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Treatment-related fertility impairment in long-term female childhood, adolescent and young adult cancer survivors: investigating dose-effect relationships in a European case-control study (PanCareLIFE)
MH. van den Berg, M. van Dijk, J. Byrne, C. Berger, U. Dirksen, JF. Winther, SD. Fossa, D. Grabow, VL. Grandage, R. Haupt, MM. van den Heuvel-Eibrink, M. Kaiser, T. Kepak, ALF. van der Kooi, LCM. Kremer, J. Kruseova, CB. Lambalk, FE. van Leeuwen,...
Language English Country Great Britain
Document type Journal Article, Research Support, Non-U.S. Gov't
NLK
Free Medical Journals
from 1996 to 1 year ago
Open Access Digital Library
from 1996-01-01
- MeSH
- Child MeSH
- Adult MeSH
- Fertility MeSH
- Cohort Studies MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Neoplasms * drug therapy MeSH
- Cancer Survivors * MeSH
- Case-Control Studies MeSH
- Fertility Preservation * MeSH
- Check Tag
- Child MeSH
- Adult MeSH
- Humans MeSH
- Adolescent MeSH
- Young Adult MeSH
- Male MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
STUDY QUESTION: Which chemotherapeutic agents and body site-specific radiation fields are dose-dependently associated with an increased risk of fertility impairment in long-term female childhood, adolescent and young adulthood (CAYA) cancer survivors? SUMMARY ANSWER: Busulfan, lower abdominal radiotherapy (RT) and total body irradiation (TBI) seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. WHAT IS KNOWN ALREADY: Several treatment-related fertility deficits, as assessed by both self-reported outcomes and hormonal markers are known to occur following treatment of CAYA cancer. However, knowledge regarding precise dose-related estimates of these treatment-related risks are scarce. STUDY DESIGN, SIZE, DURATION: The current case-control study was nested within the PanCareLIFE cohort study. In total, 1332 CAYA survivors from 8 countries, 9 institutions and 11 cohorts, participated in and contributed data to the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were female 5-year CAYA cancer survivors. In total, 450 cases (fertility impaired survivors) and 882 matched controls (not fertility impaired survivors) were included. Fertility impairment was defined using both questionnaire data (primary or secondary amenorrhea; use of artificial reproductive techniques; unfulfilled wish to conceive) and hormonal data (FSH and anti-Müllerian hormone (AMH)). Multivariable logistic regression models were used to investigate the effect of (i) alkylating agent exposure, and (ii) dose categories for individual chemotherapeutic agents and for RT-exposed body sites. MAIN RESULTS AND THE ROLE OF CHANCE: A positive dose-effect relationship between cyclophosphamide equivalent dose (CED) score and fertility impairment was found, with survivors with a CED score > 7121 mg/m2 being at a significantly increased risk of fertility impairment (odds ratio (95% CI) = 2.6 (1.9-3.6) P < 0.001). Moreover, cumulative dose variables of the following treatments were significantly associated with fertility impairment: busulfan, carmustine, cyclophosphamide, melphalan, procarbazine, lower abdominal RT and TBI. Busulfan, lower abdominal RT and TBI seem to be associated with fertility impairment at any dose, whereas gonadotoxicity of melphalan and procarbazine is suggested at medium/high (>140 mg/m2) or high dose (>5600 mg/m2) therapy, respectively. LIMITATIONS, REASONS FOR CAUTION: Our study may have been subject to selection bias since data from about half of the original base cohorts were available for the current study. This could impact the generalizability of our study results. WIDER IMPLICATIONS OF THE FINDINGS: We identified survivors at high risk for fertility impairment and, consequently, for a reduced or even absent reproductive life span. Both girls and young women who are about to start anti-cancer treatment, as well as adult female survivors, should be counselled about future parenthood and referred to a reproductive specialist for fertility preservation, if desired. STUDY FUNDING/COMPETING INTEREST(S): This study has received funding from the European Union's Seventh Framework Programme for research, technological development and demonstration under grant agreement no. 602030. There are no competing interests. TRIAL REGISTRATION NUMBER: n/a.
Boyne Research Institute Department of Epidemiology Drogheda Ireland
Danish Cancer Society Research Center Childhood Cancer Research Group Copenhagen Denmark
Department of Epidemiology and Biostatistics Netherlands Cancer Institute Amsterdam The Netherlands
Department of Epidemiology Netherlands Cancer Institute Amsterdam The Netherlands
Department of Obstetrics and Gynaecology Amsterdam UMC Vrije Universiteit Amsterdam
Department of Oncology Oslo University Hospital Oslo Norway
Department of Paediatric Haematology and Oncology University Hospital Muenster Muenster Germany
Department of Paediatric Oncology Sophia Children's Hospital Rotterdam The Netherlands
Department of Pediatric Hematology and Oncology University Hospital Saint Etienne France
Edmond and Lily Safra Children's Hospital Chaim Sheba Medical Center Ramat Gan Israel
Gaslini Children Hospital Epidemiology and Biostatistics Section Genova Italy
Great Ormond Street Children's Hospital London UK
Institute for Biostatistics and Registry Research Medical University Brandenburg Neuruppin Germany
International Clinical Research Center Brno Czech Republic
Princess Máxima Center for Pediatric Oncology Utrecht The Netherlands
The Sackler Faculty of Medicine Tel Aviv University Tel Aviv Israel
References provided by Crossref.org
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