Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

age <3 years

1st line – surgery ± shunting

Plus – chemotherapy

age ≥3 years

1st line – surgery ± shunting

Plus – craniospinal irradiation (CSI) or chemotherapy

Plus – adjuvant/maintenance chemotherapy

1st line – surgery ± shunting

Plus – CSI and/or chemotherapy

Plus – adjuvant/maintenance systemic chemotherapy

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ACUTE
|
age <3 years
1st line – 

surgery ± shunting

Surgery is performed on all patients to remove as much of the tumour as is safely possible and to obtain a pathological diagnosis.[3]​ 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 diversion with shunting or third ventriculostomy is required.

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ACUTE
|
age <3 years
Plus – 

chemotherapy

Treatment recommended for ALL patients in selected patient group

Chemotherapy is used to treat residual macro- and/or microscopic disease. Chemotherapy regimen should only be considered in consultation with a paediatric neuro-oncologist. Combinations of cisplatin (or carboplatin), lomustine, vincristine, etoposide, cyclophosphamide, and procarbazine have been used.[3] [ Cochrane Clinical Answers logo ]

The appropriate regimen should be made on an individual basis for each patient, taking into account other prognostic factors. Referral to an academic setting is recommended and access to clinical trials.

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.[47][48]

Some studies lend optimism 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. Caution should be taken in interpreting these trials, as the sample sizes are small, the followup interval short, and (in some cases) the study population skewed with a larger than expected number of subjects with favourable prognostic features.[47][49][50]

See local specialist protocol for choice of regimen and dosing guidelines.

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ACUTE
|
age ≥3 years
|
average-risk
1st line – 

surgery ± shunting

Average-risk in this age group includes patients with <1.5 cm² of residual tumour after surgery, and/or those with 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 characteristics.[3]

Surgery is performed on all patients to remove as much of the tumour as is safely possible and to obtain a pathological diagnosis.[3][25]​​​ 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 diversion with shunting or third ventriculostomy is required.

Back
ACUTE
|
age ≥3 years
|
average-risk
Plus – 

craniospinal irradiation (CSI) or chemotherapy

Treatment recommended for ALL patients in selected patient group

CSI or a chemotherapy-only approach may be used in average-risk patients aged ≥3 years.

CSI, with a boost dose to the site of disease (posterior fossa/tumour bed), is given to treat residual macro- and/or microscopic disease in patients with low- and average-risk disease.[3]​ Proton radiotherapy should be considered for potential tissue sparing, if available in a timely manner. 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.[3]

Radiotherapy has serious adverse effects on the neurocognitive development of young children; the younger the child, the greater the deleterious effects. Attempts to avoid CSI (by substituting focal radiation in infants) can result in a high rate of relapse.[43] Tissue sparing proton or photon radiotherapy ​techniques should be used per NCCN guidelines.[3]

A chemotherapy-only approach is considered by many institutions in children 3 to 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. The balance between cure versus quality of life of survivors must be taken into consideration. See local specialist protocol for choice of regimen and dosing guidelines.

Back
ACUTE
|
age ≥3 years
|
average-risk
Plus – 

adjuvant/maintenance chemotherapy

Treatment recommended for ALL patients in selected patient group

Adjuvant/maintenance chemotherapy is used to treat residual macro- and/or microscopic disease. Chemotherapy regimen should only be considered in consultation with a paediatric neuro-oncologist. Combinations of cisplatin (or carboplatin), lomustine, vincristine, etoposide, cyclophosphamide, and procarbazine have been used.[3] [ Cochrane Clinical Answers logo ]

The appropriate regimen should be made on an individual basis for each patient, taking into account other prognostic factors. Referral to an academic setting is recommended and access to clinical trials.

Preradiation chemotherapy has not been shown to improve survival compared with treatment with radiotherapy and subsequent chemotherapy. In some prospective studies, preradiation chemotherapy has been related to a poorer rate of survival.[11][53][54][55]

See local specialist protocol for choice of regimen and dosing guidelines.

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ACUTE
|
age ≥3 years
|
high-risk
1st line – 

surgery ± shunting

High-risk in this age group includes patients with metastatic disease at presentation and/or who have at least 1.5 cm² (maximum cross-sectional area) of residual tumour after surgery, have large-cell/diffuse anaplastic histology (unclear whether this alone is a high-risk feature), or tumour harbours mutation of TP53, or amplification of the MYC or MYCN oncogenes.[3]​ 

Surgery is performed on all patients to remove as much of the tumour as is safely possible and to obtain a pathological diagnosis.[3][25]​​​​ 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] However, studies have suggested that more aggressive surgery could lead to more complications, and that a delay from surgery to start radiotherapy can affect survival.[56][57]

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 diversion with shunting or third ventriculostomy is required.

Back
ACUTE
|
age ≥3 years
|
high-risk
Plus – 

CSI and/or chemotherapy

Treatment recommended for ALL patients in selected patient group

CSI with or without chemotherapy, or a chemotherapy-only approach may be used in high-risk patients aged ≥3 years.

CSI, with a boost dose to the site of disease (posterior fossa/tumour bed), is given to treat residual macro- and/or microscopic disease in patients with high-risk disease. Concurrent carboplatin chemotherapy prior to each radiation fraction is recommended for very high-risk MYC amplified group 3 tumours only per the NCCN guidelines.[3]​ Proton radiotherapy should be considered for potential tissue sparing, if available in a timely manner. 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.

Radiotherapy has serious adverse effects on the neurocognitive development of young children; the younger the child, the greater the deleterious effects. Attempts to avoid CSI (by substituting focal radiation in infants) can result in a high rate of relapse.[43] Tissue sparing proton or photon radiotherapy​ techniques should be used per current NCCN guidelines.[3]​ Current clinical trials are investigating whether lower doses of CSI for the treatment of low-risk wingless (WNT) tumours can maintain good survival outcomes while lessening the toxicity of CSI. In one study for patients with WNT tumours, omitting radiotherapy and using a chemotherapy-only approach failed to control the disease.[58]

A chemotherapy-only approach is 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. The balance between cure versus quality of life of survivors must be taken into consideration. See local specialist protocol for choice of regimen and dosing guidelines.

The best treatment regimen for high-risk patients is unclear. There is controversy regarding whether radiotherapy or chemotherapy should be delivered first postoperatively. One study suggests that survival does not differ significantly whether, after surgery, patients received chemotherapy before or after radiotherapy.[59]

Strategies to be considered in this setting include: hyperfractionated accelerated radiotherapy (HART) followed by chemotherapy; St Jude regimen of once-daily radiotherapy followed by chemotherapy; or concomitant chemo-radiotherapy with carboplatin, which showed improved survival in one phase 2 trial.[21][52][57]​ The subsequent Children’s Oncology Group randomised phase 3 trial with carboplatin during CSI for high-risk patients showed improved event-free survival by 19% at 5 years for children with high-risk group 3 medulloblastoma.[60] Concurrent carboplatin with CSI for the treatment of very high-risk MYC amplified group 3 tumours only is thus recommended by current NCCN guidelines.[3]​​ In the UK, the use of the Milan strategy of induction chemotherapy followed by HART and response-directed high-dose chemotherapy ceased in July 2014 due to unexpected neurotoxicity and lower than expected survival rates seen in a national audit.[51][61]​​ However, one subsequent report of the long-term outcome of this strategy indicated improved event-free and overall survival over previously reported outcomes across all molecular subgroups (sonic hedgehog tumours with TP53 mutation having the worst outcome among all groups).[62]

Back
ACUTE
|
age ≥3 years
|
high-risk
Plus – 

adjuvant/maintenance systemic chemotherapy

Treatment recommended for ALL patients in selected patient group

Adjuvant/maintenance chemotherapy is used to treat residual macro- and/or microscopic disease. Chemotherapy regimen should only be considered in consultation with a paediatric neuro-oncologist. Combinations of cisplatin (or carboplatin), lomustine, vincristine, etoposide, cyclophosphamide, and procarbazine have been used.[3] [ Cochrane Clinical Answers logo ]

The appropriate regimen should be made on an individual basis for each patient, taking into account other prognostic factors. Referral to an academic setting is recommended and access to clinical trials.

See local specialist protocol for choice of regimen and dosing guidelines.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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