Abstract
Non-medulloblastoma CNS embryonal tumors (former PNET/Pineoblastomas) are aggressive malignancies with poor outcome that have been historically treated with medulloblastoma protocols. The purpose of this study is to present a tumor-specific, real-world data cohort of patients with CNS-PNET/PB to analyze quality indicators that can be implemented to improve the outcome of these patients. Patients 0–21 years with CNS-PNET treated in eight large institutions were included. Baseline characteristics, treatment and outcome [progression-free and overall survival (PFS and OS respectively)] were analyzed. From 2005 to 2014, 43 patients fulfilled entry criteria. Median age at diagnosis was 3.6 years (range 0.0–14.7). Histology was pineoblastoma (9%), ependymoblastoma (5%), ETANTR (7%) and PNET (77%). Median duration of the main symptom was 2 weeks (range 0–12). At diagnosis, 28% presented with metastatic disease. Seventeen different protocols were used on frontline treatment; 44% had gross total resection, 42% craniospinal radiotherapy, 86% chemotherapy, and 33% autologous hematopoietic stem cell transplantation (aHSCT). Median follow-up for survivors was 3.5 years (range 1.7–9.3). 3-year PFS was 31.9% (95% CI 17–47%) and OS 35.1% (95% CI 20–50%). Age, extent of resection and radiotherapy were prognostic of PFS and OS in univariate analysis (p < 0.05). Our series shows a dismal outcome for CNS-PNET, especially when compared to patients included in clinical trials. Establishing a common national strategy, implementing referral circuits and collaboration networks, and incorporating new molecular knowledge into routine clinical practice are accessible measures that can improve the outcome of these patients.
Similar content being viewed by others
Abbreviations
- aHSCT:
-
Autologous hematopoietic stem cell transplantation
- CNS:
-
Central nervous system
- CT:
-
Chemotherapy
- CTCAE:
-
Common terminology criteria for adverse events
- CI:
-
Confidence interval
- CSI:
-
Craniospinal irradiation
- ETANTR:
-
Embryonal tumor with abundant neuropil and true rosettes
- ETMR:
-
Embryonal tumor with multilayered rosettes
- GTR:
-
Gross total resection
- MRI:
-
Magnetic resonance imaging
- NCI:
-
National Cancer Institute
- OS:
-
Overall survival
- PB:
-
Pineoblastomas
- PNET:
-
Primitive neuroectodermal tumors
- PFS:
-
Progression free survival
- RT:
-
Radiotherapy
- SEHOP:
-
Spanish society of pediatric hematology and oncology
- STR:
-
Subtotal resection
- WHO:
-
World Health Organization
References
Louis DN, Ohgaki H, Wiestler OD et al (2007) The 2007 WHO classification of tumours of the central nervous system (vol 114, pg 97, 2007). Acta Neuropathol 114:547. https://doi.org/10.1007/s00401-007-0243-4
Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization Classification of tumors of the central nervous system: a summary. Acta Neuropathol 131:803–820. https://doi.org/10.1007/s00401-016-1545-1
Ostrom QT, Gittleman H, Fulop J et al (2015) CBTRUS Statistical Report: primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008–2012. Neuro Oncol 17:iv1–iv62. https://doi.org/10.1093/neuonc/nov189
Gatta G, Botta L, Rossi S et al (2014) Childhood cancer survival in Europe 1999–2007: results of EUROCARE-5-a population-based study. Lancet Oncol 15:35–47. https://doi.org/10.1016/S1470-2045(13)70548-5
Li MH, Bouffet E, Hawkins CE et al (2005) Molecular genetics of supratentorial primitive neuroectodermal tumors and pineoblastoma. Neurosurg Focus 19:E3. https://doi.org/10.3171/foc.2005.19.5.4
Pfister S, Remke M, Toedt G et al (2007) Supratentorial primitive neuroectodermal tumors of the central nervous system frequently harbor deletions of the CDKN2A locus and other genomic aberrations distinct from medulloblastomas. Genes Chromosom Cancer 46:839–851. https://doi.org/10.1002/gcc.20471
Spence T, Sin-Chan P, Picard D et al (2014) CNS-PNETs with C19MC amplification and/or LIN28 expression comprise a distinct histogenetic diagnostic and therapeutic entity. Acta Neuropathol 128:291–303. https://doi.org/10.1007/s00401-014-1291-1
Sturm D, Orr BA, Toprak UH et al (2016) New brain tumor entities emerge from molecular classification of CNS-PNETs. Cell 164:1060–1072. https://doi.org/10.1016/j.cell.2016.01.015
Fangusaro J, Finlay J, Sposto R et al (2008) Intensive chemotherapy followed by consolidative myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) in young children with newly diagnosed supratentorial primitive neuroectodermal tumors (sPNETs): report of the Head Start I and I. Pediatr Blood Cancer 50:312–318. https://doi.org/10.1002/pbc.21307
Reddy aT, Janss a J, Phillips PC et al (2000) Outcome for children with supratentorial primitive neuroectodermal tumors treated with surgery, radiation, and chemotherapy. Cancer 88:2189–2193
Dirks PB, Harris L, Hoffman HJ et al (1996) Supratentorial primitive neuroectodermal tumors in children. J Neurooncol 29:75–84
Cohen BH, Zeltzer PM, Boyett JM et al (1995) Prognostic factors and treatment results for supratentorial primitive neuroectodermal tumors in children using radiation and chemotherapy: a Childrens Cancer Group randomized trial. J Clin Oncol 13:1687–1696
McBride SM, Daganzo SM, Banerjee A et al (2008) Radiation is an important component of multimodality therapy for pediatric non-pineal supratentorial primitive neuroectodermal tumors. Int J Radiat Oncol 72:1319–1323. https://doi.org/10.1016/j.ijrobp.2008.03.033
Timmermann B, Kortmann RD, Kühl J et al (2006) Role of radiotherapy in supratentorial primitive neuroectodermal tumor in young children: results of the German HIT-SKK87 and HIT-SKK92 trials. J Clin Oncol 24:1554–1560. https://doi.org/10.1200/JCO.2005.04.8074
Mathew RK, O’kane R, Parslow R et al (2014) Comparison of survival between the UK and US after surgery for most common pediatric CNS tumors. Neuro Oncol 16:1137–1145. https://doi.org/10.1093/neuonc/nou056
Dufour C, Beaugrand A, Pizer B et al (2012) Metastatic medulloblastoma in childhood: chang’s classification revisited. Int J Surg Oncol. https://doi.org/10.1155/2012/245385
Institute NC (2010) Common Terminology Criteria for Adverse Events v4.3. NCI, NIH, DHHS. http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf
Dhall G, Grodman H, Ji L et al (2008) Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols. Pediatr Blood Cancer 50:1169–1175. https://doi.org/10.1002/pbc.21525
Lannering B, Rutkowski S, Doz F et al (2012) Hyperfractionated versus conventional radiotherapy followed by chemotherapy in standard-risk medulloblastoma: results from the randomized multicenter HIT-SIOP PNET 4 trial. J Clin Oncol 30:3187–3193. https://doi.org/10.1200/JCO.2011.39.8719
Gandola L, Massimino M, Cefalo G et al (2009) Hyperfractionated accelerated radiotherapy in the Milan strategy for metastatic medulloblastoma. J Clin Oncol 27:566–571. https://doi.org/10.1200/JCO.2008.18.4176
Massimino M, Gandola L, Spreafico F et al (2006) Supratentorial primitive neuroectodermal tumors (S-PNET) in children: a prospective experience with adjuvant intensive chemotherapy and hyperfractionated accelerated radiotherapy. Int J Radiat Oncol 64:1031–1037. https://doi.org/10.1016/j.ijrobp.2005.09.026
Massimino M, Gandola L, Biassoni V et al (2013) Evolving of therapeutic strategies for CNS-PNET. Pediatr Blood Cancer 60:2031–2035. https://doi.org/10.1002/pbc.24540
Chintagumpala M, Hassall T, Palmer S et al (2008) A pilot study of risk-adapted radiotherapy and chemotherapy in patients with supratentorial PNET. Neuro Oncol 11:33–40. https://doi.org/10.1215/15228517-2008-079
Grill J, Geoerger B, Gesner L et al (2013) Phase II study of irinotecan in combination with temozolomide (TEMIRI) in children with recurrent or refractory medulloblastoma: a joint ITCC and SIOPE brain tumor study. Neuro Oncol 15:1236–1243. https://doi.org/10.1093/neuonc/not097
Robison NJ, Campigotto F, Chi SN et al (2014) A phase II trial of a multi-agent oral antiangiogenic (metronomic) regimen in children with recurrent or progressive cancer. Pediatr Blood Cancer 61:636–642. https://doi.org/10.1002/pbc.24794
Johnston DL, Keene DL, Lafay-Cousin L et al (2008) Supratentorial primitive neuroectodermal tumors: a Canadian pediatric brain tumor consortium report. J Neurooncol 86:101–108. https://doi.org/10.1007/s11060-007-9440-1
Peris Bonet R, Felipe García S, Valero Poveda SPRE. (2015) Cáncer infantil en España. Estadísticas 1980–2014. Registro Español de Tumores Infantiles (RETI-SEHOP). http://www.uv.es/rnti/pdfs/INFORME 1980-2014.pdf
Vivekanandan S, Breene R, Ramanujachar R et al (2015) The UK Experience of a treatment strategy for pediatric metastatic medulloblastoma comprising intensive induction chemotherapy, hyperfractionated accelerated radiotherapy and response directed high dose myeloablative chemotherapy or maintenance chemothera. Pediatr Blood Cancer 62:2132–2139. https://doi.org/10.1002/pbc.25663
Desandes E, Guissou S, Chastagner P, Lacour B (2014) Incidence and survival of children with central nervous system primitive tumors in the French National Registry of Childhood Solid Tumors. Neuro Oncol 16:975–983. https://doi.org/10.1093/neuonc/not309
Dobrovoljac M, Hengartner H, Boltshauser E, Grotzer M (2002) Delay in the diagnosis of paediatric brain tumours. Eur J Pediatr 161:663–667. https://doi.org/10.1007/s00431-002-1088-4
Reulecke BC, Erker CG, Fiedler BJ et al (2008) Brain tumors in children: initial symptoms and their influence on the time span between symptom onset and diagnosis. J Child Neurol 23:178–183. https://doi.org/10.1177/0883073807308692
Brasme J-F, Morfouace M, Grill J et al (2012) Delays in diagnosis of paediatric cancers: a systematic review and comparison with expert testimony in lawsuits. Lancet Oncol 13:e445–e459. https://doi.org/10.1016/S1470-2045(12)70361-3
Ferrari A, Lo Vullo S, Giardiello D et al (2016) The sooner the better? How symptom interval correlates with outcome in children and adolescents with solid tumors: regression tree analysis of the findings of a prospective study. Pediatr Blood Cancer 63:479–485. https://doi.org/10.1002/pbc.25833
Wilne S, Collier J, Kennedy C et al (2012) Progression from first symptom to diagnosis in childhood brain tumours. Eur J Pediatr 171:87–93. https://doi.org/10.1007/s00431-011-1485-7
HeadSmart Be Brain Tumour Aware HBBT (2016) A new clinical guideline from the Royal College of Paediatrics and Child Health with a national awareness campaign accelerates brain tumor diagnosis in UK children–“HeadSmart: be Brain Tumour Aware”. Neuro Oncol 18:445–454. https://doi.org/10.1093/neuonc/nov187
Sanidad M (Ministerio de, Igualdad) SS e Centros, Servicios y Unidades de Referencia del Sistema Nacional de Salud (CSUR). https://www.msssi.gob.es/profesionales/CentrosDeReferencia/CentrosCSUR.htm. Accessed 14 Apr 2017
Kann BH, Park HS, Lester-Coll NH et al (2016) Postoperative radiotherapy patterns of care and survival implications for medulloblastoma in young children. JAMA Oncol 25:62–68. https://doi.org/10.1001/jamaoncol.2016.2547
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical approval
The study protocol was approved by the Institutional Review Board of Hospital Niño Jesús, and approval for retrospective chart review was sought at all participating hospitals. All procedures performed in this study were in accordance with the declaration of Helsinki (1964) and its later amendments and comparable ethical standards.
Additional information
On behalf of the CNS Tumors Group of the Spanish Society of Pediatric Hematology and Oncology (SEHOP).
Rights and permissions
About this article
Cite this article
de Rojas, T., Bautista, F., Flores, M. et al. Management and outcome of children and adolescents with non-medulloblastoma CNS embryonal tumors in Spain: room for improvement in standards of care. J Neurooncol 137, 205–213 (2018). https://doi.org/10.1007/s11060-017-2713-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11060-017-2713-4