COMPRehensive Assessment of Prevalence, Risk Factors and Mechanisms of Impaired Medical and Psychosocial Health Outcomes Among Adolescents and Young Adults With Cancer: the Prospective Observational COMPRAYA Cohort Study
Conditions: Second Cancer, Survivorship, Fertility Issues, Distress, Emotional, Lifestyle, Genetic Disease, Cancer
Sponsor: The Netherlands Cancer Institute

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COMPRAYA  
 
 
 
 
 
 
 
COMPRehensive assessment of prevalence, risk factors and 
mechanisms of impaired medical and psychosocial health 
outcomes among Adolescents and Young Adults with cancer: the 
prospective observational COMPRAYA cohort study 
Version 1.3; 15 September 2020 
 
 
 
 
 
 

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COMPRAYA  
 
 
 
 
Protocol ID 
M20COM 
Short title 
The COMPRAYA study 
EudraCT number  
Not applicable 
Version 
1.3 
Date 
15 September 2020 
Project leader 
 
 
 
 
 
 
 
Study manager 
Prof. Winette van der Graaf,  Medical oncologist 
Netherlands Cancer Institute – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Department of Medical Oncology 
w.vd.graaf@nki.nl 
+31 20 512 6979 
 
Dr. Renske Fles  
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Department of Medical Oncology 
r.fles@nki.nl 
+31 20 512 6993 
Principal investigator(s) 
(in Dutch: hoofdonder-
zoeker/ uitvoerder) 
Dr. Olga Husson, Netherlands Cancer Institute– Antoni van 
Leeuwenhoek Hospital (NKI-AvL), Department of Medical On-
cology 
Per site:  
  
Radboud Universitair Me-
disch Centrum (Radbou-
dUMC) 
Dr. Suzanne Kaal, Medical oncologist 
Universitair Medisch Cen-
trum Groningen (UMCG 
Dr. Janine Nuver, Medical Oncologist 
University Medical Center 
Utrecht, Cancer Center 
(UMCU)  
Dr. Rhodé Bijlsma, Medical Oncologist 
Leids Universitair Medisch 
Centrum (LUMC) 
Dr.Tom van der Hulle, Medical Oncologist 
Amsterdam Universitair 
medisch centrum locatie 
Vumc 
Dr. Mathilde Kouwenhoven, Neurologist 

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Amsterdam Universitair 
medisch centrum locatie 
AMC 
Dr. Jacqueline Tromp, Medical Oncologist 
Maastricht Universitair 
Medisch Centrum 
(MUMC) 
Dr. Roy Lalisang, Medical Oncologist 
Erasmus Medisch Cen-
trum (ErasmusMC) 
Dr. Monique Bos, Medical Oncologist 
IKNL 
Prof. Dr. Lonneke van de Poll, Senior researcher 
 
Sponsor (in Dutch: 
verrichter/opdrachtgever) 
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Subsidising party 
Dutch cancer society (KWF)  
De Nederlandse Organisatie voor 
Wetenschappelijk Onderzoek (NWO) 
Independent expert (s) 
Dr. Jan Paul de Boer 
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Laboratory sites  
Dr. Tiny Korse 
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Statistics 
Dr. Karolina Sikorska  
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Data management 
Ms. Esther Derksen-Peters  
Ms. Carla Fokkema-Vlooswijk MSc 
Integraal Kankercentrum Nederlands (IKNL) 
 

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COMPRAYA  
 
 
 
PROTOCOL SIGNATURE SHEET 
 
Name 
Signature 
Date 
Sponsor or legal representative: 
Dr. J.M.L Stouthard 
Cluster head MOD 
Medical Oncologist 
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Department of Medical Oncology 
 
 
Head of Department: 
Dr. G. Sonke 
Medical Oncologist 
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Department of Medical Oncology 
 
 
Principal Investigator]: 
Prof. dr. W. vd Graaf 
Medical Oncologist 
Netherlands Cancer Institute  – Antoni van 
Leeuwenhoek Hospital (NKI-AvL) 
Department of Medical Oncology 
 
 
 
 

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TABLE OF CONTENTS 
 
1. 
INTRODUCTION AND RATIONALE ............................................................................. 11 
2. 
OBJECTIVES ................................................................................................................ 14 
3. 
STUDY DESIGN ........................................................................................................... 14 
4. 
STUDY POPULATION .................................................................................................. 15 
4.1 
Population (base) .................................................................................................. 15 
4.2 
Inclusion criteria .................................................................................................... 15 
4.3 
Exclusion criteria ................................................................................................... 15 
4.4 
Sample size calculation ........................................................................................ 16 
5. 
TREATMENT OF SUBJECTS ....................................................................................... 16 
5.1 
Investigational product/treatment .......................................................................... 16 
5.2 
Use of co-intervention (if applicable) ..................................................................... 16 
5.3 
Escape medication (if applicable) .......................................................................... 16 
6. 
INVESTIGATIONAL PRODUCT .................................................................................... 16 
6.1 
Name and description of investigational  product(s) .............................................. 16 
6.2 
Summary of findings from non-clinical studies ...................................................... 16 
6.3 
Summary of findings from clinical studies ............................................................. 17 
6.4 
Summary of known and potential risks and benefits.............................................. 17 
6.5 
Description and justification of route of administration and dosage ....................... 17 
6.6 
Dosages, dosage modifications and method of administration .............................. 17 
6.7 
Preparation and labelling of Investigational Medicinal Product .............................. 17 
6.8 
Drug accountability ............................................................................................... 17 
7. 
NON-INVESTIGATIONAL PRODUCT ........................................................................... 17 
7.1 
Name and description of non-investigational product(s) ........................................ 17 
7.2 
Summary of findings from non-clinical studies ...................................................... 17 
7.3 
Summary of findings from clinical studies ............................................................. 17 
7.4 
Summary of known and potential risks and benefits.............................................. 17 
7.5 
Description and justification of route of administration and dosage ....................... 17 
7.6 
Dosages, dosage modifications and method of administration .............................. 17 
7.7 
Preparation and labelling of Non Investigational Medicinal Product ...................... 17 
7.8 
Drug accountability ............................................................................................... 17 
8. 
METHODS .................................................................................................................... 18 
8.1 
Study parameters/endpoints ................................................................................. 18 
8.2 
Randomisation, blinding and treatment allocation ................................................. 18 
8.3 
Study procedures .................................................................................................. 18 
8.3.1 Invitation and informed consent ............................................................................... 18 
8.4 
Withdrawal of individual subjects .......................................................................... 28 
8.4.1 
Specific criteria for withdrawal (if applicable) ..................................................... 28 
8.5 
Replacement of individual subjects after withdrawal ............................................. 28 
8.6 
Follow-up of subjects withdrawn from treatment ................................................... 28 
8.7 
Premature termination of the study ....................................................................... 28 
9. 
SAFETY REPORTING .................................................................................................. 28 

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9.1 
Temporary halt for reasons of subject safety......................................................... 28 
9.2 
AEs, SAEs and SUSARs ...................................................................................... 29 
9.2.1 
Adverse events (AEs) ....................................................................................... 29 
9.2.2 
Serious adverse events (SAEs) ........................................................................ 29 
9.2.3 
Suspected unexpected serious adverse reactions (SUSARs) ........................... 29 
9.3 
Annual safety report .............................................................................................. 29 
9.4 
Follow-up of adverse events ................................................................................. 29 
10. 
STATISTICAL ANALYSIS ......................................................................................... 29 
10.1 
Primary study parameter(s) ................................................................................... 29 
10.2 
Secondary study parameter(s) .............................................................................. 30 
10.3 
Other study parameters ........................................................................................ 30 
10.4 
Interim analysis (if applicable) ............................................................................... 31 
11. 
ETHICAL CONSIDERATIONS.................................................................................. 31 
11.1 
Regulation statement ............................................................................................ 31 
11.2 
Recruitment and consent ...................................................................................... 31 
11.3 
Objection by minors or incapacitated subjects (if applicable) ................................ 32 
11.4 
Benefits and risks assessment, group relatedness................................................ 32 
11.5 
Compensation for injury ........................................................................................ 32 
11.6 
Incentives (if applicable) ....................................................................................... 32 
12. 
ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION ........................ 32 
12.1 
Handling and storage of data and documents ....................................................... 32 
12.2 
Monitoring and Quality Assurance ........................................................................ 33 
12.3 
Amendments......................................................................................................... 34 
12.4 
Annual progress report ......................................................................................... 34 
12.5 
Temporary halt and (prematurely) end of study report .......................................... 34 
12.6 
Public disclosure and publication policy ................................................................ 34 
13. 
STRUCTURED RISK ANALYSIS ............................................................................. 34 
13.1 
Potential issues of concern ................................................................................... 34 
13.2 
Synthesis .............................................................................................................. 34 
14. 
REFERENCES ......................................................................................................... 35 
 
 
 

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LIST OF ABBREVIATIONS AND RELEVANT DEFINITIONS  
 
AE 
Adverse Event 
AVG/GDPR 
 
General Data Protection Regulation; in Dutch: Algemene Verordening 
Gegevensbescherming (AVG) 
AYA 
Adolescent and Young Adult 
BIPQ 
Brief Illness Perception Questionnaire 
BMI 
Body Mass Index 
BRP 
Personal Records Database; in Dutch: Basisregistratie Persoonsgegevens 
BRS 
Brief Resilience Scale 
CAM 
Complementary and Alternative Medicine  
CBC 
Complete Blood Count 
CBS 
Statistics Netherlands; in Dutch: Centraal bureau voor de statistiek 
CERQ 
Cognitive Emotion Regulation Questionnaire 
DT 
Distress Thermometer 
eCRF 
Electronic Case Report Form 
EORTC 
European Organisation for Research and Treatment of Cancer 
EQ-5D-5L 
five-level EuroQol five-dimensional questionnaire 
EU 
European Union 
HADS 
Hospital Anxiety and Depression Scale 
HRQoL 
Health-Related Quality of Life 
IC 
Informed Consent 
ICQ 
Illness Cognition Questionnaire 
LMR 
Hospital discharge register; in Dutch LMR: Landelijke Medische Registratie 
METC  
Medical research ethics committee; in Dutch: Medisch-Ethische Toetsings 
Commissie (METC) 
NCR 
Netherlands Cancer Registry; in Dutch: Nederlandse Kanker Registratie 
NEVO 
Dutch Nutrients Database 
NPR 
Netherlands Perinatal Registry 
PALGA 
National pathology database 
PAQ 
Patient Autonomy Questionnaire  
PHARMO 
database 
network 
population-based network of electronic healthcare databases and combines 
data from different primary and secondary healthcare settings in the 
Netherlands.  
PROFILES 
Patient Reported Outcomes Following Initial treatment and Long term 
Evaluation of Survivorship 

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(S)AE 
(Serious) Adverse Event  
SOP 
Standard Operating Procedure 
Sponsor 
The sponsor is the party that commissions the organisation or performance of 
the research, for example a pharmaceutical company, academic hospital, 
scientific organisation or investigator. A party that provides funding for a study 
but does not commission it is not regarded as the sponsor, but referred to as a 
subsidising party. 
SQUASH 
Short Questionnaire to Assess Health-Enhancing Physical Activity 
SUSAR  
Suspected Unexpected Serious Adverse Reaction 
WMO 
Medical Research Involving Human Subjects Act; in Dutch: Wet Medisch-
Wetenschappelijk Onderzoek met Mensen 
 
 
 
 

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SUMMARY 
 
Rationale: Childhood cancer survivorship attracts attention globally, because successes in 
treatment have led to increasing number of survivors who reach adulthood, in which 
survivorship issues affecting health-related quality of life (HRQoL) become prominent. Most 
paediatric patients are treated intensively with irradiation and/or chemotherapy, which put them 
at risk for early and/or late adverse medical and psychosocial events. In contrast, much less is 
known about adolescent and young adult (AYA) cancer patients, diagnosed between 18-39 
years, who, with an 80% chance to survive, also have a long life ahead. AYA cancer patients, 
much more than children, suffer from delay in diagnosis, lack of centralization of care, age-
adjusted expertise, and AYA follow-up care. AYAs typically present with a rare tumour: either 
with a paediatric malignancy (e.g. acute lymphoblastic leukaemia, paediatric brain tumours), a 
more typical tumour of AYA age (e.g. Hodgkin’s disease, germ cell cancer, melanoma, thyroid 
cancer) or with an adult tumour at unusual young age (e.g. gastrointestinal, lung, breast 
carcinomas). Next to these differences in epidemiology, the tumour biology, developmental 
challenges (e.g. forming relationships, becoming financially independent, having children) and 
treatment regimens differ between AYAs and children, and therefore findings derived from 
childhood cancer survivors cannot be extrapolated to AYAs. Furthermore, novel treatments 
with targeted agents or immunotherapy are more likely to be administrated to AYAs compared 
to children. Finally, a rare group of incurable AYA cancer patients will survive for many years, 
for whom health outcome and supportive care intervention data are lacking. 
Globally, so far, the identification of AYA cancer patient subgroups that might be more 
susceptible to poor health outcomes has not been systematically addressed. The role of 
sociodemographic and treatment-associated risks, external exposures (e.g. lifestyle) and host 
factors (e.g. genetic, biological, physiological); or combinations of influences for impaired (age-
specific) health outcomes, remains largely unknown. Understanding who is at risk and why will 
support the development of evidence-based AYA prevention, treatment and supportive care 
programs and guidelines, in co-creation with AYA cancer patients. 
Objective: To examine the prevalence, risk factors and mechanisms of impaired health 
outcomes (short- and long-term medical and psychosocial effects and late effects) over time 
among a population-based sample of AYA cancer patients. 
Study design: Prospective, observational cohort study 
Study population: All AYAs diagnosed (18-39 years at primary diagnosis) with cancer (any 
type) within  the first  3 months after diagnosis (eligibility window of 1 month to ensure all 
eligible AYA cancer patients can be included) in one of the participating centres (or treated in 
one of these centres) in The Netherlands.  

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Main study parameters/endpoints: The main outcomes are medical (e.g. second tumour; 
survival; fertility) and psychosocial (e.g. distress) health outcomes. Other study parameters 
(covariates/moderators/mediators) are characteristics of the individual (e.g. age, sex, cultural 
background, partner status, educational level, occupation, tumour type, disease stage, body 
composition, comorbid conditions, coping style), characteristics of the environment (e.g. 
cancer treatment, lifestyle), and genetic and biological factors (e.g. family history of cancer, 
stress and inflammation markers (e.g. cortisol, IL-6), microbiome). 
Nature and extent of the burden and risks associated with participation, benefit and 
group relatedness: On an individual level, patients who participate are asked to complete 
questionnaires on an annual basis for at least 10 years. All sample collections will take place 
at three time points: 0-3 months after diagnosis (baseline), 2 and 5 years; except blood for 
DNA analyses which will only take place at baseline.  The collection of blood, hair and faeces 
at three occasions is minimally invasive and the risks of blood draws, hair and fecal sampling 
are negligible. All safety measures and procedures will be performed according to local 
guidelines. Patients will not experience direct benefit from participation in the COMPRAYA 
study.  
 
By participating, patients will contribute to a better insight in the prevalence of impaired medical 
and psychosocial (age-specific) health outcomes in AYA and evidence on factors associated 
with these health outcomes. This will lead to better and more personalized cancer care and 
supportive care tools for future AYA cancer patients.  
 
 
 
 
 

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1. INTRODUCTION AND RATIONALE 
 
Adolescents and young adults (AYA) are recognized as a distinct population within the 
oncology community due to the unique challenges they encounter including recognition, 
diagnosis, treatment and monitoring of their disease1-3. The US National Cancer Institute 
proposed defining AYA as those aged 15-39 years at diagnosis2, however also concluded that 
this age range should be flexibly applied, depending on health care delivery system4. In The 
Netherlands, there is a clear distinction between centralized pediatric oncology (0-18 years), 
and adult oncology. Patients diagnosed with cancer between 18 and 39 years old are often 
called the “lost tribe” as they are too old to profit from the integrated pediatric care and, 
subsequently, are treated in the adult health care system in many different hospitals throughout 
the country. 
 
Increasing incidence and limited progress in survival 
Although cancer is a disease primarily affecting older adults, around 3800 AYAs are diagnosed 
with cancer in The Netherlands every year, which is around 5% of all invasive cancer 
diagnoses5. Over the last decades, the incidence of cancer among AYAs has slightly 
increased6. AYAs typically present with a rare tumor or a common tumor at an unusual age: 
either with a pediatric malignancy (e.g. acute lymphoblastic leukemia, pediatric brain tumors), 
a tumor of AYA age (e.g. Hodgkin’s disease, germ cell cancer, melanoma, thyroid cancer) or, 
with an adult tumor (e.g. gastrointestinal, lung, breast carcinomas)7. Although five-year relative 
cancer survival for AYAs (~80%) has improved over time3,8, progress made in survival of 
specific tumors lags behind that of children and older adults9,10. Potential reasons for the lack 
of progress in survival are insufficient awareness of cancer risk and symptoms among young 
patients and healthcare professionals resulting in diagnostic delays11,12; unique and 
incompletely understood tumor biology (cancers that are histologically indistinguishable across 
the age spectrum may be characterized by particular biological features in the AYA 
population)7,13,14; distinct age-related physiology, pharmacology and genomic properties with 
respect to cancer susceptibility and treatment7; unequal access to and low participation rates 
in clinical trials1 and lack of age-adjusted treatments15 and age-specific care (“I am treated like 
my 74-year-old grandma”)16. 
 
AYA cancer experience 
Adolescence, emerging and young adulthood are complex phases of life due to the many 
physical, emotional, cognitive and social transitions17. Important developmental tasks need to 
be achieved, such as forming one’s own identity and a healthy body image, establishing 
autonomy, responsibility and independence, finishing education and starting a career, getting 
a relationship and having children17. A cancer diagnosis challenges AYAs’ abilities to achieve 
these developmental milestones18,19. Emerging investigations demonstrate an extensive age-
specific burden of cancer20, for example, changes in physical appearance resulting from 
treatment (e.g. weight changes or hair loss) can negatively impact body image (looking 
different from peers) and interfere with self-esteem (avoiding social contacts) and identity 
development17,21,22. AYA cancer patients frequently report concerns regarding sexuality and 

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fertility issues23-25 and often experience a diminished feeling of autonomy as they are forced to 
become dependent on parents or partner26. Furthermore, cancer treatment and late effects 
can interfere with completing education and getting a job, and thus contributing to increased 
risk for financial burden27. Although AYA cancer patients may face challenges similar to those 
of older and younger patients, including short-term (e.g. hair loss,28 pain29) and long-term 
effects of cancer treatment (e.g. distress30, fatigue31 and cognitive problems32), and late effects 
(cardiovascular problems33, second tumors6,34-37), the consequences are different in this phase 
of life. The way in which AYA cancer patients adjust to their cancer experience might have life-
long implications for the quality of their survival38-41. 
 
Shortcomings in current research 
With an 80% chance to survive, AYA cancer patients have a large proportion of their expected 
lifespan remaining. (Inter)nationally, large cohort studies exist that address many relevant 
long-term cancer-related health issues, but all from the perspective of tumor histology, rather 
than an AYA age-specific perspective. Given the age-related differences in tumor 
epidemiology, biology, developmental challenges and access to care, findings derived from 
childhood or older cancer cohorts cannot be extrapolated to AYAs. Globally, so far, the 
identification of AYA cancer patient subgroups that might be more susceptible to poor (age-
specific) health outcomes has not been addressed in a systematic and coordinated way. The 
role of sociodemographic and treatment-associated risks, external exposures (e.g. lifestyle) 
and host factors (e.g. genetic, biological, physiological); or combinations of influences for 
impaired (age-specific) health outcomes, remains largely unknown. Understanding who is at 
risk and why will support the development of evidence-based AYA prevention, treatment and 
supportive care programs and guidelines. 
 
Conceptual model to understand mechanisms of impaired health outcomes  
The revised Wilson & Cleary conceptual model of patient outcomes (Figure 1)42-44 was used 
for the selection of appropriate measurement parameters. The authors of the model present it 
as taxonomy of patient health outcomes that are linked with characteristics of the individual, 
characteristics of the environment and biological and physiological variables. 
 

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Figure 1. Revised Wilson & Cleary (1995) Model. Adapted from Wilson, I.B., & Cleary, P.D (1995). 
Linking Clinical Variables with Health-Related Quality of Life: A Conceptual Model of Patient Out-
comes. JAMA. 273, 59–65 (Ferrans, C. E., et al. (2005). Conceptual model of health-related quality of 
life. J Nurs Scholarsh. 37, 336–342.) 
 
The main research questions addressed in this study are: 
 
(1) Who is at risk for impaired medical and psychosocial health outcomes? What is the role 
of characteristics of the individual (e.g. age, sex, cultural background, partner status, 
educational level, tumor type, disease stage, comorbid conditions, coping style), 
characteristics of the environment (e.g. cancer treatment, lifestyle), and genetic and 
biological factors (e.g. family history, genetic profile, body composition, inflammation 
markers, organ functions, metabolic syndrome, microbiome) on (age-specific) medical 
and psychosocial health outcomes?  
 
A more specific example for a medical health outcome of interest for AYA with cancer: 
What is the effect of characteristics of the individual (age, sex, ethnicity, tumor type, disease 
stage, medical conditions, distress, coping style), characteristics of the environment (type of 
systemic or local treatment and dose and related adverse events, medication use, lifestyle 
factors including physical activity, smoking, alcohol consumption and dietary intake) and 
genetic (family history cardiovascular disease, genetic disposition), biological (IL6 and other 
inflammation markers in blood, cortisol levels hair, gut microbiome) and physiological factors 
(body composition, organ functions) on later cardiovasculair outcomes? 
 
A more specific example for a psychosocial health outcome of interest for AYA with cancer: 
What is the role of characteristics of the individual (sex, ethnicity, partner status, having 
children, educational level, breadwinner status, illness perceptions, coping style, resilience, 
autonomy, spirituality, tumor type, disease stage), characteristics of the environment (type of 
treatment, lifestyle), biological factors (inflammation markers in blood, cortisol and melatonin 
levels in hair) on AYA impact of cancer? 

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(2) What is the prevalence of impaired (age-specific) medical (e.g. second tumor) and 
psychosocial (e.g. distress) health outcomes among AYA cancer patients at each point in 
time? 
 
(3) What is the course of (age-specific) medical and psychosocial health outcomes among 
AYA cancer patients over time? 
 
(4) Why is a person at risk? What are the (underlying) mechanisms of impaired health out-
comes? 
 
 
2. OBJECTIVES 
 
Primary Objective:  
- To identify individual, environmental, biological and psychological characteristics of AYA 
cancer patients who are at high risk for impaired medical and psychosocial health outcomes. 
In other words: To develop a prediction model for impaired medical and psychosocial health 
outcomes (at baseline, 2-, 5- and 10-year follow-up). 
 
Secondary Objective(s):  
-To assess the prevalence of impaired (age-specific) medical (e.g. second tumour) and 
psychosocial (e.g. social isolation) health outcomes at each time point (at baseline, 2-, 5- and 
10-year follow-up).  
 
Exploratory Objective(s): 
-To analyse the course of medical and psychosocial health outcomes over time (all 
timepoints needed) 
-To analyse mediating mechanisms associated with impaired health outcomes in AYA cancer 
patients  (at baseline, 2-, 5- and 10-year follow-up). 
 
Other Objective(s): 
-To form a prospective observational cohort of patients diagnosed with cancer at AYA age, 
and follow them over time until death.  
 
3. STUDY DESIGN 
 
We will conduct a nationwide, multicenter, prospective, population-based, observational 
cohort study. All AYA cancer patients (aged 18-39 years at primary cancer diagnosis), 
diagnosed or treated in one of the participating hospitals, within the first 3 months post 
diagnosis, and alive at study invitation, are eligible to participate. 
 
 

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List with participating hospitals that gave consent:  
Netherlands Cancer Institute– Antoni van Leeuwenhoek Hospital (NKI-AvL) 
Radboud university medical center (Radboudumc) 
University Medical Center Groningen (UMCG) 
University Medical Center Leiden (LUMC) 
Erasmus Medical Center (ErasmusMC) 
Maastricht Medical Center (MUMC+) 
University Medical Center Utrecht (UMCU) 
Amsterdam MC – location AMC 
Amsterdam MC – location VUMC 
 
4. STUDY POPULATION 
4.1 Population (base)  
All AYA cancer patients, diagnosed at age 18-39 years in one of the participating hospitals, 
receive an invite within the first 3 months after diagnosis (eligibility window of 1 month to 
ensure all eligible AYA cancer patients can be included) and will be asked to complete the 
COMPRAYA questionnaires on an annual basis up to 10 years after diagnosis (again with a 
window of 2 months before and after). Collection of clinical data and samples (e.g. faeces, 
hair and blood) will be done at baseline, 2, and 5 years after diagnosis. Questionnaire data 
collection is guaranteed by the PROFILES registry and patients will give informed consent for 
linkage with registry data, which makes long-term follow-up possible. 
 
4.2 Inclusion criteria 
In order to be eligible to participate in this study, a subject must meet all of the following 
criteria: 
- Pathological confirmed cancer diagnosis; 
- Age 18 – 39 years at time of first cancer diagnosis; 
- Able to understand the informed consent form; 
- Provide written informed consent. 
  
4.3 Exclusion criteria 
- Mentally incompetent patients based on the opinion of treating physician . 
- Inability to understand the Dutch language 
- Life expectancy less than 6 months based on the opinion of treating physician .  
 
 

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4.4 Sample size calculation 
 
Recruitment will take place over a 4.5-year period. With an incidence of 3800 new AYA cancer 
diagnoses/year, 1-year survival of 93%, nationwide coverage of 60% by participating hospitals, 
response rate of 40%, we aim to recruit 4000 AYA cancer patients in this period.  
 
The sample size needed for regression analyses for our primary aim is based on the rule of 
thumb of Green [book discovering statistics using SAS, Andy Field, 2010, page 197]. There 
are two rules, one for the minimum number for optimal fit of the model and one to test the 
individual predictors. Minimum number for optimal fit: 50+8k (k=number of predictors). If we 
assume 25 predictors (characteristics of the individual (e.g. age, sex, cultural background, 
partner status, educational level, tumor type, disease stage, comorbid conditions), 
characteristics of the environment (e.g. cancer treatment, lifestyle, and genetic and biological 
factors) in the model, then we need 50+200=250 patients. Minimum number for individual 
predictors is 104+k=129. To be able to do subgroup analyses among patients we also need 
sufficient power in subgroups.  
 
The secondary endpoint will be describing the proportion of patients with an impaired score 
for each health outcome at each time point. 
 
No formal sample size calculation is conducted for the exploratory objectives. This project is 
designed to continuously include new AYA cancer patients (depending on funding) and will 
provide an on-going source of patient data to answer secondary research questions. 
 
5. TREATMENT OF SUBJECTS 
Not applicable 
5.1 Investigational product/treatment 
Not applicable 
5.2 Use of co-intervention (if applicable) 
Not applicable 
5.3 Escape medication (if applicable) 
Not applicable 
 
6. INVESTIGATIONAL PRODUCT  
Not applicable 
6.1 Name and description of investigational  product(s) 
Not applicable 
6.2 Summary of findings from non-clinical studies 
Not applicable 

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6.3 Summary of findings from clinical studies 
Not applicable 
6.4 Summary of known and potential risks and benefits 
Not applicable 
6.5 Description and justification of route of administration and dosage 
Not applicable 
6.6 Dosages, dosage modifications and method of administration 
Not applicable 
6.7 Preparation and labelling of Investigational Medicinal Product 
Not applicable 
6.8 Drug accountability 
Not applicable 
 
7. NON-INVESTIGATIONAL PRODUCT 
Not applicable 
7.1 Name and description of non-investigational product(s) 
Not applicable 
7.2 Summary of findings from non-clinical studies 
Not applicable 
7.3 Summary of findings from clinical studies 
Not applicable 
7.4 Summary of known and potential risks and benefits 
Not applicable 
7.5 Description and justification of route of administration and dosage 
Not applicable 
7.6 Dosages, dosage modifications and method of administration 
Not applicable 
7.7 Preparation and labelling of Non Investigational Medicinal Product 
Not applicable 
7.8 Drug accountability 
Not applicable 
 
 

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8. METHODS 
8.1 Study parameters/endpoints 
 
Medical health outcomes & psychosocial health outcomes 
 
Other study parameters / predictors (if applicable) 
 
Characteristics of the individual (Sociodemographic characteristics, disease characteristics, 
psychosocial characteristics) 
 
Characteristics of the environment (Treatment characteristics, Lifestyle) 
 
Genetic and biological factors (Genetics, Biology, Physiological characteristics) 
8.2 Randomisation, blinding and treatment allocation 
Not applicable 
8.3 Study procedures 
8.3.1 Invitation and informed consent 
Every 2 weeks, the local COMPRAYA research nurse will receive a list, derived from the 
NCR, of AYAs diagnosed with cancer approximately 0-3 months ago. A 1-month eligibility 
window for baseline recruitment ensures all eligible AYA can be included. 
  
The local COMPRAYA research nurse will receive patients’ hospital number, if known, 
otherwise name and date of birth derived from the NCR. The local COMPRAYA research 
nurse, in consultation with the treating physicians, will check the patient selection on eligibility 
criteria and invite eligible patients for the study, on behalf of their treating physician. The local 
COMPRAYA research nurse, in consultation with the treating physicians, will also check the 
completeness of the NCR selection, missing patients meeting the inclusion criteria will also be 
invited on behalf of their treating physician. AYA cancer patients will receive an invitation 
package by mail consisting of a letter, patient information and informed consent. The local 
COMPRAYA research nurse will contact the patients one week after sending the invitation 
package to give more information if necessary, check whether they want to participate and 
schedule an appointment at the outpatient clinic (preferably simultaneously with other routine 
appointments). A unique personal study number will be assigned to each AYA participant.  
Participants  will receive an information letter how to fill in a questionnaire via PROFILES 
(Patient Reported Outcomes Following Initial treatment and Long term Evaluation of 
Survivorship). This includes a link to a secure website (www.profielstudie.nl), a login name, 
and a password. If the patient prefers written rather than digital communication, paper 
questionnaires can be completed and returned to the researcher using a return envelope. All 
procedures will be in line with the Dutch/European privacy legislation (AVG/GDPR). 
 
 

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Once the AYA cancer patient has consented to participate and accomplished all the planned 
assessments at baseline, we follow them prospectively by annually sending a selection of 
questionnaires (table 1). Biological samples will be collected at baseline, 2 and 5 years after 
diagnosis (germline specimens only at baseline) and thereafter when additional funding is in 
place). 
 
8.3.2 Measures 
Table 1 describes the schedule of assessments 
 
Medical and psychosocial health outcomes (questionnaires, registries) 
 
-AYA Impact of cancer 
To identify the positive and negative psychosocial impact of cancer, participants will complete 
a modified version of the 18-item Life Impact Checklist 45,46 at each time point. Nine of the 18 
items are from the original checklist that was used in a study of breast cancer patients 46, and 
nine items related to other life domains (body image, future goal setting, plans for education 
and work) will be included that have been identified as important to AYA cancer patients 47,48. 
On a five-point Likert scale, patients specify whether cancer had a negative, positive or no 
impact on 18 life domains (1—very negative impact; 2—somewhat negative impact; 3—no 
impact; 4—somewhat positive impact; 5—very positive impact). A participant will be deemed 
to perceive ‘a negative impact’ on a life domain if their response was 1 or 2 to that item in the 
questionnaire, while a response of 4 or 5 indicates ‘a positive impact’ on that life domain. 
 
-Health-related quality of life 
The EORTC QLQ-C30 is a 30-item HRQoL questionnaire consisting of five functional scales 
(physical, role, cognitive, emotional and social), a global quality of life scale, 3 symptom scales 
(fatigue, pain, nausea and vomiting) and a number of single items assessing common 
symptoms (dyspnea, loss of appetite, sleep disturbance, constipation and diarrhea) and 
perceived financial impact of the disease49. After linear transformation, all scales and single 
item measures range in score from 0-100. A higher score on the functional scales and global 
QoL means better functioning and HRQoL, whereas a higher score on the symptom scales 
means more complaints 50. To determine cut-off for impaired HRQoL, the thresholds for clinical 
importance of Giesinger et al will be used 51.The EQ-5D-5L is a descriptive system for the 
measurement of health. It measures HRQoL on five dimensions of health: mobility, self-care, 
usual activities, pain-discomfort, and anxiety/depression 52. Dutch cut-off scores are used to 
determine impaired health outcomes 53. Both questionnaires will be part of the questionnaire 
package at each time point. 
 
 

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-Psychological distress 
Psychological distress will be assessed at each time point with the Hospital Anxiety and 
Depression Scale (HADS), with seven items each for assessing symptoms of anxiety and 
depression 54. All items will be scored on a 0- to 3-point scale, with higher scores indicating 
more symptoms. A score  on the subscale of ≥8 indicates a substantial level of psychological 
distress  54-56. 
 
-Medical history/conditions will be assessed by the COMPRAYA research nurse at the time of 
the clinic visit with a short version of the questionnaire used in the St. Jude Childhood Cancer 
Survivorship study (e.g. hearing/ vision/ speech, urinary, hormonal, heart and circulatory, 
respiratory, digestive, brain and nervous system, child births and malignancies). An impaired 
medical health outcome is defined as having the medical condition at time of assessment. At 
baseline medical history is assessed by the COMPRAYA research nurse, at 2, 5 and 10-year 
follow-up all changing medical conditions will be registered via the patient-reported 
questionnaire.  
 
-Linkage will be done with the NCR (second malignancies), PHARMO Database Network, BRP 
(Survival status), Dutch Cardiac Registry (cardiac interventions, hospitalizations), Statistics 
Netherlands (CBS) (cause-of-death, work-related outcomes including individual income, type 
of occupation, number of working hours, number of contracts, receipt of disability benefits, 
unemployment benefits and welfare), Netherlands Perinatal Registry (NPR) (pregnancy and 
children), Hospital Discharge Register (LMR) (hospitalizations and referrals) and Dutch Central 
Bureau for Genealogy (mortality). 
 
Characteristics of the individual and environment 
Sociodemographic data including age, gender, marital status, children, education, and 
breadwinner status (sole/shared) will be obtained via the COMPRAYA research nurse at 
baseline and all changes at follow-up will be registered via the patient-reported questionnaire.  
Clinical information including cancer site, size, stage, grade, pathological stage, month/year of 
diagnosis, received (and future) treatment(s), i.e., surgery, radiation, chemotherapy, 
immunotherapy, targeted treatment, hormonal therapy or combination, medication, 
recurrence(s) of the disease and comorbidity will be obtained from the medical records, the 
Netherlands Cancer Registration (NCR), and/or via self-report. The data will be registered in 
the eCRF. 
 
All adverse events occurring after treatment and the intensity of these adverse events will be 
graded according to the NCI Common Toxicity Criteria (NCICTCAE, Version 4.03, final 7 
April 2009; see http://evs.nci.nih.gov/ftp1/CTCAE/About.html  
 
 

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Data on drug use will be obtained from the PHARMO database, which was previously 
successfully done for other PROFILES studies. The drug dispensing database of PHARMO 
contains complete longitudinal information on the dispensed drug, prescriber, date and amount 
of dispensing, prescribed dose regimens and thus on duration of drug use obtained from 
community pharmacies[47].  
 
Questions on diagnostic and treatment interval [48, 49] will be registered by the COMPRAYA 
research nurse at baseline. Questions on clinical trial participation, use of over the counter 
medication and complementary and alternative medicine (CAM) will be registered by the 
COMPRAYA research nurse at baseline and added to the questionnaire package at all follow-
ups. 
 
-Psychosocial characteristics (questionnaire) 
 
Coping style  
At baseline, 2- 5- and 10-year follow-up, coping will be assessed with the Cognitive Emotion 
Regulation Questionnaire (CERQ) 57. The CERQ is a multidimensional questionnaire 
constructed in order to identify the cognitive coping strategies someone uses after having 
experienced negative events or situations. Contrary to other coping questionnaires that do 
not explicitly differentiate between an individual's thoughts and his or her actual actions, the 
present questionnaire refers exclusively to an individual's thoughts after having experienced 
a negative event.  Patients will complete this questionnaire at baseline, 2-, 5,- 10 year follow-
up. 
 
Resilience 
At baseline, 2- 5- and 10-year follow-up, resilience will be assessed by the brief resilience 
scale (BRS) 58. Resilience is a skill which helps people to recover from a life event. People 
with high (perceived) resilience have the ability to move on faster after a setback. The BRS is 
a 6-item scale with a 5 point Likert-scale.  Patients will complete this questionnaire at 
baseline, 2-, 5,- 10 year follow-up. 
 
Illness perceptions  
At baseline, 2- 5- and 10-year follow-up, illness perceptions will be assessed using the Brief 
Illness Perception Questionnaire (B-IPQ), a nine-item instrument used to assess cognitive 
and emotional representations of the illness 59. The B-IPQ uses a single-item scale approach 
to assess perceptions on a continuous linear 0-10 point scale. Five of the items assess 
cognitive illness representations: 1. How much does your illness affect your life 
(consequences); 2. How long do you think your illness will continue (timeline); 3. How much 
control do you feel you have over your illness (personal control); 4. How much do you think 
your treatment can help your illness (treatment control); 5. How much do you experience 
symptoms from your illness (identity). Two items assess emotional representations: 6. How 
concerned are you about your illness (concern) and 7. How much does your illness affect 
you emotionally (emotional representation). One item assesses illness comprehensibility:  

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8. How well do you understand your illness (coherence). Answer scales of three items 
(personal control, treatment control and coherence) were reversed for statistical analyses to 
get the same response direction as the other five items. A higher score means worse illness 
perception.  
 
Autonomy  
At each time point, the short (4-item) version of the Patient Autonomy Questionnaire (PAQ) 
will be added to the questionnaire package to assess autonomy problems 60. 
 
Spirituality 
At baseline, 2- 5- and 10-year follow-up, the 6-item SPIRIT questionnaire will be used to 
measure spirituality in 5 dimensions: experiential, cognitive, coping, moral and social 61.  
 
-Lifestyle and other environmental exposures (questionnaire) 
We will use questions previously used in American National Institute of Health studies on life-
time smoking history and current smoking status, lifetime alcohol consumption history and cur-
rent alcohol consumption, history of and current recreational drug use, history of previous ill-
nesses, disorders, lifetime physical activity history, past and present sunbathing behavior. The 
Short Questionnaire to Asses Health enhancing physical activity (SQUASH) will be used to 
assess physical activity 62. The COMPRAYA research nurse will register the answers of the 
patients at baseline, patients will complete questionnaires on current lifestyle behavior at each 
time point by themselves. 
Food intake will be assessed by asking patients to register all foods and drinks they had taken 
during the day using the ‘Eetmeter’ from the Dutch ‘Voedingscentrum’. Participants will be 
asked to complete the Eetmeter at baseline, 1-, 2-, 5-, and 10 year follow-up for three consec-
utive days (including one day in the weekend). The Eetmeter is connected to the Dutch 
Nutrients Database (NEVO) so the quantity of macro- and micronutrients will be calculated 
immediately. Patients participating in the study will receive a link to create an account for the 
Eetmeter. When patients have registered their food intake, results will be sent to the secure 
environment of PROFILES. Patients will get access to their results if they indicate they would 
like to receive these. 
 
 

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-Costs related to productivity and medical consumption 
We will use the Productivity Cost Questionnaire  (iPCQ) to evaluate the impact of disease on 
the productivity of a person and the Medical Consumption Questionnaire (iMCQ) gaining more 
insight in the frequently occurring contacts with health care providers63. The combination of 
these two questionnaires will be used for the measurement of costs. Answers on the 
questionnares will be registered by the COMPRAYA research nurse on baseline and the 
questionnaires will be completed by patients themselves at each follow-up assessment. 
 
PROductivity and DISease Questionnaire (PRODISQ) will be used to assess all relevant 
aspects of the relationship between health and productivity including absence from work, 
compensation mechanisms that may reduce productivity loss, reduced productivity at work 
(efficiency losses) and productivity costs at the level of organizations64. Answers on the 
questionnares will be registered by the COMPRAYA research nurse on baseline and the 
questionnaires will be completed by patients themselves at each follow-up assessment. 
 
 
Genetics and biology 
 
-Genetic background and family history  
For synoptic reporting of the occurrence of cancer in first and second degree relatives, the 
standard list of the Radboudumc outpatient hereditary cancer clinic will be used and added to 
the baseline COMPRAYA research nurse questionnaire. 
 
-Special phenotypic features of the patient (questionnaire): 
As genetic cancer predisposition may also be associated with other phenotypic features a 
questionnaire is made to synoptically report features, e.g. head circumference, skin lesions, 
cleft lip, an aberrant number of fingers or toes, number of miscarriages. This specific 
questionnaire will also be added to the baseline COMPRAYA research nurse questionnaire.  
  
-Tumor material (PALGA linkage):  
Patients are asked to provide consent for use of tumor and normal material, and data that is 
already registered in the nationwide PALGA system. In addition, participants are asked to 
provide consent for the use of tissue material of recurrences or new malignancies, and data 
concerning these new events.  
 
-Blood (hospital visit):  
At baseline, at 2 years and at 5 years, blood of AYA cancer patients will be collected during a 
(regular follow-up) visit after an overnight fasting by venipuncture at one of the participating 
hospitals using a standard protocol (accompied with a standard questionnaire).  
 
 

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To minimize possible differences in the processing of the samples for analysis, the blood will 
be processed according to the COMPRAYA SOPs and temporarily stored in the participating 
hospitals. On a regular basis, the blood will be collected from the hospitals and, analyzed and 
stored in line with our research questions at the Netherlands Cancer Institute.  
Study blood collection serves two purposes: 
1) Germline DNA for research on cancer susceptibility genes, SNP-array, 
methylation profile and telomere length 
2) Biomarkers of impaired health outcomes (metabolic syndrome; markers of 
inflammation, fertility hormones; methylation profile; markers of the Senescence-
associated secretory phenotype (SASP); biochemical markers for cardiovascular 
damage; telomere length assessed in white blood cell DNA as a measure of 
accelerated ageing) 
 
For these purposes, we will collect the following blood samples: 
Standard blood set:  
EDTA 1x 10 ml tube 
Li-Heparine 1x 10 ml tube 
SST-tube (with gel) (8.5 ml) 
Cell-free DNA 2x 10 ml Streck tube (only baseline): 
EDTA for DNA 1x 10 ml 
Plasma samples will be processed within 4 hours of collection and stored at –80°C until 
further analyses. 
 
Assessments for standard follow-up care will also be used (i.e. CBC, cardiovascular risk profile; 
renal and liver functions, glucose, lipids, urine albumin/creatinine). 
 
 
-Faeces: 
At baseline, at 2 years and at 5 years, AYA cancer patients from 3 participating sites 
(AvL; UMC Groningen; Radboudumc) will be asked to collect faeces samples at home the 
day before, or the day of assessment/blood collection (accompied with a standard question-
naire). The samples can be sent by mail at room temperature to the NKI-AvL where it will be 
aliquoted and stored at -80° until DNA extraction. These samples will be used to evaluate ex-
ploratory biomarkers (microbiome), which may be predictive for impaired medical health out-
come endpoints.  
 
-Hair:  
Cortisol measurement in hair is a relatively new method that allows for assessments of 
chronic stress over time. Levels of melatonin can be detected in blood and saliva, but, similar 
to cortisol, melatonin is also stored in the hair, allowing for stable assessments of melatonin 
production over extended periods of time. Melatonin can act as an indicator for prolonged 
sleep disruption65.  

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At baseline, at 2 years and at 5 years, hair sampling will be done by the trained COMPRAYA 
research nurse in the hospital. For hair sample collection for follow-up, participants will be 
asked to self-collect their hair samples according to the accompanying instruction and com-
plete the accompied questionnare, and return by postal mail. 
All hair samples will be sent to the Netherlands Cancer Institute and stored in a dark place at 
room temperature until analysis. At the end of the study, the hair samples will be sent in 
packages of multiple samples by postal mail to Erasmus Medical Center, department of Clini-
cal Chemistry. Mean cortisol and melatonin concentrations will be assessed per 1 cm hair 
segment.  
 
-Physiological characteristics (hospital):  
Physical examination during a hospital visit will include: Standardized resting blood pressure 
and heart rate, body composition (BMI (height, weight, waist-, hip-, and calf circumference), 
bioimpedance, grip strength.  
 
Bioimpedence 
Whole-body single frequency (SF) (50 kHz) BIA measurements were performed according to 
Standard Operating Procedures by trained personnel, using Bodystat 500 (Bodystat Ltd., Isle 
of Man, British Islands). Patients laid in supine position on the examination table, and had 
their right hand and foot cleaned with alcohol. For each patient two new electrodes were 
placed on the right hand, and two new electrodes on the right foot. Raw BIA data (imped-
ance, resistance, reactance, and phase angle) were registered in electronic medical records. 
Estimates of FFM (in kg, %, and kg/m2), and FM (in kg, %, and kg/m2) were obtained, using 
the Kyle equation. 
 
Percentile estimates for the fat free mass index (FFMI) (kg/m2), and fat mass index (FMI) 
(kg/m2), based on Schutz, were used to compare anthropometric outcomes of patients to 
healthy people of similar age, and gender in clinical practice. 
 
Grip strength 
All handgrip tests were executed with the dominant hand using the Jamar system, consisting 
in an adjustable handgrip handle (standard JD configuration) equipped with in-build compres-
sion load cell (capacity=0-90kg, accuracy=<1% of rated load) and connected via a strain 
gauge amplifier to a computer. This device allows continuous monitoring and recording of the 
force exerted on the handgrip handle. All data were sampled at 100Hz (low pass filtered, 
10Hz) and stored on a computer for further analysis. The system was calibrated prior to the 
start and checked during the study by applying a 20 kg load to the Jamar handle. Before 
each assessment session a zero-calibration was performed in order to adjust for environ-
mental conditions (ambient temperature). In order to avoid in-between assessment zero-cali-
brations, the handgrip handle will be calibrated in position 2 (middle grip position) and main-
tained in that position for all patients. Patients will be  asked to squeeze the handle as hard 
as possible for 3 times with 30 seconds interval. Afterwards, subjects were instructed to 
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dropped to 50% of its maximum was recorded as FR (time to fatigue) and the maximal grip 
strength value reached during the test as grip strength max. 
 
 

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Table 1: Schedule of assessments 
  
Screening/
baseline 
Follow-up 
1 year 
Follow-up 
2 year 
Follow-up 
3,4,6,7,8,9 
year 
Follow-up 
5 year 
Follow-up 
10 year 
 
 
(profiles 
only) 
 
(profiles 
only) 
 
 
Informed consent 
X  
 
 
 
 
 
Background characteristics1 
X 
x 
x 
x 
x 
x 
Clinical characteristics 
X 
 
X 
 
X 
X 
Genetic background and Family 
history / Special phenotypic 
features 
X 
 
 
 
 
 
Lifestyle and other environmental 
exposures2 
X 
 
x 
 
x 
x  
Medical history/conditions 
X 
 
x 
 
x  
x  
Physical examination/ vital 
parameters3 
X 
 
X 
 
X  
 
Blood sample + standard 
questionnaire 
X 
 
X 
 
X 
 
Faeces sample + standard 
questioannaire4 
X 
 
X  
 
X  
 
Hair sample + standard 
questionnaire 
X 
 
X  
 
X  
 
 
 
 
 
 
 
 
Questionnaires 
 
 
 
 
 
 
Impact cancer5 
X  
X 
X 
X 
X 
X 
Health-related quality of life6 
X 
X 
X 
X 
X 
X 
Psychological distress7 
X 
X 
X 
X 
X 
X 
Psychosocial characteristics8 
X 
 
X 
X 
X 
X 
Costs related to productivity and 
medical consumption9 
X 
X 
X 
X 
X 
X 
Food intake diaries/Eetmeter 
X 
 X 
X 
 
X 
X 
Survival 
----------------------------------------------------------------------------------à 
1. 
Age, gender, Ethnicity, postal code, partner status, living situation, education, employment, income, siblings, parenthood 
2. 
Smoking, alcohol, drugs, exercise (SQUASH), nutrition, sun behavior, sedentary behavior, CAM 
3. 
Blood pressure, heart rate, BMI, grip strength, bio-impedance measurement 
4. 
Faeces only collected at AvL, radboudumc and UMCG 
5. 
18-item Life Impact Checklist 
6. 
EORTC QLQ-C30; EQ5D 
7. 
HADS 
8. 
BIPQ, CERQ, BRS, PAQ, SPIRIT 
9. 
iMCQ, IPCQ, PRODISQ 
 
We are aware that the number of assessments and the length of our questionnaire could be 
burdensome for patients. Nevertheless, previous PROFILES studies show that patient do not 
have problems with donating blood or hair samples. With regard to the questionnaires, we 
will acknowledge the length and advise patients to complete the questionnaire over 2 days if 
they feel tired or are stretched for time when completing the questionnaire. Patients who fill in 
the online questionnaire can stop and save their data at each desired moment. When they 
login again they can continue with the question were they stopped. At baseline, most of the 
data will be collected by the COMPRAYA research nurse. This personal contact between 
COMPRAYA research nurse (often also AYA clinical nurse specialist) and AYA cancer 
patient will hopefully strengthen the relationship and result in lower attrition rates.  
Furthermore, AYA cancer patients are actively involved as advisors in the COMPRAYA study 
set-up. 

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We expect that the baseline assessments will take 60-90 minutes; 2 and 5 year follow-up 60 
minutes and all other follow-up assessments 30 minutes. 
Although patients will not directly benefit from participation in the COMPRAYA study we will 
highlight the importance of the study to improve care and outcomes for future AYA cancer 
patients. In addition, next to the COMPRAYA study, we will create an online “Young and 
Cancer” Platform together with and for AYAs where age-specific information, support and 
bespoke interventions will become available for the study participants and all other AYA 
cancer patients. This  online “Young and Cancer” will be strongly linked to the national AYA 
healthcare network. 
 
8.4 Withdrawal of individual subjects 
AYA cancer patients can leave the study at any time for any reason if they wish to do so 
without any consequences. The investigator can decide to withdraw a subject from the study 
for urgent medical reasons. Data and already used material will be used until the date of 
withdrawal. 
8.4.1 Specific criteria for withdrawal (if applicable) 
         Not applicable 
8.5 Replacement of individual subjects after withdrawal 
Not applicable 
 
8.6 Follow-up of subjects withdrawn from treatment 
The investigators will not follow up subjects that withdraw from the study. Subjects can 
leave the study at any time for any reason if they wish to do so without any 
consequences. 
 
8.7 Premature termination of the study 
This concerns an observational cohort study, with continuous inclusion of new participants 
and premature termination of the study is not anticipated. 
 
9. SAFETY REPORTING 
9.1 Temporary halt for reasons of subject safety 
In accordance to section 10, subsection 4, of the WMO, the sponsor will suspend the 
study if there is sufficient ground that continuation of the study will jeopardise subject 
health or safety. The sponsor will notify the accredited METC without undue delay of a 
temporary halt including the reason for such an action. The study will be suspended 
pending a further positive decision by the accredited METC. The investigator will take 
care that all subjects are kept informed.  
 
 
 

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9.2 AEs, SAEs and SUSARs 
9.2.1 Adverse events (AEs) 
Adverse events are defined as any undesirable experience occurring to a subject 
during the study, whether or not considered related to the study. All adverse events 
reported spontaneously by the subject or observed by the investigator or his staff will 
be recorded. 
9.2.2 Serious adverse events (SAEs) 
Not applicable 
9.2.3 Suspected unexpected serious adverse reactions (SUSARs) 
Not applicable 
9.3 Annual safety report 
The sponsor will submit, once a year throughout the inclusion period, a safety/progress 
report to the accredited METC 
9.4 Follow-up of adverse events 
All AEs will be followed until they have abated, or until a stable situation has been reached. 
Depending on the event, follow up may require additional tests or medical procedures as 
indicated, and/or referral to the general physician or a medical specialist. 
SAEs are not expected in this observational study  
 
10. STATISTICAL ANALYSIS 
 
All statistical analyses will be performed using R software. All statistical tests will be two-sided 
and differences considered significant if p<0.05. Missing items in the questionnaire will be han-
dled as follows. If (an) item(s) from a multi-item scale is/are missing, and at least half of the 
items from the scale have been answered, then scale scores are calculated ignoring any items 
with missing values, which is the same as assuming that the missing items have values equal 
to the average of those items. If less than half of the items from the scale have been answered, 
then the scale score is set to missing. For single-item measures, score is also set to missing. 
 
10.1 Primary study parameter(s) 
 
Primary research question: Who is at risk for impaired health outcomes? What is the role of 
characteristics of the individual (e.g. age, sex, cultural background, partner status, educational 
level, tumor type, disease stage, comorbid conditions), characteristics of the environment (e.g. 
cancer treatment, lifestyle), and genetic and biological factors (e.g. family history) on (age-
specific) medical and psychosocial health outcomes?  
 
 

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In preliminary analysis differences in outcomes between predefined groups (e.g. tumor types, 
gender) will be examined using chi-square statistics for categorical variables and 
independent t-tests, ANOVA or their nonparametric equivalences (Mann-Whitney U, 
Kruskall-Wallis tests) for continuous variables. Clinically meaningful differences will be 
determined with Norman’s ‘rule of thumb’65, or the method of Cocks for the EORTC QLQ-
C3050. Univariable logistic regression models will be fitted to test the association between 
potential risk factors (characteristics of the individual, environment and genetic and biological 
factors) and probability of impairment. The multivariable model will include all variables 
statistically significant (at p<0.1) in univariable analysis. A backward selection method will be 
used to identify a parsimonious model per outcome. Bonferroni correction (six primairy 
outcomes (medical conditions, health care consumption, AYA Impact of cancer, health-
related quality of life, psychological distress, productivity ) will be applied making a p-value of 
0.05/6= 0.008 significant.  
 
 
10.2 Secondary study parameter(s)  
What is the prevalence of impaired (age-specific) medical (e.g. second tumor) and 
psychosocial (e.g. distress) health outcomes among AYA cancer patients at each time point? 
 
Proportion with 85% CI will be used to describe the AYA cancer patient population and 
prevalence of impaired health outcomes. 
 
10.3 Other study parameters 
 
What is the course of impaired (age-specific) medical and psychosocial health outcomes 
among AYA cancer patients over time? 
 
We will carry out repeated analyses using linear mixed models, which accounts for the intra-
patient dependency of the repeated measures. Missing outcomes will be assumed missing at 
random (MAR). An advantage of linear mixed models is that all patients can be included in 
the analyses, regardless of whether they have been missing some follow-up measurements. 
 
Why is a person at risk? What are the (underlying) mechanisms of poor health outcomes 
(e.g. coping style, genetic makeup, cortisol levels, inflammation)? 
 
This research question is explorative. Moderation (a third variable that affects the strength of 
the relationship between an outcome and independent variable) will be tested by adding an 
interaction term to the regression models described above according to the principles of 
Baron and Kenny67. Mediation (another variable explains the relationship between the 
outcome and the independent variable) will be tested according to the principles of Baron 
and Kenny and via the Sobel test68. 
 

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The variables listed in section 8.1.2 will be used for description of the AYA patient group and 
they will be analyzed as covariates. 
 
10.4 Interim analysis (if applicable) 
 
 Not applicable  
 
11. ETHICAL CONSIDERATIONS 
11.1 Regulation statement 
This study will be conducted according to the principles of the Declaration of Helsinki (64th 
WMA General Assembly, Fortaleza, Brazil, October 2013) and in accordance with the 
Medical Research Involving Human Subjects Act (WMO), and this study protocol. 
11.2 Recruitment and consent 
In consultation with the treating clinician, the local COMPRAYA research nurse fully explains 
the study to the patient. 
During recruitment, a written patient information form giving details of the study will be 
provided to the patient to read and retain. After the patients have had the time they need to 
consider the information and have been encouraged to ask questions, they will be asked to 
give informed consent by signing and dating an informed consent form. All informed consent 
forms should be countersigned and dated by qualified and trained personnel (local 
COMPRAYA research nurse/ treating physician). 
Written informed consent will be obtained before any study procedures will be performed. 
Procedures that are part of standard care and not done for study-specific purposes for this 
study, can occur before informed consent is obtained. The original of the informed consent 
form will be filed according to local practices in the study file or patient file. A copy will be 
given to the patient. The patients have the right to withdraw from the study at any time, 
without giving an explanation and without prejudice to their subsequent care. 
 
The informed consent will consist of different items that are mandatory for 
inclusion.  Schedule of assesments can be found in table 1. 
   
Longitudinal clinical data collection (extraction from medical records and other registries); 
longitudinal collection of patient-reported outcomes via validated questionnaires (at 
outpatient clinic and paper or online questionnaires); collection of blood samples  for 
COMPRAYA study purposes or secondary research initiatives; collecting vital parameters 
(bio-impedence measures and grip strength; usage of tumor and normal tissue stored in the 
nationwide National Pathology Database (PALGA) system; use of material and data from 
tumor recurrences or new malignancies. 

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Faeces and hair samples for COMPRAYA study purposes or secondary research initiatives 
and hair sample for COMPRAYA study purposes or secondary research initiatives. 
 
Informed consent for invitation to participate in studies aimed at detection of germline cancer-
predisposing mutations 
 
11.3 Objection by minors or incapacitated subjects (if applicable) 
Not applicable 
11.4 Benefits and risks assessment, group relatedness  
Patients will not experience direct benefit from participation in the COMPRAYA study. Since 
this is an observational study, apart from the blood sampling there are no additional risks as-
sociated with participation (blood draw will by preference be done during a regular blood 
draw needed for routine care. The risk of a blood draw is negligible).  
By participating, patients will contribute to the evidence on factors associated with medical 
and psychosocial (age-specific) health outcomes. This may lead to better and a more 
personalized cancer care for future patients. Clinical parameters will be collected during a 
COMPRAYA hospital visit and derived from medical charts. Consenting patients will be 
asked to fill out standard questionnaires (approximately 60-90 minutes for baseline 
questionnaire together with COMPRAYA research nurse and 30 minutes for each follow-up 
questionnaire). Blood samples will be drawn during a routine blood sampling or in the context 
of the COMPRAYA hospital visit to assess clinical and physiological parameters.  
11.5 Compensation for injury 
The sponsor/investigator has obtained dispensation from the statutory obligation to provide 
insurance, because participating in the study is with limited risk.  
11.6 Incentives (if applicable) 
In case the participant travels to the hospital only for COMPRAYA purposes travelcost will be 
reimbursed.  
 
12. ADMINISTRATIVE ASPECTS, MONITORING AND PUBLICATION 
12.1 Handling and storage of data and documents 
Confidentiality and anonymity of participants will be guaranteed with the assignment of a 
study number to each participant.  
 
eCRFs are to be completed using Castor. Sites will receive training and help text for appro-
priate eCRF completion. Data collection and entry into the eCRF is the responsibility of the 
clinical study staff at the investigational site under supervision of the principle investigator. 

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Data will be subjected to validation according to the Data Validation and Medical Review 
Plan.  
 
eCRFs will be submitted electronically to the Sponsor and should be handled in accordance 
with instructions from the Sponsor. 
Prior to database lock, all eCRFs should be completed and electronically signed and dated 
by the investigator or sub-investigator. 
At the end of the study, after 10 years of follow-up, the investigator will receive patient data 
for his or her site in a readable format on a compact disc that must be kept with the study 
records. Acknowledgement of receipt of the compact disc is required.  
 
All data will be collected on specially designed data-platforms using only the unique patient 
identification code to link all data. These data-platforms will be designed by the NKI in collab-
oration with Health-RI taking all the appropriate GDPR data-protection measures into ac-
count. For the logistics of the study the program LDOT may be used, which is a study plan-
ning tool that has been developed by the University of Maastricht and has been implemented 
in the Health-RI infrastructure. 
 
As such, the returned questionnaires, blood, hair and faeces samples have no names 
attached and will be linked to registry data and eCRFs by study number. Therefore, it will not 
be possible for the researchers to track participants’ names with the study numbers. 
Returned questionnaires will be stored at a secured location for at least 20 years.  
 
The actual biomaterial samples (blood, hair, and faeces samples) will be labelled using 
unique codes and will not be traceable to individual patients without the patient identification 
code lists. The patient material and collected data will be stored for as long as data will be 
relevant for research purposes. This will be evaluated every 20 years for biomaterials and 
every 20 years for data. All participants will give separate informed consent to store data and 
materials for a longer period of time for future research. All records identifying the patients 
will be kept confidential and will not be made publicly available. Strict measurements will be 
undertaken to protect confidentiality of the data and registration of the biomaterials. Although 
the GDPR does not apply for countries outside the EU, the privacy of the patients will be 
protected in a similar way. 
 
Twenty years after the end of the study the relevance of storage of patient data and materials 
will be evaluated. If still relevant for this study purposes it will be stored an additional 20 
years”.  
 
12.2 Monitoring and Quality Assurance  
The risk of blood draws, hair and fecal sampling is negligible. Therefore, we qualify the 
risk of this study as negligible and will not perform official monitoring of the study.  

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12.3 Amendments  
Amendments are changes made to the research after a favourable opinion by the 
accredited METC has been given. All amendments will be notified to the METC that gave 
a favourable opinion.  
 
12.4 Annual progress report 
The sponsor/investigator will submit a summary of the progress of the study to the 
accredited METC once a year. Information will be provided on the date of inclusion of the 
first subject, numbers of subjects included and numbers of subjects that have completed 
the study, serious adverse events/ serious adverse reactions, other problems, and 
amendments. 
 
12.5 Temporary halt and (prematurely) end of study report 
The investigator/sponsor will notify the accredited METC of the end of the study within a 
period of 8 weeks. The end of the study is defined as the last patient’s last visit.  
 
The sponsor will notify the METC immediately of a temporary halt of the study, including 
the reason of such an action.  
    
In case the study is ended prematurely, the sponsor will notify the accredited METC 
within 15 days, including the reasons for the premature termination. 
 
 Within one year after the end of the study, the investigator/sponsor will submit a final 
study report with the results of the study, including any publications/abstracts of the study, 
to the accredited METC.  
 
12.6 Public disclosure and publication policy 
All results will be given as feedback to the treating clinicians, patients’ representatives, 
and research society involved in the field of cancer, by means of tumour working groups, 
symposia, congresses, emailed newsletters, the website of COMPRAYA 
(www.compraya.nl) and international peer-reviewed publications. 
 
13. STRUCTURED RISK ANALYSIS  
Not applicable 
 
13.1 Potential issues of concern 
Not applicable 
 
13.2 Synthesis 
Not applicable 
 
 

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