Treatment options
        Average risk
        High risk
        Children younger than 3 years

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 if the patient has 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 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.[9-12] 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 ¹.

• The Children's Oncology Group (COG) is coordinating a phase III trial (COG-ACNS0331 ²) randomizing children between 3 and 8 years of age to receive between 18 Gy and 24 Gy of craniospinal radiation, and also randomizing children between 3 and 21 years of age to receive conformal tumor-site versus posterior-fossa radiation therapy. In this study, children receive weekly vincristine during radiation therapy and lomustine, vincristine, cisplatin, etoposide, and cyclophosphamide after radiation therapy.

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 younger than 3 years, and in some studies in children younger than 6 years, 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 3 years of age.[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.

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.  [PUBMED Abstract]
   
   
2. 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.  [PUBMED Abstract]
   
   
3. 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]
   
   
4. Geyer JR, Zeltzer PM, Boyett JM, et al.: Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group. J Clin Oncol 12 (8): 1607-15, 1994.  [PUBMED Abstract]
   
   
5. Fukunaga-Johnson N, Lee JH, Sandler HM, et al.: Patterns of failure following treatment for medulloblastoma: is it necessary to treat the entire posterior fossa? Int J Radiat Oncol Biol Phys 42 (1): 143-6, 1998.  [PUBMED Abstract]
   
   
6. 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.  [PUBMED Abstract]
   
   
7. 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.  [PUBMED Abstract]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. 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.  [PUBMED Abstract]
   
   
10. 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]
    
    
11. 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]
    
    
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.  [PUBMED Abstract]
    
    
13. 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]
    
    
14. 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]
    
    
15. 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]
    
    
16. 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]
    
    
17. Dupuis-Girod S, Hartmann O, Benhamou E, et al.: Will high dose chemotherapy followed by autologous bone marrow transplantation supplant cranio-spinal irradiation in young children treated for medulloblastoma? J Neurooncol 27 (1): 87-98, 1996.  [PUBMED Abstract]
    
    
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.  [PUBMED Abstract]
    
    
19. Thorarinsdottir HK, Rood B, Kamani N, et al.: Outcome for children <4 years of age with malignant central nervous system tumors treated with high-dose chemotherapy and autologous stem cell rescue. Pediatr Blood Cancer 48 (3): 278-84, 2007.  [PUBMED Abstract]
    
    
20. 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.  [PUBMED Abstract]