Medulloblastoma Cancer Medulloblastoma
Conditions
Interventions
SIOP-HRMB is an international, prospective, phase III randomised trial in patients older than the age of 3 years with 'high-risk' medulloblastoma. Following local diagnosis of HR-MB, consenting patien
Sponsors
University of Birmingham
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion criteria for trial entry and randomisation 1: 1. Histologically proven (centrally reviewed) high-risk medulloblastoma, with any of the currently defined histological subtypes. High-risk disease is defined as patients with sonic hedgehog (SHH) subgroup or non-SHH/non-wingless-type (WNT) (Groups 3 and 4) medulloblastoma, with at least one of the following high risk features: 1.1 Metastatic disease: Chang Stage M1, M2 and M3. 1.2 Large cell/Anaplastic MB (as defined by World Health Organisation (WHO) criteria 2016 1.3 Patients with significant residual tumour ( > 1.5 cm2) following surgical resection of the primary tumour and other biological risk factors 1.4 Patients with MYC or MYCN amplified tumours (unless MYCN amplified Group 4 without any other high risk factors) 1.5 Patients with SHH subgroup tumours harbouring somatic TP53 mutations. 2. Age at diagnosis > = 3 years. The date of diagnosis is the date on which initial surgery is undertaken. 3. Submission of biological material, including fresh frozen tumour samples and blood, in accordance with national and international schemes for molecular assessment of biological markers, and for associated biological studies. 4. No prior treatment for medulloblastoma, other than surgery, with the exception of one cycle of induction chemotherapy with carboplatin and etoposide may be given prior to trial entry and randomisation where there is clinical urgency to start treatment 5. Adequate hepatic function defined as: 5.1 Total bilirubin = 1 x 109/L; platelets > = 100 x 109/L 8. No significant hearing deficit in at least one ear (significant hearing deficit defined as Chang grade 3 or above) 9. Medically fit to receive protocol treatment 10. Documented negative pregnancy test for female patients of childbearing potential 11. Patient agrees to use effective contraception whilst on treatment (patients of childbearing potential) 12. Written informed consent from the patient and/or parent/legal guardian Inclusion criteria for Randomisation 2 (R2) 13. Patient entered into the SIOP-HRMB trial at diagnosis 14. Patient treated with either Arm A (conventional radiotherapy) or Arm B (HART) as part of R1
Exclusion criteria
Exclusion criteria: Exclusion criteria for trial entry and randomisation 1: 1. Proven or high likelihood of Germline TP53, APC, PTCH, SUFU, PALB2, BRCA2 gene alteration or any other DNA repair defect. 2. Group 4 patients with MYCN amplification and no other high-risk factor 3. ß-catenin mutation positive WNT medulloblastoma irrespective of other risk factors 4. Significant residual tumour (> 1.5 cm2) following surgical resection of the primary tumour and no other biological risk factors. 5. Chang Stage M4 disease 6. Brainstem or embryonal tumours in other sites 7. Previously treated for a brain tumour or any type of malignant disease 8. Medical contraindication to radiotherapy or chemotherapy 9. Hypersensitivity to any of the treatments or excipients 10. Females who are pregnant or breastfeeding 11. Cannot be regularly followed up due to psychological, social, family, geographical or other issues 12. Patients for whom non-compliance with treatment, management guidelines or monitoring is expected.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Event-free survival (EFS). An “event” is considered to be any progression or relapse of disease, any deaths, and any occurrence of a secondary neoplasm. “Relapse” is defined as the appearance of local disease, metastasis, or both following documented complete resection, or previous complete response.“Progression” is defined as tumour growth > 25% (based on the three-dimensional measurement on the MRI) in the case of residual tumour. “Secondary neoplasm” is defined as any diagnosed neoplasm that was distinct from medulloblastoma. | — |
Secondary
| Measure | Time frame |
|---|---|
| 1. Overall survival (OS) and progression-free survival (PFS). Measured from date of randomisation to date of death, relapse or progression for PFS or to date of death for OS; patients will be censored at date last seen if lost to follow-up. 2. Pattern of relapse. The site and time to local progression will be the measures for local tumour control. Particular attention will be given to posterior fossa relapse, i.e. local relapse within the tumour bed, or metastatic relapse to the posterior fossa outside the tumour bed. The time period begins on the date of surgery and ends on the date of appearance of relapse/progression. The appearance of metastases will not be regarded as local progression. 3. Indirect and direct measures of QoS. Both indirect and direct measures will be those agreed in the Core ‘Plus’ model. Indirect measures will use standardised, patient/parent-reported questionnaires for the measurement of: health status [Health Utilities Index 3 (HUI3)], executive function (BRIEF), behavioural outcome (Strengths and Difficulties Questionnaire (SDQ), medical, educational, employment and social situation (MEES), fatigue (Paediatric Quality of Life inventory (PedsQL) Multidimensional Fatigue Scale and, in adults, the Multidimensional Fatigue Inventory (MFI), and QoL (PedsQL Core and, in adults, the EORTC Quality of Life Questionnaire (QLQ-C30)). The timepoints for measuring QoS are at baseline, 2 years after diagnosis, 5 years after diagnosis and at age 18. 4. Audiological toxicity. The extent of ototoxicity-based dose modifications of maintenance chemotherapy, as well as the results of Pure Tone Audiometry (PTA) graded by the Chang criteria evaluated 2 years after trial entry will be the measures for audiological toxicity. 5. Endocrine function. FSH levels (cut-off level >15 IU/l) will be used as a biomarker for subfertility in post-pubertal patients. Growth retardation will be calculated as the difference in height standard deviation score (SDS) from diagnosis, | — |
Countries
England, Scotland, United Kingdom, Wales
Outcome results
None listed