Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma

Study Overview
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Brief Summary
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This is an international prospective randomised trial, which will compare two radiotherapy regimens in children and adolescents (aged 4 or 5 years to 21 years inclusive) with carefully staged 'standard risk' medulloblastoma.

Detailed Description
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Patients eligible for the study will be those with non-metastatic medulloblastoma (by imaging and CSF cytology) at diagnosis. Patients randomised to the standard arm will receive conventionally fractionated (once a day) radiotherapy with a dose of 54 Gy to the posterior fossa and 23.4 Gy to the craniospinal axis. The experimental arm will be hyperfractionated (twice a day) radiotherapy (1 Gy b.d.) with a dose of 60 Gy to the posterior fossa with an additional 8 Gy to the tumour bed and 36 Gy to the craniospinal axis. Both groups will receive identical chemotherapy consisting of eight weekly doses of Vincristine given with radiotherapy and 8 courses of CCNU, cisplatin and vincristine following radiotherapy.

Official Title
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A Prospective Randomised Controlled Trial of Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma

Conditions
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Medulloblastoma

Intervention / Treatment
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* Radiation: Standard Fractionation Regimen
* Radiation: Hyperfractionated Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at diagnosis at least 4 years or 5 years (according to the policy of the National Brain Tumour Group) and less than 22 years. Histologically proven medulloblastoma, including the following variants(WHO classification - 2000): classic medulloblastoma, nodular / desmoplastic medulloblastoma, melanotic medulloblastoma, medullomyoblastoma No CNS metastasis on MRI - supratentorial, arachnoid of the posterior fossa or spine. No clinical evidence of extra-CNS metastasis No tumour cells on the cytospin of lumbar CSF. Central Review of CSF cytology is recommended but not mandatory. It will be left to national policy. Radiotherapy to start no more than 40 days after surgery. Ability to receive twice daily radiotherapy. Vital functions within normal range for their age group. CTC grades < 2 for liver, renal, haematological and audiological function. No medical contraindication to radiotherapy or chemotherapy. Written informed consent (and patient assent where appropriate) according to the laws of each participating country. Written informed consent should also be sought for biological studies. National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies). Exclusion Criteria: One of the inclusion criteria is lacking. Brainstem or supratentorial primitive neuroectodermal tumour. Atypical teratoid rhabdoid tumour. Medulloepithelioma. Ependymoblastoma. Large cell médulloblastoma. Metastatic medulloblastoma (on CNS MRI and/or positive cytospin of postoperative lumbar CSF). Patient previously treated for a brain tumour or any type of malignant disease. Patients who are pregnant. Females who are sexually active and not taking reliable contraception. Known predisposition to medulloblastoma e.g. Gorlin's syndrome.

Ages Eligible for Study
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Minimum Age: 4 Years
Maximum Age: 22 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard Fractionation Regimen<br>1.8 Gy daily, 5 fractions per week Cranio-spinal axis: 23.4 Gy in 13 fractions of 1.8 Gy Posterior fossa: 30.6 Gy in 17 fractions of 1.8 Gy | Radiation: Standard Fractionation Regimen<br>* 1.8 Gy daily, 5 fractions per week Cranio-spinal axis: 23.4 Gy in 13 fractions of 1.8 Gy Posterior fossa: 30.6 Gy in 17 fractions of 1.8 Gy<br>|
| Experimental: Hyperfractionated radiotherapy<br>1 Gy b.d. (minimum interval between fractions 8 hours). 10 fractions per week Craniospinal axis: 36 Gy in 36 fractions of 1 Gy Posterior fossa: 24 Gy in 24 fractions of 1 Gy Tumour Bed: 8 Gy in 8 fractions of 1 Gy | Radiation: Hyperfractionated Radiotherapy<br>* 1 Gy b.d. (minimum interval between fractions 8 hours). 10 fractions per week Craniospinal axis: 36 Gy in 36 fractions of 1 Gy Posterior fossa: 24 Gy in 24 fractions of 1 Gy Tumour Bed: 8 Gy in 8 fractions of 1 Gy<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Free survival rate | To compare in a randomised trial the event free survival rate for children and adolescents with standard risk medulloblastoma treated with either hyperfractionated radiotherapy or reduced dose radiotherapy with conventional fractionation. | 2 years after the start of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To compare overall survival between the two treatment arms. | Will hyperfractionated radiotherapy lead to a different progression free (PFS) and overall survival (OS) compared to the standard arm radiotherapy? | Follow-up of the last patient included up to the age of 20 years | 
| To compare the pattern of relapse between the two treatment arms | Will hyperfractionated RT lead to a different pattern of local tumour control/pattern of relapse with particular respect to local relapse (tumour bed, posterior fossa outside the tumour bed) compared to the standard arm RT? The time to local progression should be the measure for the local tumour control. | Follow-up of the last patient included up to the age of 20 years | 
| To explore the benefit and the risks of neurosurgery | To determine the toxicity of surgery.To investigate whether there are identifiable factors that correlate with toxicity. To define the impact of any complications of surgery on commencement of adjuvant therapy and on EFS. | Follow-up of the last patient included up to the age of 20 years |