 15.8 ± 3.9 52.3 ± 2.9 21.0 ± 5.4 54.4 ± 0.8 8.0 ± 3.6 53.5 ± 5.6 8.7 ± 3.5 56.0 ± 0.8 25.2 ± 10.7 52.7 ± 6.3 7.6 ± 2.7 54.7 ± 1.1
0.56 ± 0.08 9.6 ± 6.5 46.0 ± 10.9 17.3 ± 4.4 52.6 ± 1.6 15.2 ± 5.5 53.9 ± 0.7 2.8 ± 1.8 52.7 ± 3.6 7.9 ± 2.8 55.4 ± 1.3 17.9 ± 10.1 52.8 ± 3.3 6.4 ± 2.0 54.5 ± 1.0
0.73 ± 0.05 7.6 ± 5.3 45.8 ± 9.6 10.6 ± 1.6 51.4 ± 2.3 13.0 ± 5.0 53.6 ± 0.8 3.9 ± 2.3 52.7 ± 4.2 7.0 ± 2.6 55.2 ± 1.4 21.0 ± 10.0 52.2 ± 4.2 5.6 ± 1.8 54.7 ± 1.6
33.39 52.84 34.43 53.15 4.4 25.77 5.93 54.02 22.82 51.95 5.62 53.96
Dmean and Dmax units are presented in Gray. 3D-PRT, three-dimensional conformal proton radiotherapy; CN95% (conformation number for 95% of prescription dose), TVRI/TV x TVRI/VRI; TVRI, PTV volume for reference isodose; IMRT, intensity-modulated radiotherapy; Dmax, maximum dose to OAR indicated; Dmean, mean dose to OAR indicated; MCA, middle cerebral arteries; TV, target volume; VRI, total volume for reference isodose.
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Fig. 1. Images displaying dose wash for patient 1. On the left the dose range is 30%–107% and on the right is 5%–107%.
were unable to create proton plans for our three patients as no proton treatment planning system is operational in Australia, and we were unable to export the dose files for our patients to allow an overseas centre to do this on our behalf. We have reviewed the literature regarding long-term consequences of childhood craniopharyngioma to determine the relevant OAR and the impact radiotherapy has on these.
Long-term consequences of childhood CP Endocrine More than three quarters of long-term survivors of paediatric craniopharyngioma require some form of hormone replacement.12–14 Much of the deficit relates to the position of the tumour itself and is present before any treatment is directed to the tumour. There is debate whether treatment modality also has an effect. Some series report no association with treatment modality.6 Yet others have found a significantly higher number of patients developed diabetes insipidus and hypopituitarism post gross total resection (GTR) compared with sub-total resection (STR) or STR + radiotherapy.15 Others have suggested that use of FSRT following limited resection or biopsy may be able to reduce endocrine deficit.16 Delaying radiotherapy for as long as possible is a relevant strategy in children with CP who maintain endocrine function after initial resection. Whenever external radiation is delivered, the pituitary gland and hypothalamus are almost certainly contained within the high dose region, so protons will offer no endocrine advantage. Knowing when to initiate treat-
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ment for endocrine disturbances can be complex and relies on clear communication between patient, carer and multiple specialists (neurosurgeon, paediatrician, radiation oncologist, endocrinologist, general practitioner).17 Dedicated follow-up clinics for these patients are essential.
Neurocognitive/IQ A large, prospective study from St Jude of 120 children and young patients with primary brain tumours found that a diagnosis of childhood craniopharyngioma on its own, irrespective of treatment, impacts on attention and schooling.18 There is evidence from the laboratory19,20 and increasingly from clinical practice21,22 that certain areas of the brain, namely those containing neuronal stem cells (NSCs) that are critical for learning and memory, are very sensitive to radiation and are responsible for the long-term cognitive impairment seen post-radiation. NSCs are found in the subgranular zone of the hippocampal dentate gyrus.20 At present there is little data to suggest a hippocampal radiation dose at which clinically detectable differences are seen, although as low dose as achievable is appropriate with incorporation of this structure as an OAR. We achieved as good hippocampal sparing with the stereotactic photon plans for our three patients as with published proton plans, and there is potential for further improvement if hippocampal sparing is prioritised in the planning process. The St Jude experience of childhood craniopharyngioma demonstrated that while all patients experienced some decline in full-scale IQ (FSIQ) it was not clinically
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significant for those treated with STR + radiotherapy, but those treated by GTR had a worse decline in FSIQ and performance IQ scores.12 They also demonstrated that those who relapsed post-surgery had a significantly worse FSIQ. In another of the few prospective series that have been published, the volume of total brain, supratentorial brain or left temporal lobe receiving >45 Gy had a significant impact on longitudinal IQ.23 Much of the work looking at reduction in IQ following treatment for craniopharyngioma in children is retrospective. Though not specific to CP, Jalali et al. found that >43.2 Gy to >13% of the left temporal lobe correlated to a significant (>10%) drop in FSIQ.24 Others have also demonstrated that large areas receiving >30 or >50 Gy result in worse outcomes.25 Work looking at modelling radiotherapy dose characteristics and their relationship to cognitive function has suggested that a reduction in the lower-dose volumes or mean dose would have long-term clinical advantages for children with CP and that protons were able to moderately reduce the intermediate volume and substantially reduce the low dose volume.26 However, this study was comparing protons to 3D-conformal radiotherapy with a 1.3–1.5-cm expansion from GTV-PTV. Smaller margins (5 mm GTV-PTV)27 do not impact on loco-regional recurrence and will result in a reduced mean brain dose as will attention to photon technique. Other modelling studies have suggested that reducing mean dose to whole brain will reduce IQ loss.28 Our results suggest that protons are not superior in this respect as the mean brain dose was no different.
Vascular Long-term survivors treated with cranial or cervical radiation have an increased risk of stroke.29 Cerebrovascular complications may relate to compression by the tumour30 and exist prior to any treatment. Liu et al. 31 identified some type of vasculopathy in six out of twenty evaluable patients but were unable to demonstrate any relation between stroke and radiotherapy dose in survivors of childhood CP, though there was little variation in doses received in their patient cohort. Ullrich et al. suggested a 1-Gy increase in dose to the optic chiasm leads to a 7% increased risk of Moyamoya.30 Protons may reduce the dose to the vessels10 and potentially reduce the risk of cerebrovascular complications for these patients; though there is no data to support this currently. What does appear clear is that the risk of stroke is further increased by well-known atherosclerotic risk factors, for example, hypertension.32 Up to 50% of children with CP are obese and have multiple endocrine deficiencies,5 which contribute to their risk of cerebrovascular complications. Attention to modifying these risks through careful follow-up may well be more important than adopting new radiotherapy technologies.
© 2014 The Royal Australian and New Zealand College of Radiologists
Second malignancies In the largest reported craniopharyngioma series to date with 173 patients (77 under age of 16 at time of radiotherapy) from The Marsden there have been no documented second malignancies despite a median follow-up of 12 years.4 Other series have reported various second tumours11,13–15 Modelling suggests that the use of protons rather than photons can reduce the second cancer risk,33 but this has not yet been demonstrated in clinical practice, with current reviews only demonstrating that protons do not appear to increase the risk for second malignancy without proof that they actually avoid or reduce it.34,35
Quality of life (QoL) There are many factors associated with a negative impact on QoL in childhood survivors of CP. In a recent review from the UK, prognostic factors that correlate with a higher risk of postoperative long-term morbidity, poor functional outcomes and QoL were identified as: the degree of hypothalamic involvement; patient age 4 cm; a retrochiasmatic location; hydrocephalus at diagnosis and multiple surgical procedures.36 In a recent German review: younger age, pre-operative functional impairment, large tumour size, hypothalamic or 3rd ventricle involvement, surgery alone and multiple surgeries were associated with worse QOL.3 In a large series of 102 survivors of childhood CP Müller also demonstrated that on multivariate analysis, only hypothalamic involvement, tumour relapse, progression, baseline Fertigkeitenskala Münster–Heidelberg score (measures the functional capability for daily life actions), and time between diagnosis and baseline evaluation had independent impact on QoL. Hypothalamic involvement, tumour progression, and relapse had long-term QoL affects – most notably, severe obesity.37 Despite the presumed reduced radiotherapy dose to OARs from protons there has yet to be any data demonstrating an improved QoL. One small series of children treated with surgery and protons that has been published demonstrates reduced QoL for these children.38 Factors that may improve QoL include: the neurosurgical experience,39 fewer surgeries,36 extent of surgery40 and timing of radiotherapy.41 These are all factors that could potentially be improved by cases being reviewed by an experienced multidisciplinary team (MDT) and the creation of a national registry.
Conclusion There remains controversy regarding the best management of children with craniopharyngioma. These children are at high risk for significant morbidity related to the tumour and its treatment. From our review we conclude that radiotherapy is only one of the factors contributing
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to the long-term morbidity of these patients and that the potential gains in reduced dose to OAR from proton beam therapy may not translate into significant clinical benefit. These children need to be treated by an experienced MDT to ensure that rigorous baseline endocrine, ophthalmological and neurocognitive testing can be carried out prior to any treatment (when possible). They then require careful follow-up into adulthood to reduce morbidity by detecting problems and offering appropriate intervention earlier.
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