Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2021 Dec 2;13(23):6077.
doi: 10.3390/cancers13236077.

SIOP PNET5 MB Trial: History and Concept of a Molecularly Stratified Clinical Trial of Risk-Adapted Therapies for Standard-Risk Medulloblastoma

Martin Mynarek  1   2 , Till Milde  3   4   5 , Laetitia Padovani  6 , Geert O Janssens  7   8 , Robert Kwiecien  9 , Veronique Mosseri  10 , Steven C Clifford  11 , François Doz  12 , Stefan Rutkowski  1
Affiliations
Review

SIOP PNET5 MB Trial: History and Concept of a Molecularly Stratified Clinical Trial of Risk-Adapted Therapies for Standard-Risk Medulloblastoma

Martin Mynarek et al. Cancers (Basel). .

Abstract

Background: SIOP PNET5 MB was initiated in 2014 as the first European trial using clinical, histological, and molecular parameters to stratify treatments for children and adolescents with standard-risk medulloblastoma.

Methods: Stratification by upfront assessment of molecular parameters requires the timely submission of adequate tumour tissue. In the standard-risk phase-III cohort, defined by the absence of high-risk criteria (M0, R0), pathological (non-LCA), and molecular biomarkers (MYCN amplification in SHH-MB or MYC amplification), a randomized intensification by carboplatin concomitant with radiotherapy is investigated. In the LR stratum for localized WNT-activated medulloblastoma and age <16 years, a reduction of craniospinal radiotherapy dose to 18 Gy and a reduced maintenance chemotherapy are investigated. Two additional strata (WNT-HR, SHH-TP53) were implemented during the trial.

Results: SIOP PNET5 MB is actively recruiting. The availability of adequate tumour tissue for upfront real-time biological assessments to assess inclusion criteria has proven feasible.

Conclusion: SIOP PNET5 MB has demonstrated that implementation of biological parameters for stratification is feasible in a prospective multicentre setting, and may improve risk-adapted treatment. Comprehensive research studies may allow assessment of additional parameters, e.g., novel medulloblastoma subtypes, and identification and validation of biomarkers for the further refinement of risk-adapted treatment in the future.

Keywords: CNS; brain tumour; children; medulloblastoma; trial.

PubMed Disclaimer

Conflict of interest statement

S.R. and F.D. received fees for several advisory board roles. F.D. received fees for his institution for advisory board roles from Bayer, BMS, Roche, Celgene, LOXO Oncology, Servier, Tesaro; travel expenses from Bayer, BMS, Roche; and consultancy roles from Servier. All honoraria contributed to an account at Institut Curie, not to his personal funds. S.R. received fees for advisory board roles from Bayer, Novartis, BMS and Roche; for DMSC from Celgene; and for trial support by German Children’s Cancer Foundation and Riemser Pharma GmbH, Germany. The other authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Therapy overview SIOP PNET5-LR stratum. After surgery (OP), patients receive 18.0 Gy craniospinal radiotherapy followed by a boost to 54.0 Gy to the tumour bed. Subsequently, patients receive six cycles of chemotherapy, alternating B (cyclophosphamide 1000 mg/m2/d i.v. days 1 and 2 with mesna, vincristine 1.5 mg/m2/d day 1, continue with the next block day 22) with A (cisplatin 70 mg/m2/d day 1, lomustine 75 mg/m2/d day 1 and vincristine 1.5 mg/m2/d days 1, 8 and 15, continue with next block day 43).
Figure 2
Figure 2
Therapy overview SIOP PNET5-SR stratum. After surgery (OP), patients receive 23.4 Gy craniospinal radiotherapy followed by a boost to 54.0 Gy to the tumour bed. Patients are randomized to receive carboplatin 35 mg/m2/d on everyday radiotherapy (i.e., usually 5 days a week). Afterwards, patients receive eight cycles of chemotherapy, alternating B with A (see legend of Figure 1 for drug doses in A and B).
Figure 3
Figure 3
Therapy overview SIOP PNET5-WNT-HR and SHH-TP53 strata. After surgery (OP), patients in the WNT-HR stratum receive 23.4 Gy craniospinal radiotherapy followed by a boost to 54.0 Gy to the tumour bed and boosts to metastatic sites if applicable. Afterwards, younger than 16 receive six, patients 16 years or older at surgery receive eight cycles of chemotherapy, alternating B with A (see legend of Figure 1 for drug doses in A and B). Patients in the SHH-TP53 stratum receive 2 cycles of HIT-SKK like induction chemotherapy with Vincristine 1.5 mg/m2/d (max. 2.0 mg), days 1, 15, 29 and 43; Doxorubicin 37.5 mg/m2/d, days 1–2, intraventricular Methotrexate 2 mg (via Rickham/Ommaya), days 1–4, 15, 16, 29, 30, 43–46; HD-Methotrexate 5 g/m/d (24 h-infusion, 10% of dose within first 30 min, 90 over 23.5 hours), days 15 and 29; Carboplatin 200 mg/m2/d, days 43, 44, and 45. Radiotherapy is stratified according to (a) presence or absence of metastatic disease and (b) presence or absence of germline TP53-alteration (Li-Fraumeni Syndrome). Patients with non-metastatic medulloblastoma and germline TP53-alteration receive focal radiotherapy to the tumour bed to a dose of 54 Gy. Patients with metastatic medulloblastoma and germline TP53-alteration receive 23.4 Gy craniospinal radiotherapy (CSI) with boost to primary tumour bed up to 54 Gy and further boosts to intracranial (54 Gy) and spinal (45 Gy) metastasis. Patients without germline alteration in TP53 receive 36 Gy CSI with a boost to the primary tumour bed up to 54 Gy and further boosts to intracranial (54 Gy) and spinal (45 Gy) metastasis if applicable. Patients receive weekly vincristine (1.5 mg/m2/week, max 2.0 mg) up to a maximum of six doses if tolerated. After radiotherapy, patients receive weekly vinblastine (5 mg/m2/week, max 10 mg) for 24 weeks with modification to tolerance.
See this image and copyright information in PMC

References

    1. Louis D.N., Perry A., Wesseling P., Brat D.J., Cree I.A., Figarella-Branger D., Hawkins C., Ng H.K., Pfister S.M., Reifenberger G., et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro-Oncology. 2021;23:1231–1251. doi: 10.1093/neuonc/noab106. - DOI - PMC - PubMed
    1. Louis D.N., Ohgaki H., Wiestler O.D., Cavenee W.K., editors. WHO Classification of Tumours of the Central Nervous System. IARC; Lyon, France: 2007. - PMC - PubMed
    1. Gilbertson R.J. Medulloblastoma: Signalling a change in treatment. Lancet Oncol. 2004;5:209–218. doi: 10.1016/S1470-2045(04)01424-X. - DOI - PubMed
    1. Gajjar A., Chintagumpala M., Ashley D., Kellie S., Kun L.E., Merchant T.E., Woo S., Wheeler G., Ahern V., Krasin M.J., et al. Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): Long-term results from a prospective, multicentre trial. Lancet Oncol. 2006;7:813–820. doi: 10.1016/S1470-2045(06)70867-1. - DOI - PubMed
    1. Packer R.J., Gajjar A., Vezina G., Rorke-Adams L., Burger P.C., Robertson P.L., Bayer L., LaFond D., Donahue B.R., Marymont M.H., et al. Phase III study of craniospinal radiation therapy followed by adjuvant chemotherapy for newly diagnosed average-risk medulloblastoma. J. Clin. Oncol. 2006;24:4202–4208. doi: 10.1200/JCO.2006.06.4980. - DOI - PubMed