Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials

  • Ruth LadensteinEmail author
  • Bieke Lambert
  • Ulrike Pötschger
  • Maria-Rita Castellani
  • Valerie Lewington
  • Zvi Bar-Sever
  • Aurore Oudoux
  • Anna Śliwińska
  • Katerina Taborska
  • Lorenzo Biassoni
  • Gregory A. Yanik
  • Arlene Naranjo
  • Marguerite T. Parisi
  • Barry L. Shulkin
  • Helen Nadel
  • Michael J. Gelfand
  • Katherine K. Matthay
  • Julie R. Park
  • Susan G. Kreissman
  • Dominique Valteau-Couanet
  • Ariane Boubaker
Original Article



Validation of the prognostic value of the SIOPEN mIBG skeletal scoring system in two independent stage 4, mIBG avid, high-risk neuroblastoma populations.


The semi-quantitative SIOPEN score evaluates skeletal meta-iodobenzylguanidine (mIBG) uptake on a 0–6 scale in 12 anatomical regions. Evaluable mIBG scans from 216 COG-A3973 and 341 SIOPEN/HR-NBL1 trial patients were reviewed pre- and post-induction chemotherapy. The prognostic value of skeletal scores for 5-year event free survival (5 yr.-EFS) was tested in the source and validation cohorts. At diagnosis, both cohorts showed a gradual non-linear increase in risk with cumulative scores. Several approaches were explored to test the relationship between score and EFS. Ultimately, a cutoff score of ≤3 was the most useful predictor across trials. A SIOPEN score ≤ 3 pre-induction was found in 15% SIOPEN patients and in 22% of COG patients and increased post-induction to 60% in SIOPEN patients and to 73% in COG patients. Baseline 5 yr.-EFS rates in the SIOPEN/HR-NBL1 cohort for scores ≤3 were 47% ± 7% versus 26% ± 3% for higher scores at diagnosis (p < 0.007) and 36% ± 4% versus 14% ± 4% (p < 0.001) for scores obtained post-induction. The COG-A3973 showed 5 yr.-EFS rates for scores ≤3 of 51% ± 7% versus 34% ± 4% for higher scores (p < 0.001) at diagnosis and 43% ± 5% versus 16% ± 6% (p = 0.004) for post-induction scores. Hazard ratios (HR) significantly favoured patients with scores ≤3 after adjustment for age and MYCN-amplification. Optimal outcomes were recorded in patients who achieved complete skeletal response.


Validation in two independent cohorts confirms the prognostic value of the SIOPEN skeletal score. In particular, patients with an absolute SIOPEN score > 3 after induction have very poor outcomes and should be considered for alternative therapeutic strategies.


High-risk neuroblastoma MIBG SIOPEN score 



Autologous stem cell transplantation


Area under the curve


Cyclophosphamide, Adriamycin, Vincristine








Confidence interval


Children’s Oncology Group


Rapid, platinum-containing induction schedule (CBDCA, CDDP, CYC, VCR, VP16)


Complete remission/partial remission


Computed tomography




Deoxyribuncleic acid


Event free survival


High dose chemotherapy


Hazard ratios


High Risk Neuroblastoma


International Neuroblastoma Risk Group






Proportional hazard


Receiver operating characteristic


Société International d’Oncologie Pédiatrique European Neuroblastoma


Single-photon emission computed tomography


Topotecan, Vincristine, Doxorubicin







We thank Marek Nykiel, Ingrid Pribill, PhD and Claudia Zeiner-Koglin, MSc at the Children’s Cancer Research Institute (CCRI) for their support.

Authors’ contributions

Ruth Ladenstein and Bieke Lambert share first authorship.

Conception and design.

Ruth Ladenstein, Ulrike Pötschger, Valerie Lewington, Gregory Yanik, Katherine K. Matthay, Julie Park, Susan G. Kreissman, Ariane Boubaker.

Provision of study material or patients.

Ruth Ladenstein, Bieke Lambert, Valerie Lewington, Zvi Bar-Sever, Aurore Oudoux, Anna Śliwińska, Katerina Taborska, Lorenzo Biassoni, Gregory Yanik, Arlene Naranjo, Marguerite T. Parisi, Barry L. Shulkin, Helene Nadel, Michael J. Gelfand, Julie Park, Susan G. Kreissman, Dominique Valteau-Couanet, Ariane Boubaker.

Collection and assembly of data.

Ruth Ladenstein, Bieke Lambert, Maria-Rita Castellani, Zvi Bar-Sever, Aurore Oudoux, Anna Śliwińska, Katerina Taborska, Lorenzo Biassoni, Gregory Yanik, Arlene Naranjo, Marguerite T. Parisi, Barry L. Shulkin, Helene Nadel, Michael J. Gelfand, Julie Park, Susan G. Kreissman, Dominique Valteau-Couanet, Ariane Boubaker.

Data analysis and interpretation.

Ruth Ladenstein, Bieke Lambert, Ulrike Pötschger, Maria-Rita Castellani.

mIBG reviewers.

Bieke Lambert, Maria-Rita Castellani, Zvi Bar-Sever, Aurore Oudoux, Anna Śliwińska, Katerina Taborska, Lorenzo Biassoni, Ariane Boubaker.

Manuscript writing.

Ruth Ladenstein, Bieke Lambert, Ulrike Pötschger, Gregory Yanik, Ariane Boubaker.

Final approval of manuscript.

Ruth Ladenstein, Bieke Lambert, Ulrike Pötschger, Valerie Lewington, Maria-Rita Castellani, Zvi Bar-Sever, Aurore Oudoux, Anna Śliwińska, Katerina Taborska, Lorenzo Biassoni, Gregory Yanik, Arlene Naranjo, Marguerite T. Parisi, Barry L. Shulkin, Helene Nadel, Michael J. Gelfand, Katherine K. Matthay, Julie Park,

Susan G. Kreissman, Dominique Valteau-Couanet, Ariane Boubaker.


This study was funded by the European Commission Community Research, Fifth Framework Program, Quality of Life and Management of living Resources: EC Grant No. QLRI-CT-2002-01768 (11. 2002–10. 2005) []; by the National Cancer Institute Paediatric and Adolescent Solid Tumour Steering Committee and received the following travel funding: Alex’s Lemonade Stand Foundation, Ben Towne Foundation, Children’s Neuroblastoma Cancer Foundation.

Compliance with ethical standards

Disclosure of potential conflict of interest

All authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in the analysis of the studies HR-NBL1/SIOPEN and COG-A3973 involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Supplementary material


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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Ruth Ladenstein
    • 1
    • 2
    Email author
  • Bieke Lambert
    • 3
  • Ulrike Pötschger
    • 1
  • Maria-Rita Castellani
    • 4
  • Valerie Lewington
    • 5
  • Zvi Bar-Sever
    • 6
  • Aurore Oudoux
    • 7
  • Anna Śliwińska
    • 8
  • Katerina Taborska
    • 9
  • Lorenzo Biassoni
    • 10
  • Gregory A. Yanik
    • 11
  • Arlene Naranjo
    • 12
  • Marguerite T. Parisi
    • 13
  • Barry L. Shulkin
    • 14
  • Helen Nadel
    • 15
  • Michael J. Gelfand
    • 16
  • Katherine K. Matthay
    • 17
  • Julie R. Park
    • 18
  • Susan G. Kreissman
    • 19
  • Dominique Valteau-Couanet
    • 20
  • Ariane Boubaker
    • 21
  1. 1.Children’s Cancer Research InstituteViennaAustria
  2. 2.Medical University, Department of PaediatricsViennaAustria
  3. 3.Radiology and Nuclear MedicineGhent UniversityGhentBelgium
  4. 4.Nuclear Medicine DivisionFondazione IRCCS Istituto Nazionale dei TumoriMilanItaly
  5. 5.Guy’s and St Thomas’ NHS Foundation TrustLondonUK
  6. 6.Schneider Children’s Medical Center of IsraelPetah-TikvaIsrael
  7. 7.Department of Nuclear Medicine LilleOscar Lambret CenterLilleFrance
  8. 8.Children’s Memorial Health InstituteWarsawPoland
  9. 9.Motol University HospitalPragueCzech Republic
  10. 10.Great Ormond Street Hospital for Children NHS Foundation TrustLondonUK
  11. 11.University of Michigan Medical CenterAnn ArborUSA
  12. 12.Children’s Oncology Group Statistics and Data CenterUniversity of FloridaGainesvilleUSA
  13. 13.Department of RadiologyUniversity of Washington School of Medicine/ Seattle Children’s HospitalSeattleUSA
  14. 14.Department of Diagnostic ImagingSt. Jude Children’s Research HospitalMemphisUSA
  15. 15.Department of RadiologyBC Children’s HospitalVancouverCanada
  16. 16.Department of RadiologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  17. 17.Department of PediatricsUniversity of California San Francisco School of MedicineSan FranciscoUSA
  18. 18.Department of PediatricsUniversity of Washington School of Medicine/ Seattle Children’s HospitalSeattleUSA
  19. 19.Department of PediatricsDuke University Medical CenterDurhamUSA
  20. 20.Pediatric and Adolescent Oncology, Gustave Roussy InstituteUniversité Paris-SudVillejuifFrance
  21. 21.Institute of RadiologyClinique de La SourceLausanneSwitzerland

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