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Risk Factors for Primary Bone Cancer After Childhood Cancer: A PanCare Childhood and Adolescent Cancer Survivor Care and Follow-Up Studies Nested Case-Control Study

Authors: Raoul C. Reulen, PhD https://orcid.org/0000-0002-7328-0467 [email protected], David L. Winter, HNC https://orcid.org/0000-0002-1597-4081, Ibrahim Diallo, PhD https://orcid.org/0000-0002-8272-8817, Cristina Veres, MSc https://orcid.org/0000-0002-6583-0334, Damien Llanas, PhD https://orcid.org/0000-0002-7879-0300, Rodrigue S. Allodji, PhD https://orcid.org/0000-0002-1895-8415, Francesca Bagnasco, PhD https://orcid.org/0000-0003-1601-9518, Edit Bárdi, MD https://orcid.org/0000-0001-7424-6255, Elizabeth A.M. Feijen, PhD https://orcid.org/0000-0001-8930-3160, Daniela Alessi, PhD, Miranda M. Fidler-Benaoudia, PhD, Stine Høgsholt, MD, PhD https://orcid.org/0000-0003-2197-5432, Jop C. Teepen, PhD https://orcid.org/0000-0002-2647-2677, Helena Linge, MD, Nadia Haddy, PhD, Julianne Byrne, PhD https://orcid.org/0000-0002-1070-3004, Ghazi Debiche, PhD, Desiree Grabow, PhD https://orcid.org/0000-0002-4853-3303, Thorgerdur Gudmundsdottir, MD, Romain Fauchery, PhD, Wael Zrafi, MD https://orcid.org/0000-0003-4289-6821, Gisela Michel, PhD https://orcid.org/0000-0002-9589-0928, Hilde Øfstaas, PhD, Peter Kaatsch, PhD, Giao Vu-Bezin, PhD https://orcid.org/0000-0002-9553-0527, Helen Jenkinson, MD, PhD, Melanie Kaiser, PhD https://orcid.org/0000-0002-3362-2530, Roderick Skinner, MD, PhD https://orcid.org/0000-0002-1162-675X, Trevor Cole, PhD, Nicolas Waespe, PhD https://orcid.org/0000-0002-2271-8959, Grit Sommer, PhD https://orcid.org/0000-0002-4205-7932, Susanne Nordenfelt, MSc, Momcilo Jankovic, PhD, Tuomas Lähteenmäki Taalas, MD https://orcid.org/0000-0002-5243-0382, Milena M. Maule, MD https://orcid.org/0000-0003-2142-1288, Helena J.H. van der Pal, MD https://orcid.org/0000-0003-2253-2115, Cécile M. Ronckers, PhD https://orcid.org/0000-0003-3524-4657, Flora E. van Leeuwen, PhD https://orcid.org/0000-0002-5871-1484, Judith L. Kok, PhD https://orcid.org/0000-0002-6007-7195, Monica Terenziani, MD, Maria Winther Gunnes, PhD, Thomas Wiebe, MD, Carlotta Sacerdote, PhD, Zsuzsanna Jakab, MD https://orcid.org/0000-0002-5410-1187, Riccardo Haupt, MD, Päivi M. Lähteenmäki, MD https://orcid.org/0000-0002-5500-9606, Lorna Zadravec Zaletel, MD https://orcid.org/0000-0002-4423-0276, Claudia E. Kuehni, PhD https://orcid.org/0000-0001-8957-2002, Jeanette F. Winther, MD, PhD https://orcid.org/0000-0002-3440-5108, Leontien C.M. Kremer, MD, PhD, Lars Hjorth, MD https://orcid.org/0000-0002-8302-7174, Florent de Vathaire, PhD https://orcid.org/0000-0002-8374-9281, and Michael M. Hawkins, DPhil https://orcid.org/0000-0001-6496-4800Authors Info & Affiliations
Publication: Journal of Clinical Oncology

Abstract

Purpose

Radiation to the bone and exposure to alkylating agents increases the risk of bone cancer among survivors of childhood cancer, but there is uncertainty regarding the risks of bone tissue radiation doses below 10 Gy and the dose-response relationship for specific types of chemotherapy.

Methods

Twelve European countries contributed 228 cases and 228 matched controls to a nested case-control study within a cohort of 69,460 5-year survivors of childhood cancer. Odds ratios (ORs) of developing bone cancer for different levels of cumulative radiation exposure and cumulative doses of specific types of chemotherapy were calculated. Excess ORs were calculated to investigate the shape and extent of any dose-response relationship.

Results

The OR associated with bone tissue exposed to 1-4 Gy was 4.8-fold (95% CI, 1.2 to 19.6) and to 5-9 Gy was 9.6-fold (95% CI, 2.4 to 37.4) compared with unexposed bone tissue. The OR increased linearly with increasing dose of radiation (Ptrend < .001) up to 78-fold (95% CI, 9.2 to 669.9) for doses of ≥40 Gy. For cumulative alkylating agent doses of 10,000-19,999 and ≥20,000 mg/m2, the radiation-adjusted ORs were 7.1 (95% CI, 2.2 to 22.8) and 8.3 (95% CI, 2.8 to 24.4), respectively, with independent contributions from each of procarbazine, ifosfamide, and cyclophosphamide. Other cytotoxics were not associated with bone cancer.

Conclusion

To our knowledge, we demonstrate—for the first time—that the risk of bone cancer is increased 5- to 10-fold after exposure of bone tissue to cumulative radiation doses of 1-9 Gy. Alkylating agents exceeding 10,000 mg/m2 increase the risk 7- to 8-fold, particularly following procarbazine, ifosfamide, and cyclophosphamide. These substantially elevated risks should be used to develop/update clinical follow-up guidelines and survivorship care plans.

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Prior Presentation

Presented at the North American Symposium on Late Complications After Childhood Cancer, Atlanta, GA, June 20-22, 2019.

Support

The PanCareSurFup consortium and related work was supported by the European Union's Seventh Framework Programme for research, technological development, and demonstration under grant agreement no. 257505. Additional financial support was received from The Italian Association for Cancer Research and the Compagnia San Paolo; The Fondo Chiara Rama ONLUS; The Swedish Childhood Cancer Fund; the Foundation ARC (POPHarC program); The Gustave Roussy Foundation (Pediatric Program “Guérir le Cancer de l’Enfant”), The French National Agency for Research (ANR) (Hope-Epi project); Pfizer Foundation for Children and Adolescent Health; Slovenian Research Agency; the Swiss Paediatric Oncology Group; The Swiss Cancer League (KLS-3412-02-2014, KLS-3886-02-2016, KLS-5432-08-2021); The Swiss Cancer Research foundation (KFS-02783-02-2011, KFS-4157-02-2017, KLA/KFS-4825-01-2019, KFS-4722-02-2019, KFS-5302-02-2021); The Swiss National Science Foundation (31BL30_185396, PDFMP3_141775), The Dutch Cancer Society (DCOG2011-5027 and UVA2012-5517), The Norwegian Childhood Cancer Foundation, Children with Cancer UK (20457 & 17247), and The Brain Tumour Charity (GN-000624).

Information & Authors

Information

Published In

Journal of Clinical Oncology
Pages: 3735 - 3746
PubMed: 37235821

History

Published online: May 26, 2023
Published in print: July 20, 2023

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Data Sharing Statement

Access to anonymized data may be granted under conditions agreed with the relevant (local) legal and research ethics committees and with appropriate data sharing agreements and permissions from each data provider in place. Any data sharing would have to comply with the EU General Data Protection Regulation. The data that support the findings of this study are not publicly available because of privacy and ethical restrictions. Aggregated data in the form of tables may be available on reasonable request.

Authors

Affiliations

Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Rodrigue S. Allodji, PhD https://orcid.org/0000-0002-1895-8415
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Scientific Directorate, IRCCS Istituto Giannina Gaslini, Genova, Italy
St Anna Children's Hospital, Vienna, Austria
Miranda M. Fidler-Benaoudia, PhD
Nadia Haddy, PhD
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Ghazi Debiche, PhD
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Thorgerdur Gudmundsdottir, MD
Romain Fauchery, PhD
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Helen Jenkinson, MD, PhD
Susanne Nordenfelt, MSc
Maria Winther Gunnes, PhD
Carlotta Sacerdote, PhD
Jeanette F. Winther, MD, PhD https://orcid.org/0000-0002-3440-5108
Department of Clinical Medicine, Faculty of Health, Aarhus University and University Hospital, Aarhus, Denmark
Leontien C.M. Kremer, MD, PhD
Emma Children's Hospital, Amsterdam UMC, Amsterdam, the Netherlands
Florent de Vathaire, PhD https://orcid.org/0000-0002-8374-9281
Radiation Epidemiology Team, Center for Research in Epidemiology and Population Health, INSERM U1018, University Paris Saclay, Gustave Roussy, Villejuif, France
Michael M. Hawkins, DPhil https://orcid.org/0000-0001-6496-4800
Centre for Childhood Cancer Survivor Studies, Institute of Applied Health Research, University of Birmingham, Birmingham, United Kingdom

Notes

Raoul C. Reulen, PhD, Centre for Childhood Cancer Survivor Studies, College of Medical and Dental Sciences, University of Birmingham, Institute of Applied Health Research, Robert Aitken Building, Edgbaston, Birmingham B15 2T, United Kingdom; e-mail: [email protected].

Author Contributions

Conception and design: Raoul C. Reulen, David L. Winter, Edit Bárdi, Elizabeth A.M. Feijen, Julianne Byrne, Desiree Grabow, Peter Kaatsch, Roderick Skinner, Helena J.H. van der Pal, Judith L. Kok, Thomas Wiebe, Claudia E. Kuehni, Leontien C.M. Kremer, Florent de Vathaire, Michael M. Hawkins
Financial support: Claudia E. Kuehni, Florent de Vathaire, Michael M. Hawkins
Administrative support: David L. Winter, Helena Linge, Julianne Byrne, Judith L. Kok, Zsuzsanna Jakab, Michael M. Hawkins
Provision of study materials or patients: David L. Winter, Damien Llanas, Elizabeth A.M. Feijen, Daniela Alessi, Thorgerdur Gudmundsdottir, Gisela Michel, Hilde Øfstaas, Grit Sommer, Momcilo Jankovic, Milena M. Maule, Judith L. Kok, Maria Winther Gunnes, Thomas Wiebe, Riccardo Haupt, Päivi M. Lähteenmäki, Lorna Zadravec Zaletel, Claudia E. Kuehni, Leontien C.M. Kremer, Michael M. Hawkins
Collection and assembly of data: Raoul C. Reulen, David L. Winter, Ibrahim Diallo, Cristina Veres, Damien Llanas, Rodrigue S. Allodji, Francesca Bagnasco, Edit Bárdi, Elizabeth A.M. Feijen, Daniela Alessi, Miranda M. Fidler-Benaoudia, Stine Høgsholt, Jop C. Teepen, Helena Linge, Nadia Haddy, Julianne Byrne, Ghazi Debiche, Desiree Grabow, Thorgerdur Gudmundsdottir, Romain Fauchery, Wael Zrafi, Gisela Michel, Hilde Øfstaas, Peter Kaatsch, Giao Vu-Bezin, Melanie Kaiser, Grit Sommer, Susanne Nordenfelt, Momcilo Jankovic, Tuomas Lähteenmäki Taalas, Milena M. Maule, Helena J.H. van der Pal, Cécile M. Ronckers, Judith L. Kok, Monica Terenziani, Maria Winther Gunnes, Thomas Wiebe, Carlotta Sacerdote, Zsuzsanna Jakab, Riccardo Haupt, Päivi M. Lähteenmäki, Lorna Zadravec Zaletel, Claudia E. Kuehni, Jeanette F. Winther, Leontien C.M. Kremer, Lars Hjorth, Florent de Vathaire, Michael M. Hawkins
Data analysis and interpretation: Raoul C. Reulen, Ibrahim Diallo, Rodrigue S. Allodji, Edit Bárdi, Elizabeth A.M. Feijen, Jop C. Teepen, Ghazi Debiche, Gisela Michel, Helen Jenkinson, Roderick Skinner, Trevor Cole, Nicolas Waespe, Cécile M. Ronckers, Flora E. van Leeuwen, Judith L. Kok, Zsuzsanna Jakab, Riccardo Haupt, Lorna Zadravec Zaletel, Claudia E. Kuehni, Leontien C.M. Kremer, Michael M. Hawkins
Manuscript writing: All authors
Final approval of manuscript: All authors
Accountable for all aspects of the work: All authors

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Raoul C. Reulen, David L. Winter, Ibrahim Diallo, Cristina Veres, Damien Llanas, Rodrigue S. Allodji, Francesca Bagnasco, Edit Bárdi, Elizabeth A.M. Feijen, Daniela Alessi, Miranda M. Fidler-Benaoudia, Stine Høgsholt, Jop C. Teepen, Helena Linge, Nadia Haddy, Julianne Byrne, Ghazi Debiche, Desiree Grabow, Thorgerdur Gudmundsdottir, Romain Fauchery, Wael Zrafi, Gisela Michel, Hilde Øfstaas, Peter Kaatsch, Giao Vu-Bezin, Helen Jenkinson, Melanie Kaiser, Roderick Skinner, Trevor Cole, Nicolas Waespe, Grit Sommer, Susanne Nordenfelt, Momcilo Jankovic, Tuomas Lähteenmäki Taalas, Milena M. Maule, Helena J.H. van der Pal, Cécile M. Ronckers, Flora E. van Leeuwen, Judith L. Kok, Monica Terenziani, Maria Winther Gunnes, Thomas Wiebe, Carlotta Sacerdote, Zsuzsanna Jakab, Riccardo Haupt, Päivi M. Lähteenmäki, Lorna Zadravec Zaletel, Claudia E. Kuehni, Jeanette F. Winther, Leontien C.M. Kremer, Lars Hjorth, Florent de Vathaire, Michael M. Hawkins
Journal of Clinical Oncology 2023 41:21, 3735-3746

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