General Information

The National Cancer Institute provides the PDQ pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public. The PDQ childhood brain tumor treatment summaries are organized primarily according to the 2000 World Health Organization classification of nervous system tumors.[1]

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%.[2] Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.

Primary brain tumors are a diverse group of diseases that together constitute the most common solid tumor of childhood. Brain tumors are classified according to histology, but tumor location and extent of spread are important factors that affect treatment and prognosis. Immunohistochemical analysis, cytogenetic and molecular genetic findings, and measures of mitotic activity are increasingly used in tumor diagnosis and classification. Refer to the PDQ summary on Childhood Brain and Spinal Cord Tumors for information about the general classification of childhood brain and spinal cord tumors.

Diagnostic Evaluation

Every patient with newly diagnosed medulloblastoma should be evaluated with diagnostic imaging of the entire neuraxis and, when possible and safe, lumbar cerebrospinal fluid analysis.

Predictors of Outcome

Patients with disseminated disease at diagnosis are clearly at highest risk for disease relapse.[3,4,5] Other factors that portend an unfavorable outcome include younger age at diagnosis (in the absence of extensive nodularity) and possibly, a subtotal resection; however, the amount of residual disease after surgery has not been found to be a robust predictor of outcome, especially when chemotherapy was added to radiation therapy as part of postoperative treatment.[6,7] Similarly, the presence of brain stem involvement at diagnosis has not been shown to be predictive of outcome.[7,8]

In addition, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analyses to correlate with outcome.[9,10] These molecular genetic immunohistochemical and histopathologic findings have not been shown to be predictive of outcome in prospective studies and with the exception of anaplasia/large cell variant, are not yet incorporated into stratification schema. However, it is likely that one or more of these biologic findings may yet be utilized, possibly in combination with factors such as extent of dissemination at the time of diagnosis, age of the patient, and amount of residual disease after surgery to better categorize patients with medulloblastoma into risk subgroups.[11,12,13,14,15,16]

A host of biologic parameters that may be predictive of outcome have been identified. These parameters include the following:

• DNA ploidy.[17,18,19,20]
• TrkC (neurotrophin-3 receptor)expression.[21,22]
• MYCexpression.[23,24,25,26]
• ERBB 2expression.[22,27]
• Chromosomal 17p loss.[24,28]
• Overexpression of platelet-derived growth factor receptor.[29]
• p53 expression.[22,30,31]
• Chromosome 6q gains and losses.[32]
• Survivin expression.[33]
• Beta-catenin immunostaining.[34]
• mRNA expression profiling.[35]
• Multigene expression profiling.[36]

Among these genetic alterations, the most robust predictors of outcome appear to be the following:

Integrated genomics identifies multiple medulloblastoma subtypes with distinct genetic profiles, pathway signatures, and clinicopathological features. Interestingly, in a recent study of adult medulloblastomas, MYC oncogene amplifications were rarely observed and tumors with 6q deletion and nuclear beta-catenin activation did not share the excellent prognosis seen with pediatric medulloblastomas.[11,12,13,14,30,32,34,37,38,39]

Furthermore, DNA sequencing studies have demonstrated fewer mutations in medulloblastoma than in adult carcinomas and a positive correlation between patient age and the number of mutations found. The relatively low numbers of mutations suggest that fewer driver mutations are required for medulloblastoma tumorigenesis. In addition, genome-wide association studies have identified mutated genes previously not implicated in medulloblastoma pathogenesis, such as the tumor suppressors MLL2 and MLL3, from the family of genes affecting histone methylation.[40] These findings add an additional layer of complexity to the biologic understanding of medulloblastoma.

References:

Cellular Classification of Central Nervous System (CNS) Embryonal Tumors

The classification of a childhood brain tumor is based on both the histopathologic characteristics of the tumor and its location in the brain.[1,2,3] The histopathological classification of childhood central nervous system (CNS) embryonal tumors remains somewhat controversial. These tumors all develop on the background of an undifferentiated round cell tumor but show a variety of divergent patterns of differentiation. Although it has been proposed that these tumors be merged under the term primitive neuroectodermal tumor, histologically similar tumors in different locations in the CNS demonstrate different genetic alterations.[4,5,6,7] In the 2007 World Health Organization (WHO) classification, embryonal tumors include the following:[2,8]

• Medulloblastoma.
• CNS primitive neuroectodermal tumors (PNETs).
• Medulloepithelioma.
• Ependymoblastoma.
• Atypical teratoid/rhabdoid tumor. Refer to the PDQ summary onChildhood Central Nervous System Atypical Teratoid/Rhabdoid Tumorsfor more information.

Pineoblastoma, a tumor histologically similar to CNS embryonal tumors, is reviewed in this summary, although pineoblastoma is grouped with tumors of the pineal region in the WHO classification.

By definition, medulloblastomas must arise in the posterior fossa.[1,2,3] Five different subtypes of medulloblastoma are recognized by the WHO classification and includes the following:

• Classic.
• Desmoplastic/nodular.
• Medulloblastoma with extensive nodularity.
• Large cell.
• Anaplastic.[1]

Significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[9,10] Classification is a complicated matter because most medulloblastomas have some degree of anaplasia, foci of anaplasia may appear in tumors with histologic features of both classic and large cell medulloblastomas, and there is significant overlap between the anaplastic and large cell variant.[9,10,11,12] The incidence of medulloblastoma with desmoplastic variant is higher in infants, is less common in children, and increases again in adolescents and adults. The desmoplastic variant subtype is different from medulloblastoma with extensive nodularity; the nodular variant having an expanded lobular architecture. The nodular subtype occurs almost exclusively in infants and carries an excellent prognosis.[12]

CNS PNETs generally arise in the cerebrum or suprasellar region. According to the 2007 WHO classification, tumors demonstrating areas of distinct neuronal differentiation are termed cerebral neuroblastomas and, if ganglion cells are also present, ganglioneuroblastomas. The pineoblastoma is histologically similar to the medulloblastoma; however, according to the WHO, its histogenesis is linked to a pineal cell, the pineocyte. Histologically different from the pineocyte, a pineal parenchymal tumor of intermediate differentiation showing elements of pineoblastoma and pineocytoma is recognized, although its natural history is variable and poorly characterized.[1,2]

Both medulloepithelioma and ependymoblastoma are identified as histologically discrete tumors within the WHO classification system.[8,13] Medulloepithelioma and ependymoblastoma tumors are rare and tend to arise most commonly in infants and young children. Medulloepitheliomas, which histologically recapitulate the embryonal neural tube, tend to arise supratentorially, primarily intraventricularly, but may arise infratentorially, in the cauda, and even extraneural, along nerve roots.[8,13]

The existence of ependymoblastomas as a discrete entity has been questioned, although it remains in the most recent WHO classification. Ependymoblastoma is characterized by the presence of true multilayered (or ependymoblastic) rosettes.[14,15] The tumor has a supratentorial predilection, but like medulloepithelioma, it may occur in the spine, especially in the sacrococcygeal region. Histologically, the tumor shares features with other embryonal tumors and with a rare tumor type, the "embyronal tumor with abundant neuropil and true rosettes" (ETANTR).[14,15,16,17] The latter entity is characterized by young age at diagnosis (median age approximately 2 years), primarily supratentorial presentation, poor prognosis, and tumors showing true multilayered/ependymoblastic rosettes within a background of abundant neuropil-like areas.[15,17,18] In addition to sharing clinical characteristics (i.e., age, primary site, and prognosis), ependymoblastoma and ETANTR show common genomic alterations, including chromosome 2 gain and focal amplification at chromosome band 19q13.42. The latter chromosome region contains a cluster of microRNA coding genes,[19] and its amplification appears to be present in virtually all pediatric embryonal tumors with true multilayered rosettes (i.e., ependymoblastoma and ETANTR).[18,19,20] By contrast, 19q13.42 amplification has not been detected in more than 300 other pediatric brain tumors, suggesting that it may be a useful diagnostic marker for ependymoblastoma and ETANTR.[18]

The pathologic classification of pediatric brain tumors is a specialized area that is evolving. Immunohistochemical staining is now a routine component of evaluation.[9,10] Molecular genetic profiles are also being incorporated into evaluation and may radically alter classification in the future.[21,22,23,24] For example, gene expression profiling divides medulloblastoma into distinctive biological subtypes that differ in their clinical presentation, their underlying genomic abnormalities, and their immunohistochemical staining pattern.[23,24]

Possible subgroups include the following:

• Medulloblastoma with aberrations in the WNT pathway: These cases occur most commonly in older children and are characterized by beta-catenin nuclear immunoreactivity, monosomy 6, classic medulloblastoma histology, and have a highly favorable outcome in children.[22,23,24]
• Medulloblastoma with aberrations in the sonic hedgehog (SHH) pathway: These cases represent the majority of medulloblastoma arising in young children (age <3 years) and also occur commonly in older adolescents and adults. They are characterized by chromosome 9q deletions, by desmoplastic/nodular histology, and by mutations in SHH pathway genes includingPTCH1, as well asPTCH2,SMO, andSUFU. The primary histology for these cases is desmoplastic. Outcome is relatively favorable for these cases.[21,22,23,24]
• Medulloblastoma associated with other genomic alterations: These other subgroups defined by gene expression profiling are enriched for isochromosome 17q (k17q) and for poor biological prognostic factors such asMYCandMYCNamplification. These subgroups include cases with classic, as well as large cell and anaplastic histology and include most medulloblastoma cases that present with metastatic disease.[21,22,23]

References:

Staging of CNS Embryonal Tumors

Staging of Medulloblastoma

Evidence suggests that medulloblastomas originate from two different germinal zones within the cerebellum. The ventricular zone gives rise to the more common classic midline medulloblastomas, whereas granule neuron precursor cells of the external granule layer are believed to give rise to the lateral cerebellar hemispheric desmoplastic medulloblastomas. The tumors may spread contiguously to the cerebellar peduncle, along the floor of the fourth ventricle, into the cervical spine, or above the tentorium. At the time of diagnosis there is spread via the cerebrospinal fluid (CSF) to other intracranial sites, the spinal cord, or both in 10% to 30% of patients.[1,2,3]

Magnetic resonance imaging (MRI) is the method of choice to evaluate for intracranial or spinal cord subarachnoid metastases. To avoid postoperative artifacts, such imaging is best performed preoperatively, but postoperative evaluation is also useful when obtained at least 10 days following the operative procedure. The entire spine must be imaged in at least two planes, with contiguous magnetic resonance slices performed before and after gadolinium enhancement. The significance of positive CSF cytology in samples obtained within the first 7 to 10 days of diagnosis is unclear, as is the significance of tumor cells in cisternal fluid obtained at the time of surgery. However, CSF tumor cells found 2 to 3 weeks after diagnosis portends a poorer prognosis.[1,2,3] Extracranial spread of medulloblastoma at the time of diagnosis is less than 1%. Although bone scans and bone marrows have been routinely obtained in some older prospective studies, their yield was low and they are primarily recommended for infants or those with widespread intracranial disease, intraspinal disease, or those with symptoms and signs consistent with possible dissemination.[2,3] CSF shunts placed at the time of surgery have not been shown to increase the risk of leptomeningeal relapse.[2]

Historically, staging has been primarily based on an intraoperative evaluation of both the size and extent of the tumor, coupled with postoperative neuroimaging of the brain and spine and cytological evaluation of CSF. MRI of the brain and spine (often done preoperatively), postoperative MRI of the brain to determine the amount of residual disease, and lumbar CSF analysis are now used to determine staging.[1,2,3] Surgical impressions, including direct observation of dissemination at the time of diagnosis, extent of residual disease following surgery, and involvement of the brain stem, are still incorporated into staging systems.

Staging of Pineoblastoma

Staging for children with pineoblastomas is the same as that performed for children with medulloblastoma.[4] Dissemination at the time of diagnosis occurs in 10% to 30% of patients.[4] Because of the location of the tumor, total resections are uncommon, and most patients have only a biopsy or a subtotal resection before postsurgical treatment.[4,5] Similar to other central nervous system (CNS) primitive neuroectodermal tumors (PNETs), all pineoblastomas are treated as high-risk embryonal tumors. Prognosis is worse for patients with disseminated disease at the time of diagnosis.[4,5]

Staging of CNS PNETs

Patients with CNS PNETs are staged in a fashion similar to that used for children with medulloblastoma. CNS PNETs may be disseminated at the time of diagnosis, although the incidence of dissemination may be somewhat less than that of medulloblastomas or pineoblastomas, with dissemination at diagnosis being documented in approximately 10% to 20% of patients.[6,7] CNS PNETs are often amenable to resection; in series, 50% to 60% of patients were totally or near-totally resected.[6,7]

Staging of Other CNS Embryonal Tumors

Dissemination of both medulloepitheliomas and ependymoblastomas may occur, and the tumors are staged in the same way as medulloblastoma.

References:

Treatment Option Overview

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Risk Stratification for Medulloblastoma

On the basis of neuroradiographic evaluation for disseminated disease, cerebrospinal fluid (CSF) cytological examination, postoperative neuroimaging evaluation for the amount of residual disease, age of the patient, and impression of the surgeon at the time of surgery, patients with medulloblastoma have been historically stratified into the following two risk groups:

• Average risk: Children older than 3 years with tumors that are totally resected or near-totally resected (<1.5 cm of residual disease) and no metastatic disease.[1]
• High risk: Children aged 3 years and younger or those with metastatic disease and/or subtotal resection (>1.5 cm of residual disease).[1]

The 1.5 cm standard was arbitrarily chosen for evaluation in prospective studies. Metastatic disease includes neuroradiographic evidence of disseminated disease, positive cytology in lumbar or ventricular CSF obtained more than 7 days postsurgery, or extraneural disease.[2]

An intense area of study is the use of molecular and immunohistochemical analysis for disease stratification. In a large, multi-institution, retrospective biologic study, 397 medulloblastoma specimens were analyzed by transcriptional profiling (103 specimens) and immunohistochemical analysis.[3] Four unique clusters of medulloblastomas were identified. The following two subgroups clearly stood out:

• A subset with WNT signaling that occurred in those with monosomy 6 abnormalities and beta-catenin nuclear staining. This subset was primarily older children and adolescents and had a female predominance.
• A subset driven by sonic hedgehog (SHH) signaling, arising predominantly, but not exclusively, in those with desmoplastic tumors and having immunohistochemical staining of SHH pathway elements. This subset consisted of infants, adolescents, and adults.

Patients from both of these subgroups had excellent prognoses; 80% or greater 5-year progression-free survival (PFS) and overall survival (OS). The remainder of medulloblastomas, which comprise the majority of the study cohort, were separable into two other subgroups, which had greater overlap and shared a poorer prognosis, including a 30% to 45% chance of dissemination. The latter two subsets (termed Group C and Group D) differed in the following ways:

• Immunohistochemical staining.
• Histological appearance (Group C was more likely anaplastic).
• MYCamplifications (found only in Group C).
• Likelihood of metastasis (higher in Group C)
• Age at presentation (Group C occurred more commonly in childhood, whereas Group D occurred in childhood, adolescence, and adulthood).
• Overall survival (lower in Group C).

PFS for patients with Group C and D tumors ranged between 32% and 63%.[3] Other studies have confirmed the excellent prognosis of children with WNT tumors and poor prognosis of those with tumors with MYC amplification.[4,5] If this type of molecular and immunohistochemical separation can be confirmed in a homogeneously treated population of patients, preferably studied prospectively, it will dramatically alter disease stratification and likely therapy offered.[6]

Surgery

Surgery is usually the initial treatment for children with medulloblastoma, both to confirm diagnosis and to remove as much tumor as is safely possible. Evidence suggests that more extensive surgical resections are related to an improved rate of survival, primarily in children with nondisseminated disease at the time of diagnosis.[7,8] One study in high-risk patients utilized presurgical chemotherapy (after tumor biopsy) to reduce tumor bulk and make subsequent resection of the tumor easier.[9] This small study did not demonstrate a high rate of survival, and postchemotherapy surgery did not seem easier and was not related to a reduced incidence of postoperative complications.

Postoperatively, children may have significant neurologic deficits caused by preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[10][Level of evidence: 3iC] In addition, a significant number of patients with medulloblastoma will develop delayed onset of mutism, suprabulbar palsies, ataxia, hypotonia, and emotional lability. This constellation of findings has been termed the cerebellar mutism syndrome, and its etiology remains unclear, although cerebellar vermian damage has been postulated as a possible cause for the mutism.[11,12]; [13][Level of evidence: 3iC] In two Children's Cancer Group studies evaluating children with both average-risk and poor-risk medulloblastoma, the syndrome has been identified in nearly 25% of patients.[12,13]; [14][Level of evidence: 3iiiC] Many patients with this syndrome may manifest neurologic and neurocognitive sequelae posttreatment.[13,14]

Radiation Therapy

Radiation therapy is usually initiated after surgery with or without concomitant chemotherapy.[15,16,17] To date, the best survival results for children with medulloblastoma have been obtained when radiation therapy is begun within 4 to 6 weeks postsurgery.[15,16,17,18]; [19][Level of evidence: 1iA]

Prospective randomized trials and single-arm trials suggest that adjuvant chemotherapy given during and after radiation therapy improves overall survival for children with both average-risk and poor-risk medulloblastoma.[14,15,16,17,18,19] Although medulloblastoma is often sensitive to chemotherapy, preradiation chemotherapy has not been shown to improve survival compared with treatment with radiation therapy and subsequent chemotherapy. In some prospective studies, preradiation chemotherapy has been related to a poorer rate of survival.[16,17,18,19]

Children of all ages are susceptible to the adverse effects of radiation on brain development. Debilitating effects on growth and neurologic/cognitive development have been frequently observed, especially in younger children.[20,21,22,23] For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy has been and is being studied. Results suggest that chemotherapy can be used to delay and sometimes obviate the need for radiation therapy in 20% to 40% of children younger than 3 years with nondisseminated medulloblastoma.[24,25]; [26][Level of evidence: 3iiiC] Children are also at risk for long-term endocrine dysfunction.[26]

Surveillance Testing

Surveillance testing is a part of all ongoing medulloblastoma studies.[27,28,29] Although most treatment failures in patients newly diagnosed with medulloblastoma will occur within the first 18 months postdiagnosis, relapses many years after diagnosis have been noted.[30] In addition, secondary tumors have been increasingly diagnosed in long-term survivors.[29,30]; [31][Level of evidence: 2A] As with initial management, long-term management is complex and requires a multidisciplinary approach.

References:

Treatment Options for Newly Diagnosed Childhood Medulloblastoma

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Children with medulloblastoma are stratified into average-risk and poor-risk subsets. Owing to concerns about the long-term neurocognitive sequelae of whole-brain radiation therapy on the developing brain, radiation therapy for younger children has often been delayed or eliminated. Children younger than 3 years and sometimes as old as 5 years have not received the same treatment as older patients.

In all subgroups of patients, surgery is the initial means of therapy, and maximal tumor resection is the goal of treatment. Postsurgical treatment has diverged, to some degree, on the basis of risk stratification and age of the patient.

Average Risk

Standard treatment options

The traditional postsurgical treatment for patients with average-risk medulloblastoma has been 54 Gy to 55 Gy of radiation therapy to the posterior fossa and 36 Gy to the entire neuraxis (i.e., the whole brain and spine).[1,2,3,4] With radiation therapy alone, 5-year event-free survival (EFS) ranges between 50% and 65% in those with nondisseminated disease.[2,3] While the standard boost in medulloblastoma is the entire posterior fossa, patterns of failure data suggest that radiation therapy to the tumor bed instead of the entire posterior fossa would be equally effective and possibly associated with reduced toxicity.[5,6] The minimal dose of craniospinal radiation needed for disease control is unknown. Attempts to lower the dose of craniospinal radiation therapy to 23.4 Gy without chemotherapy have resulted in an increased incidence of isolated leptomeningeal relapse.[4]

Chemotherapy is now a standard component of the treatment of children with average-risk medulloblastoma; a variety of chemotherapeutic regimens have been successfully used, including the combination of cisplatin, lomustine, and vincristine or the combination of cisplatin, cyclophosphamide, and vincristine.[1,2,7] Radiation therapy and chemotherapy given during and after radiation therapy has demonstrated 5-year EFS rates of 70% to 85%.[1,2,3]; [8][Level of evidence: 2A] A lower radiation dose of 23.4 Gy to the neuraxis when coupled with chemotherapy has been shown to result in disease control in up to 85% of patients and may decrease the severity of long-term neurocognitive sequelae.[7,9,10,11]

Long-term survivors who were prepubertal at the time of diagnosis are at high risk for growth failure due to radiation-related hypothalamic failure as well as effects of radiation on spinal growth. Lower doses of craniospinal radiation therapy may decrease the incidence of hypothalamic dysfunction, but this has not yet been proven. Growth hormone replacement therapy has not been shown to increase the likelihood of disease relapse.[12]

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ACNS0331(Comparison of Radiation Therapy Regimens in Combination With Chemotherapy in Treating Young Patients With Newly Diagnosed Standard-Risk Medulloblastoma): This Children's Oncology Group (COG) phase III trial is randomly assigning children between the ages of 3 years and 8 years to receive either 18 Gy or 24 Gy of craniospinal radiation and randomly assigning children between the ages of 3 years and 21 years to receive either conformal tumor site radiation therapy or posterior fossa radiation therapy. Patients with anaplastic medulloblastoma are not eligible. In this study, children receive weekly vincristine during radiation therapy and lomustine, vincristine, cisplatinum, etoposide, and cyclophosphamide after radiation therapy for a period of about 1 year.

High Risk

Standard treatment options

In high-risk patients, numerous studies have demonstrated that multimodality therapy improves the duration of disease control and overall disease-free survival (DFS).[13,14] In contrast to standard-risk treatment, the craniospinal radiation dose is generally 36 Gy. Studies show that approximately 50% to 60% of patients with high-risk disease will experience long-term disease control.[1,13,14,15,16] The drugs that have been found to be useful in children with average-risk disease are the same drugs that have been used extensively in children with poor-risk disease, including cisplatin, lomustine, cyclophosphamide, etoposide, and vincristine.

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ACNS0332(Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor): This COG phase III trial for children older than 3 years is evaluating the efficacy of adding carboplatin to radiation therapy with vincristine, followed by maintenance chemotherapy with conventional adjuvant chemotherapy and isotretinoin.

Children Aged 3 Years and Younger

Standard treatment options

The treatment of children younger than 3 years with newly diagnosed medulloblastoma continues to evolve. Due to concerns over the likely deleterious effects of craniospinal radiation on the immature nervous system, therapeutic approaches have attempted to delay and, in some cases, avoid the use of craniospinal radiation therapy. Results have been variable, and comparison across studies has been difficult because of differences in drug regimens used and the utilization of craniospinal and local boost radiotherapy at the end of chemotherapy or when children reached age 3 years in some studies. Five-year, DFS rates have ranged between 30% and 70% with the majority of long-term survivors successfully treated with chemotherapy alone, having nondisseminated, totally resected tumors.[17,18,19] The histologic finding of desmoplasia has been found to connote a better prognosis, and preliminary results also suggest that specific molecular findings, such as elevated TrkC expression and low MYC expression may also identify subsets of patients who are more likely to be successfully treated with chemotherapy alone.[20,21,22,23]; [24][Level of evidence: 2A]

Therapies have included the use of multiagent chemotherapeutic approaches, including drugs such as cyclophosphamide, etoposide, cisplatin, and vincristine, with or without concomitant high-dose intravenous methotrexate and/or intrathecal methotrexate or mafosfamide.[17,18,19,25,26,27]; [28][Level of evidence: 2A] Another approach that utilized multiagent chemotherapy followed by radiation therapy to the primary tumor site also resulted in disease control in nearly 70% of patients with nondisseminated disease; again disease control was better in those patients with desmoplastic histology.(ISPNO abstract INF 12)[29] Those patients with desmoplastic tumors with extensive nodularity should be carefully evaluated for stigmata of Gorlin syndrome. Gorlin syndrome is an autosomal dominant disorder, also known as the nevoid basal cell carcinoma syndrome, in which those affected are predisposed to the development of basal cell carcinomas later in life, especially in the radiation portal after radiation therapy. The syndrome can be diagnosed early in life by characteristic dermatological and skeletal features including keratocysts of the jaw, bifid or fused ribs, macrocephaly, and calcifications of the falx.[29] Results of trials utilizing higher-dose, marrow ablative, chemotherapeutic regimens supported by autologous stem cell rescue or peripheral stem cell rescue have also demonstrated that a subgroup of patients with medulloblastoma who are younger than 3 years at the time of diagnosis can be treated with chemotherapy alone.[30]; [31][Level of evidence: 2A]

In contrast to children with standard-risk disease, children with disseminated disease at presentation fare poorly with less than 30% of infants and young children surviving despite the use of higher-dose therapy supplemented with methotrexate, either intravenously or intrathecally, and higher-dose chemotherapeutic regimens supported with stem cell rescue. In patients with disseminated disease, there is no consensus on when and how much radiotherapy should be given and at what age radiotherapy should be instituted.[17,18,19]

Treatment options under clinical evaluation

The following are examples of national and/or institutional clinical trials that are currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ACNS0334(Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma): This COG trial is open for children aged 3 years or younger at diagnosis with high-risk disease, which is defined as those with disseminated and/or partially resected tumors, or those younger than 8 months with otherwise standard-risk disease. This study is evaluating chemotherapy as given in the completed COG studyCOG-99703, which used multiagent chemotherapy followed by thiotepa-based higher-dose, marrow ablative, chemotherapy and peripheral stem cell rescue, and is randomizing patients to treatment with or without intravenous high-dose methotrexate. Patients with cortical primitive neuroectodermal tumors or pineoblastomas are also eligible.
• PBTC-026 (NCT00867178)(Vorinostat, Isotretinoin, and Combination Chemotherapy in Treating Young Patients Who Have Undergone Surgery for Embryonal Tumors of the Central Nervous System): The Pediatric Brain Tumor Consortium trial is investigating the addition of vorinostat and isotretinoin to the COG-99703 backbone induction chemotherapy and as maintenance therapy following completion of the consolidation high-dose chemotherapy of this regimen.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood medulloblastoma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

Treatment Options for Newly Diagnosed Pineoblastoma and Pineal Parenchymal Tumors of Intermediate Differentiation

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Children Older Than 3 Years

Standard treatment options

The usual postsurgical treatment for pineoblastomas begins with radiation therapy, although some trials have utilized preradiation chemotherapy. The total dose of radiation therapy to the tumor site is 54 Gy to 55.8 Gy using conventional fractionation.[1,2] Craniospinal irradiation with doses ranging between 23.4 Gy and 36 Gy are also recommended because of the propensity of this tumor to disseminate throughout the subarachnoid space.[1,2] Chemotherapy is usually utilized in the same way as outlined for poor-risk medulloblastomas in children with nondisseminated disease at the time of diagnosis. Five-year disease-free survival is approximately 50%.[1,2,3] For patients with disseminated disease at the time of diagnosis, survival is considerably poorer.[1,2] Similar treatment is given for pineal parenchymal tumors of intermediate differentiation; however, there are no data on response to therapy or outcome.

Treatment options under clinical evaluation

For patients with pineoblastoma, a variety of different treatment approaches are under evaluation, including the use of higher doses of chemotherapy following radiation supported by peripheral stem cell rescue and the use of chemotherapy during radiation.

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ACNS0332(Chemotherapy and Radiation Therapy in Treating Young Patients With Newly Diagnosed, Previously Untreated, High-Risk Medulloblastoma or Supratentorial Primitive Neuroectodermal Tumor): This Children's Oncology Group phase III trial for children older than 3 years is evaluating the efficacy of adding carboplatin to radiation therapy with vincristine, followed by maintenance chemotherapy with conventional adjuvant chemotherapy and isotretinoin.

Children Aged 3 Years and Younger

Children 3 years and younger with pineoblastoma are usually treated initially with chemotherapy in the hope of delaying, if not obviating, the need for radiation therapy.[4] High-dose, marrow ablative, chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue has been used with some success in young children.[5][Level of evidence: 2Di] The timing and amount of radiation therapy required following chemotherapy in children responding to chemotherapy is unclear.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with untreated childhood pineoblastoma and childhood pineal parenchymal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

Treatment Options for Newly Diagnosed CNS Primitive Neuroectodermal Tumors

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Children Older Than 3 Years

Standard treatment options

Attempting aggressive surgical resection is the first step in the management of newly diagnosed central nervous system primitive neuroectodermal tumors (CNS PNETs), although studies have yet to demonstrate that the extent of resection is predictive of outcome.[1,2,3] After surgery, children with CNS PNETs usually receive treatment similar to that received by children with poor-risk medulloblastoma. Best results have been obtained after radiation to the entire neuraxis with local boost radiation therapy, as given for medulloblastoma.[3] However, the local boost radiation therapy may be problematic because of the size of the tumor and its location in the cerebral cortex. The chemotherapeutic approaches during and after radiation therapy are similar to those used for children with poor-risk medulloblastoma. Three- to 5-year overall survival (OS) rates of 40% to 50% have been noted.[1,2,3]; [4][Level of evidence: 2A]; [5][Level of evidence: 3iiiB] Patients with disseminated disease at the time of diagnosis have poorer OS, with reported survival rates at 5 years ranging from 20% to 30%.[1,2,3]

Children Aged 3 Years and Younger

Standard treatment options

Treatment of children aged younger than 3 years with CNS PNETs is similar to that outlined for children with medulloblastoma. With the use of chemotherapy alone, outcome has been variable, with survival rates at 5 years ranging between 0% and 50%.[6,7,8]; [9][Level of evidence: 2Di]

Treatment options under clinical evaluation

The following is an example of a national and/or institutional clinical trial that is currently being conducted. Information about ongoing clinical trials is available from the NCI Web site.

• COG-ACNS0334(Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial PNETs or High-Risk Medulloblastoma): This Children's Oncology Group phase III randomized trial is studying children aged 3 years and younger with high-risk medulloblastoma or CNS PNETs. Patients are randomly assigned to intensive induction chemotherapy including or excluding methotrexate followed by consolidation with hematopoietic stem cell rescue.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood supratentorial primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

Treatment Options for Other Newly Diagnosed CNS Embryonal Tumors

There are few data on which to base treatment of medulloepithelioma and ependymoblastoma tumors. Treatment considerations are usually the same as those for children with poor-risk medulloblastoma and for children 3 years and younger at diagnosis with other embryonal tumors. Prognosis is poor, with 5-year survival rates ranging between 0% and 30%.[1,2]

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood ependymoblastoma and childhood medulloepithelioma. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

Recurrent Childhood CNS Embryonal Tumors

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more information.)

Recurrence of all forms of central nervous system embryonal tumors is not uncommon, usually occurring within 18 months of treatment; however, recurrent tumors may develop many years after initial treatment.[1,2] Disease may recur at the primary site or may be disseminated at the time of relapse. Sites of noncontiguous relapse may include the spinal leptomeninges, intracranial sites, and cerebrospinal fluid, in isolation or in any combination, and is variably associated with primary tumor relapse.[1,2,3] One series has found that, independent of the dose of radiation therapy employed or the type of chemotherapy utilized, approximately one-third of patients will relapse at the primary tumor site alone, one-third will relapse at the primary tumor site plus distant sites, and one-third will relapse at distant sites without relapse at the primary site.[1,2,3] At the time of relapse, a complete evaluation for extent of recurrence is indicated for all embryonal tumors. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities such as secondary tumors and treatment-related brain necrosis may be clinically indistinguishable from tumor recurrence. The need for surgical intervention must be individualized on the basis of the initial tumor type, the length of time between initial treatment and the reappearance of the lesion, and clinical symptomatology. Extraneural disease relapse may occur but is rare and is seen primarily in patients treated with radiation therapy alone.[4][Level of evidence: 3iiiA]

Patients with recurrent embryonal tumors who have already received radiation therapy and chemotherapy may be candidates for salvage chemotherapy and/or stereotactic radiation therapy.[5] These tumors can be responsive to chemotherapeutic agents used singularly or in combination, including cyclophosphamide, cisplatin, carboplatin, lomustine, etoposide, and topotecan.[6,7,8,9,10,11,12,13,14]; [15][Level of evidence: 2A] Approximately 30% to 50% of these patients will have objective responses to conventional chemotherapy, but long-term disease control is rare. For select patients with recurrent medulloblastoma, primarily infants and young children who were treated at the time of diagnosis with chemotherapy alone and developed local recurrence, long-term disease control may be obtained after further treatment with chemotherapy plus local radiation therapy.[16][Level of evidence: 2A] For patients who have previously received radiation therapy, higher-dose chemotherapeutic regimens, supported with autologous bone marrow rescue or peripheral stem cell support, have been used with variable results.[17,18,19,20][Level of evidence: 2A]; [21][Level of evidence: 3iiB]; [22,23][Level of evidence: 3iiiA] With such regimens, objective response is frequent, occurring in 50% to 75% of patients; however, long-term disease control is obtained in fewer than 30% of patients and is primarily seen in patients in first relapse and in those with only localized disease at the time of relapse.[19]; [21][Level of evidence: 3iiB] Long-term disease control for patients with disseminated disease is infrequent.[24][Level of evidence: 3iA]

Treatment Options Under Clinical Evaluation

Early phase therapeutic trials may be available for selected patients. These trials may be available via Children's Oncology Group phase I institutions, the Pediatric Brain Tumor Consortium, or other entities.

Current Clinical Trials

Check for U.S. clinical trials from NCI's list of cancer clinical trials that are now accepting patients with childhood pineal parenchymal tumor, recurrent childhood pineoblastoma, childhood ependymoblastoma, recurrent childhood medulloblastoma and recurrent childhood supratentorial primitive neuroectodermal tumor. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site.

References:

Changes to This Summary (12 / 14 / 2011)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment Option Overview

Added text to state that other studies have confirmed the excellent prognosis of children with WNT tumors and poor prognosis of those with tumors with MYC amplification (cited Ellison et al. [Acta Neuropathologica 2011], Cho et al., and Ellison et al. [Journal of Clinical Oncology 2011] as references 4, 5, and 6, respectively).

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood central nervous system embryonal tumors. It is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Childhood Central Nervous System Embryonal Tumors Treatment are:

• Kenneth J. Cohen, MD, MBA (Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital)
• Louis S. Constine, MD (James P. Wilmot Cancer Center at University of Rochester Medical Center)
• Roger J. Packer, MD (Children's National Medical Center)
• Malcolm Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the Web site's Contact Form. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

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The preferred citation for this PDQ summary is:

National Cancer Institute: PDQ® Childhood Central Nervous System Embryonal Tumors Treatment. Bethesda, MD: National Cancer Institute. Date last modified <MM/DD/YYYY>. Available at: http://www.cancer.gov/cancertopics/pdq/treatment/childCNSembryonal/healthprofessional. Accessed <MM/DD/YYYY>.

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Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the Coping with Cancer: Financial, Insurance, and Legal Information page.

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Last Revised: 2011-12-14