Treatment Options for Newly Diagnosed Childhood Medulloblastoma

Average Risk
        Standard treatment options
        Treatment options under clinical evaluation
High Risk
        Standard treatment options
        Treatment options under clinical evaluation
Children Aged 3 Years and Younger
        Standard treatment options
        Treatment options under clinical evaluation
Current Clinical Trials

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

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

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

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

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

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

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

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

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

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

The treatment of children younger than 3 years with newly diagnosed medulloblastoma continues to evolve. Due to concerns over the likely deleterious effects of craniospinal radiation on the immature nervous system, therapeutic approaches have attempted to delay and, in some cases, avoid the use of craniospinal radiation therapy. Results have been variable, and comparison across studies has been difficult because of differences in drug regimens used and the utilization of craniospinal and local boost radiotherapy at the end of chemotherapy or when children reached age 3 years in some studies.

Five-year DFS rates for young children with medulloblastoma have ranged between 30% and 70%, with most long-term survivors successfully treated with chemotherapy alone, having nondisseminated, totally resected tumors.[17-19] Surgical resectability is associated with histology, as patients with desmoplastic medulloblastoma or medulloblastoma with extensive nodularity (MBEN) have a higher rate of complete resection than do patients with classic medulloblastoma.[20,21]

Several studies have observed that the histologic finding of desmoplasia, seen in patients with desmoplastic medulloblastoma or MBEN, connotes a significantly better prognosis compared with outcome for patients with classic or large cell anaplastic medulloblastoma.[20-24]; [25][Level of evidence: 2A] For example, desmoplasia was an independent predictor of favorable EFS rates in the German HIT 2000 multicenter trial in which 19 patients with desmoplastic medulloblastoma or MBEN had 5-year EFS rates of 90% ± 7% and OS rates of 100% ± 0%, with all patients being treated with chemotherapy alone (including intraventricular methotrexate) prior to progression.[21] By contrast, EFS and OS rates for children with classic medulloblastoma in the HIT 2000 trial were significantly lower (EFS, 30% ± 11%; OS, 68% ± 10%).[21] The COG clinical trial CCG-9921 also observed a favorable outcome for children with desmoplastic medulloblastoma (including MBEN), with an EFS of 77% ± 9% and an OS of 85% ± 8% for the desmoplastic group compared with an EFS of 17% ± 5% and OS of 29% ± 6% for patients in the nondesmoplastic group (P < .0001 for both EFS and OS comparisons).[17] In this study, patients with desmoplastic tumors did not receive radiation prior to progression. The United Kingdom Children's Cancer Study Group and International Society of Paediatric Oncology used less-intensive chemotherapy and did not observe a difference in outcome for young children with desmoplastic versus nondesmoplastic medulloblastoma (both with an EFS of approximately 40%), suggesting the potential importance of intensive chemotherapy for favorable outcome for young children with desmoplastic tumors.[26]

Therapies for younger children with medulloblastoma 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, and/or intraventricular methotrexate..[17-19,21,27-29]; [26][Level of evidence: 2A] Results of trials utilizing higher-dose, marrow-ablative chemotherapeutic regimens supported by autologous stem cell rescue or peripheral stem cell rescue have also demonstrated that a subgroup of patients with medulloblastoma who are younger than 3 years at the time of diagnosis can be treated with chemotherapy alone.[30,31][Level of evidence: 2A]

Patients with desmoplastic tumors with extensive nodularity should be carefully evaluated for stigmata of Gorlin syndrome. One report observed that MBEN was associated with Gorlin syndrome in 5 of 12 cases.[24] Gorlin syndrome is an autosomal dominant disorder, also known as the nevoid basal cell carcinoma syndrome, in which those affected are predisposed to the development of basal cell carcinomas later in life, especially in the radiation portal after radiation therapy. The syndrome can be diagnosed early in life by characteristic dermatological and skeletal features such as keratocysts of the jaw, bifid or fused ribs, macrocephaly, and calcifications of the falx.[24]

In contrast to children with desmoplastic medulloblastoma or MBEN treated with current intensive chemotherapy regimens, children with other histologic subtypes fare less well, with EFS rates below 40% despite the use of intensive chemotherapy supplemented with methotrexate (intravenous, intrathecal, and intraventricular) and the use of high-dose chemotherapeutic regimens supported with stem cell rescue.[17,21] Outcome is particularly poor when these patients have disseminated disease, and there is no consensus on when and how much radiation therapy should be given and at what age radiation therapy should be instituted in patients with disseminated disease.[17-19]

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

• COG-ACNS0334 (Combination Chemotherapy Followed By Peripheral Stem Cell Transplant in Treating Young Patients With Newly Diagnosed Supratentorial Primitive Neuroectodermal Tumors or High-Risk Medulloblastoma): This COG trial is open for children aged 3 years or younger at diagnosis with high-risk disease, which is defined as those with disseminated and/or partially resected tumors, or those younger than 8 months with otherwise standard-risk disease. This study is evaluating chemotherapy as given in the completed COG study COG-99703, which used multiagent chemotherapy followed by thiotepa-based higher-dose, marrow ablative, chemotherapy and peripheral stem cell rescue, and is randomizing patients to treatment with or without intravenous high-dose methotrexate. Patients with cortical primitive neuroectodermal tumors or pineoblastomas are also eligible.

• PBTC-026 (NCT00867178) (Vorinostat, Isotretinoin, and Combination Chemotherapy in Treating Young Patients Who Have Undergone Surgery for Embryonal Tumors of the Central Nervous System): The Pediatric Brain Tumor Consortium trial is investigating the addition of vorinostat and isotretinoin to the COG-99703 backbone induction chemotherapy and as maintenance therapy following completion of the consolidation high-dose chemotherapy of this regimen.

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

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

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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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7. 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]
   
   
8. Carrie C, Grill J, Figarella-Branger D, et al.: Online quality control, hyperfractionated radiotherapy alone and reduced boost volume for standard risk medulloblastoma: long-term results of MSFOP 98. J Clin Oncol 27 (11): 1879-83, 2009.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
   
   
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.  [PUBMED Abstract]
    
    
11. Packer RJ, Gajjar A, Vezina G, et al.: Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 24 (25): 4202-8, 2006.  [PUBMED Abstract]
    
    
12. 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.  [PUBMED Abstract]
    
    
13. 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.  [PUBMED Abstract]
    
    
14. 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.  [PUBMED Abstract]
    
    
15. 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.  [PUBMED Abstract]
    
    
16. 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.  [PUBMED Abstract]
    
    
17. 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.  [PUBMED Abstract]
    
    
18. 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.  [PUBMED Abstract]
    
    
19. 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.  [PUBMED Abstract]
    
    
20. Rutkowski S, von Hoff K, Emser A, et al.: Survival and prognostic factors of early childhood medulloblastoma: an international meta-analysis. J Clin Oncol 28 (33): 4961-8, 2010.  [PUBMED Abstract]
    
    
21. von Bueren AO, von Hoff K, Pietsch T, et al.: Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology. Neuro Oncol 13 (6): 669-79, 2011.  [PUBMED Abstract]
    
    
22. Leary SE, Zhou T, Holmes E, et al.: Histology predicts a favorable outcome in young children with desmoplastic medulloblastoma: a report from the children's oncology group. Cancer 117 (14): 3262-7, 2011.  [PUBMED Abstract]
    
    
23. Giangaspero F, Perilongo G, Fondelli MP, et al.: Medulloblastoma with extensive nodularity: a variant with favorable prognosis. J Neurosurg 91 (6): 971-7, 1999.  [PUBMED Abstract]
    
    
24. Garrè ML, Cama A, Bagnasco F, et al.: Medulloblastoma variants: age-dependent occurrence and relation to Gorlin syndrome--a new clinical perspective. Clin Cancer Res 15 (7): 2463-71, 2009.  [PUBMED Abstract]
    
    
25. Rutkowski S, Gerber NU, von Hoff K, et al.: Treatment of early childhood medulloblastoma by postoperative chemotherapy and deferred radiotherapy. Neuro Oncol 11 (2): 201-10, 2009.  [PUBMED Abstract]
    
    
26. Grundy RG, Wilne SH, Robinson KJ, et al.: Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 46 (1): 120-33, 2010.  [PUBMED Abstract]
    
    
27. 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.  [PUBMED Abstract]
    
    
28. 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.  [PUBMED Abstract]
    
    
29. 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.  [PUBMED Abstract]
    
    
30. 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.  [PUBMED Abstract]
    
    
31. 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.  [PUBMED Abstract]