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

  • Ruth Ladenstein
  • 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
  • 325 Downloads

Abstract

Background

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

Results

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.

Conclusions

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.

Keywords

High-risk neuroblastoma MIBG SIOPEN score 

Abbreviations

ASCT

Autologous stem cell transplantation

AUC

Area under the curve

CADO

Cyclophosphamide, Adriamycin, Vincristine

CBDCA

Carboplatin

CDDP

Cisplatin

CEM

Carboplatin-Etoposide-Melphalan

CI

Confidence interval

COG

Children’s Oncology Group

COJEC

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

CR/PR

Complete remission/partial remission

CT

Computed tomography

CYC

Cyclophosphamide

DNA

Deoxyribuncleic acid

EFS

Event free survival

HDT

High dose chemotherapy

HR

Hazard ratios

HR-NBL

High Risk Neuroblastoma

INRG

International Neuroblastoma Risk Group

mIBG

Metaiodobenzylguanidine

MYCN

Proto-oncogene

PH

Proportional hazard

ROC

Receiver operating characteristic

SIOPEN

Société International d’Oncologie Pédiatrique European Neuroblastoma

SPECT

Single-photon emission computed tomography

TVD

Topotecan, Vincristine, Doxorubicin

VCR

Vincristine

VP16

Etoposide

Notes

Acknowledgements

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.

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.

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Copyright information

© Springer-Verlag GmbH Germany 2017

Authors and Affiliations

  • Ruth Ladenstein
    • 1
    • 2
  • 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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