Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version - National Cancer Institute

Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment (PDQ®)–Health Professional Version

Treatment of Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors

Recurrence of all forms of central nervous system (CNS) embryonal tumors is not uncommon and usually occurs within 36 months of treatment. However, recurrent tumors may develop many years after initial treatment.[1-3] 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 may be associated with primary tumor relapse.[1,2,4] Extraneural disease relapse may occur but is rare and is seen primarily in patients who were treated with radiation therapy alone.[5][Level of evidence: 3iiiA]

Studies have found that even in patients with nondisseminated disease at diagnosis, and independent of the dose of radiation therapy or the type of chemotherapy, 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.[1,2,4]

Treatment Options

There are no standard treatment options for recurrent childhood CNS embryonal tumors. (Refer to the Treatment for Recurrent Childhood CNS Atypical Teratoid/Rhabdoid Tumor section in the PDQ summary on Childhood Central Nervous System Atypical Teratoid/Rhabdoid Tumor Treatment for more information.)

For most children, treatment is palliative, and disease control is transient in patients previously treated with radiation therapy and chemotherapy, with more than 80% of patients progressing within 2 years.[3]; [6][Level of evidence: 3iB] For young children, predominantly those younger than 3 years at diagnosis who were never treated with radiation therapy, longer-term control with reoperation, radiation therapy, and chemotherapy is possible.[4,7-9]

Treatment approaches may include the following:

Surgery

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.

Radiation therapy

Patients with recurrent embryonal tumors who have already received radiation therapy and chemotherapy may be candidates for further radiation therapy depending on the site and dose of previous radiation, including reirradiation at the primary tumor site, focal areas of radiation therapy to sites of disseminated disease and, rarely, craniospinal radiation therapy.[10] In most cases, such therapy is palliative. Stereotactic radiation therapy and/or salvage chemotherapy can also be used (refer to the Chemotherapy subsection of this summary for more information).[11]

Chemotherapy

Recurrent CNS embryonal tumors can respond to chemotherapeutic agents used singularly or in combination, including cyclophosphamide, cisplatin, carboplatin, lomustine, etoposide, topotecan, temozolomide, and antiangiogenic metronomic therapy.[7,12-20]; [21,22][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 who developed local recurrence—long-term disease control may be obtained after further treatment with chemotherapy plus local radiation therapy; this potential may be greatest in patients who are able to undergo complete resection of the recurrent disease.[23][Level of evidence: 2A]; [24][Level of evidence: 3iiiA]

In a St. Jude Children’s Research Hospital study (SJYC07 [NCT00602667]), 29 patients with progressive disease received craniospinal irradiation (median dose, 36 Gy; interquartile range, 36–36). Of the 29 patients who received craniospinal irradiation, 18 patients (62%) were alive at the time of publication, compared with 6 of 25 patients (24%) who did not receive craniospinal irradiation.[25][Level of evidence: 2Di]

High-dose chemotherapy with stem cell rescue

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.[8,9,26-29][Level of evidence: 2A]; [30][Level of evidence: 3iiB]; [31,32][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 seen primarily in patients in first relapse and in those with only localized disease at the time of relapse.[9]; [29][Level of evidence: 2A]; [30][Level of evidence: 3iiB]
Additionally, results from national trials for relapsed medulloblastoma that specified intent to transplant as part of their treatment plan showed that only approximately 5% of patients initiating retrieval therapy achieve long-term disease-free survival with this strategy.[29,33] Thus, studies that report from the time of transplant overestimate the benefit of transplant-based approaches for the total population of relapsing patients.
Long-term disease control for patients with disseminated disease is infrequent.[34][Level of evidence: 3iA]

Molecularly targeted therapy

With the increased knowledge of the molecular and genetic changes associated with different subtypes of medulloblastoma, molecularly targeted therapy, also called precision therapy, is being actively explored in children with recurrent disease.

In patients with recurrent sonic hedgehog (SHH) medulloblastomas, the SHH PTCH1 inhibitor vismodegib demonstrated radiographic responses in 3 of 12 pediatric-aged patients, with two responses being sustained for less than 2 months and one response for more than 6 months. Only patients with upstream mutations of the SHH pathway, at the level of PTCH1 or SMO, responded.[35] However, because of the development of irreversible growth plate fusions, the use of vismodegib is limited to skeletally mature children.[36]

Treatment Options Under Clinical Evaluation for Recurrent Childhood Medulloblastoma and Other CNS Embryonal Tumors

Early-phase therapeutic trials may be available for selected patients. These trials may be available via the Children's Oncology Group (COG), the Pediatric Brain Tumor Consortium , or other entities. Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.

The following is an example of a national and/or institutional clinical trial that is currently being conducted:

APEC1621 (NCT03155620) (Pediatric MATCH: Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients with Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders): NCI-COG Pediatric Molecular Analysis for Therapeutic Choice (MATCH), referred to as Pediatric MATCH, will match targeted agents with specific molecular changes identified using a next-generation sequencing targeted assay of more than 4,000 different mutations across more than 160 genes in refractory and recurrent solid tumors. Children and adolescents aged 1 to 21 years are eligible for the trial.
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References

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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. [PUBMED Abstract]
Sabel M, Fleischhack G, Tippelt S, et al.: Relapse patterns and outcome after relapse in standard risk medulloblastoma: a report from the HIT-SIOP-PNET4 study. J Neurooncol 129 (3): 515-524, 2016. [PUBMED Abstract]
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. [PUBMED Abstract]
Mazloom A, Zangeneh AH, Paulino AC: Prognostic factors after extraneural metastasis of medulloblastoma. Int J Radiat Oncol Biol Phys 78 (1): 72-8, 2010. [PUBMED Abstract]
Johnston DL, Keene D, Strother D, et al.: Survival Following Tumor Recurrence in Children With Medulloblastoma. J Pediatr Hematol Oncol 40 (3): e159-e163, 2018. [PUBMED Abstract]
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. [PUBMED Abstract]
Kadota RP, Mahoney DH, Doyle J, et al.: Dose intensive melphalan and cyclophosphamide with autologous hematopoietic stem cells for recurrent medulloblastoma or germinoma. Pediatr Blood Cancer 51 (5): 675-8, 2008. [PUBMED Abstract]
Butturini AM, Jacob M, Aguajo J, et al.: High-dose chemotherapy and autologous hematopoietic progenitor cell rescue in children with recurrent medulloblastoma and supratentorial primitive neuroectodermal tumors: the impact of prior radiotherapy on outcome. Cancer 115 (13): 2956-63, 2009. [PUBMED Abstract]
Wetmore C, Herington D, Lin T, et al.: Reirradiation of recurrent medulloblastoma: does clinical benefit outweigh risk for toxicity? Cancer 120 (23): 3731-7, 2014. [PUBMED Abstract]
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. [PUBMED Abstract]
Friedman HS, Oakes WJ: The chemotherapy of posterior fossa tumors in childhood. J Neurooncol 5 (3): 217-29, 1987. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
Allen JC, Walker R, Luks E, et al.: Carboplatin and recurrent childhood brain tumors. J Clin Oncol 5 (3): 459-63, 1987. [PUBMED Abstract]
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. [PUBMED Abstract]
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. [PUBMED Abstract]
Friedman HS, Mahaley MS, Schold SC, et al.: Efficacy of vincristine and cyclophosphamide in the therapy of recurrent medulloblastoma. Neurosurgery 18 (3): 335-40, 1986. [PUBMED Abstract]
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. [PUBMED Abstract]
Cefalo G, Massimino M, Ruggiero A, et al.: Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial. Neuro Oncol 16 (5): 748-53, 2014. [PUBMED Abstract]
Minturn JE, Janss AJ, Fisher PG, et al.: A phase II study of metronomic oral topotecan for recurrent childhood brain tumors. Pediatr Blood Cancer 56 (1): 39-44, 2011. [PUBMED Abstract]
Peyrl A, Chocholous M, Kieran MW, et al.: Antiangiogenic metronomic therapy for children with recurrent embryonal brain tumors. Pediatr Blood Cancer 59 (3): 511-7, 2012. [PUBMED Abstract]
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. [PUBMED Abstract]
Bakst RL, Dunkel IJ, Gilheeney S, et al.: Reirradiation for recurrent medulloblastoma. Cancer 117 (21): 4977-82, 2011. [PUBMED Abstract]
Robinson GW, Rudneva VA, Buchhalter I, et al.: Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial. Lancet Oncol 19 (6): 768-784, 2018. [PUBMED Abstract]
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. [PUBMED Abstract]
Park JE, Kang J, Yoo KH, et al.: Efficacy of high-dose chemotherapy and autologous stem cell transplantation in patients with relapsed medulloblastoma: a report on the Korean Society for Pediatric Neuro-Oncology (KSPNO)-S-053 study. J Korean Med Sci 25 (8): 1160-6, 2010. [PUBMED Abstract]
Gilman AL, Jacobsen C, Bunin N, et al.: Phase I study of tandem high-dose chemotherapy with autologous peripheral blood stem cell rescue for children with recurrent brain tumors: a Pediatric Blood and MarrowTransplant Consortium study. Pediatr Blood Cancer 57 (3): 506-13, 2011. [PUBMED Abstract]
Pizer B, Donachie PH, Robinson K, et al.: Treatment of recurrent central nervous system primitive neuroectodermal tumours in children and adolescents: results of a Children's Cancer and Leukaemia Group study. Eur J Cancer 47 (9): 1389-97, 2011. [PUBMED Abstract]
Massimino M, Gandola L, Spreafico F, et al.: No salvage using high-dose chemotherapy plus/minus reirradiation for relapsing previously irradiated medulloblastoma. Int J Radiat Oncol Biol Phys 73 (5): 1358-63, 2009. [PUBMED Abstract]
Gururangan S, Krauser J, Watral MA, et al.: Efficacy of high-dose chemotherapy or standard salvage therapy in patients with recurrent medulloblastoma. Neuro Oncol 10 (5): 745-51, 2008. [PUBMED Abstract]
Dunkel IJ, Gardner SL, Garvin JH, et al.: High-dose carboplatin, thiotepa, and etoposide with autologous stem cell rescue for patients with previously irradiated recurrent medulloblastoma. Neuro Oncol 12 (3): 297-303, 2010. [PUBMED Abstract]
Gajjar A, Pizer B: Role of high-dose chemotherapy for recurrent medulloblastoma and other CNS primitive neuroectodermal tumors. Pediatr Blood Cancer 54 (4): 649-51, 2010. [PUBMED Abstract]
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. [PUBMED Abstract]
Robinson GW, Orr BA, Wu G, et al.: Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032. J Clin Oncol 33 (24): 2646-54, 2015. [PUBMED Abstract]
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Changes to This Summary (09/09/2019)

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.

This summary was comprehensively reviewed and reformatted.

This summary was renamed from Childhood Central Nervous System Embryonal Tumors Treatment.

This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® - NCI's Comprehensive Cancer Database pages.

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 medulloblastoma and other 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 Medulloblastoma and Other 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 Health System)
Malcolm A. Smith, MD, PhD (National Cancer Institute)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. 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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PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Medulloblastoma and Other Central Nervous System Embryonal Tumors Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389418]

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