M H van den Berg1, A Overbeek1,2, C B Lambalk2, G J L Kaspers1,3, D Bresters4, M M van den Heuvel-Eibrink3,5, L C Kremer3,6, J J Loonen7, H J van der Pal3, C M Ronckers6, W J E Tissing8, A B Versluys9, M van der Heiden-van der Loo10, A C Heijboer11, M Hauptmann12, J W R Twisk13, J S E Laven14, C C M Beerendonk15, F E van Leeuwen12, E van Dulmen-den Broeder1. 1. Department of Paediatrics, Division of Paediatric Oncology/Haematology, VU University Medical Center, De Boelelaan 1117, HV, Amsterdam, The Netherlands. 2. Department of Obstetrics and Gynaecology, VU University Medical Center, De Boelelaan 1117, HV, Amsterdam, The Netherlands. 3. Princess Máxima Center for Paediatric Oncology, Lundlaan 6, EA, Utrecht, The Netherlands. 4. Willem-Alexander Children's Hospital, Leiden University Medical Center, Albinusdreef 2, ZA, Leiden, The Netherlands. 5. Department of Paediatric Oncology, Sophia Children's Hospital/Erasmus MC University Medical Center, Wytemaweg 80, CN, Rotterdam, The Netherlands. 6. Department of Paediatric Oncology, Emma Children's Hospital/Academic Medical Center, Meibergdreef 9, AZ, Amsterdam, The Netherlands. 7. Department of Paediatric Oncology, Radboud University Medical Center, Geert Grooteplein Zuid 10, GA, Nijmegen, The Netherlands. 8. Department of Paediatric Oncology, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Hanzeplein 1, GZ, Groningen, The Netherlands. 9. Department of Paediatric Oncology, Wilhelmina's Children's Hospital/University Medical Center, Lundlaan 6, EA, Utrecht, The Netherlands. 10. Dutch Childhood Oncology Group, Zinkwerf 5-7, EC, The Hague, The Netherlands. 11. Department of Clinical Chemistry, Endocrine Laboratory, VU University Medical Center, De Boelelaan 1117, HV, Amsterdam, The Netherlands. 12. Department of Epidemiology and Biostatistics, Netherlands Cancer Institute, Plesmanlaan 121, CX, Amsterdam, The Netherlands. 13. Department of Epidemiology and Biostatistics and the EMGO(+) Institute for Health and Care Research, VU University Medical Centre, De Boelelaan 1117, HV, Amsterdam, The Netherlands. 14. Department of Gynaecology and Obstetrics, Division Reproductive Medicine, Erasmus MC University Medical Center, 's-Gravendijkwal 230, CE, Rotterdam, The Netherlands. 15. Department of Obstetrics and Gynaecology, Radboud University Medical Center, Geert Grooteplein Zuid 10, GA, Nijmegen, The Netherlands.
Abstract
STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the Children Cancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.
STUDY QUESTION: Which treatment-related factors are (dose-dependently) associated with abnormal hormonal and ultrasound markers of ovarian reserve in female childhood cancer survivors (CCSs)? SUMMARY ANSWER: Cyclophosphamide, procarbazine, a composite group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal radiotherapy (RT), abdominal/pelvic RT and total body irradiation were multivariably associated with abnormal ovarian reserve markers, with dose-effect relationships being established for procarbazine and abdominal/pelvic RT. WHAT IS KNOWN ALREADY: Female childhood cancer survivors are at an increased risk of reduced ovarian function and reserve, but knowledge regarding the long-term effects of individual chemotherapeutic (CT) agents and radiotherapy fields and their respective doses is limited. STUDY DESIGN, SIZE, DURATION: The DCOG LATER-VEVO is a nationwide retrospective cohort study in which measurements were performed between 2008 and 2014. In total, 1749 female 5-year CCSs, diagnosed before age 18 years between 1963 and 2002 and 1201 controls were invited for the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: Ovarian reserve was assessed by anti-Müllerian hormone (AMH), follicle stimulating hormone (FSH), inhibin B levels, and antral follicle counts (AFC). The study was a multicentre study including all seven Dutch Centers for Paediatric Oncology/Haematology. MAIN RESULTS AND THE ROLE OF CHANCE: In total, 564 CCs and 390 controls participated in the clinical part of the study. Overall, 7.0-17.7% of CCSs and 2.4-13.6% of controls had abnormal ovarian reserve markers. Above age 35, significantly more CCSs than controls had abnormal ovarian reserve markers (AMH: 26% vs. 4%; AFC: 20% vs. 3%; inhibin B: 42% vs. 16%). For AMH and FSH, significant differences were also found below age 35. Cyclophosphamide, procarbazine, a group of 'other alkylating agents', dactinomycin, doxorubicin, mitoxantrone, spinal RT, abdominal/pelvic RT and total body irradiation were multivariably associated with at least one abnormal ovarian reserve marker. Dose-effect relationships were established for procarbazine and abdominal/pelvic RT. LIMITATIONS, REASONS FOR CAUTION: Despite the large scale of the study, dose-effect relationships could not be investigated for all types of treatment due to a limited numbers of participants for specific analyses. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrated that the majority of CCSs do not show signs of a reduced ovarian reserve. However, specific subgroups of CCSs appear to be associated with a high risk. Our results are important for counselling CCSs and future patients regarding parenthood and fertility preservation. STUDY FUNDING/COMPETING INTERESTS: This study was funded by the Dutch Cancer Society (Grant no. VU 2006-3622) and by the ChildrenCancer Free Foundation (Project no. 20). Philips Health Systems Benelux supported this study by providing three ultrasound systems and concomitant analytic software. There are no competing interests. TRIAL REGISTRATION NUMBER: NTR2922 http://www.trialregister.nl/trialreg/admin/rctview.asp?TC = 2922.
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