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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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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.

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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

References

  1. London WB, Castleberry RP, Matthay KK, Look AT, Seeger RC, Shimada H, et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s oncology group. J Clin Oncol. 2005;23:6459–65.

    Article  CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  Google Scholar 

  3. Seeger RC, Brodeur GM, Sather H, Dalton A, Siegel SE, Wong KY, et al. Association of multiple copies of the N-myc oncogene with rapid progression of neuroblastomas. N Engl J Med. 1985;313:1111–6.

    Article  CAS  PubMed  Google Scholar 

  4. Shimada H, Stram DO, Chatten J, Joshi VV, Hachitanda Y, Brodeur GM, et al. Identification of subsets of neuroblastomas by combined histopathologic and N-myc analysis. J Natl Cancer Inst. 1995;87:1470–6.

    Article  CAS  PubMed  Google Scholar 

  5. Simon T, Hero B, Faldum A, Handgretinger R, Schrappe M, Klingebiel T, et al. Long term outcome of high-risk neuroblastoma patients after immunotherapy with antibody ch14.18 Or oral metronomic chemotherapy. BMC Cancer. 2011;11:21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Valteau-Couanet D, Le Deley M-C, Bergeron C, Ducassou S, Michon J, Rubie H, et al. Long-term results of the combination of the N7 induction chemotherapy and the busulfan-melphalan high dose chemotherapy. Pediatr Blood Cancer. 2014;61:977–81.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  PubMed Central  Google 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.

  9. Monclair T, Brodeur GM, Ambros PF, Brisse HJ, Cecchetto G, Holmes K, et al. The international neuroblastoma risk group (INRG) staging system: an INRG task force report. J Clin Oncol. 2009;27:298–303.

    Article  PubMed  PubMed Central  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.

    Article  CAS  PubMed  PubMed Central  Google 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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  13. Lewington V, Lambert B, Poetschger U, Sever ZB, Giammarile F, McEwan AJB, et al. 123I-mIBG scintigraphy in neuroblastoma: development of a SIOPEN semi-quantitative reporting, method by an international panel. Eur J Nucl Med Mol Imaging. 2017;44:234–41.

    Article  CAS  PubMed  Google Scholar 

  14. Kreissman SG, Seeger RC, Matthay KK, London WB, Sposto R, Grupp SA, et al. Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): a randomised phase 3 trial. Lancet Oncol. 2013;14:999–1008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Garaventa A, Luksch R, Biasotti S, Severi G, Pizzitola MR, Viscardi E, et al. A phase II study of topotecan with vincristine and doxorubicin in children with recurrent/refractory neuroblastoma. Cancer. 2003;98:2488–94.

    Article  CAS  PubMed  Google Scholar 

  16. Ladenstein R, Weixler S, Baykan B, Bleeke M, Kunert R, Katinger D, et al. Ch14.18 Antibody produced in CHO cells in relapsed or refractory stage 4 neuroblastoma patients: a SIOPEN phase 1 study. MAbs. 2013;5:801–9.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Yu AL, Gilman AL, Ozkaynak MF, London WB, Kreissman SG, Chen HX, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010;363:1324–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kaplan, E, Meier P. Nonparametric Estimation from Incomplete Observations. J Am Stat Assoc. 1958;53(282):457–81.

  19. Marubini E, Valsecchi MG. Analysing survival data from clinical trials and observational studies. New York: Wiley; 2004.

    Google Scholar 

  20. Heinzl H, Kaider A. Gaining more flexibility in cox proportional hazards regression models with cubic spline functions. Comput Methods Prog Biomed. 1997;54:201–8.

    Article  CAS  Google Scholar 

  21. Heagerty PJ, Zheng Y. Survival model predictive accuracy and ROC curves. Biometrics. 2005;61:92–105.

    Article  PubMed  Google Scholar 

  22. Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56:337–44.

    Article  CAS  PubMed  Google Scholar 

  23. YOUDEN WJ. Index for rating diagnostic tests. Cancer. 1950:32–5.

  24. Yanik GA, Parisi MT, Shulkin BL, Naranjo A, Kreissman SG, London WB, et al. Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: a report from the Children’s oncology group. J Nucl Med. 2013;54:541–8.

    Article  CAS  PubMed  PubMed Central  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.

  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.

    Article  CAS  PubMed  Google 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.

    Article  CAS  PubMed  Google Scholar 

  29. Kushner BH, Kramer K, LaQuaglia MP, Modak S, Yataghene K, Cheung N-KV. Reduction from seven to five cycles of intensive induction chemotherapy in children with high-risk neuroblastoma. J Clin Oncol. 2004;22:4888–92.

    Article  CAS  PubMed  Google 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.

  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.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

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

Funding

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.

Author information

Authors and Affiliations

  1. Children’s Cancer Research Institute, Zimmermannplatz 10, 1090, Vienna, Austria

    Ruth Ladenstein & Ulrike Pötschger

  2. Medical University, Department of Paediatrics, Vienna, Austria

    Ruth Ladenstein

  3. Radiology and Nuclear Medicine, Ghent University, Ghent, Belgium

    Bieke Lambert

  4. Nuclear Medicine Division, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy

    Maria-Rita Castellani

  5. Guy’s and St Thomas’ NHS Foundation Trust, London, UK

    Valerie Lewington

  6. Schneider Children’s Medical Center of Israel, Petah-Tikva, Israel

    Zvi Bar-Sever

  7. Department of Nuclear Medicine Lille, Oscar Lambret Center, Lille, France

    Aurore Oudoux

  8. Children’s Memorial Health Institute, Warsaw, Poland

    Anna Śliwińska

  9. Motol University Hospital, Prague, Czech Republic

    Katerina Taborska

  10. Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK

    Lorenzo Biassoni

  11. University of Michigan Medical Center, Ann Arbor, MI, USA

    Gregory A. Yanik

  12. Children’s Oncology Group Statistics and Data Center, University of Florida, Gainesville, FL, USA

    Arlene Naranjo

  13. Department of Radiology, University of Washington School of Medicine/ Seattle Children’s Hospital, Seattle, WA, USA

    Marguerite T. Parisi

  14. Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, USA

    Barry L. Shulkin

  15. Department of Radiology, BC Children’s Hospital, Vancouver, BC, Canada

    Helen Nadel

  16. Department of Radiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

    Michael J. Gelfand

  17. Department of Pediatrics, University of California San Francisco School of Medicine, San Francisco, CA, USA

    Katherine K. Matthay

  18. Department of Pediatrics, University of Washington School of Medicine/ Seattle Children’s Hospital, Seattle, WA, USA

    Julie R. Park

  19. Department of Pediatrics, Duke University Medical Center, Durham, NC, USA

    Susan G. Kreissman

  20. Pediatric and Adolescent Oncology, Gustave Roussy Institute, Université Paris-Sud, Villejuif, France

    Dominique Valteau-Couanet

  21. Institute of Radiology, Clinique de La Source, Lausanne, Switzerland

    Ariane Boubaker

Authors
  1. Ruth Ladenstein
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  2. Bieke Lambert
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  3. Ulrike Pötschger
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  4. Maria-Rita Castellani
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  5. Valerie Lewington
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  8. Anna Śliwińska
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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.

Corresponding author

Correspondence to Ruth Ladenstein.

Ethics declarations

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.

Additional information

Part of data previously presented:

ASCO Annual Meeting 2014, Chicago, USA, May 30–June 3; J Clin Oncol 32:5 s, 2014 (suppl; abstr 10,029); EANM Annual Meeting Congress 2014, Oct 20–23, Gothenburg, Sweden

Ruth Ladenstein and Bieke Lambert share first authorship

Annex

Annex

Annex 1: Consort Diagram

figure a

Annex 2

  1. a)

    Comparison of event-free survival (EFS) of patients on the SIOPEN trial and in the analysis mIBG review data set.

    figure b
  2. b)

    Comparison of event-free survival (EFS) of patients on the COG A3973 trial and in the analysis mIBG review data set.

    figure c

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Ladenstein, R., Lambert, B., Pötschger, U. et al. Validation of the mIBG skeletal SIOPEN scoring method in two independent high-risk neuroblastoma populations: the SIOPEN/HR-NBL1 and COG-A3973 trials. Eur J Nucl Med Mol Imaging 45, 292–305 (2018). https://doi.org/10.1007/s00259-017-3829-7

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