Approach
The stepwise approach to management is to stage the disease and treat it with surgery, radiation, and chemotherapy.[3][25] All patients require surgery, with age of the patient and staging determining appropriate further treatment. Referral to an academic setting with a pediatric brain tumor center is recommended for treatment of infants and children with medulloblastoma and access to molecular-based clinical trials.[3]
Referral for cancer predisposition evaluation is appropriate for patients with tumors harboring molecular features suggestive of germline predisposition to cancer, or if clinical history is consistent with an inherited predisposition to cancer.
Referral to infertility risk/fertility preservation counseling should be made for patients treated with chemotherapy.
Surgery
Surgery is performed on all patients to obtain a pathologic diagnosis and to remove as much of the tumor as is safely possible. The goal is to completely remove the tumor, with some studies showing that residual disease after surgery of at least 1.5 cm² (maximum cross-sectional area) is associated with an adverse outcome.[3][40] Relief of ventricular obstruction by resection of tumor may or may not relieve hydrocephalus. Close early postoperative patient monitoring is needed to determine whether cerebrospinal fluid (CSF) diversion with shunting or third ventriculostomy is required.
Radiation therapy and chemotherapy: general considerations
Craniospinal irradiation (CSI) and chemotherapy are given to treat residual macro- and/or microscopic disease.
Radiation therapy
Medulloblastoma is a radiosensitive tumor and CSI is considered the best adjuvant treatment for the disease.[41]
However, it has serious adverse effects on the neurocognitive development of young children; the younger the child, the greater the deleterious effects. Children <3 years of age should not receive whole-brain radiation.
A chemotherapy-only approach is also considered by many institutions in children 3-6 years of age, as the neurocognitive effects in this age group are still quite profound. It is important that the advantages and disadvantages of this approach, including the lower cure rate without adjuvant radiation therapy, be discussed carefully with the patient's parents/caregivers.
If radiation therapy is used as part of the treatment regimen, proton therapy should be considered for potential tissue sparing, if available in a timely manner.[3] The unique physical nature of proton beams allows extremely tight dose distributions, which may be beneficial with respect to the posterior fossa and spinal components of radiation therapy for medulloblastoma because it may reduce the risk of long-term adverse effects, particularly secondary cancers from the exit beam dose.[42]
Radiation therapy should start within 31-42 days of surgery (31-35 days is preferred and up to 42 days is acceptable).[3]
Restaging and/or planning MRIs are recommended if the interval since prior imaging has been >3 weeks prior to starting radiation therapy or chemotherapy.[3]
Chemotherapy
Medulloblastoma is chemosensitive.
The appropriate regimen should be made on an individual basis for each patient, taking into account tumor histopathology and other clinical and tumor molecular prognostic factors.
Depending on the regimen used, chemotherapy is started either during or after radiation therapy.
High-risk versus average-risk
After surgery, patients are staged fully with postoperative magnetic resonance imaging (MRI) and CSF analysis, and divided into risk categories based on the metastatic status, histology, tumor molecular alterations, and the age of the patient, which dictates postsurgical treatment.
High-risk patients are <3 years of age, have metastatic disease at presentation, or have at least 1.5 cm² (maximum cross-sectional area) of residual tumor after surgery, have large-cell/diffuse anaplastic histology (although unclear whether this alone is a high-risk feature), or tumor harbors TP53 mutation or amplification of the MYC or MYCN oncogenes.[3] Only one of these factors is needed for a patient to be placed in this category. Group 3 tumors with MYC amplification are considered very high-risk, while wingless tumors with no high-risk features are considered low-risk.
Average-risk patients are ≥3 years of age, have residual tumor <1.5 cm², and/or have nonmetastatic disease based on brain and spine MRI with and without gadolinium and negative lumbar puncture, as well as no high-risk tumor histology or molecular alterations.[3]
Patients <3 years of age
All patients <3 years of age are considered high-risk. CSI is contraindicated in view of the serious adverse effects on neurocognitive development.
Attempts to delay or avoid CSI (by substituting focal radiation in infants) can result in variable outcomes, with a high rate of relapse reported in specific tumor subgroups.[43]
Chemotherapy with combinations of cisplatin (or carboplatin), lomustine, vincristine, etoposide, cyclophosphamide, and procarbazine have been used. There are multiple published regimens; however, the small sample sizes and heterogeneity in methods, study population, and use of radiation therapy in a proportion of patients in some studies preclude comparison between published clinical trials. Historical data suggests 5-year event-free survival in the range of 20% to 40%.[44][45][46]
[ 
]
There appears to be a clear survival influence of histology for very young children with medulloblastoma, with patients with desmoplastic histology having an improved outcome.[43][47][48]
Some studies have suggested that survival may be improved by the intensification of therapy with high-dose methotrexate, intraventricular methotrexate, and/or the addition of high-dose chemotherapy with stem-cell rescue.[47][49][50] However, these trials should be interpreted cautiously: sample sizes are small, the follow-up interval short, and (in some cases) the study population skewed with a larger than expected number of subjects with favorable prognostic features.
Patients ≥3 years of age
Chemotherapy and CSI are indicated in all patients to treat residual macro- and/or microscopic disease.
All patients receive a larger radiation therapy boost dose to the whole posterior fossa or the involved field. However, average-risk patients receive a lower dose of CSI than high-risk patients.
Although the use of CSI in children ages 3-6 years can be considered standard of care, a chemotherapy-only approach is considered by many institutions, as the neurocognitive effects in this age group are still quite profound. It is important that the advantages and disadvantages of this approach, including the lower cure rate without adjuvant radiation therapy, be discussed carefully with the patient's parents/caregivers. The balance between cure versus quality of life of survivors must be taken into consideration. The treatment approach in these patients must take into account parent/caregiver input on this issue.
Various combinations of cisplatin (or carboplatin), lomustine, vincristine, etoposide, and cyclophosphamide have been used.[3] Depending on the regimen used, chemotherapy is started either during or after radiation therapy.
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Altered radiation therapy fractionation schedules, such as twice-daily radiation, can theoretically increase the dose to the tumor. Encouraging results using hyperfractionated accelerated radiation therapy have been reported in patients with metastatic disease.[51][52]
The exact regimen for a chemotherapy-only approach should be considered in consultation with a pediatric neuro-oncologist and in respect of national and international guidelines and clinical trials.
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