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Childhood Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma Treatment (PDQ®)

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 supratentorial primitive neuroectodermal tumors and pineoblastoma. 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.
• Stage information.
• Treatment options.

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.

In the summary, treatments are described as “standard” or “conventional” and “under clinical evaluation.” These designations 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. 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.

General Information

THIS PDQ SUMMARY CONTAINS CONTENT THAT IS ALSO INCLUDED IN THE NEW PDQ CHILDHOOD CENTRAL NERVOUS SYSTEM EMBRYONAL TUMORS SUMMARY. IN THE VERY NEAR FUTURE, THE PDQ CHILDHOOD SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMORS AND PINEOBLASTOMA SUMMARY WILL BE REMOVED FROM THE NATIONAL CANCER INSTITUTE (NCI) WEBSITE AND THE CONTENT CONTAINED IN THIS SUMMARY WILL BE FOUND IN THE PDQ CHILDHOOD CENTRAL NERVOUS SYSTEM EMBRYONAL TUMORS SUMMARY.

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.

Primary brain tumors are a diverse group of diseases that together constitutethe most common solid tumor of childhood. Brain tumors are classifiedaccording to histology, but tumor location and extent of spread are importantfactors that affect treatment and prognosis. Immunohistochemical analysis,cytogenetic and molecular genetic findings, and measures of mitotic activityare increasingly used in tumor diagnosis and classification.

Refer to the PDQ Childhood Brain and Spinal Cord Tumors Treatment summary for information about the general classification of childhood brain and spinal cord tumors.

Cellular Classification

The classification of brain tumors is based on both histopathologiccharacteristics and location in the brain. Undifferentiated neuroectodermaltumors of the cerebellum have historically been referred to asmedulloblastomas, while tumors of identical histology in the pineal region arediagnosed as pineoblastomas, and cortical lesions have been called central neuroblastomas or cortical primitive neuroectodermal tumors. Studies have suggested that the tumor cells of medulloblastomas andsupratentorial primitive neuroectodermal tumors have different molecular genetic aberrations.[1,2] This group also includessome tumors formerly called central neuroblastomas. The nomenclature ofpediatric brain tumors is controversial and potentially confusing. Somepathologists advocate abandoning the traditional morphologically basedclassifications such as medulloblastoma in favor of a terminology that reliesmore extensively on the phenotypic characteristics of the tumor. In such asystem, medulloblastoma is referred to as primitive neuroectodermal tumor andthen subdivided on the basis of cellular differentiation. The World Health Organization 2000 classification of brain tumors maintains the termmedulloblastoma for posterior fossa undifferentiated tumors.[3] It alsomaintains separate categories for cerebral primitive neuroectodermal tumors andfor pineal small round cell tumors (pineoblastomas). The pathologicclassification of pediatric brain tumors is a specialized area that isevolving; review of the diagnostic tissue by a neuropathologist whohas particular expertise in this area is strongly recommended.

References:

1. 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.
2. 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.
3. Kleihues P, Cavenee WK, eds.: Pathology and Genetics of Tumours of the Nervous System. Lyon, France: International Agency for Research on Cancer, 2000.

Stage Information

Poorly differentiated small round cell tumors of the cerebrum have beenreferred to as cerebral neuroblastoma and as primitive neuroectodermal tumors. These tumors in the pineal body have classically been called pineoblastomas. Histologically, these tumors may be similar to cerebellar medulloblastoma withvarying proportions of features that suggest astrocytic or ependymaldifferentiation. Genetic aberrations of supratentorial brain tumors appear tobe different from those of infratentorial primitive neuroectodermal tumors(PNET, medulloblastoma).[1] Tumors may spread throughout the subarachnoidspace. Every patient with a primitive neuroectodermal tumor or withpineoblastoma should be evaluated with diagnostic imaging of the spinal cordand whole brain. The most sensitive method currently available for evaluatingspinal cord subarachnoid metastasis is spinal magnetic resonance imagingperformed with gadolinium. Cerebrospinal fluid should be examinedcytologically for tumor cells. There is no generally accepted staging systemfor supratentorial primitive neuroectodermal tumors and for pineoblastomas, butthe staging system used for medulloblastoma is conventionally used for tumordissemination. Prognosis is probably related to the extent of disease both atdiagnosis and after surgery.[2,3,4,5] Patients with cystic tumors may fare better.2-year survival rate: 30% to 50%

References:

1. 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.
2. Edwards MS, Hudgins RJ, Wilson CB, et al.: Pineal region tumors in children. J Neurosurg 68 (5): 689-97, 1988.
3. Disclafani A, Hudgins RJ, Edwards MS, et al.: Pineocytomas. Cancer 63 (2): 302-4, 1989.
4. D'Andrea AD, Packer RJ, Rorke LB, et al.: Pineocytomas of childhood. A reappraisal of natural history and response to therapy. Cancer 59 (7): 1353-7, 1987.
5. Abay EO 2nd, Laws ER Jr, Grado GL, et al.: Pineal tumors in children and adolescents. Treatment by CSF shunting and radiotherapy. J Neurosurg 55 (6): 889-95, 1981.

Treatment Option Overview

Many of the improvements in survival in childhood cancer have been made as aresult of clinical trials that have attempted to improve on the best available, accepted therapy. Clinical trials in pediatrics are designed to compare newtherapy with therapy that is currently accepted as standard. This comparisonmay be done in a randomized study of two treatment arms or by evaluating a singlenew treatment and comparing the results with those that were previously obtained withexisting therapy.

Because of the relative rarity of cancer in children, all patients with braintumors should be considered for entry into a clinical trial. To determine andimplement optimum therapy, treatment planning by a multidisciplinary team ofcancer specialists who have experience treating childhood brain tumors isrequired. Radiation therapy, if needed, is technically very demanding andshould be carried out in centers that have experience in that area to ensureoptimal results.

In the past, treatment has included surgery with radiation therapy. Evidence suggests that more extensive surgical resections are related to animproved rate of survival for patients with medulloblastoma withoutdissemination at diagnosis, primarily in children with nondisseminatedposterior fossa disease at diagnosis. This has not yet been proven forchildhood supratentorial primitive neuroectodermal and pineal (pineoblastoma)tumors. The results of prospective, randomized trials and largesingle-arm trials have suggested that adjuvant chemotherapy given during andafter radiation therapy may improve overall survival in childrenwith medulloblastoma. Several nonrandomized trials suggest potential benefit of postradiation chemotherapy.[1,2,3,4,5] Children younger than 3 years are particularlysusceptible to the adverse effects of radiation on brain development. Debilitating effects on growth and neurologic development have frequently beenobserved, especially in younger children.[6,7,8] For this reason, the role ofchemotherapy in allowing for a delay in the administration of radiation therapy isunder study, and preliminary results suggest that chemotherapy can be used todelay, if not obviate, the need for radiation therapy in some children younger than 3 years with primitive neuroectodermal tumors.[9] Surveillance testing is presently a part ofall ongoing supratentorial primitive neuroectodermal studies.[10] Long-termmanagement of these patients is complex and requires a multidisciplinaryapproach.

The designations in PDQ that treatments are “standard” or “under clinicalevaluation” are not to be used as a basis for reimbursement determinations.

References:

1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. Packer RJ, Sutton LN, Goldwein JW, et al.: Improved survival with the use of adjuvant chemotherapy in the treatment of medulloblastoma. J Neurosurg 74 (3): 433-40, 1991.
9. 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.
10. Kramer ED, Vezina LG, Packer RJ, et al.: Staging and surveillance of children with central nervous system neoplasms: recommendations of the Neurology and Tumor Imaging Committees of the Children's Cancer Group. Pediatr Neurosurg 20 (4): 254-62; discussion 262-3, 1994.

Untreated Childhood Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma

Careful evaluation to fully determine the extent of disease must precede thetreatment of childhood supratentorial primitive neuroectodermal tumors (SPNET) and pineoblastoma. Surgery should be an attempt at maximal tumor reduction. Postoperatively, studies should be conducted to determine if the patient hasdisseminated disease.[1] Risk criteria are outlined in the stage informationsection. Patients with extensive tumors should be considered at the highestrisk of relapse and should be treated on protocols specifically designed forthem.[2] Children with pineal primitive neuroectodermal tumors may have a morefavorable prognosis when treated with surgery, radiation therapy, andchemotherapy than children with SPNETs.[2,3]

The usual postsurgical treatment is radiation therapy.[4] The suggested tumordose is 54 Gy to 56 Gy using conventional fractionation. Craniospinalirradiation with 23.4 Gy to 36 Gy is also recommended because of the propensityof this tumor to disseminate through the subarachnoid space. Given the overallpoorer prognosis for patients with extensive disease, the addition ofchemotherapy before or after radiation therapy is being explored.[5,6] Therole of chemotherapy to delay irradiation and its consequences is underclinical evaluation; preliminary results suggest that chemotherapy can be usedto delay, modify, or, in selected cases, obviate the need for radiationtherapy.[1]

CHILDREN YOUNGER THAN 3 YEARS:

Some patients younger than 3 years with newly diagnosed SPNETs and pineoblastomas will respond at leastpartially to chemotherapy.[1,2,3,7] Some patients, especially those withminimal residual postoperative disease, may have a long-lasting response. Forthis reason, studies that use chemotherapy to delay, modify, orpossibly obviate the need for radiation therapy have been undertaken. Results of such studies for young children with SPNET and pineoblastomas have been disappointing.[1,8] Although chemotherapy isbeing used to prevent neurologic damage caused by radiation therapy in veryyoung patients, neurologic deficits may be present in children prior to theinitiation of therapy, and progressive neurologic damage has been noted duringtherapy.[9]

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 supratentorial primitive neuroectodermal tumor, childhood pineoblastoma and untreated childhood pineoblastoma. 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. 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.
2. 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.
3. 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.
4. Disclafani A, Hudgins RJ, Edwards MS, et al.: Pineocytomas. Cancer 63 (2): 302-4, 1989.
5. 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.
6. Massimino M, Gandola L, Spreafico F, et al.: Supratentorial primitive neuroectodermal tumors (S-PNET) in children: A prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy. Int J Radiat Oncol Biol Phys 64 (4): 1031-7, 2006.
7. Duffner PK, Cohen ME, Sanford RA, et al.: Lack of efficacy of postoperative chemotherapy and delayed radiation in very young children with pineoblastoma. Pediatric Oncology Group. Med Pediatr Oncol 25 (1): 38-44, 1995.
8. Timmermann B, Kortmann RD, Kühl J, et al.: Role of radiotherapy in supratentorial primitive neuroectodermal tumor in young children: results of the German HIT-SKK87 and HIT-SKK92 trials. J Clin Oncol 24 (10): 1554-60, 2006.
9. Mulhern RK, Horowitz ME, Kovnar EH, et al.: Neurodevelopmental status of infants and young children treated for brain tumors with preirradiation chemotherapy. J Clin Oncol 7 (11): 1660-6, 1989.

Recurrent Childhood Supratentorial Primitive Neuroectodermal Tumors and Pineoblastoma

Recurrence is not uncommon in both benign and malignant childhood brain tumorsand may develop many years after initial treatment.[1] Disease can be at theprimary tumor site or, especially in malignant tumors, at noncontiguous centralnervous system sites. Systemic relapse is rare but may occur. At time ofrelapse, a complete evaluation for extent of recurrence is indicated for allmalignant tumors and, at times, for benign lesions. Biopsy or surgicalresection may be necessary for confirmation of relapse because other entities,such as secondary tumor and treatment-related brain necrosis, may be clinicallyindistinguishable from tumor recurrence. The need for surgical interventionmust be individualized on the basis of the initial tumor type, the length oftime between initial treatment and the reappearance of the lesion, and theclinical picture. Patients with supratentorial primitive neuroectodermaltumors or pineoblastomas that recur after radiation therapy alone should beconsidered for treatment with known active agents, which include vincristine,cyclophosphamide, cisplatin, carboplatin, and etoposide; response is seen inmore than 50% of patients.[2,3] Entry into studies of novel therapeuticapproaches at the time of relapse after radiation therapy alone or radiationtherapy and chemotherapy should be considered.[4,5] 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 recurrent childhood supratentorial primitive neuroectodermal tumor, recurrent childhood pineoblastoma and childhood pineoblastoma. 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. Jenkin D, Greenberg M, Hoffman H, et al.: Brain tumors in children: long-term survival after radiation treatment. Int J Radiat Oncol Biol Phys 31 (3): 445-51, 1995.
2. Cangir A, van Eys J, Berry DH, et al.: Combination chemotherapy with MOPP in children with recurrent brain tumors. Med Pediatr Oncol 4 (3): 253-61, 1978.
3. 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.
4. 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.
5. 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.

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Changes to This Summary (04/09/2008)

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

Editorial changes were made to this summary.

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  Treatment options for childhood cancers.

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Date Last Modified: 2008-04-09