Current Treatment Options in Oncology

, Volume 15, Issue 4, pp 581–594 | Cite as

Management of Pediatric and Adult Patients with Medulloblastoma

  • Allison M. Martin
  • Eric Raabe
  • Charles Eberhart
  • Kenneth J. Cohen
Neuro-oncology (GJ Lesser, Section Editor)
First Online:

Opinion Statement

Approximately 70 % of newly diagnosed children with medulloblastoma (MB) will be classified as “standard risk”: their tumor is localized to the posterior fossa, they undergo a near or gross total resection, the tumor does not meet the criteria for large cell/anaplastic histology, and there is no evidence of neuroaxis dissemination by brain/spine MRI and lumbar puncture for cytopathology. Following surgical recovery, they are treated with craniospinal radiation therapy with a boost to the posterior fossa or tumor bed. Adjuvant therapy for approximately 1 year follows anchored by the use of alkylators, platinators, and microtubule inhibitors. This approach to standard risk MB works; greater than 80 % of patients will be cured, and such approaches are arguably the standard of care worldwide for such children. Despite this success, some children with standard risk features will relapse and die of recurrent disease despite aggressive salvage therapy. Moreover, current treatment, even when curative causes life-long morbidity in those who survive, and the consequences are age dependent. For the 20-year-old patient, damage to the cerebellum from surgery conveys greater risk than craniospinal radiation; however, for the 3-year-old patient, the opposite is true. The challenge for the neuro-oncologist today is how to identify accurately patients who need less therapy as well as those for whom current therapy is inadequate. As molecular diagnostics comes of age in brain tumors, the question becomes how to best implement novel methods of risk stratification. Are we able to obtain specific information about the tumor’s biology in an increasingly rapid and reliable way, and utilize these findings in the upfront management of these tumors? Precision medicine should allow us to tailor therapy to the specific drivers of each patient’s tumor. Regardless of how new approaches are implemented, it is likely that we will no longer be able to have a single standard approach to standard risk medulloblastoma in the near future.

Keywords

Medulloblastoma Brain tumor Pediatric 
This is a preview of subscription content, log in to check access.

Notes

Compliance with Ethics Guidelines

Conflict of Interest

Allison M. Martin, Eric Raabe, Charles Eberhart, and Kenneth J. Cohen declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Smoll NR, Drummond KJ. The incidence of medulloblastomas and primitive neuroectodermal tumours in adults and children. J Clin Neurosci. 2012;19:1541–4.PubMedCrossRefGoogle Scholar
  2. 2.
    Bailey P, Cushing H. Medulloblastoma cerebelli, a common type of mid-cerebellar glioma of childhood. Arch Neurol Psychiatry. 1999;14:192–224.CrossRefGoogle Scholar
  3. 3.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK. WHO classification of tumours of the central nervous system. Lyon: IARC; 2007. p. 1–309.Google Scholar
  4. 4.
    Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114(2):97–109.PubMedPubMedCentralCrossRefGoogle Scholar
  5. 5.
    Eberhart CG, Kepner JL, Goldthwaite PT, et al. Histopathologic grading of medulloblastomas. Cancer. 2002;94(2):552–60.PubMedCrossRefGoogle Scholar
  6. 6.••
    Northcott PA, Korshunov A, Witt H, et al. Medulloblastoma comprises four distinct molecular variants. J Clin Oncol. 2011;29(11):1408–14. This paper is the first to describe the molecular subgroups as they are now accepted.PubMedCrossRefGoogle Scholar
  7. 7.••
    Taylor M, Northcott PA, Korshunov A, et al. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012;123:464–72. This paper provides a consensus guideline for the clinical significance of the molecular subgroups and also provides a great overview of this topic.CrossRefGoogle Scholar
  8. 8.•
    Shih DJ, Northcott PA, Remke M, et al. Cytogenetic prognostication within medulloblastoma subgroups. J Clin Oncol. 2014;32(9):886–96. Proposes a potential way to identify molecular subgroups in real time to be incorporated into patient care.PubMedCrossRefGoogle Scholar
  9. 9.
    Ellison DW, Dalton J, Kocak M, et al. Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups. Acta Neuropathol. 2011;121:381–96.PubMedPubMedCentralCrossRefGoogle Scholar
  10. 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. 2006;24(25):4202–8. Even though this is an older study it provides the backbone for current standard risk therapy in medulloblastoma. Due to smaller sample sizes pediatric trials are slower to complete.PubMedCrossRefGoogle Scholar
  11. 11.
    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. 1999;17(3):832.PubMedGoogle Scholar
  12. 12.
    Packer RJ, Sutton LN, Elterman R, et al. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. J Neurosurg. 1994;81:690–8.PubMedCrossRefGoogle Scholar
  13. 13.•
    Packer RJ, Zhou T, Holmes E, et al. Survival and secondary tumors in children with medulloblastoma receiving radiotherapy and adjuvant chemotherapy: results of children’s oncology group trial A9961. Neuro-Oncology. 2013;15(1):97–103. The first long-term follow-up study to document comparable survival in patients treated with therapy nearly equivalent to the current standard.PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Tarbell NJ, Friedman H, Polkinghorn WR, et al. High risk medulloblastoma: a pediatric oncology group randomized trial of chemotherapy before or after radiaton therapy (POG 9031). J Clin Oncol. 2013;31(23):2936–41.PubMedPubMedCentralCrossRefGoogle Scholar
  15. 15.
    Ashley DM, Merchant TE, Strother D, et al. Induction chemotherapy and conformal radiation therapy for very young children with nonmetastatic medulloblastoma: children’s oncology group study P9934. J Clin Oncol. 2012;30(26):3181–6.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Von Bueren AO, von Hoff K, Torsten P, 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-Oncology. 2011;13(6):669–79.CrossRefGoogle Scholar
  17. 17.
    Gopalakrishnan CV, Dhakoji A, Menon G, et al. Factors predicting the need for cerebrospinal fluid diversion following posterior fossa tumor surgery in children. Pediatr Neurosurg. 2012;48(2):93–101.PubMedCrossRefGoogle Scholar
  18. 18.
    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. 1996;38(2):265–71.PubMedCrossRefGoogle Scholar
  19. 19.•
    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 Pediatr. 2006;105:444–51. The only prospective study on cerebellar mutism.CrossRefGoogle Scholar
  20. 20.
    Kortman RD, Kuhl J, Timmerman 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. 2000;46(2):269–79.CrossRefGoogle Scholar
  21. 21.
    Polkinghorn WR, Dukel IJ, Souweidane MM, et al. Disease control and ototoxicity using intensity-modulated radiation therapy tumor-bed boost for medulloblastoma. Int J Radiat Oncol Biol Phys. 2011;81(3):1–6.Google Scholar
  22. 22.
    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. 2008;50(6):1169–75.PubMedCrossRefGoogle Scholar
  23. 23.
    Groll AH, Ritter J, Müller FM. Guidelines for prevention of pneumocystis Carinii pneumonitis in children and adolescents with cancer. Klin Padiatr. 2001;213:A38–49.PubMedCrossRefGoogle Scholar
  24. 24.
    Fossati P, Ricardi U, Orecchia R. Pediatric medulloblastoma: toxicity of current treatment and potential role of proton therapy. Cancer Treat Rev. 2009;35(1):79–96.PubMedCrossRefGoogle Scholar
  25. 25.
    Liu J, Pan S, Hsieh MH, et al. Targeting Wnt-driven cancer through the inhibition of porcupine by LGK974. Proc Natl Acad Sci. 2013;110(50):20224–9.PubMedPubMedCentralCrossRefGoogle Scholar
  26. 26.
    Lin TL, Matsui W. Hedgehog pathway as a drug target: smoothened inhibitors in development. OncoTargets Ther. 2012;5:47–58.CrossRefGoogle Scholar
  27. 27.
    Kool M, Jones DT, Jäger N, et al. Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell. 2014;25(3):393–405.PubMedCrossRefGoogle Scholar
  28. 28.
    Kotecha RS, Pascoe EM, Rushing EJ, et al. Meningiomas in children and adolescents: a meta-analysis of individual patient data. Neuropathol Appl Neurobiol. 2014;12(13):1229–39.Google Scholar
  29. 29.
    Chung CS, Keating N, Yock T, et al. Comparative analysis of second malignancy risk in patients treated with proton therapy versus conventional photon therapy. Int J Radiat Oncol Biol Phys. 2008;72:S8.CrossRefGoogle Scholar
  30. 30.
    Yuh GE, Loredo LN, Yonemoto LT, et al. Reducing toxicity from craniospinal irradiation: using proton beams to treat medulloblastoma in young children. Cancer J. 2004;10(6):386–90.PubMedCrossRefGoogle Scholar
  31. 31.
    Wolden SL. Protons for craniospinal radiation: are clinical data important? Int J Radiat Oncol Biol Phys. 2013;87(2):231–2.PubMedCrossRefGoogle Scholar
  32. 32.
    Friedrich C, von Bueren AO, von Hoff K, et al. Treatment of adult nonmetastatic medulloblastoma patients according to the paediatric HIT 2000 protocol: a prospective observational multicentre study. Eur J Cancer. 2013;49(4):893–903.PubMedCrossRefGoogle Scholar
  33. 33.
    Von Hoff DD, Schilsky R, Reichert CM, et al. Toxic effects of cis-dichlorodiammineplatinum (II) in Man. Cancer Treat Rep. 1979;63:1527–31.Google Scholar
  34. 34.
    McHaney VA, Thibadoux G, Hayes FA, et al. Hearing loss in children receiving cisplatin chemotherapy. J Pediatr. 1983;102:314–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Hows JM, Mehta A, Ward L, et al. Comparison of mesna with forced diuresis to prevent cyclophosphamide induced haemorrhagic cystitis in marrow transplantation: a prospective randomised study. Br J Cancer. 1984;50:753–6.PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Kenney LB, Laufer MR, Grant FD, et al. High risk of infertility and long term gonadal damage in males treated with high dose cyclophosphamide for sarcoma during childhood. Cancer. 2001;91:613–21.PubMedCrossRefGoogle Scholar
  37. 37.
    Rowinsky EK, Donehower RC. The clinical pharmacology and use of antimicrotubule agents in cancer chemotherapeutics. Pharmacol Ther. 1991;52:35–84.PubMedCrossRefGoogle Scholar
  38. 38.
    Green DM, Zevon MA, Reese PA, et al. Second malignant tumors following treatment during childhood and adolescence for cancer. Med Pediatr Oncol. 1994;22(1):1–10.PubMedCrossRefGoogle Scholar
  39. 39.
    Legha SS. Vincristine neurotoxicity. Med Toxicol. 1986;1(6):421–7.PubMedGoogle Scholar
  40. 40.
    Tabori U, Sung L, Hukin J, et al. Canadian pediatric brain tumor consortium. Medulloblastoma in the second decade of life: a specific group with respect to toxicity and management: a Canadian pediatric brain tumor consortium study. Cancer. 2005;103(9):1874–80.PubMedCrossRefGoogle Scholar
  41. 41.
    Brandes AA, Ermani M, Amista P, et al. The treatment of adults with medulloblastoma: a prospective study. Int J Radiat Oncol Biol Phys. 2003;57(3):755–61.PubMedCrossRefGoogle Scholar
  42. 42.
    Ross SG, Northman L, Morris M, et al. Cerebellar mutism after posterior fossa tumor resection case discussion and recommendations for psychoeducational intervention. J Pediatr Oncol Nurs. 2014;31(2):78–83.PubMedCrossRefGoogle Scholar
  43. 43.
    Pizer BL, Clifford SC. The potential impact or tumour biology on improved clinical practice for medulloblastoma: progress towards biologically driven clinical trials. Br J Neurosurg. 2009;23(4):364–75.PubMedCrossRefGoogle Scholar
  44. 44.
    Goschzik T, zur Mühlen A, Kristiansen G, et al. Molecular Stratification of Medulloblastoma: comparison of histological and genetic methods to detect Wnt activated tumors. Pediatr Blood Cancer. 2010;54(4):519-25Google Scholar
  45. 45.
    Huang SM, Mishina YM, Liu S, et al. Tankyrase inhinition stabilizes axin and antagonizes Wnt signalling. Nature. 2009;461(7264):614–20.PubMedCrossRefGoogle Scholar
  46. 46.
    Castellone MD, Teramoto H, Williams BO, et al. Prostaglandin E2 promotes colon cancer cell growth through a Gs-axin-beta-catenin signaling axis. Science. 2005;310(5753):1504–10.PubMedCrossRefGoogle Scholar
  47. 47.
    Dijkgraaf GJ, Alicke B, Weinmann L, et al. Small molecule inhibition of GDC-0449 refractory smoothened mutants and downstream mechanisms of drug resistance. Cancer Res. 2011;71(2):435–44.PubMedCrossRefGoogle Scholar
  48. 48.
    Kim J, Lee JJ, Gardner D, et al. Arsenic antagonizes the hedgehog pathway by preventing ciliary accumulation and reducing stability of the Gli2 transcriptional effector. Proc Natl Acad Sci U S A. 2010;107(30):13432–7.PubMedPubMedCentralCrossRefGoogle Scholar
  49. 49.
    Beauchamp EM, Ringer L, Bulut G, et al. Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking hedgehog/GLI pathway. J Clin Investig. 2011;121(1):148–60.PubMedPubMedCentralCrossRefGoogle Scholar
  50. 50.
    Raabe E, Eberhart CG. Therapeutic targeting of developmental signaling pathways in medulloblastoma: hedgehog, notch, Wnt and Myc. Curr Signal Transduct Ther. 2013;8:1–12.CrossRefGoogle Scholar
  51. 51.
    Shalaby T, von Bueren AO, Hurlimann ML, et al. Disabling c-MYC in childhood medulloblastoma and atypical teratoid/rhabdoid tumor cells by the potent G-quadraplex interactive agent S2T1-6OTD. Mol Cancer Ther. 2010;9(1):167–79.PubMedCrossRefGoogle Scholar
  52. 52.
    Je D, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic strategy to target c-Myc. Cell. 2011;146(6):904–17.CrossRefGoogle Scholar
  53. 53.
    Li XN, Shu Q, Su JM, et al. Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC. Mol Cancer Ther. 2005;4(12):1912–22.PubMedCrossRefGoogle Scholar
  54. 54.
    Northcott PA, Shih DJ, Peacock J, et al. Subgroup-specific structural variation across 1,000 medulloblastoma genomes. Nature. 2012;488(7409):49–56.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Ardon H, De Vleeschower S, Van Calenbergh F, et al. Adjuvant dendritic cell-based tumour vaccination for children with malignant brain tumours. Cancer Immun 2008;8(7):54519–525.Google Scholar
  56. 56.
    Oba-Shinjo SM, Caballero OL, Jungbluth AA, et al. Cancer-testis (CT) antigen expression in medulloblastoma. J Clin Oncol. 2005;23(24):5511-9.Google Scholar
  57. 57.
    Ahmed N, Ratnayake M, Savoldo B, et al. Regression of experimental medulloblastoma following transfer of HER2-specific T cells. Cancer Res. 2007;67:5957–64.PubMedCrossRefGoogle Scholar
  58. 58.
    Castriconi R, Dondero A, Negri F, et al. Both CD133+ and CD133- medulloblastoma cell lines express ligands for triggering NK receptors and are susceptible to NK-mediated cytotoxicity. Eur J Immunol. 2007;37:3190–6.PubMedCrossRefGoogle Scholar
  59. 59.
    Fernández L, Portugal R, Valentín J, et al. In vitro natural killer cell immunotherapy for medulloblastoma. Front Oncol. 2013;3(94):1–7.Google Scholar
  60. 60.
    Martin A, Nirschl C, Polanczyk M, et al. MYC amplification status influences tumor immune evasion in medulloblastoma. Neuro-Oncol. 2013;15 suppl 1:15––16 [Abstract].Google Scholar
  61. 61.
    Mulhern KR, Palmer SL, Merchant TE, et al. Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma. J Clin Oncol. 2005;23(24):5511–9.PubMedCrossRefGoogle Scholar
  62. 62.
    Sklar CA, Constine LS. Chronic neuroendocrinologic sequelae of radiation therapy. Int J Radiat Oncol Biol Phys. 1995;31(5):1113–21.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Allison M. Martin
    • 1
  • Eric Raabe
    • 1
  • Charles Eberhart
    • 1
  • Kenneth J. Cohen
    • 1
  1. 1.The Sidney Kimmel Comprehensive Cancer Center at Johns HopkinsBaltimoreUSA

Personalised recommendations