Treatment Option Overview

Risk Stratification for Medulloblastoma
Surgery
Radiation Therapy
Surveillance Testing

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence ¹ for more information.)

On the basis of neuroradiographic evaluation for disseminated disease, cerebrospinal fluid (CSF) cytological examination, postoperative neuroimaging evaluation for the amount of residual disease, age of the patient, and impression of the surgeon at the time of surgery, patients with medulloblastoma have been historically stratified into the following two risk groups:

• Average risk: Children older than 3 years with tumors that are totally resected or near-totally resected (<1.5 cm of residual disease) and no metastatic disease.[1]
• High risk: Children aged 3 years and younger or those with metastatic disease and/or subtotal resection (>1.5 cm of residual disease).[1]

The 1.5 cm standard was arbitrarily chosen for evaluation in prospective studies. Metastatic disease includes neuroradiographic evidence of disseminated disease, positive cytology in lumbar or ventricular CSF obtained more than 7 days postsurgery, or extraneural disease.[2]

An intense area of study is the use of molecular and immunohistochemical analysis for disease stratification. In a large, multi-institution, retrospective biologic study, 397 medulloblastoma specimens were analyzed by transcriptional profiling (103 specimens) and immunohistochemical analysis.[3] Four unique clusters of medulloblastomas were identified. The following two subgroups clearly stood out:

• A subset with WNT signaling that occurred in those with monosomy 6 abnormalities and beta-catenin nuclear staining. This subset was primarily older children and adolescents and had a female predominance.
• A subset driven by sonic hedgehog (SHH) signaling, arising predominantly, but not exclusively, in those with desmoplastic tumors and having immunohistochemical staining of SHH pathway elements. This subset consisted of infants, adolescents, and adults.

Patients from both of these subgroups had excellent prognoses; 80% or greater 5-year progression-free survival (PFS) and overall survival (OS). The remainder of medulloblastomas, which comprise the majority of the study cohort, were separable into two other subgroups, which had greater overlap and shared a poorer prognosis, including a 30% to 45% chance of dissemination. The latter two subsets (termed Group C and Group D) differed in the following ways:

• Immunohistochemical staining.
• Histological appearance (Group C was more likely anaplastic).
• MYC amplifications (found only in Group C).
• Likelihood of metastasis (higher in Group C)
• Age at presentation (Group C occurred more commonly in childhood, whereas Group D occurred in childhood, adolescence, and adulthood).
• Overall survival (lower in Group C).

PFS for patients with Group C and D tumors ranged between 32% and 63%.[3] Other studies have confirmed the excellent prognosis of children with WNT tumors and poor prognosis of those with tumors with MYC amplification.[4,5] If this type of molecular and immunohistochemical separation can be confirmed in a homogeneously treated population of patients, preferably studied prospectively, it will dramatically alter disease stratification and likely therapy offered.[6]

Surgery is usually the initial treatment for children with medulloblastoma, both to confirm diagnosis and to remove as much tumor as is safely possible. Evidence suggests that more extensive surgical resections are related to an improved rate of survival, primarily in children with nondisseminated disease at the time of diagnosis.[7,8] One study in high-risk patients utilized presurgical chemotherapy (after tumor biopsy) to reduce tumor bulk and make subsequent resection of the tumor easier.[9] This small study did not demonstrate a high rate of survival, and postchemotherapy surgery did not seem easier and was not related to a reduced incidence of postoperative complications.

Postoperatively, children may have significant neurologic deficits caused by preoperative tumor-related brain injury, hydrocephalus, or surgery-related brain injury.[10][Level of evidence: 3iC] In addition, a significant number of patients with medulloblastoma will develop delayed onset of mutism, suprabulbar palsies, ataxia, hypotonia, and emotional lability. This constellation of findings has been termed the cerebellar mutism syndrome, and its etiology remains unclear, although cerebellar vermian damage has been postulated as a possible cause for the mutism.[11,12]; [13][Level of evidence: 3iC] In two Children’s Cancer Group studies evaluating children with both average-risk and poor-risk medulloblastoma, the syndrome has been identified in nearly 25% of patients.[12-14]; [15][Level of evidence: 3iiiC] Many patients with this syndrome may manifest neurologic and neurocognitive sequelae posttreatment.[13,15]

Radiation therapy is usually initiated after surgery with or without concomitant chemotherapy.[16-18] To date, the best survival results for children with medulloblastoma have been obtained when radiation therapy is begun within 4 to 6 weeks postsurgery.[16-19]; [20][Level of evidence: 1iA]

Prospective randomized trials and single-arm trials suggest that adjuvant chemotherapy given during and after radiation therapy improves overall survival for children with both average-risk and poor-risk medulloblastoma.[15-20] Although medulloblastoma is often sensitive to chemotherapy, preradiation chemotherapy has not been shown to improve survival compared with treatment with radiation therapy and subsequent chemotherapy. In some prospective studies, preradiation chemotherapy has been related to a poorer rate of survival.[17-20]

Children of all ages are susceptible to the adverse effects of radiation on brain development. Debilitating effects on growth and neurologic/cognitive development have been frequently observed, especially in younger children.[21-24] For this reason, the role of chemotherapy in allowing a delay in the administration of radiation therapy has been and is being studied. Results suggest that chemotherapy can be used to delay and sometimes obviate the need for radiation therapy in 20% to 40% of children younger than 3 years with nondisseminated medulloblastoma.[25,26]; [27][Level of evidence: 3iiiC] Children are also at risk for long-term endocrine dysfunction.[27]

Surveillance testing is a part of all ongoing medulloblastoma studies.[28-30] Although most treatment failures in patients newly diagnosed with medulloblastoma will occur within the first 18 months postdiagnosis, relapses many years after diagnosis have been noted.[31] In addition, secondary tumors have been increasingly diagnosed in long-term survivors.[30,31]; [32][Level of evidence: 2A] As with initial management, long-term management is complex and requires a multidisciplinary approach.

References

1. Dubuc AM, Northcott PA, Mack S, et al.: The genetics of pediatric brain tumors. Curr Neurol Neurosci Rep 10 (3): 215-23, 2010.  [PUBMED Abstract]
   
   
2. Zeltzer PM, Boyett JM, Finlay JL, et al.: Metastasis stage, adjuvant treatment, and residual tumor are prognostic factors for medulloblastoma in children: conclusions from the Children's Cancer Group 921 randomized phase III study. J Clin Oncol 17 (3): 832-45, 1999.  [PUBMED Abstract]
   
   
3. Northcott PA, Korshunov A, Witt H, et al.: Medulloblastoma comprises four distinct molecular variants. J Clin Oncol 29 (11): 1408-14, 2011.  [PUBMED Abstract]
   
   
4. Ellison DW, Dalton J, Kocak M, et al.: Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol 121 (3): 381-96, 2011.  [PUBMED Abstract]
   
   
5. Cho YJ, Tsherniak A, Tamayo P, et al.: Integrative genomic analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical outcome. J Clin Oncol 29 (11): 1424-30, 2011.  [PUBMED Abstract]
   
   
6. Ellison DW, Kocak M, Dalton J, et al.: Definition of disease-risk stratification groups in childhood medulloblastoma using combined clinical, pathologic, and molecular variables. J Clin Oncol 29 (11): 1400-7, 2011.  [PUBMED Abstract]
   
   
7. 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]
   
   
8. 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.  [PUBMED Abstract]
   
   
9. Grill J, Lellouch-Tubiana A, Elouahdani S, et al.: Preoperative chemotherapy in children with high-risk medulloblastomas: a feasibility study. J Neurosurg 103 (4 Suppl): 312-8, 2005.  [PUBMED Abstract]
   
   
10. Stargatt R, Rosenfeld JV, Maixner W, et al.: Multiple factors contribute to neuropsychological outcome in children with posterior fossa tumors. Dev Neuropsychol 32 (2): 729-48, 2007.  [PUBMED Abstract]
    
    
11. Pollack IF, Polinko P, Albright AL, et al.: Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery 37 (5): 885-93, 1995.  [PUBMED Abstract]
    
    
12. 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]
    
    
13. Wells EM, Khademian ZP, Walsh KS, et al.: Postoperative cerebellar mutism syndrome following treatment of medulloblastoma: neuroradiographic features and origin. J Neurosurg Pediatr 5 (4): 329-34, 2010.  [PUBMED Abstract]
    
    
14. Gudrunardottir T, Sehested A, Juhler M, et al.: Cerebellar mutism: review of the literature. Childs Nerv Syst 27 (3): 355-63, 2011.  [PUBMED Abstract]
    
    
15. Wolfe-Christensen C, Mullins LL, Scott JG, et al.: Persistent psychosocial problems in children who develop posterior fossa syndrome after medulloblastoma resection. Pediatr Blood Cancer 49 (5): 723-6, 2007.  [PUBMED Abstract]
    
    
16. 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]
    
    
17. 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]
    
    
18. 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]
    
    
19. Taylor RE, Bailey CC, Robinson KJ, et al.: Impact of radiotherapy parameters on outcome in the International Society of Paediatric Oncology/United Kingdom Children's Cancer Study Group PNET-3 study of preradiotherapy chemotherapy for M0-M1 medulloblastoma. Int J Radiat Oncol Biol Phys 58 (4): 1184-93, 2004.  [PUBMED Abstract]
    
    
20. von Hoff K, Hinkes B, Gerber NU, et al.: Long-term outcome and clinical prognostic factors in children with medulloblastoma treated in the prospective randomised multicentre trial HIT'91. Eur J Cancer 45 (7): 1209-17, 2009.  [PUBMED Abstract]
    
    
21. 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]
    
    
22. 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.  [PUBMED Abstract]
    
    
23. 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.  [PUBMED Abstract]
    
    
24. Walter AW, Mulhern RK, Gajjar A, et al.: Survival and neurodevelopmental outcome of young children with medulloblastoma at St Jude Children's Research Hospital. J Clin Oncol 17 (12): 3720-8, 1999.  [PUBMED Abstract]
    
    
25. 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]
    
    
26. 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]
    
    
27. Laughton SJ, Merchant TE, Sklar CA, et al.: Endocrine outcomes for children with embryonal brain tumors after risk-adapted craniospinal and conformal primary-site irradiation and high-dose chemotherapy with stem-cell rescue on the SJMB-96 trial. J Clin Oncol 26 (7): 1112-8, 2008.  [PUBMED Abstract]
    
    
28. Saunders DE, Hayward RD, Phipps KP, et al.: Surveillance neuroimaging of intracranial medulloblastoma in children: how effective, how often, and for how long? J Neurosurg 99 (2): 280-6, 2003.  [PUBMED Abstract]
    
    
29. Jenkin D: Long-term survival of children with brain tumors. Oncology (Huntingt) 10 (5): 715-9; discussion 720, 722, 728, 1996.  [PUBMED Abstract]
    
    
30. Goldstein AM, Yuen J, Tucker MA: Second cancers after medulloblastoma: population-based results from the United States and Sweden. Cancer Causes Control 8 (6): 865-71, 1997.  [PUBMED Abstract]
    
    
31. Stavrou T, Bromley CM, Nicholson HS, et al.: Prognostic factors and secondary malignancies in childhood medulloblastoma. J Pediatr Hematol Oncol 23 (7): 431-6, 2001.  [PUBMED Abstract]
    
    
32. Allen J, Donahue B, Mehta M, et al.: A phase II study of preradiotherapy chemotherapy followed by hyperfractionated radiotherapy for newly diagnosed high-risk medulloblastoma/primitive neuroectodermal tumor: a report from the Children's Oncology Group (CCG 9931). Int J Radiat Oncol Biol Phys 74 (4): 1006-11, 2009.  [PUBMED Abstract]