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National Cancer Institute
Ultima Vez Modificado: 18 de agosto del 2008
This PDQ® cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood medulloblastoma. This summary is reviewed regularly and updated as necessary by the PDQ® Pediatric Treatment Editorial Board.
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. [Note: The PDQ® childhood brain tumor treatment summaries are in the process of being substantially revised. This revision process was prompted by changes in the nomenclature and classification for pediatric central nervous system tumors. New PDQ® childhood brain tumor treatment summaries will be added and some existing summaries will be replaced or their content combined with other PDQ® childhood brain tumor treatment summaries in the near future.]
[Note: This PDQ® summary contains content that is also included in the new PDQ® Childhood Central Nervous System Embryonal Tumors summary. In the future, the PDQ® Childhood Medulloblastoma summary will be removed from the National Cancer Institute's (NCI's) Cancer.gov Website, and the content contained in this summary will be found in the PDQ® Childhood Central Nervous System Embryonal Tumors summary.]
The NCI 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.
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® Late Effects of Treatment for Childhood Cancer summary 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 the tumor diagnosis and classification.
Refer to the PDQ® Childhood Brain and Spinal Cord Tumors Treatment Overview summary for information about the general classification of childhood brain and spinal cord tumors.
The classification of brain tumors is based on both histopathological characteristics and location in the brain. Undifferentiated neuroectodermal tumors of the cerebellum have historically been referred to as medulloblastomas, while tumors of identical histology in the pineal region are diagnosed as pineoblastomas, and cortical lesions have been called central neuroblastomas or cortical primitive neuroectodermal tumors. There are different molecular genetic aberrations in the tumor cells of medulloblastomas and supratentorial primitive neuroectodermal tumors. 1 2 3 The nomenclature of pediatric brain tumors is controversial and potentially confusing. Some pathologists advocate abandoning the traditional morphologically based classifications such as medulloblastoma in favor of a terminology that relies more extensively on the phenotypic characteristics of the tumor. In such a system, medulloblastoma is referred to as primitive neuroectodermal tumor and then subdivided on the basis of cellular differentiation. 4 5 6 7 The most recent World Health Organization classification of brain tumors maintains the term medulloblastoma for posterior fossa undifferentiated tumors. 7 8 It also maintains separate categories for cerebral primitive neuroectodermal tumors and for pineal small round cell tumors (pineoblastomas). The pathologic classification of pediatric brain tumors is a specialized area that is undergoing evolution; review of the diagnostic tissue by a neuropathologist who has particular expertise in this area is strongly recommended.
This tumor usually originates in the cerebellum. It may spread contiguously to the cerebellar peduncle, floor of the fourth ventricle, into the cervical spine, or above the tentorium. In addition, it may spread via the cerebrospinal fluid (CSF) intracranially and/or to the spinal cord. Every patient with medulloblastoma should be evaluated with diagnostic imaging of the entire neuraxis, and when possible, lumbar CSF analysis for free-floating tumor cells. 1 The most sensitive method available for evaluating spinal cord subarachnoid metastasis is spinal magnetic resonance imaging performed with gadolinium. Because medulloblastoma occasionally metastasizes outside the central nervous system, especially to bone, a bone scan with plain film correlation as well as a bone marrow aspiration and biopsy may be useful in symptomatic patients or in those with abnormal blood cell counts at diagnosis. CSF shunts at the time of surgery have not been shown to increase the risk of leptomeningeal relapse. The most commonly used staging system has been proposed in a system that rates the tumor by an intraoperative evaluation of both size and extent as well as by the presence of metastatic disease. Alternative postoperative staging systems are now being used that are based on surgical impression and postoperative imaging studies. Patients with disseminated disease at diagnosis are clearly at highest risk for disease relapse. 2 Other factors that may portend an unfavorable outcome include younger age at diagnosis, brain stem involvement, subtotal resection, and anaplastic histologic features. 2 3 4 5 These prognostic variables must be evaluated in the context of the treatment received.
Biologic tumor characteristics have been associated with prognosis, though not all reports have consistently identified prognostic significance for the same markers. Nuclear expression of p53 and disruption of the p53/ARF tumor suppressor pathway, HER2/ErbB2 expression, and survivin expression have been associated with poor prognosis. 6 7 8 9 Amplification and overexpression of MYCC/MYCN have been associated with poor prognosis in some studies, 10 11 12 13 14 but not others. 8 Conversely, TrkC mRNA or protein expression has been linked to favorable outcome, 6 15 though not universally. 8 Gene expression profiling can also provide prognostic information that is independent of clinical variables. 16 There is no consensus for how these biological features should be applied to direct therapeutic decisions, though ongoing studies are seeking to provide data that will allow a valid risk classification scheme to be developed based on biological characteristics. 8 17
Many of the improvements in survival in childhood cancer have been made as a result of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare new therapy with therapy that is currently accepted as standard. This comparison may be done in a randomized study of two treatment arms or by evaluating a single new treatment and comparing the results with those previously obtained with existing therapy.
Because of the relative rarity of cancer in children, all patients with brain tumors should be considered for entry into a clinical trial. To determine and implement optimum treatment, treatment planning by a multidisciplinary team of cancer specialists who have experience treating childhood brain tumors is required. Both surgery and radiation therapy of pediatric brain tumors is technically very demanding and should be carried out in centers that have experience in these areas in order to ensure optimal results. Less than optimal techniques have resulted in failure at the junction of the brain and spine radiation fields or in the cribriform plate region. 1 Patients should be treated in a center experienced with this therapy.
In the past, treatment has included surgery with radiation therapy. There is evidence to suggest that more extensive surgical resections are related to an improved rate of survival, primarily in children with nondisseminated posterior fossa disease at diagnosis. Chemotherapy has been shown to be active in patients with medulloblastomas. Prospective, randomized trials and large single-arm trials suggest that adjuvant chemotherapy given during and after radiation therapy improves overall survival for the subset of children with medulloblastoma who have less favorable prognostic factors, and there has been considerable data supporting the role of chemotherapy in the treatment of medulloblastoma. 2 3 4 5 Children aged 3 years and younger are particularly susceptible to the adverse effect of radiation on brain development. Debilitating effects on growth and neurologic development have frequently been observed, especially in younger children. 6 7 8 9 For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy is under study, and preliminary results suggest that chemotherapy can be used to delay, and sometimes obviate, the need for radiation therapy in children with medulloblastoma. 2 10 Surveillance testing is presently a part of all ongoing medulloblastoma studies. 11 12 Secondary tumors have increasingly been diagnosed in long-term survivors. 13 14 15 Long-term management of these patients is complex and requires a multidisciplinary approach.
The designations in PDQ® that treatments are standard or under clinical evaluation are not to be used as a basis for reimbursement determinations.
Careful evaluation to determine fully the extent of disease must precede the treatment of medulloblastoma. Surgery should be an attempt at maximal tumor reduction; children without disseminated disease at diagnosis have improved progression-free survival if there is minimal residual disease present after surgery. 1 Surgery may be associated with temporary or permanent neurologic worsening due to postoperative infection, direct brain or cerebellar damage, or the development of the postoperative cerebellar mutism syndrome. This syndrome of delayed onset, typically hours after surgery, presents with mutism, emotional lability and usually hypotonia, dysphagia, ataxia supranuclear cranial neuropathy, and has been reported to occur in nearly 25% of patients. The etiology of posterior fossa mutism is unclear, but has been related to tumor brainstem invasion, and vermian damage and possibly disruption of the dentatothalamocortical pathways. It causes permanent sequelae in nearly one-half of all moderately to severely affected patients. 2 Postoperatively, studies should be conducted to determine whether the patient is at high risk of relapse. Risk criteria are outlined in the stage information section. 3 4 Patients with metastatic or significant local residual tumor should be considered at high risk for relapse and be treated on protocols specifically designed for them.
The following describes treatment options by risk grouping: 4
The traditional postsurgical treatment for these patients has been radiation therapy consisting of 54 Gy to 55.8 Gy to the posterior fossa and approximately 36 Gy to the entire neuraxis (i.e., the whole brain and spine). While the standard boost in medulloblastoma is the entire posterior fossa, patterns of failure data suggest that the use of a tumor-bed boost would be equally effective 5 yet associated with reduced toxicity. 6 7 The minimal dose of radiation therapy 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. 8 The lower radiation dose to the neuraxis (23.4 Gy), when coupled with chemotherapy, has been shown to result in disease control in up to 80% of patients and may decrease the severity of neurocognitive sequelae. 9 10 11 12 Long-term survivors who were prepubertal at the time of diagnosis are at high risk for growth failure due to hypothalamic failure, and growth hormone replacement therapy has not been shown to increase the likelihood of disease relapse. 13
The following is an example of a national and/or institutional clinical trial that is currently being conducted. For more information about clinical trials, please see the NCI Web site.
In poor-risk patients, the addition of chemotherapy has improved the duration of disease-free survival. 12 14 Some studies show that approximately 50% to 65% of such patients will experience long-term disease control. 3 These are patients who, at diagnosis, have locally extensive and often unresectable tumor in the posterior fossa and/or noncontiguous metastatic disease within or outside of the central nervous system. Adjuvant chemotherapy has improved progression-free survival for patients with these high-risk parameters at diagnosis. 3 12 14 15 Such patients should be considered for entry into a clinical trial. 3 4 Long-term survivors who were prepubertal at the time of diagnosis are at high risk for growth failure due to hypothalamic failure, and growth hormone replacement therapy has not been shown to increase the likelihood of disease relapse. 13
Because of the reluctance to use extensive radiation therapy (especially craniospinal radiation therapy) in young children due to concerns about resultant severe neurocognitive deficits, chemotherapy has been extensively explored in children aged 3 years and younger, and in some studies in children aged 6 years and younger, with medulloblastoma. 4 16 17 Different chemotherapeutic regimens have been employed, and most have utilized an alkylator (cyclophosphamide or ifosfamide), cisplatin and/or carboplatin, oral or intravenous etoposide, and vincristine. Outcome of such treatment has been relatively disappointing, resulting in disease control in only 20% to 30% of patients. In some of the earlier studies, craniospinal and local boost radiation therapy were utilized after completion of chemotherapy or when the children reached the age of 3 years. 16 Despite this approach, overall disease control still remained only in the 30% to 35% range. Most of the children who had long-term benefit were those who had nondisseminated, totally resected disease.
In attempts to make chemotherapy even more effective, other drugs have been added to these multiagent approaches, including intravenous and intraventricular methotrexate. 18 In patients who had nondisseminated tumors that were completely resected, 5-year progression-free survival after the addition of methotrexate was approximately 60%. Studies have been completed suggesting improved survival rates in a similar subset of children using higher-dose chemotherapy without methotrexate, supported by peripheral stem cell rescue. 19 Given its potential neurotoxicity, methotrexate remains a problematic drug to incorporate in the treatment of children with medulloblastoma. In one study that used high-dose methotrexate and intraventricular methotrexate, a high incidence of leukoencephalopathy was found, although the significance of such leukoencephalopathy as regards long-term neurocognitive outcome was unclear. 18 There seems to be a subset of patients who can be effectively treated with chemotherapy alone, and it is likely that the wider availability and application of molecular genetic markers will, in time, better identify this subset. 20 Another approach for children aged 3 years or younger at diagnosis with localized medulloblastoma is the use of multiagent chemotherapy followed by conformal radiation therapy to the primary tumor site. Results from this study are still pending.
Check for U.S. clinical trials from NCI's PDQ® Cancer Clinical Trials Registry that are now accepting patients with untreated 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.
Recurrence is not uncommon and may develop many years after initial treatment. 1 Disease may recur at the primary tumor site or by cerebrospinal fluid (CSF) dissemination. Sites of noncontiguous relapse may include the spinal leptomeninges, intracranial sites, and CSF, in isolation, or in any combination, and is variably associated with primary tumor site relapse. Approximately 60% of patients with localized disease at diagnosis will have some component of disseminated disease at relapse, even after 36 Gy of craniospinal radiation therapy. 2 Extraneural disease relapse may occur, but is rare (1% to 2% of relapses), and is primarily reported in patients who were treated with radiation therapy alone. 2 Systemic relapse is rare, but may occur. At time of relapse, a complete evaluation for extent of recurrence is indicated for all malignant tumors and, at times, for more benign lesions. Biopsy or surgical resection may be necessary for confirmation of relapse because other entities such as secondary tumor 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 the clinical picture. Patients with recurrent medulloblastoma ,who have already received radiation and chemotherapy, may be candidates for salvage chemotherapy and/or stereotactic irradiation, 3 although long-term disease control is rare. 4 5 6 For select patients, 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 high-dose chemotherapy plus local radiation therapy. 7 Entry into studies of novel therapeutic approaches including high-dose chemotherapy and autologous stem cell rescue at the time of relapse after radiation therapy alone or radiation therapy and chemotherapy should be considered. 8 9 10 Information about ongoing clinical trials is available from the NCI Web site.
Check for U.S. clinical trials from NCI's PDQ® Cancer Clinical Trials Registry that are now accepting patients with recurrent 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.
For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.
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