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Proton Radiotherapy for Paediatric Tumours: Potential Areas for Clinical Research
Clinical Oncology (2003) 15: S32–S36 doi:10.1053/clon.2002.0183
Proton Radiotherapy for Paediatric Tumours: Potential Areas for Clinical Research R. E. Taylor Cookridge Hospital, Leeds LS16 6QB, U.K. ABSTRACT: Radiotherapy plays an important role in the management of children with cancer. The aim is to achieve local tumour control while minimizing long-term effects. In the treatment of tumours of the central nervous system (CNS) the most important long-term effects are neuropsychological. Elsewhere orthopaedic long-term effects may compromise function or be cosmetically harmful. Proton therapy has the potential for homogeneous irradiation of the target volume while reducing the magnitude and/or extent of the low dose area outside the target volume. This may be clinically relevant for long-term effects in children. Proton radiotherapy has an established role in the treatment of children with chordomas and chondrosarcomas of the base of skull. Planning studies have demonstrated the potential for improving the therapeutic ratio for radiotherapy for tumours of the central nervous system by achieving a uniform dose within the target volume while minimizing the severity of neuropsychological sequelae. Clinical experience of proton radiotherapy for children remains limited with potential areas for clinical research. Taylor R. E. (2003). Clinical Oncology 15, S32–S36 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Proton radiotherapy, paediatric cancer Received: 17 October 2002
Accepted: 21 October 2002
Introduction
Late Effects of Cancer Treatment in Children
Despite the increased use of chemotherapy in the management of paediatric tumours, radiotherapy remains a very important modality in the management of approximately 50% of children with cancer, particularly brain tumours [1]. However, despite this modality being effective at eradicating subclinical or even macroscopic disease in many patients, the quality of survival is frequently compromised by long-term sequelae. The aims of most clinical research programmes involving radiotherapy for children are to achieve the maximum long-term survival rate with the minimum of long-term sequelae. As in adult practice, proton radiotherapy has been employed to treat children with tumours requiring dose escalation within a target volume adjacent to a critical structure, such as for chordoma of the skull base. In paediatric practice the ‘low dose bath’ effect from photon radiotherapy is frequently clinically relevant in relation to long-term effects. The marked reduction in dose beyond the proton Bragg peak may be used reduce the extent of the ‘low dose bath’ effect and thus may be clinically beneficial in paediatric radiotherapy practice.
Of major concern in paediatric oncology practice are the neuropsychological long-term effects of radiotherapy to the central nervous system. These include impaired neuro-cognitive development and behaviour disorders. These effects are greater for whole brain than partial brain irradiation, and for younger children particularly those aged less than three at diagnosis [2]. Other late effects from central nervous system (CNS) radiotherapy include endocrine deficiencies, particularly dose-related growth hormone deficiency from irradiation of the hypothalamic-pituitary axis, and late effects on hearing from irradiation of the inner ear. There has been considerable debate concerning the question of a radiation dose–response effect for longterm neuropsychological effects. There is evidence from prophylactic whole-brain irradiation for leukaemia of a dose–response effect for long-term neuropsychological effects [3]. In the case of radiotherapy for brain tumours the situation is more complex because of the interaction of other factors such as the direct effects of the tumour, and the effects of surgery. There have been a number of studies of the late effects of the whole-brain component of craniospinal radiotherapy for medulloblastoma. Several small studies do appear to show a dose–effect relationship between 24 and 36 Gy to the brain, although such studies usually contain small numbers and/or a heterogeneous population in terms of disease and treatment. In a recent study of children treated for
Author for correspondence: Dr R. E. Taylor, Consultant Clinical Oncologist, Cookridge Hospital, Leeds LS16 6QB, U.K. Tel: 0113 392 4397; Fax: 0113 392 4052; E-mail: [email protected] 0936–6555/03/010S32+05 $30.00/0
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
medulloblastoma, Grill et al. [4] showed there is a significant coloration between the full-scale IQ score (FSIQ) and the craniospinal radiotherapy dose, with mean FSIQ scores at 84.5, 76.9 and 63.7 for 0 Gy (i.e., posterior fossa radiotherapy alone), 25 Gy and 35 Gy of craniospinal radiotherapy respectively. An analysis of the neuropsychological sequelae supported in the literature [3] has been used to construct a dose–response curve, which relates to the probability of neuropsychological sequelae to the brain radiotherapy dose. This pooling of data suggests a dose–response effect with greater morbidity seen with increasing cranial radiation dose. There has only been one study that attempted to examine this dose effect in the context of a randomized control trial. Mulhern examined the neuropsychological functioning of children with medulloblastoma entered into the POG 8631/CCG 923 study [5]. This showed that children treated with 23.4 Gy craniospinal radiotherapy experience less neuropsychological toxicity than those treated with 36 Gy. However, the number of patients studied was small, the individual patients’ IQ changes varied considerable, and the results of this cross-section analyses were not confirmed on a longitudinal basis. Attempts to minimize the long-term neuropsychological effects of brain radiotherapy include the following: (1) Avoidance of, or delay to, radiotherapy for young children, particularly those under the age of 3–5 years, by the use of chemotherapy or for some low-grade tumours an ‘observation policy’. (2) Use of focal rather than craniospinal radiotherapy where feasible, when evidence suggests that craniospinal radiotherapy does not influence outcome, i.e., ependymoma. (3) Reduction in the dose of the cranial component of craniospinal radiotherapy, e.g., in North American standard risk medulloblastoma studies dose reduction to 23.4 Gy compared with conventional dose of 35–36 Gy. The current European protocol for intracranial germinoma employs a relatively low dose (24 Gy) for craniospinal radiotherapy. (4) Improved immobilization resulting in reduced planning target volume (PTV), e.g., stereotactic fractionated radiotherapy for small volume focal brain irradiation. (5) Proton radiotherapy: benefit may be achieved by the ability to irradiate the target volume with a reduced dose to the surrounding normal brain and also organs at risk (OARs) e.g. hypothalamicpituitary axis, inner ears. Long-term effects from radiotherapy for paediatric tumours include bone and soft tissue hypoplasia. In a series of children treated in the U.K. with abdominal radiotherapy for Wilms’ tumour, 19.6% of children were reported to have clinically significant orthopaedic longterm effects [6]. There is evidence from a series of children treated for Hodgkin’s disease at Stanford that the severity of these effects is dose-related [7]. Other long-term effects include primary hypothyroidism
S33
related to direct irradiation of the thyroid and cardiomyopathy after treatment with radiotherapy combined with anthracycline chemotherapy. The fact that many of the long-term effects of radiotherapy in children appear to be dose related provided the rationale for exploring the role of proton radiotherapy for reducing some of the effects that result from irradiating structures outside the target volume. Clinical Experience of Proton Therapy for Paediatric Brain Tumours
Proton therapy has been used for several decades, but only in very few institutions world-wide. However, there is now increasing interest in its use, one of the indications being paediatric brain tumours. The major advantage of proton therapy over conventional radiation techniques is based on its physical characteristics. As a result of the Bragg peak, protons have no significant exit dose beyond the target volume. Thus a high degree of dose conformity around the tumour (conformity index) can be achieved. Proton Therapy for Tumours of the Skull Base in Children
This physical dose distribution from proton radiotherapy has been used in adults to treat chordomas of the base of skull. These tumours are generally difficult to irradiate because of their close proximity to the brain stem. In a report from the Massachusetts General Hospital [8] actuarial local control rates for 115 adult patients with base of skull chordomas treated between 1978 and 1993 were 59% at 5 years and 44% at 10 years. Treatment of base of skull and cervical spine chordomas in children has also been shown to be safe and effective [9]. Eighteen children aged 4–18 were treated at the Massachusetts General Hospital and Harvard Medical School with a mixed Photon/160 MeV Proton (80% proton contribution) 69 CGE. With a median follow-up of 72 months the 5-year actuarial survival was 68% and disease-free survival 63%. Long-term effects were acceptable. Two children developed growth hormone deficiency. Three children developed impaired hearing and one required surgical excision of an area of temporal necrosis, which had resulted in epilepsy. A later series of children aged 1–19 treated with proton radiotherapy for a variety of skull-base tumours has been reported from the same institution [10]. Malignant diagnoses in this group included chordoma (10), chondrosarcoma (three), rhabdomyosarcoma (four) and other sarcomas (three). Benign diagnoses included giant cell tumours (six), angiofibroma (two) and chondroblastoma (one). Radiotherapy doses ranged from 50.4 and 78.6 CGE. With a median follow-up of 40 months (range: 13–92 months) local tumour was controlled in six (60%) with chordoma, three (100%) with chondrosarcoma, four (100%) with rhabdomyosarcoma and two (66%) with other sarcomas. One patient with a
S34
giant cell tumour experienced a local failure, and the other patients with benign diagnoses have maintained local tumour control.
Proton Radiotherapy for Other Tumours of the CNS
An advantage of proton therapy over photon therapy in irradiation of the spinal component of craniospinal irradiation has been suggested by Miralbell [11]. For 6 MV photons more than 60% of the dose prescribed to the target was delivered to 44% of the heart volume while proton beams were able to completely avoid the heart. When comparing the dose distribution with electrons, however, no definitive advantage can be seen. In a series of children treated for brain tumours McAllister suggested that proton therapy can significantly reduce treatment-related morbidity [12]. The cohort of 28 children, however, was very heterogeneous and although treatment-related morbidity was found to be low, the results were not convincing. Mirabell performed dosimetric studies in whole-brain component of craniospinal irradiation on for protons and photons [3]. In his analysis proton beams succeeded better in reducing the dose to the brain hemispheres. In a model to predict normal tissue complication probabilities for neuropsychological sequelae, proton therapy revealed only a slight advantage over photon beams (2.5%). Children between the ages of 4 and 8 years benefited most from the dose reduction suggesting that modulated proton beams may help to reduce the irradiation of normal brain while optimally treating all meningeal sites. In Loma Linda University Medical Centre a study has been carried out to compare irradiation of normal tissue, and conformity to the target volume for a series of seven children with optic pathway gliomas [13]. The plans with protons offered better sparing of normal brain tissue than three-dimensional (3D) conformal photon plans. This advantage was greater for larger tumours. In a further study from the same institution [14], the use of protons resulted in a reduced radiation dose to the middle ear compared with 3D photon plans. In another study [15] conformal proton radiotherapy produced a higher conformity index than conformal photon radiotherapy particularly for more complex shaped PTVs (concave, ellipsoid, irregular complex) or for a PTV close to critical structures. In addition to studies comparing coverage of the PTV with proton compared with photons another method of analysis is to compare NTCP (normal tissue complication probability). However, this method of comparison [16] is highly dependent on the quality of the clinical data on complication probability. In a series of 27 children with lowgrade gliomas treated at Loma Linda, with a median follow-up of 3.3 years, 21/27 (78%) have achieved local control an outcome which is acceptable in comparison with other series of children treated by photons [17].
Potential Benefits for Proton Radiotherapy for Paediatric Brain Tumours
(1) Irradiation of base of skull chordoma and chondrosarcoma. Proton radiotherapy has an established role in the treatment of tumours of the skull base, allowing dose escalation adjacent to radiosensitive structures such as the brain stem. (2) For involved field radiotherapy for localized brain tumours, irradiation of the PTV with a reduced dose to the surrounding normal brain and OARs leading to reduced neuropsychological and endocrine long-term effects. (3) For craniospinal radiotherapy with posterior fossa boost for medulloblastoma, irradiation of the posterior fossa primary. This should have the potential for reducing the dose to the supratentorial brain and also the inner ears, which may benefit children receiving cisplatin-containing adjuvant chemotherapy. (4) Irradiation of other tumours involving the skull base adjacent to brain, e.g., rhabdomyosarcomas of nasopharynx or orbit. Proton Radiotherapy for Paediatric Tumours Arising Outside the CNS
There is as yet no established role for proton radiotherapy for tumours arising outside the CNS and experience is limited. However, proton radiotherapy may be potentially useful for achieving an appropriate dose in a target volume close to critical structures such as spinal cord, such as a paraspinal sarcoma. In a patient with Ewing’s sarcoma a conformal radiotherapy plan was compared with a proton plan for a ‘boost’ to the tumour. The comparison showed an advantage for protons. At a 1% normal tissue complication probability (NTCP) in the spinal cord, the calculated tumour control probability (TCP) was on average 5% higher [18]. Unlike radiotherapy for adult cancers, the low-dose effects of radiotherapy may be important for the causation of long-term orthopaedic effects. There is evidence from follow-up studies of children treated by radiotherapy for Hodgkin’s disease that the late orthopaedic effects are dose related. Thus the improved dose distribution of proton radiotherapy might be useful for irradiating target volumes and limiting the dose to surrounding structures. In a study from Loma Linda [19], a patient with locally advanced abdominal neuroblastoma achieved an appropriate dose distribution to the target volume while acceptable dose limits to kidneys, liver and spinal cord were maintained. Potential Areas for Clinical Research of Proton Radiotherapy for Paediatric Tumours
(1) Experience with proton radiotherapy for base of skull tumours is still relatively limited, and the knowledge base in this area will benefit from additional clinical studies.
(2) Irradiation of tumours of the CNS requiring involved field radiotherapy: low-grade glioma, ependymoma, and craniopharyngioma. Comparison of conformally planned photon radiotherapy with proton radiotherapy. These studies would need to include analyses of whole-brain dose– volume histograms (DVHs), with calculation of NTCP, and radiation doses to OARs – eyes, inner ears, pituitary, hypothalamus, and optic chiasm. As with all clinical studies of children treated with radiotherapy for tumours of the CNS, long-term neuropsychological and endocrine follow-up will be required. There is considerable discussion about the optimum method for assessing and recording the long-term effects of treatment. Currently under development is a questionnaire method of assessment, the HUI (Health Utilities Index) which is a global assessment of physical functioning [20]. An assessment of the outcome following proton radiotherapy should include plans for assessment of long-term outcome with the HUI. (3) For children with medulloblastoma the role of proton radiotherapy for the posterior fossa boost could be assessed. In addition proton radiotherapy for the spinal component of craniospinal radiotherapy may have potential for homogeneous irradiation of the spinal axis, while sparing structures anterior to the spine, such as the heart. (4) For children with parameningeal and orbital rhabdomyosarcoma proton radiotherapy could be employed, with comparisons of proton with photon plans and assessment of long-term effects as for tumours of the CNS. (5) A proportion of children with retinoblastoma require ‘lens sparing’ [21] or orbital radiotherapy. Proton radiotherapy has been used in the management of adults with ocular melanoma [22]. Longterm effects of irradiating the orbit include enophthalmos, dry eye and cataract as well as potentially distressing orbital hypoplasia. The use of a precisely collimated single proton beam may have the potential for reducing irradiation of orbital structures surrounding the target volume, and reducing long-term effects. (6) The role of proton radiotherapy could be explored for children with tumours adjacent to critical structures, such as paraspinal tumours, and for tumours in situations where protons may achieve homogeneous irradiation to the target volume while observing appropriate normal tissue tolerance doses. For 25 years clinical research into the management of children with cancer in the U.K. has been overseen and coordinated by the United Kingdom Children’s Cancer Study Group (UKCCSG). The establishment of a proton therapy research programme in collaboration with the UKCCSG would significantly enhance the international status of U.K. paediatric oncology research.
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References 1 Taylor RE. Cancer in children: radiotherapeutic approaches. Br Med Bull 1996;52:873–876. 2 Jannoun L, Bloom HJG. Long-term psychological effects in children treated for intracranial tumors. Int J Radiat Oncol Biol Phys 1990;18:747–753. 3 Miralbell R, Lomax A, Bortfeld T, et al. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: reduction of the supratentorial target volume. Int J Radiat Oncol Biol Phys 1997;38:477–484. 4 Grill J, Kieffer Renaux V, Bulteau C, et al. Long-term intellectual outcome in children with posterior fossa tumors according to radiation doses and volumes. Int J Radiat Oncol Biol Phys 1999; 45:137–145. 5 Mulhern RK, Kepner JL, Thomas PR, et al. Neuropsychologic functioning of survivors of childhood medulloblastoma randomized to receive conventional or reduced-dose craniospinal irradiation: a Pediatric Oncology Group Study. J Clin Oncol 1998;16:1723–1728. 6 Willman K, Cox, Donaldson S. Radiation induced height impairment in pediatric Hodgkin’s disease. Int J Radiat Oncol Biol Phys 1994;28:85–92. 7 Taylor RE. Morbidity from abdominal radiotherapy in the first United Kingdom Childrens’ Cancer Study Group (UKCCSG) Wilms’ Tumour study. Clin Oncol 1997;9:381–384. 8 Terahara A, Niermierko A, Goietin M, et al. Analysis of the relationship between tumor dose inhomogeneity and local control in patients with skull base chordoma. Int J Radiat Oncol Biol Phys 1999;45:351–358. 9 Benk V, Liebsch NJ, Munzenrider JE et al. Base of skull and cervical spine chordomas in children treated by high-dose irradiation. Int J Radiat Oncol Biol Phys 1995;31:577–581. 10 Hug EB, Sweeney RA, Nurre PM, et al. Proton radiotherapy in management of pediatric base of skull tumors. Int J Radiat Oncol Biol Phys 2002;52:1017–1024. 11 Miralbell R, Lomax A, Russo M. Potential role of proton therapy in the treatment of pediatric medulloblastoma/primitive neuroectodermal tumors: spinal theca irradiation. Int J Radiat Oncol Biol Phys 1997;38:805–811. 12 McAllister B, Archambeau JO, Nguyen MC et al. Proton therapy for pediatric cranial tumors: preliminary report on treatment and disease-related morbidities. Int J Radiat Oncol Biol Phys 1997; 39:455–460. 13 Fuss M, Hug EB, Schaefer RA et al. Proton radiation therapy (PRT) for pediatric optic pathway gliomas: comparison with 3D planned conventional photons and a standard photon technique. Int J Radiat Oncol Biol Phys 1999;45:1117–1126. 14 Lin R, Hug EB, Schaefer RA, et al. Conformal proton radiation therapy of the posterior fossa: a study comparing protons with three-dimensional planned photons in limiting dose to auditory structures. Int J Radiat Oncol Biol Phys 2000;48:1219–1226. 15 Baumert BG, Lomax AJ, Miltchev V, et al. A comparison of dose distributions of proton and photon beams in stereotactic conformal radiotherapy of brain lesions. Int J Radiat Oncol Biol Phys 2001;49:1439–1449. 16 Fuss M, Poljanc K, Miller DW, et al. Normal tissue complication probability (NTCP) calculations as a means to compare proton and photon plans and evaluation of clinical appropriateness of calculated values. Int J Cancer 2000;90:351–358. 17 Hug EB, Muenter MW, Archambeau JO, et al. Conformal proton radiation therapy for pediatric low-grade astrocytomas. Strahlenther Onkol 2002;178:10–17. 18 Isacsson U, Hagberg H, Johansson KA, et al. Potential advantages of protons over conventional radiation beams for paraspinal tumours. Radiother Oncol 1997;45:63–70. 19 Hug EB, Nevinny-Stickel M, Fuss M, et al. Conformal proton radiation treatment for retroperitoneal neuroblastoma: introduction of a novel technique. Med Pediatr Oncol 2001;37:36–41. 20 Glaser A, Kennedy CR, Punt J, et al. A standardised strategy for qualitative assessment of brain tumour survivors treated within clinical trials in childhood. Int J Cancer 1999;83(Suppl.):77–82.
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21 Toma NMG, Hungerford JL, Plowman PN, et al. External beam radiotherapy for retinoblastoma: II lens sparing technique. Br J Ophthalmol 1995;79:112–117.
22 Gragoudas ES, Seddon JM, Egan K et al. Long term results of proton beam irradiated uveal melanomas. Ophthalmology 1987;94:349–353.
Proton Radiotherapy for Paediatric Tumours: Potential Areas for Clinical Research R. E. Taylor Cookridge Hospital, Leeds LS16 6QB, U.K. ABSTRACT: Radiotherapy plays an important role in the management of children with cancer. The aim is to achieve local tumour control while minimizing long-term effects. In the treatment of tumours of the central nervous system (CNS) the most important long-term effects are neuropsychological. Elsewhere orthopaedic long-term effects may compromise function or be cosmetically harmful. Proton therapy has the potential for homogeneous irradiation of the target volume while reducing the magnitude and/or extent of the low dose area outside the target volume. This may be clinically relevant for long-term effects in children. Proton radiotherapy has an established role in the treatment of children with chordomas and chondrosarcomas of the base of skull. Planning studies have demonstrated the potential for improving the therapeutic ratio for radiotherapy for tumours of the central nervous system by achieving a uniform dose within the target volume while minimizing the severity of neuropsychological sequelae. Clinical experience of proton radiotherapy for children remains limited with potential areas for clinical research. Taylor R. E. (2003). Clinical Oncology 15, S32–S36 2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved. Key words: Proton radiotherapy, paediatric cancer Received: 17 October 2002
Accepted: 21 October 2002
Introduction
Late Effects of Cancer Treatment in Children
Despite the increased use of chemotherapy in the management of paediatric tumours, radiotherapy remains a very important modality in the management of approximately 50% of children with cancer, particularly brain tumours [1]. However, despite this modality being effective at eradicating subclinical or even macroscopic disease in many patients, the quality of survival is frequently compromised by long-term sequelae. The aims of most clinical research programmes involving radiotherapy for children are to achieve the maximum long-term survival rate with the minimum of long-term sequelae. As in adult practice, proton radiotherapy has been employed to treat children with tumours requiring dose escalation within a target volume adjacent to a critical structure, such as for chordoma of the skull base. In paediatric practice the ‘low dose bath’ effect from photon radiotherapy is frequently clinically relevant in relation to long-term effects. The marked reduction in dose beyond the proton Bragg peak may be used reduce the extent of the ‘low dose bath’ effect and thus may be clinically beneficial in paediatric radiotherapy practice.
Of major concern in paediatric oncology practice are the neuropsychological long-term effects of radiotherapy to the central nervous system. These include impaired neuro-cognitive development and behaviour disorders. These effects are greater for whole brain than partial brain irradiation, and for younger children particularly those aged less than three at diagnosis [2]. Other late effects from central nervous system (CNS) radiotherapy include endocrine deficiencies, particularly dose-related growth hormone deficiency from irradiation of the hypothalamic-pituitary axis, and late effects on hearing from irradiation of the inner ear. There has been considerable debate concerning the question of a radiation dose–response effect for longterm neuropsychological effects. There is evidence from prophylactic whole-brain irradiation for leukaemia of a dose–response effect for long-term neuropsychological effects [3]. In the case of radiotherapy for brain tumours the situation is more complex because of the interaction of other factors such as the direct effects of the tumour, and the effects of surgery. There have been a number of studies of the late effects of the whole-brain component of craniospinal radiotherapy for medulloblastoma. Several small studies do appear to show a dose–effect relationship between 24 and 36 Gy to the brain, although such studies usually contain small numbers and/or a heterogeneous population in terms of disease and treatment. In a recent study of children treated for
Author for correspondence: Dr R. E. Taylor, Consultant Clinical Oncologist, Cookridge Hospital, Leeds LS16 6QB, U.K. Tel: 0113 392 4397; Fax: 0113 392 4052; E-mail: [email protected] 0936–6555/03/010S32+05 $30.00/0
2002 The Royal College of Radiologists. Published by Elsevier Science Ltd. All rights reserved.
medulloblastoma, Grill et al. [4] showed there is a significant coloration between the full-scale IQ score (FSIQ) and the craniospinal radiotherapy dose, with mean FSIQ scores at 84.5, 76.9 and 63.7 for 0 Gy (i.e., posterior fossa radiotherapy alone), 25 Gy and 35 Gy of craniospinal radiotherapy respectively. An analysis of the neuropsychological sequelae supported in the literature [3] has been used to construct a dose–response curve, which relates to the probability of neuropsychological sequelae to the brain radiotherapy dose. This pooling of data suggests a dose–response effect with greater morbidity seen with increasing cranial radiation dose. There has only been one study that attempted to examine this dose effect in the context of a randomized control trial. Mulhern examined the neuropsychological functioning of children with medulloblastoma entered into the POG 8631/CCG 923 study [5]. This showed that children treated with 23.4 Gy craniospinal radiotherapy experience less neuropsychological toxicity than those treated with 36 Gy. However, the number of patients studied was small, the individual patients’ IQ changes varied considerable, and the results of this cross-section analyses were not confirmed on a longitudinal basis. Attempts to minimize the long-term neuropsychological effects of brain radiotherapy include the following: (1) Avoidance of, or delay to, radiotherapy for young children, particularly those under the age of 3–5 years, by the use of chemotherapy or for some low-grade tumours an ‘observation policy’. (2) Use of focal rather than craniospinal radiotherapy where feasible, when evidence suggests that craniospinal radiotherapy does not influence outcome, i.e., ependymoma. (3) Reduction in the dose of the cranial component of craniospinal radiotherapy, e.g., in North American standard risk medulloblastoma studies dose reduction to 23.4 Gy compared with conventional dose of 35–36 Gy. The current European protocol for intracranial germinoma employs a relatively low dose (24 Gy) for craniospinal radiotherapy. (4) Improved immobilization resulting in reduced planning target volume (PTV), e.g., stereotactic fractionated radiotherapy for small volume focal brain irradiation. (5) Proton radiotherapy: benefit may be achieved by the ability to irradiate the target volume with a reduced dose to the surrounding normal brain and also organs at risk (OARs) e.g. hypothalamicpituitary axis, inner ears. Long-term effects from radiotherapy for paediatric tumours include bone and soft tissue hypoplasia. In a series of children treated in the U.K. with abdominal radiotherapy for Wilms’ tumour, 19.6% of children were reported to have clinically significant orthopaedic longterm effects [6]. There is evidence from a series of children treated for Hodgkin’s disease at Stanford that the severity of these effects is dose-related [7]. Other long-term effects include primary hypothyroidism
S33
related to direct irradiation of the thyroid and cardiomyopathy after treatment with radiotherapy combined with anthracycline chemotherapy. The fact that many of the long-term effects of radiotherapy in children appear to be dose related provided the rationale for exploring the role of proton radiotherapy for reducing some of the effects that result from irradiating structures outside the target volume. Clinical Experience of Proton Therapy for Paediatric Brain Tumours
Proton therapy has been used for several decades, but only in very few institutions world-wide. However, there is now increasing interest in its use, one of the indications being paediatric brain tumours. The major advantage of proton therapy over conventional radiation techniques is based on its physical characteristics. As a result of the Bragg peak, protons have no significant exit dose beyond the target volume. Thus a high degree of dose conformity around the tumour (conformity index) can be achieved. Proton Therapy for Tumours of the Skull Base in Children
This physical dose distribution from proton radiotherapy has been used in adults to treat chordomas of the base of skull. These tumours are generally difficult to irradiate because of their close proximity to the brain stem. In a report from the Massachusetts General Hospital [8] actuarial local control rates for 115 adult patients with base of skull chordomas treated between 1978 and 1993 were 59% at 5 years and 44% at 10 years. Treatment of base of skull and cervical spine chordomas in children has also been shown to be safe and effective [9]. Eighteen children aged 4–18 were treated at the Massachusetts General Hospital and Harvard Medical School with a mixed Photon/160 MeV Proton (80% proton contribution) 69 CGE. With a median follow-up of 72 months the 5-year actuarial survival was 68% and disease-free survival 63%. Long-term effects were acceptable. Two children developed growth hormone deficiency. Three children developed impaired hearing and one required surgical excision of an area of temporal necrosis, which had resulted in epilepsy. A later series of children aged 1–19 treated with proton radiotherapy for a variety of skull-base tumours has been reported from the same institution [10]. Malignant diagnoses in this group included chordoma (10), chondrosarcoma (three), rhabdomyosarcoma (four) and other sarcomas (three). Benign diagnoses included giant cell tumours (six), angiofibroma (two) and chondroblastoma (one). Radiotherapy doses ranged from 50.4 and 78.6 CGE. With a median follow-up of 40 months (range: 13–92 months) local tumour was controlled in six (60%) with chordoma, three (100%) with chondrosarcoma, four (100%) with rhabdomyosarcoma and two (66%) with other sarcomas. One patient with a
S34
giant cell tumour experienced a local failure, and the other patients with benign diagnoses have maintained local tumour control.
Proton Radiotherapy for Other Tumours of the CNS
An advantage of proton therapy over photon therapy in irradiation of the spinal component of craniospinal irradiation has been suggested by Miralbell [11]. For 6 MV photons more than 60% of the dose prescribed to the target was delivered to 44% of the heart volume while proton beams were able to completely avoid the heart. When comparing the dose distribution with electrons, however, no definitive advantage can be seen. In a series of children treated for brain tumours McAllister suggested that proton therapy can significantly reduce treatment-related morbidity [12]. The cohort of 28 children, however, was very heterogeneous and although treatment-related morbidity was found to be low, the results were not convincing. Mirabell performed dosimetric studies in whole-brain component of craniospinal irradiation on for protons and photons [3]. In his analysis proton beams succeeded better in reducing the dose to the brain hemispheres. In a model to predict normal tissue complication probabilities for neuropsychological sequelae, proton therapy revealed only a slight advantage over photon beams (2.5%). Children between the ages of 4 and 8 years benefited most from the dose reduction suggesting that modulated proton beams may help to reduce the irradiation of normal brain while optimally treating all meningeal sites. In Loma Linda University Medical Centre a study has been carried out to compare irradiation of normal tissue, and conformity to the target volume for a series of seven children with optic pathway gliomas [13]. The plans with protons offered better sparing of normal brain tissue than three-dimensional (3D) conformal photon plans. This advantage was greater for larger tumours. In a further study from the same institution [14], the use of protons resulted in a reduced radiation dose to the middle ear compared with 3D photon plans. In another study [15] conformal proton radiotherapy produced a higher conformity index than conformal photon radiotherapy particularly for more complex shaped PTVs (concave, ellipsoid, irregular complex) or for a PTV close to critical structures. In addition to studies comparing coverage of the PTV with proton compared with photons another method of analysis is to compare NTCP (normal tissue complication probability). However, this method of comparison [16] is highly dependent on the quality of the clinical data on complication probability. In a series of 27 children with lowgrade gliomas treated at Loma Linda, with a median follow-up of 3.3 years, 21/27 (78%) have achieved local control an outcome which is acceptable in comparison with other series of children treated by photons [17].
Potential Benefits for Proton Radiotherapy for Paediatric Brain Tumours
(1) Irradiation of base of skull chordoma and chondrosarcoma. Proton radiotherapy has an established role in the treatment of tumours of the skull base, allowing dose escalation adjacent to radiosensitive structures such as the brain stem. (2) For involved field radiotherapy for localized brain tumours, irradiation of the PTV with a reduced dose to the surrounding normal brain and OARs leading to reduced neuropsychological and endocrine long-term effects. (3) For craniospinal radiotherapy with posterior fossa boost for medulloblastoma, irradiation of the posterior fossa primary. This should have the potential for reducing the dose to the supratentorial brain and also the inner ears, which may benefit children receiving cisplatin-containing adjuvant chemotherapy. (4) Irradiation of other tumours involving the skull base adjacent to brain, e.g., rhabdomyosarcomas of nasopharynx or orbit. Proton Radiotherapy for Paediatric Tumours Arising Outside the CNS
There is as yet no established role for proton radiotherapy for tumours arising outside the CNS and experience is limited. However, proton radiotherapy may be potentially useful for achieving an appropriate dose in a target volume close to critical structures such as spinal cord, such as a paraspinal sarcoma. In a patient with Ewing’s sarcoma a conformal radiotherapy plan was compared with a proton plan for a ‘boost’ to the tumour. The comparison showed an advantage for protons. At a 1% normal tissue complication probability (NTCP) in the spinal cord, the calculated tumour control probability (TCP) was on average 5% higher [18]. Unlike radiotherapy for adult cancers, the low-dose effects of radiotherapy may be important for the causation of long-term orthopaedic effects. There is evidence from follow-up studies of children treated by radiotherapy for Hodgkin’s disease that the late orthopaedic effects are dose related. Thus the improved dose distribution of proton radiotherapy might be useful for irradiating target volumes and limiting the dose to surrounding structures. In a study from Loma Linda [19], a patient with locally advanced abdominal neuroblastoma achieved an appropriate dose distribution to the target volume while acceptable dose limits to kidneys, liver and spinal cord were maintained. Potential Areas for Clinical Research of Proton Radiotherapy for Paediatric Tumours
(1) Experience with proton radiotherapy for base of skull tumours is still relatively limited, and the knowledge base in this area will benefit from additional clinical studies.
(2) Irradiation of tumours of the CNS requiring involved field radiotherapy: low-grade glioma, ependymoma, and craniopharyngioma. Comparison of conformally planned photon radiotherapy with proton radiotherapy. These studies would need to include analyses of whole-brain dose– volume histograms (DVHs), with calculation of NTCP, and radiation doses to OARs – eyes, inner ears, pituitary, hypothalamus, and optic chiasm. As with all clinical studies of children treated with radiotherapy for tumours of the CNS, long-term neuropsychological and endocrine follow-up will be required. There is considerable discussion about the optimum method for assessing and recording the long-term effects of treatment. Currently under development is a questionnaire method of assessment, the HUI (Health Utilities Index) which is a global assessment of physical functioning [20]. An assessment of the outcome following proton radiotherapy should include plans for assessment of long-term outcome with the HUI. (3) For children with medulloblastoma the role of proton radiotherapy for the posterior fossa boost could be assessed. In addition proton radiotherapy for the spinal component of craniospinal radiotherapy may have potential for homogeneous irradiation of the spinal axis, while sparing structures anterior to the spine, such as the heart. (4) For children with parameningeal and orbital rhabdomyosarcoma proton radiotherapy could be employed, with comparisons of proton with photon plans and assessment of long-term effects as for tumours of the CNS. (5) A proportion of children with retinoblastoma require ‘lens sparing’ [21] or orbital radiotherapy. Proton radiotherapy has been used in the management of adults with ocular melanoma [22]. Longterm effects of irradiating the orbit include enophthalmos, dry eye and cataract as well as potentially distressing orbital hypoplasia. The use of a precisely collimated single proton beam may have the potential for reducing irradiation of orbital structures surrounding the target volume, and reducing long-term effects. (6) The role of proton radiotherapy could be explored for children with tumours adjacent to critical structures, such as paraspinal tumours, and for tumours in situations where protons may achieve homogeneous irradiation to the target volume while observing appropriate normal tissue tolerance doses. For 25 years clinical research into the management of children with cancer in the U.K. has been overseen and coordinated by the United Kingdom Children’s Cancer Study Group (UKCCSG). The establishment of a proton therapy research programme in collaboration with the UKCCSG would significantly enhance the international status of U.K. paediatric oncology research.
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