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Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma (SIOP-PNET-4)

Primary Purpose

Medulloblastoma

Status
Unknown status
Phase
Phase 3
Locations
France
Study Type
Interventional
Intervention
Standard Fractionation Regimen
Hyperfractionated Radiotherapy
Sponsored by
Institut Curie
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Medulloblastoma

Eligibility Criteria

4 Years - 22 Years (Child, Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Institut Curie

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Experimental

Arm Label

Standard Fractionation Regimen

Hyperfractionated radiotherapy

Arm Description

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

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

Outcomes

Primary Outcome Measures

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.

Secondary Outcome Measures

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?
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.
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.

Full Information

First Posted
May 9, 2011
Last Updated
February 11, 2020
Sponsor
Institut Curie
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1. Study Identification

Unique Protocol Identification Number
NCT01351870
Brief Title
Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma
Acronym
SIOP-PNET-4
Official Title
A Prospective Randomised Controlled Trial of Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma
Study Type
Interventional

2. Study Status

Record Verification Date
February 2020
Overall Recruitment Status
Unknown status
Study Start Date
April 2004 (undefined)
Primary Completion Date
December 2008 (Actual)
Study Completion Date
February 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Institut Curie

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Medulloblastoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 3
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
52 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Standard Fractionation Regimen
Arm Type
Active Comparator
Arm Description
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
Arm Title
Hyperfractionated radiotherapy
Arm Type
Experimental
Arm Description
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
Intervention Type
Radiation
Intervention Name(s)
Standard Fractionation Regimen
Intervention Description
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
Intervention Type
Radiation
Intervention Name(s)
Hyperfractionated Radiotherapy
Intervention Description
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
Primary Outcome Measure Information:
Title
Free survival rate
Description
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.
Time Frame
2 years after the start of the study
Secondary Outcome Measure Information:
Title
To compare overall survival between the two treatment arms.
Description
Will hyperfractionated radiotherapy lead to a different progression free (PFS) and overall survival (OS) compared to the standard arm radiotherapy?
Time Frame
Follow-up of the last patient included up to the age of 20 years
Title
To compare the pattern of relapse between the two treatment arms
Description
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.
Time Frame
Follow-up of the last patient included up to the age of 20 years
Title
To explore the benefit and the risks of neurosurgery
Description
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.
Time Frame
Follow-up of the last patient included up to the age of 20 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
4 Years
Maximum Age & Unit of Time
22 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
DOZ François, MD
Organizational Affiliation
Institut Curie
Official's Role
Principal Investigator
Facility Information:
Facility Name
Institut Curie
City
Paris
ZIP/Postal Code
75005
Country
France

12. IPD Sharing Statement

Citations:
PubMed Identifier
30392813
Citation
Goschzik T, Schwalbe EC, Hicks D, Smith A, Zur Muehlen A, Figarella-Branger D, Doz F, Rutkowski S, Lannering B, Pietsch T, Clifford SC. Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol. 2018 Dec;19(12):1602-1616. doi: 10.1016/S1470-2045(18)30532-1. Epub 2018 Nov 1.
Results Reference
derived

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Hyperfractionated Versus Conventionally Fractionated Radiotherapy in Standard Risk Medulloblastoma

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