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 paediatric brain tumour centre 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 tumours harbouring 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 counselling should be made for patients treated with chemotherapy.
Surgery
Surgery is performed on all patients to obtain a pathological diagnosis and to remove as much of the tumour as is safely possible. The goal is to completely remove the tumour, 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 tumour 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.
Radiotherapy and chemotherapy: general considerations
Craniospinal irradiation (CSI) and chemotherapy are given to treat residual macro- and/or microscopic disease.
Radiotherapy
Medulloblastoma is a radiosensitive tumour 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 aged <3 years should not receive whole-brain radiotherapy.
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 radiotherapy, be discussed carefully with the patient's parents/carers.
If radiotherapy 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 radiotherapy for medulloblastoma because it may reduce the risk of long-term adverse effects, particularly secondary cancers from the exit beam dose.[42]
Radiotherapy 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 radiotherapy or chemotherapy.[3]
Chemotherapy
Medulloblastoma is chemosensitive.
The appropriate regimen should be made on an individual basis for each patient, taking into account tumour histopathology and other clinical and tumour molecular prognostic factors.
Depending on the regimen used, chemotherapy is started either during or after radiotherapy.
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, tumour molecular alterations, and age of the patient, which dictates post-surgical treatment.
High-risk patients are aged <3 years, have metastatic disease at presentation, or have at least 1.5 cm² (maximum cross-sectional area) of residual tumour after surgery, have large-cell/diffuse anaplastic histology (although unclear whether this alone is a high-risk feature), or tumour harbours 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 tumours with MYC amplification are considered very high-risk, while wingless tumours with no high-risk features are considered low-risk.
Average-risk patients are aged ≥3 years, have residual tumour <1.5 cm², and/or have non-metastatic disease based on brain and spine MRI with and without gadolinium and negative lumbar puncture, as well as no high-risk tumour histology or molecular alterations.[3]
Patients aged <3 years
All patients aged <3 years are considered high-risk. CSI is contra-indicated 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 tumour 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 radiotherapy 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 favourable 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 radiotherapy 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 aged 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 radiotherapy, be discussed carefully with the patient's parents/carers. 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/carer 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 radiotherapy.
[ ]
Altered radiotherapy fractionation schedules, such as twice-daily radiation, can theoretically increase the dose to the tumour. Encouraging results using hyperfractionated accelerated radiotherapy 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 paediatric neuro-oncologist and in respect of national and international guidelines and clinical trials.
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