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Brain dose-sparing radiotherapy techniques for localized intracranial germinoma: Case report and literature review of modern irradiation
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Case report
Brain dose-sparing radiotherapy techniques for localized intracranial germinoma: Case report and literature review of modern irradiation Radiothérapie conformationnelle avec modulation d’intensité avec épargne du cerveau pour des germinomes intracrâniens localisés : à propos d’un cas et analyse de la littérature moderne H.W.C. Leung a,b , A.L.F. Chan c,∗ , M.B. Chang a a
Department of radiation therapy, An Nan hospital, China Medical University, No. 66, Sec. 2, Changhe road, Annan Dist, 71710 Tainan, Taiwan Department of information management, Chia Nan university of pharmacy and science, No. 60, Sec. 1, Erren road, Rende Dist, 71710 Tainan, Taiwan c Department of pharmacy, An Nan hospital, China Medical University, No. 66, Sec 2, Changhe road, Annan Dist, 71710 Tainan, Taiwan b
a r t i c l e
i n f o
Article history: Received 29 December 2015 Received in revised form 5 February 2016 Accepted 13 February 2016 Keywords: Localized CNS germinoma Radiotherapy OAR
a b s t r a c t We examined the effects of intensity-modulated radiation therapy with dose-sparing and avoidance technique on a pediatric patient with localized intracranial germinoma. We also reviewed the literature regarding modern irradiation techniques in relation to late neurocognitive sequelae. A patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland received a dosesparing intensity-modulated radiation therapy. The planning was compared to the radiation oncologist’s guide of organs at risk and dose constraints for dosimetric analyses. The patient received radiation therapy alone. The total dose was 54 Gy delivered in 2.0 Gy fractions to the primary tumour and 37 Gy in 1.4 Gy fractions to whole ventricles using a dose-sculpting plan. Dosimetry analyses showed that dose-sparing intensity-modulated radiation therapy delivered reduced doses to the whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With a follow-up of 22 months, failure-free survival was 100% for the patient and no adverse events during radiation treatment process. Intensity-modulated radiation therapy with dose sparing and avoidance technique can spare the limbic circuit, central nervous system, and hippocampus for pineal germ cell tumours. This technique reduces the integral dose delivered to the uninvolved normal brain tissues and may reduce late neurocognitive sequelae caused by cranial radiotherapy. © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Germinome du système nerveux central localisé Radiothérapie Organes à risque
Nous avons examiné les effets de la radiothérapie avec modulation d’intensité (RCMI) avec économie de dose et épargne de structures chez un enfant atteint de germinome intracrânien localisé. Nous avons aussi revu la littérature sur les séquelles neurocognitives de l’irradiation moderne. Un patient atteint de germinome localisé entre l’avant du troisième ventricule et la glande pinéale a rec¸u ce type de radiothérapie. La planification a été comparée au guide de la radiothérapie oncologique et des contraintes de dose dans les organes à risque pour les analyses dosimétriques. La radiothérapie était exclusive et a délivré une dose totale de 54 Gy par fractions de 2 Gy dans la tumeur primitive et 37 Gy par fractions de 1,4 Gy dans la totalité des ventricules. L’analyse dosimétrique a montré une diminution de la dose dans tout le cerveau, les lobes temporaux, les hippocampes, les cochlées et les nerfs optiques. Avec un suivi de 22 mois, il n’a été observé aucun échec et aucun événement indésirable n’a non plus été constaté pendant le traitement. La RCMI pour tumeur germinale pinéale peut épargner le circuit
∗ Corresponding author. E-mail address: [email protected] (A.L.F. Chan). http://dx.doi.org/10.1016/j.canrad.2016.02.007 1278-3218/© 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Leung HWC, et al. Brain dose-sparing radiotherapy techniques for localized intracranial germinoma: Case report and literature review of modern irradiation. Cancer Radiother (2016), http://dx.doi.org/10.1016/j.canrad.2016.02.007
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limbique, l’encéphale et les hippocampes. Elle permet de réduire la dose dans le cerveau sain, ce qui peut réduire les séquelles tardives neurocognitives de la radiothérapie crânienne. © 2016 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction Intracranial germinomas are rare primary central nervous system germ cell tumours that account for 2.5% to 4.4% of all paediatric central nervous system (CNS) tumours in Western countries [1–3]. In Asia, germ cell tumours of the central nervous system in children are common, representing 15 to 18% of all childhood CNS tumours [4,5]. The reported incidence rate at the largest hospital in Taipei was approximately 14%. The mean age of onset was approximately 10- to 12-year-old [6]. There are two main types of germ cell tumours: germinomas and non-germinomatous germ-cell tumours. Non-germinomatous germ cell tumours are more common in younger children and pure germinomas are more common among older patients. Treatment outcome of nongerminomatous germ cell tumours are worse than intracranial germinomas [7]. Radiotherapy is curative for pure germinoma. The standard dose is 45 to 50 Gy to the primary tumour, in combination with about 24 Gy of whole ventricular irradiation, the 5-year control rate was 88% [8]. The long-term radiotherapy-induced brain injury is raising significant concerns due to the high curability of many germ cell tumours and the large treatment volumes often used in these young patients [9,10]. Therefore, there are ongoing efforts to explore the feasibility of delivering reduced radiotherapy doses to patients with germ cell tumours and spare brain structure from irradiation. Standard intensity-modulated radiation therapy (IMRT) for whole ventricular irradiation has already been shown to spare a significant amount of normal central nervous tissue for patients with localized germ cell tumours as compared to whole brain irradiation using opposed lateral beams [11,12]. Whole brain irradiation can be associated with subacute and late decline in memory and other cognitive functions, which is likely to be caused by the damage to the neural stem cell compartment, limbic circuit and hippocampus [9,13,14]. Therefore, its use in different primary paediatric intracranial tumours has been limited [15,16]. In reducing the incidence and severity of late adverse cognitive effects, the idea of sparing of these critical structures using intensity-modulated radiation therapy with dose sculpting was suggested: the technique escalates the dose to the tumour and spares normal tissues. It has not been well studied in paediatric patients with intracranial tumour [17]. We thus examined the case of a patient with pineal germinoma treated with dose-sparing intensity-modulated radiation therapy and avoidance techniques in our institution and reviewed the literature regarding modern irradiation for localized germ cell tumours and the adverse events of neurocognitive dysfunction.
2. Clinical case After approval by the institutional review committee, the medical records of patients with a CNS germ cell tumour treated at our institution over a 2-year period were examined. A patient who received intensity-modulated radiotherapy with dose-sparing and avoidance techniques was identified and selected for study. The patient, age 16, had a pineal tumour in the third ventricle anterior to the pineal gland and marked dilation of the ventricle with obstructive hydrocephalus. Magnetic resonance (MR) imaging of the brain showed a 6 × 6 cm isointense pineal gland lesion on T1 and T2 with bright enhancement on contrast studies (Fig. 1). An
infratentorial supracerebellar approach was performed to remove the lesion. The patient received intensity-modulated radiotherapy (IMRT) in our department 1 week after surgery. The radiation oncologist used dose-sparing techniques with four phases of treatment planning via the dynamic IMRT to spare the limbic circuit, hippocampus, and neural stem cell compartment. The treatment planning target volume was contoured and varied by diagnosis using computed tomography simulation with a custom-made immobilization device. The planning target volume was generally consisted of the gross tumour as it was identified on imaging. For the primary tumour, the gross tumour volume was defined as the extent of disease at diagnosis. The clinical target volume was designed to allow 0.8 cm margin beyond the gross tumour volume to obtain the planning target volume in phase 1, and 1.2 cm margin beyond the residual tumour in phases 3 and 4 to obtain the planning target volume. For whole ventricular irradiation, the clinical target volume comprised bilateral ventricles with a 0.5-cm expansion to obtain the planning target volume. In this case, 6 MV photons were used. The planning objectives were delivered non-uniform dose to different target volume with minimizing the dose to critical organs at risk. The treatment delivery was on Clinac® iX linear accelerator (Varian). After four phases of radiotherapy, the follow-up MRI imaging revealed that the patient’s lesion was decreased from 5.17 cm to 2 cm (Fig. 2). The patient’s neurological symptoms remained stable; no optic neuropathy appeared throughout the radiation treatment courses. Unfortunately, he developed impaired recent memory 3 months after radiotherapy; as a result, he refused to receive a boost dose. The follow-up MRI imaging after 6 months revealed a dramatic reduction in the size of the germinoma (Fig. 3). The patient did not receive chemotherapy due to the diagnosis of a localized tumour and excellent response to radiotherapy. At 22 months follow-up, MRI imaging revealed no progression of the disease and the patient’s condition remained stable upon clinical evaluation. The calculation of ventricles dose was based on the patient’s neuroanatomy and required superimposing the radiation therapy isodose lines over the average anatomy. The total dose was 54 Gy delivered in 2.0 Gy fractions to the primary tumour and 37 Gy in 1.4 Gy fractions to whole ventricles using dose-sparing and avoidance techniques. The dose distribution is shown on Fig. 4. The germinoma located in the third ventricle was treated with multileaf dose-sparing intensity-modulated radiation therapy only. Table 1 compares the total dose constraints (standard Table 1 Whole ventricular radiotherapy of central nervous system germinoma: organs at risk dose constraints for sparing plans. Radiothérapie crânienne avec épargne de dose pour un germinome intracrânien : contraintes de dose dans les organes à risque. Standard organs at risk
Literature data
Current study
Eyes Lenses Optic nerves Optic chiasms Cochleae Brainstem Temporary lobe Hippocampus
Dmean < 25 Gy [18] Dmax < 6 Gy [19] Dmax < 54 Gy [20] Dmax < 55 Gy [20] Dmean < 35 Gy [21] Dmax < 54 Gy [22] Dmax < 30 Gy [23] Dmean < 30 Gy [24]
Dmean = 10.2 Gy Dmax = 5.02 Gy Dmax = 52 Gy Dmax = 50 Gy Dmean = 19.6 Gy Dmax = 50.6 Gy Dmax = 30 Gy Dmean = 50 Gy
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Fig. 1. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: preoperative T1-weighted magnetic resonance images with gadolinium showing a heterogenously enhancing lesion of the pineal region. A. Axial view. B. Coronal view. C. Sagittal view. Patient de 16 ans atteint d’un germinome intracrânien localisé : imagerie par résonance magnétique préopératoire (séquence T1 avec gadolinium) montrant une lésion hétérogène de la région pinéale. A. Coupe axiale. B. Coupe coronaire. C. Coupe sagittale.
and sparing) for critical structures using dose-sparing intensitymodulated radiation therapy techniques with the literature recommendations. This technique was able to deliver a lower mean dose (DM ) or maximum dose (Dmax) to all structures atrisk, including eyes, lenses, optic nerves, optic chiasms, cochleae, brainstem, hippocampal and temporary lobe. The patient did not have any severe toxicity during radiotherapy. However, early delayed mildly impaired recent memory appeared 3 months post-radiation. He was tested using Wechsler Adult Intelligence Scale (WAIS III) [25]. The Full Scale (overall) IQ score was 69, which was slightly below the borderline IQ score (70–79) and his Working Memory Index was in the average range. The psychologist suggested that the impaired recent memory may probably be reversed after rehabilitation. The patient is currently alive with no evidence of local recurrence for 22 months follow-up.
3. Discussion
Fig. 2. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: magnetic resonance of image of the tumour after four phases of intensity-modulated radiation therapy with dose-sparing and avoidance technique. Patient de 16 ans atteint d’un germinome intracrânien localisé : IRM après 4 cures de radiothérapie avec modulation d’intensité avec économie de dose et épargne de structures.
Pineal germinoma is rare disease and exquisitely radiosensitive. Most previous case reports focused on treatment and survival. Studies on radiotherapy dose constraints to organs at risk and their effect on patients’ intelligence quotient are rare. We thus examined the patient and reviewed literature regarding radiotherapy, organs at risk dose constraints and neurocognitive dysfunction. According to the published review, radiation-induced brain injury is classified as acute, early delayed, and late delayed injury. Acute brain injury is rare with modern radiation therapy techniques
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Fig. 3. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: 6 months postradiotherapy follow-up T1-weighted magnetic resonance images with gadolinium showing a heterogenously enhancing lesion of the pineal region. A. Axial view. B. Coronal view. C. Sagittal view. Patient de 16 ans atteint d’un germinome intracrânien localisé : imagerie par résonance magnétique 6 mois après la radiothérapie avec modulation d’intensité (RCMI) avec économie de dose et épargne de structures (séquence T1 avec gadolinium) montrant une lésion hétérogène de la région pinéale. A. Coupe axiale. B. Coupe coronaire. C. Coupe sagittale.
and will appear within days to weeks after whole brain irradiation. Early delayed brain injury can involve transient demyelination with somnolence and occurs 1–6 months post-irradiation. Both of these early injuries are normally reversible and resolve spontaneously [26]. However, late delayed brain injury is irreversible and progressive, due to vascular abnormalities, demyelination, and white matter necrosis [27]. It usually occurred over 6 months after radiation therapy. Many of the late adverse cognitive effects of cranial irradiation may associate with damage to the neuron stem cell compartment, limbic circuit and hippocampus. Sparing of these critical structures dosimetrically may reduce the incidence and severity of late adverse neurocognitive adverse events in children receiving the treatment [15,17]. Furthermore, the dose administered may directly result in late adverse neurocognitive dysfunction, which are expressed as a decline in overall IQ [14,28,29]. With respect to the recently published radiation oncologist’s guide for organs at risk in brain and the dose constraints in adults and children, we compared the dose constraints for intracranial organs at risk in our patient with the literature recommendations. The dose for the organs at risk was within the range proposed in the literature [30]. However, the dose constraint for the hippocampus was slightly higher than the literature recommendations. The reasons were the size of the tumour, critical condition of the patient and the location of tumour near the hippocampus. Some study proposed that the clinical target volume crossing the midline of the brain was not feasible in order to spare the hippocampus; this could be overcome by a steep dose gradient of intensity-modulated radiation therapy [24]. There is no good evidence of the clinical tolerance of the hippocampus to radiation. It likely depends on patient age,
total dose, dose per fraction and dose distributions in the structure. Armstrong et al. indicated that memory impairment was associated with a dose of more than 30 Gy to the temporal lobe in children [23]. Other factors, such as direct and indirect tumour effects, seizures, medication, and oncological treatment, may also affect the neurocognitive outcome [31]. Because the neurocognitive dysfunction can have a large impact on self-care, social and professional functioning as well as health-related quality of life, we need to minimize the effect of other risk factors on the impaired memory. In the past few decades, patients with localized germinomas received craniospinal irradiation at a dose of 36 Gy, with a total of 50 to 54 Gy including a boost delivered to the primary tumour. Studies have indicated that whole-brain or whole-ventricle irradiation in patients with localized germinomas could replace craniospinal irradiation based on the outcome of a spinal failure rate of less than 10% [24,30,32]. Afterwards, several studies reported that whole brain irradiation caused clinically significant late neurocognitive effects, such as subacute and late decline in memory, hearing loss, severe global cognitive deficiencies, and neuro-endocrine deficit as well as endocrine effects [33–36]. Thus, the idea of sparing the organs at risk by adjusting the dosimetry in intensity-modulated radiotherapy was suggested. However, some studies raised concern about the possibility of delivering more total monitor units (MU) at a given dose, creating a greater integral dose delivered to the patient during cranial intensity-modulated radiation therapy [37–39]. Other dosimetric studies found that reducing the internal dosimetry may reduce the risk of late second malignancies and cognitive dysfunction, but this hypothesis has not been conclusively proven [37,38].
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Fig. 4. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: dose distribution of planning target volume in four courses of intensity-modulated radiation therapy with dose-sparing and avoidance technique. Summed dose distributions are represented as colourwash. A. Doses from 9 Gy (blue) to 10 Gy and above (red) for course 1. B. Doses from 14.4 Gy (blue) to 18 Gy and above (red) for course 2. C. From 14.4 Gy (blue) to 18 Gy and above (red) for course 3. D. Doses from 6.4 Gy (blue) to 8.0 Gy and above (red) for course 4. Patient de 16 ans atteint d’un germinome intracrânien localisé : distribution de doses de radiothérapie avec modulation d’intensité (RCMI) avec économie de dose et épargne de structures. A. Cure 1. B. Cure 2. C. Cure 3. D. Cure 4.
Another approach to normal organ sparing in cranial radiotherapy for paediatric pineal germinoma is the volumetric modulated arc therapy. Investigators have reported that this technique may provide the advantages of sparing normal tissues and reducing the treatment delivery time compared with conventional static field intensity-modulated radiotherapy, which may result in improvements in the IQ of children with intracranial pure germinomas [40]. In addition, Qi et al. reported that decreasing the mean temporal lobe dose to 11.4–13.1 Gy in patients who are 10 years of age may increase the IQ by 7 points at 5 years after volumetric modulated arc therapy [41]. Another modern cranial radiotherapy technique for paediatric brain tumours, with normal tissue sparing, is proton radiotherapy [42–54]. Investigators at several institutions have performed dosimetry studies comparing the dose delivered to normal tissues with proton therapy, intensity-modulated radiation therapy and/or conventional radiotherapy. They found that proton therapy had consistently lower doses to critical normal tissues and integral doses to the body compared with intensity-modulated radiation
therapy. A reduction of the integral dose is expected to result in a lower rate of secondary tumour induction after treatment [51–54]. Afterwards, investigators have devoted their effort to determining whether proton radiotherapy has clinical advantages over photon radiotherapy for dose characteristics and their relationship to cognitive function. One study modeled the dose characteristics of both modalities to critical normal tissue volumes using data from patients with four types of childhood brain tumours. Comparing protons to photons for the effects on the cognitive outcomes (estimated IQ score), relatively small critical normal tissue volumes, such as the cochlea and hypothalamus, may be spared from radiation exposure, but larger normal tissue volumes such as the supratentorial brain or temporal lobes receive less of the low and intermediate doses [55]. These differences resulted in clinically significant higher IQ scores for patients with intracranial tumours. Later, a clinical study that was only presented at the American Society of Clinical Oncology (ASCO) 2013 Meeting discussed the IQ change in paediatric patients within 3 years of radiation therapy for brain tumour treated with proton beams versus photons.
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In over 3 years follow-up, children who received conventional photon radiation lost an average of 10.3 IQ points per year compared to only 0.1 IQ point lost per year in the proton group. The age of the patients did not affect the result (assuming that younger patients are more severely affected). They concluded that there is an advantage in terms of the cognitive toxicity as measured by IQ in patients receiving partial brain proton radiation. However, no difference in IQ was demonstrated between proton and photon treatment for patients receiving craniospinal irradiation, which treats the entire brain [56]. Proton therapy is very expensive and is only available in a few centers in the United States and is not used in our country. As a result, more clinical reports from the clinical setting are needed before we are able to make a conclusion about its benefit regarding the cognitive function decline of children with intracranial tumours.
[12] [13]
[14]
[15] [16]
[17] [18]
4. Conclusion [19]
The physical dose to the critical structures, such as the limbic circuit, hippocampus, and neural stem cell compartment can be dosimetrically reduced during the administration of partial brain radiotherapy for treating different types of paediatric primary intracranial tumours. However, such a treatment does not fully comply with the dosimetric coverage of the treatment target or dosimetric sparing of other critical normal structures including the pituitary-hypothalamic axis. The organs at risk dose constraints and sparing in our study were within the standard ranges reported in the literature. Therefore, this approach used in our study should reduce the late adverse cognitive effects of radiotherapy in children, but further evaluation in a prospective clinical trial that includes a formal evaluation of the neurocognitive outcomes is needed. Disclosure of interest
[20]
[21]
[22]
[23]
[24]
[25]
The authors declare that they have no competing interest. [26]
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[49] MacDonald SM, Safai S, Trofimov A, Wolfgang J, Fullerton B, Yeap BY, et al. Proton radiotherapy for childhood ependymoma: initial clinical outcomes and dose comparisons. Int J Radiat Oncol Biol Phys 2008;71:979–86. [50] Palm A, Johansson K. A review of the impact of photon and proton external beam radiotherapy treatment modalities on the dose distribution in field and out-of-field; implications for the long-term, morbidity of cancer survivors. Acta Oncol 2007;47:462–73. [51] Mu X, Bjork-Eriksson T, Nill S, Oelfke U, Johansson KA, Gagliardi G, et al. Does electron and proton therapy reduce the risk of radiation induced cancer after spinal irradiation for childhood medulloblastoma? A comparative treatment planning study. Acta Oncol 2005;44:554–62. [52] Hall EJ, Phil D. Intensity-modulated radiation therapy, protons, and the risk of second cancers. Int J Radiat Oncol Biol Phys 2006;65:1–7. [53] Schneider U, Lomax A, Pemler P, et al. The impact of IMRT and proton radiotherapy on secondary cancer incidence. Strahlenther Onkol 2006;11:647–52. [54] Yoon M, Ahn SH, Kim J, Shin DH, Park SY, Lee SB, et al. Radiation-induced cancers from modern radiotherapy techniques: intensity-modulated radiotherapy versus proton therapy. Int J Radiat Oncol Biol Phys 2010;77:1477–85. [55] Merchant TE, Hua CH, Shukla H, Ying X, Nill S, Oelfke U, 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;51:110–7. [56] Kahalley LS, Okcu MF, Ris MD, Grosshans D, Paulino A, Chintagumpala MM, et al. IQ change within three years of radiation therapy in pediatric brain tumor patients treated with proton beam versus photon radiation therapy. J Clin Oncol 2013;31:10009 [ASCO Meeting 2013; Abstract 10009].
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Case report
Brain dose-sparing radiotherapy techniques for localized intracranial germinoma: Case report and literature review of modern irradiation Radiothérapie conformationnelle avec modulation d’intensité avec épargne du cerveau pour des germinomes intracrâniens localisés : à propos d’un cas et analyse de la littérature moderne H.W.C. Leung a,b , A.L.F. Chan c,∗ , M.B. Chang a a
Department of radiation therapy, An Nan hospital, China Medical University, No. 66, Sec. 2, Changhe road, Annan Dist, 71710 Tainan, Taiwan Department of information management, Chia Nan university of pharmacy and science, No. 60, Sec. 1, Erren road, Rende Dist, 71710 Tainan, Taiwan c Department of pharmacy, An Nan hospital, China Medical University, No. 66, Sec 2, Changhe road, Annan Dist, 71710 Tainan, Taiwan b
a r t i c l e
i n f o
Article history: Received 29 December 2015 Received in revised form 5 February 2016 Accepted 13 February 2016 Keywords: Localized CNS germinoma Radiotherapy OAR
a b s t r a c t We examined the effects of intensity-modulated radiation therapy with dose-sparing and avoidance technique on a pediatric patient with localized intracranial germinoma. We also reviewed the literature regarding modern irradiation techniques in relation to late neurocognitive sequelae. A patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland received a dosesparing intensity-modulated radiation therapy. The planning was compared to the radiation oncologist’s guide of organs at risk and dose constraints for dosimetric analyses. The patient received radiation therapy alone. The total dose was 54 Gy delivered in 2.0 Gy fractions to the primary tumour and 37 Gy in 1.4 Gy fractions to whole ventricles using a dose-sculpting plan. Dosimetry analyses showed that dose-sparing intensity-modulated radiation therapy delivered reduced doses to the whole brain, temporal lobes, hippocampi, cochleae, and optic nerves. With a follow-up of 22 months, failure-free survival was 100% for the patient and no adverse events during radiation treatment process. Intensity-modulated radiation therapy with dose sparing and avoidance technique can spare the limbic circuit, central nervous system, and hippocampus for pineal germ cell tumours. This technique reduces the integral dose delivered to the uninvolved normal brain tissues and may reduce late neurocognitive sequelae caused by cranial radiotherapy. © 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
r é s u m é Mots clés : Germinome du système nerveux central localisé Radiothérapie Organes à risque
Nous avons examiné les effets de la radiothérapie avec modulation d’intensité (RCMI) avec économie de dose et épargne de structures chez un enfant atteint de germinome intracrânien localisé. Nous avons aussi revu la littérature sur les séquelles neurocognitives de l’irradiation moderne. Un patient atteint de germinome localisé entre l’avant du troisième ventricule et la glande pinéale a rec¸u ce type de radiothérapie. La planification a été comparée au guide de la radiothérapie oncologique et des contraintes de dose dans les organes à risque pour les analyses dosimétriques. La radiothérapie était exclusive et a délivré une dose totale de 54 Gy par fractions de 2 Gy dans la tumeur primitive et 37 Gy par fractions de 1,4 Gy dans la totalité des ventricules. L’analyse dosimétrique a montré une diminution de la dose dans tout le cerveau, les lobes temporaux, les hippocampes, les cochlées et les nerfs optiques. Avec un suivi de 22 mois, il n’a été observé aucun échec et aucun événement indésirable n’a non plus été constaté pendant le traitement. La RCMI pour tumeur germinale pinéale peut épargner le circuit
∗ Corresponding author. E-mail address: [email protected] (A.L.F. Chan). http://dx.doi.org/10.1016/j.canrad.2016.02.007 1278-3218/© 2016 Société française de radiothérapie oncologique (SFRO). Published by Elsevier Masson SAS. All rights reserved.
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limbique, l’encéphale et les hippocampes. Elle permet de réduire la dose dans le cerveau sain, ce qui peut réduire les séquelles tardives neurocognitives de la radiothérapie crânienne. © 2016 Société française de radiothérapie oncologique (SFRO). Publié par Elsevier Masson SAS. Tous droits réservés.
1. Introduction Intracranial germinomas are rare primary central nervous system germ cell tumours that account for 2.5% to 4.4% of all paediatric central nervous system (CNS) tumours in Western countries [1–3]. In Asia, germ cell tumours of the central nervous system in children are common, representing 15 to 18% of all childhood CNS tumours [4,5]. The reported incidence rate at the largest hospital in Taipei was approximately 14%. The mean age of onset was approximately 10- to 12-year-old [6]. There are two main types of germ cell tumours: germinomas and non-germinomatous germ-cell tumours. Non-germinomatous germ cell tumours are more common in younger children and pure germinomas are more common among older patients. Treatment outcome of nongerminomatous germ cell tumours are worse than intracranial germinomas [7]. Radiotherapy is curative for pure germinoma. The standard dose is 45 to 50 Gy to the primary tumour, in combination with about 24 Gy of whole ventricular irradiation, the 5-year control rate was 88% [8]. The long-term radiotherapy-induced brain injury is raising significant concerns due to the high curability of many germ cell tumours and the large treatment volumes often used in these young patients [9,10]. Therefore, there are ongoing efforts to explore the feasibility of delivering reduced radiotherapy doses to patients with germ cell tumours and spare brain structure from irradiation. Standard intensity-modulated radiation therapy (IMRT) for whole ventricular irradiation has already been shown to spare a significant amount of normal central nervous tissue for patients with localized germ cell tumours as compared to whole brain irradiation using opposed lateral beams [11,12]. Whole brain irradiation can be associated with subacute and late decline in memory and other cognitive functions, which is likely to be caused by the damage to the neural stem cell compartment, limbic circuit and hippocampus [9,13,14]. Therefore, its use in different primary paediatric intracranial tumours has been limited [15,16]. In reducing the incidence and severity of late adverse cognitive effects, the idea of sparing of these critical structures using intensity-modulated radiation therapy with dose sculpting was suggested: the technique escalates the dose to the tumour and spares normal tissues. It has not been well studied in paediatric patients with intracranial tumour [17]. We thus examined the case of a patient with pineal germinoma treated with dose-sparing intensity-modulated radiation therapy and avoidance techniques in our institution and reviewed the literature regarding modern irradiation for localized germ cell tumours and the adverse events of neurocognitive dysfunction.
2. Clinical case After approval by the institutional review committee, the medical records of patients with a CNS germ cell tumour treated at our institution over a 2-year period were examined. A patient who received intensity-modulated radiotherapy with dose-sparing and avoidance techniques was identified and selected for study. The patient, age 16, had a pineal tumour in the third ventricle anterior to the pineal gland and marked dilation of the ventricle with obstructive hydrocephalus. Magnetic resonance (MR) imaging of the brain showed a 6 × 6 cm isointense pineal gland lesion on T1 and T2 with bright enhancement on contrast studies (Fig. 1). An
infratentorial supracerebellar approach was performed to remove the lesion. The patient received intensity-modulated radiotherapy (IMRT) in our department 1 week after surgery. The radiation oncologist used dose-sparing techniques with four phases of treatment planning via the dynamic IMRT to spare the limbic circuit, hippocampus, and neural stem cell compartment. The treatment planning target volume was contoured and varied by diagnosis using computed tomography simulation with a custom-made immobilization device. The planning target volume was generally consisted of the gross tumour as it was identified on imaging. For the primary tumour, the gross tumour volume was defined as the extent of disease at diagnosis. The clinical target volume was designed to allow 0.8 cm margin beyond the gross tumour volume to obtain the planning target volume in phase 1, and 1.2 cm margin beyond the residual tumour in phases 3 and 4 to obtain the planning target volume. For whole ventricular irradiation, the clinical target volume comprised bilateral ventricles with a 0.5-cm expansion to obtain the planning target volume. In this case, 6 MV photons were used. The planning objectives were delivered non-uniform dose to different target volume with minimizing the dose to critical organs at risk. The treatment delivery was on Clinac® iX linear accelerator (Varian). After four phases of radiotherapy, the follow-up MRI imaging revealed that the patient’s lesion was decreased from 5.17 cm to 2 cm (Fig. 2). The patient’s neurological symptoms remained stable; no optic neuropathy appeared throughout the radiation treatment courses. Unfortunately, he developed impaired recent memory 3 months after radiotherapy; as a result, he refused to receive a boost dose. The follow-up MRI imaging after 6 months revealed a dramatic reduction in the size of the germinoma (Fig. 3). The patient did not receive chemotherapy due to the diagnosis of a localized tumour and excellent response to radiotherapy. At 22 months follow-up, MRI imaging revealed no progression of the disease and the patient’s condition remained stable upon clinical evaluation. The calculation of ventricles dose was based on the patient’s neuroanatomy and required superimposing the radiation therapy isodose lines over the average anatomy. The total dose was 54 Gy delivered in 2.0 Gy fractions to the primary tumour and 37 Gy in 1.4 Gy fractions to whole ventricles using dose-sparing and avoidance techniques. The dose distribution is shown on Fig. 4. The germinoma located in the third ventricle was treated with multileaf dose-sparing intensity-modulated radiation therapy only. Table 1 compares the total dose constraints (standard Table 1 Whole ventricular radiotherapy of central nervous system germinoma: organs at risk dose constraints for sparing plans. Radiothérapie crânienne avec épargne de dose pour un germinome intracrânien : contraintes de dose dans les organes à risque. Standard organs at risk
Literature data
Current study
Eyes Lenses Optic nerves Optic chiasms Cochleae Brainstem Temporary lobe Hippocampus
Dmean < 25 Gy [18] Dmax < 6 Gy [19] Dmax < 54 Gy [20] Dmax < 55 Gy [20] Dmean < 35 Gy [21] Dmax < 54 Gy [22] Dmax < 30 Gy [23] Dmean < 30 Gy [24]
Dmean = 10.2 Gy Dmax = 5.02 Gy Dmax = 52 Gy Dmax = 50 Gy Dmean = 19.6 Gy Dmax = 50.6 Gy Dmax = 30 Gy Dmean = 50 Gy
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Fig. 1. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: preoperative T1-weighted magnetic resonance images with gadolinium showing a heterogenously enhancing lesion of the pineal region. A. Axial view. B. Coronal view. C. Sagittal view. Patient de 16 ans atteint d’un germinome intracrânien localisé : imagerie par résonance magnétique préopératoire (séquence T1 avec gadolinium) montrant une lésion hétérogène de la région pinéale. A. Coupe axiale. B. Coupe coronaire. C. Coupe sagittale.
and sparing) for critical structures using dose-sparing intensitymodulated radiation therapy techniques with the literature recommendations. This technique was able to deliver a lower mean dose (DM ) or maximum dose (Dmax) to all structures atrisk, including eyes, lenses, optic nerves, optic chiasms, cochleae, brainstem, hippocampal and temporary lobe. The patient did not have any severe toxicity during radiotherapy. However, early delayed mildly impaired recent memory appeared 3 months post-radiation. He was tested using Wechsler Adult Intelligence Scale (WAIS III) [25]. The Full Scale (overall) IQ score was 69, which was slightly below the borderline IQ score (70–79) and his Working Memory Index was in the average range. The psychologist suggested that the impaired recent memory may probably be reversed after rehabilitation. The patient is currently alive with no evidence of local recurrence for 22 months follow-up.
3. Discussion
Fig. 2. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: magnetic resonance of image of the tumour after four phases of intensity-modulated radiation therapy with dose-sparing and avoidance technique. Patient de 16 ans atteint d’un germinome intracrânien localisé : IRM après 4 cures de radiothérapie avec modulation d’intensité avec économie de dose et épargne de structures.
Pineal germinoma is rare disease and exquisitely radiosensitive. Most previous case reports focused on treatment and survival. Studies on radiotherapy dose constraints to organs at risk and their effect on patients’ intelligence quotient are rare. We thus examined the patient and reviewed literature regarding radiotherapy, organs at risk dose constraints and neurocognitive dysfunction. According to the published review, radiation-induced brain injury is classified as acute, early delayed, and late delayed injury. Acute brain injury is rare with modern radiation therapy techniques
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Fig. 3. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: 6 months postradiotherapy follow-up T1-weighted magnetic resonance images with gadolinium showing a heterogenously enhancing lesion of the pineal region. A. Axial view. B. Coronal view. C. Sagittal view. Patient de 16 ans atteint d’un germinome intracrânien localisé : imagerie par résonance magnétique 6 mois après la radiothérapie avec modulation d’intensité (RCMI) avec économie de dose et épargne de structures (séquence T1 avec gadolinium) montrant une lésion hétérogène de la région pinéale. A. Coupe axiale. B. Coupe coronaire. C. Coupe sagittale.
and will appear within days to weeks after whole brain irradiation. Early delayed brain injury can involve transient demyelination with somnolence and occurs 1–6 months post-irradiation. Both of these early injuries are normally reversible and resolve spontaneously [26]. However, late delayed brain injury is irreversible and progressive, due to vascular abnormalities, demyelination, and white matter necrosis [27]. It usually occurred over 6 months after radiation therapy. Many of the late adverse cognitive effects of cranial irradiation may associate with damage to the neuron stem cell compartment, limbic circuit and hippocampus. Sparing of these critical structures dosimetrically may reduce the incidence and severity of late adverse neurocognitive adverse events in children receiving the treatment [15,17]. Furthermore, the dose administered may directly result in late adverse neurocognitive dysfunction, which are expressed as a decline in overall IQ [14,28,29]. With respect to the recently published radiation oncologist’s guide for organs at risk in brain and the dose constraints in adults and children, we compared the dose constraints for intracranial organs at risk in our patient with the literature recommendations. The dose for the organs at risk was within the range proposed in the literature [30]. However, the dose constraint for the hippocampus was slightly higher than the literature recommendations. The reasons were the size of the tumour, critical condition of the patient and the location of tumour near the hippocampus. Some study proposed that the clinical target volume crossing the midline of the brain was not feasible in order to spare the hippocampus; this could be overcome by a steep dose gradient of intensity-modulated radiation therapy [24]. There is no good evidence of the clinical tolerance of the hippocampus to radiation. It likely depends on patient age,
total dose, dose per fraction and dose distributions in the structure. Armstrong et al. indicated that memory impairment was associated with a dose of more than 30 Gy to the temporal lobe in children [23]. Other factors, such as direct and indirect tumour effects, seizures, medication, and oncological treatment, may also affect the neurocognitive outcome [31]. Because the neurocognitive dysfunction can have a large impact on self-care, social and professional functioning as well as health-related quality of life, we need to minimize the effect of other risk factors on the impaired memory. In the past few decades, patients with localized germinomas received craniospinal irradiation at a dose of 36 Gy, with a total of 50 to 54 Gy including a boost delivered to the primary tumour. Studies have indicated that whole-brain or whole-ventricle irradiation in patients with localized germinomas could replace craniospinal irradiation based on the outcome of a spinal failure rate of less than 10% [24,30,32]. Afterwards, several studies reported that whole brain irradiation caused clinically significant late neurocognitive effects, such as subacute and late decline in memory, hearing loss, severe global cognitive deficiencies, and neuro-endocrine deficit as well as endocrine effects [33–36]. Thus, the idea of sparing the organs at risk by adjusting the dosimetry in intensity-modulated radiotherapy was suggested. However, some studies raised concern about the possibility of delivering more total monitor units (MU) at a given dose, creating a greater integral dose delivered to the patient during cranial intensity-modulated radiation therapy [37–39]. Other dosimetric studies found that reducing the internal dosimetry may reduce the risk of late second malignancies and cognitive dysfunction, but this hypothesis has not been conclusively proven [37,38].
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Fig. 4. Sixteen-year-old patient with a localized intracranial germinoma in the third ventricle anterior to the pineal gland: dose distribution of planning target volume in four courses of intensity-modulated radiation therapy with dose-sparing and avoidance technique. Summed dose distributions are represented as colourwash. A. Doses from 9 Gy (blue) to 10 Gy and above (red) for course 1. B. Doses from 14.4 Gy (blue) to 18 Gy and above (red) for course 2. C. From 14.4 Gy (blue) to 18 Gy and above (red) for course 3. D. Doses from 6.4 Gy (blue) to 8.0 Gy and above (red) for course 4. Patient de 16 ans atteint d’un germinome intracrânien localisé : distribution de doses de radiothérapie avec modulation d’intensité (RCMI) avec économie de dose et épargne de structures. A. Cure 1. B. Cure 2. C. Cure 3. D. Cure 4.
Another approach to normal organ sparing in cranial radiotherapy for paediatric pineal germinoma is the volumetric modulated arc therapy. Investigators have reported that this technique may provide the advantages of sparing normal tissues and reducing the treatment delivery time compared with conventional static field intensity-modulated radiotherapy, which may result in improvements in the IQ of children with intracranial pure germinomas [40]. In addition, Qi et al. reported that decreasing the mean temporal lobe dose to 11.4–13.1 Gy in patients who are 10 years of age may increase the IQ by 7 points at 5 years after volumetric modulated arc therapy [41]. Another modern cranial radiotherapy technique for paediatric brain tumours, with normal tissue sparing, is proton radiotherapy [42–54]. Investigators at several institutions have performed dosimetry studies comparing the dose delivered to normal tissues with proton therapy, intensity-modulated radiation therapy and/or conventional radiotherapy. They found that proton therapy had consistently lower doses to critical normal tissues and integral doses to the body compared with intensity-modulated radiation
therapy. A reduction of the integral dose is expected to result in a lower rate of secondary tumour induction after treatment [51–54]. Afterwards, investigators have devoted their effort to determining whether proton radiotherapy has clinical advantages over photon radiotherapy for dose characteristics and their relationship to cognitive function. One study modeled the dose characteristics of both modalities to critical normal tissue volumes using data from patients with four types of childhood brain tumours. Comparing protons to photons for the effects on the cognitive outcomes (estimated IQ score), relatively small critical normal tissue volumes, such as the cochlea and hypothalamus, may be spared from radiation exposure, but larger normal tissue volumes such as the supratentorial brain or temporal lobes receive less of the low and intermediate doses [55]. These differences resulted in clinically significant higher IQ scores for patients with intracranial tumours. Later, a clinical study that was only presented at the American Society of Clinical Oncology (ASCO) 2013 Meeting discussed the IQ change in paediatric patients within 3 years of radiation therapy for brain tumour treated with proton beams versus photons.
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In over 3 years follow-up, children who received conventional photon radiation lost an average of 10.3 IQ points per year compared to only 0.1 IQ point lost per year in the proton group. The age of the patients did not affect the result (assuming that younger patients are more severely affected). They concluded that there is an advantage in terms of the cognitive toxicity as measured by IQ in patients receiving partial brain proton radiation. However, no difference in IQ was demonstrated between proton and photon treatment for patients receiving craniospinal irradiation, which treats the entire brain [56]. Proton therapy is very expensive and is only available in a few centers in the United States and is not used in our country. As a result, more clinical reports from the clinical setting are needed before we are able to make a conclusion about its benefit regarding the cognitive function decline of children with intracranial tumours.
[12] [13]
[14]
[15] [16]
[17] [18]
4. Conclusion [19]
The physical dose to the critical structures, such as the limbic circuit, hippocampus, and neural stem cell compartment can be dosimetrically reduced during the administration of partial brain radiotherapy for treating different types of paediatric primary intracranial tumours. However, such a treatment does not fully comply with the dosimetric coverage of the treatment target or dosimetric sparing of other critical normal structures including the pituitary-hypothalamic axis. The organs at risk dose constraints and sparing in our study were within the standard ranges reported in the literature. Therefore, this approach used in our study should reduce the late adverse cognitive effects of radiotherapy in children, but further evaluation in a prospective clinical trial that includes a formal evaluation of the neurocognitive outcomes is needed. Disclosure of interest
[20]
[21]
[22]
[23]
[24]
[25]
The authors declare that they have no competing interest. [26]
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