3

Executive Functions in Survivors of Pediatric Brain Tumor and Consequences for

Societal Participation

Anita Puhr

Oslo University Hospital, Rikshospitalet

Department of Pediatric Medicine, Department of Pediatric Neurology

-

Department of Psychology

Faculty of Social Sciences

University of Oslo

2020

© Anita Puhr, 2020 Series of dissertations submitted to the Faculty of Social Sciences, University of Oslo No. 825 ISSN 1564-3991 All rights reserved. No part of this publication may be reproduced or transmitted, in any form or by any means, without permission. Cover: Hanne Baadsgaard Utigard. Print production: Reprosentralen, University of Oslo.

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TABLE OF CONTENTS

ACKNOWLEDGEMENTS ....................................................................................................... 4

ABBREVIATIONS .................................................................................................................... 6

LIST OF PAPERS ...................................................................................................................... 8

GENERAL SUMMARY ............................................................................................................ 9

1. INTRODUCTION ................................................................................................................ 12

1.1 Pediatric brain tumors and their treatment ..................................................................... 14

1.1.1 Epidemiology and etiology ..................................................................................... 14

1.1.2 Tumor classification ................................................................................................ 15

1.1.3 Symptoms, treatment, and survival rates ................................................................ 15

1.2 Late effects and long-term outcomes ............................................................................. 17

1.2.1 Medical late effects ................................................................................................. 18

1.2.2 Neurocognitive late effects ...................................................................................... 20

1.2.3 Mental health outcomes .......................................................................................... 23

1.2.4 Fatigue ..................................................................................................................... 25

1.2.5 Long-term outcomes; psychosocial adjustment and socioeconomic outcomes ...... 26

1.3 Executive functions ........................................................................................................ 28

1.3.1 Conceptualizations and developmental models ...................................................... 28

1.3.2 Hierarchical developmental models ........................................................................ 30

1.3.3 Neurodevelopmental cascade models for declines in IQ and academic achievement

in PBT survivors ............................................................................................................... 30

1.3.4 Adding temperature and context to the mix: the hot/cool distinction ..................... 32

1.3.5 Assessment of EFs .................................................................................................. 34

2. AIMS .................................................................................................................................... 36

2.1 Paper I ............................................................................................................................ 36

2.2 Paper II ........................................................................................................................... 36

2.3 Paper III .......................................................................................................................... 36

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3. METHODS ........................................................................................................................... 37

3.1 Participants and procedure ............................................................................................. 37

3.2.1 Questionnaires (papers I, II and III) ........................................................................ 40

3.2.2 Performance-based measures (paper III) ................................................................. 42

3.3 Statistical analyses .......................................................................................................... 44

3.4 Ethical considerations .................................................................................................... 45

4. RESULTS ............................................................................................................................. 46

4.1 Paper I ............................................................................................................................ 46

4.2 Paper II ........................................................................................................................... 46

4.3 Paper III .......................................................................................................................... 47

5. DISCUSSION ...................................................................................................................... 48

5.1 Discussion of main findings ........................................................................................... 48

5.1.1 Executive function in the PBT survivor sample ...................................................... 48

5.1.2 What’s hot and what’s not; towards an idiosyncratic executive function profile ... 53

5.1.3 Executive function involvement in long-term adaptive functioning and

socioeconomic outcomes .................................................................................................. 56

5.2. Methodological issues, strengths and limitations .......................................................... 61

5.2.1 Cross-sectional design and possible impact of environmental factors .................... 62

5.2.2 Response rates and generalizability of study findings ............................................ 62

5.2.3 The use of self-reports and performance-based data for assessing EF ................... 64

5.2.4 Sample size for subgroup analyses .......................................................................... 65

5.3 Clinical implications ...................................................................................................... 66

6. CONCLUSION AND DIRECTIONS FOR FUTURE RESEARCH .................................. 67

REFERENCES ......................................................................................................................... 68

3.2 Long-term outcome measures........................................................................................ 40

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ACKNOWLEDGEMENTS

Completing this thesis has been one of most arduous ordeals I have taken on, but also one of

the most educational, satisfying, and now at the end of it all, liberating, empowering and

relieving experiences I might ever have had. The relief of completing is most likely not only

felt by me; I imagine several people around me may feel somewhat relieved themselves to see

that I finally reached the finish line. Parallel to working on this thesis, these years since I first

started have been the most eventful of my life, both good and bad. I lost a father, but gained

the two great loves of my life; my daughters, Eira and Frida. These two little girls have no

doubt largely contributed to keeping me sane throughout this process, and have reminded me

along the way of what really matters. The same must be said for Vegard; I am profoundly

thankful for your patience, support, and for being my rock in all our years together. Thank

you. And to my family and friends, thank you all for your kind, supportive words and

understanding.

I would like to thank one person in particular who has been of invaluable support to me in all

things that matter; my friend, colleague and co-author, Anne-Britt Skarbø. I cannot express

how much I appreciate how you have encouraged and cheered me on throughout this long

process, in moments when I needed it the most. A very special thank you also to co-

cheerleader and former colleague, Torhild Berntsen, a strong and inspiring advocate for

children with acquired brain injury, who initiated the idea of a study investigating long-term

functioning in survivors of childhood brain tumor, and who has believed in this study ever

since.

I am very proud to present the final product of this study! This is all my own product; from

forming the idea for the project, to achieving funding, collecting data, and finally, reporting

findings. However, none of this could have been achieved without my team players. First of

all, to my main supervisor, Stein Andersson. Stein, you have been the ideal supervisor in my

view; knowledgeable, steadfast, straightforward, encouraging, easy going, providing clarity

and a dash of pragmatism, and calming my nerves in a moment or two of frustration. Thank

you for sticking with me throughout this endeavor! Also, a special thank you to my co-

supervisors, Ellen Ruud and Arnstein Finset. To Ellen, for immediately believing in and

contributing to the project from the beginning, and for guiding me through the jungle that it is

to implement a clinical study, and to Arnstein, for sharing your valuable academic experience

and insights.

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I wish to thank my co-author Vicki Anderson, one of the world’s foremost leading capacities

within the field of child neuropsychology and acquired brain injury in childhood. Thank you

for your willingness to join in on this little study in the North, and for your valuable

contribution to this work. I greatly appreciate the opportunity I had to have an exchange

period at the MCRI in Melbourne in 2018, which was a wonderful learning experience. To my

co-author, Bernt Due-Tønnessen, thank you for your much appreciated contribution and your

relentless concern and commitment towards improving the quality of life of these patients

post-treatment. A big thanks also to the rest of my co-workers, to the BAKOPP nurses, Elna

Larsen and Karin Hammeren, for your helpful hand in managing endless amounts of

envelopes and organizing patient participation, to Bjørg-Eli Eide and Oddmar Steinsvik for

helping me collect data from participants in Western and Northern Norway, and lastly, to the

head of my section, Kjersti Ramstad, for giving me the space I needed for finalizing the

thesis.

A study is merely an idea without the financial means to be realized, and I wish to express my

gratitude to the Norwegian ExtraFoundation for Health and Rehabilitation, the Norwegian

Cancer Society, the Norwegian Children’s Cancer Society, Oslo University Hospital’s

Children’s Foundation, the BAKOPP-network (BArneKreftOPPfølgings-Nettverket)/South-

Eastern Norway Regional Health Authority (who knew stamps would cost so much!), and the

Renée and Bredo Grimsgaard Foundation, for the funding that made this study possible.

Lastly, but importantly, a special thank you to all the participants and their parents/caregivers

for their contribution to this research study. Their participation has contributed to provide a

clearer picture of future directions for helping survivors of pediatric brain tumors return to

their everyday lives and to reach their goals.

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ABBREVIATIONS

ABCL – Adult Behavior Checklist (ASEBA)

ADHD – Attention deficit/hyperactivity disorder

ADL – Activities of daily life

ALL – Acute lymphoblastic leukemia

ASEBA – Achenbach System of Empirically Based Assessment

ASR – Adult Self-Report (ASEBA)

BRIEF – Behavior Rating Inventory of Executive Function – Parent report version

BRIEF-A – Behavior Rating Inventory of Executive Function – Adult version

CAVLT-2 – Children’s Auditory Verbal Learning Test – Second edition

CBCL – Child Behavior Checklist (ASEBA)

CCS – Childhood cancer survivors

CNS – Central nervous system

CWIT – Color-Word Interference Test

CPT 3 – Conners’ Continuous Performance Test – Third edition

CRT – Cranial/craniospinal radiation therapy

D-KEFS – Delis-Kaplan Executive Function System

EF – Executive functions

FQ – Fatigue Questionnaire

HPA – Hypothalamic–pituitary–adrenal (HPA) axis

HRQoL – Health-related quality of life

HRT BC - Hit Reaction Time Block Change (CPT 3)

ICCC-3 – International Classification of Childhood Cancer – Third edition

ICD-10 – International Classification of Disease - 10th edition

ICP – Intracranial pressure

IQ – Intelligence quotient

MRI – magnetic resonance imaging

pABI – Pediatric acquired brain injury

PBT – Pediatric brain tumor

PedsQL – Pediatric Quality of Life Inventory 4.0

PedsQL-MFS – PedsQL-Multidimensional Fatigue Scale

QoL – Quality of life

RAVLT – Rey Auditory Verbal Learning Test

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SCL-90-R – Symptom Checklist 90 Revised

SES – Socioeconomic status

TBI – Traumatic brain injury

TMT – Trail Making Test

YSR - Youth Self-Report (ASEBA)

WAIS-IV – Wechsler Adult Intelligence Scale –IV

WASI – Wechsler Abbreviated Scale of Intelligence

WHO – World Health Organization

WISC-IV – Wechsler Intelligence Scale for Children –IV

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LIST OF PAPERS

This thesis is based on the following papers which are referred to in the text by their Roman

numbers I – III.

Paper I

Puhr, A., Ruud, E., Anderson, V., Due-Tonnesen, B. J., Skarbø, A. B., Finset, A., &

Andersson, S. (2019). Self-Reported Executive Dysfunction, Fatigue, and Psychological and

Emotional Symptoms in Physically Well-Functioning Long-Term Survivors of Pediatric

Brain Tumor. Developmental Neuropsychology, 44(1), 88-103.

doi:10.1080/87565641.2018.1540007

Paper II

Puhr, A., Ruud, E., Anderson, V., Due-Tønnessen, B. J., Skarbø, A.-B., Finset, A., &

Andersson, S. (2019). Social attainment in physically well-functioning long-term survivors of

pediatric brain tumour; the role of executive dysfunction, fatigue, and psychological and

emotional symptoms. Neuropsychological Rehabilitation, 1-25.

doi:10.1080/09602011.2019.1677480

Paper III

Puhr, A., Ruud, E., Anderson, V., Due-Tønnessen, B. J., Skarbø, A.-B., Finset, A., &

Andersson, S. (2020). Executive function and psychosocial adjustment in adolescent survivors

of pediatric brain tumor. Developmental Neuropsychology. Manuscript in revision for

publication.

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GENERAL SUMMARY

Pediatric brain tumors (PBTs) are the second most common neoplasm after leukemia, and the

most common of the childhood solid tumors, with about 40 new cases in Norway per year.

The overall prognosis after treatment is encouraging and continuously improving, leading to

an increasing number of long-term survivors. However, survivors of PBT often experience

serious debilitating late effects, such as physical and sensory sequelae, persistent symptoms of

fatigue, neurocognitive impairments, and psychological problems. This is particularly true of

PBT survivors who have undergone complex treatment regimens, i.e., a combination of

surgery, chemotherapy and/or cranial/craniospinal radiation therapy (CRT). These late effects

may have major impacts on quality of life (QoL), and may potentially reduce survivors’

possibilities of functioning independently and participating in society. Neurocognitive

impairments, and especially executive dysfunction, may play a special role in this respect.

Executive functions (EFs) refer to a subset of cognitive functions involved in controlling,

organizing and directing neurocognitive activity, behavioral actions, emotional responses and

social learning. They encompass cognitive (“cool”) skills that operate in emotionally neutral

contexts, e.g., attention, working memory, planning, problem-solving, and behavioral (“hot”)

skills, e.g., the ability to adapt to changes in one's environment, to monitor and regulate

emotions and behaviors, and to exert socially appropriate inhibitory control. EFs develop all

through childhood and early adult life, paralleling the maturation of the brain, and disruptions

to the development of these skills may have negative consequences for social functioning,

academic/educational achievement, and vocational goal attainment.

The literature on the presence of executive dysfunction and how it affects psychosocial

functioning and social attainment in this subset of childhood cancer survivors is sparse.

Hence, this cross-sectional study aimed to provide a better understanding of EF and their

associations to long-term functional outcomes in adolescent and young adult survivors of

PBT, by utilizing self- and informant reports of EF, psychological and social functioning,

fatigue, educational adjustments, employment/training status, and government benefit uptake.

For a subgroup of participants, performance-based measures of neurocognitive functioning

were also employed.

The purpose of this thesis was to investigate the presence of executive dysfunction and

possible idiosyncratic EF profile in young adult survivors of PBT, as well as the presence of

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psychological problems and symptoms of fatigue (Paper I), and the association between

executive dysfunction, psychosocial adjustment, and social attainment (i.e.,

educational/vocational achievement and financial independence) in young adult survivors of

PBT (Paper II) and adolescent survivors of PBT (Paper III).

The findings in Paper I demonstrated that young adult PBT survivors reported significantly

more psychological and emotional difficulties and fatigue compared to a healthy control

group. However, between group differences in these domains were small, and the largest

effects were found on measures reflecting EF. Furthermore, the young adult PBT survivors

reported significantly more difficulties with metacognitive (“cool”) aspects of EF compared to

behavioral (“hot”) aspects. The findings also confirmed that certain PBT treatment-related

factors and medical late effects are of particular concern for the development of negative

long-term outcomes. A history of seizures represented a particular risk factor in the

development of executive dysfunction, and surgery combined with CRT and chemotherapy

was significantly associated with higher levels of reported mental fatigue in this survivor

group. Other known medical and demographic risk factors such as younger age at diagnosis,

hydrocephalus, and having undergone multiple surgeries (including patients with combined

treatment), were not found to be associated with poorer outcomes in this sample.

In Paper II¸ the findings showed that young adult PBT survivors are at increased risk of poor

social attainment compared to their healthy peers, as significantly more PBT survivors than

controls reported to have received educational adjustments and substantial government

benefits, and significantly more survivors than controls were currently not engaged in regular

employment/training. However, young adult PBT survivors and healthy controls did not differ

on educational level or living situation (i.e., living with caregivers vs. independently). Further,

we expanded on the findings from Paper I by demonstrating that self-reported problems with

EF, along with symptoms of fatigue, were most strongly associated with problems with social

attainment, with psychological symptoms less impactful. Complex treatment regimens were

significantly related to poorer social outcomes, and the presence of post-treatment psychiatric

comorbidity was significantly associated with government benefit uptake.

In Paper III¸ we demonstrated the presence of executive dysfunction also in a group of

adolescent PBT survivors, as evidenced by both parent and self-reports, as well as

performance-based results. A similar EF profile to that of the young adult group emerged (i.e.,

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more difficulties with metacognitive/”cool” aspects of EF compared to behavioral/”hot”

aspects), and we again demonstrated a link between executive dysfunction and problems with

psychosocial adjustment. Similar to the young adult PBT survivor group, surgery combined

with CRT and chemotherapy was significantly related to higher rates of parent and self-

reported problems on various questionnaires, as was male sex, and embryonal tumor or

astrocytoma.

In summary, the findings from the three studies indicate the presence of impairments of both

“hot” and “cool” aspects of EF in long-term survivors of PBT, but with relatively more

prominent impairments in the “cool” domain, and that negative long-term social outcomes

were strongly related to executive dysfunction.

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1. INTRODUCTION

Half a century ago, Bloom, Wallace, and Henk (1969) of the Royal Marsden Hospital in

London, UK, were among the first physicians to raise concern about the threat that PBTs and

their treatment pose to the long-term quality of life (QoL) in children. They observed a high

risk of “producing an impaired intellect, or disturbed emotions” in children with

medulloblastomas treated with cranial or craniospinal radiotherapy, especially in children

younger than 2 years. Since then, the PBT literature has become increasingly sophisticated,

investigating factors and mechanisms related to adverse long-term outcomes, and expanding

on physical and sensory late effects by also taking into account aspects of cognitive,

emotional and social development. Initially, studies assessing neurocognitive late effects were

focused primarily on intellectual ability, i.e., IQ, and its decline. More recently however,

possible underlying processes of this decline have been recognized, acknowledging problems

of attention, processing speed, and working memory as important mechanisms. As the number

of aging PBT survivors is steadily increasing, the risk of adverse long-term outcomes that

they carry into adulthood has become increasingly apparent. Compared to other childhood

cancer survivors, this patient subset seems particularly vulnerable, as many struggle to

negotiate the transition into adulthood and achieve adult milestones (e.g., independence,

social adjustment, education, vocation). Although studies have identified several

demographic, treatment-related and physical risk factors, there remains a need for more

knowledge on the underlying mechanisms of poor long-term outcomes, such as the link

between psychological factors, e.g., cognitive and emotional functioning, and how PBT

survivors function in the “real world”. Do psychological problems contribute to poorer social

engagement and less than optimal educational and vocational outcomes, and in which way?

Are some psychological domains more essential than others in contributing to poorer long-

term functioning?

Executive functions (EFs), a subset of higher-order cognitive functions dedicated to

maintaining an overarching control over mental activity and behavior, are now firmly

acknowledged for their importance for social adjustment and academic, educational and

vocational success (Muscara, Catroppa, & Anderson, 2008; Sirois et al., 2017; Willard, Allen,

Hardy, & Bonner, 2015; Wolfe et al., 2013; Zelazo, Blair, & Willoughby, 2016). The first

descriptions of EF appeared in the mid 1800’s, with the famous case of Phineas Gage

(Damasio, Grabowski, Frank, Galaburda, & Damasio, 1994), linking executive dysfunction,

i.e., changes in personality and behavior, to frontal lobe pathology. The research field was

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later expanded by descriptions of abnormal cognition and behavior after frontal lobe lesions

in Luria’s (1966, 1973) influential work on victims of war injuries, and also case descriptions

of frontal lobectomies performed in order to treat psychiatric conditions (Walsh, 1978).

Fascinating case accounts thus became the starting point of a fast-growing research field

within cognitive neuroscience, and knowledge about these functions is continuously refined.

Today, the terms “executive functions” and “frontal lobe functions” are no longer used

interchangeably, as it has become clear that these functions rely not only on the frontal lobes,

but also on the intactness of multiple cooperating brain structures and networks (Gioia,

Isquith, & Guy, 2001; Kalbfleisch, 2017; Stuss & Alexander, 2000). For example, the

cerebellum, which is the most frequent location for PBTs, has rich neuroanatomical

connections to the rest of the brain, including the frontal lobes, and thus plays a crucial role in

EF and their development (Moberget et al., 2015; Stoodley & Schmahmann, 2009). Also, it

has been acknowledged that the developmental trajectory of EFs is prolonged, spanning

across the first three decades of life, paralleling the structural maturation and remodeling of

the frontal lobes (Anderson, 2010; De Luca & Leventer, 2008) . Therefore, sustaining a brain

tumor at any time point during childhood, and in any location, may seriously hamper the

development of EF.

For these reasons, EF has increasingly been the subject of studies in the PBT literature,

especially over the past decade, and although still limited in numbers, findings indicate that

survivors of PBT are at risk of executive dysfunction. However, although it is generally

acknowledged that EF plays an important role in the successful navigation through life, there

are currently few studies exploring the presence and degree of long-term executive

dysfunction in PBT survivors beyond the neurocognitive domains processing speed, attention

span and working memory. Moreover, few studies have investigated the extent to which

executive dysfunction contributes to negative long-term social, academic and vocational

outcomes in PBT survivors.

The main purposes of the study presented in this thesis are to explore the EF profile of

adolescent and young adult PBT survivors, and to investigate the association between EF

difficulties and long-term outcomes, such as living situation, social adjustment, educational

level, and vocational and financial status, while also taking into account reports of fatigue and

psychological and emotional problems. In this introduction, current knowledge regarding

PBTs, PBT treatment and PBT-related late effects is summarized in chapters 1 and 2,

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respectively. As EFs are the main outcome of interest in the thesis, chapter 3 is devoted to

presenting EF conceptualizations and developmental models, methods of assessing EFs and

related challenges, presence of executive dysfunction in PBT survivors, and the role of EFs in

negotiating and achieving educational, vocational and social goals in this patient population.

1.1 Pediatric brain tumors and their treatment

1.1.1 Epidemiology and etiology

In Norway, the yearly incidence rate of central nervous system (CNS) tumors (i.e.,

intracranial and intraspinal tumors) in children is 3.9 per 100,000 (Nasjonalt kvalitetsregister

for barnekreft, Årsrapport 2018). CNS tumors are the most common form of solid tumors, and

the second most common form of cancer in children after leukemia. For unknown reasons, the

incidence of CNS tumors in the Nordic countries is the highest in the world (Johannesen,

Angell-Andersen, Tretli, Langmark, & Lote, 2004; Schmidt et al., 2011, Nasjonalt

kvalitetsregister for barnekreft, Årsrapport 2018). However, it is not unlikely that the high

incidence rate reflects the completeness of the Nordic registries, as well as international

variations in classification.

There are a few key differences between brain tumors that occur in adults and those that occur

in children. For example, the histology of PBTs is different from that which is more

commonly seen in adults, as children are more prone to developing astrocytomas,

medulloblastomas and ependymomas, whereas adults are more likely to develop brain

metastases, glioblastomas and meningiomas (see section 1.1.3 for tumor classification in

children) (Gjerstad, Helseth, & Rootwelt, 2010; Helseth et al., 2003). Also, PBTs are more

often localized infratentorially (brain stem and cerebellum), while brain tumors in adults are

more often found supratentorially (the cerebrum) (Gjerstad et al., 2010; Helseth et al., 2003).

Furthermore, brain tumors in children are more often benign than in adults, and have a better

prognosis than adults with a similar condition.

The etiology of PBT is for a vast majority of patients poorly understood, and only for a few

patients may the development of a brain tumor be linked to a genetic predisposition (e.g.,

tuberous sclerosis, neurofibromatosis types 1 and 2) (Gjerstad et al., 2010). Changes in

environmental risk factors have been considered an unlikely explanation, as the incidence

rates have remained stable over the last decades (Schmidt et al., 2011). The only well-

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documented environmental risk factor is ionizing radiation, for example as a consequence of

CRT for other malignancies (Wilne, Dineen, Dommett, Chu, & Walker, 2013).

1.1.2 Tumor classification

In the current standard classification system for childhood cancer, i.e., the third edition of the

International Classification of Childhood Cancer (ICCC-3; Steliarova-Foucher, Stiller,

Lacour, & Kaatsch, 2005), diagnostic groups and subgroups are categorized according to

tumor morphology (histological classification) and primary site of origin, with an emphasis on

morphology. Diagnostic Group III in the ICCC-3 corresponds to CNS and miscellaneous

intracranial and intraspinal neoplasms, with Diagnostic Subgroup IIIa-f corresponding to:

ependymomas and choroid plexus tumors, astrocytomas, intracranial and intraspinal

embryonal tumors, other gliomas, other specified intracranial and intraspinal neoplasms, and

unspecified intracranial and intraspinal neoplasms, respectively (see Table 1). Astrocytomas

(malignant and benign) are the most numerous of the PBTs, followed by intracranial and

intraspinal embryonal tumors (Nasjonalt kvalitetsregister for barnekreft, Årsrapport 2018).

For grading the severity of CNS tumors, the World Health Organization has four categories:

grade I and II for non-cancerous, slow growing (benign) tumors, and grade III and IV for

cancerous, faster growing (malignant) tumors that pose greater challenges to treatment (Louis

et al., 2016). This classification is based on histological characteristics, and lately also more

frequently on molecular markers.

1.1.3 Symptoms, treatment, and survival rates

Presenting symptoms of PBTs may include diffuse signs such as nausea, vomiting, headache,

personality changes, irritability, and drowsiness. These symptoms may be due to an increase

of intracranial pressure (ICP) caused by the tumor blocking one or more of the ventricles that

drain cerebrospinal fluid (Ullrich, 2009). Depending on the localization of the tumor, focal

symptoms may include uncoordinated muscle movements, problems walking (ataxia),

seizures, endocrine problems (diabetes and/or hormone regulation), visual changes or double

vision, hearing loss, facial paralysis, hemiparesis/-plegia, and changes in respiratory and

cardiac function (Gjerstad et al., 2010). Several types of procedures aid the diagnostic

process, and may include neurological examination, brain imaging (e.g., computed

tomography [CT], magnetic resonance imaging [MRI]), lumbar puncture (cerebrospinal fluid

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analysis), tumor biopsy, and analyses of genetic mutations and the molecular basis of the

tumor.

Table 1 Diagnostic Group III of the ICCC-3 (Steliarova-Foucher et al., 2005): CNS and

miscellaneous intracranial and intraspinal neoplasms (simplified).

ICCC-3 Tumor types

IIIa. Ependymomas and choroid plexus tumors Ependymomas, choroid plexus tumors

IIIb. Astrocytomas High and low grade gliomas, chiasmatic/opticus

gliomas

IIIc. Intracranial and intraspinal embryonal

tumors

Medulloblastomas , medulloepitheliomas

Atypical teratoid/rhabdoid tumors (AT/RTs)

IIId: Other gliomas

Oligodendrogliomas, mixed and unspecified

gliomas, neuroepithelial glial tumors of

uncertain origin

IIIe: Other specified intracranial and intraspinal

neoplasms

Pituitary adenomas and carcinomas, tumors of

the sellar region (craniopharyngiomas), pineal

parenchymal tumors, neuronal and mixed

neuronal-glial tumors (dysembryoplastic

neuroepithelial tumors [DNETs],

gangliogliomas), meningiomas

IIIf: Unspecified intracranial and intraspinal

neoplasms

Over the past decades considerable advances have been made in neurosurgery, CRT, and

chemotherapy, and PBT treatment may include one or a combination of these approaches.

Selection of treatment regimen depends largely on the type, size, and location of the tumor, as

well as the age and overall health of the child. Neurosurgical resection of the tumor is usually

considered the first and most important step in the treatment process, and total resection of

benign tumors with clear borders is in many cases curative (Nasjonalt kvalitetsregister for

barnekreft, Årsrapport 2018). However, in many cases, chemotherapy and/or CRT is

necessary, for example in cases where the tumor is inoperable or only partly operable (e.g.,

due to location in eloquent or vital regions), or not curative (i.e., malign tumors) (Ullrich et

al., 2015). Proton beam radiation therapy has increasingly taken over for photon therapy in

recent decades, as the former has been shown to minimize radiation to the healthy tissue

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surrounding the tumor, all the while maintaining the maximum dose to the tumor itself

(Kahalley et al., 2016; King et al., 2017). In Norway, CRT is not administered to children

below the age of four, due to the potential negative long-term sequelae such as neuro-

cognitive decline, developmental delay and endocrine deficiencies (Nasjonalt kvalitetsregister

for barnekreft, Årsrapport 2018). Chemotherapy, which has significantly less severe long-

term side effects than CRT, was initially used mainly as an adjuvant treatment to

neurosurgery and CRT, but is now also used in order to postpone or replace radiation therapy

in the youngest patients (Karajannis, Allen, & Newcomb, 2008). Advancements in the

knowledge of molecular markers have led to personalized chemotherapy, which is showing

promising results as a new treatment strategy (Nasjonalt kvalitetsregister for barnekreft,

Årsrapport 2018).

The overall prognosis after treatment for intracranial tumors in children is encouraging, as

improved medical treatment has led to considerably higher 5-year survival rates, i.e., about

66-75% (Gatta et al., 2014; Noone et al., 2018). For Norway specifically, the 5-year survival

rate is about 78% for all CNS tumors, but subgroup variations are considerable, as treatments

and prognoses vary widely based on age, tumor location, size, histology, and staging

(Nasjonalt kvalitetsregister for barnekreft, Årsrapport 2018).

1.2 Late effects and long-term outcomes

As the number of childhood cancer survivors is continuously growing, research efforts have

increasingly been aimed at monitoring and managing late effects, applying both clinical and

patient-reported outcome measures. Late effects may, separately and together, hamper normal

development across the lifespan, and have a cumulative negative effect on educational

attainment, employment, financial independence, independent living, social relationships and

overall QoL (Brand, Chordas, Liptak, Manley & Recklitis, 2016; Brinkman et al., 2016;

Hocking et al., 2015; Moyer et al., 2012; Zebrack et al., 2007; Zeltzer et al., 2008). However,

children treated for brain tumors have often been excluded from childhood cancer research

protocols because of probable brain pathology. Further, studies of pediatric acquired brain

injury (pABI) do often not include PBT survivors, due to confounding cancer treatment

effects (Brand et al., 2016; de Ruiter et al., 2016).

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The question of which survivors are at risk of poor long-term outcomes is profoundly

complex, involving a vast array of disease-related, individual and environmental factors.

Figure 1 (adopted and modified from Stavinoha, Askins, Powell, Pillay Smiley, and Robert

[2018] ) summarizes factors that may contribute to and moderate late effects and long-term

outcomes in PBT survivors, mirroring the cumulative burden of PBT and its treatment, as

well as the developmental complexity involved in long-term outcomes. In the following

sections, a summary of current knowledge on PBT-related late effects and associated risk

factors is presented.

1.2.1 Medical late effects

Medical late effects may be summarized in 5 categories; physical, endocrinological,

neurological, and sensory late effects, and secondary neoplasms (Turner, Rey-Casserly,

Liptak, & Chordas, 2009), all of which have the potential to negatively impact long-term

socioeconomic outcomes and overall QoL. Physical late effects may include changes to body

image and physical appearance, i.e., either localized changes, such as scars from

craniotomies, alopecia, and alterations in bone structure of the skull caused by CRT, or global

changes, such as short stature (e.g., due to hypothalamic-pituitary axis disruption after CRT)

(Turner et al., 2009). Physical late effects such as these will often represent a psychological

burden for the young patient.

Disruptions to the hypothalamic-pituitary axis caused by the tumor itself or its treatment may

lead to various endocrinopathies. Endocrinological late effects may include growth hormone

deficiency, hypothyroidism, diabetes insipidus, obesity, osteopenia/osteonecrosis (especially

after frequent use of glucocorticoids), long-term gonadotropin deficiency and deficiencies in

sex hormones (e.g., hyperprolactinemia, central precocious puberty, premature ovarian failure

in females), and are particularly common after CRT (Turner et al., 2009).

19

Figure 1 Factors that may contribute to and moderate late effects and long-term outcomes in

PBT survivors (adopted and modified from Stavinoha, Askins, Powell, Pillay Smiley, and

Robert [2018] ).

20

Neurological and sensory late effects such as vasculopathy (e.g., strokes, moyamoya disease),

seizures, peripheral neuropathy, motor dysfunction (e.g., motor clumsiness, decreased distal

sensation, ataxia, hemiparesis), and auditory and visual impairments, are relatively common

in PBT survivors, and may occur as a consequence of tumor involvement, neurotoxicity

caused by treatment, and/or neurological complications (seizures, hydrocephalus) (Ullrich &

Embry, 2012). Cerebellar mutism, or posterior fossa syndrome, may occur postoperatively in

15% to 25% of patients (Ullrich & Embry, 2012), and involves a loss of speech, commonly

accompanied by pseudobulbar dysfunction, irritability, ataxia, poor attention and eye contact,

vomiting, and incontinence. Speech is typically regained within days to months, whereas

difficulties with vomiting/appetite may take months to recover from. Emotional symptoms

may possibly last for several years, although such symptoms are often confounded by other

aspects of surviving a PBT and its treatment.

1.2.2 Neurocognitive late effects

Neurocognitive impairment, and more specifically, executive function (EF), may be of

particular relevance to long-term functional outcomes in PBT survivors. EF and its definitions

and theoretical conceptualizations will be addressed in more detail in chapter 3. In the

following, knowledge on risk factors in PBT survivors associated with neurocognitive

impairments in general is summarized.

Neurocognitive late effects are relatively common in PBT survivors (40-100 %), as PBT and

its treatment disrupt the development of the immature brain and have a negative cascading

impact on neurocognitive skills, intellectual ability (IQ) and academic learning (Bull &

Kennedy, 2013; de Ruiter, van Mourik, Schouten-van Meeteren, Grootenhuis, & Oosterlaan,

2013; Duffner, 2010; King, Ailion, Fox, & Hufstetler, 2019; Palmer, 2008; Stavinoha et al.,

2018). Over the last decade, several neurodevelopmental models explaining this cascade have

been put forward, describing the interrelations between impairments of processing speed,

attention, working memory and general EFs, and the combined and unique impact of these

domains on IQ and academic achievement (King et al., 2019; Palmer, 2008; Wolfe, Madan-

Swain, & Kana, 2012). As the impact of EFs is at the center of these models, they will be

addressed in further detail in chapter 3.

21

Several risk factors for developing long-term neurocognitive sequelae have been identified,

involving individual factors (e.g., age at diagnosis/treatment), tumor- and treatment variables,

neurological comorbidities, and nondisease-related factors (e.g., environmental support,

parental socioeconomic status [SES]) (Bull & Kennedy, 2013; Stavinoha et al., 2018).

Younger age at diagnosis and treatment may put patients at higher risk of developing

neurocognitive impairment (e.g., lower IQ, processing speed, working memory, attention and

academic performance), due to the vulnerability of the immature brain and the interruption of

development (e.g., rapid cell proliferation, dendritic and axonal outgrowth, myelination) (de

Ruiter et al., 2013; Stavinoha et al., 2018). Furthermore, time lapse since treatment

completion seems to be a significant influencing factor, with PBT survivors “growing into”

deficits, especially as social engagement and academic demands increase (Anderson,

Northam, & Wrennall, 2019; Stavinoha et al., 2018) .

Several studies have investigated the effects of tumor location on long-term neurocognitive

functioning. The cerebellum, with its connections to extensive regions of the cerebrum, is the

most common site of PBTs, and is known to be involved in both motor and cognitive

functions, including EF (Moberget et al., 2015). The cerebellum appears to play a crucial role

during neurodevelopment, as lesions to the cerebellum and disruptions of the cerebello-

cerebral connectivity in children generally lead to more pronounced neurocognitive deficits

than in adults (Ailion et al., 2016; Moberget et al., 2015). Moreover, some findings suggest

that patients with infratentorial tumors (i.e., below the tentorium) have greater neurocognitive

impairments than those with supratentorial tumors (i.e., above the tentorium) (Stavinoha et al.,

2018). A possible explanation for this difference may be that patients with infratentorial

locations are more often treated with CRT (Corti et al., 2020; Raghubar, Mahone, Yeates, &

Ris, 2017). However, studies on tumor location have in general shown mixed results, as both

supra- and infratentorial tumor locations have been associated to poorer neurocognitive

outcomes (Corti et al., 2020; de Ruiter et al., 2013; Mulhern, Merchant, Gajjar, Reddick, &

Kun, 2004; Olsson, Lundgren, Hjorth, & Perrin, 2016; Raghubar et al., 2017; Stavinoha et al.,

2018). Moreover, infra- and supratentorial tumor locations may show different patterns of

neurocognitive outcomes, possibly because tumors and their treatment in either locations

affect different neuroanatomical areas, and/or because of the different neuroplastic

reorganization processes that take place after tumor occurrence (Corti et al., 2020). Also, not

surprisingly, larger tumor size causing more widespread neuroanatomical effects, has been

associated with poorer long-term neurocognitive outcomes (Stavinoha et al., 2018).

22

One of the most well-documented treatment-related risk factors for neurocognitive late

effects in survivors of PBT is CRT, due to its severe neurotoxic effects on the immature brain,

e.g., compromised white matter integrity and impaired growth of new neurons post-treatment

(Ailion et al., 2016; Bledsoe, 2016; de Ruiter et al., 2013; Stavinoha et al., 2018). CRT is

associated with deficits of attention, processing speed and EF, as well as yearly declines of

two to four intelligence quotient (IQ) points. Patients with younger age at treatment, higher

radiation doses, larger radiation fields, and CRT combined with chemotherapy, are at

increased risk of poorer neurocognitive outcomes (Bull, Spoudeas, Yadegarfar, & Kennedy,

2007; Duffner, 2010; Kahalley et al., 2016; Raghubar et al., 2017; Stavinoha et al., 2018).

However, a growing body of literature on PBT survivors treated with proton therapy suggests

a decrease in exposure to healthy brain tissue, and thereby overall toxicity, thus reducing the

risk of neurocognitive impairment (Gross et al., 2019; Rey-Casserly & Diver, 2019).

The independent effects of chemotherapy on neurocognitive functioning is notoriously

difficult to isolate, because of the confounding effects of the tumor mass itself and

administration of other treatment paradigms (Stavinoha et al., 2018). Although chemotherapy

is considered less neurotoxic than CRT, there are several chemotherapeutic agents that are

known to increase the risk of neurocognitive impairments (e.g., Methotrexate) (Liu et al.,

2015). Furthermore, studies on neurocognitive late effects in children treated

chemotherapeutically for acute lymphoblastic leukemia (ALL) have shown long-term deficits

of processing speed, attention, and aspects of EF, possibly due to disruption of white matter

integrity (Kanellopoulos et al., 2016; McCurdy, Rane, Daly, & Jacobson, 2016; Raghubar et

al., 2017).

Although patients treated with surgery only (i.e., without CRT or chemotherapy) have shown

some advantage compared to those treated with CRT and chemotherapy, findings nevertheless

show persistent neurocognitive dysfunction also in the surgery only subset, particularly for

those who have undergone multiple surgeries (McCurdy, Rane, et al., 2016; Riva & Giorgi,

2000; Rønning, Sundet, Due-Tønnessen, Lundar, & Helseth, 2005).

Secondary neurological comorbidities and complications, such as seizures and hydrocephalus

caused by the mass effect of the tumor, tumor treatment, or a combination of these, may result

in damage and/or alterations to neuroanatomical structures and networks, and have also been

23

linked to poorer neurocognitive outcomes in adulthood (Aarsen et al., 2009; Brinkman,

Krasin, et al., 2016; Liu et al., 2015; McCurdy, Rane, et al., 2016; Vingerhoets, 2006).

Nondisease-related factors such as pre-existing neurodevelopmental disorders and poorer

premorbid developmental, neurocognitive, and neurological functioning, may be significant

predictors of long-term neurocognitive dysfunction (Ullrich & Embry, 2012). Also, high

stress levels and female sex have been associated to a risk of poorer neurocognitive outcomes,

although studies have failed to replicate findings regarding sex (Olsson et al., 2016; Stavinoha

et al., 2018; Ullrich & Embry, 2012). Environmental characteristics such as social support and

family factors, e.g., parental health, education, and SES, and the impact of PBT on family

interactions, may with time become increasingly important and contribute to observable

differences between PBT survivors and peers (Klassen, Anthony, Khan, Sung, & Klaassen,

2011; Stavinoha et al., 2018; Ullrich & Embry, 2012).

1.2.3 Mental health outcomes

Although the majority of long-term childhood cancer survivors are psychologically well-

adjusted, survivors of CNS tumors remain a vulnerable subset in this regard, and have been

found to be at risk of experiencing significantly more psychological and emotional distress,

including symptoms of depression, anxiety, posttraumatic stress, negative self-appraisal,

suicidal ideation, psychoses, behavioral problems and somatization, compared to other CCS

populations, siblings and healthy peers (e.g., Brinkman, Recklitis, Michel, Grootenhuis, &

Klosky, 2018; Brinkman et al., 2013; Cousino et al., 2017; Shah et al., 2015; Zebrack et al.,

2004; Zebrack et al., 2007; Zeltzer et al., 2008; Zeltzer et al., 2009) . Further, it seems that

PBT survivors may have a distinct pattern of psychological symptoms compared to other

pABI populations, as they seem to struggle more with internalizing than externalizing

problems (Brinkman, Li, et al., 2016; Poggi et al., 2005; Zebrack et al., 2004; Zebrack et al.,

2007; Zeltzer et al., 2009). PBT survivors, particularly adolescent and young adult survivors,

may be placed at increased risk of low self‐esteem and self‐identity issues due to social

factors, such as the sense of being “left behind”, feeling disconnected from their peers, or

having anxieties about altered physical appearance (Vetsch et al., 2017). Psychological

problems may persist into adulthood, as findings indicate that psychological distress may

emerge several decades after the original diagnosis (Brinkman et al., 2013).

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Several risk factors for elevated distress symptoms in adulthood have been identified.

Demographic and socioeconomic risk factors of psychological distress are much the same

as for the general population, and include female sex, older age at diagnosis (i.e ., during

adolescence), single or divorced marital status, lower education, unemployment, and an

annual household income of <$20.000 (Bitsko et al., 2016; Ness et al., 2008; Stavinoha et

al., 2018; Zebrack et al., 2007; Zeltzer et al., 2008; Zeltzer et al., 2009). On the other hand,

psychological symptoms may also mediate poorer QoL, lower income, lower education,

and disability status, and the causal direction between these factors remains unclear (Bell,

Ownsworth, Lloyd, Sheeran, & Chambers, 2018; Brinkman, Li, et al., 2016; Brinkman,

Recklitis, et al., 2018).

Treatment-related and medical risk factors, such as severe medical late effects (e.g.,

relapses, secondary malignancies), functional or sensorimotor deficits, pain, and

cardiovascular, endocrine, and/or pulmonary conditions subsequent to cancer treatment

(particularly CRT) are linked to a risk of developing symptoms of depression, anxiety, and

posttraumatic stress (e.g., Cousino et al., 2017; Greenberg, Kazak, & Meadows, 1989;

Ozono et al., 2007; Vuotto et al., 2017). Also, self-perceptions of poor physical health

status and physical symptoms has been linked to higher levels of psychological distress,

along with other individual psychological characteristics such as inefficient coping styles,

social skill development and temperament in both adolescent and young adult survivors

(Brinkman et al., 2013; Kupst & Patenaude, 2016; Schwartz et al., 2012; Stavinoha et al.,

2018; Vuotto et al., 2017). Furthermore, psychological distress may predict poor health

behaviors, i.e., smoking, alcohol use, fatigue, and altered sleep (Zeltzer et al., 2009).

Lastly, and importantly, neurocognitive dysfunction, particularly EF problems, has been

consistently associated with emotional and behavioral health concerns (Stavinoha et al.,

2018).

The importance of social factors, such as increased parental psychological symptoms,

family dysfunction, and separation from peers and social networks, have increasingly been

associated to negative impacts on psychological outcomes in survivors of childhood

cancers (Cousino et al., 2017; Klassen et al., 2011). For example, one study showed an

indirect effect of illness-specific family burden on the number of late effects and parent

reported survivor internalizing problems (Cousino et al., 2017). Also, the influence of

demographic factors, such as marital status and income, may underline the importance of

25

socioemotional and instrumental support for long-term psychological functioning.

Altogether, these findings demonstrate that PBT survivors may, for a wide variety of

reasons, be at risk of negative long-term psychological and emotional functioning.

However, there are some important short-comings in the extant studies of long-term mental

health in childhood cancer survivors that need to be considered. Compared to the literature

on the adult PBT survivor population, current knowledge on mental health in adolescent

PBT survivors is sparser, as only a few studies have examined mental health among

adolescent CCS populations, especially among adolescent PBT survivors (Bell et al., 2018;

Brinkman, Li, et al., 2016; Brinkman, Recklitis, et al., 2018). Furthermore, according to a

systematic review by Bell et al. (2018) focusing on studies of younger PBT survivors, most

of the extant studies of QOL and mental health have utilized proxy reports (i.e.,

parent/caregiver and/or teacher reports), with only a small number of studies investigating

the children’s own reports of mental health or QOL. This is methodologically problematic,

as several studies have found systematic discrepancies in child and parent reports for

children suffering from cancer and other chronic illnesses, where parents typically have

poorer reports of social or emotional functioning than their children (Jurbergs, Russell,

Long, & Phipps, 2008; Sung et al., 2008). There have been offered different explanations

for these discrepancies regarding report tendencies in both children and parents. For

example, a repressive adaptive style of the child, psychological defense mechanisms (e.g.,

a need to move forward and to be “normal”) and possible impairments in self-awareness,

may lead to the underreporting of difficulties in young survivors, whereas parental reports

may become inflated due to parental distress (Jurbergs et al., 2008; Lund, Schmiegelow,

Rechnitzer, & Johansen, 2011; Meeske, Katz, Palmer, Burwinkle, & Varni, 2004; O’Leary,

Diller, & Recklitis, 2007; Phipps, Steele, Hall, & Leigh, 2001). Therefore, the impact of

PBT on subjective well-being in the younger survivors is not yet well known. Also, the

studies that have employed subjective reports have shown mixed results (Bell et al., 2018).

Whether the discrepancies between self- and proxy reports persist into adulthood, is not yet

known.

1.2.4 Fatigue

One of most frequent and debilitating late effects following PBT treatment is excessive

fatigue (van Deuren et al., 2020). Fatigue refers to the persistent, subjective experience of

26

physical, emotional, and/or cognitive tiredness and lack of energy, not proportional to recent

activity, and interfering with usual functioning (Bower, 2014; Zeller et al., 2014).

Furthermore, there are findings to suggest that survivors of PBT experience more fatigue than

other childhood cancer survivors (e.g., patients with ALL) (Meeske et al., 2004).

While fatigue reduces upon treatment completion in many PBT survivors, for some the

symptoms may persist several years, and the etiology of persistent post-treatment fatigue

remains somewhat unclear (Boonstra et al., 2017; Brand et al., 2016; Clanton et al., 2011;

Mulrooney et al., 2008). However, fatigue after childhood cancer has been linked to several

predisposing, triggering, maintaining and modulating factors, such as demographic factors

(e.g., age, sex, unmarried status, low income), genetic disposition (i.e., genetic components

that affect proinflammatory cytokine activity), biological and treatment-related mechanisms

(e.g., inflammatory processes, cytokine dysregulation, anemia, hypothalamic–pituitary–

adrenal (HPA) axis dysregulation, 5-hydroxytryptophan neurotransmitter dysregulation, and

alterations in ATP and muscle metabolism), medical factors (e.g., medical comorbidities,

medications, nutritional issues), and psychological and biobehavioral factors (e.g.,

depression, coping and appraisal of the diagnosis and/or treatment, emotional support, sleep

disturbance, physical inactivity and body mass) (Bower, 2014; van Deuren et al., 2020).

Severe fatigue may in many cases be one of the most debilitating late effects, leading to

lowered levels of societal participation (e.g., an inability to work or attend school, engage

socially), and as such, having a negative impact on overall QoL (Bower, 2014; Brand et al.,

2016; Meeske, Patel, Palmer, Nelson, & Parow, 2007; Zeltzer et al., 2009).

1.2.5 Long-term outcomes; psychosocial adjustment and socioeconomic outcomes

Separately or together, late effects after PBT and treatment exposure may have a cumulative

negative impact on survivors’ long-term outcomes in terms of social engagement, educational

achievement, vocational attainment, financial independence, and thus, overall QoL. Within all

these areas, PBT survivors have been shown through several studies to be particularly

vulnerable to adverse outcomes, compared to other CCS populations (Frederiksen et al.,

2019).

Social difficulties are not uncommon among long-term PBT survivors (Barrera, Shaw,

Speechley, Maunsell, & Pogany, 2005; Brinkman, Recklitis, et al., 2018; Warner et al., 2016).

27

Due to potentially lengthy treatment protocols and recovery periods, children/adolescents with

PBT may have significant absences from the home environment, friends, and school. Because

schools and educational facilities are vital arenas for social competence learning and

achieving a sense of normality and participation, such absences, combined with the presence

of late effects, can influence the development of age appropriate social behavior and skills.

Social difficulties, such as poor peer acceptance, isolation, and difficulties developing and

maintaining social relationships (friendship, partnership, family relationships), may have a

fundamental negative effect on psychological well-being, QoL, and societal integration and

participation.

Several studies have shown that PBT survivors are at risk of lower levels of academic and

educational achievement compared to other CCS populations and the general population (e.g.,

Barrera et al., 2005; Brinkman, Recklitis, et al., 2018; Vetsch et al., 2017). Late effects, such

as poor neurocognitive functioning, physical health problems, fatigue, and pain, significantly

hinder successful engagement in schooling and academic learning. Social difficulties, low

self‐esteem, and self‐identity issues may further impede survivors’ successful return to school

(Fardell et al., 2018). The impact of neurocognitive impairments, more specifically executive

dysfunction, on academic achievement is addressed further in chapter 3.

As a growing number of PBT survivors are aging into adulthood, negative long-term

outcomes such as an inability to achieve independent living and poorer socioeconomic

outcomes (e.g., vocational attainment, need for financial support), is becoming more apparent.

These problems put psychosocial and financial strain on the individual survivor and his/her

family, and place a financial burden on society. Studies of long-term survivors of CNS tumors

have consistently reported lower income, lower occupational position, higher numbers of

unemployment, and higher need of government disability benefits compared to siblings, the

general population, and other CCS populations (Brinkman, Ness, et al., 2018; Brinkman,

Recklitis, et al., 2018; Frederiksen et al., 2019; Ghaderi et al., 2013; Kirchhoff et al., 2011;

Mader, Michel, & Roser, 2017). In fact, results from a large CCS study in the U.S., i.e., the

Childhood Cancer Survivor Study, indicated that only 40% of adult CNS tumor survivors

achieve complete independence, and that nonindependent survivors were more likely to be

living dependently (e.g., with caregivers), to be unemployed, to require assistance with

personal care and routine needs, to be unable to drive, and to be unmarried (Brinkman, Ness,

et al., 2018). Associated factors to adverse socioeconomic outcomes are CRT, younger age at

28

diagnosis, impaired IQ, limitations in physical performance and adaptive physical function,

female sex, and cancer-related late effects (Brinkman, Ness, et al., 2018; Brinkman, Recklitis,

et al., 2018).

Although several important risk factors have been identified, few studies have investigated the

unique contribution of psychological mechanisms in this patient population, such as EFs,

which may be of particular importance for academic learning, social skills development, and

educational and vocational outcomes (Frederiksen et al., 2019). In the following chapter, EF

conceptualizations and developmental models are summarized (i.e., both general models, and

models focusing on the PBT survivor population). These conceptualizations and models

illustrate how this skill set plays a fundamental role in academic and social development, and

further, how it is “necessary for appropriate, socially responsible and effectively self-serving

adult conduct”, as described by Lezak, Howieson, Bigler, and Tranel (2012).

1.3 Executive functions

1.3.1 Conceptualizations and developmental models

In the early literature, EFs were mainly linked to (pre)frontal lobe functioning, as the patients

that were observed with executive dysfunction had damages to frontal lobe regions (Lezak et

al., 2012). Since then, knowledge on the underlying neural circuitry of these functions has

expanded considerably. It is now generally acknowledged that EFs rely greatly on the

intactness of multiple cooperating cortical and subcortical networks, and that the prefrontal

regions may be viewed as analog to a “conductor” or orchestrator of EF skills (Gioia et al.,

2001; Goldberg, 2001; Kalbfleisch, 2017; Stuss & Alexander, 2000). EFs are therefore

vulnerable not only to frontal lobe lesions, but also to lesions in other parts of the brain, for

example the cerebellum, a common site for PBT (Anderson, Jacobs, & Harvey, 2008;

Moberget et al., 2015; Riva & Giorgi, 2000). Furthermore, as the structural maturation and

remodeling of the frontal lobes is prolonged, spanning from infancy to young adulthood, so is

the developmental trajectory of EFs, thus creating a vulnerability to damages at any time point

of brain development (De Luca & Leventer, 2008).

Although there is no universal consensus on the definition of EF, it may be characterized as a

multidimensional construct, consisting of collection of higher-order cognitive processes and

skills that make up the natural human capacity to control, organize, and direct cognitive,

29

behavioral, and emotional responses in a dynamic environment (Gioia et al., 2001;

Kalbfleisch, 2017; Lezak et al., 2012; Miyake et al., 2000; Stuss & Alexander, 2000). Lezak

et al. (2012) describe the fundamental difference between EFs and other neurocognitive

functions as follows: while the latter are related to the “what” and “how much” a person can

do (e.g., “what/how much do you know?”), EFs are involved in the “how” and “whether” a

person will go about doing something (e.g., “will you do x? If so, when and how will you do

it?”). One of the purposes of EFs is thus setting and reaching goals in a dynamic environment

(e.g., “will you reach your goal, and how?”), and goal attainment is therefore central in

several definitions of EFs. For example, the International Neuropsychological Society’s

dictionary of neuropsychology defines EFs as “cognitive abilities necessary for complex goal-

directed behavior and adaptation to a range of environmental changes and demands.

Executive function includes the ability to plan and anticipate outcomes (cognitive flexibility),

and to direct attentional resources to meet the demands of nonroutine events” (INS dictionary

of neuropsychology, 2015, p.143). Successful complex goal-directed behavior rely on EF

processes such as the ability to identify, plan and organize steps involved; to be aware of

one’s behavior in relation to situational demands; to initiate purposive action; to persevere in

the presence of distraction; and to monitor and flexibly self-correct or shift to more effective

strategies for achieving the anticipated outcome (Lezak et al., 2012). Put simply, EFs

constitute capacities that enable the individual to manage and self-regulate him- or herself,

and to engage successfully with the environment (Kalbfleisch, 2017).

Regardless of the definition one ascribes to, they generally have in common that they reflect

shared, but diverse functions, a pattern that has been described as “unity and diversity”

(Friedman & Miyake, 2017). Miyake et al.’s (2000) influential model expanded the

knowledge on the relations between subdomains of EF, and showed how they, by controlling

and coordinating specific cognitive processes, are involved not only in behavior regulation,

but also in the performance of complex cognitive tasks. In their model, they focus on three of

the most commonly discussed EFs in the literature; (a) shifting between mental tasks or sets,

(b) updating, monitoring and manipulation of working memory representations (i.e.,

maintaining information active in consciousness while performing mental operations to

achieve a goal), and (c) inhibitory control of dominant or prepotent responses (e.g., stopping

automatic (incorrect) responses or resisting attending to irrelevant information). Their

findings showed that these three processes are separable, but interrelated cognitive EF factors,

and that each may be observed by employing certain neuropsychological tests. Since then,

30

several studies have replicated the unity and diversity of these three EFs. However, the

authors did not intend for the model to be considered exhaustive, and maintain that it is likely

that there are also other EF subdomains (Friedman & Miyake, 2017).

1.3.2 Hierarchical developmental models

The unity and diversity of EFs is reflected also in developmental models, and recently the

literature has begun to move beyond describing the protracted developmental trajectories of

individual EFs, to investigating the mechanisms for this development. Several developmental

theories suggest that EFs may emerge hierarchically throughout childhood, i.e., that simple

EFs with earlier developmental periods, such as sustained attention and inhibitory control,

may facilitate and be the foundation for more complex EFs with more prolonged

developmental curves, such as working memory and shifting (Tillman, Brocki, Sørensen, &

Lundervold, 2013). More specifically, it is suggested that as inhibitory control becomes more

efficient, sustained attention is consequently improved, thereby facilitating working memory

resources. This theoretical perspective harmonizes with trajectory studies showing that,

parallel to the maturation and remodeling of brain structures, inhibitory control is in active

development between the early preschool years to about age 11 (e.g., Brocki & Bohlin, 2004;

Garon, Bryson, & Smith, 2008; Romine & Reynolds, 2005, Tillman et al., 2013), whereas

working memory and shifting, although also relatively early developing, seem to have a

slower and more prolonged trajectory, developing into middle adolescence (e.g., Garon et al.,

2008; Gathercole, Pickering, Ambridge, & Wearing, 2004; Huizinga, Dolan, & van der

Molen, 2006; Luciana, Conklin, Hooper, & Yarger, 2005). The complexity and protraction of

EF development is a likely explanation as to why studies in pABI populations have shown

that although EF deficits may be subtle upon injury, there is a tendency to “grow into deficit”

with time, with a delayed onset and increase of impairments (Anderson et al., 2019).

Environmental factors no doubt contribute to this tendency, as difficulty levels and cognitive

demands (e.g., in social and academic settings) gradually increase throughout childhood,

adolescence and young adulthood (Anderson, Jacobs, & Harvey, 2008; de Vries et al., 2017).

1.3.3 Neurodevelopmental cascade models for declines in IQ and academic achievement

in PBT survivors

Research findings in the field of child neuropsychology have repeatedly shown that EFs in

childhood predict later academic achievement and educational level, and that this effect has

31

primacy over the effects of intelligence (Zelazo et al., 2016). Within the PBT literature,

developmental models of neurocognitive mechanisms involved in the declines in both IQ and

academic achievement have emerged over the past decade. Several models take into account

tumor and treatment factors that interact with the child’s age, sex, and neurodevelopment, to

predict the declines in core cognitive functions such as processing speed, attention span, and

working memory that have been consistently demonstrated in the PBT population (Edelstein

et al., 2011; King et al., 2019; Palmer, 2008; Rey-Casserly & Diver, 2019; Wolfe et al., 2012).

Based on a cognitive cascade model explaining IQ improvements in typically developing

children (Fry & Hale, 2000), Palmer (2008) proposed a pathway model where impaired

processing speed and selective attention disrupt working memory, which in turn leads to a

negative cascading effect on IQ and academic achievement in survivors of medulloblastomas.

Wolfe et al. (2012) later expanded on this work, arguing for a more comprehensive theoretical

model, in which they incorporate similar core cognitive functions as the Palmer (2008) model

(i.e., attention, processing speed, working memory), but also include general EFs, such as

planning and metacognition. They argue that each core cognitive function has a unique, and

potentially combined, impact on IQ and academic achievement in survivors of posterior fossa

patients treated with CRT.

The models put forward by Palmer (2008) and Wolfe et al. (2012) both have strong scientific

foundations. More recently, with the purpose of testing these models empirically, King et al.

(2019) found evidence for Wolfe et al.’s (2012) theoretical model in a sample of survivors of

pediatric posterior fossa tumors treated with CRT. However, they also showed that a hybrid

model combining the two models had the best fit in their sample. In their hybrid model,

neurodevelopmental risk factors have a direct impact on processing speed, in turn disrupting

attention and working memory (cf., Palmer [2008]) model), and that all three core skills

contribute to later declines in IQ and academic achievement (cf., Wolfe et al. [2012]).

However, an important limitation to the hybrid model is that the authors were not able to

include general EFs as contributing factors. Moreover, while these models offer strong

explanations of factors culminating in negative long-term outcomes, neither take into account

the social-affective or behavioral aspects of EF, which are equally important for everyday

functioning. The significance of these aspects of EF is presented in the following section.

32

1.3.4 Adding temperature and context to the mix: the hot/cool distinction

Interestingly, although impaired control and regulation of behavior after frontal lobe lesions

were initially the focus of research on EF (e.g., the well-known case of the unfortunate

Phineas Gage), EF research continued for a long time to emphasize the cognitive aspects of

EF, i.e., the abstract, decontextualized and non-emotional EFs, such as the three core skills in

Miyake et al.’s (2000) influential model. However, to many authors, this conceptualization

did not capture the executive processes that are needed additionally for successful interaction

with everyday surroundings, and for behavior regulation in contexts that evoke emotions. Nor

could adaptive decision making and goal-oriented behavior be explained solely on the basis of

this traditional view. In response to this need, several authors called for a distinction between

so-called “cool” and “hot” EF processes (Anderson, Jacobs, & Anderson, 2008, p. xxviii;

Happaney, Zelazo, & Stuss, 2004; Metcalfe & Mischel, 1999; Peterson & Welsh, 2014;

Zelazo & Carlson, 2012; Zelazo, Qu, & Kesek, 2010). Cool EF skills, i.e., the cognitive

aspects of EF, operate in emotionally neutral contexts, and include functions such as

attentional control, working memory, initiation, planning and organizing, selection of efficient

problem-solving strategies, mental flexibility and utilization of feedback. Hot EF skills, on the

other hand, operate in contexts that evoke emotions, motivation, and the competition between

instant gratification and long-term rewards (Peterson & Welsh, 2014; Zelazo et al., 2010).

They are involved in the ability to exert appropriate control and regulation of emotional and

behavioral responses, e.g., by adapting to change, and by initiating, monitoring, and inhibiting

impulses and responses in accordance with situational and social demands and expectations

(Anderson, Jacobs, & Anderson, 2008, p. xxviii; Metcalfe & Mischel, 1999; Zelazo &

Carlson, 2012). Hot EFs are essential components in empathy, emotion regulation, moral

understanding, and affective decision-making (De Luca & Leventer, 2008). Importantly,

despite the theoretical distinction between cool and hot functions, they are very much

interconnected and work together in concert in everyday functioning. This may be the reason

why research findings have not consistently been able to differentially predict adaptive “real-

world” behaviors on the basis of hot or cool EFs, although there is some evidence that cool

EFs are associated to academic performance (Peterson & Welsh, 2014).

Studies in brain injury populations lend strong scientific support to the hot/cool distinction, as

findings show that impairments of hot EF may exist in the absence of impaired cool EF, and

vice versa (Anderson, Anderson, Jacobs, & Smith, 2010). Further supporting this distinction

are studies of adult patients with damages to orbitofrontal and ventromedial prefrontal

33

regions. These are brain regions that are highly overlapping, with rich neuroanatomical

connections to limbic areas involved in emotional and social processing. Patients with

damages to these areas exhibit social regulation impairments, as well as an inability to

consider future consequences during decision-making (Bechara, 2004; Beer, 2006; Peterson

& Welsh, 2014; Yeates et al., 2007). Impairments such as these may occur in spite of

relatively intact general cognitive abilities, and without significant impairment in traditional

cognitive EF processes like working memory and planning, which are associated with

dorsolateral areas of the prefrontal cortex. In a developmental perspective, some studies have

shown that hot and cool EF skills are in active development in the age period of 3–5 years,

and moreover, that cool processes may mature ahead of hot processes (Peterson & Welsh,

2014). Unfortunately, research efforts have yet to provide conclusive evidence for the

developmental trajectories of these two EF domains, likely due to methodological challenges,

and that the task of detangling this question is rarely undertaken.

The development of hot and cool aspects of EF are intimately related to the development of

social information processing and social competence (Peterson & Welsh, 2014; Riggs,

Jahromi, Razza, Dillworth-Bart, & Mueller, 2006; Ryan et al., 2016; Yeates et al., 2007). In

several developmental models of social competence and interpersonal skills, EFs are key

components underlying and facilitating this development (Beauchamp & Anderson, 2010).

For example, Yeates et al. (2007) propose a heuristic model of social competence in children

with brain disorder, where social–affective (hot EFs, e.g., emotional control) and cognitive–

executive processes (cool EFs, e.g., working memory) facilitate social information processing,

which in turn mediates social interaction and adjustment. Working memory and inhibitory

control in particular have been found to be in involved in social behavior. For example, a

study in typically developing children found evidence that poor working memory is linked to

social impairments such as peer rejection, poor overall social competence, and impaired

conflict resolution skills (McQuade, Murray-Close, Shoulberg, & Hoza, 2013). Also, studies

in various pABI populations, including PBT survivors, have shown a link between various

aspects of executive dysfunction and impaired social functioning and societal participation

(Muscara et al., 2008; Sirois et al., 2017; Willard et al., 2015; Wolfe et al., 2013).

Altogether, executive dysfunction, and its subsequent impact on other functional domains

(e.g., social and academic difficulties), may contribute to account for poorer outcomes in

survivors of PBT in terms of educational attainment, employment, financial independence,

34

independent living and social relationships. Further knowledge on the idiosyncratic EF profile

of PBT survivors is needed, in order to help tailor suitable interventions.

1.3.5 Assessment of EFs

As challenging as it is to capture the complexity of EFs in a single definition, so is the task of

operationalization and assessing these functions. Traditionally, performance-based

neuropsychological measurements employing pencil-and/or-paper tests have been the “gold

standard” for identifying and quantifying executive dysfunction. For example,

neuropsychological tests such as the Trail Making Test 4 (i.e., number-letter switching) and

the Color-Word Interference Test 3 (i.e., inhibition) from the Delis-Kaplan Executive

Function System (D-KEFS; Delis, Kaplan & Kramer, 2001) are frequently used to tap the

domains “shifting” and “inhibitory control”, respectively, while the subtest Digit Span

Backward from the Wechsler Intelligence scales Adult Intelligence Scale –IV (WAIS-IV;

Wechsler, 2008 WISC-IV; Wechsler, 2003) may be utilized to tap the “working memory”

domain.

However, the performance-based approach has been strongly criticized for lack of ecological

validity, i.e., for not reflecting the complexity and demands of real life situations. The

assessments are administered in a clinical laboratory-like setting that is structured, free from

distractions, and lasting over a relatively short period of time. The examiner prompts the

patient to comply with test requirements, leaving no need for initiative, self-regulation or

creativity from the patient. Consequently, executive dysfunction may go undetected by the

examiner. Moreover, while performance-based assessments are considered suitable for

assessing cognitive (cool) aspects of EF, they do not as effectively capture the social-

affective/behavioral (hot) aspects. For these reasons, performance-based results do often not

match observed behavior in the home and/or school environment (Anderson, Anderson,

Northam, Jacobs, & Mikiewicz, 2002; Gioia, Kenworthy, & Isquith, 2010) .

In order to meet the need for a more comprehensive assessment of EFs, neuropsychologists

and researchers have increasingly incorporated the use of questionnaires over the past two

decades. Importantly, questionnaires reflecting both self-report and informant report are

recommended, as executive dysfunction has been linked to diminished levels of self-

awareness in several pABI populations, including PBT survivors (Krasny-Pacini et al., 2015;

35

McCurdy, Turner, et al., 2016; Sølsnes, Skranes, Brubakk, & Løhaugen, 2014). For example,

studies have found that PBT survivors tend to overestimate their own EF skills, and

underestimate peer relationship difficulties (Devine et al., 2016; McCurdy, Turner, et al.,

2016). Also, as mentioned in chapter 1, several studies have identified reporter discrepancies

in pediatric populations, including CCS populations, where chronically ill children tend to

report fewer problems than their parents (Jurbergs et al., 2008; Lund et al., 2011). A

commonly applied questionnaire both in clinical settings and research, is the Behavior Rating

Inventory of Executive Function, for which there are several versions, including self-report,

parent report, and informant report versions for most age groups (BRIEF; Gioia, Isquith, Guy

& Kenworthy, 2000; BRIEF-A; Roth et al., 2005).

36

2. AIMS

The overall aim of this cross-sectional study was to determine the presence and degree of

executive dysfunction in adolescent and young adult survivors of PBT compared to a healthy

control group, and to explore the significance of executive dysfunction for long-term

outcomes, i.e., adaptive functioning/psychosocial adjustment, academic and vocational

achievement, and financial independence, compared to psychological problems and symptoms

of fatigue.

2.1 Paper I

In the first paper, the aim was to investigate the presence and degree of self-reported long-

term executive dysfunction, psychological and emotional problems in young, physically well-

functioning adult survivors of PBT, and to determine whether this population has a specific

profile of self-reported EF with respect to the hot and cool aspects of EF.

2.2 Paper II

In the second paper, the aim was to investigate self-reported social attainment in young,

physically well-functioning adult survivors of PBT compared to the healthy control group,

and to investigate how self-reports of executive dysfunction, psychological and emotional

problems, and fatigue, were related to less favorable social outcomes.

2.3 Paper III

In the third paper, the aim was to explore the long-term neurocognitive consequences of PBT

in adolescent survivors, with a special focus on the EF profile (i.e., regarding the “hot” and

“cool” aspects of EF), as evidenced by parent and self-reports and performance-based

measures. Furthermore, the purpose was to explore whether adolescent PBT survivors

experience more problems with adaptive functioning (i.e., academic achievement and social

functioning) compared to a healthy control group, and to which degree executive dysfunction

was associated to poor adaptive functioning compared to psychological problems and fatigue.

37

3. METHODS

3.1 Participants and procedure

A flowchart of the study is shown in Figure 2. Survivors of PBT were identified by The

Cancer Registry of Norway, and included when fulfilling inclusion criteria defined as

treatment for PBT at 0-16 years, between 1990-2012, aged 13-30 at recruitment, and having

completed treatment no later than 2 years prior to study participation. Exclusion criteria

included self-/parent reported severe difficulties with activities of daily life (ADL), self-

/parent reported severe sensory and motor disabilities, and pre-tumor cognitive/neurological

deficits due to non-tumor diagnoses, evidenced in patient records. The exclusion criteria

regarding ADL and sensory-motor functions are factors that may affect participation in

society irrespective of the status of EF, and as such, could interrupt the main research goal.

Participants were divided into two groups; an adolescent survivor group, aged 13-17 years,

and a young adult survivor group, aged 18-30 years.

All eligible PBT survivors were invited to complete self-report forms on EF, psychological

and emotional functioning. The adolescent PBT survivor group also received parent report

forms. The young adult PBT survivors received informant forms, and were asked to distribute

these forms to a person of their own choosing, i.e., a person who knows them well.

Information on tumor histology, location, age at diagnosis, and type of treatment was obtained

from patient records, and the third version of the International Classification of Childhood

Cancer (ICCC-3) was used to classify participants into larger diagnostic subgroups. Treatment

regimens (e.g., surgery, CRT, chemotherapy), neurological late effects and psychiatric

comorbidity (i.e., as classified by the International Classification of Disease -10 codes F01-

F99) were registered as yes/no. Clinical characteristics for both age groups are presented in

Table 2. For both age groups, healthy control groups were recruited from The National

Population Register of Norway. The PBT survivor and control groups were matched for age

and sex. The healthy young adults received self-report forms identical to those of the young

adult PBT survivor group. In addition to identical self-reports, the healthy adolescent control

group received parent report forms identical to that of the adolescent PBT survivor group.

Papers I and II present findings in the young adult survivor group, and paper III presents

findings in the adolescent survivor group.

38

Figure 2 Flowchart of the study

Deceased: n=2

Non-tumor cerebri diagnoses: 18-30 years: n=30

(e.g., cortical dysplasia, cysts, extracranial tumors)

No longer living in Norway/unknown address: 18-30 years: n=6

Patient records unavailable: 18-30 years: n=3

Target population:

452 eligible survivors from the Norwegian Cancer Registry

13-17 years: n=99, 18-30 years: n=353

Survivors receiving self- and informant report forms:

13-17 years: n=99, 18-30 years: n=312

Responded,

13-17 years: n=57 (57.6%)

18-30 years: n=131 (42.0%)

Did not respond,

13-17 years: n=42 (42.4%)

18-30 years: n=181 (58.0%)

Treatment for recurrent/residual tumor < two years:

13-17 years: n=3, 18-30 years: n=12

Pre-tumor cognitive/neurological problems:

13-17 years: n=2, 18-30 years: n=5

Non-tumor cerebri diagnoses: 13-17-years: n=4

Total survey response:

13-17 years:

Self- and parent reports: n=48 (53.3%)

18-30 years:

Self-reports: n=114 (38.6%)

Self- and informant reports: n=89 (30.2%)

Adolescent survivors invited for

neuropsychological assessments:

n=36

Total participation, neuropsychological

assessments:

n=26 (72.2%)

39

Table 2 Clinical characteristics

N adolescent group

(n=48)

%

N young adult

group (n=48)

%

Tumor diagnosis

Ependymomas and choroid

plexus tumors

6 12.5 6 5.3

Astrocytomas 23 47.9 49 43.0

Embryonal tumors 16 33.3 32 28.1

Other gliomas 1 2.1 14 12.3

Other CNS-tumors 2 4.2 11 9.6

Unidentified 0 0 2 1.8

Tumor location

Supratentorial 14 29.2 61 55.5

Infratentorial 32 66.7 46 41.8

Both 2 4.2 3 2.7

Treatment

No treatment 0 0 3 2.8

Surgery only 28 58.3 74 69.2

Chemotherapy only 0 0 1 .9

Surgery and chemotherapy 9 18.8 2 1.9

Surgery and CRTa

1 2.1 5 4.7

Surgery, chemotherapy and

CRTa

10 20.8 22 20.6

Number of surgeries

One surgery 40 83.3 77 74.8

Two or more surgeries 8 16.7 26 25.2

Postoperative hydrocephalus

treatmentb

Yes 7 14.6 20 18.5

No 41 85.4 88 81.5

Postoperative seizures

Yes 6 12.5 25 23.4

No 42 87.5 82 76.6

40

Hormone replacement treatmentc

Yes 12 25.0 25 22.1

No 36 75.0 88 77.9

Psychiatric comorbidity

Yes 8 15.7 19 16.7

No 43 84.3 95 83.3

a CRT=cranial/craniospinal irradiation therapy

b Ventriculoatrial shunt (VA),

ventriculperitoneal shunt (VP) or third ventriculostomy (3CVS), c Hormone replacement

treatment, e.g., growth hormone, cortisol, thyroid stimulating hormone, testosterone and

estrogen, and antidiuretic hormone.

3.2 Long-term outcome measures

3.2.1 Questionnaires (papers I, II and III)

The questionnaires utilized in this study were selected from the need to assess several

domains, i.e., EF, psychological problems, fatigue and adaptive functioning. In order to cover

all domains in both age groups, several questionnaires were needed, as no single questionnaire

could suffice.

Executive functioning

The self- and informant report versions of the Behavior Rating Inventory of Executive

Function - Adult Version (BRIEF-A; Roth et al., 2005) and the parent report version of the

Behavior Rating Inventory of Executive Function (BRIEF; Gioia, Isquith, Guy & Kenworthy,

2000) were used to assess EF in everyday activities over the past 6 months. Three indices are

generated: the Behavior Regulation Index (BRI), the Metacognitive Index (MI;) and a Global

Executive Composite (GEC). The BRIEF-A BRI contains subscales reflecting

behavioral/emotional aspects of EF (Inhibit, Shift, Emotional Control, and Self-Monitor), as

does the BRIEF BRI, although it does not contain the Self-Monitor subscale. The BRIEF-A

MI subscales reflects cognitive aspects of EF (Initiate, Working Memory, Plan/Organize,

Task Monitor, and Organization of Materials), as do the BRIEF MI subscales, although

instead of the Task Monitor subscale, the BRIEF MI contains the more general Monitor

subscale. The BRI and the MI indices serve as measures of the hot and cool aspects of EF,

respectively.

41

Psychological and behavioral problems and adaptive functioning

For psychological and behavioral problems, we used the Achenbach System of Empirically

Based Assessment questionnaires (ASEBA; Achenbach & Rescorla, 2001; Achenbach &

Rescorla, 2003), which is a family of screening tools for psychological symptoms and

behavioral problems. We used the Youth Self-Report version (YSR), the Child Behavior

Checklist (CBCL; parent report version), the Adult Self-Rating (ASR), and the Adult

Behavior Checklist (ABCL; informant report version). The YSR and the CBCL consist of

eight syndrome scales; Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints,

Social Problems, Thought Problems, Attention Problems, Rule-Breaking Behavior, and

Aggressive Behavior. The ASR and ABCL yield similar syndrome scales;

Anxious/Depressed, Withdrawn, Somatic Complaints, Thought Problems, Attention

Problems, Aggressive Behavior, Rule-Breaking Behavior, and Intrusive Behavior. For all four

versions, three composite scores are produced; Total Problems, Internalizing Problems (sum

of the scales Anxious/Depressed, Withdrawn/Depressed [YSR, CBCL]/Withdrawn [ASR,

ABCL] and Somatic Complaints), and Externalizing Problems (sum of the scales Aggressive

[ASR, ABCL]/ Aggressive Behavior [YSR, CBCL], Rule-Breaking Behavior and Intrusive

behavior [ASR, ABCL]). The subscales Attention (YSR, CBCL) and Attention Problems

(ASR, ABCL) reflect subjective cognitive complaints. The ASEBA questionnaires also

contain a subscale reflecting adaptive functioning, generating the subscale Total Competence

for the YSR and the CBCL (i.e., items on the adolescent’s activities, social relations, and

academic performance), and the Adaptive Functioning subscale for the ASR and the ABCL

(i.e., items relating to friends, spouse or partner, family, education, and work).

For the adolescent survivor group, we also employed the self-report and parent report version

of the Pediatric Quality of Life Inventory 4.0 (PedsQL; Varni, Seid, & Kurtin, 2001)

measuring QoL, yielding the subscales Physical, Emotional, Social, and School Functioning,

as well as a total score; PedsQL Total. For the young adult survivor group, we used the

Symptom Checklist-90-Revised (SCL-90-R; Derogatis, 1994) to assess the presence and

severity of psychological symptoms. Nine symptom scales are generated; Somatization,

Obsessive-Compulsive, Interpersonal Sensitivity, Depression, Anxiety, Hostility, Phobic

Anxiety, Paranoid Ideation, and Psychoticism, and a measure of global symptom severity

(Global Severity Index; GSI).

42

Fatigue

In order to assess the presence of fatigue in the adolescent survivor group, we employed The

PedsQL-Multidimensional Fatigue Scale (PedsQL-MFS; Varni, Burwinkle, Katz, Meeske &

Dickinson, 2002), which is a self-report questionnaire, consisting of the subscales General

Fatigue, Sleep/Rest Fatigue and Cognitive Fatigue subscales, as well as a total score; PedsQL-

MFS Total. For the young adult survivor group, we used the Fatigue Questionnaire (FQ;

Chalder et al., 1993) which includes subscales reflecting mental fatigue (MF; 4 items) and

physical fatigue (PF; 7 items), and yielding a total fatigue score (TF).

Socioeconomic outcomes

In addition to the questionnaires, the young adult PBT survivor group and young adult healthy

control group were asked to provide personal data on social outcomes, i.e., living situation,

education, work, and governmental benefits. More detailed descriptions of this personal data

and the questionnaires employed in this study can be found in Papers I-III.

3.2.2 Performance-based measures (paper III)

A subgroup of the adolescent PBT survivors, who have been followed up with multiple

neuropsychological assessments after treatment completion at Oslo University Hospital, also

underwent cognitive retesting. Of 36 invited, 26 (72.2%) underwent retesting. For this

subgroup, the mean age at diagnosis was 6.3 years (range=.3-13.3, SD=3.97) and mean time

since treatment completion was 8.9 years (range=4.0-14.1, SD=3.63). Mean age at cognitive

retesting was 16.6 years (SD=1.37). Clinical characteristics for the retested subgroup are

presented in Paper III. No survivors in the subgroup undergoing cognitive retesting reported

sensory or motor impairments seriously disrupting everyday functioning. The tests were

grouped into neurocognitive domains, i.e., estimated current IQ, processing speed, auditory

attention span, sustained attention, verbal learning and recall, verbal fluency and executive

functions, by calculating the average T-scores within each domain. Clinical cutoff was

defined as a score of 1.5 standard deviations or more below the normative mean.

Estimated current IQ

The Vocabulary and Matrix Reasoning subtests from the Wechsler Abbreviated Scale of

Intelligence (WASI; Wechsler, 1999) were employed to estimate current IQ.

43

Processing speed

The subtests Trail Making Test 2 (TMT 2; number sequencing) and 3 (TMT 3; letter

sequencing), and Color-Word Interference Test 1 (CWIT 1; color naming) and 2 (CWIT 2;

word reading), from the Delis-Kaplan Executive Function System (D-KEFS; Delis, Kaplan &

Kramer, 2001) were used to assess processing speed.

Auditory attention span

The Digit Span Forward scores from the Wechsler Adult Intelligence Scale –IV (WAIS-IV;

Wechsler, 2008) for participants aged >16, and the Wechsler Intelligence Scale for Children

–IV (WISC-IV; Wechsler, 2003) for participants aged 16-17, was employed in order to assess

auditory attention span.

Sustained attention

The Hit Reaction Time Block Change measure (HRT BC) from the Conners’ Continuous

Performance Test – Third Version (CPT 3; Conners, 2013), a well-known computerized test

of different aspects of attention, was selected as a measure of sustained attention.

Verbal learning and recall

In order to assess the two domains verbal learning and recall, The Children’s Auditory Verbal

Learning Test (CAVLT-2; Talley, 1993) was employed. For technical reasons, the Rey

Auditory Verbal Learning Test (RAVLT; Schmidt, 1996) was utilized for assessing verbal

learning and memory in 8 participants.

Verbal fluency

The subtest Verbal Fluency 1 (phonemic fluency) and 2 (category fluency) from the D-KEFS

battery was employed to assess verbal fluency, i.e., the ability to rapidly produce words

according to required criteria.

Executive functions

For the assessment of the EF domain “shifting”, we utilized the subtests Trail Making Test 4

(TMT 4; number-letter switching) and Color-Word Interference Test 4 (CWIT 4;

inhibition/switching) from the D-KEFS battery. For the “working memory” domain, we used

the subtest Digit Span Backward (WAIS–IV, WISC–IV). For the EF domain “inhibitory

44

control”, we employed the commissions score from the CPT 3 and the subtest Color-Word

Interference Test 3 (CWIT 3; inhibition) from the D-KEFS battery.

3.3 Statistical analyses

Data analyses were performed using the statistical package SPSS for Windows, version 25.0

(SPSS, Inc., Chicago, Illinois). Missing item scores in the questionnaires were replaced by the

participant’s subscale mean where at least 2/3 of the subscale items were completed

(Tabachnick & Fidell, 2007). Non-parametric statistics were conducted for questionnaire data

due to non-normally distributed variables. Data from performance-based tests was normally

distributed, and parametric analyses were performed.

Between-group differences were investigated by Pearson Chi Square and Mann-Whitney U

test (Papers I, II and III). The Wilcoxon signed-rank test was applied for within-group

differences and self- and informant report differences (Papers I and III). Bonferroni

corrections for multiple comparisons were employed. Effect size (ES) is reported as r for

continuous data, and as φ for categorical data, in both cases defining small ES as =.1 - .3;

medium ES as =.3–.5; large ES as >.5 (Field, 2009). Associations between various

questionnaire subscales, and between performance-based test scores and questionnaire

subscales reflecting neurocognitive functioning and adaptive functioning, were investigated

by Spearman’s rho (rs) test (Paper III). One sample T-tests were conducted in order to

investigate deviations from the normative mean (T=50) in performance-based test scores

(Paper III). The social outcome variables for which there were significant between group

differences were retained for univariate and logistic regression analyses within the young

adult PBT survivor group (Paper II). The questionnaires for which there were significant

differences between the various social outcome subgroups of young adult PBT survivors,

were retained as variables for social outcome models. Associations between questionnaire

data (i.e., indices, composite scores and total scores) and demographic (sex, age at time of

survey), tumor-related (age at diagnosis, location [i.e., supra- vs. infratentorial locations],

tumor type), and treatment-related (time since treatment completion, type of treatment

[surgery only vs. complex treatment regimens combining CRT treatment and/or

chemotherapy]), were explored by univariate analyses (Papers I, II and III).

45

3.4 Ethical considerations

The study was conducted in compliance with the Declaration of Helsinki by the World

Medical Association Assembly, and was approved by the Regional Committee for Medical

Research Ethics in Norway (REC; 2014/379). Written informed consent was obtained after a

complete description of the study.

46

4. RESULTS

4.1 Paper I

Self-reported executive dysfunction, fatigue, and psychological and emotional symptoms

in physically well-functioning long-term survivors of pediatric brain tumor (Puhr et al.,

2019a).

Paper I investigates the presence and possible distinct profile of executive dysfunction in the

young adult subgroup of the PBT sample, reporting four main findings:

i. Young adult survivors of PBT reported significantly higher levels of psychological

and emotional problems and mental fatigue compared to matched healthy controls, as

evidenced by significant group differences in scale scores and caseness frequency on

measures surveying these domains.

ii. Significant group differences were found on measures of most EFs, and ESs were

generally larger for EF measures than for psychological and emotional problems and

mental fatigue. Moreover, although problems of behavioral regulation (hot) aspects of

EF were reported, the PBT survivors had relatively more complaints concerning

metacognitive (cool) aspects.

iii. Informants reported significantly less EF problems than the PBT survivors themselves.

iv. PBT survivors who had undergone surgery combined with CRT and chemotherapy,

and for whom the time interval since treatment completion was shorter, had

significantly higher levels of mental fatigue complaints.

4.2 Paper II

Social attainment in physically well-functioning long-term survivors of pediatric brain

tumour; the role of executive dysfunction, fatigue, and psychological and emotional

symptoms (Puhr et al., 2019b).

In paper II, building on the findings from paper I, we investigate self-reported social

attainment in young, physically well-functioning adult survivors of PBT compared to healthy

controls, and to which degree self-reports of executive dysfunction, psychological and

emotional problems, and fatigue, are related to less favorable social outcomes. We reported

three main findings:

i. Compared to healthy controls, significantly more PBT survivors reported having

received educational adjustments and substantial government benefits, and were

currently not engaged in regular employment/training.

47

ii. In general, poor social outcomes were most strongly associated to subscales measuring

self-reported executive dysfunction, difficulties with adaptive functioning, and fatigue.

iii. Complex treatment regimen (i.e., multiple surgeries, chemotherapy, CRT, and/or

hormone therapy) was significantly related to poorer social outcomes, and the

presence of post-treatment psychiatric comorbidity was significantly associated with

government benefit uptake.

4.3 Paper III

Executive function and psychosocial adjustment in adolescent survivors of pediatric

brain tumor (Puhr et al, 2020, in revision for publication).

Paper III presents three main findings on the presence and possible distinct profile of

executive dysfunction in the adolescent PBT survivor group, the association between EF

difficulties and adaptive functioning complaints in the PBT survivors, and the association

between demographic and tumor and treatment-related variables and questionnaire measures

of EF, psychological problems and fatigue:

i. Significantly elevated rates of neurocognitive impairment, including executive

dysfunction, were found both in PBT survivors’ parent reports of EF compared to

matched controls, and on performance-based tests of EF compared to normative data.

ii. Adolescent PBT survivors and their parents reported significantly more adaptive

functioning complaints (i.e., academic and social difficulties) than healthy controls

and their parents. These difficulties were most strongly associated with parent reported

problems with executive dysfunction, internalizing symptoms of

withdrawal/depression and thought problems, and physical functioning, as well as to

self-reported problems with EF, physical functioning and sleep/need for rest.

iii. Being male, having sustained an embryonal tumor or an astrocytoma, and having

undergone surgery combined with CRT treatment and chemotherapy was significantly

related to higher levels of parent and self-reported problems on the questionnaires

assessing EF, QoL and fatigue.

48

5. DISCUSSION

5.1 Discussion of main findings

5.1.1 Executive function in the PBT survivor sample

The results presented in papers I and III confirm earlier findings of poorer neurocognitive

functioning, including poorer EF, in long-term survivors of PBT. This was evidenced by

young adult PBT survivor self-reports and adolescent PBT survivor parent reports, showing

significantly higher levels of EF complaints compared to matched healthy controls (Papers I

and III), as well as by performance-based tests of EF compared to normative data in the

adolescent PBT survivor sample (Paper III). Complex treatment regimens, including surgery

combined with CRT and chemotherapy, were significantly associated with higher rates of

parent reported problems on a composite scale reflecting cognitive aspects of EF and a global

EF scale (Paper III). However, treatment effects for self-reported EF were not found in the

young adult PBT survivor group, although post-treatment psychiatric comorbidity and

postoperative seizures were related to significantly more self-reported problems on the global

EF scale (Paper I). These findings are in line with previous studies demonstrating the

association between the added burden of complex treatment regimen involving CRT, and late

effects on long-term neurocognitive functioning (de Ruiter et al., 2013; Duffner, 2010; King

et al., 2019; Palmer, 2008; Stavinoha et al., 2018). However, contrary to past studies, the

present findings did not reveal significant effects regarding tumor location, age, or time since

treatment completion.

Along with physical problems and fatigue, the largest ESs in the adolescent group were for

between group differences in neurocognitive complaints, including problems with aspects of

EF in everyday life (Paper III). Parents of PBT survivors generally reported more EF

problems than parents of controls, but only differences on a subscale measuring working

memory problems survived correction for multiple comparisons, with a near to medium ES.

Nonetheless, the presence of EF weaknesses was also found in performance-based

neuropsychological results, with significant deviations from the normative mean within the

processing speed domain, and in two out of the three EF domains from Miyake et al.’s (2000)

model; shifting and inhibitory control. Furthermore, for the cognitive domains processing

speed, auditory attention span, verbal learning, verbal recall, and shifting, there was a larger

percentage of PBT survivors than expected from the normal distribution performing in the

clinically impaired range (i.e., with T-scores 1.5 standard deviation below the normative

49

mean). These are all domains positively correlated and interrelated with EF skills (Zelazo et

al., 2016). Unfortunately, the number of participants who underwent neuropsychological

assessments was not large enough to enable subgroup analyses based on tumor- and

treatment-related variables.

The young adult PBT survivors reported a significantly higher rate of EF problems compared

to their healthy peers, with medium ESs (Paper I). Significant group differences in T-scores

were identified on almost all scales assessing EF skills, i.e., subscales reflecting shifting, self-

monitoring, initiating action/activity, working memory, planning/organizing tasks/activities,

and task monitoring, as well as composite scales indexing behavioral and cognitive aspects of

executive function, and a global EF scale. In addition to significant group differences in T-

scores, a significantly higher frequency of caseness was found for the young adult PBT

survivor group compared to the control group for the same EF domains, including problems

with emotional control.

Although the PBT sample’s mean scores on subscales reflecting aspects of EF are within one

standard deviation from the normative mean (i.e., within the normal range by clinical

standards) in both age groups, there are several studies showing that mean scores in

Norwegian and non-U.S. healthy samples on both the BRIEF and BRIEF-A are significantly

below the U.S. normative mean of T = 50 (Grane, Endestad, Pinto, & Solbakk, 2014; Hovik et

al., 2017; Løvstad et al., 2012; Løvstad et al., 2016; Sølsnes et al., 2014). This raises concern

about the appropriateness of these norms in a Norwegian setting, and indicates that mean

scores from a matched Norwegian sample of healthy controls are a more suitable basis for

comparisons, both in clinical and research settings. Altogether, the present findings are in line

with the PBT literature, consistently demonstrating impaired functioning in these

neurocognitive/EF domains, not only in survivors treated with CRT and chemotherapy, but

also after surgery only (Edelstein et al., 2011; King et al., 2019; Krivitzky, Walsh, Fisher, &

Berl, 2016; Moberget et al., 2015; Palmer, 2008; Rey-Casserly & Diver, 2019; Rønning et al.,

2005; Wolfe et al., 2012) .

In the young adult PBT group, informants (consisting of mainly parents) reported

significantly less problems with EF than the PBT survivors themselves (Paper I). Although

the opposite pattern has generally been found in pediatric populations (i.e., parents reporting

higher rates of problems in various domains compared to their child, especially for

50

subjective symptoms) (Brinkman, Li, et al., 2016; Jurbergs et al., 2008; Lund et al., 2011;

Sung et al., 2008), for the EF domain specifically, there are a few studies that are in line

with the findings from this study. For example, studies have demonstrated low levels of

parental endorsement of EF problems in survivors of PBT, even in the presence of

performance-based findings of executive dysfunction (Krivitzky et al., 2016; Wochos,

Semerjian, & Walsh, 2014). In comparison, teacher reports have been found to be more in

accordance with performance-based data (Wochos et al., 2014). This discrepancy may be

explained by a possible rater bias in parents, such as psychological defense mechanisms and

adjusting to the needs/challenges of their medically fragile child, and/or differences in EF

demands across the home and school settings.

Altogether, the findings presented in Papers I and III provide evidence for the presence of

EF difficulties in long-term survivors of PBT, not only in adolescent survivors who are

temporally closer to treatment completion, but also in young adult survivors, indicating that

these are long-term weaknesses persisting into adulthood.

EF complaints vs. reports of psychological problems and fatigue in the PBT survivor

sample

Interestingly, in both the adolescent and young adult PBT survivor groups, there emerged a

pattern where neurocognitive concerns, including EF concerns, showed generally larger ESs

compared to psychological and emotional problems (Papers I and III). ESs in both age

groups were small for psychological and emotional problems, and compared to normative

data, the mean scores were well within one standard deviation from the normative mean.

For symptoms of psychological distress in the adolescent group, the between group

differences with the largest ESs were found for parent reports, with parents of PBT survivors

reporting significantly more problems than parents of controls on subscales and indices

reflecting internalizing problems (i.e., symptoms of withdrawal, depression and somatization)

relative to externalizing problems (Paper III). This is in line with earlier findings noting that

PBT survivors may exhibit more internalizing than externalizing problems compared to other

pABI and adolescent CCS populations (Brinkman, Li, et al., 2016; Poggi et al., 2005). This

pattern was less apparent in the young adult PBT survivor group, probably due to relatively

few reported psychological distress symptoms in general. However, informants in the young

51

adult PBT survivor group did report significantly fewer problems on subscales and indices

reflecting externalizing problems (i.e., aggressive and rule-breaking behavior) compared to

the young adult PBT survivors themselves.

Importantly, the adolescent PBT survivors themselves did not report a significant increase of

psychological distress compared to the healthy controls (Paper III). Earlier studies have

shown a tendency of parent-child report discrepancies in pediatric populations, with parents

typically reporting poorer emotional functioning than their child (Brinkman, Li, et al.,

2016; Jurbergs et al., 2008; Lund et al., 2011; Sung et al., 2008). It is therefore unclear

whether the findings reflect an actual risk of psychological problems, or inflated parental

reports due to parental distress and sensitivity to changes in their child after serious illness,

or alternatively, a repressive adaptive style in the adolescent leading to underreporting of

difficulties (Brinkman, Li, et al., 2016; Jurbergs et al., 2008; Meeske et al., 2004). Further

uncertainty concerning this question is brought on by the fact that there are few significant

discrepancies between parent and self-reports of psychological distress in this study, with

the only exception of subscales reflecting somatization (i.e., PBT survivor parents reported

significantly more problems than their adolescent) and externalizing problems (i.e., PBT

survivor adolescents reported significantly more problems than their parents). Interestingly,

a review of the CCS literature by Bitsko et al. (2016) indicated that survivor self-report may

be the most accurate way to assess emotional functioning. In the case of our adolescent

sample, emphasizing the findings from the PBT survivors’ self-reports would indicate no

significantly increased risk of psychological problems compared to healthy peers.

The findings in Papers I and III indicating low levels of reported psychological distress

symptoms is in conflict with earlier findings showing an increased risk of psychological

problems in PBT survivors compared to other CCS populations and the general population

(Bitsko et al., 2016; Brinkman, Li, et al., 2016). There are several possible explanations for

the findings. One possible explanation for the low levels of psychological distress observed in

the young adult PBT survivor group may be that the participants in this age group were

physically well-functioning, as physical and sensory late effects have previously been

associated with higher rates of global and internalizing symptoms (e.g., self-isolation)

(Brinkman, Li, et al., 2016; Cousino et al., 2017; Ozono et al., 2007). Alternatively,

promising psychological outcomes in this subset of the CCS population may gradually

become more common with the continuous improvement of modern treatment modalities

52

(Macartney, Harrison, VanDenKerkhof, Stacey, & McCarthy, 2014). Also, findings from

several studies in other CCS populations reflect a tendency towards resiliency,

posttraumatic growth, and benefit finding after life-threatening illness (Bitsko et al., 2016;

Brinkman et al., 2013; Vetsch et al., 2017; Zebrack et al., 2012). Altogether, these findings

may indicate that the PBT survivors in our sample are at relatively low risk of psychological

and emotional problems.

In both age groups, PBT survivors reported significantly more symptoms of fatigue than their

healthy peers (Papers I and III). Our findings suggest that fatigue seems to be a more salient

problem in the adolescent PBT survivor group compared to the young adult PBT survivor

group, i.e., with medium and small ESs for between group differences, respectively. Smaller

ESs for fatigue in the young adult group may be due to longer time since treatment

completion, with initial symptoms of fatigue having subsided with time. This is consistent

with previous findings showing that although there is a subgroup for whom symptoms may

persist several years upon treatment completion, in many PBT survivors fatigue reduces post-

treatment (Boonstra et al., 2017; Brand et al., 2016; Clanton et al., 2011; Mulrooney et al.,

2008; van Deuren et al., 2020).

Presence of fatigue is associated with neurocognitive impairment in CCS populations and

brain injury populations, e.g., impaired processing speed, attention, memory and EF (Clanton

et al., 2011; Ponsford, Schönberger, & Rajaratnam, 2015), and thus may have contributed to

neurocognitive problems reported in the adolescent PBT survivor group. However, for the

young adult PBT survivor group, EF concerns are present despite low levels of subjective

fatigue, indicating that fatigue cannot be the full explanation. Moreover, the cognitive and

mental fatigue scales utilized in the adolescent and young adult PBT survivor groups,

respectively, mainly contain items reflecting subjective cognitive complaints. Moreover, two

out of six items on the general fatigue scale utilized in the adolescent group reflect problems

with initiating and completing tasks, which in addition to fatigue includes involvement of EF.

Although symptoms of fatigue were significantly present in the adolescent PBT survivor

group, the findings in general seem to suggest that the long-term PBT survivors in our sample

struggle relatively more within the EF domain, compared to psychological problems and

symptoms of fatigue. Within the EF domain, difficulties with certain aspects of EF seem to be

more prominent than others in the present PBT survivor sample, and in the following,

53

evidence for a distinct EF profile in light of the hot/cool distinction of EF processes is

presented.

5.1.2 What’s hot and what’s not; towards an idiosyncratic executive function profile

PBT survivors constitute a subset of both the CCS population and the pABI population, i.e.,

two patient populations known to be neurologically compromised and demonstrating a range

of impairments in the neurocognitive domain (e.g., Anderson, Jacobs, & Anderson, 2008;

Beauchamp & Anderson, 2013; Beauchamp, Dooley, & Anderson, 2010; Kanellopoulos et al.,

2016; McCurdy, Rane, Daly, & Jacobson, 2016; Raghubar, Mahone, Yeates, & Ris, 2017) .

Our findings are in line with numerous past studies demonstrating neurocognitive difficulties

in long-term PBT survivors (de Ruiter et al., 2013; Duffner, 2010; King et al., 2019; Palmer,

2008; Stavinoha et al., 2018). However, fewer studies have focused specifically on EF in this

particular population, and even fewer on the different aspects that make up the EF construct.

Our findings are not only in line with past studies demonstrating EF problems in the PBT

survivor population (King et al., 2019; Palmer, 2008; Wolfe et al., 2012), but also expand on

the current knowledge. Our studies identify a possible distinct EF profile compared to that of

other CCS and pABI populations, and explain it within the theoretical hot/cool framework for

understanding EF. For instance, do long-term PBT survivors struggle relatively more with

metacognitive, i.e., cool aspects of EF, compared to emotional and behavioral, i.e., hot aspects

of EF? Our findings indicate that this may be the case, as this pattern was found in both the

adolescent and the young adult PBT survivor group.

Cool versus hot EF domains

In the adolescent PBT survivor group (Paper III), although there were significant between

group differences on parent reports of EF for both cool and hot EF processes, most of these

differences had small ESs, and only parent reported problems with working memory, i.e., a

cool EF aspect, survived corrections for multiple comparisons, having a near to medium ES.

Evidence for weaknesses within cool EF processes in the adolescent PBT survivor group was

further found in data from performance-based assessments, i.e., for the EF domains shifting

and inhibitory control, as well as for the domains processing speed, auditory attention span,

and verbal learning and recall.

54

Self-report data from young adult PBT survivors and healthy controls showed the same

pattern, i.e., self-reports of problems with both hot and cool aspects of EF, but with more

problems reported for cool EF processes (Paper I). Furthermore, in the young adult PBT

survivor group, the “cool pattern” in the self-report data seemed to be more prominent than in

the parent report data from the adolescent PBT survivor group. On several of the measures of

hot aspects of EF, i.e., subscales measuring aggressive and intrusive behavior, and problems

of emotional control and behavioral inhibition, there were no significant differences between

the young adult PBT survivor group and the healthy control group. Conversely, there were

significant differences between the two groups on all but one of the subscales measuring cool

aspects of EF, i.e., a subscale reflecting the ability to keep one’s surroundings in an orderly

manner. Moreover, within group analyses in the young adult PBT survivor group, showed that

significantly more difficulties in the cool EF domain than in the hot EF domain were reported

by both the survivors themselves, and their informants. Also, as noted in the previous section,

informants reported significantly less problems with EF than the young adult PBT survivors

themselves. Taking into account that difficulties with cognitive aspects of EF may be less

detectable to the surroundings than behavioral symptoms, but more readily experienced by the

PBT survivors themselves, this discrepancy may support the notion that executive dysfunction

experienced by PBT survivors is of a more cognitive/cool than behavioral/hot nature.

Notably, there were no significantly higher rates of reported problems with behavioral

inhibition, i.e., an important hot EF aspect, either in the adolescent or in the young adult PBT

survivor group. This is in line with previous findings noting that PBT survivors are less likely

to demonstrate clinically significant problems with behavioral inhibition, even compared to

healthy controls (Brinkman, Li, et al., 2016; Krivitzky et al., 2016).

A pediatric brain tumor survivor profile?

The present findings lend support to studies demonstrating that PBT survivors, survivors of

ALL, other pABI populations (e.g., traumatic brain injury [TBI]), and congenital brain

disorder populations (e.g., attention deficit/hyperactivity disorder [ADHD]) may share some

executive dysfunction similarities. However, PBT survivors seem to have a distinct

cognitive/EF profile, somewhat unique compared to the aforementioned clinical populations

(Anderson et al., 2002; Araujo et al., 2017; Krivitzky et al., 2016; Pennington & Ozonoff,

1996; Poggi et al., 2005; Winter et al., 2014) . For example, although patients with ADHD,

TBI, and PBT may have deficits in working memory in common, patients with ADHD and

55

TBI (i.e., especially focal frontal lobe lesions) exhibit more behavioral/hot EF problems, e.g.,

difficulties with behavioral inhibition (Anderson et al., 2002; Gioia, Isquith, Kenworthy, &

Barton, 2002; Konrad, Gauggel, Manz, & Schöll, 2000). Our results indicate that this seems

not to be the case for PBT survivors. Furthermore, within the CCS population, studies have

shown that, although both the PBT and the ALL subset demonstrate lower-level EF problems

(i.e., simple processing speed), PBT survivors who more global and higher-level EF problems

(i.e., inhibitory control, planning, and flexibility) (Kahalley et al., 2013; Krivitzky, Blaufuss,

& VanDenHeuvel, 2015; Winter et al., 2014). This might be due to the differences in the

amount and type of damage to the developing brain caused by the respective illnesses and

treatment regimens.

Treatment effects (e.g., Araujo et al., 2017; Brinkman et al. 2016), cerebellar tumor location

(Moberget et al., 2015), and neurological complications such as hydrocephalus (Anderson et

al., 2002), which may cause more diffuse damage, including white matter pathology and

compromised cerebral wiring, may play a contributing role in the development of an

idiosyncratic EF profile in the PBT population. For example, although executive dysfunction

is frequently noted in the CCS population, some studies have noted an absence of an

externalizing profile among survivors treated with CRT, as many show impaired inattention,

slowed processing speed, and lack of initiation rather than hyperactivity or impulsivity

(Brinkman, Li, et al., 2016). It has been suggested that impairments in processing speed, and

what has been described as “sluggish cognitive tempo”, defined by lethargy, impaired focus,

and disorganization, may in part preclude disinhibited behavior (Kahalley et al., 2013;

Krivitzky et al., 2016; Willard et al., 2013). Although the number of PBT survivors having

received CRT was small in our sample (11 [22.9 %] in the adolescent group and 27 [25.3%]

in the young adult group), reports from this subgroup may have contributed to the distinctive

EF profile observed in our sample. Indeed, parents of adolescent PBT survivors who had

undergone complex treatment regimens including CRT reported significantly more problems

on a composite scale reflecting cognitive/cool EF processes compared to parents of adolescent

PBT survivors who had undergone surgery only, whereas the composite scale reflecting

behavioral/hot aspects of EF showed no such subgroup differences.

Altogether, our findings may support previous findings demonstrating that it is mainly the

cognitive/cool aspects of EF that are affected by PBT and PBT treatment, sooner than the

emotional and behavioral/hot aspects of EF. However, further studies are needed to better

56

understand the idiosyncratic EF profiles of PBT survivors. Although the literature does not

place the EF impairment within the hot/cool EF framework, findings seem generally to be in

line with the notion that they struggle more with the cool EF processes relative to the hot.

Furthermore, whether nuances in the EF profile of PBT survivors are due to differential

damage to the specific frontal–subcortical circuits that underlie these abilities warrants further

research, for example by utilizing advanced neuroimaging techniques. For instance, while hot

EF processes (e.g., inhibitory control, emotional and social processing), may be more greatly

affected by damage to ventromedial prefrontal regions, problems in cool EF processes (e.g.,

working memory, shifting, planning) may be more prominent as a result from damage to

dorsolateral prefrontal regions (Anderson et al., 2002; Araujo et al., 2017; Bechara, 2004;

Beer, 2006; Peterson & Welsh, 2014; Yeates et al., 2007). Nonetheless, in a “real life”

perspective, the integrity of and cooperation between both hot and cool functions is essential

for everyday functioning and long-term psychosocial adjustment and socioeconomic

outcomes. In the following, findings of long-term adaptive functioning and socioeconomic

outcomes in the present PBT survivor sample are presented, as well as the importance of EF

in regard to these outcomes.

5.1.3 Executive function involvement in long-term adaptive functioning and

socioeconomic outcomes

Interestingly, compared to most measures of subjective symptoms (with the exception of

measures reflecting neurocognitive/EF problems), the largest between group differences in

both age groups were found for measures of adaptive functioning and socioeconomic

outcomes. This includes social relations (e.g., number of friendships, getting along with

peers), educational functioning (e.g., completing school work efficaciously, need for

educational adjustments), employment/training status (i.e., engagement in regular work,

studies or military service), and financial independence (i.e., need for government benefits)

(Papers II and III). More specifically, the only difference between the adolescent PBT

survivor group and the healthy control group to survive corrections for multiple comparisons

on a self-report measure of psychological problems, was for a subscale assessing adaptive

functioning, i.e., difficulties with social adjustment and academic performance (Paper III).

Similarly, on a screening measure of QoL, the largest ESs were found for subscales reflecting

social and school functioning. In our sample of young adults, significantly more PBT

survivors compared to healthy controls reported having received educational adjustments and

57

substantial government benefits, and were currently not engaged in regular

employment/training (Paper II). This was particularly true of the survivors that had

undergone complex treatment regimens (i.e., multiple surgeries, chemotherapy, CRT, and/or

hormone therapy). These findings confirm conclusions from previous studies demonstrating

that PBT survivors struggle in negotiating important adult milestones, and that they are at risk

of experiencing social difficulties (e.g., poor peer acceptance, isolation), lower

academic/educational achievement, and poor socioeconomic attainment (e.g., employment

and financial independence) compared to other CCS populations and to the general population

(Boman, Lindblad, & Hjern, 2010; Brinkman, Krasin, et al., 2016; Brinkman, Ness, et al.,

2018; Brinkman, Recklitis, et al., 2018; de Boer, Verbeek, & van Dijk, 2006; Frederiksen et

al., 2019; Ghaderi et al., 2016; Ghaderi et al., 2013; Mader et al., 2017; Ness et al., 2008).

However, the study showed also some encouraging findings; the young adult PBT survivors

did not differ from the healthy controls regarding educational level or living situation, i.e.,

living independently or with parents/caregivers. Furthermore, although there was a difference

between the groups in activity status, it is worth noting that more young adult PBT survivors

than not were currently engaged in regular work, studies or military service. Because the

participants in our young adult sample are relatively young, this may in part account for why

there were no significant differences in living situation between PBT survivors and healthy

controls, as participants in either groups may not yet have established an independent living

situation (e.g., for financial reasons). However, similar levels of education in the groups is

most likely a reflection of the equality of the Norwegian welfare and educational system, as

all citizens are entitled to education at a high school level, and educational services and

adjustments are offered to those who are struggling academically. Indeed, some studies

demonstrate significant geographic variations in educational attainment among childhood

cancer survivors, arguing that these differences are due to substantial differences between

countries regarding educational systems and accessibility of special education and

rehabilitation services (Boman et al., 2010; de Boer et al., 2006; Frederiksen et al., 2019;

Lund et al., 2011; Mader et al., 2017; Mehnert, de Boer, & Feuerstein, 2013). For example,

survivors of childhood cancer in Europe have been found to have significantly better

educational outcomes compared to survivors in the U.S., with many survivors showing similar

educational levels to the background population. Similar variations have been shown for

employment outcomes, with European countries showing more positive outcomes than the

U.S. (Boman et al., 2010; de Boer et al., 2006; Frederiksen et al., 2019; Lund et al., 2011;

58

Mader et al., 2017; Mehnert et al., 2013). In addition to differences in educational

possibilities, differences in access to health care, (vocational) rehabilitation services and labor

markets may be significant contributors in this respect. For example, it is plausible that many

childhood cancer survivors are, to a larger extent, rejected as employees in the U.S., due to

employer-sponsored health insurance coverage and the high risk of late effects that this

patient population carries (Frederiksen et al., 2019).

Altogether, the present findings show that not only medical late effects and physical

disabilities impede PBT survivors from academic achievement, educational and vocational

success and financial independency, and that psychological and psychosocial aspects are

important for long-term outcomes in these domains. This is demonstrated by the fact that the

participants in the young adult PBT survivor group were all physically well-functioning, as

survivors with severe difficulties with activities of daily life (ADL) and sensory and motor

disabilities were excluded. In spite of this, there were striking differences between the young

adult survivors and their healthy peers with regard to educational adjustments, substantial

government benefits, and the number of survivors who were currently not engaged in regular

employment/training.

The impact of executive function impairment on long-term adaptive functioning and

socioeconomic outcomes

The present findings confirmed past studies demonstrating the negative impact of CCS late

effects such as emotional and physical problems and persistent fatigue on their possibilities to

participate in social and educational settings (Bell et al., 2018; Boonstra et al., 2017; Brand et

al., 2016; Brinkman, Li, et al., 2016; Brinkman, Recklitis, et al., 2018; Ness et al., 2005).

However, in both age groups, there emerged a pattern where poor adaptive functioning and

academic and vocational outcomes were most strongly related to difficulties within the EF

domain, with emotional and psychological distress less impactful. In the adolescent group,

problems of adaptive functioning in the PBT survivors were most strongly related to parent

reported problems with executive dysfunction, internalizing symptoms of

withdrawal/depression and thought problems, and physical functioning, as well as to self-

reported cognitive problems (e.g., attention problems), physical functioning and sleep/need

for rest. However, parent reported neurocognitive complaints, including executive

59

dysfunction (i.e., problems with attention, working memory, mental shifting, and initiation),

exhibited the strongest correlations to parent reported problems with adaptive functioning.

Similar findings were uncovered across most of the administered self-report measures in the

young adult PBT survivor group: along with symptoms of fatigue, cognitive and executive

dysfunction were more strongly associated to poorer social outcomes, with emotional and

psychological distress showing less impact. Specifically, neurocognitive complaints including

aspects of EF (e.g., problems with attention, working memory, and the ability to initiate

activity) were significantly associated with educational adjustments and substantial

government benefits, and reduced employment/training. These findings, along with findings

from several past studies, confirm the interrelation between impairments of EF and poor long-

term adaptive functioning and socioeconomic outcomes (Evans, 2008; Ness et al., 2008;

Papazoglou, King, Morris, & Krawiecki, 2008a, 2008b; Wolfe, Vannatta, Nelin, & Yeates,

2015; Wolfe et al., 2013).

Although we were not able to establish any age effects (i.e., younger age at diagnosis

resulting in poorer outcomes) in either age group, the findings are interesting in a lifetime

perspective. The present findings indicate that in adolescence, difficulties with adaptive

functioning and EF may still be relatively subtle compared to early adulthood. Problems seem

to gradually arise as the PBT survivors leave the support of caregivers and the educational

system, and transition into adulthood, with all the demands of independency that this entails

(Anderson et al., 2019; Stavinoha et al., 2018). Also, considering the protracted nature of EF

development and hierarchical developmental models maintaining that the development of

more complex EFs build on simple, earlier developing EFs, it is plausible that findings may

reflect what has been described as “growing into deficit” in pABI populations (Anderson et

al., 2019; Tillman et al., 2013). Thus, adolescents may present with more difficulties as they

get older, with a delayed onset and increase of impairments combined with increasing

expectations for independent work, organization, and self-regulation (Anderson, Jacobs, &

Harvey, 2008; Anderson et al., 2019; de Vries et al., 2017; Krivitzky et al., 2016).

The present findings harmonize well with neurodevelopmental cascade models of the

neurocognitive mechanisms (i.e., impaired processing speed, attention span, and working

memory) involved in the declines in both IQ and academic achievement in long-term PBT

survivors (Edelstein et al., 2011; King et al., 2019; Palmer, 2008; Rey-Casserly & Diver,

60

2019; Wolfe et al., 2012). However, the present thesis expands on these models in two ways.

First, we took a step further by including not only academic achievement, but also data on

socioeconomic outcomes (e.g., work/training status and financial situation). Second, neither

of these models includes emotional/behavioral, or hot, EF processes, but focuses mainly on

the cool, cognitive processes. Thus, several EF processes that are crucial for successful

interaction with the everyday surroundings and long-term goal achievement in “the real

world” are not taken into account by these models. Our findings demonstrate the association

between both cool/cognitive and hot/behavioral aspects of executive dysfunction and

academic and occupational concerns, thus lending support to, but also expanding on the

current neurodevelopmental cascade models.

Interestingly, in the adolescent PBT survivor group, difficulties within the hot EF domain

seemed more impactful on outcomes compared to the young adult PBT survivor group.

Within the adolescent PBT survivor group, subscales reflecting the cool EF domain, i.e.,

initiation, working memory, planning/organizing skills and monitoring, and subscales

reflecting the hot EF domain, i.e., shifting between activities and emotional control, were all

significantly correlated with poorer adaptive functioning outcomes, although subscales

reflecting problems with emotional control and monitoring did not survive corrections for

multiple comparisons. Thus, although hot EF processes were significant for adaptive

functioning outcomes, associations between measures assessing cool EF processes and poorer

adaptive functioning were both more numerous and yielded in general somewhat stronger

correlations than the subscales assessing hot EF processes. This tendency, i.e., for cool EF

processes to have greater impact on negative functional outcomes, was found more clearly

within the young adult PBT survivor group: on a self-report measure of EF problems, only

difficulties with cool EF processes were significantly associated to poorer socioeconomic

outcomes, with working memory and initiation most impactful. Thus, our findings seem to

yield support for the neurodevelopmental cascade models, but underscore the importance of

attending also to difficulties within the hot EF domain, especially in the adolescent years.

Although significant, the differences between the PBT survivors and the controls on a

majority of measures of executive dysfunction, psychological and emotional problems, and

physical and mental fatigue generally displayed generally small ESs (with the exception of

measures neurocognitive/ EF complaints). This stands in contrast to the fact that they

simultaneously report struggling significantly more with academic performance, education,

61

work and financial independency. A similar discrepancy was found in a CCS study by

Brinkman, Krasin, et al. (2016) where severe performance-based neurocognitive impairment

was associated with lower educational attainment, unemployment and non-independent living,

yet only a few of the survivors’ self-reports reflected a similar degree of cognitive and

behavioral impairment in daily life. This discrepancy may have several explanations. For

example, even though scores on questionnaires were within a standard deviation below the

normative mean, the difference was nonetheless significant, and the findings may reflect the

total accumulation of subtle problems over time translating into bigger and more concrete

issues of independent functioning, similar to that noted in adult survivors of pABI

(Beauchamp et al., 2010). Furthermore, diminished impairment awareness, which is often

related to executive dysfunction, has been found in several pABI populations, possibly

accounting for the close to normal levels of self-reported functioning (Krasny-Pacini et al.,

2015; McCurdy, Turner, et al., 2016; Sølsnes et al., 2014). The issue of impairment awareness

may be further exacerbated by the fact that PBTs occur in the earliest years of life, often

leading survivors to habituate and gradually adapt to a subnormal level of functioning

(Beauchamp et al., 2010). In this case, this subnormal functioning level may become a

subjective normality, not necessarily perceived by the survivor as impaired, or different to that

of their peers. Also, a systematic tendency to underreport or deny difficulties frequently noted

in CCS populations, which has been linked to a repressive adaptive coping style and

psychological defense mechanisms (e.g., a need to be “normal” and move past the illness),

may result in an overly positive impression of outcomes (Lund et al., 2011; O’Leary et al.,

2007; Phipps et al., 2001).

In summary, the present findings confirm earlier studies demonstrating that disruptions to EF

development may lead to serious negative functional outcomes (Ness et al., 2008; Wolfe et

al., 2012; Ylvisaker & Feeney, 2008), and that both the cognitive and the behavioral aspects

of executive dysfunction are related to social, academic and occupational concerns (Zelazo et

al., 2016). However, there are several important methodological concerns and limitations that

need to be taken into account, and these issues are discussed in the following section.

5.2. Methodological issues, strengths and limitations

A few methodological issues have already been discussed in the previous sections; i.e., report

discrepancies (e.g., self- and proxy report discrepancies, discrepancies between self-reports of

62

subjective symptoms versus socioeconomic attainment). In the following, issues regarding

study design, outcomes measures, response rates, sample size and generalizability of findings

are discussed.

5.2.1 Cross-sectional design and possible impact of environmental factors

The present study employed a cross-sectional design (Papers I, II and III). This type of

design precludes the possibility of making causal inferences, and therefore there may be

alternative explanations for the observed differences between the PBT survivors and healthy

controls other than those presented in this thesis. For example, data on socio-environmental

factors like coping style, family factors (e.g., parental responsiveness, health, education and

socioeconomic status, and impact of serious illness on family interactions), and social support

was not collected. These are all factors that may become increasingly important with time,

and contribute to observable differences between PBT survivors and peers (Klassen et al.,

2011; Kupst & Patenaude, 2016; Ryan et al., 2016; Van Schoors et al., 2017). In the

developmental psychology literature, it has long been known that the development of

cognitive and socio- emotional skills and behaviors, including EF skills, is to a large extent

dependent on the quality of the home environment and the role models provided by parents

(Anderson et al., 2019). Within the CCS population, family dysfunction and parental stress

has been associated with more functional impairment, including a greater number of

medical and psychosocial late effects experienced (Cousino et al., 2017; Hile, Erickson,

Agee, & Annett, 2014; Peterson, Cousino, Donohue, Schmidt, & Gurney, 2012). A

longitudinal design including socio-environmental information would have been more

appropriate for isolating the contributory effects of socio-environmental factors, and for

establishing how the symptoms and outcomes may vary over time (e.g., increase vs. reduction

of impairment/symptoms). However, such an approach was not possible within the scope and

time frame of the present study.

5.2.2 Response rates and generalizability of study findings

For the young adult PBT survivor group, the response rate was relatively low (38.6%, Paper

I), which raises questions of the representativeness of the sample and the validity of the

findings. Unfortunately, as data collection on non-responding survivors was limited by ethical

regulations, an analysis of non-response bias which, in part, could explain possible variations

between responding and non-responding participants, was not possible in the present study.

63

However, all PBT survivors in Norway meeting diagnostic and age criteria were identified by

The Cancer Registry of Norway (a database of all cancer cases in Norway), and were invited

to participate, ensuring a high level of representativeness.

There are several plausible explanations for the relatively low response rate in the young adult

PBT survivor group. Because the goal of the study was to explore how EF impairment may

affect PBT survivors’ level of societal participation, only physically well-functioning PBT

survivors were included, as severe ADL, sensory and motor disabilities are factors that may

have a negative impact participation in society regardless of the status of EF. The relatively

low response rate may, to some extent, be explained by these exclusion criteria, as past

studies on long-term outcomes in this CCS population have demonstrated relatively frequent

performance and participation limitations, with up to 26 % of adult PBT survivors reporting

limitations in physical performance and daily activities (Ness et al., 2005). Although

information on physical and sensory impairments in non-responding survivors was not

available, the actual response rate for our target population may therefore be considerably

higher than 38.6%, considering that up to 26 % of the original 295 invited PBT survivors may

not have met the inclusion criteria. In light of this, it is possible that the PBT survivors that

did respond constitute a relatively representative sample of this specific PBT survivor

population. Furthermore, as established throughout this thesis, the presence of EF

impairments has repeatedly been noted in the PBT survivor population. Considering that the

process of completing and returning the questionnaire by mail is in essence an “EF task”, it is

not unlikely that PBT survivors with more serious cognitive impairments and executive

dysfunction may have found participation too demanding, and therefore refrained from

responding. However, alternate methods of survey distribution, e.g., electronic surveys, may

not have yielded any higher response rates, as people today are continuously inundated with

surveys of all kinds, subsequently lowering response rates in general. Indeed, a meta-analysis

comparing response rates in e-mail and paper surveys distributed to healthy respondents,

found paper survey more efficient than e-mail survey in terms of response rates (Shih & Fan,

2009). Also, the response rate in the present young adult PBT survivor sample seems

comparable to previous studies in the child brain injury literature. Moreover, the response rate

in the adolescent PBT survivor sample was substantially higher than that of the young adult

group (53.3%, Paper III), and is, as such, relatively high compared to previous studies in the

child brain injury and CCS literature, ensuring an adequate level of representativeness in this

age group. Nonetheless, the issues concerning the low response rate caution the

64

generalizability of the findings, as they may provide a different and/or overly optimistic

picture of long-term outcomes for the PBT population in general.

5.2.3 The use of self-reports and performance-based data for assessing EF

In this study, self-report and parent report measures were employed for the exclusion criteria

and for the key variables and outcomes (Papers I, II and III). There are several possible

sources of confounding influence on the findings associated with this methodological

approach, such as psychological defense mechanisms/coping style, demand characteristics,

cognitive deficits, social desirability bias, acquiescent responding, and extreme responding

(Logan, Claar, & Scharff, 2008; Lund et al., 2011; McCambridge, de Bruin, & Witton, 2012;

O’Leary et al., 2007; Phipps et al., 2001). These issues may be present in both self- and proxy

reports, and threaten the accuracy and validity of the information obtained. In this population,

the possibility of impaired self-awareness is a particularly relevant issue, potentially having

had a confounding influence on the findings. For example, it is possible that some of the

young adult PBT survivors may not have had a realistic perception of the severity of their

physical limitations, and as such, may not in fact have met the inclusion criteria.

Alternatively, considering the possibility of impaired awareness of cognitive deficits and

social functioning, the difference between the healthy controls and the adolescent and young

adult PBT survivors may in reality be greater than what the current findings have shown.

Despite these limitations, self- and proxy reports offer the advantage of efficiently collecting

large amounts of information from many participants, i.e., from those persons who have first-

hand knowledge and experience with the participants’ functioning in their everyday settings,

without the interference of the researcher (Manchester, Priestley, & Jackson, 2004).

Moreover, there are currently few other available methods to assess EF processes in real-

world settings as efficiently as questionnaires, especially with regard to social-

emotional/behavioral skills and hot EF processes.

For a subgroup in the adolescent PBT survivor group, performance-based measures were

administered in addition to questionnaires (Paper III). Unlike questionnaires, performance-

based assessments are regarded more suitable for assessing the cognitive aspects of EF, and

are administered in laboratory-like settings. Previous findings from these two different

methodological approaches confirm that they most likely tap separate, but related, constructs

within the EF domain, and that performance varies across settings that place different and/or

65

higher demands on cognitive functioning (Anderson et al., 2002; de Vries et al., 2017;

McCurdy, Turner, et al., 2016). In this study, the self- and proxy report assessing EF were the

BRIEF and BRIEF-A. These methods have shown to be powerful tools in assessing EF,

distinctive from performance-based measures (Anderson et al., 2002; Toplak, West, &

Stanovich, 2013), including accounting for variance in neuroimaging findings in studies of

both typically developing and patient populations (Wang et al., 2012; Warren et al., 2013;

Ziegler, Dahnke, Winkler, & Gaser, 2013). Indeed, the present findings demonstrated only a

few significant correlations between performance-based data and questionnaire data. Only the

verbal fluency domain was significantly associated with parent and self-reported problems of

neurocognitive functioning, i.e., problems with attention, working memory, initiation, ability

to plan and organize, and overall problems with EF in everyday life. However, these

correlations did not survive corrections for multiple comparisons. Furthermore, although

parents of PBT survivors reported significantly more problems with working memory,

significant deviations in this EF domain were not found in the performance-based data. For

these reasons, the two approaches cannot simply replace one another without risking loss of

valuable information, and both were therefore employed in the present study in order to

capture both cool and hot EF processes. Unfortunately, the subgroup for which performance-

based data was collected was small, and the results should therefore be viewed as exploratory.

However, as discussed in the previous sections, despite the small number of participants in

this subgroup, the findings are in line with the broader literature on neurocognitive

functioning in survivors of PBT.

5.2.4 Sample size for subgroup analyses

Another area of concern is the small number of participants for some of the subgroup

analyses, which could account for why age, tumor type and location, and treatment-related

effects on long-term outcomes measures were not consistently found in the present PBT

survivor sample. The results from these analyses should therefore be considered merely

exploratory, also because the variables were less well defined (e.g., information regarding

treatment regimen registered as yes/no, and tumor location defined as either supra- or

infratentorial). Nonetheless, the present study invited all eligible survivors in the Norwegian

patient population, in order to enhance the number of participants as much as possible.

66

5.3 Clinical implications

Despite these limitations, the findings from this study provide important insights into long-

term adaptive functioning, socioeconomic attainment and societal participation in PBT

survivors. The study contributes to provide a more comprehensive picture of the

psychological and psychosocial mechanisms underlying poor social outcome in this CCS

subset, for which there traditionally has been limited research. Further, the findings provide

important insights into the difficulties experienced by adolescent PBT survivors, for which

there traditionally has been limited knowledge. These insights have important clinical

implications. The findings confirm the need for clinical follow-ups both shortly after

treatment completion, and years after treatment is completed, i.e., as survivors enter

adulthood, as problems such as neurocognitive decline, including EF impairment, and

psychological and emotional distress symptoms may gradually develop years after treatment

completion. Furthermore, PBT survivors both with and without severe physical sequelae after

treatment completion should be followed.

Due to its complex and dynamic nature, executive dysfunction may remain undetected by

professionals, and is often misinterpreted, e.g., as negative volitional aspects dependent on the

individual’s character and psychological functioning (Anderson et al., 2010; Lezak et al.,

2012), underlining the need for assessing EF in follow-ups. Also, the findings demonstrate the

importance of awareness of the tendency of underreporting difficulties, and caution that even

discrete problems may gradually accumulate and cause serious negative consequences for

social attainment across the lifespan.

Long-term assessments may help to uncover EF impairments, to form a basis on which to

implement suitable compensatory strategies and educational/occupational adjustments, and

for advising health and education professionals on appropriate intervention strategies. The

importance of suitable, tailored interventions is reflected in the findings: although a majority

of the PBT survivors had received educational adjustments, they nonetheless had poorer

outcomes compared to their healthy peers. In light of findings from this study, to improve

outcome from the educational and rehabilitation resources offered, future efforts should focus

more on improving EF skills and tailoring compensatory strategies for executive dysfunction.

Fortunately, EFs are relatively malleable, and may be improved by supportive caregiving and

EF skills practice (Zelazo et al., 2016; Zelazo & Carlson, 2012).

67

Furthermore, the findings indicate the presence of a distinct EF profile in this population, with

cool EF processes more strongly affected than hot EF processes, which is important

information when tailoring interventions to the specific needs of PBT survivors.

Encouragingly, interventions aimed at improving hot and cool aspects of EF in pediatric

populations are rapidly emerging. For example, a recent meta-analysis found that caregiver

involvement may improve the effectiveness of rehabilitation interventions aimed at hot EF

processes, while high intervention session frequency may be essential in improving cold EF

processes (Chavez-Arana et al., 2018). However, so far the findings are mixed as to the

effectiveness of current interventions, warranting further research (Godfrey, Catroppa, Kaizar,

Yeates, & Robinson, 2014; Riccio & Gomes, 2013).

6. CONCLUSION AND DIRECTIONS FOR FUTURE RESEARCH

In conclusion, our findings suggest that PBT survivors with well-preserved sensory and

physical function are at increased risk to develop neurocognitive impairments that persist into

adulthood compared to healthy peers. This includes executive dysfunction, and within the EF

domain, problems with cognitive/cool aspects of EF seem to be greater than problems with

emotional and behavioral/hot aspects of EF. Also, the findings demonstrate that survivors in

the present PBT sample struggle with symptoms of fatigue years after treatment, as well as

problems in the areas of psychological and emotional functioning, although the latter to a

lesser degree compared to problems with EF and fatigue. Further, our findings suggest that

PBT survivors, although physically well-functioning, have significant long-term problems

with adaptive functioning and achieving important adult milestones such as occupational

success and financial independency, and that these problems are associated with self-reports

of executive dysfunction, cognitive problems, and fatigue, in addition to having undergone

complex treatment regimens.

Future research efforts should focus on further discerning the possible idiosyncratic EF profile

in this CCS and pABI subset, e.g., with more finely tuned hot vs. cool EF measures, and with

longitudinal studies demonstrating their respective developmental trajectories and associated

real-world outcomes. Also, further research into the effectiveness of tailored interventions is

essential in order to optimize PBT survivors’ chances of succeeding in the transition to

adulthood and of participating in society, and to prevent social inequity for survivors of PBT

in a lifetime perspective.

68

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III

1

Executive function and psychosocial adjustment in adolescent survivors of

pediatric brain tumor

Puhr, A.1, Ruud, E.2, Anderson, V.3, Due-Tønnessen, B.J.4, Skarbø, A.B.5, Finset, A.6 &

Andersson, S.7

Funding:

This work was supported by the Norwegian Cancer Society under grant 6865381; the

Norwegian ExtraFoundation for Health and Rehabilitation under grant 2013/2/0234; Oslo

University Hospital’s Childrens’ Foundation under grant 36219; and The Renée and Bredo

Grimsgaard Foundation (grant number N/A).

1 Corresponding author: Puhr, Anita (Cand. Psychol.) Affiliation: Dept. of Pediatric Medicine, Oslo University Hospital & Dept. of Psychology, University of Oslo, Norway Postal address: c/o Stein Andersson Postbox 1094, Blindern, 0317 Oslo, Norway E-mail: anitapuh@medisin.uio.no Telephone: +47 90 57 36 50 2 Ruud, Ellen

(PhD Adjunct Professor) Affiliation: Dept. of Pediatric Medicine, Oslo University Hospital & Faculty of Medicine, University of Oslo, Norway Postal address: Postbox 4956 Nydalen, 0424 Oslo, Norway E-mail: elruud@ous-hf.no Telephone: +47 23 07 45 60 3 Anderson, Vicki (PhD Professor) Affiliation: Royal Children's Hospital, Melbourne & Depts of Psychology & Paediatrics, University of Melbourne, Australia Postal address: Psychology Service, The Royal Children's Hospital, 50 Flemington Road, Parkville VIC 3052, Australia E-mail: vicki.anderson@rch.org.au Telephone: + 61 3 8341 6200 4 Due-Tønnessen, Bernt Johan (MD PhD) Affiliation: Dept. of Neurosurgery, Oslo University Hospital, Norway Postal address: Postbox 4956 Nydalen, 0424 Oslo, Norway E-mail: bdue@ous-hf.no Telephone: +47 23 07 43 32 5 Skarbø, Anne-Britt (Cand. Psychol.) Affiliation: Dept. of Pediatric Neurology, Oslo University Hospital, Norway Postal address: Postbox 4956 Nydalen, 0424 Oslo, Norway E-mail: anska@ous-hf.no Telephone: +47 23 07 02 15 6 Finset, Arnstein (PhD Professor Emeritus) Affiliation: Faculty of Medicine, University of Oslo, Norway Postal address: Postbox 1110, Blindern, 0317 Oslo, Norway E-mail: arnstein.finset@medisin.uio.no Telephone: +47 22 85 10 81 7 Andersson, Stein (PhD Professor) Affiliation: Dept. of Psychology, University of Oslo, Norway

Postal address: Postbox 1094, Blindern, 0317 Oslo, Norway E-mail: stein.andersson@psykologi.uio.no Telephone: +47 22 84 59 28

2

Abstract

Adolescent survivors of pediatric brain tumor (PBT) are a sparsely studied subset of

childhood cancer survivors. Sustaining a PBT may complicate the development of executive

functions (EF), which play a vital role in long-term psychosocial adjustment. In this study, 48

adolescent survivors and their parents completed questionnaires assessing EF, psychological

symptoms, fatigue and adaptive functioning, and 26 survivors underwent neuropsychological

assessment. Survivors reported significantly more problems with adaptive functioning than a

healthy control group, and executive dysfunction was most strongly associated to problems

with adaptive functioning, compared to psychological symptoms and fatigue. The findings

have important implications for long-term follow-ups.

3

1. Introduction

Adolescence is a critical period for the development of executive functions (EF),

emotional functioning, and social skills, laying the foundation for the transition into adulthood

and for achieving adult milestones, such as social independence and socioeconomic

attainment (e.g., education, vocation, financial independence) . Having sustained a brain

tumor at an early stage in life may complicate these normative developmental processes in

several ways. Studies have repeatedly shown that compared not only to the general

population, but also other childhood cancer survivors (CCS), survivors of pediatric brain

tumors (PBT) are at increased risk of negative functional outcomes, such as fatigue, emotional

problems, greater challenges with social relationships (e.g., poor peer acceptance, isolation),

and poorer socioeconomic attainment (Bell, Ownsworth, Lloyd, Sheeran, & Chambers, 2018;

Boonstra et al., 2017; Bower, 2014; Brand, Chordas, Liptak, Manley, & Recklitis, 2016;

Brinkman, Li, et al., 2016; Brinkman, Recklitis, Michel, Grootenhuis, & Klosky, 2018;

Clanton et al., 2011; Husson, Zebrack, Block, et al., 2017; Meeske, Katz, Palmer, Burwinkle,

& Varni, 2004; Poggi et al., 2005; Puhr et al., 2019b; Speechley, Barrera, Shaw, Morrison, &

Maunsell, 2006; Walter, Nixon, Davey, Downie, & Horne, 2015; Zeltzer et al., 2009). This

vulnerability may likely be due to brain pathology caused by treatment or the tumor itself, and

within PBT survivor population, irradiation therapy, physical and sensory sequelae,

hydrocephalus, younger age at diagnosis, and infratentorial tumor location, have been

associated with poorer social outcomes and quality of life (QoL) (Barrera et al., 2017; Bell et

al., 2018; Frederiksen et al., 2019; Husson, Zebrack, Aguilar, Hayes-Lattin, & Cole, 2017;

Mulhern, Merchant, Gajjar, Reddick, & Kun, 2004; Ness et al., 2005; Robinson et al., 2015;

Turner, Rey-Casserly, Liptak, & Chordas, 2009). However, findings are mixed as to the

effects of tumor location and age, and negative outcomes (i.e., neurocognitive dysfunction)

have also been found in patients treated with surgery only (Bell et al., 2018; Riva & Giorgi,

4

2000; Rønning, Sundet, Due-Tønnessen, Lundar, & Helseth, 2005). Optimal executive

functioning may play a particularly significant role in long-term functional outcomes, as even

in the context of preserved intellectual, perceptual, communication and memory skills,

impairments in EF may cause the greatest handicap for adaptive functioning and social

attainment (Evans, 2008).

Although there is no consensus on the definition of EF, they are often described as the

human capacity to control, organize and direct cognitive, behavioral and emotional responses,

which, although linked to prefrontal lobe functioning, rely greatly on the intactness of

multiple cooperating brain networks (Gioia, Isquith, & Guy, 2001; Stuss & Alexander, 2000).

Traditionally, the cognitive aspects of EF has mainly been understood as abstract,

decontextualized and non-emotional functions, often referring to Miyake et al.’s (2000)

influential model comprising three separate, but interrelated cognitive EF core factors: (a)

shifting between tasks or mental sets, (b) updating and monitoring of working memory

representations, and (c) inhibitory control of dominant or prepotent responses. However, it is

becoming increasingly more common to use the umbrella term ‘EF’ to refer to both cognitive

functions and behavioral and social/affective skills, and furthermore, to consider different

methodological approaches to the clinical assessment of EF in light of this diversity. This

distinction is often referred to as the “cool” and “hot” EF. “Cool” EFs operate in affectively

neutral contexts (e.g., attentional control, working memory, initiation, planning and

organizing, selection of efficient problem-solving strategies, mental flexibility and utilization

of feedback), whereas “hot” EF operate in situations that evoke emotion, motivation, and the

contest between immediate gratification and long-term rewards, and involve the capacity to

exert appropriate control and regulation of emotional and behavioral impulses and responses

(Zelazo, Qu, & Kesek, 2010). Although linked to different developmental trajectories, both

“hot” and “cool” EF develop rapidly throughout early childhood into adolescence and early

5

adulthood; paralleling the development and maturation of neuroanatomical structures and

networks (Peterson & Welsh, 2014; Zelazo & Carlson, 2012). Damage to the developing

brain at any time and in any location can cause persistent impairments in EF along with social

dysfunction, as the development of “hot” and “cool” aspects of EF are closely related to the

development of social information processing and social competence (Peterson & Welsh,

2014; Riggs, Jahromi, Razza, Dillworth-Bart, & Mueller, 2006; Ryan et al., 2016; Yeates et

al., 2007).

While performance-based neuropsychological tasks are generally considered as

methodologically suitable measures for assessing the “cool” aspects of EF (Peterson & Welsh,

2014), more ecologically valid measures are needed to assess the “hot” aspects, considering

that these functions are more readily observed in everyday settings, than in standard, highly

structured neuropsychological test settings. Questionnaires reflecting both self-report and

informant report are therefore recommended, to address the confounding influence of possible

impairments in self-awareness and reporter discrepancies, which is not uncommon in

pediatric acquired brain injury (pABI) and CCS populations (Jurbergs, Russell, Long, &

Phipps, 2008; Krasny-Pacini et al., 2015; Lund, Schmiegelow, Rechnitzer, & Johansen, 2011;

McCurdy et al., 2016; Roth, Isquith, & Gioia, 2005).

Studies focusing on EF in PBT survivors have shown that this population are at risk of

developing problems with EF, both in the short and long term, and impairments in EF may be

of particular significance for long-term outcomes (de Ruiter, van Mourik, Schouten-van

Meeteren, Grootenhuis, & Oosterlaan, 2013; Koustenis, Hernaiz Driever, de Sonneville, &

Rueckriegel, 2016; Netson et al., 2016; Wolfe, Madan-Swain, & Kana, 2012). In a recent

study of long-term outcomes among physically well-functioning adult PBT survivors

compared to healthy controls, the largest effect sizes were for group differences in self-

reported EF, along with fatigue, compared to self-reported psychological and emotional

6

problems (Puhr et al., 2019a). Furthermore, a study following up on these findings, showed

that negative adaptive functioning and poor socioeconomic attainment (e.g., employment

outcome, financial independence) was most strongly associated to executive dysfunction, with

psychological and emotional problems showing less impact (Puhr et al., 2019b). The

survivors in these studies had all been treated for a PBT during the first 16 years of life, and,

although historical data were not available, it is plausible that impairments in EF with the

potential to hamper the negotiation of adult milestones were present already in adolescence,

post treatment. These findings point to the need for further knowledge on the presence of

impairments in EF in adolescent PBT survivors, in order to prevent negative long-term

outcomes and enhance psychosocial adjustment.

The purpose of this study is threefold. The primary aim was to explore the long-term

neurocognitive consequences of PBT in adolescent survivors, with a special focus on

executive dysfunction, by comparing parent-reports of EF and performance-based

neuropsychological assessments to matched controls and normative data, respectively. Based

on previous findings, we expected parents of adolescent PBT survivors to report more overall

problems with EF than parents of healthy peers, and that the presence of executive

dysfunction would be further confirmed by the survivors’ results on performance-based tests.

Also, we explored possible associations between performance-based measures and self- and

parent-reports of neurocognitive functioning, expecting few significant associations, as these

methods assess different aspects of EF. The second aim was to explore whether PBT

survivors experience more problems with adaptive functioning (i.e., academic achievement

and social functioning) compared to healthy controls, and to what degree executive

dysfunction is associated to adaptive functioning compared to psychological problems and

fatigue. As we have previously reported (Puhr et al., 2019b), EF is linked to adaptive

functioning and social attainment in adult PBT survivors. In this study, we focused on the

7

association between adaptive functioning and EF in adolescent PBT survivors. We also

expected this association to be confirmed by performance-based assessments of EF in the

PBT subgroup. The third aim was to investigate how reports of executive dysfunction,

psychological and behavioral problems and fatigue are associated with tumor-related factors

(age at diagnosis, location, and tumor type) and treatment-related factors (type of treatment,

time since treatment completion). We expected younger age at onset, infratentorial tumor

location, and complex treatment regimens to be more strongly associated with negative self-

and parent-reported outcomes.

2. Methods

2.1 Study participants

Figure 1 shows a flowchart of the study. Survivors of PBT fulfilling inclusion criteria defined

as treatment for PBT at ≤16 years, aged 13-17 at the time of recruitment, and having

completed treatment ≥2 years prior to study participation, were identified by The Cancer

Registry of Norway. Exclusion criteria were self-reported severe difficulties with activities of

daily life (ADL), self-reported severe sensory and motor disabilities, and pre-treatment

cognitive/neurological deficits unrelated to the tumor diagnosis, evidenced in patient reports

and/or patient records.

Ninety-nine teenage PBT survivors received self-report and parent-report forms by

mail to assess EF, psychological and emotional functioning, and fatigue. Of the 99 PBT

survivors, four were excluded due to non-tumor diagnoses (e.g. cysts, lipomas), three due to

treatment for recurrent/residual tumor within last two years, and two because of pre-tumor

cognitive/neurological problems due to non-tumor diagnoses. In total, 48 of 90 (53.3%) of

eligible PBT survivors and their parents/caregivers completed the self-report and parent-

report forms, respectively. Mean age at time of survey was 15.7 (SD=1.37), 54.2% of the

8

survivors were female. Mean age at illness debut was 6.8 years (range: 0.1-14.1, SD=4.13)

and mean time since treatment completion was 8.4 years (range=2.7-17.0, SD=3.98).

Seventeen survivors (35.4%) reported minor sensory and/or motor impairments partly

disrupting everyday functioning.

Figure 1. Study flowchart

A subgroup of the PBT survivors, who have been followed up with multiple

neuropsychological assessments after treatment completion at Oslo University Hospital, also

Target population: 99 PBT survivors and their parents/caregivers from

the Norwegian Cancer Registry fulfilling inclusion criteria (treatment for PBT at ≤16 years, aged 13-17, treatment completion ≥2 years)

Self- and parent report forms distributed by mail: N=99

Responded, n=57 (57.6%)

Did not respond, n=42 (42.4%)

Excluded after participation (n=9):

Non-tumor cerebri diagnoses; n=4 (e.g. cysts, lipomas)

Treatment for recurrent/residual tumor within last two

years; n=3

Pre-tumor cognitive/neurological problems due to non-

tumor diagnoses; n=2

Total response from 90 eligible PBT survivors and their

parents/caregivers: n=48 (53.3%)

9

underwent cognitive retesting. Of 36 invited, 26 (72.2%) underwent retesting. For this

subgroup, the mean age at diagnosis was 6.3 years (range: 0.3-13.3, SD=3.97) and mean time

since treatment completion was 8.9 years (range=4.0-14.1, SD=3.63). Mean age at cognitive

retesting was 16.6 years (SD=1.37). No survivors in the subgroup undergoing cognitive

retesting reported sensory and/or motor impairments seriously disrupting everyday

functioning.

Clinical characteristics for the PBT survivor group and the PBT subgroup that

underwent cognitive retesting are presented in Table 1. Information on age at diagnosis,

histology, location, and treatment type was collected from patient records. For the purpose of

classifying PBT survivors into larger diagnostic subgroups, the third version of the

International Classification of Childhood Cancer (ICCC-3) was used. The following

information on treatment and late effects was registered as yes/no: surgery, CRT,

chemotherapy, hormone replacement treatment (i.e., growth hormones, cortisol, thyroid

stimulating hormones, testosterone and estrogen, or antidiuretic hormones), postoperative

seizures (i.e., ≥1 seizure after tumor surgery), postoperative hydrocephalus treatment

(ventriculoatrial shunt, ventriculoperitoneal shunt, or third ventriculostomy), and psychiatric

comorbidity (i.e., as classified by the International Classification of Disease -10 codes F01-

F99).

A group of healthy controls was recruited from The National Population Register of

Norway, and received self-report and parent-report forms identical to those of the patient

group. Of the 300 controls invited, 73 (24.3 %) controls and caregivers/parents returned

completed self-report and parent-report forms, respectively. There was a significant age

difference between the PBT survivor group and the control group: mean age at time of survey

was 15.7 (SD=1.4) in the PBT survivor group and 14.7 (SD=1.4) in the healthy control group

10

(p<.001). The groups were matched for sex: 55.1 % of the survivors and 50.7 % of the

controls were female (p=.632).

Table 1. Clinical characteristics

N survey group (n=48)

% N retested subgroup (n=26)

%

Tumor diagnosis Ependymomas and choroid plexus

tumors 6 12.5 4 15.4

Astrocytomas 23 47.9 13 50.0 Embryonal tumors 16 33.3 6 23.1 Other gliomas 1 2.1 - - Other CNS-tumors 2 4.2 3 11.5 Tumor location Supratentorial 14 29.2 7 26.9 Infratentorial 32 66.7 18 69.2 Both 2 4.2 1 3.8 Treatment Surgery only 28 58.3 17 65.4 Surgery and chemotherapy 9 18.8 5 19.2 Surgery and CRTa 1 2.1 - - Surgery, chemotherapy and CRTa 10 20.8 4 15.4 Number of surgeries One surgery 40 83.3 20 76.9 Two or more surgeries 8 16.7 6 23.1 Postoperative hydrocephalus treatmentb Yes 7 14.6 3 11.5 No 41 85.4 23 88.5 Postoperative seizures Yes 6 12.5 3 11.5 No 42 87.5 23 88.5 Hormone replacement treatmentc Yes 12 25.0 6 23.1 No 36 75.0 20 76.9 Psychiatric comorbidity Yes 8 15.7 3 11.5 No 43 84.3 23 88.5 a CRT=cranial/craniospinal irradiation therapy b Ventriculoatrial shunt (VA), ventriculperitoneal shunt (VP) or third ventriculostomy (3CVS), c Hormone replacement treatment, e.g., growth hormone, cortisol, thyroid stimulating hormone, testosterone and estrogen, and antidiuretic hormone.

11

2.2 Long-term outcome measures

2.2.1 Self- and parent-reports of neurocognitive functioning, psychological

symptoms, and fatigue.

BRIEF. The parent-report version of the Behavior Rating Inventory of Executive

Function (BRIEF; Gioia, Isquith, Guy & Kenworthy, 2000) contains 86 items surveying

teenagers’ EF in everyday activities over the past 6 months. The items are rated on a three-

point scale (1=never; 2=sometimes; 3=often) and three indices are generated: the Behavior

Regulation Index (BRI), the Metacognitive Index (MI), and a Global Executive Composite

(GEC). The BRI subscales Inhibit, Shift, and Emotional Control, reflect behavioral and

social/affective aspects of EF, i.e., the “hot” EF aspects, whereas the subscales Initiate,

Working Memory, Plan/Organize, Organization of Materials and Monitor, reflect cognitive,

or “cool”, aspects of EF. Higher scores on the subscales and indices reflect more problems

with EF. The BRIEF questionnaire showed high levels of internal consistency; Cronbach’s

alpha of =.96 for both the survivor and control group, respectively.

YSR, CBCL. The Achenbach System of Empirically Based Assessment (ASEBA;

Achenbach & Rescorla, 2001) is a family of screening tools for psychological symptoms and

behavioral problems, which, amongst others, include the Youth Self-Report (YSR), and the

parent version Child Behavior Checklist (CBCL). The YSR and the CBCL consist of 112

questions, scored on a three-point Likert scale (0 = statement not true; 1 = statement

sometimes true; 2 = statement very true), yielding the eight syndrome scales

Anxious/Depressed, Withdrawn/Depressed, Somatic Complaints, Social Problems, Thought

Problems, Attention Problems, Rule-Breaking Behavior, and Aggressive Behavior. Three

composite scores are produced; Total Problems, Internalizing Problems (sum of the scales

Anxious/Depressed, Withdrawn/Depressed, and Somatic Complaints), and Externalizing

Problems (sum of the scales Rule-Breaking Behavior and Aggressive Behavior). Higher

12

scores on the syndrome scales reflect more psychological symptoms and behavioral problems.

The subscale Attention reflects subjective cognitive complaints. The YSR and the CBCL also

measure competence and adaptive functioning, generating the subscale Total Competence

which is comprised of items on the teenager’s activities, social relations, and academic

performance, with lower scores reflecting more problems in these areas. The YSR and CBCL

had high internal consistency for both survivor and control groups; Cronbach’s alpha of =.92

and .94, and .91 and .87, respectively.

PedsQL. The self-report and parent-report version of the Pediatric Quality of Life

Inventory 4.0 (PedsQL; Varni, Seid, & Kurtin, 2001) measure QoL over the past month in

teenagers aged 13 to 18. The 23 items are rated on a five-point Likert scale (0=never;

1=almost never, 2=sometimes; 3=often, 4=almost always), and items are reverse-scored and

linearly transformed to a 0–100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that lower scores

reflecting more problems. Four subscales are generated: Physical, Emotional, Social, and

School Functioning, as well as a total score; PedsQL Total, and subscale scores are computed

as the sum of the items divided by the number of items answered. Varni, Burwinkle, Seid,

and Skarr (2003) recommend a cutoff score of 1 standard deviation below the population

mean. However, the appropriateness of this cutoff score has been questioned because of its

sample-dependence, as is its applicability across age and diagnostic groups and cultural

contexts (Huang et al., 2009; Petersen, Hägglöf, Stenlund, & Bergström, 2009). Internal

consistency was high; Cronbach’s alpha of =.89 and =.75 for the PedsQL parent version for

the survivor group and control group, respectively, and = .92 and .90 for the PedsQL self-

report version.

PedsQL-MFS. The PedsQL-Multidimensional Fatigue Scale (PedsQL-MFS; Varni,

Burwinkle, Katz, Meeske & Dickinson, 2002) is a self-report questionnaire that consists of 18

items measuring problems with fatigue during the last month. The items are scored as for the

13

PedsQL, with lower scores reflecting more problems. From the 18 items, the subscales

General Fatigue, Sleep/Rest Fatigue and Cognitive Fatigue are generated, as well as a total

score; PedsQL-MFS Total. The subscale Cognitive Fatigue may be considered a measure of

subjective cognitive complaints rather than a measure of fatigue, as it comprises items all

reflecting everyday cognition. To the best of our knowledge, there are currently no

recommended clinical cutoff scores for the PedsQL-MFS. The PedsQL-MFS showed high

levels of internal consistency; Cronbach’s alpha of =.88 for both the survivor and control

group.

2.2.2 Performance-based measures of neurocognitive domains. A battery of well-

known neuropsychological tests commonly employed in clinical settings was used to assess

neurocognitive functioning in a subset of the PBT survivor group. The tests were grouped into

larger neurocognitive domains, i.e. estimated current IQ, processing speed, auditory attention

span, sustained attention, verbal learning and recall, verbal fluency and executive functions,

by converting all raw scores to T-scores and calculating an average T- scores within each

domain. A score of 1.5 standard deviations or more below the normative mean was defined as

a clinical cutoff.

Estimated current IQ. The Vocabulary and Matrix Reasoning subtests from the

Wechsler Abbreviated Scale of Intelligence (WASI; Wechsler, 1999) were used to estimate

current IQ.

Processing speed. The subtests Trail Making Test 2 (TMT 2; number sequencing) and

3 (TMT 3; letter sequencing), and Color-Word Interference Test 1 (CWIT 1; color naming)

and 2 (CWIT 2; word reading), from the Delis-Kaplan Executive Function System (D-KEFS;

Delis, Kaplan & Kramer, 2001) were employed in order to assess processing speed.

Auditory attention span. The Digit Span Forward scores from the Wechsler Adult

Intelligence Scale –IV (WAIS-IV; Wechsler, 2008) for participants aged >16, and the

14

Wechsler Intelligence Scale for Children –IV (WISC-IV; Wechsler, 2003) for participants

aged <16 was used to assess auditory attention span.

Sustained attention. From the Conners’ Continuous Performance Test – Third

Version (CPT 3; Conners, 2013), which is a well-known computerized test of different

aspects of attention, the Hit Reaction Time Block Change measure (HRT BC) was selected as

the measure of sustained attention.

Verbal learning and recall. The Children’s Auditory Verbal Learning Test (CAVLT-

2; Talley, 1993) was used to assess the two domains verbal learning and recall. For technical

reasons, the Rey Auditory Verbal Learning Test (RAVLT; Schmidt, 1996) was used for

assessing verbal learning and memory in 8 participants.

Verbal fluency. The subtest Verbal Fluency from the D-KEFS battery was used to

assess verbal fluency, i.e. the ability to rapidly produce words compatible with required

criteria.

EF. For the assessment of the EF domain “shifting”, we used the subtests Trail

Making Test 4 (TMT 4; number-letter switching) and Color-Word Interference Test 4 (CWIT

4; inhibition/switching) from the D-KEFS battery. For the EF domain “working memory”, we

used the subtest Digit Span Backward (WAIS–IV, WISC –IV). For the “inhibitory control”

domain, we used the commissions score from the CPT 3 and the subtest Color-Word

Interference Test 3 (CWIT 3; inhibition) from the D-KEFS battery.

2.3 Data analyses

Analyses were performed using the statistical package SPSS for Windows, version 25.0

(SPSS, Inc., Chicago, Illinois). Non-parametric statistics were conducted for questionnaire

data due to non-normally distributed variables. Data from performance-based tests were

normally distributed, and parametric analyses were performed. Bonferroni corrections for

15

multiple comparisons were employed. Between-group differences were investigated by

Pearson Chi Square and Mann-Whitney U test. Because of the significant age difference

between the groups, univariate analyses with age as a covariate were also performed. The

Wilcoxon signed-rank test was applied for self- and informant-report differences on the

CBCL/YSR and PedsQL questionnaires. Effect sizes (ES) for non-parametric statistics are

reported as r defining small ES as r=.1 - .3; medium ES as r=.3–.5; large ES as r >.5 (Field,

2009, p. 57). Associations between the YSR/CBCL Total Competence scale and other

questionnaire subscales, and between performance-based test scores and questionnaire

subscales reflecting neurocognitive functioning and adaptive functioning (i.e., the BRIEF

subscales, the CBCL and YSR subscales Attention and Total Competence, and the PedsQL-

MFS Cognitive Fatigue), were investigated by Spearman’s rho (rs) test. One sample T-tests

were conducted in order to investigate deviations from the normative average (T=50) in

performance-based test scores. Associations between questionnaire data (i.e., indices,

composite scores and total scores) and a) demographic (sex, age at time of survey), b) tumor-

related (age at diagnosis, location [i.e., supra- vs. infratentorial locations], tumor type), and c)

treatment-related (time since treatment completion, type of treatment [surgery only vs.

surgery combined with chemotherapy vs. surgery combined with CRT and chemotherapy]),

were explored by Kruskal-Wallis H test (multivariate analyses). Due to the small number of

participants with postoperative hydrocephalus, postoperative seizures, hormone replacement

therapy, psychiatric comorbidity, and tumors classified as “other gliomas” and “other CNS-

tumors”, these medical late effect variables and tumor types were excluded from the analyses

on associations between tumor types and questionnaire data.

16

2.4 Ethics

The study was conducted in compliance with the Declaration of Helsinki by the World

Medical Association Assembly, and was approved by the Regional Committee for Medical

Research Ethics in Norway (REC; 2014/379). Written informed consent was obtained after a

complete description of the study.

3. Results

3.1 Self- and parent-reported EF, social/emotional adjustment, QoL and fatigue

Neurocognitive functioning. Between group differences on self- and parent-reports

are presented in Table 2. On the BRIEF, parents of PBT survivors generally reported more EF

problems than parents of controls. The differences that survived correction for multiple

comparisons included the Working Memory subscale (corrected p=.044, r= -.26). Parents of

PBT survivors reported more problems than parents of controls on the CBCL Attention

Problems, and this difference survived corrections for multiple comparisons (corrected

p<.011, r=-.35). On the PedsQL-MFS Cognitive Fatigue, PBT survivors reported significantly

more problems than the controls, and this difference survived corrections for multiple

comparisons (corrected p<.011, r=-.36).

Social/emotional adjustment. As shown in Table 2, significantly more problems

were reported by parents of PBT survivors compared to parents of controls on the CBCL

subscales Withdrawn/Depressed, Somatic Complaints, Social Problems, as well as for the

composite scales Internalizing Problems and Total Problems.. The differences that survived

corrections for multiple comparisons included the CBCL subscale Social Problems (corrected

p<.012, r=-.37) and the composite scales Internalizing Problems (corrected p<.012, r=-.28)

and Total Problems (corrected p<.012, r=-.32). PBT survivors reported significantly more

problems than the controls on the YSR subscale Social Problems, though this difference did

not survive corrections for multiple comparisons.

17

QoL. On the PedsQL, the PBT survivors and their parents generally reported

significantly more problems. The differences that survived corrections for multiple

comparisons included the self-report subscales Emotional Functioning (corrected p=.025, r=-

.25), Social Functioning (corrected p=.005, r=-.30), School Functioning (corrected p<.005,

r=-.40), the total score (corrected p<.005, r=-.39), as well as the parent-report subscales

Physical Functioning (corrected p<.005, r=-.34), Social Functioning (corrected p=.005, r=-

.29), School Functioning (corrected p<.005, r=-.39), and the total score (corrected p<.005, r=-

.39).

Fatigue. PBT survivors reported significantly more problems than the controls on the

PedsQL-MFS subscales General Fatigue and the total score, (corrected p=.004 and .004, r

=.30 and .31, respectively).

PBT survivor self- and parent-report discrepancies. Parents of PBT survivors

reported significantly less problems on the CBCL composite scale Externalizing (self-report

mean = 47.3, ± 8.43; parent-report mean =45.0, ± 9.37; p=.032) than the PBT survivors

themselves, but significantly more problems on the CBCL subscale Somatic Problems (self-

report mean = 54.8, ± 5.86; parent-report mean =60.4, ± 9.99; p<.001). Only the CBCL the

CBCL subscale Somatic Problems (corrected p<.012; r=.63)survived corrections for multiple

comparisons. No significant discrepancies between parent and self-reports were found for the

PedsQL in the PBT survivor group.

3.2 Self- and parent-reported aspects of adaptive functioning

As shown in Table 2, PBT survivors and their parents reported significantly more problems

than the controls on the YSR and CBCL Total Competence scale, with both differences

surviving corrections for multiple comparisons (corrected p<.012 and <.012, r=.36 and .40,

respectively).

18

Tab

le 2

Sel

f- a

nd p

are

nt

report

ed e

xec

uti

ve f

un

ctio

nin

g, psy

cholo

gic

al

sym

pto

ms,

and f

ati

gue

at ≥

2 y

ears

aft

er P

BT

-tre

atm

ent

com

ple

tion

com

pare

d t

o h

ealt

hy

contr

ols

.

PB

T s

urv

ivors

(n=

48)

Con

trols

(n=

73)

Man

n-

Wh

itn

ey

test

Eff

ect

size

Paren

ts

of

PB

T

surv

ivors

Paren

ts

of

con

trols

Man

n-W

hit

ney

tes

t E

ffec

t

size

M

ean (

SD

) M

ean (

SD

)

p

(unco

rrec

ted

) r

Mea

n

(SD

) M

ean

(SD

) p

(unco

rrec

ted

) r

BR

IEF

sca

les

(T-s

core

s)

Inhib

it

- -

- -

45.6

(8

.01)

45.6

(7

.51)

.726

.03

Shif

t -

- -

- 48.2

(1

1.0

1)

43.4

(6

.99)

.017

2

-.22

Em

oti

onal

Contr

ol

- -

- -

48.3

(9

.56)

43.9

(8

.23)

.012

2

-.23

Init

iate

-

- -

- 49.1

(1

3.4

4)

45.6

(8

.91)

.049

-.18

Work

ing M

emory

-

- -

- 54.1

(1

4.0

6)

47.0

(9

.34)

.004

1,2

-.26

Pla

n/O

rgan

ize

- -

- -

51.2

(1

1.6

1)

46.3

(9

.22)

.012

2

-.23

Org

aniz

atio

n o

f M

ater

ials

-

- -

- 44.6

(1

0.9

5)

44.9

(1

0.7

3)

.798

.02

Monit

or

- -

- -

47.9

(1

0.4

9)

44.2

(9

.18)

.035

2

-.19

BR

I -

- -

- 47.0

(9

.19)

43.5

(7

.52)

.045

2

-.18

MI

- -

- -

49.1

(1

3.8

1)

45.2

(9

.59)

.026

-.20

GE

C

- -

- -

47.9

(1

2.9

8)

44.2

(9

.07)

.017

-.22

19

YS

R, C

BC

L s

ub

scale

s

(T-s

core

s)

Tota

l C

om

pet

ence

38.5

(11.0

9)

47.1

(10.9

7)

<.0

01

1,2

.36

38.3

(1

0.4

5)

47.5

(9

.81)

<.0

01

1,2

.40

Anx

ious/

Dep

ress

ed

55.8

(6.5

3)

53.9

(7.5

2)

.120

-.14

56.4

(9

.99)

52.0

(3

.47)

.095

2

-.15

Wit

hdra

wn/D

epre

ssed

55.1

(5.5

8)

54.4

(7.0

0)

.301

-.09

57.3

(8

.24)

53.5

(4

.75)

.008

2

-.24

Som

atic

Com

pla

ints

54.8

(5.8

6)

53.6

(6.0

8)

.088

-.16

60.4

(9

.99)

55.0

(5

.56)

.005

2

-.25

Soci

al P

roble

ms

55.9

(8.1

1)

52.7

(4.8

1)

.019

2

-.21

56.4

(8

.45)

51.4

(3

.36)

<.0

01

1,2

-.37

Thought

Pro

ble

ms

54.1

(5.2

9)

53.3

(5.9

5)

.459

-.07

54.6

(7

.03)

51.9

(4

.03)

.094

2

-.15

Att

enti

on P

roble

ms

55.1

(7.6

4)

52.3

(5.3

2)

.074

2

-.16

55.9

(6

.22)

52.5

(4

.40)

<.0

01

1,2

-.35

Rule

-Bre

akin

g B

ehav

iou

r 52.5

(3.2

9)

52.7

(4.5

7)

.321

-.09

52.0

(3

.46)

51.4

(2

.92)

.149

-.13

Aggre

ssiv

e B

ehav

iou

r 52.7

(4.5

9)

51.5

(3.9

2)

.141

-.14

52.3

(4

.64)

51.5

(3

.92)

.432

-.07

Inte

rnal

izin

g P

roble

ms

52.4

(9.4

6)

49.9

(9.7

6)

.066

-.17

55.2

(1

2.3

1)

48.0

(8

.91)

.002

1,2

-.28

Ex

tern

aliz

ing P

roble

ms

47.3

(8.4

3)

45.0

(8.9

0)

.088

-.16

45.0

(9

.37)

42.5

(8

.51)

.117

-.14

Tota

l P

roble

ms

49.7

(9.6

7)

46.5

(9.3

6)

.079

-.16

50.9

(1

1.3

6)

43.5

(9

.10)

<.0

01

1,2

-.32

Ped

sQL

sca

les

(Lik

ert-

score

s)

Ph

ysi

cal

Funct

ionin

g

82.8

(19.9

5)

91.4

(10.0

7)

.023

2

.21

79.2

(2

2.1

7)

92.7

(1

1.0

6)

<.0

01

1,2

.34

20

Em

oti

onal

Funct

ionin

g

72.3

(19.6

8)

82.0

(16.4

9)

.005

1,2

.25

74.2

(2

1.9

1)

82.9

(1

4.1

8)

.044

2

.18

Soci

al F

unct

ionin

g

81.3

(21.0

9)

93.0

(10.8

9)

.001

1,2

.30

76.4

(2

4.3

0)

91.7

(1

1.5

8)

.001

1,2

.29

Sch

ool

Funct

ionin

g

66.6

(20.8

1)

82.6

(15.9

8)

<.0

01

1,2

.40

65.6

(2

2.4

0)

82.9

(1

5.5

2)

<.0

01

1,2

.39

Tota

l sc

ore

75.7

(17.2

3)

87.2

(11.2

5)

<.0

01

1,2

.39

73.8

(1

8.3

5)

87.6

(8

.83)

<.0

01

1,2

.39

Ped

sQL

-MF

S s

cale

s (L

iker

t-sc

ore

s)

Gen

eral

Fat

igue

71.2

(18.9

7)

81.7

(16.3

4)

.001

1,2

.30

- -

- -

Sle

ep/R

est

Fat

igu

e 65.1

(16.7

7)

67.8

(20.3

6)

.280

.10

- -

- -

Cognit

ive

Fat

igue

62.6

(25.4

3)

80.9

(17.0

1)

<.0

01

1,2

.36

- -

- -

Tota

l sc

ore

66.2

(17.0

7)

76.7

(14.7

8)

.001

1,2

.31

- -

- -

1 in

dic

ate

bet

wee

n g

roup d

iffe

ren

ces

that

surv

ived

corr

ecti

ons

for

mult

iple

com

par

isons.

2 i

ndic

ate

bet

wee

n g

roup d

iffe

ren

ces

that

wer

e si

gnif

ican

t af

ter

adju

stm

ent

for

age.

21

Associations between aspects of adaptive functioning and self- and parent-

reported EF, social/emotional adjustment, and fatigue. The CBCL Total Competence

scale was significantly associated with: the BRIEF subscales Shift (rs= -.52, p<.001),

Emotional Control (rs= -.41, p=.006), Initiate (rs= -.59, p<.001), Working Memory (rs = -.63,

p<.001), Plan/Organize (rs= -.59, p<.001), and Monitor (rs= -.39, p=.008), as well as the

indices BRI (rs= -.49, p=.001) and MI (rs= -.56, p<.001), and the GEC (rs= -.57, p<.001); the

CBCL syndrome scales Withdrawn/Depressed (rs -.50, p<.001), Social Problems (rs= -.53,

p<.001), Thought Problems (rs -.32, p=.003), and Attention Problems (rs -.61, p<.001), as

well as the CBCL composite scores Internalizing Problems (rs -.45, p=.002) and Total

Problems (rs= -.56, p<.001); and the PedsQL (parent-report version) subscales Physical

Functioning (rs=.61, p<.001), Social (rs=.58, p<.001), and School Functioning (rs=.45,

p=.002), as well as the PedsQL Total (rs=.57, p<.001). The associations between the CBCL

Total Competence scale and the BRIEF subscales Emotional Control and Monitor did not

survive corrections for multiple comparisons.

The YSR Total Competence scale was significantly associated with: the PedsQL (self-

report version) subscales Physical (rs=.40, p=.006) and Social Functioning (rs=.32, p=.034),

and the PedsQL Total (rs=.33, p=.026); and the PedsQL-MFS subscales Sleep/Rest Fatigue

(rs=.42, p=.005) and Cognitive Fatigue (rs=.40, p=.007), as well as the PedsQL-MFS Total

(rs=.45, p=.002). The associations between the YSR Total Competence scale and the PedsQL

subscale Social Functioning and PedsQL Total did not survive corrections for multiple

comparisons.

3.3. Performance-based measures of neurocognitive function

Data from performance-based measures of neurocognitive function (composite domain T-

scores) are presented in Table 3. One-sample T-test showed no significant deviations from the

22

normative mean (T=50) on estimated IQ, but significantly below normative mean on

measures of processing speed and two of three EF domains; shifting and inhibitory control.

There was a larger percentage of PBT survivors than expected from the normal distribution

performing clinically impaired, i.e., T-scores 1.5 standard deviation below the normative

mean, in the cognitive domains processing speed, auditory attention span, verbal learning,

verbal recall, and shifting.

Table 3 Performance-based measures of neurocognitive domains reported as T-scores; one

sample t-test and percentage ≤ 1.5 standard deviation under the mean

One sample t-test % < 1.5 SD Mean SD t p Estimated current IQ 48.3 10.26 -.828 .415 7.7 Processing speed 43.5 9.79 -3.373 .002 26.9 Auditory attention span 47.8 11.34 -.991 .331 19.2 Sustained attention 49.0 7.08 -.693 .495 3.8 Verbal learning 47.3 16.42 -.849 .404 19.2 Verbal recall 46.7 17.15 -.972 .340 34.6 Verbal fluency 48.6 11.15 -.645 .525 7.7 EF: shift 41.7 12.44 -3.417 .002 38.5 EF: updating 49.2 9.30 -.422 .677 3.8 EF: inhibition 46.1 8.75 -2.302 .030 7.7 Numbers in bold indicate p <.05. SD = standard deviation.

Associations between performance-based measures and self- and parent-reports of

neurocognitive functioning. The strongest associations between performance-based

measures and self- and parent-reports of neurocognitive functioning were for the cognitive

domain verbal fluency, which correlated significantly with the CBCL Attention (rs = -.41, p=

.046); the YSR Attention (rs = -.54, p=.006); the BRIEF subscales Initiate (rs = -.44, p=.031),

Working Memory (rs = -.43, .037), Plan/Organize (rs = -.51, p=.011), and the GEC (rs = -.45,

p=.028); and the MFS Cognitive Fatigue (rs =.49, p=.018). The association between verbal

fluency and the BRIEF MI was near significant (rs = -.40, p=.052), as was the association

23

between the neurocognitive domain speed and the BRIEF Inhibit (rs = -.39, p=.057).

However, neither of these correlations survived corrections for multiple comparisons.

Associations between aspects of adaptive functioning and performance-based

measures of EF. The CBCL Total Competence scale was significantly associated with the

neurocognitive domain verbal fluency (ρ=.46, p=.027), and the YSR Total Competence scale

was significantly associated with Auditory Attention Span (ρ=.44, p=.035), i.e., good

performance on tests of verbal fluency and auditory attention span were associated with

positive parent and self-reported adaptive functioning, respectively. However, these

associations did not survive corrections for multiple comparisons.

3.4 Associations between demographic/medical variables and reports on EF,

psychological symptoms, and fatigue

Demographic variables. There were no significant associations between age at time

of survey and any of the questionnaire indices, composite scales or total scores. Male PBT

survivors reported significantly more problems than female PBT survivors on the BRIEF MI

index (female mean = 45.3, ± 13.94; male mean =53.6, ± 12.53; p=.031; r=.31).

Tumor-related variables. There were no significant associations between age at

diagnosis and location (i.e., supra- vs. infratentorial locations) and any of the questionnaire

indices, composite scales or total scores. Tumor type subgroup differences on questionnaire

indices, composite scales and total scores are presented in Table 4. Parents of survivors of

ependymomas and choroid plexus tumors reported significantly less problems than parents of

survivors of embryonal tumors on the BRIEF BRI (corrected p=.017, r=-.59), MI (corrected

p=.004, r=-.68) and GEC (corrected p=.006, r=-.66) and the PedsQL Total (corrected

p=.015, r=.60). Significantly less problems were reported by parents of survivors of

ependymomas and choroid plexus tumors than parents of survivors of astrocytomas on the

24

BRIEF MI (corrected p=.022, r=-.50) and GEC (corrected p=.047, r=-.45). Survivors of

ependymomas and choroid plexus tumors reported significantly less problems than survivors

of embryonal tumors on the YSR Total Problems (corrected p=.049, r=-.51), the PedsQL

Total (corrected p<.001, r=.82) and the MFS Total (corrected p=.012, r=.61). Survivors of

ependymomas and choroid plexus tumors reported significantly less problems than survivors

of astrocytomas on the YSR Externalizing Problems (corrected p=.047, r=-.45) and the

PedsQL Total (corrected p=.035, r=.47).

Treatment-related variables. There were no significant associations between time

since treatment completion and any of the questionnaire indices, composite scales, or total

scores. Treatment type subgroup differences on questionnaire indices, composite scales and

total scores are presented in Table 5. Parents of PBT survivors treated with surgery combined

with CRT and chemotherapy reported significantly more problems than parents of PBT

survivors treated with surgery only on the BRIEF MI (corrected p=.035, r=-.41) and GEC

(corrected p=.046, r=-.39) and the PedsQL Total (corrected p=.007, r=.49). PBT survivors

treated with surgery combined with CRT and chemotherapy reported significantly more

problems on the PedsQL Total than PBT survivors treated with surgery only (corrected

p=.007, r=.49).

25

Tab

le 4

Sel

f- a

nd p

are

nt

report

ed e

xec

uti

ve f

un

ctio

nin

g, psy

cholo

gic

al

sym

pto

ms,

and f

ati

gue

in I

CC

C-3

tum

or

type

subgro

ups

E

pen

dym

om

as

an

d

choro

id p

lexu

s tu

mors

(EC

PT

)

(n=

6)

Ast

rocy

tom

as

(A)

(n=

23)

Em

bry

on

al

tum

ors

(ET

)

(n=

16)

Post

hoc

test

s E

ffec

t si

ze

M

ean

S

D

Mea

n

SD

M

ean

S

D

p (

un

corr

ecte

d)

r

BR

IEF

BR

I 40.2

7.2

8

46.6

6.9

8

51.6

11.1

5

EC

PT

< E

T;

p=

.006*

EC

PT

< A

; p=

.042

-.59

-.38

BR

IEF

MI

38.0

2.3

7

49.6

9.5

6

53.3

19.6

4

EC

PT

< E

T;

p=

.001*

EC

PT

< A

; p=

.007*

-.68

-.50

BR

IEF

GE

C

38.3

4.3

7

48.1

8.0

1

52.1

19.0

6

EC

PT

< E

T;

p=

.002*

EC

PT

< A

; p=

.016*

-.66

-.45

CB

CL

In

tern

ali

zin

g P

rob

lem

s 46.5

13.6

8

57.0

13.5

1

57.4

9.5

9

- -

CB

CL

Exte

rnali

zin

g P

rob

lem

s 37.7

5.7

2

47.0

7.6

6

46.4

11.5

0

- -

CB

CL

Tota

l P

rob

lem

s 39.5

14.6

8

52.2

10.0

6

54.4

10.2

7

- -

YS

R I

nte

rnali

zin

g P

rob

lem

s 47.2

9.3

0

54.3

8.9

1

53.1

9.3

4

- -

YS

R E

xte

rnali

zin

g P

rob

lem

s 39.8

6.0

1

50.0

8.0

5

48.0

7.8

3

EC

PT

< E

T;

p=

.040

EC

PT

< A

; p=

.008*

-.44

-.49

YS

R T

ota

l P

rob

lem

s 41.0

6.2

9

51.7

9.5

4

51.7

8.2

4

EC

PT

< E

T;

p=

.016*

EC

PT

< A

; p=

.016*

-.51

-.45

Ped

sQL

Tota

l -

pare

nt

rep

ort

88.7

11.3

6

75.0

18.1

1

65.1

17.6

7

EC

PT

> E

T;

p=

.005*

.60

Ped

sQL

Tota

l -

self

-rep

ort

93.2

4.7

5

78.0

11.8

4

64.3

20.6

9

EC

PT

> E

T;

p<

.001*

EC

PT

> A

; p=

.012*

A >

ET

, p=

.037

.82

.47

.33

MF

S T

ota

l 83.6

11.9

3

66.4

15.5

3

58.4

16.8

1

EC

PT

> E

T;

p=

.004*

EC

PT

> A

; p=

.040

.61

.38

Note

: -

indic

ates

bet

wee

n s

ubgro

up d

iffe

rence

s th

at d

id n

ot

reac

h s

tati

stic

al s

ignif

ican

ce,

and f

or

whic

h p

-val

ues

and e

ffec

t si

ze r

ther

efo

re c

ould

not

be

obta

ined

.

*in

dic

ates

bet

wee

n s

ub

gro

up d

iffe

ren

ces

that

surv

ived

Bonfe

rroni

corr

ecti

ons

for

mult

iple

com

par

isons.

26

Tab

le 5

Sel

f- a

nd p

are

nt

report

ed e

xec

uti

ve f

un

ctio

nin

g, psy

cholo

gic

al

sym

pto

ms,

and f

ati

gue

in t

reatm

ent

type

subgro

ups

S

urg

ery o

nly

(S

O)

(n=

28)

Su

rger

y a

nd

chem

oth

erap

y

(SC

)

(n=

9)

Su

rger

y, C

RT

1 a

nd

chem

oth

erap

y

(SC

C)

(n=

10)

Post

Hoc T

ests

E

ffec

t si

ze

M

ean

S

D

Mea

n

SD

M

ean

S

D

p (

un

corr

ecte

d)

r

BR

IEF

BR

I 44.0

6.8

3

49.2

8.4

2

52.1

12.5

6

- -

BR

IEF

MI

44.3

12.4

4

53.8

12.2

3

57.7

14.7

0

SO

< S

CC

, p=

.012*

-.41

BR

IEF

GE

C

43.1

11.1

9

52.3

10.4

8

56.1

15.0

8

SO

< S

CC

, p=

.015*

SO

< S

C, p=

.034

-.39

-.35

CB

CL

In

tern

ali

zin

g P

rob

lem

s 54.1

14.3

0

55.7

9.4

7

58.4

8.9

0

- -

CB

CL

Exte

rnali

zin

g P

rob

lem

s 45.0

8.2

9

45.1

11.0

8

44.8

11.9

2

- -

CB

CL

Tota

l P

rob

lem

s 49.2

12.1

1

52.2

11.3

0

54.5

9.7

1

- -

YS

R I

nte

rnali

zin

g P

rob

lem

s 51.9

9.9

4

53.9

6.3

1

52.0

11.2

5

- -

YS

R E

xte

rnali

zin

g P

rob

lem

s 48.0

8.4

4

47.8

9.5

6

45.2

8.7

4

- -

YS

R T

ota

l P

rob

lem

s 48.9

9.8

1

51.1

10.8

2

50.4

9.1

3

- -

PE

DS

QL

Tota

l -

pare

nt

rep

ort

78.9

17.7

0

74.2

17.7

8

58.7

14.1

3

SO

> S

CC

, p=

.002*

.49

PE

DS

QL

Tota

l -

self

-rep

ort

81.8

11.9

6

73.2

15.5

1

59.9

23.4

7

SO

> S

CC

, p=

.002*

.49

MF

S T

ota

l 70.4

16.6

8

64.9

17.4

6

54.8

16.0

3

- -

Note

: -

indic

ates

those

bet

wee

n s

ub

gro

up d

iffe

rence

s th

at d

id n

ot

reac

h s

tati

stic

al s

ignif

ican

ce,

and f

or

whic

h p

-val

ues

and e

ffec

t si

ze r

ther

efore

co

uld

not

be

obta

ined

.

1 C

RT

=cr

ania

l ra

dia

tion t

her

apy

*in

dic

ates

bet

wee

n s

ub

gro

up d

iffe

ren

ces

that

surv

ived

Bonfe

rroni

corr

ecti

ons

for

mult

iple

com

par

isons.

27

3. Discussion

The present cross-sectional study of EF, psychological symptoms, behavioral problems and

fatigue in adolescent PBT survivors has four main findings. First, we found significantly

elevated rates of neurocognitive impairment, including executive dysfunction, both in PBT

survivors’ parent-reports of EF compared to matched controls, as well as on performance-

based tests of EF compared to normative data. Second, PBT survivors and their parents

reported significantly more difficulties with aspects of adaptive functioning and QoL (i.e.,

social relationships, school functioning, academic performance, and participation in activities

) than healthy controls and their parents, and these difficulties were most strongly related to

parent-reported problems with executive dysfunction, internalizing symptoms of

withdrawal/depression and thought problems, and physical functioning, as well as to self-

reported problems with EF, physical functioning and sleep/need for rest. Also, corrected for

multiple comparisons, there were no significant associations between self- or parent-reported

aspects of adaptive functioning and QoL, and performance-based data. Third, we found that

being male, having sustained an embryonal tumor or an astrocytoma, and having undergone

surgery combined with CRT and chemotherapy, was significantly associated with higher rates

of parent and self-reported problems on the various questionnaires.

The findings altogether show that, along with problems with physical functioning and

fatigue, the largest differences between the adolescent PBT survivor group and the healthy

control group were for parent and self-reported neurocognitive concerns and problems with

academic and social functioning, as evidenced by the medium effect sizes. Neurocognitive

weaknesses were also evident on performance-based tasks, showing significant deviations

from the normative mean within the processing speed domain, and within two out of three EF

domains; shift and inhibitory control. These findings confirm the presence of neurocognitive

dysfunction, including difficulties with “cool”, or cognitive, aspects of EF, in this group of

28

adolescent PBT survivors. Furthermore, between-group differences on parent-reports of

working memory were significant, i.e., a “cool” EF aspect, having a near to medium ES. .

Although parents of PBT survivors reported significantly more EF difficulties than

parents of healthy controls, the PBT survivor mean scores are well within the normal range by

clinical standards, i.e., within one standard deviation from the normative mean. However,

several studies have shown that mean scores in healthy Norwegian and non-U.S. samples on

both the BRIEF and BRIEF- Adult Version (BRIEF-A; Roth et al., 2005) are significantly

below the U.S. normative mean of T = 50 (Grane, Endestad, Pinto, & Solbakk, 2014; Hovik et

al., 2017; Løvstad et al., 2012; Løvstad et al., 2016; Sølsnes, Skranes, Brubakk, & Løhaugen,

2014). The appropriateness of using the U.S. norms in a Norwegian setting is therefore

questioned. Furthermore, a tendency of low levels of parental endorsement of problems of EF

in survivors of PBT has been demonstrated in previous studies, even in the presence of

performance-based findings of executive dysfunction (Krivitzky, Walsh, Fisher, & Berl,

2016; Wochos, Semerjian, & Walsh, 2014). Interestingly, teacher reports have been found to

be more in line with performance-based findings (Wochos et al., 2014). Low levels of

parental endorsement of EF difficulties may be explained by a possible rater bias in parents,

such as psychological defense mechanisms and adjusting to the needs/challenges of their

medically fragile child, and/or differences across home and school settings in EF demands.

Similar to the parent-reports of EF, mean scores for parent-reported psychological and

emotional problems on a culturally acceptable questionnaire (Ivanova et al., 2007; Nøvik,

1999) were well within the normal range, indicating that, as a group, PBT survivors are

psychologically relatively well-functioning, with the exception of difficulties within the EF

domain.

No significant correlations between performance-based results and results on

questionnaires survived correction for multiple comparisons, and although parents of PBT

29

survivors reported significantly more problems with working memory, significant deviations

in this EF domain were not found in the performance-based data. The discrepancy between

the findings from these two methodological approaches is in line with previous studies, and

confirms the notion that they most likely tap separate, but associated, constructs within the EF

domain, and that functioning varies in different settings that place different or higher demands

on cognitive functioning (Anderson, Anderson, Northam, Jacobs, & Mikiewicz, 2002; de

Vries et al., 2017; McCurdy et al., 2016). For this reason, the two approaches simply cannot

replace one another without potentially losing valuable information.

In addition to confirming previous studies noting neurocognitive impairment in PBT

survivors, the findings from this study expand on current knowledge by investigating

neurocognitive impairment in PBT survivors in their adolescence specifically. For this age

group, there are relatively few studies, despite this critical period for adult adjustment and

outcomes. Furthermore, the findings expand on the knowledge as to the nuances within the

neurocognitive profile, by showing that adolescent PBT survivors seemingly struggle more

with the “cool”/cognitive aspects of EF relative to the “hot”/behavioral aspects. This finding

lends support to studies showing that although PBT survivors, survivors of acute

lymphoblastic leukemia, other pABI populations (i.e., traumatic brain injury, arterial ischemic

stroke), and congenital brain disorder populations (i.e., ADHD, autism spectrum disorder)

may have executive dysfunction in common, there seems to exist a distinctive

cognitive/executive profile in PBT survivors different from that of the other populations

(Anderson et al., 2002; Araujo et al., 2017; Krivitzky et al., 2016; Puhr et al., 2019a; Winter

et al., 2014).

Contrary to earlier findings from studies of survivors of childhood cancers noting an

increased risk of psychological problems in PBT survivors compared to other CCS

populations and the general population, the findings in this study showed few significantly

30

elevated parent-reported symptoms of psychological distress in PBT survivors, compared to

parents of healthy peers. Group differences were mainly evident for parent-reported

internalizing problems, i.e., symptoms of withdrawal, depression and somatization, a finding

which is in line with findings from other studies showing that, compared to other pABI and

adolescent CCS populations, PBT survivors may exhibit more internalizing than externalizing

problems (Brinkman, Li, et al., 2016; Poggi et al., 2005), a distinction that may further be

comparable to the findings from this and previous studies indicating more problems with

cognitive than behavioral aspects of EF. However, the group differences for parent-reported

internalizing problems yielded small ESs, and PBT survivors’ and healthy controls’ own

reports did not differ significantly on measures of psychological distress, other than for a

single subscale screening emotional symptoms. These findings suggest that in terms of

psychological adjustment, PBT survivors do not differ notably from their healthy peers. Also,

contrary to findings in pediatric populations (Jurbergs et al., 2008; Lund et al., 2011), there

were no significant discrepancies between parent and self-reports of psychological distress,

physical functioning or aspects of adaptive functioning and QoL within the PBT survivor

group other than PBT survivor parents reporting more symptoms of somatization than the

PBT survivors themselves. Thus, in light of this, parents and their adolescents in the PBT

survivor group seemed to be in agreement in this study. However, on the whole, the number

of group differences on parent-reports exceed the number of group differences found between

PBT survivors’ and the healthy controls’ self-reports. Altogether, these findings seem

somewhat conflicting as to whether or not parent and self-reports are in alignment, and can

therefore neither lend support to studies showing more parent-reported mental health

problems and lower QoL compared to child-reported, nor to studies showing the opposite.

The largest group differences in this study were for problems with aspects of adaptive

functioning and QoL, i.e., problems with academic achievement and social functioning, with

31

PBT survivors and their parents reporting significantly more difficulties than healthy controls

and their parents. This finding confirms conclusions from previous studies in pediatric and

adult populations, demonstrating that PBT survivors are at heightened risk of experiencing

social difficulties (e.g., poor peer acceptance, isolation, and diminished leadership roles),

lower academic/educational achievement, and poor socioeconomic attainment (e.g., being

engaged in regular employment or training and being financially independent), both in

comparison to other CCS populations, and to the general population (Boman, Lindblad, &

Hjern, 2010; Brinkman, Krasin, et al., 2016; Brinkman, Ness, et al., 2018; Brinkman,

Recklitis, et al., 2018; de Boer, Verbeek, & van Dijk, 2006; Frederiksen et al., 2019; Ghaderi

et al., 2016; Ghaderi et al., 2013; Mader, Michel, & Roser, 2017; Ness et al., 2008).

Not surprisingly, parent and self-reported problems of physical functioning and self-

reported symptoms of fatigue were strongly related to problems with aspects of adaptive

functioning and QoL, and is in accordance with previous studies (Boonstra et al., 2017; Brand

et al., 2016; Ness et al., 2005). Fatigue is one of the most distressing and debilitating late

effects after childhood cancer, hampering the individual’s possibilities of participating in

social and educational settings, even in the absence of other impairments. However, as

hypothesized, neurocognitive complaints, including executive dysfunction, exhibited the

strongest correlations to problems with adaptive functioning, demonstrating the particular

importance of these functions with respect to participating in society. More specifically,

problems with attention, working memory, mental shifting, and initiation were reported to

stand in the way of successful academic functioning and social participation. Certain

psychological symptoms were also significantly related to problems with adaptive

functioning, but to a lesser degree, as demonstrated by smaller ESs. Several studies have

established a link between impairments in EF and adaptive functioning (Evans, 2008; Ness et

al., 2008; Wolfe, Vannatta, Nelin, & Yeates, 2015; Wolfe et al., 2013). For example, a recent

32

study demonstrates how impairments in EF, although subtle, may play an especially

significant role in the development of these negative long-term outcomes compared to other

personal factors (Puhr et al., 2019b). The findings from this study are important, as they

indicate that the same pattern is present also at an earlier time point, i.e., in adolescence,

although future outcomes in our survivors remain to be seen.

There are several ways in which executive dysfunction may hamper scholastic and

social functioning in adolescence, potentially translating/accumulating in a long-term

perspective into difficulties transitioning successfully into adulthood and participating in

society. In order to succeed in academic/educational settings, intact EF is paramount (Brock,

Rimm-Kaufman, Nathanson, & Grimm, 2009; Duckworth & Seligman, 2005; Jacobson,

Williford, & Pianta, 2011; Poon, 2018; Treble-Barna et al., 2017). For example, children with

impaired working memory have difficulties retaining crucial information long enough to

perform adequate mental operations or store the information, leading to insufficient learning.

Poor organizational skills, impaired cognitive flexibility, difficulties initiating new tasks and

deploying effective strategies for reading/studying, interfere with academic/educational

efficiency.

The link between intact EF and the development of social competence and

interpersonal skills has for some time been noted in the child neuropsychology literature

(Beauchamp & Anderson, 2010), with findings demonstrating an association between

executive dysfunction and impaired social functioning across different pediatric brain injury

populations, including PBT survivors (Muscara, Catroppa, & Anderson, 2008; Sirois et al.,

2017; Willard, Allen, Hardy, & Bonner, 2015; Wolfe et al., 2013). For example, again

considering working memory, impairments in this area have been associated with social

difficulties, such as peer rejection, poor overall social competence, and impaired conflict

33

resolution skills in normally developing children (McQuade, Murray-Close, Shoulberg, &

Hoza, 2013).

Altogether, executive dysfunction in PBT survivors may play a pivotal role for long-

term outcomes. Further, in a developmental perspective, although neurocognitive impairments

may initially be discreet upon treatment completion, a tendency to “grow into deficit” has

been noted in pABI populations (Anderson, Northam, & Wrennall, 2019). Subtle EF

impairments present immediately after injury to brain networks may be followed by a delayed

onset and increase of impairments, as difficulty levels and cognitive demands increase with

time (Anderson, Jacobs, & Harvey, 2008; de Vries et al., 2017). Combined with symptoms of

fatigue, which also may a negative impact on neurocognitive functioning (Clanton et al.,

2011), the challenges are compounded further. Continued experiences of social and academic

failure, may well discourage an adolescent from pursuing educational and vocational goals.

As expected from previous findings in the PBT literature, certain tumor- and

treatment-related risk factors were identified in this study; having sustained an embryonal

tumor or an astrocytoma, and having undergone with surgery combined with CRT and

chemotherapy, was significantly associated with overall higher rates of parent and self-

reported problems on most questionnaires, with the exception of psychological problems, for

which there were few significant associations. Although these findings should be viewed as

explorative due to the small number of cases in some of the subgroups, they are nonetheless

in line with previous studies showing a considerably increased risk of negative outcomes after

complex treatment regimens (i.e., including CRT and/or chemotherapy, in addition to

surgery) (Bell et al., 2018; Brinkman, Recklitis, et al., 2018; Turner et al., 2009).

This study has several important limitations that need to be addressed, including a

cross-sectional design and the small number of participants in the PBT survivor group for

subgroup analyses of tumor- and treatment-related factors. Data on coping styles, family

34

factors (e.g., parental responsiveness, health and socioeconomic status, impact of serious

disease on family interactions), and social support were not collected, although these are all

factors that may have contributed to the observed differences (Kupst & Patenaude, 2016;

Ryan et al., 2016; Van Schoors et al., 2017). However, the response rate was relatively high

(53.3%) compared to previous studies in the child brain injury and CCS literature, ensuring an

adequate level of representativeness of this particular PBT population, and increasing

possibilities of generalization of the findings.

Despite study limitations, the findings provide important insights into the difficulties

experienced by adolescent PBT survivors, for which there traditionally has been limited

knowledge. The findings have clinical implications, as they demonstrate the importance of

assessing neurocognitive impairment in the critical phase that adolescence and young

adulthood presents. Fortunately, EF are relatively malleable (Zelazo & Carlson, 2012), all the

more implicating the importance of improving efficient interventions aimed at preventing

further impairments and improving EF skills. Short- and long-term assessments and tailored

interventions are as such essential in order to optimize PBT survivors’ chances of succeeding

in the transition to adulthood and participating in society, and to improve social equity in

survivors in a lifetime perspective.

Acknowledgments

Bjørg Eli Eide (Cand. Psychol.), Child Habilitation Services, Haukeland University Hospital,

Norway.

Oddmar Steinsvik (Cand. Psychol.), Child Habilitation Services, University Hospital of North

Norway, Norway.

Disclosure of interest: The authors report no conflict of interest.

35

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