Implementation of a clinical long-term follow-up database for adult childhood cancer survivors in Germany - A feasibility study at two specialised late effects clinics

Abstract

Purpose: Childhood cancer survivors (CCS) are at risk for increased morbidity and reduced quality of life associated with treatment-related late effects. In Germany, however, only a few of the more than 40,000 CCS registered in the German Childhood Cancer Registry (GCCR) currently benefit from adequate clinical long-term follow-up (LTFU) structures. To establish a comprehensive knowledge base on CCS’ long-term health in Germany, a database was developed in cooperation with the GCCR. Following a first evaluation phase at two German university centres, this database will be implemented more widely within Germany allowing longitudinal documentation of clinical LTFU data.
Methods: The feasibility study cohort comprised 208 CCS aged 18 or older whose medical, mental and psychosocial health data were collected during routine LTFU or first clinic visits in adult care. CCS were enrolled from 04/2021 to 12/2022, and data entry was completed by 03/2023. Descriptive data analysis was conducted. All CCS were stratified into three risk groups (RG) based on their individual risk for developing late effects resulting from their respective diagnoses and treatments.
Results: Chronic health conditions of various organ systems associated with late and long-term effects of cancer therapy affected CCS in all RG supporting the clinical relevance of risk-adapted LTFU. Enrolment into the database was feasible and broadly accepted among CCS.
Conclusion: Implementation of a clinical follow-up care infrastructure and database in Germany will pave the way to collect clinically evaluated and regularly updated health data of potentially over 40,000 German CCS and facilitate future national and international cooperation.

Full text

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Implementation of a clinical long-term follow-up
database for adult childhood cancer survivors in
Germany - A feasibility study at two specialised late
effects clinics
Madelaine Sleimann
Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Luebeck
Magdalena Balcerek
Department of Paediatric Oncology and Haematology, Charité-Universitätsmedizin Berlin, Corporate
Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Chirine Cytera
Paediatric Haematology and Oncology, University Hospital of Schleswig-Holstein, Campus Luebeck
Franziska Richter
Paediatric Haematology and Oncology, University Hospital of Schleswig-Holstein, Campus Luebeck
Anja Borgmann-Staudt
Department of Paediatric Oncology and Haematology, Charité-Universitätsmedizin Berlin, Corporate
Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Bernhard Wörmann
Department of Haematology, Oncology and Tumor Immunology, Charité-Universitätsmedizin Berlin,
Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health
Lea Louisa Kronziel
Institute of Medical Biometry and Statistics, University of Luebeck
Gabriele Calaminus
Department of Paediatric Haematology/Oncology, University Hospital Bonn
Ann-Kristin Kock-Schoppenhauer
IT Center for Clinical Research, University of Luebeck
Desiree Grabow
German Childhood Cancer Registry, Institute of Medical Biostatistics, Epidemiology and Informatics
(IMBEI), University Medical Centre of the Johannes Gutenberg University Mainz
Katja Baust
Department of Paediatric Haematology/Oncology, University Hospital Bonn
Anke Neumann
IT Center for Clinical Research, University of Luebeck
Thorsten Langer
Paediatric Haematology and Oncology, University Hospital of Schleswig-Holstein, Campus Luebeck

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Judith Gebauer (  judith.gebauer@uksh.de )
Department of Internal Medicine I, University Hospital of Schleswig-Holstein, Campus Luebeck
Research Article
Keywords: health, quality of life, epidemiology, childhood cancer survivors, long-term follow-up, late
effects
Posted Date: July 13th, 2023
DOI: https://doi.org/10.21203/rs.3.rs-3147996/v1
License:   This work is licensed under a Creative Commons Attribution 4.0 International License. 
Read Full License

Page 3/25
Abstract
Purpose: Childhood cancer survivors (CCS) are at risk for increased morbidity and reduced quality of life
associated with treatment-related late effects. In Germany, however, only a few of the more than 40,000
CCS registered in the German Childhood Cancer Registry (GCCR) currently benet from adequate clinical
long-term follow-up (LTFU) structures. To establish a comprehensive knowledge base on CCS’ long-term
health in Germany, a database was developed in cooperation with the GCCR. Following a rst evaluation
phase at two German university centres, this database will be implemented more widely within Germany
allowing longitudinal documentation of clinical LTFU data.
Methods: The feasibility study cohort comprised 208 CCS aged 18 or older whose medical, mental and
psychosocial health data were collected during routine LTFU or rst clinic visits in adult care. CCS were
enrolled from 04/2021 to 12/2022, and data entry was completed by 03/2023. Descriptive data analysis
was conducted. All CCS were stratied into three risk groups (RG) based on their individual risk for
developing late effects resulting from their respective diagnoses and treatments.
Results: Chronic health conditions of various organ systems associated with late and long-term effects of
cancer therapy affected CCS in all RG supporting the clinical relevance of risk-adapted LTFU. Enrolment
into the database was feasible and broadly accepted among CCS.
Conclusion: Implementation of a clinical follow-up care infrastructure and database in Germany will pave
the way to collect clinically evaluated and regularly updated health data of potentially over 40,000
German CCS and facilitate future national and international cooperation.
Introduction
Long-term survival of childhood cancer has steadily increased during the last decades resulting in a
growing community of childhood cancer survivors (CCS) worldwide (Robison and Hudson 2014). As
many CCS face therapy-related chronic health conditions (“late effects”), adequate and risk-adapted
clinical long-term follow-up (LTFU) care that aims at timely diagnosis and treatment of late effects is
important to prevent subsequent morbidity and reduced health-related quality of life (Bhakta et al. 2017;
Dixon et al. 2018). Most LTFU recommendations are based on experiences from large CCS cohorts that
have been followed up regularly as part of regional or nationwide CCS programs (Kremer et al. 2013). At
the beginning of this century, one of the largest CCS cohorts, the multi-centre North-American Childhood
Cancer Survivor Study (CCSS), was established to facilitate research on long-term health outcomes in this
patient group (Robison et al. 2002). It started out with a survey of over 20,000 CCS who had been
diagnosed prior to the age of 21 between 1970 and 1986 and had survived for ve years or more (Wang
et al. 2022). The CCSS continues to assess various health issues in this expanding cohort of currently
over 35,000 CCS. In addition, a clinical follow-up program (SJLIFE) was set up, initially including over
9,000 adult 10-year CCS originally treated at St. Jude Children´s Research Hospital, who periodically
return to Memphis for comprehensive clinical evaluations (Hudson et al. 2011). Similar programs have

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been set up in several European countries such as the Netherlands (Winther et al. 2015; Feijen et al.
2023).
In Germany, since 1980, childhood cancer-related data of all children and adolescents with cancer have
been routinely collected by the German Childhood Cancer Registry (GCCR), embedded in the Division of
Childhood Cancer Epidemiology (EpiKiK) at the University Medical Centre of Mainz of Johannes
Gutenberg University. The GCCR-based cohort now exceeds 40,000 ve-year CCS (Kaatsch et al. 2022). At
least every ve years, the GCCR carries out questionnaire-based follow-up on relapses and subsequent
neoplasms as part of mandated duties (Kaatsch et al. 2022; Erdmann et al. 2020; Grabow et al. 2011;
Langer et al. 2018). In addition, EpiKiK/GCCR-aliated investigators have initiated and collaborate on
numerous (inter)national studies on long-term health-related outcomes (Kaatsch et al. 2022; Byrne et al.
2022; van den Oever et al. 2023; Kaatsch, Byrne, and Grabow 2021; Aleshchenko et al. 2022; Botta et al.
2022).
Multidisciplinary LTFU clinics have been established at several university clinics in Germany recently
(Gebauer et al. 2018), offering specialised and risk-adapted surveillance in CCS according to current
guidelines (Gebauer et al. 2020). During CCS’ routine LTFU clinic visits, data on their current health status
is routinely collected. We intend to document this clinically validated and prospectively assessed
information comprehensively in a common database. These data can serve as a basis for future
cooperation in national and international projects on chronic health conditions in CCS and facilitate joint
analysis with CCS cohorts from other countries. We now present this clinical LTFU database including an
analysis of the data collected during a rst evaluation phase.
MATERIAL AND METHODS
The database includes seven categories on CCS’ health and psychosocial status as well as on previous
cancer disease(s) and corresponding treatment. The categories are based on common late effects
addressed in LTFU guidelines (van Kalsbeek et al. 2021) and allow free text entry for the documentation
of rare chronic health conditions. Subcategories include further specications of diseases according to
standard diagnostic procedures and, if applicable, to the International Classication of Diseases (ICD)
(Harrison et al. 2021).
Following a pre-test in Luebeck in 2018 (Gebauer et al. 2018), the clinical LTFU database was modied
for technical and pragmatic reasons before a rst evaluation period. From April 2021 until December
2022, all CCS who survived ≥ 5 years after rst cancer diagnosis and attended the LTFU clinics in
Luebeck and Berlin were asked to provide their written informed consent for inclusion of their data in the
database. This study was approved by the ethics committee of the University to Luebeck (registration
number 180 − 87) and the ethics committee in Berlin waived this requirement.
Depending on the type of information, required data were entered into the database either once or
repeatedly during each LTFU clinic visit. Risk-adapted LTFU in the participating clinics was carried out
according to published guidelines (Gebauer et al. 2020) and served as the basis for the documentation of

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clinical data. At inclusion into the database, participants were asked to complete ve validated self-report
questionnaires and one questionnaire on their living situation via a study tablet to assess mental health,
psychosocial burden and fatigue (Table1). Information from the tablet was automatically transferred to
the database following data protection guidelines. Psychologists or social workers specialised in LTFU
assessed the psychosocial status of the CCS during the LTFU visit considering the answers to the
questionnaires to identify if further support was required.

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Table 1
Content of the clinical long-term follow-up (LTFU) database for German childhood cancer survivors.
Category Content Frequency
Cancer diagnosis and treatment information required for risk stratication
Initial cancer diagnosisa• Cancer entity
• Treatment details
Once
Relapse
(initial cancer diagnosis)a
• Time and localisation of relapse
• Treatment of relapse
Once for each
relapse
Subsequent cancera• Cancer entity
• Treatment details
Once for each
subsequent cancer
Relapse of subsequent cancera• Time and localisation of relapse
• Treatment of relapse
Once for each
relapse of each
subsequent cancer
Health outcomes

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Category Content Frequency
Cancer diagnosis and treatment information required for risk stratication
Clinical examination and chronic
diseasesa
• Results of physical examination
Assessment of:
• Endocrine/metabolic diseases
• Cardiac diseases
• Pulmonary diseases
• Liver diseases
• Renal diseases
• Gastrointestinal disorders
• Immunodeciency/ splenic
dysfunction
• Skin disorders
• Haematological diseases
• Hearing/ Visual impairment
• Substance abuse
• Medical history
• Vaccination record
• Medications
• Movement disorders
• (Neuro)psychiatric diseases
• Dental disorders
• Subsequent neoplasms (benign)
Every LTFU clinic
visit
Family history/ geneticsa• Tumour predisposition syndrome
• Cardiovascular disease and cancer in
rst-degree relatives
Once and in case
of change
Psychosocial historya• Content of consultation
• Need for further support/therapy
Every LTFU clinic
visit

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Category Content Frequency
Cancer diagnosis and treatment information required for risk stratication
Living situationb• Marital status
• Education/ employment
• Parenthood/ fertility
• Degree of disability
Every LTFU clinic
visit
(RG1: Once and
after ve years)
PHQ-9-D (Gräfe et al. 2004)b• Depression severity Once and after ve
years
GAD-7 (Spitzer et al. 2006)b• Generalised anxiety disorder Once and after ve
years
NCCN Distress-Thermometer
(Mehnert et al. 2006)b
• Distress due to problems in 5 areas of
life: practical, family, emotional,
spiritual/religious, and physical problems
Every LTFU clinic
visit (RG1: Once
and after ve
years)
IES-R (Maercker and Schützwohl
1998)b
• Post-traumatic stress disorder (PTSD)
symptoms Once and after ve
years
EORTC QLQ-C30 (Aaronson et al.
1993; Giesinger et al. 2020) and -
FA12 (Weis et al. 2017)b
• Quality of life in cancer patients and
cancer-related fatigue Once and after ve
years
acompleted from available clinical records at rst clinical follow-up; bcompleted by the patient via tablet;
RG1 = risk group 1 (for details see Risk group (RG) stratication within Materials and Methods); PHQ-D =
Patient Health Questionnaire – German version, includes PHQ-9-D (on depression) and GAD-7 =
Generalised Anxiety Disorder (on anxiety); NCCN = National Comprehensive Cancer Network (U.S.); IES-R
= Impact of Event-Scale revised; EORTC QLQ-C30 = EORTC Core Quality of Life of Cancer Patients; EORTC
QLQ-FA12 = EORTC Module Cancer related Fatigue.
Risk group (RG) stratication
A previously published denition of RG based on former risk stratication models (Frobisher et al. 2017)
and adopted to the German health care system (Gebauer et al. 2020) was used to stratify CCS according
to their risk for late effects. RG1 with a low risk for developing late effects comprises CCS who had only
required surgical therapy (with exception of CCS with a central nervous system (CNS) tumour) as well as
CCS of acute lymphatic leukaemia (ALL) or non-hereditary retinoblastoma who received chemotherapy
only. CCS with intermediate risk for late effects (RG2) had received chemotherapy (excluding ALL and
non-hereditary retinoblastoma) or, in case of a CNS tumour, had merely undergone surgical therapy. RG3
includes CCS at high(er) risk for late effects, such as after haematopoietic stem cell transplantation
and/or irradiation.

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Statistical analysis
Statistical analyses were conducted using SPSS IBM Version 29. Descriptive statistics were carried out
for CCS whose data were completed in the database until March 22, 2023. All continuous variables are
presented as means and standard deviations (SD) and as median values and interquartile ranges (IQR).
Comparisons according to RG and for numerical variables were made using Kruskal-Wallis-Test to
compare means of metric variables such as age and body mass index, for which data were not normally
distributed, and chi-square-test for other non-metric variables. Generated asymptotic p-values are of
purely descriptive nature. Cancer diagnoses were grouped into main categories for analyses (see
Table2). Survivors of a malignancy in adulthood, who, considering the nature of their diagnoses, had
required treatment in paediatric oncology (e.g. young adults with medulloblastoma), were included in the
analyses.
In case the day of cancer diagnosis was missing, it was replaced by the rst day of the month. If the
month was missing, it was set as January. Missing years were analysed as missing data.
Additional to describing general patient characteristics, we present the database by assessing data on
health conditions in CCS at time of (rst) database entry according to organ system and by RG. Late
effects are also presented by the number of affected (organ) systems per patient in the respective RG.
Further health-related information, e.g. family history, genetic tumour predisposition, cardiovascular risk
prole as well as detailed information on mental health and psychosocial status, have also been
documented in the database (see Table1) and will be evaluated in a prospective fashion in future
observational studies and embedded trials. For this rst evaluation, we decided to focus on somatic
health conditions.
RESULTS
Participant characteristics
Overall, 208 patients out of 212 agreed to participate in the study (response rate: 98,1%). Mean age of
patients at enrolment into the study was 26.5 years (range 18.0–60.0), of which the majority were young
adults aged 18–24 years (62.5%). On average, 16.4 years (range 5.0-57.7) had passed since cancer
diagnosis. Detailed patient characteristics are presented in Table 2. CCS in our cohort were mainly
diagnosed with leukaemia (36.5%) or lymphoma (26.4%) in childhood or adolescence, while 13.9% had
previously suffered from a brain tumour (Fig. 1). According to RG stratication 19.2% of participating
patients had a low (RG1), 25.0% an intermediate (RG2) and 55.8% a high risk (RG3) for late effects
following their cancer treatment (Table 2).


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Table 2
General characteristics of adult childhood cancer survivors enrolled into the database between 04/2021-
12/2022 (n = 208).
MD Total
Characteristics  
Age at Time of Inclusiona[years] 0 
Mean ± SD (Range)  26.5 ± 10.3 (18.0–60.0)
Median (IQR)  21.6 (14.2)
Sex [n] 0 
Female  120 (57.7%)
Male  88 (42.3%)
Risk Group [n] 0 
1 - Low Risk for Late Effects  40 (19.2%)
2 - Intermediate Risk for Late Effects  52 (25.0%)
3 - High Risk for Late Effects  116 (55.8%)
Oncological Diagnosis [n] 0 
Leukaemia  76 (36.5%)
Lymphoma  55 (26.4%)
Central Nervous System Tumour  31 (13.9%)
Bone & Soft-Tissue Tumour  20 (9.6%)
Embryonal Tumour  12 (5.8%)
Othersb 16 (7.7%)
Age at Time of Diagnosis [years] 1 
Mean ± SD (Range)  10.0 ± 6.8 (0.0-34.7)
Median (IQR)  9.3 (10.1)
Year of Diagnosis [n] 1c
1961–1980  8 (3.9%)
1981–2000  54 (26.1%)
2001–2017  145 (70.0%)

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MD Total
Characteristics  
Time since Diagnosisd[years]/[n] 1 
Mean ± SD (Range)  16.4 ± 9.5 (5.0-57.7)
Median (IQR)  14.6 (12.2)
5 years  11 (5.3%)
6–10 years  60 (29.0%)
11–15 years  49 (23.7%)
> 15 years  87 (42.0%)
Treatment Details [n/N]  
Surgical Therapy, yes 73 73/135 (54.1%)
Chemotherapy, yes 23 173/185 (93.5%)
Irradiation, yes 0 85/208 (40.9%)
Mean Dose [Gy] 11 31.69 ± 17.76 (12.00–
72.00)
First Haematopoietic Stem Cell Transplantation, yes 0 19/208 (9.1%)
Autologous  8/19 (42.1%)
Allogenic  11/19 (57.9%)
Chronic Graft-versus-Host Disease, yes 15 1/4 (25.0%)
Antibody Therapy, yes 90 1/118 (0.8%)
Endocrine Therapy, yes 92 0/116 (0.0%)
First Relapse  
yes [n] 0 32 (15.4%)
Age at Time of Relapse Diagnosis [years] 0 
Mean ± SD (Range)  11.1 ± 7.3 (1.4–27.5)
Median (IQR)  11.0 (11.4)
Time since Primary Diagnosis [years] 0 
Mean ± SD (Range)  2.7 ± 2.6 (0.5–13.5)
Median (IQR)  1.8 (2.2)

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MD Total
Characteristics  
Relapse occurred following primary therapy, yes 17 15/15 (100.0%)
Relapse Diagnosis 1 
Relapse of Primary Oncological Disease  28/31 (90.3%)
Type of Relapse Diagnosis 26 
Local  5/6 (83.3%)
Metastasised  1/6 (16.7%)
Disseminated  0
Subsequent Neoplasm 0 
Yes [n]  12 (5.8%)
1 Subsequent Neoplasm  9 (4.3%)
2 Subsequent Neoplasms  2 (1.0%)
3 Subsequent Neoplasms  1 (0.5%)
Age at Time of First Subsequent Neoplasm [years] 0 
Mean ± SD (Range)  35.5 ± 13.9 (10.5–58.7)
Median (IQR)  34.4 (16.8)
Time since Primary Diagnosis to First Subsequent Neoplasm
[years] 0 
Mean ± SD (Range)  22.3 ± 9.4 (7.3–37.3)
Median (IQR)  23.7 (15.4)
Type of First Subsequent Neoplasm 0 
Skin Cancer  6/12 (50.0%)
Cancer of Gender-Specic Organs  3 (25.0%)
Lymphoma  1 (8.3%)
Central Nervous System Tumour  1 (8.3%)
Small Bowel Cancer  1 (8.3%)
Relapse of Subsequent Neoplasm 1 3 (25.0%)

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MD: missing data; SD: standard deviation; IQR: interquartile range; a referring to age at time of rst
clinical follow-up examination; bothers: extracranial germ cell tumour, neuroendocrine tumour, adrenal
cortex tumour, colon cancer, Langerhans cell histiocytosis. cDespite missing year of diagnosis, this
patient is still evaluable as part of the study as per the inclusion criteria considering their date of
clinical/oncological examination was documented as 2016, presupposing cancer diagnosis prior to that
(> 5 years since diagnosis). dtimespan between dates of primary oncological diagnosis and rst clinical
follow-up examination. Percentages may not add up to 100% due to rounding; percentages of same
absolute numbers might differ as only valid values were analysed per variable.
Health conditions in CCS according to RG and organ system
Chronic health conditions were documented in a considerable number of CCS (Table 3). Endocrinological
disorders were found in half of all CCS documented in the database (113/208, 54.3%). For a third of our
cohort (75/207, 36.2%) at least one cardiovascular health condition was documented, and about a fth
of CCS had a degree of disability (20/95, 21.1%).
Table 3: Health conditions in adult childhood cancer survivors documented from medical records,
presented per organ system and risk group (RG).

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MD RG1 (n=40) RG2 (n = 52) RG3 (n =
116) Total (= 208) p-
Value*
Age at Time of
Inclusiona
0     
Mean ± SD
(Range)  19.5 ± 3.3
(18.0-37.1) 24.6 ± 8.9
(18.0-54.1) 29.8 ± 11.2
(18.0–60.0) 26.5 ± 10.3
(18.0–60.0) <
0.001
Median (IQR)  18.7 (0.7) 20.8 (8.4) 25.1 (16.9) 21.6 (14.2) 
Lifestyle
Variables      
Body Mass
Indexb[kg/m2] /
[n]
4     
Mean ± SD
(Range)  23.31 ± 5.51
(15.02–
36.44)
24.87 ± 6.70
(15.24–
54.69)
23.77 ± 5.17
(13.81–
49.25)
23.96 ± 5.65
(13.81–
54.69)
0.402
Median (IQR)  21.27 (6.88) 22.73 (7.61) 22.94 (6.58) 22.50 (6.83) 
Underweightb 5 (12.8%) 4 (7.8%) 15 (13.2%) 24 (11.8%) 
Normal Weightb 22 (56.4%) 28 (54.9%) 56 (49.1%) 106 (52.0%) 
Overweightb 7 (17.9%) 10 (19.6%) 30 (26.3%) 47 (23.0%) 
Obesitiyb 5 (12.8%) 9 (17.6%) 13 (11.4%) 27 (13.2%) 
Substance Usec     
Nicotine 0     
Yes  1/7 (14.3%) 4/37 (10.8%) 13/98
(13.3%) 18/142
(12.7%) 0.894
No  6/7 (85.7%) 33/37
(89.2%) 81/98
(82.7%) 120/142
(84.5%) 0.894
Not examined  0 (0.0%) 0 (0.0%) 4/98 (4.1%) 4/142 (2.8%) 
Alcohold0     
Yes  4/7 (57.1%) 26/37
(70.3%) 61/98
(62.2%) 91/142
(64.1%) 0.742
No  3/7 (42.9%) 11/37
(29.7%) 33/98
(33.7%) 47/142
(33.1%) 0.742
Not examined  0 (0.0%) 0 (0.0%) 4/98 (4.1%) 4/142 (2.8%) 

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MD RG1 (n=40) RG2 (n = 52) RG3 (n =
116) Total (= 208) p-
Value*
Complete
Vaccination
Statuse
3     
Yes  8 (20.0%) 26 (51.0%) 46 (40.4%) 80 (39.0%) 0.093
No  1 (2.5%) 2 (3.9%) 16 (14.0%) 19 (9.3%) 0.093
Unknown  13 (32.5%) 14 (27.5%) 34 (29.8%) 61 (29.8%) 
Not examined  18 (45.0%) 9 (17.6%) 18 (15.8%) 45 (22.0%) 
Organ System Affected by at least One Health Condition, yes
Endocrinological
Disorders 0 11 (27.5%) 22 (42.3%) 80 (69.0%) 113 (54.3%) <
0.001
Cardiovascular
Disorders 1 9 (22.5%) 11 (21.2%) 55 (47.8%) 75 (36.2%) 0.007
Pulmonary
Diseases 0 4 (10.0%) 7 (13.5%) 14 (12.1%) 25 (12.0%) 0.879
Liver Diseases 0 2 (7.5%) 4 (7.7%) 14 (12.1%) 21 (10.1%) 0.639
Kidney Diseases 0 1 (2.5%) 6 (11.5%) 11 (9.5%) 18 (8.7%) 0.280
Gut Disorders 1 5 (12.5%) 9 (17.3%) 32 (27.8%) 46 (22.2%) 0.071
Ear-Nose-Throat
Disorders 2 0 (0.0%) 6 (11.8%) 24 (20.7%) 30 (14.6%) 0.006
Eye Disordersf1 0 (0.0%) 2 (3.8%) 6 (5.2%) 8 (3.9%) 0.337
Dental Status 1 2 (5.0%) 4 (7.7%) 25 (21.7%) 31 (15.0%) 0.068
Neurological
Disorders 0 1 (2.5%) 9 (17.3%) 17 (14.7%) 27 (13.0%) 0.077
Psychological
Disordersg
0 0 (0.0%) 2 (3.8%) 10 (8.6%) 12 (5.8%) 0.096
Recognised
Degree of
Disability
113 2 (5.7%) 6 (21.4%) 12 (37.5%) 20 (21.1%) 0.003
Subsequent
Neoplasm 0 1 (2.5%) 0 (0.0%) 11 (9.5%) 12 (5.8%) 0.035
Occurrence of health conditions in CCS differed among RG. In most categories, disorders consistently
affected more CCS allocated to RG3 than CCS of RG1 or RG2 (Table 3). Overall, the number of affected
organ systems increased with each RG (Fig. 1).

Page 16/25
Information from the database also allows a breakdown of single conditions within one organ system,
e.g. specication of 11 different endocrinological conditions (Fig. 2).
Number of endocrinological conditions ranged from 0–5 per CCS, with the majority having at least one
specic condition (Fig. 3). While two-thirds of CCS of RG1 had no endocrinological disorders and none
had more than two, CCS of RG2 and RG3 suffered from up to three and ve endocrinological conditions,
respectively, with a lower proportion of CCS having none.
Furthermore, each subcategory was divided into several specications providing detailed information on
CCS’ health status. As an example, bone status comprised “unremarkable” (114/206, 55.3%), “vitamin D
deciency” (81/206, 39.3%), “osteopenia” (9/206, 4.4%), “osteoporosis” (3/206, 1.5%), “osteonecrosis”
(3/206, 1.5%) and “not examined” (3/206, 1.5%). Percentages add up to more than 100% due to multiple
selections (conditions) being possible per patient.
DISCUSSION
Long-term health consequences of cancer and its therapy affect most CCS, resulting in a reduced health-
related quality of life and life expectancy in this growing cohort (Byrne et al. 2022; van Erp et al. 2021).
Comprehensive risk-based care facilitates timely diagnosis and treatment of late effects and is
recommended in numerous guidelines (Frobisher et al. 2017; Kremer et al. 2013). These
recommendations are based on regularly updated, extensive analyses of CCS’ health status during LTFU.
For some late effects specic surveillance strategies are lacking as reliable data on occurrence and
complications of some chronic health conditions are not available yet (Bowers et al. 2021).
Recommendations in favor of or against surveillance modalities, however, require careful balancing of
potential benets and harms (Clement et al. 2018; Heinzel et al. 2022). Prospectively documented and
evaluated late effects in nationwide CCS cohorts can ll these knowledge gaps (Yeh et al. 2022) and
serve as a basis for future joint projects. In several countries national cohorts of CCS, who are regularly
followed up by questionnaire surveys or clinically in specialised LTFU clinics, have been established
(Winther et al. 2015). To provide comprehensive information on CCS’ health status in Germany, which
goes beyond the current regular follow-up on subsequent neoplasms and relapses conducted by the
GCCR, a database was created to support standardised prospective and longitudinal clinical data
collection from routine LTFU assessments. Generally, acceptance of the database was successful in both
participating clinics with almost all eligible CCS participating in this feasibility study.
Nationwide implementation of this database over the following years will provide clinically evaluated and
regularly updated health data of potentially over 40,000 German CCS. These prospectively collected data
can contribute to larger international analyses of CCS data, thus creating the basis for better tailored and
individualised, risk-adapted LTFU recommendations.
According to the risk stratication approach (Frobisher et al. 2017) which was applied to our cohort, a
considerable larger proportion of CCS allocated to RG3 (high risk for late effects) suffered from chronic
health conditions than CCS of RG1 (low risk) and RG2 (intermediate risk). This difference is most

Page 17/25
pronounced for occurrence of endocrinological and cardiovascular disorders, as well as ear-nose-throat
disorders, degree of disability and occurrence of subsequent neoplasms thus supporting the clinical
relevance of the proposed risk stratication. Yet, it also needs to be considered that CCS in RG3 were
generally older, so time since treatment was longest in this group. This limitation in this rst data analysis
will potentially be diminished once the cohort documented in the database exceeds a higher number of
CCS. Number of health conditions with time increased in our cohort as has also been previously
described (Suh et al. 2020), emphasising the necessity of LTFU, potentially life-long. However, our
ndings also demonstrate an already high number of chronic health conditions in a cohort of young adult
CCS, illustrated e. g. by a high occurrence of endocrinological disorders, which is in line with previous
work and underlines the need for regular, life-long surveillance from the beginning of survivorship on
(Bhakta et al. 2017; Brignardello et al. 2013).
LTFU aims at holistic health assessment. The database correspondingly includes data on physical and
mental health conditions, assessment of general health information such as vaccination record, medical
history and substance use as well as psychosocial and socioeconomic parameters. Analyses of this data
provide an overview of the CCS’ characteristics as well as overall and in-depth assessment of their health
status, e.g. alongside the documentation of organ systems affected by health conditions, also their type
and extent are documented. Specic information on health care provision derived from data analyses can
be directly transferred back into LTFU care and support its improvement by adapting to CCS’ needs.
To optimise data quality for future projects, careful consideration of possible imprecisions and errors in
data assessment and documentation was conducted. In this context, some limitations were detected, e.g.
some variables generating high numbers of missing data due to a missing “no” option. Interpretation of
such missings as negation might distort results. For this rst analysis within the feasibility study, we
regard our approach as justiable, seeing as ndings in the affected variables would have likely been
entered into the database had they been clear and available. For example, we argue that a relapse, had it
occurred, would have been documented. For future use and implementation a “no” option was added to
these variables; for “infertility” the variable “no clinical and laboratory evidence of infertility” will be added
to the assessment. In addition, occurrence of hypogonadism could not be evaluated in women taking
contraceptives if no further medical history was available. That is why our numbers might differ from
expected prevalences from former studies (Mostou-Moab et al. 2016). Careful documentation of
medical history and medications is essential to generate plausible data. A checklist will be forwarded to
all participating LTFU centres to ensure complete data acquisition and to minimise missing data (Online
Resource 1). Furthermore, to prevent systematic errors in data entry, a database manual containing
background information on respective variables was provided and will be adapted for all future study
centres. All identied limitations will be addressed in a database update to optimise future analyses.
CONCLUSION AND OUTLOOK
Risk-adapted clinical LTFU is crucial for CCS to ensure early detection of late effects of cancer treatment.
However, in Germany not all CCS benet from such LTFU. Current structures need to be expanded to

Page 18/25
guarantee optimal health monitoring in all CCS. Our database enables a comprehensive assessment of
health status in German CCS, including both general and detailed analyses of health aspects. Following a
feasibility study in two LTFU clinics, data of further CCS that receive LTFU in German LTFU centres will be
documented. Additionally, our database will be implemented in over ten centres in Germany as part of the
prospective LE-Na trial (Evaluation and implementation of multidisciplinary, standardised, guideline-
based long-term follow-up care for adult survivors of childhood cancer in Germany) which started in
January 2023. During the study period of 5 years, over 5,000 CCS who have not received standardised
LTFU yet, will be invited to attend LTFU care in participating centres and asked for their data to be
documented in the database. This comprehensive base on validated and prospectively collected CCS
LTFU data will improve ongoing LTFU care and facilitate future national and international collaboration
and research.
STATEMENTS & DECLARATIONS
Acknowledgements
This work was funded by the “Lübeck-Hilfe für krebskranke Kinder e.V.”.
We thank Stefanie Braun, Lea Hildebrand, Anne-Kathrin Jahnke, Wiebke Stritter and Jana Vachek for their
assistance with recruitment and documentation of study participants in the database as well as Samuel
Hahn for his assistance with our list of references for psychosocial questionnaires and Cécile Ronckers
for her assistance with manuscript preparation and revisions.
Funding
This work was supported by the “Lübeck-Hilfe für krebskranke Kinder e.V.”.
Competing Interests
The authors declare that they have no conicts of interest.
Author Contributions
Conceptualisation: Judith Gebauer, Thorsten Langer; Methodology: Madelaine Sleimann, Magdalena
Balcerek, Judith Gebauer; Software: Ann-Kristin Kock-Schoppenhauer, Anke Neumann; Formal analysis:
Madelaine Sleimann, Magdalena Balcerek, Lea Louisa Kronziel; Investigation: Madelaine Sleimann,
Franziska Richter; Resources: Ann-Kristin-Kock Schoppenhauer, Anke Neumann; Data curation: Madelaine
Sleimann; Writing – Original Draft: Madelaine Sleimann, Magdalena Balcerek, Judith Gebauer; Writing –
Review & Editing: Madelaine Sleimann, Magdalena Balcerek, Chirine Cytera, Franziska Richter, Anja
Borgmann-Staudt, Bernhard Wörmann, Lea Louisa Kronziel, Gabriele Calaminus, Ann-Kristin Kock-
Schoppenhauer, Desiree Grabow, Katja Baust, Anke Neumann, Thorsten Langer, Judith Gebauer;
Visualisation: Madelaine Sleimann; Supervision: Thorsten Langer, Judith Gebauer; Project administration:
Chirine Cytera; Funding acquisition: Thorsten Langer, Judith Gebauer.

Page 19/25
Data Availability
The anonymised data that support the ndings of this study are available from the corresponding author
upon reasonable request.
COMPLIANCE WITH ETHICAL STANDARDS
Ethics Approval
This study was performed in line with the principles of the Declaration of Helsinki.Approval was granted
by the Ethics Committee of University to Luebeck (registration number 180-87) and the Ethics Committee
in Berlin waived this requirement.
Consent to participate
Informed consent was obtained from all individual participants included in the study.
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Figures

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Figure 1
Rate of number of organ systems affected by health conditions documented in the database per
childhood cancer survivor (CCS). RG1: low risk, RG2: intermediate risk, RG3: high risk for late effects.
Order of legend labels/sections of respective bars: from bottom (“0 affected organ systems”) to top (“8
affected organ systems”)

Page 24/25
Figure 2
Endocrinological conditions in childhood cancer survivors (CCS) presented by risk group (RG). RG1: low
risk, RG2: intermediate risk, RG3: high risk for late effects. Order of legend labels of respective bars within
conditions: from top (“RG1”) to bottom (“Total”). a: only medically conrmed cases of infertility; b:
excluding cases with growth hormone deciency only; c: Bone status of survivors, for whom only vitamin
D deciency was selected, was regarded as unremarkable for statistical analysis of endocrinological
conditions so as not to distort the results

Page 25/25
Figure 3
Rate of number of endocrinological disorders documented in the database per childhood cancer survivor
(CCS). RG1: low risk, RG2: intermediate risk, RG3: high risk for late effects. Order of legend
labels/sections of respective bars: from bottom (“0 endocrinological disorders”) to top (“5
endocrinological disorders”).
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