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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

Reulen, Raoul C ; Winter, David L ; Diallo, Ibrahim ; Veres, Cristina ; Llanas, Damien ; Allodji, Rodrigue S ; Bagnasco, Francesca ; Bárdi, Edit ; Feijen, Elizabeth A M and Alessi, Daniela , et al. (2023) In Journal of clinical oncology : official journal of the American Society of Clinical Oncology 41(21). p.3735-3746
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... (More)

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.

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organization
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type
Contribution to journal
publication status
published
subject
keywords
Child, Humans, Adolescent, Cancer Survivors, Follow-Up Studies, Ifosfamide, Case-Control Studies, Procarbazine, Risk Factors, Bone Neoplasms, Cyclophosphamide, Osteosarcoma/epidemiology, Alkylating Agents, Neoplasms, Second Primary/chemically induced, Dose-Response Relationship, Radiation
in
Journal of clinical oncology : official journal of the American Society of Clinical Oncology
volume
41
issue
21
pages
3735 - 3746
publisher
American Society of Clinical Oncology
external identifiers
  • scopus:85165219722
  • pmid:37235821
ISSN
0732-183X
DOI
10.1200/JCO.22.02045
language
English
LU publication?
yes
id
00973243-1a1a-4570-a2cc-08689a42aef3
date added to LUP
2023-11-01 08:45:03
date last changed
2024-02-18 21:48:49
@article{00973243-1a1a-4570-a2cc-08689a42aef3,
  abstract     = {{<p>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.</p><p>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.</p><p>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 (<br>
 P<br>
 trend &lt; .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 <br>
 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.<br>
 </p><p>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<br>
 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.<br>
 </p>}},
  author       = {{Reulen, Raoul C and Winter, David L and Diallo, Ibrahim and Veres, Cristina and Llanas, Damien and Allodji, Rodrigue S and Bagnasco, Francesca and Bárdi, Edit and Feijen, Elizabeth A M and Alessi, Daniela and Fidler-Benaoudia, Miranda M and Høgsholt, Stine and Teepen, Jop C and Linge, Helena and Haddy, Nadia and Byrne, Julianne and Debiche, Ghazi and Grabow, Desiree and Gudmundsdottir, Thorgerdur and Fauchery, Romain and Zrafi, Wael and Michel, Gisela and Øfstaas, Hilde and Kaatsch, Peter and Vu-Bezin, Giao and Jenkinson, Helen and Kaiser, Melanie and Skinner, Roderick and Cole, Trevor and Waespe, Nicolas and Sommer, Grit and Nordenfelt, Susanne and Jankovic, Momcilo and Lähteenmäki Taalas, Tuomas and Maule, Milena M and van der Pal, Helena J H and Ronckers, Cécile M and van Leeuwen, Flora E and Kok, Judith L and Terenziani, Monica and Winther Gunnes, Maria and Wiebe, Thomas and Sacerdote, Carlotta and Jakab, Zsuzsanna and Haupt, Riccardo and Lähteenmäki, Päivi M and Zadravec Zaletel, Lorna and Kuehni, Claudia E and Winther, Jeanette F and Hjorth, Lars}},
  issn         = {{0732-183X}},
  keywords     = {{Child; Humans; Adolescent; Cancer Survivors; Follow-Up Studies; Ifosfamide; Case-Control Studies; Procarbazine; Risk Factors; Bone Neoplasms; Cyclophosphamide; Osteosarcoma/epidemiology; Alkylating Agents; Neoplasms, Second Primary/chemically induced; Dose-Response Relationship, Radiation}},
  language     = {{eng}},
  month        = {{07}},
  number       = {{21}},
  pages        = {{3735--3746}},
  publisher    = {{American Society of Clinical Oncology}},
  series       = {{Journal of clinical oncology : official journal of the American Society of Clinical Oncology}},
  title        = {{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}},
  url          = {{http://dx.doi.org/10.1200/JCO.22.02045}},
  doi          = {{10.1200/JCO.22.02045}},
  volume       = {{41}},
  year         = {{2023}},
}