International Society of Paediatric Oncology (SIOP) PNET 5 Medulloblastoma
Brain Tumors
About this trial
This is an interventional treatment trial for Brain Tumors focused on measuring pediatric brain tumor, medulloblastoma, event-free survival (EFS), progression-free survival (PFS), overall survival (OS), PNET, posterior fossa, chemotherapy, radiotherapy, biological profile, ß-catenin
Eligibility Criteria
Inclusion Criteria:
- Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22 years (LR-arm: less than 16 years). The date of diagnosis is the date on which surgery is undertaken.
- Histologically proven medulloblastoma, including the following subtypes, as defined in the WHO classification (2007): classic medulloblastoma, desmoplastic/nodular medulloblastoma. Pre-treatment central pathology review is considered mandatory.
Standard-risk medulloblastoma, defined as;
- total or near total surgical resection with less than or equal to 1.5 cm2 (measured on axial plane) of residual tumour on early post-operative MRI, without and with contrast, on central review;
- no central nervous system (CNS) metastasis on MRI (cranial and spinal) on central review;
- no tumour cells on the cytospin of lumbar CSF
- no clinical evidence of extra-CNS metastasis; Patients with a reduction of postoperative residual tumor through second surgery to less than or equal to 1.5 cm2 are eligible, if if timeline for start of radiotherapy can be kept.
- Submission of high quality biological material including fresh frozen tumor samples for the molecular assessment of biological markers (such as the assessment of myelocytomatosis oncogene (MYC) copy number status) in national biological reference centers. Submission of blood is mandatory for all patients, who agree on germline DNA studies. Submission of CSF is recommended.
- No amplification of MYC or MYCN (determined by FISH).
For LR-arm: Low-risk biological profile, defined as WNT subgroup positivity. The WNT subgroup is defined by the presence of (i) ß-catenin mutation (mandatory testing), or (ii) ß-catenin nuclear immuno-positivity by IHC (mandatory testing) and ß-catenin mutation, or (iii) ß-catenin nuclear immuno-positivity by IHC and monosomy 6 (optional testing).
For SR-arm: average-risk biological profile, defined as ß-catenin nuclear immuno-negativity by IHC (mandatory) and mutation analysis (optional).
- No prior therapy for medulloblastoma other than surgery.
- Radiotherapy aiming to start no more than 28 days after surgery. Foreseeable inability to start radiotherapy within 40 days after surgery renders patients ineligible for the study.
- Screening for the compliance with eligibility criteria should be completed, and patient should be included into the study within 28 days after first surgery (in case of second surgery within 35 days after first surgery). Inclusion of patients is not possible later than 40 days after first tumour surgery, or after start of radiotherapy.
- Common toxicity criteria (CTC) grades < 2 for liver, renal, haematological function
- no significant sensorineural hearing deficit as defined by pure tone audiometry with bone conduction or air conduction and normal tympanogram showing no impairment ≥ 20 decibel (dB) at 1-3 kilohertz (kHz). If performance of pure tone audiometry is not possible postoperatively, normal otoacoustic emissions are acceptable, if there is no history for hearing deficit.
- No medical contraindication to radiotherapy or chemotherapy, such as preexisting DNA breakage syndromes (e.g. Fanconi Anemia, Nijmegen breakage syndrome), Gorlin Syndrome or other reasons as defined by patient's clinician.
- No identified Turcot and Li Fraumeni syndrome.
- Written informed consent (and patient assent where appropriate) for therapy according to the laws of each participating country. Information must be provided to the patient on biological studies (tumour and germline), and written informed consent obtained of agreement for participation.
- 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 neuro-ectodermal tumour.
- Atypical teratoid rhabdoid tumour.
- Medulloepithelioma; Ependymoblastoma
- Large-cell medulloblastoma, anaplastic medulloblastoma, or medulloblastoma with extensive nodularity (MBEN), centrally confirmed.
- Unfavourable or undeterminable biological profile, defined as amplification of MYC or MYCN, or MYC or MYCN or WNT subgroup status not determinable.
- 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.
- DNA breakage syndromes (e.g. Fanconi anemia, Nijmegen breakage syndrome) or other, or identified Gorlin,Turcot, or Li Fraumeni syndrome.
- Patients who are pregnant.
- Female patients who are sexually active and not taking reliable contraception.
- Patients who cannot be regularly followed up due to psychological, social, familial or geographic reasons.
- Patients in whom non-compliance with toxicity management guidelines can be expected.
Sites / Locations
- Medical University of Graz
- University Hospital Gasthuisberg
- University Hospital Brno
- Rigshospitalet
- CHU de Grenoble
- Institute Curie
- CHU-TOURS - Hôpital Clocheville
- Hôpital NANCY-BRABOIS
- University Hospital Aachen
- Klinikum Augsburg
- Helios Klinikum Berlin-Buch
- Charite Campus, University of Berlin
- Evangelisches Krankenhaus Bielefeld
- University Hospital Bonn
- Klinikum Braunschweig
- Klinikum Bremen-Mitte
- Klinikum Chemnitz
- University Hospital Cologne
- Carl-Thiem-Klinikum Cottbus
- Vestische Kinder- und Jugendklinik, University Witten/Herdecke
- Klinikum Dortmund
- University Hospital Dresden
- Klinikum Duisburg
- University Hospital Düsseldorf
- HELIOS Klinikum-Erfurt
- University Hospital Erlangen
- University Hospital Essen
- University Hospital Frankfurt/Main
- University Hospital Freiburg
- University Hospital Gießen and Marburg
- University Hospital Greifswald
- University Hospital Göttingen
- University Hospital Halle/Saale
- University Medical Center Hamburg-Eppendorf
- Medizinische Hochschule Hannover
- Angelika-Lautenschläger-Klinik
- Gemeinschaftskrankenhaus Herdecke
- University Hospital Homburg/Saar
- University Hospital Jena
- Städtisches Klinikum Karlsruhe
- Klinikum Kassel
- UK-SH Campus Kiel
- Gemeinschaftsklinikum Koblenz-Mayen
- HELIOS Klinikum Krefeld
- Kliniken der Stadt Köln
- University Hospital Leipzig
- University Hospital Lübeck
- University Hospital Magdeburg
- University Hospital Mainz
- University Hospital Mannheim
- Johannes Wesling Klinikum Minden
- University Hospital München, Dr. von Haunersches Kinderspital
- Klinikum Schwabing, Pediatric Hospital of Technical University
- University Hospital Münster
- Cnopf'sche Kinderklinik
- Klinikum Oldenburg
- University Hospital Regensburg
- University Hospital Rostock
- Asklepios Klinik Sankt Augustin
- HELIOS-Kliniken Schwerin
- Klinikum Stuttgart
- Mutterhaus der Borromäerinnen
- University Hospital Tübingen
- University Hospital Ulm
- Dr. Horst Schmidt Kliniken
- Klinikum der Stadt Wolfsburg
- University Hospital Würzburg
- Our Lady's Children's Hospital
- Fondazione IRCCS Istituto Nazionale Tumori
- Prinses Máxima Center for Pediatric Oncology
- Rigshospitalet
- The Children's Memorial Health Institute
- University Hospital S.Joao
- Oncology Hospital Cruces Bilbao
- Barncancercentrum Drottning Silvias Barnochungdomssjukhus
- University Children's Hospital
- Great Ormond Street Hospital
Arms of the Study
Arm 1
Arm 2
Arm 3
Arm 4
Experimental
Experimental
Experimental
Experimental
PNET 5 MB-LR (low-risk)
PNET 5 MB-SR (standard-risk)
PNET 5 MB WNT-HR
PNET 5 MB SHH-TP53
Radiotherapy and reduced-intensity maintenance chemotherapy. Total treatment duration is 39 weeks.
Radiotherapy with carboplatin or radiotherapy without carboplatin and maintenance chemotherapy. Total treatment duration is 48 weeks.
Radiotherapy adapted to age and metastatic Status and maintenance chemotherapy adapted to age. Total treatment duration is 39 to 48 weeks.
Reduced chemotherapy with Doxorubicin, VCR, HD-MTX, Carboplatin, and MTX intraventricularly Stratification of radiotherapy according to presence of metastasis germline mutation in TP53 (including mosaicism) Maintenance chemotherapy with VBL Total treatment duration is 1 year