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
Raoul Reulen
(1)
,
David Winter
(1)
,
Ibrahim Diallo
(2, 3)
,
Cristina Veres
(2, 3)
,
Damien Llanas
(2, 3)
,
Rodrigue Allodji
(2, 3)
,
Francesca Bagnasco
(4)
,
Edit Bárdi
(5, 6)
,
Elizabeth A.M. Feijen
(7)
,
Daniela Alessi
(8, 9)
,
Miranda Fidler-Benaoudia
(10)
,
Stine Høgsholt
(11, 12)
,
Jop Teepen
(7)
,
Helena Linge
(11, 12)
,
Nadia Haddy
(2, 3)
,
Julianne Byrne
(13)
,
Ghazi Debiche
(2, 3)
,
Desiree Grabow
(14, 15)
,
Thorgerdur Gudmundsdottir
(16)
,
Romain Fauchery
(2, 3)
,
Wael Zrafi
(2, 3)
,
Gisela Michel
(17)
,
Hilde Øfstaas
(18)
,
Peter Kaatsch
(14, 19)
,
Giao Vu-Bezin
(2, 3)
,
Helen Jenkinson
(20)
,
Melanie Kaiser
(14, 19)
,
Roderick Skinner
(21, 22, 23)
,
Trevor Cole
(24)
,
Nicolas Waespe
(25, 26)
,
Grit Sommer
(26)
,
Susanne Nordenfelt
(11, 12)
,
Momcilo Jankovic
(27, 28)
,
Tuomas Lähteenmäki Taalas
(29, 30)
,
Milena Maule
(8, 9)
,
Helena J.H. van der Pal
(7)
,
Cécile Ronckers
(14, 19)
,
Flora van Leeuwen
(31)
,
Judith Kok
(7)
,
Monica Terenziani
(32)
,
Maria Winther Gunnes
(33)
,
Thomas Wiebe
(11, 12)
,
Carlotta Sacerdote
(8, 9)
,
Zsuzsanna Jakab
(34)
,
Riccardo Haupt
(4)
,
Päivi Lähteenmäki
(29, 30)
,
Lorna Zadravec Zaletel
(35)
,
Claudia Kuehni
(25, 26)
,
Jeanette Winther
(36, 37)
,
Leontien C.M. Kremer
(38, 39)
,
Lars Hjorth
(11, 12)
,
Florent de Vathaire
(2, 3)
,
Michael Hawkins
(1)
1
University of Birmingham [Birmingham]
2 CESP - Centre de recherche en épidémiologie et santé des populations
3 IGR - Institut Gustave Roussy
4 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
5 JKU - University of Linz - Johannes Kepler Universität Linz
6 Kepler University Hospital
7 Princess Máxima Center for Pediatric Oncology
8 UNITO - Università degli studi di Torino = University of Turin
9 A.O.U - Città della Salute e della Scienza di Torino
10 University of Calgary
11 Lund University
12 Skane University Hospital [Lund]
13 BRI - Boyne Research Institute [Drogheda, Irlande]
14 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
15 Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI)
16 Landspitali National University Hospital of Iceland
17 UNILU - Université de Lucerne = Universität Luzern
18 Cancer Registry of Norway
19 University Medical Center [Mainz]
20 Birmingham Children’s Hospital
21 Newcastle Upon Tyne Hospitals NHS Foundation Trust
22 Great North Children’s Hospital [Newcastle Upon Tyne, UK]
23 Newcastle University [Newcastle]
24 Birmingham Women's and Children's NHS Foundation Trust
25 Inselspital - Bern University Hospital [Berne]
26 UNIBE - Universität Bern / University of Bern
27 UNIMIB - Università degli Studi di Milano-Bicocca = University of Milano-Bicocca
28 SGH - San Gerardo Hospital [Monza, Italy]
29 TYKS - Turku University Hospital
30 University of Turku
31 NKI - Netherlands Cancer Institute
32 IRCCS Istituto Nazionale dei Tumori [Milano]
33 Oslo University Hospital [Oslo]
34 Semmelweis University [Budapest]
35 Institute of Oncology [Ljubljana]
36 Aarhus University [Aarhus]
37 Aarhus University Hospital
38 Academic Medical Center - Emma Children's Hospital [Amsterdam, Netherlands]
39 Amsterdam UMC - Amsterdam University Medical Center
2 CESP - Centre de recherche en épidémiologie et santé des populations
3 IGR - Institut Gustave Roussy
4 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
5 JKU - University of Linz - Johannes Kepler Universität Linz
6 Kepler University Hospital
7 Princess Máxima Center for Pediatric Oncology
8 UNITO - Università degli studi di Torino = University of Turin
9 A.O.U - Città della Salute e della Scienza di Torino
10 University of Calgary
11 Lund University
12 Skane University Hospital [Lund]
13 BRI - Boyne Research Institute [Drogheda, Irlande]
14 JGU - Johannes Gutenberg - Universität Mainz = Johannes Gutenberg University
15 Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI)
16 Landspitali National University Hospital of Iceland
17 UNILU - Université de Lucerne = Universität Luzern
18 Cancer Registry of Norway
19 University Medical Center [Mainz]
20 Birmingham Children’s Hospital
21 Newcastle Upon Tyne Hospitals NHS Foundation Trust
22 Great North Children’s Hospital [Newcastle Upon Tyne, UK]
23 Newcastle University [Newcastle]
24 Birmingham Women's and Children's NHS Foundation Trust
25 Inselspital - Bern University Hospital [Berne]
26 UNIBE - Universität Bern / University of Bern
27 UNIMIB - Università degli Studi di Milano-Bicocca = University of Milano-Bicocca
28 SGH - San Gerardo Hospital [Monza, Italy]
29 TYKS - Turku University Hospital
30 University of Turku
31 NKI - Netherlands Cancer Institute
32 IRCCS Istituto Nazionale dei Tumori [Milano]
33 Oslo University Hospital [Oslo]
34 Semmelweis University [Budapest]
35 Institute of Oncology [Ljubljana]
36 Aarhus University [Aarhus]
37 Aarhus University Hospital
38 Academic Medical Center - Emma Children's Hospital [Amsterdam, Netherlands]
39 Amsterdam UMC - Amsterdam University Medical Center
Raoul Reulen
- Fonction : Auteur
- PersonId : 1297193
- ORCID : 0000-0002-7328-0467
David Winter
- Fonction : Auteur
- PersonId : 1297194
- ORCID : 0000-0002-1597-4081
Ibrahim Diallo
- Fonction : Auteur
- PersonId : 1297195
- ORCID : 0000-0002-8272-8817
Cristina Veres
- Fonction : Auteur
- PersonId : 1297196
- ORCID : 0000-0002-6583-0334
Damien Llanas
- Fonction : Auteur
- PersonId : 1297197
- ORCID : 0000-0002-7879-0300
Rodrigue Allodji
- Fonction : Auteur
- PersonId : 4839
- IdHAL : rodrigue-setcheou-allodji
- ORCID : 0000-0002-1895-8415
Francesca Bagnasco
- Fonction : Auteur
- PersonId : 1260536
- ORCID : 0000-0003-1601-9518
Edit Bárdi
- Fonction : Auteur
- PersonId : 1297198
- ORCID : 0000-0001-7424-6255
Elizabeth A.M. Feijen
- Fonction : Auteur
- PersonId : 1297199
- ORCID : 0000-0001-8930-3160
Stine Høgsholt
- Fonction : Auteur
- PersonId : 1297200
- ORCID : 0000-0003-2197-5432
Jop Teepen
- Fonction : Auteur
- PersonId : 1297201
- ORCID : 0000-0002-2647-2677
Julianne Byrne
- Fonction : Auteur
- PersonId : 1297202
- ORCID : 0000-0002-1070-3004
Desiree Grabow
- Fonction : Auteur
- PersonId : 1297203
- ORCID : 0000-0002-4853-3303
Wael Zrafi
- Fonction : Auteur
- PersonId : 1297204
- ORCID : 0000-0003-4289-6821
Gisela Michel
- Fonction : Auteur
- PersonId : 1260539
- ORCID : 0000-0002-9589-0928
Giao Vu-Bezin
- Fonction : Auteur
- PersonId : 1297205
- ORCID : 0000-0002-9553-0527
Melanie Kaiser
- Fonction : Auteur
- PersonId : 1297206
- ORCID : 0000-0002-3362-2530
Roderick Skinner
- Fonction : Auteur
- PersonId : 1297207
- ORCID : 0000-0002-1162-675X
Nicolas Waespe
- Fonction : Auteur
- PersonId : 1279025
- ORCID : 0000-0002-2271-8959
Grit Sommer
- Fonction : Auteur
- PersonId : 1297208
- ORCID : 0000-0002-4205-7932
Tuomas Lähteenmäki Taalas
- Fonction : Auteur
- PersonId : 1297209
- ORCID : 0000-0002-5243-0382
Milena Maule
- Fonction : Auteur
- PersonId : 1260538
- ORCID : 0000-0003-2142-1288
Helena J.H. van der Pal
- Fonction : Auteur
- PersonId : 1297210
- ORCID : 0000-0003-2253-2115
Cécile Ronckers
- Fonction : Auteur
- PersonId : 1260537
- ORCID : 0000-0003-3524-4657
Flora van Leeuwen
- Fonction : Auteur
- PersonId : 1297211
- ORCID : 0000-0002-5871-1484
Judith Kok
- Fonction : Auteur
- PersonId : 1297212
- ORCID : 0000-0002-6007-7195
Zsuzsanna Jakab
- Fonction : Auteur
- PersonId : 1297213
- ORCID : 0000-0002-5410-1187
Päivi Lähteenmäki
- Fonction : Auteur
- PersonId : 1260541
- ORCID : 0000-0002-5500-9606
Lorna Zadravec Zaletel
- Fonction : Auteur
- PersonId : 1260542
- ORCID : 0000-0002-4423-0276
Claudia Kuehni
- Fonction : Auteur
- PersonId : 804838
- ORCID : 0000-0001-8957-2002
- IdRef : 186420374
Jeanette Winther
- Fonction : Auteur
- PersonId : 1297214
- ORCID : 0000-0002-3440-5108
Lars Hjorth
- Fonction : Auteur
- PersonId : 1297215
- ORCID : 0000-0002-8302-7174
Florent de Vathaire
- Fonction : Auteur
- PersonId : 1162629
- IdHAL : florent-de-vathaire
- ORCID : 0000-0002-8374-9281
Michael Hawkins
- Fonction : Auteur
- PersonId : 1297216
- ORCID : 0000-0001-6496-4800
Résumé
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 ( P trend < .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/m 2 , 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/m 2 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.