Consideraciones de seguridad y diseño

First author: Friederike Erdmann

Order of authors: Friederike Erdmann, Jeanette Falck Winther, Susanne Oksbjerg Dalton, Tracy Lightfoot, Hajo Zeeb, Karen Sofie Simony, Isabelle Deltour, Gilles Ferro, Andrea Bautz, Kjeld Schmiegelow, Joachim Schüz

Contribution statement: FE and JS developed the study concept and design. JS, JFW, FE, TL, AB and GF contributed to the data collection and AB and GF helped with the data

management. FE conducted the statistical data analyses. FE, JS, JFW, KS, SOD, HZ, ID, TL and KSS participated in the interpretation of the results. FE prepared the first draft of the

manuscript. FE, JS, JFW, KS, SOD, HZ, ID, TL and KSS revised it critically for intellectual content. All authors read and approved the final version of the manuscript.

Manuscript statistics:3,800 words (abstract: 200); 2 tables; 2 figure

Family characteristics and survival from childhood

haematological malignancies in Denmark, 1973-2006

Friederike Erdmann1_{, Jeanette Falck Winther}2_{, Susanne Oksbjerg Dalton}2_{, Tracy}

Lightfoot3_{, Hajo Zeeb}4_{, Karen Sofie Simony}2_{, Isabelle Deltour}1_{,Gilles Ferro}1_,Andrea.

Bautz2_{,Kjeld Schmiegelow}5_{, Joachim Schüz}1

1_{Section of Environment and Radiation, International Agency for Research on Cancer}

(IARC), 150 Cours Albert Thomas, 69372 Lyon, France

2_{Survivorship Unit, Danish Cancer Society Research Center, 2100 Copenhagen, Denmark}

3_{Epidemiology & Cancer Statistics Group, Department of Health Sciences, University of}

York, Seebohm Rowntree Building, Heslington, York YO10 5DD, UK

4_{Department of Prevention and Evaluation, Leibniz - Institute for Prevention Research and}

Epidemiology - BIPS GmbH, Achterstraße 30, 28359 Bremen, Germany

5_{Department of Pediatrics & Adolescent Medicine, University Hospital Rigshospitalet,}

2100 Copenhagen, Denmark

Corresponding author: Friederike Erdmann, MPH

Section of Environment and Radiation

International Agency for Research on Cancer (IARC) 150 Cours Albert Thomas

69372 Lyon Cedex 08, France Tel. +33 (0)4 72 73 84 63 Fax +33 (0)4 72 73 83 20

Manuscript statistics:

3 800 words (abstract: 200); 2 tables; 2 figures

Short running title:

Family factors and childhood haematological malignancies survival

Key words:

Childhood haematological malignancies; Acute lymphoblastic leukaemia, Acute myeloid leukaemia, Lymphoma; Non-Hodgkin lymphoma, Survival; Family characteristics; Birth order; Number of siblings; Parental age; Place of residence

Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.

Acknowledgements:

No specific funding was received for this study. Costs for obtaining data were covered by a collaboration agreement between the International Agency for Research on Cancer and the Danish Cancer Society Research Center.

Abstract

Little is known about the role of family characteristics on survival from childhood

haematological malignancies, which we studied in a nationwide cohort of Danish children. All children with haematological malignancies born and diagnosed between 1973 and 2006 before the age of 20 years (N=1 819) were followed for 10 years. Cox proportional hazards models estimating hazard ratios (HR) and 95% confidence intervals (CI) were calculated. Increasing birth order and having siblings was associated with worse survival from acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML); the associations with AML were stronger and statistically significant. HRs of 1.62 (CI 0.85;

3.09) and of 5.76 (CI 2.01; 16.51) were observed for 4th _{or later born children with ALL and}

AML, respectively. Children with older parents showed a tendency of inferior ALL survival, while for AML young maternal age was related to poorer survival. Based on small

numbers, NHL survival showed associations with having siblings and with parental age. Overall, results for the full cohort were similar to those diagnosed from 1990 onwards. Family characteristics may have an impact on survival from haematological malignancies in Danish children. Further research should elaborate potential underlying mechanisms, in particular adherence to therapy and physicians-parents interaction.

Introduction

Childhood haematological cancers are a heterogeneous group of malignancies, treated differently and with dissimilar prognosis (1). Over the past decades, advances in tumour biology, risk grouping, and pharmacology have led to substantial improvements in treatment of childhood cancers in particular for acute lymphoblastic leukaemia (ALL) and non-Hodgkin lymphoma (NHL)(1-3). Diagnostic procedures and treatment protocols are nowadays largely standardized within developed countries (3-8). In the Nordic countries treatment of childhood cancers has virtually been identical since the early 1990s (3, 5, 6). Almost all paediatric haematological malignancy patients are treated according to the treatment schemes developed by the collaborative study group NOPHO (Nordic Society of Paediatric Haematology and Oncology) (3, 5, 6) with specific treatment protocols

depending on type, prognostic risk group and stage of cancer.

One of the basic principles of the Danish welfare system is equal rights to social security for all citizens, including benefits for families with children as well as tax-funded free health care services.(9) Childhood cancer treatment is centralized to four highly specialized paediatric oncology centres that offer uniform diagnostics and treatment independently of family circumstances or socioeconomic background. Therefore it would be expected that there are fairly equal survival rates across social groups and

independent of family circumstances. However, besides physician’s compliance to the treatment protocols, parents’ and child’s adherence to the treatment and supportive care as well as the interaction between families and physicians may affect survival.

For adult cancers in Denmark, it is well established that socioeconomic characteristics influence survival, with cancer patients with higher education or higher income reaching superior survival rates (10). Little is known about the potential role of social conditions and family circumstances on childhood cancer survival. Only one ongoing study addressed survival differences related to socioeconomic position in Danish children(11).