Childhood Central Nervous System Embryonal Tumors Treatment (PDQ®): Treatment - Health Professional Information [NCI]

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Childhood Central Nervous System Embryonal Tumors

Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood central nervous system (CNS) embryonal tumors. This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board.

Information about the following is included in this summary:

  • Cellular classification of CNS embryonal tumors.
  • Stage information and treatment options for:
    • Medulloblastoma.
    • Pineoblastoma and pineal parenchymal tumors of intermediate differentiation.
    • Supratentorial primitive neuroectodermal tumors.
    • Medulloepithelioma.
    • Ependymoblastoma.

This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

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 and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for reimbursement determinations.

This summary is also available in a patient version, which is written in less technical language, and in Spanish.

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]

In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. 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.

References:

1. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000.

Cellular Classification of Central Nervous System 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] 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.[2,3,4,5] In the 2000 World Health Organization (WHO) classification, embryonal tumors include medulloblastoma, ependymoblastoma, supratentorial primitive neuroectodermal tumor (SPNET), medulloepithelioma, and atypical teratoid/rhabdoid tumor.[1]Refer to the PDQ Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumors summary for more information. Pineoblastoma, a histologically similar tumor, is reviewed in this summary, although pineoblastoma is grouped with the pineal parenchymal tumors in the WHO classification.

By definition, medulloblastomas must arise in the posterior fossa.[1] Four different subtypes of medulloblastoma are recognized by the WHO: desmoplastic medulloblastoma, large cell medulloblastoma, medullomyoblastoma, and melanocytic medulloblastoma.[1] Recently, significant attention has been focused on medulloblastomas that display anaplastic features, including increased nuclear size, marked cytological pleomorphism, numerous mitoses, and apoptotic bodies.[6,7] 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.[6,7,8]

SPNETs arise in the cerebrum or suprasellar region. According to the 2000 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]

The pathologic classification of pediatric brain tumors is a specialized area that is undergoing evolution. Immunohistochemical staining is now a routine component of evaluation.[6,7,8] Molecular genetic profiles are also being incorporated into evaluation and may radically alter classification in the future.[9]

References:

1. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000.
2. Rorke LB: The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol 42 (1): 1-15, 1983.
3. Dehner LP: Peripheral and central primitive neuroectodermal tumors. A nosologic concept seeking a consensus. Arch Pathol Lab Med 110 (11): 997-1005, 1986.
4. Russo C, Pellarin M, Tingby O, et al.: Comparative genomic hybridization in patients with supratentorial and infratentorial primitive neuroectodermal tumors. Cancer 86 (2): 331-9, 1999.
5. Nicholson JC, Ross FM, Kohler JA, et al.: Comparative genomic hybridization and histological variation in primitive neuroectodermal tumours. Br J Cancer 80 (9): 1322-31, 1999.
6. Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999.
7. McManamy CS, Lamont JM, Taylor RE, et al.: Morphophenotypic variation predicts clinical behavior in childhood non-desmoplastic medulloblastomas. J Neuropathol Exp Neurol 62 (6): 627-32, 2003.
8. Eberhart CG, Kratz J, Wang Y, et al.: Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. J Neuropathol Exp Neurol 63 (5): 441-9, 2004.
9. Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415 (6870): 436-42, 2002.

Staging of 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.)

Evidence suggests that medulloblastomas originate in the granular cells of the cerebellum near the roof of the fourth ventricle. 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] Every patient with newly diagnosed medulloblastoma should be evaluated with diagnostic imaging of the entire neuroaxis and, when possible and safe, lumbar CSF analysis for free-floating tumor cells. 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. 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 infrequent. Although bone scans and bone marrows have been routinely obtained in some older prospective studies, their yield was low and they are primarily now recommended for infants or those with widespread intracranial disease, intraspinal disease or both.[2] 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 incorporated into staging systems.

Patients with disseminated disease at diagnosis are clearly at highest risk for disease relapse.[1,2,3] Other factors that portend an unfavorable outcome include younger age at diagnosis 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.[2,4,5] Similarly, the presence of brainstem involvement at diagnosis has not been shown to be predictive of outcome.[5,6]

On the basis of neuroradiographic evaluation for disseminated disease, 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 (less than 1.5 cm of residual disease) and no metastatic disease.[2]
  • High risk: children aged 3 years and younger, or those with metastatic disease [2] and/or subtotal resection (>1.5 cm of residual disease).

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

A host of biologic parameters that may be predictive of outcome have been identified. These parameters include DNA ploidy, expression of neurotrophin-3 receptor (TrkC), MYCC expression, ERBB 2 expression, chromosomal 17p loss, overexpression of platelet-derived growth factor receptor, p53 expression, survivin expression, B-catenin immunostaining, and multigene expression profiling.[7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22][Level of evidence: 3iiiDi] In addition, histopathologic features such as large cell variant, anaplasia, and desmoplasia have been shown in retrospective analysis to correlate with outcome. These molecular genetic immunohistochemical and histopathological findings have not been shown to be predictive of outcome in prospective studies and 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.[23,24,25,26][Level of evidence: 3iiiDi][27][Level of evidence: 3iiiDi]

References:

1. Fouladi M, Gajjar A, Boyett JM, et al.: Comparison of CSF cytology and spinal magnetic resonance imaging in the detection of leptomeningeal disease in pediatric medulloblastoma or primitive neuroectodermal tumor. J Clin Oncol 17 (10): 3234-7, 1999.
2. Zeltzer PM, Boyett JM, Finlay JL, et al.: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol 17 (3): 832-45, 1999.
3. Yao MS, Mehta MP, Boyett JM, et al.: The effect of M-stage on patterns of failure in posterior fossa primitive neuroectodermal tumors treated on CCG-921: a phase III study in a high-risk patient population. Int J Radiat Oncol Biol Phys 38 (3): 469-76, 1997.
4. Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery 38 (2): 265-71, 1996.
5. Packer RJ, Siegel KR, Sutton LN, et al.: Efficacy of adjuvant chemotherapy for patients with poor-risk medulloblastoma: a preliminary report. Ann Neurol 24 (4): 503-8, 1988.
6. Taylor RE, Bailey CC, Robinson K, et al.: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 21 (8): 1581-91, 2003.
7. Zerbini C, Gelber RD, Weinberg D, et al.: Prognostic factors in medulloblastoma, including DNA ploidy. J Clin Oncol 11 (4): 616-22, 1993.
8. Schofield DE, Yunis EJ, Geyer JR, et al.: DNA content and other prognostic features in childhood medulloblastoma. Proposal of a scoring system. Cancer 69 (5): 1307-14, 1992.
9. Tomita T, Yasue M, Engelhard HH, et al.: Flow cytometric DNA analysis of medulloblastoma. Prognostic implication of aneuploidy. Cancer 61 (4): 744-9, 1988.
10. Gajjar AJ, Heideman RL, Douglass EC, et al.: Relation of tumor-cell ploidy to survival in children with medulloblastoma. J Clin Oncol 11 (11): 2211-7, 1993.
11. Grotzer MA, Janss AJ, Fung K, et al.: TrkC expression predicts good clinical outcome in primitive neuroectodermal brain tumors. J Clin Oncol 18 (5): 1027-35, 2000.
12. Grotzer MA, Hogarty MD, Janss AJ, et al.: MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7 (8): 2425-33, 2001.
13. Gilbertson RJ, Perry RH, Kelly PJ, et al.: Prognostic significance of HER2 and HER4 coexpression in childhood medulloblastoma. Cancer Res 57 (15): 3272-80, 1997.
14. Pomeroy SL, Tamayo P, Gaasenbeek M, et al.: Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 415 (6870): 436-42, 2002.
15. Lamont JM, McManamy CS, Pearson AD, et al.: Combined histopathological and molecular cytogenetic stratification of medulloblastoma patients. Clin Cancer Res 10 (16): 5482-93, 2004.
16. Pan E, Pellarin M, Holmes E, et al.: Isochromosome 17q is a negative prognostic factor in poor-risk childhood medulloblastoma patients. Clin Cancer Res 11 (13): 4733-40, 2005.
17. Aldosari N, Bigner SH, Burger PC, et al.: MYCC and MYCN oncogene amplification in medulloblastoma. A fluorescence in situ hybridization study on paraffin sections from the Children's Oncology Group. Arch Pathol Lab Med 126 (5): 540-4, 2002.
18. Herms J, Neidt I, Lüscher B, et al.: C-MYC expression in medulloblastoma and its prognostic value. Int J Cancer 89 (5): 395-402, 2000.
19. Pizem J, Cört A, Zadravec-Zaletel L, et al.: Survivin is a negative prognostic marker in medulloblastoma. Neuropathol Appl Neurobiol 31 (4): 422-8, 2005.
20. Ellison DW, Onilude OE, Lindsey JC, et al.: beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee. J Clin Oncol 23 (31): 7951-7, 2005.
21. MacDonald TJ, Brown KM, LaFleur B, et al.: Expression profiling of medulloblastoma: PDGFRA and the RAS/MAPK pathway as therapeutic targets for metastatic disease. Nat Genet 29 (2): 143-52, 2001.
22. Grotzer MA, von Hoff K, von Bueren AO, et al.: Which clinical and biological tumor markers proved predictive in the prospective multicenter trial HIT'91--implications for investigating childhood medulloblastoma. Klin Padiatr 219 (6): 312-7, 2007 Nov-Dec.
23. Gajjar A, Hernan R, Kocak M, et al.: Clinical, histopathologic, and molecular markers of prognosis: toward a new disease risk stratification system for medulloblastoma. J Clin Oncol 22 (6): 984-93, 2004.
24. Ray A, Ho M, Ma J, et al.: A clinicobiological model predicting survival in medulloblastoma. Clin Cancer Res 10 (22): 7613-20, 2004.
25. Fernandez-Teijeiro A, Betensky RA, Sturla LM, et al.: Combining gene expression profiles and clinical parameters for risk stratification in medulloblastomas. J Clin Oncol 22 (6): 994-8, 2004.
26. Polkinghorn WR, Tarbell NJ: Medulloblastoma: tumorigenesis, current clinical paradigm, and efforts to improve risk stratification. Nat Clin Pract Oncol 4 (5): 295-304, 2007.
27. Giangaspero F, Wellek S, Masuoka J, et al.: Stratification of medulloblastoma on the basis of histopathological grading. Acta Neuropathol 112 (1): 5-12, 2006.

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.)

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.[1,2] One study utilized presurgical chemotherapy (after tumor biopsy) to reduce tumor bulk and make subsequent resection of the tumor easier.[3] 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 due to preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[4][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.[5] 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.[6] Many patients with this syndrome, may manifest neurologic and neurocognitive sequelae posttreatment.[7][Level of evidence: 3iiiC]

Radiation therapy is usually initiated after surgery with or without concomitant chemotherapy.[2,3] To date, the best survival results for children with medulloblastoma have been obtained when radiation therapy is begun within 4 to 6 weeks postsurgery.[2,3,8,9,10,11] 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.[8,9,10,11] 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.[9,10]

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.[12,13,14,15] 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.[16] Children are also at risk for long-term endocrine dysfunction.[17][Level of evidence: 3iiiC]

Surveillance testing is a part of all ongoing medulloblastoma studies.[18] 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.[19] In addition, secondary tumors have been increasingly diagnosed in long-term survivors.[20,21] As with initial management, long-term management is complex and requires a multidisciplinary approach.

References:

1. Albright AL, Wisoff JH, Zeltzer PM, et al.: Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery 38 (2): 265-71, 1996.
2. Taylor RE, Bailey CC, Robinson K, et al.: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 21 (8): 1581-91, 2003.
3. Grill J, Lellouch-Tubiana A, Elouahdani S, et al.: Preoperative chemotherapy in children with high-risk medulloblastomas: a feasibility study. J Neurosurg 103 (4 Suppl): 312-8, 2005.
4. Stargatt R, Rosenfeld JV, Maixner W, et al.: Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors. Dev Neuropsychol 32 (2): 729-48, 2007.
5. Pollack IF, Polinko P, Albright AL, et al.: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 37 (5): 885-93, 1995.
6. Robertson PL, Muraszko KM, Holmes EJ, et al.: Incidence and severity of postoperative cerebellar mutism syndrome in children with medulloblastoma: a prospective study by the Children's Oncology Group. J Neurosurg 105 (6): 444-51, 2006.
7. Wolfe-Christensen C, Mullins LL, Scott JG, et al.: Persistent psychosocial problems in children who develop posterior fossa syndrome after medulloblastoma resection. Pediatr Blood Cancer 49 (5): 723-6, 2007.
8. Packer RJ, Sutton LN, Elterman R, et al.: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81 (5): 690-8, 1994.
9. Bailey CC, Gnekow A, Wellek S, et al.: Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 25 (3): 166-78, 1995.
10. Kortmann RD, Kühl J, Timmermann B, et al.: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys 46 (2): 269-79, 2000.
11. Taylor RE, Bailey CC, Robinson KJ, et al.: Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma. Int J Radiat Oncol Biol Phys 58 (4): 1184-93, 2004.
12. Ris MD, Packer R, Goldwein J, et al.: Intellectual outcome after reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a Children's Cancer Group study. J Clin Oncol 19 (15): 3470-6, 2001.
13. Packer RJ, Sutton LN, Atkins TE, et al.: A prospective study of cognitive function in children receiving whole-brain radiotherapy and chemotherapy: 2-year results. J Neurosurg 70 (5): 707-13, 1989.
14. Johnson DL, McCabe MA, Nicholson HS, et al.: Quality of long-term survival in young children with medulloblastoma. J Neurosurg 80 (6): 1004-10, 1994.
15. Walter AW, Mulhern RK, Gajjar A, et al.: Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 17 (12): 3720-8, 1999.
16. Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005.
17. Laughton SJ, Merchant TE, Sklar CA, et al.: Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26 (7): 1112-8, 2008.
18. Saunders DE, Hayward RD, Phipps KP, et al.: Surveillance neuroimaging of intracranial medulloblastoma in children: how effective, how often, and for how long? J Neurosurg 99 (2): 280-6, 2003.
19. Jenkin D: Long-term survival of children with brain tumors. Oncology (Huntingt) 10 (5): 715-9; discussion 720, 722, 728, 1996.
20. Goldstein AM, Yuen J, Tucker MA: Second cancers after medulloblastoma: population-based results from the United States and Sweden. Cancer Causes Control 8 (6): 865-71, 1997.
21. Stavrou T, Bromley CM, Nicholson HS, et al.: Prognostic factors and secondary malignancies in childhood medulloblastoma. J Pediatr Hematol Oncol 23 (7): 431-6, 2001.

Treatment 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 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 neuroaxis (i.e., the whole brain and spine).[1,2,3] With radiation therapy alone, 5-year event-free survival (EFS) ranges between 50% and 65% in those with nondisseminated disease.[1,2,3] 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.[4,5] 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.[6] Radiation therapy and chemotherapy given during and after radiation therapy has demonstrated 5-year EFS rates of 70% to 85%.[1,2,3] Chemotherapy is now a standard component of the treatment of children with average-risk medulloblastoma; a variety of chemotherapeutic regimens has been successfully used, including the combination of cisplatin, lomustine, and vincristine.[1,2,7,8] A lower radiation dose of 23.4 Gy to the neuroaxis when coupled with chemotherapy has been shown to result in disease control in up to 80% of patients and may decrease the severity of long-term neurocognitive sequelae.[8,9,10]

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.[11]

Treatment options under clinical evaluation

The Children's Oncology Group (COG) phase III trial, COG-ACNS0331, 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 received weekly vincristine during radiation therapy and lomustine, vincristine, cisplatinum, etoposide, and cyclophosphamide after radiation therapy.

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).[12,13,14] Studies show that approximately 50% to 60% of patients with high-risk diseases will experience long-term disease control.[1,15] 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 COG phase III trial for children older than 3 years, COG-ACNS0332, is evaluating the efficacy of adding carboplatin to radiation therapy with vincristine, followed by maintenance chemotherapy with isotretinoin. Information about ongoing clinical trials is available from the NCI Web site.

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 due to differences in drug regimens used and the utilization in some studies , but not all, of craniospinal and local boost radiotherapy at the end of chemotherapy or when children reached age 3 years. 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.[16,17,18] The histological 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 MYCC expression may also identify subsets of patients who are more likely to be successfully treated with chemotherapy alone.[18,19,20,21]

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.[16,17,18,22,23,24] 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.[25] Results of trials utilizing higher-dose 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.[26,27][Level of evidence: 2A]

In contrast to those 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.[16,17,18]

Treatment options under clinical evaluation

The COG trial, COG-ACNS0334, 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. This study is evaluating chemotherapy as given in the completed COG study COG-99703, which used multiagent chemotherapy followed by thiotepa-based higher-dose 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.

An alternative treatment strategy under clinical evaluation is the Head Start III trial (CHLA-HEAD-START-IIII) which uses combination chemotherapy with or without etoposide followed by an autologous stem cell transplant to treat children younger than 10 years with newly diagnosed brain tumors.

Information about ongoing clinical trials is available from the NCI Web site

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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:

1. Packer RJ, Sutton LN, Elterman R, et al.: Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg 81 (5): 690-8, 1994.
2. Bailey CC, Gnekow A, Wellek S, et al.: Prospective randomised trial of chemotherapy given before radiotherapy in childhood medulloblastoma. International Society of Paediatric Oncology (SIOP) and the (German) Society of Paediatric Oncology (GPO): SIOP II. Med Pediatr Oncol 25 (3): 166-78, 1995.
3. Kortmann RD, Kühl J, Timmermann B, et al.: Postoperative neoadjuvant chemotherapy before radiotherapy as compared to immediate radiotherapy followed by maintenance chemotherapy in the treatment of medulloblastoma in childhood: results of the German prospective randomized trial HIT '91. Int J Radiat Oncol Biol Phys 46 (2): 269-79, 2000.
4. Fukunaga-Johnson N, Sandler HM, Marsh R, et al.: The use of 3D conformal radiotherapy (3D CRT) to spare the cochlea in patients with medulloblastoma. Int J Radiat Oncol Biol Phys 41 (1): 77-82, 1998.
5. Huang E, Teh BS, Strother DR, et al.: Intensity-modulated radiation therapy for pediatric medulloblastoma: early report on the reduction of ototoxicity. Int J Radiat Oncol Biol Phys 52 (3): 599-605, 2002.
6. Thomas PR, Deutsch M, Kepner JL, et al.: Low-stage medulloblastoma: final analysis of trial comparing standard-dose with reduced-dose neuraxis irradiation. J Clin Oncol 18 (16): 3004-11, 2000.
7. Jenkin D: Long-term survival of children with brain tumors. Oncology (Huntingt) 10 (5): 715-9; discussion 720, 722, 728, 1996.
8. Packer RJ, Goldwein J, Nicholson HS, et al.: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol 17 (7): 2127-36, 1999.
9. Oyharcabal-Bourden V, Kalifa C, Gentet JC, et al.: Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. J Clin Oncol 23 (21): 4726-34, 2005.
10. Merchant TE, Kun LE, Krasin MJ, et al.: Multi-institution prospective trial of reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa (36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for average-risk medulloblastoma. Int J Radiat Oncol Biol Phys 70 (3): 782-7, 2008.
11. Packer RJ, Boyett JM, Janss AJ, et al.: Growth hormone replacement therapy in children with medulloblastoma: use and effect on tumor control. J Clin Oncol 19 (2): 480-7, 2001.
12. Gajjar A, Chintagumpala M, Ashley D, et al.: Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial. Lancet Oncol 7 (10): 813-20, 2006.
13. Verlooy J, Mosseri V, Bracard S, et al.: Treatment of high risk medulloblastomas in children above the age of 3 years: a SFOP study. Eur J Cancer 42 (17): 3004-14, 2006.
14. Gandola L, Massimino M, Cefalo G, et al.: Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 27 (4): 566-71, 2009.
15. Evans AE, Jenkin RD, Sposto R, et al.: The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone. J Neurosurg 72 (4): 572-82, 1990.
16. Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005.
17. Grill J, Sainte-Rose C, Jouvet A, et al.: Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 6 (8): 573-80, 2005.
18. Rutkowski S, Bode U, Deinlein F, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy alone. N Engl J Med 352 (10): 978-86, 2005.
19. Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999.
20. Eberhart CG, Kratz J, Wang Y, et al.: Histopathological and molecular prognostic markers in medulloblastoma: c-myc, N-myc, TrkC, and anaplasia. J Neuropathol Exp Neurol 63 (5): 441-9, 2004.
21. Grotzer MA, Hogarty MD, Janss AJ, et al.: MYC messenger RNA expression predicts survival outcome in childhood primitive neuroectodermal tumor/medulloblastoma. Clin Cancer Res 7 (8): 2425-33, 2001.
22. Duffner PK, Horowitz ME, Krischer JP, et al.: Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors. N Engl J Med 328 (24): 1725-31, 1993.
23. Ater JL, van Eys J, Woo SY, et al.: MOPP chemotherapy without irradiation as primary postsurgical therapy for brain tumors in infants and young children. J Neurooncol 32 (3): 243-52, 1997.
24. Blaney SM, Boyett J, Friedman H, et al.: Phase I clinical trial of mafosfamide in infants and children aged 3 years or younger with newly diagnosed embryonal tumors: a Pediatric Brain Tumor Consortium study (PBTC-001). J Clin Oncol 23 (3): 525-31, 2005.
25. Sanders R, Schaiquevich P, Broniscer A: Methotrexate pharmacokinetics in children less than 3 years of age with embryonal brain tumors. [Abstract] Neuro-Oncology 10 (3): A-INF10, 436-7, 2008.
26. Chi SN, Gardner SL, Levy AS, et al.: Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma. J Clin Oncol 22 (24): 4881-7, 2004.
27. Dhall G, Grodman H, Ji L, et al.: Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the "Head Start" I and II protocols. Pediatr Blood Cancer 50 (6): 1169-75, 2008.

Staging of Pineoblastoma

Staging for children with pineoblastomas is the same as that performed for children with medulloblastoma.[1] Dissemination at the time of diagnosis occurs in 10% to 30% of patients.[1] 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.[1,2] Prognosis is worse for patients with disseminated disease at the time of diagnosis.[1]

References:

1. Jakacki RI, Zeltzer PM, Boyett JM, et al.: Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol 13 (6): 1377-83, 1995.
2. Timmermann B, Kortmann RD, Kühl J, et al.: Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20 (3): 842-9, 2002.

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 2.34 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 poor-risk medulloblastoma or 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.

Children Aged 3 Years and Younger

Children aged 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 chemotherapy with autologous bone marrow rescue or peripheral stem cell rescue have 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 PDQ Cancer Clinical Trials Registry 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:

1. Jakacki RI, Zeltzer PM, Boyett JM, et al.: Survival and prognostic factors following radiation and/or chemotherapy for primitive neuroectodermal tumors of the pineal region in infants and children: a report of the Childrens Cancer Group. J Clin Oncol 13 (6): 1377-83, 1995.
2. Timmermann B, Kortmann RD, Kühl J, et al.: Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20 (3): 842-9, 2002.
3. Gururangan S, McLaughlin C, Quinn J, et al.: High-dose chemotherapy with autologous stem-cell rescue in children and adults with newly diagnosed pineoblastomas. J Clin Oncol 21 (11): 2187-91, 2003.
4. Mason WP, Grovas A, Halpern S, et al.: Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors. J Clin Oncol 16 (1): 210-21, 1998.
5. Fangusaro J, Finlay J, Sposto R, et al.: Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer 50 (2): 312-8, 2008.

Staging of Supratentorial Primitive Neuroectodermal Tumors

Patients with supratentorial primitive neuroectodermal tumors (SPNET) are staged in a fashion similar to that used for children with medulloblastoma. SPNET 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.[1,2] SPNETs are often amenable to resection; in series, 50% to 60% of patients were totally or near-totally resected.[1,2]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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:

1. Cohen BH, Zeltzer PM, Boyett JM, et al.: Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial. J Clin Oncol 13 (7): 1687-96, 1995.
2. Reddy AT, Janss AJ, Phillips PC, et al.: Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 88 (9): 2189-93, 2000.

Treatment Options for Newly Diagnosed Supratentorial 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 supratentorial primitive neuroectodermal tumors (SPNET), although studies have yet to demonstrate that the extent of resection is predictive of outcome.[1,2,3] After surgery, children with SPNET usually receive treatment similar to that received by children with poor-risk medulloblastoma. Best results have been obtained after radiation to the entire neuroaxis 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: 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 SPNET 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%.[5,6,7,8][Level of evidence: 2Di]

Treatment options under clinical evaluation

The Children's Oncology Group (COG) phase III randomized trial, COG-ACNS0334, is studying children aged 3 years and younger with high-risk medulloblastoma or SPNETs. Patients are randomized 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 PDQ Cancer Clinical Trials Registry 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:

1. Cohen BH, Zeltzer PM, Boyett JM, et al.: Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial. J Clin Oncol 13 (7): 1687-96, 1995.
2. Reddy AT, Janss AJ, Phillips PC, et al.: Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 88 (9): 2189-93, 2000.
3. Timmermann B, Kortmann RD, Kühl J, et al.: Role of radiotherapy in the treatment of supratentorial primitive neuroectodermal tumors in childhood: results of the prospective German brain tumor trials HIT 88/89 and 91. J Clin Oncol 20 (3): 842-9, 2002.
4. Johnston DL, Keene DL, Lafay-Cousin L, et al.: Supratentorial primitive neuroectodermal tumors: a Canadian pediatric brain tumor consortium report. J Neurooncol 86 (1): 101-8, 2008.
5. Geyer JR, Sposto R, Jennings M, et al.: Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group. J Clin Oncol 23 (30): 7621-31, 2005.
6. Marec-Berard P, Jouvet A, Thiesse P, et al.: Supratentorial embryonal tumors in children under 5 years of age: an SFOP study of treatment with postoperative chemotherapy alone. Med Pediatr Oncol 38 (2): 83-90, 2002.
7. Grill J, Sainte-Rose C, Jouvet A, et al.: Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children. Lancet Oncol 6 (8): 573-80, 2005.
8. Fangusaro J, Finlay J, Sposto R, et al.: Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and II experience. Pediatr Blood Cancer 50 (2): 312-8, 2008.

Medulloepithelioma and Ependymoblastoma

Although medulloepithelioma and ependymoblastoma are identified as histologically discrete tumors within the World Health Organization classification system, there are few data on which to base treatment for these embryonal tumors.[1] Both tumors are rare and tend to arise most commonly in infants and young children. Dissemination may occur, and the tumors are staged in the same way as medulloblastoma. 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%.[2]

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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:

1. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000.
2. Moftakhar P, Fan X, Hurvitz CH, et al.: Long-term survival in a child with a central nervous system medulloepithelioma. J Neurosurg Pediatr 2 (5): 339-45, 2008.

Recurrent Childhood Central Nervous System 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.

Patients with recurrent embryonal tumors who have already received radiation therapy and chemotherapy may be candidates for salvage chemotherapy and/or stereotactic irradiation.[4] These tumors can be responsive to chemotherapeutic agents used singularly or in combination, including cyclophosphamide, cisplatin, carboplatin, lomustine, and etoposide.[5,6,7,8,9,10,11,12,13] 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.[14][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.[15] 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.[16][Level of evidence: 3iA] Long-term disease control for patients with disseminated disease is infrequent.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry 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:

1. Taylor RE, Bailey CC, Robinson K, et al.: Results of a randomized study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic medulloblastoma: The International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 Study. J Clin Oncol 21 (8): 1581-91, 2003.
2. Packer RJ, Goldwein J, Nicholson HS, et al.: Treatment of children with medulloblastomas with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A Children's Cancer Group Study. J Clin Oncol 17 (7): 2127-36, 1999.
3. Oyharcabal-Bourden V, Kalifa C, Gentet JC, et al.: Standard-risk medulloblastoma treated by adjuvant chemotherapy followed by reduced-dose craniospinal radiation therapy: a French Society of Pediatric Oncology Study. J Clin Oncol 23 (21): 4726-34, 2005.
4. Abe M, Tokumaru S, Tabuchi K, et al.: Stereotactic radiation therapy with chemotherapy in the management of recurrent medulloblastomas. Pediatr Neurosurg 42 (2): 81-8, 2006.
5. Friedman HS, Oakes WJ: The chemotherapy of posterior fossa tumors in childhood. J Neurooncol 5 (3): 217-29, 1987.
6. Needle MN, Molloy PT, Geyer JR, et al.: Phase II study of daily oral etoposide in children with recurrent brain tumors and other solid tumors. Med Pediatr Oncol 29 (1): 28-32, 1997.
7. Gaynon PS, Ettinger LJ, Baum ES, et al.: Carboplatin in childhood brain tumors. A Children's Cancer Study Group Phase II trial. Cancer 66 (12): 2465-9, 1990.
8. Gentet JC, Doz F, Bouffet E, et al.: Carboplatin and VP 16 in medulloblastoma: a phase II Study of the French Society of Pediatric Oncology (SFOP). Med Pediatr Oncol 23 (5): 422-7, 1994.
9. Allen JC, Walker R, Luks E, et al.: Carboplatin and recurrent childhood brain tumors. J Clin Oncol 5 (3): 459-63, 1987.
10. Ashley DM, Longee D, Tien R, et al.: Treatment of patients with pineoblastoma with high dose cyclophosphamide. Med Pediatr Oncol 26 (6): 387-92, 1996.
11. Lefkowitz IB, Packer RJ, Siegel KR, et al.: Results of treatment of children with recurrent medulloblastoma/primitive neuroectodermal tumors with lomustine, cisplatin, and vincristine. Cancer 65 (3): 412-7, 1990.
12. Friedman HS, Mahaley MS Jr, Schold SC Jr, et al.: Efficacy of vincristine and cyclophosphamide in the therapy of recurrent medulloblastoma. Neurosurgery 18 (3): 335-40, 1986.
13. Castello MA, Clerico A, Deb G, et al.: High-dose carboplatin in combination with etoposide (JET regimen) for childhood brain tumors. Am J Pediatr Hematol Oncol 12 (3): 297-300, 1990.
14. Ridola V, Grill J, Doz F, et al.: High-dose chemotherapy with autologous stem cell rescue followed by posterior fossa irradiation for local medulloblastoma recurrence or progression after conventional chemotherapy. Cancer 110 (1): 156-63, 2007.
15. Dunkel IJ, Boyett JM, Yates A, et al.: High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children's Cancer Group. J Clin Oncol 16 (1): 222-8, 1998.
16. Bowers DC, Gargan L, Weprin BE, et al.: Impact of site of tumor recurrence upon survival for children with recurrent or progressive medulloblastoma. J Neurosurg 107 (1 Suppl): 5-10, 2007.

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Changes to This Summary (08 / 13 / 2009)

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 FOR NEWLY DIAGNOSED CHILDHOOD MEDULLOBLASTOMA

This section was extensively revised.

MEDULLOEPITHELIOMA AND EPENDYMOBLASTOMA

Added Moftakhar et al. as reference 2.

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