SIOP PNET 5 MB

Primary objective LR-group

To confirm that the 3-year Event-Free Survival (EFS) rate in children and adolescents with standard-risk medulloblastoma having a low-risk biological profile remains in excess of 80% when patients are treated with 23.4 Gy neuraxis irradiation plus boost to the primary tumor, and reduced-intensity chemotherapy.

Primary objective SR-group

To test whether the Event-Free Survival (EFS) in children and adolescents with standard-risk medulloblastoma having an average-risk biological profile is different for patients treated with or without carboplatin concomitantly with radiotherapy (23.4 Gy neuraxis irradiation plus boost to the primary tumor) followed by a modified maintenance chemotherapy.

Low-risk-group (LR)

• WNT positives MB (CMB, DMB)
• mit CTNNB1 somatischer Mutation
• Alter <16 Jahre
• M0
• -Resttumor <1,5cm2

Radiotherapy:
CNS: 23,4 Gy
Spine: 23,4 Gy
Primary tumour boost: 30,6 Gy
Total dose to primary: 54 Gy in 30 daily fractions of 1.80 Gy

Chemotherapy:

Maintenance chemotherapy starts 6 weeks after radiotherapy.
6 cycles alternating Regimen A and Regimen B.
Regimen A (cycles 1, 3, 5): cisplatin , CCNU, vincristine
Regimen B: (cycles 2, 4, 6): cyclophosphamide, vincristine
Total duration of 27weeks.

Standard-risk-group (SR)

• Gruppe 3/4 (non WNT/ non SHH) oder SHH-TP53 Wildtype
• CMB / DMB
• CMYC/NMYC neg. oder Gruppe 4 NMYC pos./CMYC neg.
• M0
• Resttumor <1,5cm2

Radiotherapy:
CNS: 23,4 Gy
Spine: 23,4 Gy
Primary tumor boost: 30,6 Gy
Total dose to primary – 54 Gy in 30 daily fractions of 1.80 Gy
With or without carboplatin 35 mg/m2 5 times/week.

Chemotherapy:
Maintenance chemotherapy starts 6 weeks after radiotherapy. 8 cycles alternating Regimen A and Regimen B.
Regimen A (cycles 1, 3, 5, 7): cisplatin, CCNU, vincristine
Regimen B: (cycles 2, 4, 6, 8): cyclophosphamide, vincristine

WNT-HR:

• WNT positiv mit HR-features:
• Alter ≥ 16 years und / oder
• M+ und / oder
• Resttumor +
• CMB, DMB oder LCAMB
• MYC/MYCN negativ oder positiv
• WNT ohne CTNNB1 Mutation (falls keine Keimbahn APC-Mutation)

Strahlentherapie:
<16 Jahre und >= 16 Jahre ohne Metastasen: CSI 23.4 Gy, Primärtumor 54.0 Gy
≥ 16 Jahre und < 16 Jahre mit Metastasen: CSI 36.0 Gy, Primärtumor 54.0 Gy

Chemotherapie:
Die Erhaltungschemotherapie startet 6 Wochen nach der Strahlentherapie. Es werden insgesamt 6-8 Blöcke abwechselnd Regime A und B verabreicht. (Regime A: Cisplatin, CCNU, VCR, Regime B: Cyclophosphamid, VCR). Gesamtlänge mindestens 36 Wochen.

SHH-TP53

• TP53 Keimbahn Analyse mandatorisch
• alle histologischen Subtypen
• M0 and M+
• >3-5 Jahre ohne Alterslimit nach oben

Strahlentherapie (mit wöchentlichem VCR 1,5mg/m2):

Keimbahn TP53mut M0: Fokale RT
Sicherheitsabstand 23.4 Gy, Tumor 54.0 Gy,

Keimbahn TP53mut M+:CSI 23.4 Gy, Tumor 54.0 Gy

Somatische TP53mut: CSI 36.0 Gy, Tumor 54.0 Gy

Chemotherapie:
SKK-like” Chemotherapie (mit i.ventr. MTX):
Woche 1: Doxorubicin (oder Carboplatin)/VCR
Woche 3, Woche 5: HD-MTX/VCR
Woche 7: Carboplatin/VCR

PNET5-Register

• Keimbahnveränderungen, die eine Krebsprädisposition verursachen oder die Toleranz von Chemo- und oder Radiotherapie betreffen, außer TP53 für SHH Typ MB
• Jedes Alter, alle histologischen Subtypen, alle molekularen Untergruppen, alle klinische Stadien
• Verpflichtende Eindendung von qualitativ hochwertigem biologischen Material, inklusive frisch gefrorenem Tumormaterial und Blut

Registerziele:
Dokumentation der initialen Präsentation, der Behandlung und des Outcomes.
Es findet keine spezielle Therapieempfehlung von Seiten der Studienzenttrale statt.

• Age at diagnosis, at least 3 - 5 years (depending on the country) and less than 22 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
• Submission of high quality biological material including fresh frozen tumor samples for the molecular assessment of biological markers (such as the assessment of MYC gene copy number status) in national biological reference centers.
• No amplification of MYC or MYCN (determined by FISH)
• LR: Low-risk biological profile, defined as ß-catenin nuclear immunopositivity by IHC (mandatory) and / or mutation analysis (optional);
• SR: average-risk biological profile, defined as ß-catenin nuclear immunonegativity by IHC (mandatory) and mutation analysis (optional) .
• CTC grades < 2 for liver, renal, haematological function
• no significant sensineural hearing deficit
• No medical contraindication to radiotherapy or chemotherapy,
• 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.
• National and local ethical committee approval according to the laws of each participating country (to include approval for biological studies).

• One of the inclusion criteria is lacking;
• Other histology than classic medulloblastoma or desmoplastic/nodular medulloblastoma;
• Medulloblastoma is no standard-risk;
• 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.