Medulloblastoma Treatment & Management
- Author: George I Jallo, MD; Chief Editor: Amy Kao, MD more...
For the patient with few neurological signs and little hydrocephalus, the entire presurgical workup can be facilitated on an outpatient basis. Admit patients with significant neurological symptoms (especially those with either change in mental status or imaging evidence of considerable hydrocephalus such as transependymal edema) to the hospital in a monitored setting.[4, 5]
The cranium initially can accommodate a small increase of CSF volume with little change in intracranial pressure. However, since the skull is a rigid container with a finite volume (threshold), further increases in ventricular size lead to dramatic increases of intracranial pressure. Decreased mental status is an indication that the ventricular volume is approaching that threshold; enlargement of ventricles beyond the threshold is accompanied by potentially disastrous consequences.
Frequent neurologic assessment by the nursing staff is extremely important. Any further decline in mental status is indication for administration of mannitol and emergent neurosurgical consultation for placement of an external ventricular drain.
Postoperatively, medical care revolves around staging, chemotherapy, and irradiation. Within 48 hours of surgery, a follow-up gadolinium-enhanced MRI is necessary to assess residual tumor size prior to the onset of enhancing reactive gliosis, which may be interpreted as tumor.
Staging is dependent upon extent of resection, radiographic evidence of tumor spread, and CSF cytology. Recently, a move away from the Chang TNM staging system to a simplified high-risk/low-risk categorization has occurred. Those patients who undergo gross total resection, with no radiographic evidence of spread and no malignant cells on CSF cytology, are considered in a low-risk category; however, presence of any of the 3 would place the patient into the high-risk group.
In addition to alterations in the Hedgehog and Wnt pathways,inactivating mutations of the histone-lysine N-methyltransferase genes MLL2 or MLL3 were identified in 16% of MB patients
G-protein coupled receptor expression patterns delineate medulloblastoma subgroups which act as imaging and therapeutic targets.
Radiation therapy for medulloblastoma is aimed at destroying cells along the entire neuraxis. Local recurrence has been associated with a lower radiation dose at the primary site. Patients receiving less than 5000 centigray (cGy) have over twice the local recurrence rate as those receiving at least this dose.
Rieken et al found that craniospinal irradiation following complete resection of medulloblastoma yielded overall survival and local and distant progression-free survival rates of 73%, 62%, and 77% at 60 months in children and adults. The authors delivered a median craniospinal dose of 35.5 Gy and administered additional boosts to the posterior fossa up to 54.0 Gy. Initiating treatment within 28 days, macroscopic complete tumor resection, and desmoplastic histology were associated with improved outcome.
In addition, clinical trials have documented that radiation therapy to only the cranium results in metastasis to the spine (even in the absence of positive cytology or radiographic evidence of spread). Most standard therapy for low-stage disease includes 36 cGy to both the brain and spinal cord with a boost of 18-20 cGy to the primary tumor site. Some institutions use different regimens including higher doses in several fractions. Others recommend proton beam therapy.
Unfortunately, radiation can have a destructive influence on the developing nervous system. Complications of radiotherapy can include lowered intelligence quotient (IQ) score, small stature, endocrine dysfunction, behavioral abnormalities, and secondary neoplasms (experienced by those fortunate to have prolonged survival).
A small study by Gupta et al reported a good overall survival rate for standard-risk children treated with hyperfractionated therapy (two daily fractions) with a total tumor bed dose of 68 Gy for 6-7 weeks. This treatment approach may be reasonable in centers without access to chemotherapy, but caution must be undertaken as the median follow-up was only 33 months. The authors found preserved cognitive function at 2 years posttreatment but long-term results were not available. In addition, secondary malignancies were not reported.
White matter necrosis, which can enlarge and produce significant mass effect and vascular disorders, is another feared long-term complication of radiation. Reduction in IQ and neurobehavioral function is related directly to the age at which radiation is administered. Radiotherapy, however, remains the most effective adjunct for medulloblastoma and is used in children despite its consequences.
Chemotherapy has evolved from use for advanced recurrent disease to use as a common tool in the modern armamentarium against medulloblastoma. However, despite the common use of chemotherapy today, exact benefits remain unclear.
To reduce radiation dose or postpone irradiation until it can be better tolerated, chemotherapy utilization is focusing on young children. Among the several regimens now being used, one of the most aggressive is the "8 drugs in 1 day" protocol, which employs vincristine, carmustine, procarbazine, hydroxyurea, cisplatin, cytarabine, prednisone, and cyclophosphamide.
Children's Cancer Group recently reported better results with a vincristine, lomustine, and prednisone (VCP) protocol. The study reported a 63% 5-year progression-free survival rate for VCP as opposed to 45% in the same group for the "8 in 1 day" regimen.
Pediatric Oncology Group showed similar survival results in the same age group when chemotherapy was followed by radiation. That study protocol utilized vincristine, cyclophosphamide, etoposide, and cisplatin. Thus far, the greatest benefit from the addition of chemotherapy has been seen in those patients with more advanced disease.
New studies are looking at sensitizing the tumor to irradiation with the concomitant use of chemotherapy. Also, the use of presurgical chemotherapy to treat patients in extremis prior to surgery has been reported.
Like radiation, chemotherapy involves toxic effects. Adverse effects include renal toxicity, ototoxicity, hepatotoxicity, pulmonary fibrosis, and gastrointestinal disturbances. Most of these effects are transient and reverse with the withdrawal of the drug. However, when methotrexate is used in combination with irradiation, irreversible necrotizing leukoencephalopathy can occur.
In children with metastatic MB, tandem HDCT (high dose chemotherapy) with ASCT (autologous stem cell therapy) followed by conventional craniospinal RT proved its feasibility without jeopardizing survival.
Other data suggest that oncolytic measles viruses encoding anti-angiogenic proteins may have therapeutic benefit against medulloblastoma and support ongoing efforts to target angiogenesis in medulloblastoma.
Aside from histologic confirmation, the fundamental goal of surgery is removal of as much tumor as possible. Patients in whom gross total resection is possible are found to have longer recurrence-free intervals than patients who have residual tumor at the end of surgery.[9, 10]
Surgery also has the added benefit of restoring the natural CSF pathways in the brain. A majority of patients will have resolution of their hydrocephalus after surgery.
At the time of surgery, the extent of subarachnoid spread of the tumor can be assessed. When involved with tumor, the surrounding subarachnoid space is opaque, with a granular appearance often referred to as "sugar coating." This condition is associated with early subarachnoid seeding along the entire neuraxis and early recurrence.
In one third of cases, the tumor adheres to the floor of the fourth ventricle, precluding gross total resection.
The purpose of postoperative MRI within 48 hours after surgery is 2-fold. Aside from staging, the MRI delineates any residual tumor; if the surgeon believes the residual tumor is removable, re-exploration of the patient during the same hospitalization for additional tumor removal is a reasonable possibility. The patient spends the first postoperative night in ICU.
If the surgery entails significant manipulation or invasion of the brain stem, the patient should remain intubated for the first postoperative night and be extubated carefully once lower cranial nerve function has been assessed. However, if the surgeon believes that involvement of the floor of the fourth ventricle was minimal, the patient may be extubated in the operating room.
If the patient has not had an external ventricular drain placed preoperatively, one usually is placed at the time of surgery.
Postoperative drainage is maintained for 3 days, after which the drain is clamped and connected to pressure monitoring. If the patient tolerates 24 hours of having the drain clamped, the ventriculostomy is removed.
Decrease in mental status is an indication for opening the ventriculostomy and continuing drainage. Continued drainage will allow blood and postoperative cellular debris to clear; clamping can be reattempted after an additional 5 days.
If repeated drainage fails to relieve symptoms, a ventriculoperitoneal shunt must be placed for long-term control of hydrocephalus; however, this is necessary in only approximately 15% of patients. The alternative to shunting is a third ventriculostomy. This can reestablish CSF flow without the potential for peritoneal seeding of tumor.
See the list below:
No special diet is beneficial.
No activity restrictions are necessary.
Bailey P, Cushing H. A common type of midcerebellar glioma of childhood. Arch Neurol Psychiatr. 1925. 14:192-224.
Salaroli R, Ronchi A, Buttarelli FR, Cortesi F, Marchese V, Bella ED, et al. Wnt activation affects proliferation, invasiveness and radiosensitivity in medulloblastoma. J Neurooncol. 2014 Sep 28. [Medline].
Rorke LB. The cerebellar medulloblastoma and its relationship to primitive neuroectodermal tumors. J Neuropathol Exp Neurol. 1983 Jan. 42(1):1-15. [Medline].
Bode U, Zimmermann M, Moser O, Rutkowski S, Warmuth-Metz M, Pietsch T, et al. Treatment of recurrent primitive neuroectodermal tumors (PNET) in children and adolescents with high-dose chemotherapy (HDC) and stem cell support: results of the HITREZ 97 multicentre trial. J Neurooncol. 2014 Sep 2. [Medline].
Yamada A, Moritake H, Kamimura S, Yamashita S, Takeshima H, Nunoi H. Proposed strategy for the use of high-dose chemotherapy with stem cell rescue and intrathecal topotecan without whole-brain irradiation for infantile classic medulloblastoma. Pediatr Blood Cancer. 2014 Aug 30. [Medline].
Rieken S, Mohr A, Habermehl D, Welzel T, Lindel K, Witt O, et al. Outcome and prognostic factors of radiation therapy for medulloblastoma. Int J Radiat Oncol Biol Phys. 2011 Nov 1. 81(3):e7-e13. [Medline].
Gupta T, Jalali R, Goswami S, Nair V, Moiyadi A, Epari S, et al. Early Clinical Outcomes Demonstrate Preserved Cognitive Function in Children with Average-Risk Medulloblastoma When Treated with Hyperfractionated Radiation Therapy. Int J Radiat Oncol Biol Phys. 2012 Feb 16. [Medline].
Haddy N, Mousannif A, Tukenova M, et al. Relationship between the brain radiation dose for the treatment of childhood cancer and the risk of long-term cerebrovascular mortality. Brain. 2011 May. 134:1362-72. [Medline].
Martin AM, Raabe E, Eberhart C, Cohen KJ. Management of Pediatric and Adult Patients with Medulloblastoma. Curr Treat Options Oncol. 2014 Sep 7. [Medline].
Albright AL, Wisoff JH, Zeltzer PM, Boyett JM, Rorke LB, Stanley P. Effects of medulloblastoma resections on outcome in children: a report from the Children's Cancer Group. Neurosurgery. 1996 Feb. 38(2):265-71. [Medline].
Allen JC, Epstein F. Medulloblastoma and other primary malignant neuroectodermal tumors of the CNS. The effect of patients' age and extent of disease on prognosis. J Neurosurg. 1982 Oct. 57(4):446-51. [Medline].
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. 1997 May. 32(3):243-52. [Medline].
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. 1995 Sep. 25(3):166-78. [Medline].
Balter-Seri J, Mor C, Shuper A, et al. Cure of recurrent medulloblastoma: the contribution of surgical resection at relapse. Cancer. 1997 Mar 15. 79(6):1241-7. [Medline].
Blaser SI, Harwood-Nash DC. Neuroradiology of pediatric posterior fossa medulloblastoma. J Neurooncol. 1996 Jul. 29(1):23-34. [Medline].
Carrie C, Muracciole X, Gomez F, et al. Conformal radiotherapy, reduced boost volume, hyperfractionated radiotherapy, and online quality control in standard-risk medulloblastoma without chemotherapy: results of the French M-SFOP 98 protocol. Int J Radiat Oncol Biol Phys. 2005 Nov 1. 63(3):711-6. [Medline].
Chang CH, Housepian EM, Herbert C. An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas. Radiology. 1969 Dec. 93(6):1351-9. [Medline].
Cohen BH, Packer RJ. Chemotherapy for medulloblastomas and primitive neuroectodermal tumors. J Neurooncol. 1996 Jul. 29(1):55-68. [Medline].
Dennis M, Spiegler BJ, Hetherington CR, et al. Neuropsychological sequelae of the treatment of children with medulloblastoma. J Neurooncol. 1996 Jul. 29(1):91-101. [Medline].
Dufour C1, Kieffer V, Varlet P, Raquin MA, Dhermain F, Puget S, et al. Tandem high-dose chemotherapy and autologous stem cell rescue in children with newly diagnosed high-risk medulloblastoma or supratentorial primitive neuro-ectodermic tumors. [Full Text].
Dunkel IJ, Boyett JM, Yates A, Rosenblum M, Garvin JH Jr, Bostrom BC, et al. High-dose carboplatin, thiotepa, and etoposide with autologous stem-cell rescue for patients with recurrent medulloblastoma. Children's Cancer Group. J Clin Oncol. 1998 Jan. 16(1):222-8. [Medline].
Friedberg MH, David O, Adelman LS. Recurrence of medulloblastoma: violation of Collins' law after two decades. Surg Neurol. 1997 Jun. 47(6):571-4. [Medline].
Giordana MT, Cavalla P, Dutto A, et al. Is medulloblastoma the same tumor in children and adults?. J Neurooncol. 1997 Nov. 35(2):169-76. [Medline].
Giordana MT, Migheli A, Pavanelli E. Isochromosome 17q is a constant finding in medulloblastoma. An interphase cytogenetic study on tissue sections. Neuropathol Appl Neurobiol. 1998 Jun. 24(3):233-8. [Medline].
Giordana MT, Schiffer P, Schiffer D. Prognostic factors in medulloblastoma. Childs Nerv Syst. 1998 Jun. 14(6):256-62. [Medline].
Giralt J, SÃ¡nchez de Toledo J, Moraga F, et al. Improving survival of medulloblastoma: results in two groups of patients. Oncology. 1996 Jan-Feb. 53(1):38-42. [Medline].
Hutzen B, Bid HK, Houghton PJ, Pierson CR, Powell K, Bratasz A, et al. Treatment of medulloblastoma with oncolytic measles viruses expressing the angiogenesis inhibitors endostatin and angiostatin. March,19,2014. [Full Text].
Hye Sook Min,* Ji Yeoun Lee,† Seung-Ki Kim,† and Sung-Hye Park*‡. Genetic Grouping of Medulloblastomas by Representative Markers in Pathologic Diagnosis1. [Full Text].
Jenkin D. The radiation treatment of medulloblastoma. J Neurooncol. 1996 Jul. 29(1):45-54. [Medline].
Kiltie AE, Lashford LS, Gattamaneni HR. Survival and late effects in medulloblastoma patients treated with craniospinal irradiation under three years old. Med Pediatr Oncol. 1997 May. 28(5):348-54. [Medline].
Kool M1, Korshunov A, Pfister SM. Update on molecular and genetic alterations in adult medulloblastoma. Sep 5,2012. [Full Text].
Miralbell R, Bieri S, Huguenin P, et al. Prognostic value of cerebrospinal fluid cytology in pediatric medulloblastoma. Swiss Pediatric Oncology Group. Ann Oncol. 1999 Feb. 10(2):239-41. [Medline].
Parsons DW1, Li M, Zhang X, Jones S, Leary RJ, Lin JC, et al. The genetic landscape of the childhood cancer medulloblastoma. [Full Text].
Pollack IF, Polinko P, Albright AL, et al. Mutism and pseudobulbar symptoms after resection of posterior fossa tumors in children: incidence and pathophysiology. Neurosurgery. 1995 Nov. 37(5):885-93. [Medline].
Rajurkar M1, Huang H, Cotton JL, Brooks JK, Sicklick J, McMahon AP, et al. Distinct cellular origin and genetic requirement of Hedgehog-Gli in postnatal rhabdomyosarcoma genesis. [Full Text].
Rossi A, Caracciolo V, Russo G, Reiss K, Giordano A. Medulloblastoma: from molecular pathology to therapy. Clin Cancer Res. 2008 Feb 15. 14(4):971-6. [Medline].
Rutka JT, Hoffman HJ. Medulloblastoma: a historical perspective and overview. J Neurooncol. 1996 Jul. 29(1):1-7. [Medline].
Saran FH, Driever PH, Thilmann C, et al. Survival of very young children with medulloblastoma (primitive neuroectodermal tumor of the posterior fossa) treated with craniospinal irradiation. Int J Radiat Oncol Biol Phys. 1998 Dec 1. 42(5):959-67. [Medline].
Schmandt S, Kuhl J. Chemotherapy as prophylaxis and treatment of meningosis in children less than 3 years of age with medulloblastoma. J Neurooncol. 1998 Jun-Jul. 38(2-3):187-92. [Medline].
Sure U, Berghorn WJ, Bertalanffy H. Collins' law. Prediction of recurrence or cure in childhood medulloblastoma?. Clin Neurol Neurosurg. 1997 May. 99(2):113-6. [Medline].
Sutton LN, Phillips PC, Molloy PT. Surgical management of medulloblastoma. J Neurooncol. 1996 Jul. 29(1):9-21. [Medline].
Tomita T. Medulloblastomas. Youmans JR, ed. Neurolgical Surgery. 5th ed. Philadelphia: WB Saunders; 1996. Vol 4: 2570-92.
Weil MD, Lamborn K, Edwards MS, Wara WM. Influence of a child's sex on medulloblastoma outcome. JAMA. 1998 May 13. 279(18):1474-6. [Medline].
Weitman DM, Cogen PH. Contemporary management of medulloblastoma. Contemporary Neurosurgery. 1998. 20(2):1-8.
Whelan HT, Krouwer HG, Schmidt MH, et al. Current therapy and new perspectives in the treatment of medulloblastoma. Pediatr Neurol. 1998 Feb. 18(2):103-15. [Medline].
Whittier KL1, Boese EA, Gibson-Corley KN, Kirby PA, Darbro BW, Qian Q, et al. G-protein coupled receptor expression patterns delineate medulloblastoma subgroups. Oct,10,2013. [Full Text].
Yang SY, Wang KC, Cho BK, et al. Radiation-induced cerebellar glioblastoma at the site of a treated medulloblastoma: case report. J Neurosurg. 2005 May. 102(4 Suppl):417-22. [Medline].
Zeltzer PM, Boyett JM, Finlay JL, Albright AL, Rorke LB, Milstein JM, 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 Mar. 17(3):832-45. [Medline].