Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials
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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.
KeywordsHigh-risk neuroblastoma MIBG SIOPEN score
Autologous stem cell transplantation
Area under the curve
Cyclophosphamide, Adriamycin, Vincristine
Children’s Oncology Group
Rapid, platinum-containing induction schedule (CBDCA, CDDP, CYC, VCR, VP16)
Complete remission/partial remission
Event free survival
High dose chemotherapy
High Risk Neuroblastoma
International Neuroblastoma Risk Group
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.
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.
Bieke Lambert, Maria-Rita Castellani, Zvi Bar-Sever, Aurore Oudoux, Anna Śliwińska, Katerina Taborska, Lorenzo Biassoni, Ariane Boubaker.
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) [https://www.siopen-r-net.org]; 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.
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 was obtained from all individual participants included in the study.
- 2.Moroz V, Machin D, Faldum A, Hero B, Iehara T, Mosseri V, et al. Changes over three decades in outcome and the prognostic influence of age-at-diagnosis in young patients with neuroblastoma: a report from the international neuroblastoma risk group project. Eur J Cancer. 2011;47:561–71.CrossRefPubMedGoogle Scholar
- 7.Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D, et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study. J Clin Oncol. 2009;27:1007–13.CrossRefPubMedPubMedCentralGoogle Scholar
- 8.Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11(8):1466–77.Google Scholar
- 10.Matthay KK, Shulkin B, Ladenstein R, Michon J, Giammarile F, Lewington V, et al. Criteria for evaluation of disease extent by (123)I-metaiodobenzylguanidine scans in neuroblastoma: a report for the international neuroblastoma risk group (INRG) task force. Br J Cancer. 2010;102:1319–26.CrossRefPubMedPubMedCentralGoogle Scholar
- 11.Ladenstein R, Valteau-Couanet D, Brock P, Yaniv I, Castel V, Laureys G, et al. Randomized trial of prophylactic granulocyte colony-stimulating factor during rapid COJEC induction in pediatric patients with high-risk neuroblastoma: the European HR-NBL1/SIOPEN study. J Clin Oncol. 2010;28:3516–24.CrossRefPubMedGoogle Scholar
- 12.Ladenstein R, Pötschger U, Pearson ADJ, Brock P, Luksch R, Castel V, et al. Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): an international, randomised, multi-arm, open-label, phase 3 trial. Lancet Oncol. 2017;18:500–14.CrossRefPubMedGoogle Scholar
- 18.Kaplan, E, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc. 1958;53(282):457–81.Google Scholar
- 19.Marubini E, Valsecchi MG. Analysing survival data from clinical trials and observational studies. New York: Wiley; 2004.Google Scholar
- 23.YOUDEN WJ. Index for rating diagnostic tests. Cancer. 1950:32–5.Google Scholar
- 25.Heagerty PJ. and packaging by PS-C. survivalROC: Time-dependent ROC curve estimation from censored survival data. 2013. p. R package version 1.0.3. 2013.Google Scholar
- 26.Decarolis B, Schneider C, Hero B, Simon T, Volland R, Roels F, et al. Iodine-123 metaiodobenzylguanidine scintigraphy scoring allows prediction of outcome in patients with stage 4 neuroblastoma: results of the cologne interscore comparison study. J Clin Oncol. 2013;31:944–51.CrossRefPubMedGoogle Scholar
- 27.Yanik GA, Parisi MT, Naranjo A, Nadel H, Gelfand MJ, Park JR, et al. Validation of post-induction Curie scores in high risk neuroblastoma. A Children's Oncology Group (COG) and SIOPEN group report on SIOPEN/HR-NBL1. J Nucl Med. 2017. https://doi.org/10.2967/jnumed.117.195883
- 28.Hartmann O, Valteau-Couanet D, Vassal G, Lapierre V, Brugières L, Delgado R, et al. Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: a multivariate analysis in 218 patients treated in a single institution. Bone Marrow Transplant. 1999;23:789–95.CrossRefPubMedGoogle Scholar
- 30.Park JR, Kreissman SG, London WB, Naranjo A, Cohn SL, Hogarty MD, et al. A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children’s Oncology Group (COG) study. J Clin Oncol Am Soc Clin Oncol. 2016;34(suppl; abstr LBA3):LBA3–LBA3.Google Scholar
- 31.Ladenstein R, Philip T, Lasset C, Hartmann O, Garaventa A, Pinkerton R, et al. Multivariate analysis of risk factors in stage 4 neuroblastoma patients over the age of one year treated with megatherapy and stem-cell transplantation: a report from the European bone marrow transplantation solid tumor registry. J Clin Oncol. 1998;16:953–65.CrossRefPubMedGoogle Scholar