Pediatric Central Nervous System Tumors

Published on 09/04/2015 by admin

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53 Pediatric Central Nervous System Tumors

Epidemiology and Etiology

Pediatric central nervous system (CNS) tumors account for nearly 20% of all childhood neoplasms, exceeded in incidence only by leukemia, and are the leading cause of cancer death in childhood. Incidence is about 1 per 30,000 children each year.1 Although roughly two thirds of all patients are alive 5 years after diagnosis, survivors suffer from neurologic, cognitive, psychologic, and endocrinologic sequelae of both the disease and its treatment. Boys and girls are equally affected, except for medulloblastoma, germ cell tumors, and ependymoma, in which more boys are affected.24 Tumors can rarely appear in association with genetic syndromes (Table 53-1), but more often appear to arise spontaneously. The tumors are sometimes found to harbor somatic genetic changes, such as mutations in single genes in atypical teratoid rhabdoid tumor (ATRT; INI1) or high-grade astrocytoma (p53), aberrant gene expression pathways in medulloblastoma (SHH, Wnt, and Notch), and chromosomal losses or gains in high-grade astrocytoma (10), medulloblastoma (17p, 8q24), ependymoma (22), and germ cell tumors (12p).5 Some tumors, do not have a consistent genetic or chromosomal abnormality. Environmental exposures, aside from radiation, have been difficult to associate consistently with development of any CNS tumor. High-dose ionizing radiation clearly increases the risk of developing a meningioma or malignant glioma.6

Table 53-1 Syndromes Associated With Pediatric Central Nervous System Tumors

Syndrome Associated CNS Tumors
Basal cell nevus (Gorlin) Medulloblastoma
Cowden Dysplastic gangliocytoma of the cerebellum (Lhermitte-Duclos)
Li-Fraumeni Astrocytomas, medulloblastoma, choroid plexus tumors
Neurofibromatosis 1 Pilocytic astrocytoma, malignant peripheral nerve sheath tumor
Neurofibromatosis 2 Schwannoma, meningioma, ependymoma
Rhabdoid tumor predisposition Atypical teratoid rhabdoid tumor
Tuberous sclerosis Subependymal giant cell astrocytoma
Turcot Medulloblastoma, glioblastoma
von Hippel-Lindau Hemangioblastoma

CNS, Central nervous system.

Anatomy

In contrast to adults, the majority of pediatric CNS tumors are infratentorial (i.e., cerebellum, brain stem, and fourth ventricle) and primary in origin. The location of the tumor may be related to cause; for example, germ cell tumors are likely to develop in the midline periventricular region after abnormal migration of stem cells, and medulloblastoma may arise in the cerebellar external granule cell layer. Tumor location also dictates presenting symptoms (see Clinical Presentations, in the following text). For example, intrasellar or parasellar lesions may produce hormonal and visual abnormalities. Anatomy likewise plays a key role in determination of treatment and prognosis. For instance, pilocytic astrocytomas of the cerebrum or cerebellum are often completely resected and fully cured, whereas those in the diencephalon or brainstem can less easily be resected and require radiotherapy or chemotherapy. Patients with ependymoma, or embryonal and germ cell tumors involving the ventricles, may require more extensive postoperative irradiation as the circulation of the cerebrospinal fluid (CSF) is an important route for tumor dissemination.

Pathologic Conditions

Whereas most adult primary brain tumors are high-grade astrocytomas, the heterogeneity of histologic diagnoses in children is striking. Photomicrographs of the most common tumors, pilocytic astrocytoma, medulloblastoma, ependymoma, and germinoma, are shown in Fig. 53-1 through Fig. 53-4. Historically, brain tumors have been identified by correlative normal cells of putative origin: astrocytes, neurons, and oligodendroglia. However, biologic proof of such derivation is wanting.7 There is only minimal correlation between the incidence of particular histologic types of cancer in the brain and the absolute number of potential precursor cells in that region.8

image

FIGURE 53-1 • Astrocytoma. A, Grade I; B, grade II; C, grade III.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

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FIGURE 53-2 • Ependymoma.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

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FIGURE 53-3 • Medulloblastoma: Homer-Wright rosettes.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

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FIGURE 53-4 • Germinoma.

(Courtesy Dr. Richard Davis, University of California–San Francisco.)

At present, the most recent classification by the World Health Organization (WHO) sorts CNS tumors as follows: tumors of neuroepithelial tissue, tumors of cranial and paraspinal nerves, tumors of the meninges, tumors of the sellar region, lymphomas and hematopoietic neoplasms, germ cell tumors, or metastatic tumors.5 Neuroepithelial tumors can be subtyped further into astrocytic, oligodendroglial, oligoastrocytic, ependymal, choroid plexus, neuronal, pineal, or embryonal tumors. Although the majority of pediatric brain tumors are reported to be glial in origin (e.g., pilocytic and diffuse astrocytomas), children also display a diversity of tumors seldom or never seen in adults: medulloblastoma, choroid plexus papilloma and carcinoma, ganglioglioma, astroblastoma, pleomorphic xanthoastrocytoma (PXA), and dysembryoplastic neuroepithelial tumor (DNT). Previously, medulloblastoma and other embryonal neoplasms were all lumped together as primitive neuroectodermal tumors (PNETs), but now are known to be biologically distinct as medulloblastoma, atypical teratoid rhabdoid tumor, pineoblastoma, ependymoblastoma, and other supratentorial PNETs.9 Certain adult tumors, such as oligodendroglioma, oligoastrocytoma, and well-differentiated astrocytoma, are relatively uncommon in children, and such diagnoses should be questioned for accuracy. For example, DNT is commonly mistaken as oligodendroglioma and PXA sometimes misinterpreted as glioblastoma.10 Calcification and cyst formation are representative of a chronic course and typically indicative of more indolent tumors, such as craniopharyngioma, epidermoid tumor, ganglioglioma, and pilocytic astrocytoma. For the pediatric patient with a CNS tumor, consultation with a neuropathologist skilled in the range of childhood brain tumor diagnoses is highly warranted, especially because diagnosis determines treatment planning.

Tumor grade less often determines treatment and outcome, compared with adults. Although the WHO employs a traditional I to IV scale of increasing anaplasia, some tumors have no variability in grade, or, for some, tumor grade may not distinguish outcome or be mistakenly reassuring of outcome. All medulloblastomas are recorded as grade IV, although there is now a movement to subclassify these neoplasms based on anaplasia, desmoplasia, and nodularity.10 Ependymomas are graded only as well-differentiated (WHO grade II) or anaplastic (WHO grade III), although numerous studies have failed to show a difference in outcome.11 All pilocytic astrocytomas are graded as I. Nevertheless, suprasellar and other midline pilocytic tumors often require chemotherapy or irradiation and result sometimes in death, unlike the grade I cerebral and cerebellar gangliogliomas and pilocytic astrocytomas cured simply by surgical removal. The majority of astrocytomas in children are pilocytic astrocytomas (WHO grade I) and do not undergo anaplastic transformation, in distinction to diffuse astrocytomas (well-differentiated astrocytoma [WHO II], anaplastic astrocytoma [WHO III], and glioblastoma multiforme [WHO IV]), more commonly seen in adults. Recently the diagnosis of pilomyxoid astrocytoma has been adopted by the WHO as a grade II, more aggressive variant of pilocytic astrocytoma.5

Clinical Presentations

The presenting symptoms and signs of intracranial lesions in the developing child vary, depending on tumor location, grade or growth rate, and age at presentation (Table 53-2). These factors also influence the time to diagnosis. A long prodrome over months to years often indicates a more favorable histology and grade, whereas a short prodrome of just weeks or months may indicate an aggressive neoplasm. Symptoms and signs may be generalized (e.g., developmental delay, irritability, growth failure), or secondary to an increase in intracranial pressure (e.g., headache, vomiting, papilledema). If the sutures have not yet fused, toddlers often manifest increased intracranial pressure chronically by macrocephaly with an increased head circumference, and sometimes split cranial sutures or tense, open anterior fontanelle.

Table 53-2 Frequent Symptoms and Signs of Pediatric Central Nervous System Tumors

Infants Children
Failure to thrive Headaches
Bulging fontanelles Nausea and vomiting
Arrested development Lethargy
Head nodding Ataxia
Nystagmus Cranial nerve palsies
Seizures
Visual field abnormalities

Some symptoms and signs are more specific and localizing (e.g., change in handedness, focal motor or sensory deficit, ataxia, optic nerve atrophy). Infratentorial tumors present most often with headache, vomiting, ataxia, and strabismus. Supratentorial lesions may be heralded by seizures and focal deficits. Involvement of the optic nerves, chiasm, or tracts produces visual field deficits and loss of visual acuity. In a child younger than 2 years of age, developmental delays and “failure to thrive” are seen with diencephalic lesions. Involvement of the hypothalamus or sellar region may produce endocrinologic aberrations (e.g., diabetes insipidus, abnormal weight gain, precocious puberty, amenorrhea, acromegaly, and galactorrhea). Pineal tumors may cause pressure on the tectum, resulting in Parinaud syndrome (i.e., upgaze paralysis, sluggish pupillary responses, and abnormal convergence). Brainstem lesions typically produce cranial nerve palsies and motor, sensory, and cerebellar deficits.

Diagnostic and Staging Studies

With the exception of germ cell tumors, there are presently no biochemical markers for brain tumors that can be evaluated from the blood. Germinomas may produce low levels of beta-human chorionic gonadotropin in some cases, but its elevated presence or that of any alpha fetoprotein is always indicative of choriocarcinoma or endothermal sinus (yolk sac) tumor, respectively, or mixed nongerminomatous germ cell tumors (NGGCTs). CSF should be evaluated for cellular metastases in all patients with medulloblastoma and other embryonal tumors, including ATRTs, along with ependymoma and germ cell tumors. Cytology and biochemical studies of the CSF should be performed 10 to 14 days after surgical extirpation to avoid misinterpretation by postoperative cellular debris. Patients with lesions involving the optic nerve, chiasm, or pituitary gland should undergo formal ophthalmologic examination and visual-field testing after surgery and before radiation therapy. Furthermore, all lesions in the region of the hypothalamus or pituitary require careful pretreatment as well as post-treatment evaluation of hormonal function. Pediatric patients who undergo cranial irradiation should be evaluated for cognitive function before and after treatment. Documentation of growth and hearing by audiometry should be performed as well. In addition to these studies, the emotional needs of the family, parents, and siblings, as well as the patient, should not be overlooked.

Dramatic improvement in neuroimaging during the past 2 decades have resulted in major advances in diagnosis and targeting of therapy for lesions of the CNS. Young children often require sedation or general anesthesia for any study, but magnetic resonance imaging (MRI) yields the best definition of parenchymal lesions, as well as clear views of the posterior and middle cranial fossa. MRI has replaced myelography for evaluation of the spine, and is therefore the modality of choice for evaluation of the craniospinal axis. Preoperative MRI with gadolinium contrast should include images of the brain, and when there is a posterior fossa tumor or a supratentorial tumor suspected to be embryonal or germ cell, the entire neuraxis should be imaged. Postoperative MRI scan with gadolinium contrast needs to be performed within 48 hours of surgery to evaluate the extent of resection, prior to the onset of postoperative edema and potentially artifactual enhancement. All these MRI data are of critical importance for planning further treatment and for defining the gross tumor volume (GTV) and the clinical treatment volume. Following radiotherapy, the results of treatment are followed by routine interval MRI scans, and in cases of ambiguous findings, MRI techniques such as spectroscopy and diffusion-weighted imaging, or positron emission tomography (PET), may be used to distinguish between recurrent tumor and treatment effects, such as radiation necrosis. Figure 53-5 demonstrates the radiographic appearance of the common tumors by MRI.

Staging System

In contrast to staging systems for other types of cancer, CNS tumors are staged mostly by extent of metastasis using the M scoring of the Chang staging system (Table 53-3), with some consideration of extent of resection.13 Tumor extent at diagnosis by the Chang T score is no longer used. Indeed, T3B brainstem invasion in medulloblastoma was once considered to place a patient at higher risk of recurrence, but has now been shown not to be predictive.14 At present, medulloblastoma in children ages 3 and older is risk-stratified as average- and high-risk. Less than total resection (>1.5 cm2 residual), any metastasis (M+), or severe anaplasia on the histologic specimen place a child into high-risk status. Only complete resection, no metastasis, and absence of diffuse anaplasia are consistent with average risk. For other pediatric CNS tumors, histologic type and M-stage largely indicate risk and dictate dosage and volume of radiotherapy, whereas extent of removal merits therapy based only on the histologic type.

Table 53-3 Chang Staging System

T1 Tumor <3 cm
T2 Tumor >3 cm
T3A Extension into the aqueduct of foramen
T3B Invasion of brain stem
T4 Midbrain, third ventricle, or upper cord involved
M0 No metastasis
M1 Microscopic cerebrospinal fluid involvement
M2 Gross seeding of third ventricle
M3 Gross seeding of cord
M4 Extracentral nervous system metastasis

Standard Therapeutic Approaches

Pediatric brain tumors require initial surgical evaluation in almost all cases. During the past 20 years, the availability and resolution of MRI has improved the ability to diagnose and localize CNS tumors, thereby decreasing postoperative morbidity. Surgical intervention provides a histologic diagnosis and offers therapeutic benefit by tumor debulking or removal. In selected cases, especially when the lesion is inaccessible, computed tomography (CT) or MRI-guided stereotactic biopsy can limit the morbidity of obtaining a tissue diagnosis. Endoscopy can also be successfully employed to take biopsy samples of periventricular tumors under direct visualization. Endoscopy can also be used sometimes to perform a third ventriculostomy, rather than place a ventriculoperitoneal shunt, and redirecting CSF flow while avoiding shunt dependency. Should the normal CSF pathways be severely compromised, children may nonetheless require CSF diversion via a ventriculoperitoneal or ventriculoatrial shunt to relieve obstructive hydrocephalus.

Functional mapping to distinguish the motor and sensory cortex permits the identification of critical brain structures to be avoided. In addition, stereotactic surgery and techniques using handheld, computer-guided instruments offers the opportunity to localize the surgical procedure with much greater accuracy than was previously possible. Surgical resection using ultrasonic aspirators improves the probability of achieving a gross total resection and decreases the risk of damage to normal tissues.

The benefit of performing maximal debulking of the tumor mass safely should be sought, because it improves prognosis and limits adjuvant therapy.15 Only for germ cell tumors has extent of removal been shown not to influence outcome.16 In some instances, surgical resection or biopsy is not performed, namely some optic pathway gliomas (i.e., pilocytic astrocytomas), diffuse intrinsic pontine gliomas, and some germ cell tumors diagnosed by tumor markers. Diffuse intrinsic pontine gliomas are often diagnosed simply by radiographic appearance on MRI of a ventral pontine tumor engulfing the basilar artery in a child with strabismus, ataxia, and weakness over just weeks or several months. Elevated serum or CSF alpha-fetoprotein in the setting of a sellar or pineal tumor is considered diagnostic of an NGGCT, and some individuals consider an elevated serum or CSF beta-human chorionic gonadotropin of less than 50 IU/L without elevation of alpha-fetoprotein diagnostic of germinoma. Except in very young children, incomplete surgical resection of most high-grade malignancies requires postoperative radiotherapy.

Chemotherapy provides in some children the opportunity to delay radiation therapy until older or to augment the survival benefit of radiation alone, or in some cases allows reductions in volumes or dosages of radiation. Whether based on prospective, randomized clinical trials; single-arm prospective studies; or parallels drawn from adult experiences; the modern era has seen chemotherapy incorporated into the treatment of most pediatric brain tumors.

Radiotherapy is a key component of treatment for most pediatric CNS tumors. Although planning techniques and the ability to localize tumor volumes have improved significantly in recent years, it is difficult to correlate this progress with improvements in survival. Likewise, it has been difficult to prove any benefit from altered fractionation schemes that have come from radiobiologic studies. In contrast, recent studies have suggested that sophisticated treatment planning and sparing of normal tissues have perhaps mitigated neurocognitive sequelae associated with radiation therapy to the young brain (see Toxicity of Radiation Therapy, in the following text).

Radiotherapy of childhood brain tumors should be performed at centers with dedicated pediatric oncology departments. Although radiation therapy plays a key role in the treatment of CNS tumors, delivery of adequate therapy must always be balanced against potential treatment-related toxicity. Both biologic and physical techniques can maximize the therapeutic ratio of radiation, thus enhancing tumor kill while protecting normal tissues. Precise planning and delivery of radiation have evolved rapidly in the past decade.

Improved imaging technology, specifically MRI and CT, and biologic, metabolic imaging such as PET, have improved delineation of tumor and surrounding critical structures. Novel techniques capitalize on an improved definition of tumor volumes, allowing clinicians to decrease the dosages delivered to critical structures while maintaining or increasing the dose to tumor. The advent of other technical advances such as multileaf collimation, digitally reconstructed radiographs, and electronic portal imaging have contributed to the integration of conformal radiation delivery. Intensity-modulated radiation therapy (IMRT) has the potential to reduce morbidity (e.g., spare the inner ear in posterior fossa treatment).

CT images are analyzed jointly by radiation oncologists, diagnostic radiologists, and occasionally by other treating clinicians, such as pediatric oncologists and pediatric neurosurgeons. The treatment volume is dictated by the natural history of the tumor. GTV is defined by physical examination and imaging studies, and encompasses the macroscopic extent of the tumor, as defined by preoperative MRI contrast and fluid-attenuation image recovery (FLAIR) MRI images. Clinical target volume (CTV) contains both the GTV and areas at risk for microscopic spread of disease. Planning target volume (PTV) is defined as the CTV surrounded by adequate margin to account for variation in patient position, organ motion, and other movement.

Once target volumes and critical structures are defined, beam geometry and weighting are defined and dose distribution is calculated. Selection of beam angles can be done by referencing axial images or by using beam’s-eye view (BEV). BEV allows visualization of the relationship of tumor volumes to the volumes of critical normal tissues as if looking from the origin of the beam. This allows beam angles and beam shaping to be selected more intelligently. Once an initial plan has been developed, the resulting dose distributions are calculated and evaluated by the clinician. The plan can then be altered to improve on initial results, if necessary. The beam directions as well as their relative weights and shapes are modified finally to optimize the three-dimensional (3-D) plan.

The last decade has seen rapid development of novel technical approaches to radiotherapy and its application to pediatric CNS malignancies. These include 3-D conformal radiation therapy (CRT), IMRT, proton-beam radiotherapy, intraoperative radiotherapy, radiosurgery, and temporary or permanent interstitial brachytherapy.

Interstitial brachytherapy allows for the delivery of high doses of radiation to a tumor region. One retrospective study reports the largest series of pediatric brain tumors treated with iodine-125 (I-125) brachytherapy.17 Twenty-eight children were treated with temporary, high-activity 125I brachytherapy for recurrent or persistent supratentorial tumors. The study is most useful in its documentation of acute and late toxicities. No grade 3 or grade 4 acute or late toxicities occurred. However, 22 patients (79% of 28 total patients) required at least one repeat operation following brachytherapy, and 17 of these 22 patients had evidence of necrosis in the resected specimen. Furthermore, little improvement was found compared with conventional methods.

Proton-beam radiotherapy has emerged as an exciting modality that may reduce long-term toxicities of radiation. Physical properties of proton beams differentiate them from photon beams and offer potentially superior dose distributions. Salient among these physical characteristics are a finite range in tissue corresponding to the energy of the incident beam and a sharply defined lateral beam edge that together produce a steeper falloff dose than can be achieved with photon-beam radiotherapy. These advantages must be weighed against proton beam contamination by neutrons that may contribute significantly to risks of second malignancies, particularly in children. Passive scatter techniques, currently used in the United States, are likely to be replaced in the future by active scanning approaches that offer better conformity of highest doses, potentially lower doses to normal structures, and reduced beam contamination by neutrons.

To date, outcome data with use of proton beam radiotherapy for CNS tumors is limited, and advocated mostly on theoretical grounds. Merchant and colleagues compared models of photon and proton dose characteristics and their predicted relationship to cognitive function in children treated for brain tumors.18 They found that small critical normal structures such as the cochlea and hypothalamus, which were anatomically separated from the PTV, received substantially less radiation using protons compared with photons. Proton radiotherapy would therefore be expected to reduce the risks of endocrine deficits and hearing loss. In addition, protons decreased the low (0-20 Gy) and intermediate (20-40 Gy) doses to the cerebrum in patients receiving focal radiation. Using longitudinal models of radiation dose-cognitive effects, their data indicate that proton radiotherapy would mitigate intellectual decline from radiation treatment.

The benefit of proton beam radiotherapy in children may be best exemplified by its use for craniospinal irradiation (CSI). Comparisons of proton beam, conventional 3-D radiation, and IMRT for treatment of the posterior fossa and spinal column suggest superior sparing of normal structures by protons. In particular, protons are likely to mitigate long-term toxicities related to hearing, endocrine, and cardiac functions. For example, 90% of the cochlea received 101.2% of posterior fossa boost dose with conventional radiation techniques, 33.4% with IMRT, and only 2.4% with protons. Similarly, 50% of the heart received 72.2%, 29.5%, and 0.5% of the posterior fossa boost dose for conventional x-ray, IMRT, and protons, respectively.19

Toxicity of Radiation Therapy

A wide range of potential toxicities complicates the implementation of radiation therapy in the treatment of tumors of the craniospinal axis. These toxicities can be severe and debilitating, particularly in pediatric patients. Care should be taken to minimize these effects. Treatment of intracranial tumors can result in damage to the eye, ear structures, brain, and hypothalamic-pituitary axis, as well as growth abnormalities. Treatment of the spine can result in growth deficits and damage to the spinal cord. Specific potential acute side effects of radiation to the CNS include epilation, skin reactions, otitis, hematopoietic depression, and somnolence. Specific late toxicities of such radiation include radionecrosis, myelopathy, leukoencephalopathy, vascular injury, neuropsychologic sequelae, endocrine dysfunction, bone and tooth abnormalities, ocular complications, ototoxicity, and induction of second primary tumors. Table 53-4 delineates the radiation doses associated with late toxicities that may result from radiation therapy to the CNS.

Table 53-4 Late Toxicities of Central Nervous System Irradiation

Structure Late Effect Threshold Dose
Spinal cord Chronic progressive myelitis 45 Gy
Brain Radiation necrosis
Intellectual deficits
54 Gy
12-18 Gy
Lens of eye Cataract formation 8 Gy
Retina Radiation retinopathy 45 Gy
Optic nerve Optic neuritis 50 Gy
Inner ear Sensorineural hearing loss 40-50 Gy

Brain

Acute reactions during radiation therapy, thought to result from disruption of the blood-brain barrier, are uncommon. However, there are reports of edema following single conventional fractions.22 Clinically, apparent acute changes are more common with hypofractionated doses, such as are used in radiosurgery.23 Subacute reactions are more common and are thought to be due to transient demyelination.24 These effects typically occur within the first few months following radiation and usually resolve within 6 to 9 months. Cranial nerve palsies have also been reported.25 Severe subacute effects such as rapidly progressive ataxia are rarer and are generally associated with fractions larger than 2.0 Gy and total doses larger than 50 Gy.26

The late effects of radiation are primarily due to radiation necrosis. Symptoms are related to the neuroanatomic location of necrosis (sensory, motor, speech/receptive deficits, seizures) and may, in addition, be due to increased intracranial pressure. Focal necrosis is uncommon with doses less than 60 Gy given with conventional fractionation.27

Large-volume radiation therapy can result in diffuse white matter changes. Clinically, these can result in lassitude, personality change, or neurocognitive deficits. Multiple studies have examined the effect of whole-brain radiation therapy on intellect in patients treated for leukemia. Radiation-associated depression in intelligence quotient (IQ) has been noted by a number of authors.28,29 Halberg and colleagues30 compared three groups of patients. The first group received 18 Gy (1.8 Gy per daily fraction) cranial irradiation, and the second received 24 Gy cranial irradiation. The third group consisted of other oncology patients who did not receive cranial irradiation. Lower IQ scores were noted in the group receiving 24 Gy. High-dose methotrexate and female sex appear to increase risk of intellectual deficits.31,32 The effects of cranial irradiation are also more severe the younger the child. Intellectual deficits resulting from radiation most commonly result in difficulty acquiring new knowledge, decreased processing speed, and memory deficits (most frequently short-term).33

Studies of children irradiated for primary brain tumors have also shown intellectual deficits. Effects of radiation are more difficult to evaluate in this setting, as most of these patients also have had surgical resection. However, as with acute lymphoblastic leukemia patients, younger age appears to result in a higher rate of neurocognitive deficits. Larger fields and higher doses also appear to cause higher rates of toxicity.

Pediatric CNS tumors require a multimodality approach, including surgery, chemotherapy, and radiation. Attribution of toxicities such as neurocognitive decline to a single modality, most often radiotherapy, is not supported by the literature. Kiehna and colleagues34 conducted a prospective trial of 120 children and young adults to evaluate neurocognitive aptitudes before, during, and after CRT. In this comprehensive study from St. Jude Children’s Research Hospital, investigators used the Conners continuous performance test to measure selective attention, sustained attention, impulsivity, and reaction time. During a 6- to 7-week course of CRT, children exhibited problems with cognitive processing, attention, and reaction times. Overall attention indices worsened during CRT, with significant risk factors including progression of symptoms prior to CRT, young age, and diagnoses of craniopharyngioma or low-grade astrocytoma.34

After completion of CRT, serial assessments were performed at regular intervals and revealed that overall attentional capacity remained relatively stable over time, with some important exceptions. Specifically, the data documented significant worsening of inattentiveness and deterioration of global attention deficits that were particularly associated with craniopharyngiomas, optic pathway and diencephalic tumors, supratentorial tumors, subtotal resection, more than two surgeries, and the presence of an Ommaya reservoir. Analyses by tumor histology were particularly instructive, as inattentiveness steadily increased in those with incompletely resected craniopharyngiomas and optic pathway gliomas, and conversely, limited effects were observed in ependymoma patients despite their significantly younger age. Taken together, these results suggest that the tumor itself contributes significantly to such cognitive decline, and CRT is clearly not the sole or central culprit. Rather, acquired attentional disorders during and following CRT are due to a multitude of insults and are associated with tumor type, location, comorbidities, and surgical resections.

The group at St. Jude Children’s Research Hospital has also evaluated academic achievement and verbal memory performance in children after CRT. Factors including female gender, number of surgeries, and hydrocephalus, predicted worse verbal memory performance at baseline. Of key importance, however, verbal memory stabilized and improved over time, rather than declined.35 In a similar study from the same group, serial assessments of academic achievement revealed that reading was the aptitude most susceptible to decline after CRT, whereas math and spelling skills remained stable.36

Ear

Radiation-induced sensorineural hearing loss is dose-dependent and is more severe in younger patients. Hearing loss can result from doses greater than 40 to 50 Gy, usually developing within 6 to 12 months of treatment.37 High-frequency hearing loss is seen in 25% to 50% of patients who received greater than 50 to 60 Gy to inner ear structures.3840 Hearing loss is typically attributed to radiation changes induced in the cochlea and vasculature. Ototoxicity related to cisplatinum chemotherapy is well documented.41,42 Cranial irradiation before or concurrent with cisplatinum chemotherapy enhances ototoxicity.41,43 Chronic otitis can also develop following radiation therapy because of obstruction of the eustachian canal.

Endocrine

Whole-cranial irradiation or more focal radiation that includes the hypothalamic-pituitary axis can result in neuroendocrine abnormalities. The neuroendocrine complications that can result from radiation therapy are summarized in Table 53-5. Growth hormone (GH) production appears to be the most prone to disruption by radiation therapy. GH deficiency worsens over time and may follow radiation doses as low as 12 Gy.44 This appears to be a result of decreased GH-releasing hormone (GH-RH) in the hypothalamus, as GH deficiency is seen in patients undergoing hypothalamic radiation with pituitary sparing. Clinically, GH deficiency can result in short stature, bone loss, and metabolic abnormalities. Treatment with synthetic GH can allow children to maintain their expected growth percentile despite irradiation.

Table 53-5 Endocrine Abnormalities Resulting From Radiation

Hormone Abnormality Threshold Dose to Hypothalamic Axis
Growth hormone deficit 18–25 Gy
ACTH deficit 40 Gy
TRH/TSH deficit 40 Gy
Precocious puberty 20 Gy
LH/FSH deficit 40 Gy
Hyperprolactinemia 40 Gy

ACTH, Corticotropin; LH/FSH, luteinizing hormone/follicle-stimulating hormone; TRH/TSH, thyrotropin-releasing hormone/thyrotropin.

Other endocrine deficiencies, including decreased thyroid-stimulating hormone, corticotropin, follicle-stimulating hormone, and luteinizing hormone appear to have a higher threshold. These effects are typically seen following doses greater than 40 Gy. It is important that children treated for tumors in the region of the hypothalamic-pituitary axis be followed closely for endocrine abnormalities, so that replacement therapy can be initiated in a timely fashion.

Results in Selected Specific Central Nervous System Tumors

It can be assumed that the reported outcomes of treatment for pediatric tumors of the CNS are somewhat better than the actual outcome. This is because the most aggressive presentations of the various histologic types disable or kill the patient before therapy is completed, and, therefore, the very worst cases are excluded from most studies.

Medulloblastoma

Medulloblastoma comprises approximately 20% of pediatric CNS tumors, although one third of medulloblastomas occur in adults.45 Up to one third of medulloblastomas in children are associated with dissemination beyond the primary site at the time of diagnosis. Age younger than 3 years, inability to perform a gross total surgical removal of tumor, metastases, and diffuse anaplasia in the histologic specimen are associated with poor survival. Historically, standard treatment delivered 36 Gy to the brain and spine with a boost to the posterior fossa totalling 54 Gy. Significant abnormalities in intellectual development, growth, and hormonal function commonly occurred after CSI.46,47

Today, CSI followed by chemotherapy is the standard of care for both average- and high-risk children ages 3 and older. In average-risk disease (defined as gross totally resected tumor without severe anaplasia, and no metastases), 23.4 Gy to the craniospinal axis, plus a boost to 54 Gy to the posterior fossa, followed by chemotherapy, is standard and has resulted in 5-year survival of 80% or better.48 Areas of active investigation in average-risk disease are lowering of the craniospinal dosage to 18 Gy, conformal posterior fossa radiotherapy to the tumor volume, and intensification of chemotherapy with autologous peripheral blood stem cell support.49 In high-risk disease (defined as subtotally resected tumor, severely anaplastic histology, or presence of metastases), 36 Gy craniospinal plus a boost at the posterior fossa to 54 Gy, followed by chemotherapy is standard, and results in 5-year survival rates of 50% to 70%. Incorporation of chemotherapy during irradiation and intensification of chemotherapy following radiation therapy are subjects of current trials. Among infants with medulloblastoma, many approaches are competing in trials, particularly chemotherapy with limited posterior fossa radiation, high-dose methotrexate with or without later CSI,50 or very-high-dose chemotherapy without radiation therapy. Chemotherapeutics typically used in medulloblastoma include cisplatin, vincristine, cyclophosphamide, sometimes lomustine, and etoposide, or occasionally topotecan or thiotepa.

Until recently, standard of care has dictated that medulloblastoma and other lesions of the posterior fossa, be treated to the contents of the posterior fossa, with at least a 1-cm margin and the inferior border at C2. Volumes that target the entire posterior fossa deliver significant doses to the parietal, occipital, and temporal lobes. Limiting radiation doses to these regions of normal brain may reduce long-term toxicity. Hearing may be spared by reducing cochlear dose, endocrine function may be preserved by reducing pituitary-hypothalamic dose, and neurocognitive aptitude may be protected by reducing temporal lobe dose. Therefore, ongoing cooperative studies are evaluating whether the target volume for the primary site tumor boost in average-risk medulloblastoma can be reduced from whole posterior fossa to the tumor volume plus margin without compromising disease control.

Radiation Therapy Guidelines

Today, both average- and high-risk patients ages 3 years and older are treated with CSI followed by posterior fossa boost and adjuvant chemotherapy. Radiation therapy should start within 30 days of definitive surgery. CSI is best done with either 4- or 6-mV x-rays. Higher energies may result in relative underdose of lateral areas of the brain. The boost volume may be treated with nominal energies of 4 mV or more, provided that dosimetric constraints are achieved. Whenever possible, International Commission on Radiation Units and Measurements Report 50 and 62 (ICRU-50/62) definitions of treatment and critical structure volumes should be used. The GTV should include all gross residual tumor and the walls of the resection cavity at the primary site. Both pre- and postoperative imaging studies should be used to define the tissues initially involved with disease anatomically, the postoperative and preirradiation residual disease, and the tumor bed. In accordance with ICRU-50/62, the GTV is defined as the contrast-enhanced tumor in the brain and spine, unless the preoperative tumor is predominantly nonenhancing, in which case GTV represents the preoperative tumor extent on a T2-weighted MRI sequence. The CTV includes the GTV with a geometric margin that is meant to cover subclinical microscopic disease. In all cases, the CTV should be constrained anatomically to the confines of the bony calvarium and tentorium where applicable. Treatment of medulloblastoma patients requires multiple CTVs.

The CTV for CSI (CTVcsi) is the entire craniospinal axis. The craniospinal axis PTV for CSI (PTVcsi) should be defined according to the immobilization techniques used and the resulting inherent setup uncertainties. Consequently, PTV margins are variably defined by treatment facilities and may range from 0.5 cm to 1.0 cm. A larger margin is generally encouraged when treating the craniospinal volumes because of daily variations in spinal-field repositioning. The whole-brain field must extend anteriorly and include the entire frontal lobe, including the cribriform plate region. The volume should cover the superior orbital tissues only sufficiently to ensure coverage of the cribriform plate; there is no need to treat posterior globe as in leukemia protocols. A margin of at least 0.5 cm below the base of skull and foramen magnum is recommended for CTVcsi. PTVcsi should be defined to account for setup error. The caudal border of the whole-brain field must be chosen carefully and placed superiorly enough to allow for two junction shifts during treatment with a matching posterior spinal field. The spinal target volume includes the entire thecal sac. CTVcsi for the spinal field should extend laterally to cover the recesses of the vertebral bodies; at least 1-cm PTVcsi margin should be added on either side to account for setup variation and uncertainty. The superior border is the junction with the whole-brain field. The inferior border of the treatment volume should be placed 2 cm below the termination of the subdural space as seen on a spinal MRI. Generally, the inferior border of the spinal field extends to the S2–S3 interspace, but may be lower. If the entire spinal target volume cannot be adequately covered with a single posterior field, two spinal fields should be used with an appropriately matched junction between them. Caution should be applied when using an extended source-to-skin distance (SSD) when attempting to encompass the entire spine in a single treatment field, as this will result in a significant increase in dose inhomogeneity.

The CTV posterior fossa (CTVpf) boost volume should encompass the entire posterior fossa. The posterior fossa should be defined on a planning CT scan, and MRI should be used to assist in the identification of the tentorium cerebelli. The CTVpf extends from the foramen magnum inferiorly, to the bony walls of the occiput and temporal fossae posteriorly and laterally, and superiorly to the tentorium cerebelli. The anterior borders of the brainstem and midbrain bind the posterior fossa contents anteriorly. The PTV posterior fossa (PTVpf) consists of a 0.3- to 0.5-cm geometric margin around the CTVpf and accounts for day-to-day setup variation. Again, PTVpf should be limited to the bony confines of the skull, except at the foramen magnum where it extends to the level of C1. The PTVpf should extend anteriorly to the posterior clinoids, excluding the pituitary gland, and inferiorly to the C1-C2 junction. Three-dimensional treatment planning is highly recommended to define these volumes.

It is worth noting that limited target-volume boost is currently being evaluated in clinical trials by the Children’s Oncology Group (COG ACNS 0331) as a potential method of mitigating late effects of treatment. For the limited boost, the GTVlimited is defined as previously explained, using a contrast-enhanced T1-weighted MRI or other MR sequences if the original tumor volume is nonenhancing (e.g., T2 or FLAIR). GTVlimited generally does not include tissue defects caused by surgical approaches. The CTVlimited is defined as a GTVlimited plus a 1.5-cm geometric margin confined by the bony and tentorial limits of the posterior cranial fossa. The PTVlimited margin should be an additional 0.3 to 0.5 cm around the CTVlimited Following these guidelines, there is generally only a modest difference between the CTVlimited and CTVpf. Despite these modest differences in target volumes, the use of 3-D conformal planning and delivery results in significant reduction in the mean dose to the temporal lobes, cochleae, pituitary, and hypothalamus. Despite encouraging results suggesting preserved control rates and dose reduction to the organs at risk, the boost treatment of limited posterior fossa volumes is currently not a treatment standard. This question will hopefully be resolved once the results of the ACNS 0331 trial are published.

Patients with average-risk medulloblastoma are treated to the craniospinal axis to a dose of 23.4 Gy using conventional fractionation (1.8 Gy/fraction) and receive an additional boost of 30.6 to 32.4 Gy. The cumulative dose to the PTVpf should be 54.0 to 55.8 Gy. When using a 3-D conformal technique, the 95% of the PTVpf should receive at least 95% of the prescription dose. No part of the PTVpf should receive a dose less than 50.0 Gy. High-risk medulloblastoma patients are treated to 36.0 Gy to the craniospinal axis (1.8 Gy/fraction) followed by a boost of 18.0 to 19.8 Gy to achieve posterior fossa doses of 54.0 to 55.8 Gy.

Simulation

Most contemporary CSI treatment and planning approaches rely on the availability of MRI and CT data sets and 3-D capabilities of modern radiation treatment planning (3D-RTP) systems. Consequently, CT or MR simulations of CSI treatments are now more prevalent. The field setup and matching principles previously used during fluoroscopic simulation can now be easily reproduced and manipulated in the virtual space of the 3D-RTP system. For these and historical reasons, a “classic” fluoroscopic simulation is described in the following text, helping to illustrate potential pitfalls and treatment planning considerations related to the CSI. Although we describe a prone setup, the reader should be aware that a variety of supine techniques have also been reported in literature. The main historical reason for the prone setup was the ability to visualize and monitor skin gaps for junction matching and junctional shifts. Such visual monitoring is no longer required in the presence of alternative setup verification techniques such as daily portal imaging or on-board cone-beam CT. Furthermore, junction shifts can be simulated in the 3D-RTP system and automated during treatment delivery. Additionally, dose inhomogeneities observed during 3D-RTP session can now be considered and adequate compensations calculated using field-in-field techniques. This is particularly relevant when correcting for the inhomogeneities related to variations in the SSD for different portions of the spine field. Often, potential limitations of the conventional (two-dimensional [2-D]) CSI treatment can be uncovered, visualized, and corrected before commencing treatment of the patient.

The boost phase of medulloblastoma treatment also benefits from 3D-RTP and the use of highly-conformal 3D-CRT or IMRT techniques. These techniques offer a distinct advantage over conventional 2-D or early 3-D techniques in their ability to spare normal, or uninvolved, tissues both in the vicinity and at a distance from the target, thereby minimizing late treatment-related morbidity. As a general principle, the full scope of imaging and 3-D treatment planning techniques should be used to simulate, plan, and treat pediatric patients with medulloblastoma. At the heart of effective treatment planning is the thorough understanding of CSI setup, simulation, and inherent treatment limitations—these are discussed in the following text.

The vast majority of patients receiving CSI are children. Many have neurologic deficits, making it difficult for them to be motionless and cooperative for any length of time. More than any other patients, they require proper stabilization during treatment setup, and often assistive anesthesia. The field arrangement usually consists of opposed lateral brain portals and a posterior spinal axis field, all of which are matched in the region of the cervical spine. This set-up usually requires that patients be placed in the prone position. For most patients, the prone position is less comfortable than the supine, and it is therefore less likely to be consistently maintained throughout the treatment course unless the patient is positioned in a thermoplastic mold or a similar device (e.g., an Alpha Cradle). This is less problematic for cooperative adult patients than with children. Small children requiring anesthesia present a problem because the anesthesiologist requires access to the airway. These patients are usually treated in either a full-body plaster cast with an open facial area or using a customizable immobilization device that supports the forehead and the mandible (Fig. 53-6), with access for anesthesia and airway suction devices.

Fluoroscopic Simulation

With an immobilized patient in the prone position, lead markers are placed on the lateral canthus of each eye to facilitate design of eye blocks for the whole-brain portals. With fluoroscopy, the patient’s midline is aligned with the central axis of the beam. This may require moving the couch with respect to the gantry to ensure that the central axis indicator always overlies the center of the patient’s entire spine, from the cervical region to the sacrum. The sagittal laser alignment line is then marked on the immobilization device both cephalad of the head and between the legs. Reproducing this alignment in the treatment room prior to the treatment is vital for the accurate treatment delivery. The gantry, couch, and collimator angles should be set to 0 degrees prior to the procedure.

A cross-table lateral radiograph with a lead wire on the skin along the spine will help determine the depth of the spinal cord and also the depth at which the beams should converge without causing an overlap in the spinal cord. Alternatively, the cord depth can be obtained from either a CT or an MRI. The two posterior spine fields are set up using an SSD technique, and a gap is calculated between the fields in the usual manner. Because the field junction is shifted during the course of treatment by increasing and decreasing the length of these fields, the initial length must be set such that the length can be increased by 4 to 6 cm without exceeding the maximum field length possible on a particular treatment machine. For setting up the lateral brain fields, it is also helpful to mark the projection of the posterior spine field on the lateral aspect of the neck. This can be accomplished by widening the spine field such that the cephalad field margin flashes over the sides of the neck.

The lateral brain fields are then simulated. The patient’s position on the simulation couch must not be changed between the simulation of the spinal axis and the lateral brain fields. Without moving the simulation couch, the gantry is turned 90 degrees to either side. The couch is then moved until the entire brain lies within the field of the simulator and there is adequate flash over the skull in all directions. The collimator is turned until the caudal margin is parallel with the diverging posterior field. The necessary degree of collimator rotation depends on the length and the SSD of the posterior field (or superior posterior field, if two posterior fields are necessary) and can be derived from the following:

image

The foot of the couch is then turned toward the collimator to prevent the lateral field from diverging into the superior aspect of the posterior spine field. The necessary degree of couch rotation depends on the length of the cranial field in the direction of the gap (distance from the central axis to the caudal margin), and the source-to-axis distance (SAD) and can be found from this equation, substituting SAD for SSD. A visual check should be made to verify that the caudal margins of the lateral fields in fact match the cephalad margin of the posterior spine field. When the opposite lateral cranial field is simulated, the couch and collimator angles are in the opposite direction. In addition to shifting the location of the field match point during the treatment course, it is also recommended that a small gap (∼0.5 cm) be set between fields. A radiograph should be taken of each of the lateral fields. The central axis of each field is marked on the patient or, alternatively, on the immobilization device. It is recommended that the laser alignment lines also be marked.

Craniospinal Irradiation Considerations

When treating the craniospinal axis, it is essential to be aware of potential technique limitations. Different techniques to deliver CSI have been described and variously address some of these known limitations.5153

Craniospinal treatment is complicated by the fact that several adjacent fields must be used. Typically, the brain is treated through lateral opposed fields, whereas the spinal axis is treated with one or two posterior spinal fields (depending on the length of the spine). Field matching between the two posterior fields is usually accomplished by calculating the separation between the two fields on the skin surface, the so-called “skin-gap” calculation. It is important to match the adjacent radiation treatment fields at the anterior edge of the spinal cord, or alternatively at the posterior edge of the vertebral column. This approach prevents relative overdose of the spinal cord, but will result in a relative cold spot. Matching the inferior border of the lateral cranial fields with the superior border of the most cephalad spinal field is more complicated, because the cephalad aspect of the posterior spine field is diverging cephalad and the caudal aspect of the brain fields is diverging caudad and posteriorly. The first step is to rotate the collimator of the lateral fields so that its inferior border is parallel to the divergence of the superior aspect of the spinal field (Fig. 53-7). This prevents the superior aspect of the spinal field from exiting into the anterior-superior aspect of the brain fields. In effect, it moves the anterior portion of the lateral brain fields cephalad and out of the path of the spine field. Second, to avoid overlap resulting from inferior divergence of the caudal border of the lateral fields into the cephalad aspect of the posterior spinal field, the foot of the couch is rotated toward the collimator so that the caudal field margins of the two fields become parallel and cross the patient’s neck in a straight line, that is, perpendicular to the patient’s sagittal axis (Fig. 53-8).

Field junctions are usually moved two or three times during a course of treatment to spread out the dose inhomogeneities at the junction.54 The field junctions are often shifted by adjusting either cranial or caudal portions of the abutting fields using asymmetric jaws.

Although the practice of turning the couch for the lateral cranial fields solves the field-matching problem, depending on the location of the cranial field central axes (or anterior-superior position of the isocenter), it may cause the most inferior aspect of the opposite temporal fossa to be underdosed or missed (Fig. 53-9). This problem is generally avoided in practice by placing the isocenter for the brain fields in the central portion of the brain in the midsagittal plane.

Another note of caution should be added here, because when the foot of the couch is rotated toward the collimator for treatment of each of the lateral brain fields, the treatment distance (SSD) in the caudal half of the lateral brain field is effectively decreased whereas the cephalad half is increased (Fig. 53-10). The change in SSD becomes larger as the distance from the isocenter increases. The SSD is usually shorter by 1 to 2 cm in the cervical spine, depending on the couch angle and the location of the isocenter of the lateral brain fields. The length by which the distance is decreased, which must be measured at the appropriate distance from the isocenter, can be found by measuring the distance between the sagittal laser line when the couch is set to 0 degrees versus where it is when the couch is rotated to the treatment position. It is important to recognize that this change in SSD is in the same direction for both of the lateral brain fields.

The shorter SSD causes the dose in the cervical spine to increase. The dose here is also higher than in the midbrain because of the smaller thickness of the neck. For this reason, it is important always to calculate and record the cervical spine dose in the daily treatment record, taking into account both the reduced separation and the shorter SSD. The same issues that apply to the cervical spine also apply to the posterior fossa. This area is also moved toward the collimator when the couch is rotated, but this is of lesser consequence than in the cervical spine because it is closer to the isocenter and therefore change in SSD is smaller. The transverse separation is usually larger here than in the cervical spine, thus excessive dose is less likely. These problems can easily be overcome with the use of 3D-RTP systems.

It is difficult to treat the entire brain without having divergence into the eye on the opposite side. The problem is analogous to that described in Fig. 53-9, in which the contralateral temporal lobe may be underdosed. One solution is to set the isocenter, and thereby the central axis of the beam, at the lateral canthus of the eye, thereby eliminating the beam divergence. Although this approach may reduce eye irradiation, this technique generally cannot be used in the setting of CSI. In the setting of CSI, when the couch is rotated to eliminate the caudal beam divergence of the lateral cranial fields, the opposite eye is projected more cephalad and cannot be adequately shielded without also blocking brain tissue. A gantry angle here will not solve the problem because that motion causes both eyes to move posteriorly with respect to the beam. Although the anterior-posterior motion can be changed only by a gantry angle, the cephalad-caudad motion can be changed only by a couch rotation.

The dose along the spinal axis varies because of varying depth and SSD, which usually is most noticeable near the surface and in large fields. An isodose distribution calculated on the patient’s sagittal midline contour provides an estimate of the dose heterogeneity along the spinal axis. Obtaining a sagittal contour and the depth of the spinal cord may not always be possible using a fluoroscopic simulator, but this is usually not a problem when CT simulation is used. It is best to prescribe the dose on the central axis at a depth as determined on a CT simulator, or, if the depth can be determined from diagnostic CT or MRI images, at an average of depths measured at several points along the spinal cord. In our institutional experience, the dose varies along the spinal axis from about 80% to 95%. This variation can be greater in patients who are unable to lie prone without propping up of the chest. In such patients, the SSD, which is shorter in the thoracic spine where the spinal cord is usually shallow, can be reduced by positioning the patient flat with the arms raised above the head. Alternatively, the dose can be calculated and appropriate compensation using field-in-field technique devised when using 3D-RTP systems.

In general, an attempt should be made to keep the patient’s posterior surface horizontal, an isodose distribution should be calculated on a sagittal contour, and the dose gradient within the spinal canal should be considered when the dose prescription is formulated. All fields must be carefully matched to prevent relative overdose or underdose at junctional sites (Fig. 53-11).54,55

Ependymomas

Ependymomas occur most frequently in the posterior fossa and are treated with 54 Gy with a local field, achieving relatively good 5-year survival rates.56 Less-than-complete surgical resection leads to a very high rate of recurrence, in spite of adjuvant radiotherapy. Most centers treat with local therapy only. There is no proven benefit from chemotherapy in children with ependymoma, although novel agents are now bing investigated at relapse as well as radiosurgery.

Radiation Therapy Guidelines

Successful treatment of localized ependymoma requires maximal safe resection followed by high-dose radiation therapy. Because doses of 54 to 59.4 Gy are required, 3-D conformal radiation techniques, including IMRT, should be used whenever possible to mitigate treatment-related toxicity. Adjuvant radiation treatment should start no later than 30 days after surgical resection, or as soon as adequate postresection healing and recovery takes places (usually no earlier than the third postoperative week). In select patients with residual disease, a referral to a tertiary medical center specialized in treating pediatric patients may be warranted for second surgery to maximally debulk any remaining tumor prior to adjuvant radiation treatment. Radiation, even at high doses, cannot compensate for inadequate resection. Both pre- and postoperative contrast-enhanced MRI and CT scans should be used whenever possible for treatment planning.

The GTV includes the tumor bed and all residual gross disease at the primary site based on the preoperative imaging. Preoperative imaging is useful in defining the tissues initially involved with disease and the postoperative or preirradiation neuroimaging identifies any residual disease and the surgical bed. In majority of cases, the GTV is a collapsed surgical bed. The CTV includes the GTV with a 1.0- to 1.5-cm anatomically-constrained margin meant to treat subclinical microscopic disease. The CTV should be limited by the bony calvarium, tentorium, and falx. A geometric expansion beyond the CTV of 0.3 to 0.5 cm generates the PTV. The choice of PTV margin depends on the expected immobilization, image registration and fusion, and daily variability in patient positioning. The PTV may extend into or beyond the bone, but usually does not extend beyond the surface of the patient.

The dose should be prescribed to the highest isodose surface that encompasses both PTV and CTV with the least inhomogeneity (Fig. 53-12). Ideally, 95% of the PTV should be covered by 95% of the prescription dose; PTV dose should be within +10% and −5% of the prescription. These guidelines aim to minimize target dose heterogeneity and consequently possible associated irreversible neurologic sequelae. Without compromising the target coverage, the treatment plan should aim to minimize dose to the spinal cord, brainstem, optic chiasm, optic nerves, auditory system (cochleae), hypothalamic-pituitary complex, and temporal lobes. In situations in which the critical structure tolerance will be exceeded, a reduction in the target volume (staged cone-down) will be required after the tolerance dose has been reached. This may require that portions of the PTV, CTV, or GTV in or near the region of the critical structure will be underdosed. For example, when the cumulative spinal cord dose has reached 50 Gy, the spinal cord should be excluded from the treatment (or excluded after 54 Gy if disease extends into foramen magnum).

The recommended total dose for localized ependymoma is 54 to 59.4 Gy using conventional fractionation (1.8 Gy/fraction), given the propensity of these tumors to recur locally. Patients younger than 18 months old with gross total resection of a localized disease may be treated to a total dose of 54 Gy; all other patients, even those younger than 18 months old, with residual disease must be treated to a total dose of 59.4 Gy.

Simulation

The patient may be treated in the supine or prone position. It is critical to select a reproducible setup with immobilization devices compatible with administration of deep sedation or general anesthesia because treated patients tend to be very young and less cooperative. Our institutional preference is to treatment patients in the supine position with a headrest and thermoplastic head-only mask for immobilization. More rigid thermoplastic masks are encouraged in patients who are not sedated during simulation and treatments, paying special attention not to compromise the mold of the nasal bridge and the chin. A CT study with the patient in the treatment position is required for treatment planning (slice thickness ≈ 3 mm) of the region bounded caudally by the thoracic inlet and the most cephalad aspect of the skull. MRI and CT registration (fusion) is strongly encouraged for patients with ependymoma. MRI should ideally be performed with the patient as close to the treatment position as possible, paying particular attention to spinal cord flexion and extension, given that the majority of patients have disease in the posterior fossa. Both the simulation CT and MRI should be obtained as close as possible to the initiation of radiation therapy, allowing for ample treatment planning time. It is suggested that imaging take place within 2 weeks of the start of radiation therapy. Both contrast-enhanced and unenhanced MRI sequences should be obtained (slice thickness ≈ 3 mm, slice spacing ≈ 3 mm).

Brainstem Gliomas

Diffuse brainstem gliomas are nearly universally fatal within 3 years of diagnosis.57,58 Children present abruptly, often with a month or less of weakness, ataxia, and cranial neuropathies, and typically an abducens paresis producing horizontal strabismus. These poor-prognosis, diffuse pontine gliomas are usually treated with radiation only. Although radiotherapy is often performed without biopsy, the influence of surgical intervention or biopsy on this disease (excluding dorsally exophytic lesions) is uncertain. Hyperfractionated radiotherapy of 1.17 Gy twice a day to a total dose of 70.2 Gy has been shown to produce similar survival to that of other treatment schemes, with an acceptable rate of morbidity.59 Current clinical trials are testing novel molecular therapeutics, antiangiogenesis agents, and radiosensitizers in this tumor.

Attention should be paid to the exception of dorsally exophytic lesions and other focal brainstem tumors, often pilocytic astrocytomas or sometimes gangliogliomas, which can sometimes be cured by surgery alone. Radiotherapy may be effective against tumor progression or tumors that prove refractory to surgical resection.

Radiation Therapy Guidelines

Brainstem gliomas are currently treated with conventionally-fractionated radiation therapy (1.8 Gy/fraction) to doses of 54 to 55.8 Gy, after many trials demonstrated no benefit to dose escalation, hyperfractionation, or radiosensitization using conventional agents. For delineation of target volumes, MR neuroimaging is mandatory. The MRI sequence that best defines the extent of disease should be used; the T2 sequence is usually the most appropriate to define the GTV. The CTV includes the GTV with a 1.0- to 1.5-cm geometric expansion in all directions. It is, however, permissible to use asymmetric geometric margins. For example, a 1.5-cm expansion may be used in the craniocaudal direction within the brainstem and a 1.0-cm margin may be used in the anterior-posterior direction. The PTV includes the CTV with 0.3- to 0.5-cm margin, depending on the immobilization techniques and the expected daily setup variation. With the exception of dorsally exophytic lesions, in which surgical resection has a role in the management, the majority of patients are treated with radiation shortly after diagnosis.

Three-dimensional conformal treatment techniques, including IMRT, should be used in the treatment of brainstem glioma patients (Fig. 53-13). Two-dimensional techniques, with a midline prescription point, are discouraged, given their inherent limitations to spare uninvolved surrounding anatomic structures and tendency to deposit higher doses within the temporal lobes. More than 95% of the PTV should be covered by the 95% isodose surface (CTV and GTV must be within the prescription volume); the PTV dose should be within +10% and −5% of the prescription to minimize dose heterogeneity within the brainstem. Doses to the spinal cord, brainstem, optic chiasm, optic nerves, auditory system (cochleae), hypothalamic-pituitary complex, and temporal lobes should be monitored, recorded, and maintained within the accepted tolerance limits.

Cerebral and Cerebellar Astrocytomas

The prognosis for astrocytomas is much better for children than for adults, particularly because many of the tumors are low-grade pilocytic (WHO grade I) or diffuse astrocytomas (WHO grade II). Even the rate of diffuse WHO grade II astrocytomas that undergo anaplastic transformation is much less than that in adults.60 Thus, the role of radiotherapy following surgery for low-grade astrocytomas is controversial, and, in practice today, is deferred following gross total resection and frequently in subtotally resected low-grade gliomas until there is further evidence of growth.61 The majority of cerebellar astrocytomas carry a good prognosis when treated with surgery alone and are often of the pilocytic type. Even with recurrent or subtotally resected cerebellar tumors, irradiation is withheld and repeat surgery usually pursued in lieu of radiotherapy.

For diencephalic or chiasmatic astrocytomas at the hypothalamus or chiasm, often minimally amenable to resection, carboplatin and vincristine chemotherapy are used in children presenting before age 10 to stabilize or reduce tumor burden and delay radiotherapy until the child is older and can better tolerate acute and long-term effects of radiation.62

Radiation Therapy Guidelines

External-beam radiation therapy guidelines for the treatment of localized low-grade pediatric gliomas have not been developed. A margin of 1 cm or less beyond the GTV generally defines the CTV. An additional geometric expansion of 0.3 to 0.5 cm for immobilization and daily setup uncertainty is added to create the PTV. For WHO grade I or II tumors, a dose of 54 Gy of conventionally-fractionated (1.8 Gy/fraction) external-beam radiation is recommended. Patients with disseminated low-grade astrocytomas are generally treated with curative intent using CSI. In this setting, the CSI doses have not been established, given the relative rarity of disseminated disease at presentation. Occasionally, well-defined residual tumors are treated with stereotactic radiosurgery.

Patients with high-grade astrocytomas (glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, malignant PXA, and other malignant glial-neuronal tumors) represent a minority of pediatric brain-tumor patients, and are often treated in a manner analogous to that in adults. Maximal safe resection followed by postoperative conventionally fractionated radiation therapy (1.8 Gy/fraction) with concurrent and adjuvant chemotherapy is the standard treatment approach.

Contrast-enhanced pre- and postoperative MRI (slice thickness ≈ 3 mm, slice spacing [gap] ≈ 3 mm) is generally used in conjunction with the treatment planning CT scan in the registration (fusion) process that is part of treatment planning. The GTVinitial includes all tissues initially involved with disease and the entire residual tumor as defined by both the pre- and postoperative MRI scans. The GTVinitial must include both enhancing and nonenhancing areas of tumor. All available sequences, whether T1, T2, or FLAIR should be reviewed and used to best define the extent of disease. This initial volume should also take into account any distortions in brain anatomy that have occurred as a result of tumor resection or CSF shunt placement. The CTVinitial includes GTVinitial plus a 2-cm geometric margin (anatomically constrained by the bony calvarium, tentorium, or the falx) meant to account for subclinical microscopic disease. In cases of primary spinal-cord tumors, the CTVinitial is generated by expanding the GTVinitial in both cranial and caudal directions by the length equivalent to a height of two vertebral bodies. PTVinitial includes CTVinitial plus a 0.3- to 0.5-cm geometric margin in all directions (not anatomically constrained) to account for immobilization and daily setup uncertainty.

The GTVboost includes only the residual tumor after resection, both enhancing and nonenhancing disease, as seen on the postoperative MRI scans. All available MRI sequences should be used to delineate residual disease. In biopsy-only cases, GTVboost is the same as GTVinitial, and after complete resection, GTVboost represents the resection cavity volume. The CTVboost includes GTVboost plus a 1-cm anatomically-constrained margin in all directions. For primary spinal cord tumors, CTVboost is defined by expanding the GTVboost volume in both cranial and caudal directions by the length equivalent to one vertebral body. PTVboost includes CTVboost plus a 0.3- to 0.5-cm geometric margin in all directions.

The treatment of cerebellar and cerebral astrocytomas is best done with 3-D CRT techniques, including IMRT. During staged treatment of brain tumors, PTVinit is treated to 50.4 to 54.0 Gy followed by a boost dose of additional 5.4 to 9.0 Gy to achieve total PTVboost dose of 59.4 Gy. For spinal cord tumors, PTVinit is treated to 45 Gy followed by a boost of additional 5.4 Gy to PTVboost if there is no residual disease (total dose 50.4 Gy), and by a boost of 9.0 Gy in cases of gross residual disease (total dose 54.0 Gy). Ideally, the 95% prescription surface should cover at least 95% of the PTV. Dose heterogeneity within the target volume should be within +10% and −5% of the prescription dose. Distribution of relative “hot spots” within the target volume should be carefully documented. When treating spinal disease, the use of fractional doses of more than 1.8 Gy is discouraged.

Germ Cell Tumors

Intracranial germ-cell tumors (GCTs) represent 3% to 11% of pediatric and 1% of adult brain tumors.63 Intracranial GCTs compose two distinct histologic groupings: germinomas are the most common histologic subtype, whereas NGGCT represent less than one third of intracranial GCTs and consist of embryonal carcinoma, endodermal sinus (yolk sac) tumor, choriocarcinoma, mature and immature teratoma, and GCT of mixed cellular origin.5 Historically, radiation alone, frequently encompassing a large treatment volume, constituted the gold standard of treatment for intracranial GCTs.6466 However, the morbidity of radiation therapy in children,6772 particularly CSI, prompted many investigators to explore approaches that reduce the volume and dose of radiotherapy while preserving high cure rates.

The development of strategies to reduce the morbidity of radiotherapy has been hampered by an absence of randomized trials comparing treatment approaches. Several large retrospective studies have shed light on persistent controversies in the management of intracranial GCTs. Current literature supports distinct therapeutic approaches for germinomas versus NGGCT. Although many published studies group germinomas with NGGCT, their distinct prognosis points to the need to approach these clinical entities individually.

Published reports corroborate poorer prognosis for patients with NGGCT compared with those with germinomas.65,73 Radiation alone produces 5-year survival rates as low as 30% to 40%.74 More recent studies that demonstrate excellent response rates to chemotherapy have shifted the standard treatment of NGGCT to combined-modality therapy consisting of chemotherapy and radiation, and these approaches are now being explored in North America.75 Many or most investigators still consider craniospinal rather than local-field radiotherapy standard in this disease.

Of the various histologic subtypes of intracranial GCTs, germinomas represent the most common and prognostically favorable subgroup. Historically, intracranial germinoma has been treated with radiation alone, producing excellent cure rates.63,64,66 The significant long-term toxicity of radiation, particularly in children,6772 has prompted investigation to explore alternative treatment that minimizes the dose and volume of irradiation. However, these alternative approaches must preserve the high cure rates established with radiation alone.

Several series have reported excellent clinical outcome with preirradiation chemotherapy followed by focal irradiation.7681 The appeal of this approach lies in lower radiation dose and smaller radiation fields that presumably translate into reduced long-term toxicity. Radiation alone continues to be the gold standard for the treatment of intracranial germinoma. Promising approaches such as combined chemotherapy and focal, reduced-dose irradiation are being compared with radiation alone in a prospective, randomized trial.

In addition to the role of chemotherapy, a point of controversy in the treatment of localized germinoma has been the appropriate field of radiation.82 Current evidence substantiates omitting CSI from the treatment of localized germinoma. Spinal failure rates of less than 10% in the absence of CSI, reported in most contemporary series, do not justify routine incorporation of CSI into the treatment strategy for localized germinoma.73,8387 Nevertheless, the precise irradiation field appropriate for localized germinoma remains unclear. Several studies report higher recurrence rates associated with radiation targeting the tumor volume only.73,83,88,89 We recommend whole-ventricular irradiation, followed by a boost to the primary tumor for localized germinoma when using radiation alone.90 The literature supports a dose of greater than or equal to 45 Gy to the primary tumor for germinomas treated with radiation alone. In the context of combined chemotherapy and radiation, many investigators have tailored the dose of radiation to the tumor response observed following chemotherapy. Doses of radiation following chemotherapy range from 24 to 40 Gy.

Radiation Therapy Guidelines

NGGCTs, just like their nonseminoma analogs outside of the CNS, tend to be resistant to most forms of therapy. Many different combined-modality approaches were tested in clinical trials, but most suffered from poor event-free survival and high rates of clinical progression. A recently closed COG protocol (ACNS 0122) aimed to assess the ability of 18 weeks of neoadjuvant chemotherapy (alternating combinations of carboplatin/etoposide and ifosfamide/etoposide every 3 weeks) to eliminate measurable disease prior to radiation therapy (with or without preirradiation surgery). Patients with complete response (CR) or less than CR and second-look surgery went on to receive CSI if they experienced normalization of serum and CSF markers. On this study, patients were treated with conventionally-fractionated CSI (1.8 Gy/fraction) to a total dose of 36 Gy followed by a conformal boost radiation for additional 18 Gy, resulting in the total boost volume dose of 54 Gy.

For CSI, the CTVcsi included the entire craniospinal axis (whole-brain and spinal volumes). To create the PTVcsi, a 0.5-cm margin was added to the brain-only portion of the CTVcsi, and 1-cm lateral and inferior margins were added to the spinal portion. For boost treatments, the GTVboost was defined as the prechemotherapy volume, including the tumor bed and any residual disease. The CTVboost included the GTVboost with a 1-cm anatomically-constrained margin. The PTVboost was defined as the CTVboost with 0.3- to 0.5-cm, institution-specific geometric margin to account for immobilization and daily setup uncertainties. To define these volumes, both contrast-enhanced and unenhanced MRI were necessary and MRI and CT registration (fusion) was mandated for conformal planning. The study permitted treatment of multiple intracranial tumors, each of which was defined as a separate GTV volume. The GTV for spinal metastases was also defined as the prechemotherapy volume, the tumor bed, and any residual disease. Spinal disease was treated with a 9 Gy boost after 36 Gy of CSI for a total dose of 45 Gy. Dose heterogeneity limits are similar to those described previously for CSI of medulloblastoma.

In contrast to NGGCTs, the treatment volumes for localized germinoma are controversial. A current COG study (ACNS 0232) in patients with pure germinoma is designed to examine whether the addition of preradiotherapy chemotherapy will permit response-based reduction in radiation volumes and doses to improve functional outcomes while preserving disease control. Because of increasing tendency to treat smaller volumes, the importance of proper staging cannot be overemphasized in the radiotherapeutic management of these patients. The diagnosis of germinoma requires a biopsy, especially in the setting of negative serum or CSF biomarkers, and even if the lesion has a characteristic radiographic appearance. Localized germinoma is treated with whole-ventricular (WV) radiation to 24 Gy followed by a 21 Gy focal boost to the primary tumor. The standard treatment of disseminated disease is CSI to 24 Gy with a 21 Gy involved-field boost, for a total primary site dose of 45 Gy. Unlike the treatment of other pediatric CNS tumors, radiation is delivered using 1.5 Gy daily fractions.

Treatment volumes for disseminated germinoma are analogous to those used for NGGCTs. The GTV is defined as contrast-enhancing tumor on the initial diagnostic MRI (before patient receives any form of therapy). In the unlikely circumstances that the gross disease is nonenhancing, a “mass-like” T2-signal abnormality corresponding to the primary or metastatic tumor should be designated as the GTV. The CTVboost includes the GTV plus a 1.5-cm, anatomically-constrained margin, limited by the tentorium or calvarium. The PTVboost is defined as institution-specific 0.3- to 0.5-cm expansion beyond CTVboost that accounts for immobilization and daily setup variation. Generally, PTVboost does not extend beyond the subcutaneous tissues of the scalp. In cases of localized germinoma, patients are treated with WV radiation before proceeding with involved-field boost. For WV irradiation, the CTVwv must encompass the lateral, third, and fourth ventricles as outlined on co-registered (fused) CT and MRI volumes with a 1-cm geometric margin. If a shunt was placed or ventriculostomy performed at the time of diagnosis to relieve hydrocephalus, or if preradiation chemotherapy was administered and resulted in a ventricular volume decrease, the ventricular volume immediately prior to radiation (not at diagnosis) should be used for treatment planning. A 0.5-cm geometric expansion beyond the CTVwv generates the PTVwv.

Patients with intracranial, localized germinoma are generally simulated in a supine position with maximal comfortable neck flexion and head-only thermoplastic mask for immobilization. It is critical to ensure that the chin, forehead, and nasal bridge fit snugly inside the mask to minimize patient motion. Whenever possible, WV irradiation should be delivered with photon energies of 6 mV or more and either a four-field plan, consisting of an opposed lateral pair and anterior-to-posterior beams (angled to avoid the orbits), or IMRT (Fig. 53-14). The use of an opposed lateral pair should be avoided because of a relative increase in the temporal lobe dose compared with more conformal multibeam techniques.91 Similar principles should be followed for the involved-field boost.

Craniopharyngiomas

These lesions are not malignant but, because of their location in the suprasellar region, are often associated with high morbidity. The judgment and skill of the operating surgeon is therefore critical if significant endocrine and visual problems are to be avoided. There is a suggestion that subtotal resection followed by local irradiation to 54 Gy offers progression-free survival similar to that of gross total resection with a much lower rate of morbidity, but contradictory studies are published as well.92

Radiation Therapy Guidelines

Because these are relatively rare tumors, with fewer than 100 cases annually, radiation guidelines have not been developed.93 After decompressive surgery, patients may be observed even in the presence of residual disease and treated at the time of progression. Radiosurgery can be used to treat small solid residual tumors and intracystic isotopes (e.g., 32p colloid) are useful for treating recurrent or persistent cystic components 2 to 3 cm in diameter or larger. Mixed solid-cystic masses are best addressed by decompressive surgery followed by adjuvant radiation. The treatment volume should include both solid and cystic tumor (GTV) as designated on an MRI, a conservative CTV expansion, usually 1.0 cm or smaller, and an appropriate PTV margin (0.3-0.5 cm). A dose of 54 Gy is delivered to the target volume using conventional fractionation (1.8 Gy/fraction). Highly-conformal techniques, such as IMRT or 3D-CRT, should be employed in the treatment of these patients to minimize radiation dose outside of the tumor volume. Because these tumors generally arise in the sellar and suprasellar region, it is important to carefully monitor the dose to the optic apparatus (optic nerves, chiasm, and optic radiations) as well as to the hypothalamus and bilateral temporal lobes during treatment planning. Target dose heterogeneity should be carefully manipulated to avoid placing areas of relative high dose (“hot spots”) in the vicinity of critical structures. Because cyst formation in response to radiation therapy is frequently observed, patients should ideally receive at least biweekly MRI scans to ensure that the tumor target remains within the radiation field. Radiation-related morbidity is quite common and includes a variety of endocrinologic, neurologic, and cognitive sequelae.94,95

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