Edinburgh Research Explorer
Fertility preservation for male childhood, adolescent and young
adult patients with cancer: recommendations from the
PanCareLIFE consortium and the International Late Effects of
Childhood Cancer Guideline Harmonization Group
Citation for published version:
PanCareLIFE Consortium 2021, 'Fertility preservation for male childhood, adolescent and young adult
patients with cancer: recommendations from the PanCareLIFE consortium and the International Late Effects
of Childhood Cancer Guideline Harmonization Group', The Lancet Oncology, vol. 22, no. 2.
https://doi.org/10.1016/S1470-2045(20)30582-9
Digital Object Identifier (DOI):
10.1016/S1470-2045(20)30582-9
Link:
Link to publication record in Edinburgh Research Explorer
Document Version:
Peer reviewed version
Published In:
The Lancet Oncology
General rights
Copyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)
and / or other copyright owners and it is a condition of accessing these publications that users recognise and
abide by the legal requirements associated with these rights.
Take down policy
The University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorer
content complies with UK legislation. If you believe that the public display of this file breaches copyright please
contact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately and
investigate your claim.
Download date: 10. Aug. 2022
1
Fertility preservation for male childhood, adolescent and young adult patients
with cancer: recommendations from the PanCareLIFE consortium and the
International Late Effects of Childhood Cancer Guideline Harmonization Group
Renée L Mulder*, Anna Font-Gonzalez*, Daniel M Green, Erik A H Loeffen, Melissa M Hudson, Jacqueline
Loonen, Richard Yu, Jill P Ginsberg, Rod T. Mitchell, Julianne Byrne, Roderick Skinner, Antoinette Anazodo,
Louis S Constine, Andrica de Vries, Kirsi Jahnukainen, Armando Lorenzo, Andreas Meissner, Leena Nahata,
Marij Dinkelman-Smit, Herman Tournaye, Riccardo Haupt, Marry M van den Heuvel-Eibrink, Hanneke M van
Santen, Ans M M van Pelt, Uta Dirksen, Jaap den Hartogh, Eline van Dulmen-den Broeder, W Hamish Wallace,
Jennifer Levine, Wim J E Tissing, Leontien C M Kremer
‡
, Lisa B Kenney
‡
, Marianne D van de Wetering
‡
on
behalf of the PanCareLIFE Consortium
#
*Shared first authorship
‡
Shared last authorship
#
Members listed in the Appendix
Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands (R L Mulder PhD, A Font-Gonzalez PhD, A
de Vries MD, E van Dulmen-den Broeder PhD, H M van Santen PhD, Prof M M van den Heuvel-Eibrink PhD, Prof L C
M Kremer PhD, Prof W J E Tissing PhD, M D van de Wetering PhD);
Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Pediatric oncology, Amsterdam,
Netherlands (A Font-Gonzalez PhD, Prof L C M Kremer PhD);
Departments of Epidemiology and Cancer Control, and Oncology, St. Jude Children’s Research Hospital,
Memphis, TN, USA (D M Green MD, M M Hudson MD);
Department of Pediatric Oncology/Hematology, Beatrix Children’s Hospital, University of Groningen, University
Medical Center Groningen, Groningen, Netherlands (E A H Loeffen PhD, Prof W J E Tissing PhD);
Department of Hematology, Radboudumc, Nijmegen, Netherlands (J Loonen MD);
Boston Children's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA (R Yu
MD, L B Kenney MD);
Children’s Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia,
PA, USA (prof J P Ginsberg MD);
Medical Research Council Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK (Prof R T
Mitchell PhD)
Boyne Research Institute, Drogheda, Ireland (J Byrne PhD);
Department of Paediatric and Adolescent Haematology/Oncology, Great North Children’s Hospital and
Newcastle University Centre for Cancer, Newcastle upon Tyne, UK (R Skinner FRCPCH);
Kids Cancer Centre, Sydney Children's Hospital, New South Wales, Sydney, Australia (A Anazodo PhD);
Nelune Comprehensive Cancer Centre, Prince of Wales Hospital, New South Wales, Sydney, Australia (A Anazodo
PhD);
School of Women's and Children's, University of New South Wales, New South Wales, Sydney, Australia (A
Anazodo PhD);
Departments of Radiation Oncology and Pediatrics, University of Rochester Medical Center, Rochester, NY, USA
(L S Constine MD);
Department of Pediatric Hematology and Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam,
Netherlands (A de Vries MD);
Children's Hospital, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland (K
Jahnukainen MD);
Division of Urology, Hospital for Sick Children and Department of Surgery, University of Toronto, Toronto,
Ontario, Canada; Hospital for Sick Children, Toronto, Ontario, Canada (A Lorenzo MD);
Center for Reproductive Medicine and Department of Urology, Amsterdam UMC, University of Amsterdam,
Amsterdam, Netherlands (A Meissner PhD);
2
Department of Pediatrics, Division of Endocrinology and Center for Biobehavioral Health, The Ohio State
University/Nationwide Children's Hospital, Columbus, OH, USA (L Nahata MD);
Division of Andrology, Department of Urology, Erasmus MC University Medical Center Rotterdam, Rotterdam,
Netherlands (M Dinkelman-Smit PhD);
Centre for Reproductive Medicine, Free University of Brussels, Brussels, Belgium (Prof H Tournaye PhD);
Epidemiology and Biostatistics Unit and DOPO clinic, IRCCS Istituto Giannina Gaslini, Genova, Italy (R Haupt MD);
Department of Pediatric Hematology and Oncology, Erasmus MC-Sophia Children's Hospital, Rotterdam,
Netherlands (Prof M M van den Heuvel-Eibrink PhD);
Department of Pediatric Endocrinology, Wilhelmina Children's Hospital, UMC Utrecht, Utrecht, Netherlands (H
M van Santen PhD);
Laboratory for Reproductive Biology, Center for Reproductive Medicine, Amsterdam UMC (location AMC),
Amsterdam, Netherlands (Prof A M M van Pelt, PhD);
Department of Pediatrics III, West German Cancer Centre, University Hospital Essen, Germany (Prof U Driksen
PhD);
German Cancer Consortium (DKTK), partner site Essen, Germany (Prof U Dirksen PhD);
Dutch Childhood Cancer Parent Organization/VOX, Nieuwegein, Netherlands
(J den Hartogh MA);
Emma Children’s Hospital, Amsterdam UMC, Vrije Universiteit Amsterdam, Pediatric oncology, Amsterdam,
Netherlands (E van Dulmen-den Broeder PhD);
Department of Paediatric Haematology and Oncology, Royal Hospital for Sick Children, Edinburgh, UK (Prof W H
Wallace MD);
Division of Pediatric Hematology and Oncology, Weill Cornell Medicine, New York, NY, USA (J Levine MD)
Correspondence to:
Dr Renée Mulder, Princess Máxima Center for Pediatric Oncology, Heidelberglaan 25, 3584 CS Utrecht,
Netherlands
R.L.Mulder@prinsesmaximacentrum.nl
Keywords: Paediatric oncology, fertility preservation, CAYA, clinical practice guideline
Numbers:
Word count: 5136
Abstract word count: 160
Tables: 1
Figures: 2
3
Summary
Children, adolescent and young adult (CAYA) males with cancer are at an increased risk for infertility, if
their treatment adversely impacts reproductive organ function. Future fertility is a primary concern of
patients and their families. Variations in clinical practice are barriers to the timely implementation of
fertility preserving interventions. The PanCareLIFE consortium in collaboration with the International
Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG) reviewed the current literature
and developed a clinical practice guideline (CPG) for fertility preservation in male CAYA cancer patients
diagnosed before age 25 years, including guidance on risk assessment and available fertility preservation
methods. The GRADE (Grading of Recommendations Assessment, Development and Evaluation)
methodology was used to grade the evidence and recommendations. Recognizing the need for global
consensus, this CPG used existing evidence and international expertise to develop transparent, easy-to-
use and rigorously-developed recommendations that can facilitate the care of CAYA males with cancer
at risk of fertility impairment and enhance their quality of life.
4
Introduction
Advances in childhood cancer treatment have produced 5-year survival rates that exceed 80% in Europe
and the United States.
1-2
This progress has focussed attention on reducing the late effects of treatment
and optimizing future quality of life for the growing population of childhood, adolescent and young
adult (CAYA) cancer survivors. Male CAYA cancer patients are at increased risk for hypogonadism and
infertility if treatment includes gonadotoxic chemotherapy, radiotherapy to volumes exposing the testes
or hypothalamic-pituitary region and/or abdominal surgery that adversely impacts reproductive organ
function.
3-5
Impaired spermatogenesis and secondary sequelae of androgen deficiency can result in
reduced fertility or infertility.
6,7
Newly diagnosed male cancer patients, survivors and their parents
highly value biological children,
8
and for them fertility is a significant concern later in life.
9,10
Studies indicate that CAYA cancer patients are not always adequately counselled about the adverse
effects of cancer treatment on reproductive function and options for fertility preservation.
11-13
CAYAs
with cancer and their healthcare providers need accurate, evidence-based clinical practice guidelines
(CPGs) that provide personalized infertility risk assessment and guidance on fertility-preserving options
to facilitate informed decision-making. A previous report has shown that existing CPGs for fertility
preservation vary extensively and only about one-third are derived from rigorous methodology.
14
To
facilitate global consensus on this topic we present a systematic review and recommendations for
fertility preservation in male CAYA cancer patients diagnosed before the age of 25 years that have been
proposed by the European Union-funded research project PanCareLIFE
15
in collaboration with the
International Late Effects of Childhood Cancer Guideline Harmonization Group (IGHG).
16
Guideline panel formation
A multidisciplinary panel of 31 international experts in paediatric oncology/haematology, radiation
oncology, (paediatric) endocrinology, reproductive medicine, urology, andrology, psychology,
epidemiology and guideline methodology was convened (appendix p. 2-3). Members of the expert
panels were selected because of their experience, publications and knowledge in the fields of paediatric
and reproductive medicine. An overview of the guideline development process and the guideline
development structure are presented in the appendix (p. 4-5).
Scope and definitions
The aim of this CPG is to help healthcare providers to communicate the potential risk for hypogonadism
(impaired spermatogenesis, testosterone deficiency and central hypogonadism) and/or infertility and
options for fertility preservation to male patients diagnosed with childhood cancer tumour types before
age 25 years, and their parents, caregivers, or partners (hereafter referred to as families); and to provide