Embryonal Central Nervous System Tumors

Embryonal tumors of the CNS are the most common malignant brain tumors in children. They are characterized by their infiltrative nature, aggressive patterns of growth, propensity for dissemination, and common need for intensive combined modality therapy. These tumors are found throughout the CNS and are further classified according to histologic and molecular features into two groups: primitive neuroectodermal tumors (PNET) and atypical teratoid rhabdoid tumors (ATRT). The PNET group includes two distinct entities—medulloblastoma (Fig. 65-1) and pineoblastoma (Fig. 65-2)—named for their site of origin in the posterior fossa and pineal region, respectively. ATRT are rare aggressive embryonal tumors that most commonly arise in young children in the brain and at peripheral soft tissue sites. With some exceptions, the diagnosis of ATRT is made on molecular grounds by demonstrating the deletion or mutation of the SMARCB1 gene found on chromosome 22q11.2.² Atypical teratoid rhabdoid tumors unknowingly were considered the same as other PNET but are now known to carry a worse prognosis.

Figure 65-1 Medulloblastoma as shown on axial postgadolinium T1-weighted (left) and T2-weighted (right) MR images.

Figure 65-2 Pineoblastoma evident on axial fluid-attenuated inversion recovery (FLAIR) (left) and T2-weighted (right) MR images.

Medulloblastoma and supratentorial PNET are commonly diagnosed in young children. The relatively large numbers of patients and a cooperative spirit among caregivers have led to considerable understanding and progress in the treatment of these tumors. Patients are risk classified for treatment based on the three most important prognostic factors for tumor control— extent of disease, extent of resection, and histological subtype—and the most important prognostic factor for functional outcome—age at the time of irradiation. The radiation oncologist should be aware of the aggressive histologic variant of medulloblastoma (large cell or anaplastic medulloblastoma) that is more prone to dissemination through the cerebrospinal fluid (CSF).3,4 One also should be aware that there is a less aggressive variant (desmoplastic medulloblastoma) that may not require irradiation under certain conditions.

Medulloblastoma is a heterogeneous tumor and is now recognized as a number of different diseases based on specific molecular markers that have been retrospectively evaluated. Depending on the series, investigators have identified from four to six different subtypes based on the combination of molecular and classic histopathologic evaluation. A report by Northcott and associates⁵ described four distinct molecular variants of medulloblastoma, including WNT, SHH, and two non-WNT/SHH. The former two have clinical features that are associated with less aggressive phenotypes and the latter two, described as groups C and D in their report, have molecular and clinical features associated with more aggressive phenotypes, including overexpression of MYC and disseminated disease (group C) and the most common cancer isochromosome i17q and children between the ages of 4 and 15 years. One of the more striking findings by this group was the variation in molecular characteristics by age. Many of these findings have been confirmed by others groups,⁶ which suggests that tumor biologic information will be combined with clinical prognostic data to stratify patients in future trials.

At present, the treatment of embryonal tumors of the CNS is remarkably similar regardless of subtype or tumor location and consists of surgery, postoperative RT, and chemotherapy. The requirement of craniospinal irradiation, regardless of extent of disease, is the element that differentiates the treatment of these tumors. Approximately one third of patients present with neuraxis dissemination at the time of diagnosis as determined by magnetic resonance imaging (MRI) of the brain and spine (Fig. 65-3) or CSF cytology.⁷ Because the negative predictive value of these staging procedures remains relatively low, and the most common mode of failure remains distant, craniospinal irradiation is a mainstay in the treatment of these tumors with few exceptions.⁸

Figure 65-3 Evidence of leptomeningeal spread of medulloblastoma involving the cerebellum (A) and infundibular recess (B) on a postgadolinium T1-weighted MR image. Insets show disease by subtraction imaging (A, left) or in the alternative (sagittal) plane (B, right).

The side effects attributed to RT have been a primary concern for patients with medulloblastoma. The concern has been greatest for patients with average-risk disease, for whom long-term disease control is likely and the side effects of therapy have a lasting impact. The treatment of this tumor is technically demanding and consists of craniospinal irradiation and boost treatment of the anatomic posterior fossa. Until recently, the standard of care for an average-risk patient was postoperative craniospinal irradiation (CSI) to 36 Gy and boost treatment to 54 Gy using conventional fractionation of 1.8 Gy/day. In a cooperative group trial the CSI dose was lowered to 23.4 Gy for average-risk patients in a randomized comparison with 36 Gy CSI. This trial showed an increased risk of relapse in patients receiving the reduced CSI dose.⁹ Multiple-agent chemotherapy combined with reduced-dose CSI was found to be equivalent to standard-dose CSI and was subsequently adopted as a treatment standard for average-risk patients.¹⁰ Cognitive impairment continues to be a significant problem, with intelligence quotient (IQ) loss most commonly seen in children younger than the age of 8 years and those treated for high-risk medulloblastoma in which high-dose craniospinal irradiation (36 Gy) is required.¹¹

The most recently completed Children’s Oncology Group study sought to define the best chemotherapy regimen (lomustine [CCNU], cisplatin, and vincristine vs. cyclophosphamide, cisplatin, and vincristine) to accompany low-dose craniospinal irradiation and the standard posterior fossa boost. No differences were observed in disease control (3-year event-free survival >83% in both arms); however, patients treated with the cyclophosphamide-containing regimen appeared to have more severe toxicity (18% vs. 25%).¹² Attention has now turned to combining the two chemotherapy regimens and randomizing patients between 18.0 Gy and 23.4 Gy CSI followed by a second randomization between conventional boost treatment and treatment of less than the entire posterior fossa in an ambitious four-arm randomized trial developed for pediatric patients between the ages of 3 and 8 years. For those older than 8 years, the CSI dose remains at 23.4 Gy. The trial also includes a randomized comparison of conventional posterior fossa boost and boost treatment of the tumor bed using a 1.5-cm clinical target volume (CTV) margin.

Reducing the CSI dose does little to reduce the volume that receives the highest doses because the boost dose is prescribed to the entire posterior fossa. Reducing the boost volume for patients at average risk from the entire posterior fossa to the tumor bed with a limited margin has been recognized as critical to the goal of reducing the normal tissue volume that receives the highest doses.

Treatment of less than the entire posterior fossa after 23.4 Gy of CSI using focal radiation delivery techniques appears to be as effective as treatment of the entire posterior fossa based on recent trial results from St. Jude Children’s Research Hospital and participating centers involving 84 patients. In this prospective trial the cumulative incidence of posterior fossa failure was only 6.3% at 3 years.¹³ Treatment of these patients included postoperative CSI to 23.4 Gy, conformal posterior fossa boost to 36 Gy, and focal treatment of the tumor bed with a 2-cm margin. Chemotherapy was administered after RT. Patients on this study experienced a dose reduction to the anatomic posterior fossa of approximately 13%. The risks associated with reducing the CSI dose and limiting the boost treatment to the postoperative tumor bed with a limited margin must be balanced against the observed effects of RT on cognition, neurologic function, and growth and development.

Hyperfractionation has been tested in Europe to reduce toxicity.¹⁴ Although these investigations have shown that hyperfractionation may be isoeffective, lacking are the data that indicate side effects are reduced by this strategy. Considering logistics including the need for anesthesia in this often young patient population, investigators demand some certainty that there would be a benefit associated with hyperfractionated treatment before planning future trials.

Current cooperative group trials for very young children (<3 years of age) with medulloblastoma highlight the importance of RT in the treatment of these tumors. The recently completed Children’s Oncology Group protocol for children younger than the age of 3 years with localized medulloblastoma included 20 weeks of combination chemotherapy followed by second surgery when indicated and sequential irradiation of the posterior fossa and primary site before 20 additional weeks of maintenance chemotherapy.¹⁵ CSI was been omitted for these patients, and the doses to the posterior fossa (18 and 23.4 Gy) and primary site (45 to 54 Gy) were prescribed based on patient age, response, and risk status. A similar strategy was used in the Pediatric Brain Tumor Consortium (PBTC) protocol for similar patients with one exception: intrathecal chemotherapy (mafosfamide) was given during the first 20 weeks of chemotherapy as a substitute for CSI.¹⁶ Both protocols included RT after 20 weeks based on results from prior trials that showed a median time to progression of approximately 24 weeks.^17,18 The targeting guidelines used in these studies were largely empirical: investigators attempted to minimize the dose to normal tissues while maintaining an acceptable rate of local tumor control.

Fear of cognitive deficits has been the driving force in the design of current treatment trials for this young patient population. Age has the greatest impact on cognitive outcome after irradiation (Fig. 65-4). For very young children with medulloblastoma, a persistent decline in cognitive function has been observed by Walter and colleagues.¹⁹ The decline is not surprising given the median cranial dose of 35.2 Gy for patients with a median age of 2.6 years and the additive effects of tumor, surgery, and chemotherapy. Because a significant decline has also been observed for older children with medulloblastoma treated with lower craniospinal doses,¹¹ CSI for the youngest children no longer appears to be a reasonable treatment option. Data concerning the effectiveness of yet lower CSI doses are extremely limited.²⁰ These findings form the basis of the most recent trials for very young children. CSI has been omitted with the hope that the side effects of treatment will be reduced enough to provide for a meaningful quality of life among long-term survivors. There is a move to increase the age at which CSI is considered acceptable from age 3 years to 5 years at the time of treatment. Investigators acknowledge that they are trading fewer side effects for an increase in the rate of disseminated failure.

Figure 65-4 The cognitive effects of medulloblastoma depend on the age at the time of irradiation: estimated IQ (A), Wechsler Individual Achievement Test (WIAT) Math (B), WIAT Spelling (C), and WIAT Reading (D) scores.

From Merchant TE, Palmer SL, Lukose R, et al: Critical combinations of radiation dose and volume predict IQ and academic achievement after craniospinal irradiation in children, Int J Radiat Oncol Biol Phys 78:S17, 2010.

Ependymoma

Ependymoma is the third most common CNS tumor in children, affecting approximately 236 individuals younger than the age of 19 years annually in the United States.¹ It shares many of the clinical characteristics of more common gliomas, embryonal tumors, and less common germ cell tumors. Ependymoma may occur anywhere within the CNS and has the highest prevalence within the posterior fossa, arising from the floor or roof of the fourth ventricle or cerebellopontine angle, where it is known to invade the brainstem or envelop cranial nerves or vascular structures. Ependymoma also arises within the parenchyma of the cerebral hemispheres in older patients and rarely in the spinal cord. The interval from the onset of symptoms to diagnosis may be influenced by the young age at the time of diagnosis, the perceived slow growth rate of this tumor, and the remitting signs and symptoms of increased intracranial pressure resulting from obstructive hydrocephalus (Fig. 65-5).

Figure 65-5 Ependymoma of fourth ventricle and left cerebellopontine angle evident on preoperative axial T2-weighted MRI. Associated displacement of brainstem (yellow) by tumor (light blue) is shown in mirror images on the right.

Ependymoma is most commonly diagnosed in children who are younger than 4 years of age. For the past two decades, progress in the treatment of this tumor has been slowed by concerns about late effects. Recent advances in neuroimaging, surgery, and RT have moved the field of neuro-oncology forward in the treatment of this tumor, resulting in more acceptable outcomes and providing new disease control benchmarks. Investigators treating these patients with contemporary surgery and RT have been able to increase event-free survivals measured at 3 years from 55% to 62% to 75% when measured at 7 years with remarkably limited treatment-related effects.^21,22

The standard of care for a child with localized ependymoma is to attempt gross-total resection, perform second surgery for potentially resectable residual tumor, and proceed with postoperative RT directed at the primary site using a 10-mm, anatomically confined CTV surrounding the residual tumor and/or tumor bed as defined on postoperative neuroimaging. The recommended total dose is 59.4 Gy using conventional fractionation because these tumors are prone to recur locally. Conventions regarding organs at risk apply; thus, for patients with tumors arising in the lower aspect of the posterior fossa, avoidance of the spinal cord and/or chiasm should be considered after approximately 54 Gy. Special considerations for patients with posterior fossa tumors may apply to very young children (generally those younger than the age of 18 months) with no evidence of residual tumor or patients who are noted to have signs and symptoms of severe brainstem injury after resection (postoperative seizure, hypertension, and ischemic changes on neuroimaging) who are at increased risk for necrosis. The recent trial of the Children’s Oncology Group showed that there was consensus to irradiate children younger than the age of 3 years and as young as 12 months postoperatively. The newest study from the Children’s Oncology Group, known as ACNS0831 and initiated in 2010, deploys a similar treatment algorithm and methods of irradiation with a smaller (5 mm) CTV margin. Children are randomized to receive four cycles of postirradiation chemotherapy (Fig. 65-6).

Figure 65-6 Fourth ventricle, left cerebellopontine angle ependymoma. A, The relationship between the preoperative extent of tumor (black) and postoperative tumor bed (red) is demonstrated on treatment planning CT (upper row), preoperative T2-weighted MRI (middle row), and postoperative, postcontrast T1-weighted MRI (lower row). B, The relationship between the gross tumor volume (black), anatomically confined clinical target volume margin (3 mm) (yellow), and planning target volume (3 mm) (red) is demonstrated on the treatment planning CT (upper row), preoperative T2-weighted MRI (middle row), and postoperative, postcontrast T1-weighted MRI (lower row).

The prognosis for a patient with ependymoma is determined by tumor grade and extent of resection.23,24,25 Patients with overtly anaplastic tumors have inferior disease control when compared with those with differentiated tumors; however, the assignment of tumor grade can be difficult for those cases in which focal anaplasia occurs in the setting of a largely differentiated tumor. All patients should be treated with curative intent regardless of tumor grade. Extent of resection is an unequivocal prognostic factor: patients with substantial residual tumor have the worst prognosis. Because patients with varying amounts of residual tumor have achieved long-term survival after RT and modern surgical resection has altered the definition of near-total and subtotal resection, the volume of residual tumor differentiating between patients with good and poor prognosis remains unknown. It is incumbent on the radiation oncologist to question whether additional resection might be safely achieved in a patient with residual tumor referred for irradiation.

Research performed to evaluate molecular prognostic markers in ependymoma has revealed gain of 1q and homozygous deletion of CDKN2A as valuable predictors of poor survival in this disease²⁶ and other markers associated with more favorable outcomes. Although molecular markers are not likely to supplant standard histopathologic evaluation, they will certainly contribute beneficial information for separating tumors that appear to have features of both differentiated and anaplastic ependymoma and determining which patients might require additional treatment after gross-total resection and irradiation.

High-Grade Astrocytoma

Despite the fact that astrocytoma is the most common brain tumors in adults and children, major differences exist in the relative proportion of the various tumor subtypes and their management and outcomes. Tumors such as glioblastoma multiforme, anaplastic astrocytoma, anaplastic oligodendroglioma, malignant pleomorphic xanthoastrocytoma, and other malignant glial-neuronal tumors are uncommon in children, representing fewer than 10% of pediatric brain tumors and rarely found in children younger than the age of 4 years. Extent of resection compatible with acceptable neurologic outcome followed by postoperative RT to dose levels approaching 59.4 Gy using generous CTV margins surrounding residual tumor, tumor bed, and any suspicious abnormality on neuroimaging is standard therapy. Concurrent or postirradiation chemotherapy using conventional or investigational agents is routinely administered in patients with glioblastoma and anaplastic astrocytoma and on an individual basis for the other tumor types. For targeting purposes, the radiation oncologist should be aware that children with high-grade brain tumors may present with extensive changes throughout the brain that represent tumor extension along white matter tracts. Neuraxis dissemination is rare but should be ruled out before irradiation. Treatment volumes for these patients may appear to be relatively large but should not be compromised because of the patient’s age despite some indications that children with high-grade brain tumors stand a better chance of survival than their adult counterparts.

One study has shown a benefit for chemotherapy.²⁷ This study included a randomization of 58 patients with high-grade astrocytoma to local irradiation versus local irradiation plus weekly vincristine followed by 12 month of carmustine, vincristine, and prednisone. The reported 5-year progression-free survival rate was 18% versus 46% favoring the use of chemotherapy, and patients with glioblastoma multiforme (n = 40) had a 5-year progression-free survival of 6% versus 42% favoring the use of chemotherapy. A larger study that included 172 patients randomized between local irradiation versus local irradiation plus preirradiation and postirradiation 8-in-1 chemotherapy (i.e., with vincristine, carmustine, procarbazine, cytarabine, hydroxyurea, cisplatin, dacarbazine, and methylprednisolone) showed no difference between the two study arms with 5-year progression-free survivals of 26% and 33%, respectively.²⁸ This study was illustrative for the lack of concordance between institutional and expert pathology review. Thirty percent of patients in this study were found not to have high-grade glioma, and the survival estimates were in fact lower than originally reported.²⁹

Radiologists other than radiation oncologists may be under the impression that children with high-grade glioma are treated with lower doses than adults with the same diagnosis. The current standard is 59.4 Gy regardless of extent of resection; however, some recent studies have used only 54 Gy for those irradiated after gross total resection. The experience of the past two decades of the CCG-9921 study (activated 1993) for malignant infant tumors, including high-grade glioma, advised deferred RT after surgery and multiple-agent chemotherapy. Patients were randomized between regimens of cyclophosphamide, vincristine, etoposide, and cisplatin (five cycles) versus ifosfamide, vincristine, etoposide, and carboplatin (five cycles) and maintenance carboplatin, vincristine, cyclophosphamide, and etoposide (eight cycles). RT was administered at the time of progression or for those with metastatic disease or less than a complete response to induction chemotherapy. The timing of RT was attainment of 3 years of age or the completion of maintenance chemotherapy, whichever was earliest. The protocol specified local irradiation to 54 Gy except for patients younger than 18 months, who were to receive 50 Gy. The POG9431 study (activated 1996) included radiation dose regimens stratified according to residual disease. Those with no measurable disease received postoperative RT to 54 Gy with concurrent vincristine followed by postirradiation lomustine and vincristine for eight cycles. Patients with residual disease received two courses of preirradiation procarbazine or topotecan and a similar regimen of vincristine concurrent with RT. This was followed by postirradiation lomustine and vincristine for eight cycles. Those with measurable residual disease were irradiated to 54 Gy using standard margins (edema + 2 cm) followed by boost treatment of the enhancing residual tissue to 59.4 Gy using a 1-cm margin. Radiosurgery (10 to 12 Gy, single fraction) was allowed after 54 Gy in selected cases.

This was followed by the ACNS0126 study (activated 2002) that included concurrent temozolomide and RT followed by 10 cycles of postirradiation temozolomide. A total dose of 59.4 Gy was proposed using a combination of initial and boost volume treatment techniques. Those treated with gross total resection before RT received only 54 Gy. The CTV margins were 2 cm and 1 cm, respectively, with the addition of a 3- to 5-mm planning target volume using conformal methods. The guidelines for the ACNS0423 (activated 2005) were identical to those used earlier, and the patients received concurrent temozolomide with RT followed by six cycles of temozolomide and lomustine.

The ADVL0011 study followed in 2000 and included two 5-day courses of preirradiation temozolomide and lomustine in a phase I dose escalation and RT without concurrent chemotherapy followed by postirradiation temozolomide and lomustine for six cycles. The guidelines for this study included a volume reduction after 45 Gy followed by supplemental irradiation to 59.4 Gy because all patients had residual disease to be eligible for this study. The most recent cooperative group study for high-grade glioma, ACNS0822 (activated 2010), will include a volume reduction after 54 Gy, and all patients will receive 59.4 Gy. This complicated trial includes a randomized phase II/III design with suberoylanilide, arsenic trioxide, or temozolomide concurrent with irradiation followed by postirradiation bevacizumab and irinotecan for 12 cycles.

Low-Grade Astrocytoma

Low-grade astrocytomas are found throughout the nervous system in children yet are clustered predominantly in subsites of the cerebellum (cerebellum, cerebellar peduncles, dorsally exophytic brainstem glioma) or diencephalon, including the optic chiasm, optic pathways, hypothalamus, and thalami (Fig. 65-7). Slow-growing tumors located in these critical links of the nervous and endocrine systems result in presenting signs and symptoms that differ markedly from the other types of pediatric tumors that are prone to obstruction of CSF pathways. Loss of vision, dysdiadokinesia, dysmetria, ataxia, tremor, the spectrum of endocrinopathies including precocious puberty, and cognitive dysfunction are a few of the insidious signs and symptoms that are often overlooked in the developing child and lead to well-established deficits.

Figure 65-7 Pediatric low-grade glioma involving the third ventricle. Images show the pseudotumor response to irradiation. Axial postcontrast T1-weighted images from before (upper, left) and at 3 months (upper, right), 6 months (lower, left), and 15 months (lower, right) after the initiation of radiation therapy. Serial images show brilliant tumor enhancement and enlargement after treatment; enhancement and tumor volume diminish with time and conservative management.

Few inroads have been made in RT for pediatric low-grade astrocytoma in recent years, mainly because most who would be candidates for RT are younger children with optic pathway tumors. Indeed, advances in surgery have resulted in successful primary resection of most cerebellar and peripheral cerebral lesions, with long-term disease control exceeding 90% when measured at 5 years. In the setting of residual tumor after initial resection and in the absence of persistent symptoms, most children should follow a course of observation, with second surgery at the time of progression contingent on the associated risks. In a landmark study conducted from 1991 to 1996 and enrolling 726 patients with the intention of observation after surgery, the progression-free survival at 5 years was 92% for patients after gross-total resection, 53% after near-total resection, and 61% after subtotal resection. More than 75% of patients had juvenile pilocytic astrocytoma, and progression-free survival was lowest in midline (59%) and hypothalamic-chiasmatic tumors (50%) compared with tumors of the cerebellar hemisphere (89%), cerebellar vermis (84%), or cerebral hemisphere (89%).³⁰ Without information regarding the ability of follow-up surgery to render these patients disease free or asymptomatic, a large proportion of patients remain candidates for adjuvant therapy, including external beam RT.

Newly diagnosed patients with optic pathway tumors present a formidable challenge to the entire oncology team, and many radiation oncologists avoid rendering opinions. RT is the most effective treatment for optic pathway tumors, combining noninvasive therapy with durable tumor control in the majority of patients and an excellent track record in stabilizing and, in rare cases, reversing symptoms. Surgery may have a role to play when decompression of chiasm or nerves may be safely accomplished or when neuroimaging suggests that the tumor is localized and extrinsic to critical structures. Resection should be avoided or curtailed when disability is certain and the treatment plan calls for RT regardless of outcome.

In some centers, chemotherapy is recommended regardless of patient age, and in these settings the patient is seldom seen by the radiation oncologist. Chemotherapy has a track record of success in delaying RT for patients with pediatric low-grade astrocytoma but cannot be considered curative because the majority of patients will eventually require RT.^31,32 The results from a landmark study comparing two chemotherapy regimens for pediatric patients with low-grade glioma were surprising when they demonstrated that the progression-free survival rates were less than 50% even when stratified by age.³³ The progression-free survival rate estimated at 5 years was 35% for those treated with carboplatin and vincristine versus 48% for those treated with thioguanine, procarbazine, lomustine, and vincristine.

These results pale in comparison to RT series as outlined by Merchant and colleagues,³⁴ in which, in addition to profiling and comparing the results from different chemotherapy and RT series, they reported the results from their prospective series of 78 patients and 10-year event-free (74.3% ± 15.4%) and overall (95.9% ± 5.8%) survival estimates. The cumulative incidence of local failure at 10 years was only 16.4% ± 5.4%.

Indeed, fractionated RT remains the standard of care and CTV margins have been reduced from 10 to 5 mm in the current study of the Children’s Oncology Group. Although single-fraction irradiation (radiosurgery) has been used to treat well-defined areas of residual disease, experience is limited and, if the lesion is resectable, surgery is the preferred approach. Most children with low-grade astrocytoma have WHO grade I tumors, and conventionally fractionated RT to 54 Gy is recommended (see Fig. 65-7). Patients with disseminated low-grade astrocytoma should be approached with curative intent using craniospinal irradiation. Although dissemination is rare at presentation, the natural history of hypothalamic low-grade astrocytoma suggests a pattern of failure that is distant. Spinal imaging might be considered in the evaluation of these patients, especially those with hypothalamic tumors that have a relatively higher propensity to disseminate.

Given the natural history of these tumors, and experience gained through the observation of patients after a primary surgical approach that resected only a portion of the tumor, it is plausible that a certain proportion of these tumors might have stabilized or waxed and waned in terms of progression. A number of the patients included in the reported series include children with neurofibromatosis type 1, and 15% of patients with this type have optic pathway glioma. These patients are often diagnosed through screening procedures at an early age and have tumors that are prone to spontaneous progression and regression.

In the future, research will focus on molecular risk factors for disease progression after chemotherapy and it will be important to monitor outcomes after RT based on the same data when corrected for disease progression on chemotherapy and before RT. Research should be directed to help determine which patients are candidates for RT as a frontline approach and improve our understanding of the complications of this modality. A recent study has clarified the incidence and time to onset of clinically significant late effects such as cognitive effects (Fig. 65-8), hearing loss, or endocrinopathy, which appear to be low or predictable.³⁵ In a companion article,³⁴ the risk of vasculopathy was reported to be 4.8% ± 2.7% at 6 years and was higher for those younger than 5 years of age. Despite the number of irradiated children with optic pathway glioma, solid data regarding visual outcomes after irradiation are lacking in the modern era. Awdeh and colleagues³⁶ showed that patients treated with chemotherapy had significantly worse visual acuity at the start of irradiation compared with those who did not receive chemotherapy and that acuity declined significantly in those who received chemotherapy compared with those who did not. Their data suggested a role for decompressive surgery. Those who underwent a single surgical procedure before irradiation had significantly better visual acuity at the start of RT; however, there was no difference in change over time based on surgery.

Figure 65-8 IQ modeled during the first 60 months after conformal irradiation of pediatric low-grade glioma. The model [IQ = 95.5545 + Age × 0.3291 + Time × (0.0273 × Age − 0.0027 × V_0-30 Gy − 0.0047 × V_30-60 Gy)] suggests that the effect of age is an order of magnitude greater than the effect of the high-dose volume and that the effect of the high-dose volume is twice that of the low-dose volume.

Data from Merchant TE, Conklin HM, Wu S, et al: Late effects of conformal radiation therapy for pediatric patients with low-grade glioma. Prospective evaluation of cognitive, endocrine, and hearing deficits. J Clin Oncol 27:3691-3697, 2009.

Brainstem Glioma

Brainstem glioma refers to a diffuse intrinsic tumor most often involving the pons. This tumor has a characteristic appearance on MRI and does not require biopsy. Its outcome is uniformly fatal despite excellent responses to RT and corticosteroids. After years of attempting to escalate dose, alter fractionation, and sensitize this tumor to the effects of radiation, investigators have now turned to more targeted therapies in conjunction with conventionally fractionated RT to 54.0 to 55.8 Gy (Fig. 65-9).

Figure 65-9 Diffuse intrinsic brainstem glioma shown on axial and sagittal (inset) T2-weighted MR images.

Germ Cell Tumors

CNS germ cell tumors are rare among brain tumors affecting adults and children. Based on data from the Central Brain Tumor Registry of the United States, fewer than 197 are expected to be diagnosed annually in the United States. These tumors affect males more than females.¹

Progress in the treatment of CNS germ cell tumors has been slowed by the number of patients for protocol enrollment, the diversity of tumor histiotypes, the multitude of clinical presentations, the range of disease extent at diagnosis, the presence or absence of tumor markers, and the variable radiographic characteristics. The approach to the treatment of these tumors can be separated by histology into two groups, germinomatous and nongerminomatous germ cell tumors, with little overlap. Germinoma, which is analogous to seminoma in the extra-CNS setting, is highly sensitive to all forms of therapy, making decisions regarding management difficult with a major emphasis on side effects of treatment instead of disease control. Nongerminomatous germ cell tumors, in contradistinction to their extra-CNS analogues, are less sensitive to all forms of therapy.

The importance of staging cannot be overemphasized in the management of these patients. Poor staging affects classification for outcomes analysis, response evaluation, radiation dose and volume prescriptions, and the cure of these patients. High-quality spinal MRI is required as well as adequate CSF sampling. The negative predictive value of a single lumbar CSF cytologic analysis remains unclear and should be considered an important secondary objective in any major study. Serum and CSF α-fetoprotein and β-human chorionic gonadotropin studies are important for diagnostic and staging purposes, including response evaluation and making decisions regarding the use of surgery and RT; however, each institution and cooperative group has their own criteria for cutoff values and risk classification. Standardization in the use of serum and CSF markers is required as well as in the assays used for their measurement. In addition, markers such as carcinoembryonic antigen, placental alkaline phosphatase, lactate dehydrogenase, and the soluble form of c-KIT, a transmembrane tyrosine kinase receptor, should be investigated.³⁷

The diagnosis of a germinoma should require a biopsy. Although the radiographic appearance and location may be characteristic, because of the absence of markers and the differences in management between germinoma and other tumor types, a tissue diagnosis should be established. Histopathology in the setting of elevated markers is not necessary; however, when the tumor markers are negative, when β-human chorionic gonadotropin levels are low but elevated, or when there is any question concerning the diagnosis, I favor biopsy when it can be performed with a low risk of side effects. Although most biopsy specimens are extremely small and provide limited detail regarding tumor heterogeneity, a tissue sample can be invaluable after a poor or mixed response to therapy.

Based on the curability of extra-CNS germ cell tumors with multiple-agent chemotherapy it was logical for investigators to consider chemotherapy alone as a treatment option, and this option was pursued for a number of years because of concerns about the effects of RT. There have been two approaches with chemotherapy: chemotherapy alone and chemotherapy as a component of a combined modality approach involving the use of reduced dose and volume irradiation. There have been two successive trials attempting to treat tumors with chemotherapy alone.^38,39 These trials differed in the types of agents used as well as their intensity and sequencing. My impression from the first trial is that the event-free survival was short, the progression rate was high, and that there were a noticeable number of toxic deaths. My impression from the second trial was that outcomes were similarly poor and toxicity remained high. The key finding from these trials is that there is a subset of patients who may be effectively treated without irradiation and that salvage with RT, at least for the patients with germinoma, may be feasible. It would be important to find a way to determine which patients might be candidates to avoid RT and to consider this treatment approach only for the youngest patients. Toxic deaths using chemotherapy alone have made a bad impression; however, it has been acknowledged that such studies were carried out at centers that might not have been equipped to handle this type of patient and such treatment intensity.

There are too many combined modality approaches for CNS germ cell tumors to list, and it is hoped that the current and proposed studies through the Children’s Oncology Group comprise the best of prior experiences. The aim of the most recent nongerminomatous germ cell tumor study was to assess the ability of neoadjuvant chemotherapy, with or without preirradiation surgery, to reduce or eliminate measurable disease before RT. Patients received alternating combinations of carboplatin/etoposide and ifosfamide/etoposide every 3 weeks for 18 weeks (induction) followed by response assessment. Patients with progressive disease were taken off protocol; those with a complete response proceeded to craniospinal irradiation, which included neuraxis irradiation to 36 Gy and a focal boost to 54 Gy using a 1-cm CTV margin based on assessment of preinduction and postinduction neuroimaging. Those with less than a complete response had the option of surgical resection. Patients with more than 65% reduction in their volume of disease (partial response) after induction chemotherapy or induction chemotherapy and preirradiation surgery were treated with craniospinal irradiation, provided that their markers normalized. Those with stable disease or less than partial response and abnormal markers received consolidative chemotherapy using thiotepa/etoposide and peripheral stem cell rescue before RT. The combined complete and partial response rates are expected to be above 70% for this study group and it is hoped will translate into improved outcomes.

The proposed Children’s Oncology Group study for localized nongerminomatous germ cell tumors takes a similar approach to the prior study to include induction therapy at the time of enrollment, regardless of prior surgery, and risk adapted consolidation based on the two most important prognostic factors: serum α-fetoprotein and residual disease. Those in complete response at the end of induction will receive whole-ventricle irradiation to 30 Gy and primary site treatment to 54 Gy using a limited CTV margin. Those in less than complete response will undergo surgery to determine the nature of the residual disease. Those lacking malignant elements will proceed to consolidative irradiation as outlined earlier, and those with malignant elements will undergo myeloablative chemotherapy and standard irradiation: craniospinal (36 Gy) and primary site (54 Gy) irradiation. Those who are do not achieve complete response and who are not surgical candidates will receive the same intensive consolidation if their markers are elevated, whereas those with only residual disease and normal markers will receive standard irradiation.

The recent Children’s Oncology Group study for CNS germinoma did not successfully recruit enough patients to meet its objectives and was closed early. It proposed to randomize patients between “standard” RT and combined modality therapy consisting of two cycles of carboplatin and etoposide (induction) followed by RT (complete responders) or further chemotherapy and RT based on response assessment, mainly including those with minimal residual disease, partial responses, or stable disease. There were eight possible treatment groups combining the different possible stages of disease, responses, and randomization arms. For this trial, radiation oncologists developed a consensus for the RT guidelines: standard RT for patients with localized disease was considered ventricular irradiation to 24 Gy, followed by focal irradiation with 21 Gy for a total primary site dose of 45 Gy. Standard RT for patients with disseminated disease was considered craniospinal irradiation to 24 Gy, followed by focal irradiation with 21 Gy, for a total primary site dose of 45 Gy. Patients treated in the combined modality arm would receive response- and risk-adapted RT to include focal irradiation to 30 Gy for patients with localized disease with complete response after induction or focal irradiation to 40.5 Gy for patients with partial response after induction and complete response or minimal residual disease after two additional cycles of cisplatin and cyclophosphamide (Fig. 65-10). Variations to the proposed regimen were included for those patients with neuraxis dissemination at diagnosis. They were to receive combined modality treatment with craniospinal irradiation to 24 Gy, except for those patients who had a complete response to induction, in whom 21 Gy was proposed. In the future study, patients with localized CNS germinoma will undergo evaluation after the second and fourth of four 21-day cycles of carboplatin (600 mg/m² on day 1) and etoposide (150 mg/m² on days 1 to 3). Those in complete response will receive whole-ventricle irradiation to 18 Gy and primary site irradiation to 30 Gy, cumulative. Those in less than complete response will receive 24 Gy whole-ventricle irradiation and 36 Gy, cumulative, to the primary site after surgery is performed to determine the histologic response.

Figure 65-10 Example of whole-ventricle irradiation (WVI). The whole-ventricle volume includes the lateral third and fourth ventricles.

Craniopharyngioma

Craniopharyngioma represents one of the most difficult brain tumors treated by the radiation oncologist because of concerns about postirradiation morbidity and the technical and medical aspects of the treatment. Radical surgery is appropriate for certain patients when complete resection may be achieved without damaging the hypothalamus and affecting personality and quality of life. For other patients, limited surgery followed by fractionated external beam RT is recommended. The limited surgery approach includes surgical decompression of the cystic or solid components of the tumor to alleviate symptoms, restore vision, improve CSF flow, and reduce the volume of irradiation. The use of radiosurgery and intracystic isotopes should be reserved for recurrence. Radiosurgery has been shown to be useful for the treatment of small solid residual tumor. Intracystic isotopes have some usefulness in the treatment of cystic components measuring more than 2 to 3 cm in diameter; however, there is potential risk for significant morbidity. Neither is effective for the treatment of both cystic and solid components. Furthermore, concerns have been raised about irradiation of the optic nerves, chiasm, and proximal optic pathways.

Combined modality therapy (limited surgery and RT) was first proposed by colleagues at the St. Georges and Royal Marsden Hospitals more than 50 years ago. Long-term survivors treated using this approach were found to have good functional outcomes, whereas those treated with primary surgery seldom reached any level of independence and productivity. The Royal Marsden Hospital results for limited surgery and RT remain the standard to which others compare for disease control, reporting 10- and 20-year progression-free survivals of 83% and 79%, respectively.⁴⁰

Because there are fewer than 100 pediatric patients diagnosed with craniopharyngioma in the United States each year, the experience of any given institution in the treatment of these patients is limited. It may be difficult to determine the resectability of craniopharyngioma in some patients by imaging alone. Exploration can be undertaken with the goal of limiting surgery when indicated because RT can achieve disease control independent of the extent of resection. The greatest potential for injury from surgery has been noted in patients who undergo more than one attempt at resection.

Because the arachnoid layer is often adherent to the brain after the initial operation, bleeding may be difficult to control and identification of critical structures impossible, leading to a problematic postoperative course and increased late effects.

In some reports, the type of imaging, extent of resection, and preirradiation progression is a prognostic factor; however, there are no recent prospective series to confirm these reports. When the tumor recurs after treatment there are a number of options, ranging from surgery followed by aspiration and observation to radiosurgery and use of intracystic isotopes.

The debate between surgery and RT surrounds the side effects of each treatment. Surgical morbidity tends to be acute and permanent. Side effects from exposure to radiation may be early and transient and late and permanent. These patients experience a wide range of side effects that may affect neurologic, endocrine, and cognitive function and are at risk for vasculopathy, necrosis, and second tumors. The indication for RT includes any patient whose tumor cannot be completely resected without resulting in significant damage to the hypothalamus. External beam RT is recommended to the entire solid and cystic tumor using a limited CTV margin and doses in the range of 50.4 to 54 Gy. Although specific age criteria for the treatment of these patients has not been established, young patients with these centrally located tumors are at risk for late sequelae. In patients in whom the tumor has been resected and there remains minimal residual disease, most would be observed if the patient is very young (<5 years). Patients in whom cystic progression is likely should receive RT because accelerated cyst formation in response to RT is frequent. Treatment of these tumors should not be urgent. The time to response is approximately 9 months. Considerations should be given to imaging studies during RT when there is a chance that cystic enlargement might occur. Craniopharyngioma is amenable to the spectrum of focal irradiation delivery methods. The major debate between surgery and RT surrounds side effects. Prominent side effects of RT include effects on neurologic endocrine and cognitive function. In addition, there is the risk of vasculopathy (affecting the circle of Willis and its branches into the basal ganglia) and the risk of secondary malignant tumors and malignant degeneration of the original craniopharyngioma. Patients who receive RT regardless of preirradiation status are likely to develop panhypopituitarism. Diabetes insipidus is common but not attributable to RT. Patients may develop metabolic syndromes, in part owing to the combined effects of surgery and poorly treated endocrine deficiencies. Patients develop short-term and long-term side effects from radiation: changes in appetite, nausea and vomiting, headache, and the effects of increased cyst formation.

Choroid Plexus Tumors

Choroid plexus papilloma is treated with surgery and observation. Choroid plexus carcinomas, because of their vascular nature, are often treated with pre-resection chemotherapy and postoperative focal RT when localized, and residual microscopic or macroscopic tumor is known to remain at the primary site. Craniospinal irradiation has fallen from favor because of the young age at presentation and the effectiveness of chemotherapy but remains an option (Fig. 65-11).

Figure 65-11 Preoperative T2-weighted MR image of a choroid plexus carcinoma associated with the left lateral ventricle. Note the two flow voids at the anterior aspect of the tumor and the solitary flow void central to the tumor representing large feeder vessels for the highly vascular and cellular tumor.

Spinal Cord Tumors

Spinal cord tumors are rare and require special consideration.^41,42 The most common presentation is a localized low-grade astrocytoma involving the cervicothoracic spinal cord. Other locations and tumor types include myxopapillary ependymoma, generally involving the cauda equina or conus medullaris, localized ependymoma, and a variety of high-grade neoplasms, including anaplastic astrocytoma, glioblastoma multiforme, and PNET.

Neuraxis imaging should be performed in the absence of inflammatory or paramagnetic artifact from surgery. This is especially true for high-grade tumors and myxopapillary ependymoma in which metastatic spread occurs with a relatively high frequency. In the latter case, craniospinal irradiation may be given with curative intent when dissemination is documented early in the course of planning. Irradiation of the spinal cord–bearing tumor should not be undertaken unless the patient has been evaluated and even undergone exploratory surgery by an expert neurosurgeon. Because uncomplicated gross-total resection makes irradiation of ependymal and low-grade spinal cord tumors unnecessary, every effort should be made to consider resection. Because most practicing radiation oncologists fear spinal cord injury and resist irradiation of the spinal cord to dose levels above 45 Gy, treatment should be left to those who will consider curative dose levels, generally 54 Gy and above. Finally, care must be taken to ensure that the rostral and caudal extent of disease is encompassed with an appropriate margin despite the relatively large volume in a small individual. Homogeneity of dose and minimizing dose to normal tissues are requisite in the treatment of these patients.

Normal Tissue Tolerances and Side Effects

Long-term complications are central to decisions about the use of RT in children with CNS tumors. Despite their significance, until recently, the data have been limited, which has made it difficult to estimate the long-term effects of treatment.⁴³

RT for pediatric CNS tumors may affect neurologic, endocrine, and cognitive function and lead to somatic effects, parenchymal or vascular damage, and secondary neoplasms (Fig. 65-12). The risk of a particular side effect is governed by the age of the patient, time after treatment, location of the primary site, and the prescribed dose and volume. The effects of tumor such as hydrocephalus, irreversible neurologic impairment, and prior treatment, including surgery and chemotherapy, may exceed those expected from RT or RT alone, meaning that combinations of clinical and treatment factors should be considered. Genetic features of the individual may include mutations involving chromosome 17 (NF1), 11q22-q23 (ATM), and chromosome 7 (BRAF).

Figure 65-12 Extensive white matter leukoencephalopathy throughout the supratentorial brain and lacunar infarcts in various stages of progression as shown by T2-weighted MRI 5 years after surgery, craniospinal irradiation (36 Gy), and chemotherapy for left frontal atypical teratoid rhabdoid tumor.

When approaching the family of a child with a brain tumor to obtain permission for RT, the focus of discussion regarding side effects should be very specific, be balanced by the long-term prospects for disease control, and consider independent functional outcome. Because the dose and treatment volume have been systematically studied and specifically tailored for certain groups, the expected side effects may be driven largely by the diagnosis and reliably predicted or depend on tumor location and preexisting morbidity.

Children with the most common CNS tumors may experience a broad range of side effects. Those effects that appear in the perioperative period from tumor or surgery may contribute significantly to the side effect risk profile of RT when they exceed in scope the expected effects of irradiation, result in side effects normally attributable to irradiation, or reduce the tolerance of normal tissues to irradiation. Poignant examples include vision loss or endocrinopathies resulting from the direct compressive or infiltrative effects of tumor or hydrocephalus, resection of infiltrative tumors in the region of the cerebellum and brainstem to cause cerebellar mutism syndrome,⁴⁴ and ischemia of normal tissues through the compressive effects of tumor or from tumor resection. In the absence of such factors, predictions regarding side effects are driven by logical factors of treatment site, total dose, and the targeted volume. The weight of age is an order of magnitude greater than the effect of dose in most models that estimate cognitive effects based on dose and volume.

The cognitive effects of RT include effects on global intelligence, learning, memory, attention, and behavior. The adverse cognitive effects of RT in children with brain tumors are generally known only for children who have received whole-brain irradiation as a component of their treatment to dose levels of 18, 24, and 36 Gy. These doses are representative of those customarily used in the treatment of medulloblastoma. Fewer data are available showing the effects of partial brain irradiation in patients with other tumor types,^45,46 although data are forthcoming regarding this issue. Most studies have shown a relationship between discrete doses and age at treatment.⁴⁷ Age- and dose-related decline in IQ was first demonstrated in children who received 36 Gy. These patients had IQ scores approximately 8.2 points lower than those who received 24 Gy, and 12.3 points lower than those who received 18 Gy.⁴⁸ At least one study found no difference in effect on IQ between doses of 18 and 24 Gy among children older than 6 years but doses over 24 Gy adversely affected IQ.⁴⁵ Young age at the time of irradiation is the most important prognostic factor regardless of dose. Volume of irradiation is an important prognostic factor for functional outcome.⁴⁶ Children treated with partial-brain irradiation were more likely to have an IQ greater than 90 points at 5 years (60%) compared with those who received craniospinal irradiation. There is a need for additional data that describe the effects of focal irradiation to more limited volumes. The use of focal radiation techniques in the treatment of children with brain tumors, especially those who do not require craniospinal irradiation, presents a unique opportunity to study the cognitive effects of radiation dose to more limited volumes. The combined advantages of newer treatment methods and more limited volume guidelines have been demonstrated in children with ependymoma. Among 88 patients with localized ependymoma who received RT using a 1-cm CTV margin, there was no decline in IQ, memory, or academic achievement, including 48 children who were younger than the age of 3 years at the time of irradiation.⁴⁹ These same patients have contributed to separate reports correlating the effects of hydrocephalus and treatment dosimetry on outcome.^50,51 Similar encouraging findings have been demonstrated for a variety of patients in the assessment of attention, impulsivity, and reaction time.⁵²

Irradiation of the hypothalamic-pituitary unit leads to endocrine deficiencies. The incidence and time to onset of clinically significant endocrinopathies depends on the total dose to the hypothalamic-pituitary axis, time after irradiation, and other factors, namely, the direct (tumor invasion or mass effect) and indirect (hydrocephalus) effects of tumor. Residents have been taught that the pituitary is the organ at risk for the intracranial portion of the endocrine system and that panhypopituitarism is a foregone conclusion after irradiation of the sellar or suprasellar region. More recent data show the importance of the hypothalamus and the intrinsic and differential sensitivity of the hypothalamic nuclei.⁵³ Among hormone deficiencies observed after RT, growth hormone deficiency is most common, followed by adrenocorticotropic hormone and gonadotropin secretion abnormality, and, finally, less common, hypothyroidism (central). Growth hormone deficiency has been observed after doses as low as 10 Gy and as early as 6 to 12 months after RT at higher doses.⁵⁴

Although recent attention has been focused on the contribution of RT to hypothalamic obesity, other deficiencies, such as diabetes insipidus and hyperprolactinemia, are attributed to local tumoral effects and often surgery when it affects the structural integrity of the hypothalamic-pituitary axis. Supporting what radiation oncologists often suspected, provocative endocrine testing before the administration of RT has revealed a surprising level of preexisting endocrine deficiencies. These experiences illustrate the importance of prospective baseline and serial testing for side effects and the presence of transient or permanent effects due to the effects of tumor, surgery, and chemotherapy. The radiation oncologist should be aware of the potential to contribute to thyroid injury and ovarian failure in patients who receive craniospinal irradiation. The thyroid is often included in the posteroanterior spinal field and the lower border of the spinal field, and the divergent nature of the field used to treat the lower aspect of the thecal sac may incidentally irradiate the ovaries.

Hearing loss is a potential complication of RT in children. Radiation may affect the conducting system of the ear. The best example is serous otitis media resulting from mucociliary dysfunction during and after RT. Soft tissue infections of the ear should be treated aggressively, and instrumentation of the external auditory canal should be undertaken cautiously. Sensorineural hearing loss may occur as a result of damage to the cochlea or other parts of the auditory system. Because the doses administered are below the threshold for obvious neurologic impairment of hearing, effects of radiation on the cochlea are more common and usually noted months or years after treatment. The incidence and time course due to radiation is unknown. Most children also receive ototoxic chemotherapy and are therefore at risk for the combined effects of both treatments.⁵⁵

Dental complications are uncommon but may occur in patients with brain tumors who receive craniospinal irradiation when the salivary glands are subtended by the irradiated volume. Medications used to treat seizure disorders and other neurologic conditions may contribute to tooth decay. Other long-term somatic complications include permanent hair loss, wound healing problems, softening of the bone and ligaments of the spine, and spinal growth impairment and small head size. Patients with optic pathway glioma and, to a lesser extent, craniopharyngioma appear to have a higher incidence of vasculopathy in general, a higher incidence after RT, and an acceleration of preexisting abnormalities. As more children become long-term survivors and neuroimaging improves, subclinical abnormalities on follow-up imaging are seen with increasing frequency, including microangiopathy with calcifications, lacunar infarcts, and transient or permanent enhancing or T2-signal abnormalities, most often but not always in the region that receives the highest dose (see Fig. 65-12). Some changes are more apparent in patients who receive chemotherapy or those known to have suffered ischemia at the time of surgery. Second tumors are an unfortunate complication of RT for CNS tumors. They tend to occur years after treatment, usually when the patient is considered cured. The reported incidence of malignant brain tumors at 10 years is approximately 1% when considering patients with medulloblastoma or ependymoma. Secondary malignancies are a common cause of late morbidity and mortality in medulloblastoma survivors.

Certain caveats are important for the long-term predictions about the quality of survivorship and are often difficult to make because of the tremendous differences in current treatments compared with those administered in the past. In addition, the unfortunate competing risk of treatment failure reduces the weight of side effects in the consent discussion for some patients. Long-term survivors of brain tumor are more likely to have diminished social function.

Supportive Care

Supportive care for children with brain tumors is required throughout the course of RT. Short-term side effects may include nausea, vomiting, fatigue, loss of appetite, headache, and recurrence of neurologic symptoms present at the time of diagnosis. Prophylactic treatment with antiemetics may be appropriate because many children are not able to articulate their feelings of nausea and reversal of appetite suppression may be difficult once established. First-line medications may include ondansetron (Zofran) or a similar serotonin antagonist, second-line medications include promethazine (Phenergan), or diphenhydramine (Benadryl), and third-line medications include corticosteroids, which should be reserved for patients with intractable nausea, vomiting, and neurologic symptoms including headache. Persistent nausea over several months after treatment has been observed in patients whose tumors arose along the dorsum of the brainstem.

Children are unlikely to require antiseizure medication after surgery and corticosteroids during RT. It is important to determine the need for antiseizure medications when encountering a patient who is in the immediate postoperative period and destined to receive RT. Those administered phenytoin are at increased risk for Stevens-Johnson syndrome and toxic epidermal necrolysis. Those administered levetiracetam risk interactions with a broad range of commonly used over-the-counter and prescribed medications used commonly for ongoing care. It is important to encourage and monitor corticosteroid tapering. Patients treated with corticosteroids preferentially gain weight, which increases head size, affecting immobilization. Those taking corticosteroids need to be monitored for oral candidiasis and require gastrointestinal prophylaxis. For some patients, the need for CSF shunting may not be apparent in the perioperative period and should be monitored carefully. The need for CSF shunting is highest among children who have more than one surgical procedure.

Headache is a complaint that spans the time from diagnosis to beyond treatment for many patients. And although it is a relatively common complaint attributed to the effects of tumor and surgery it may represent a number of underlying conditions: hydrocephalus, shunt failure, infection, brain shift, cyst progression, subdural fluid collection or hemorrhage, vasculopathy, and tumor progression. In the absence of an obvious cause there are a number of first-line medications (e.g., amitriptyline, divalproex, topiramate) that can be used to reduce headaches, which may be frustrating if not debilitating for some patients.

Sedation and anesthesia are imperative in the treatment of young children with brain tumors. The demand has increased because of the requirements of focal radiation delivery protocols and the need to reduce the setup margin component of the planning target volume. At most centers, the majority of children younger than the age of 6 to 7 years require RT. Sedation or anesthesia is generally safe and does not appear to add to the acute effects of treatment, but the use of sedation on a repeated basis does not appear to be as effective as anesthesia.