Neuropsychological Outcome Following Cranio-spinal ... · Medulloblastoma is the most common...

Neuropsychological Outcome Following Cranio-spinal

Radiation in Medulloblastoma Patients: a Longitudinal Analysis

of Predictors

by

Iska Moxon-Emre

A thesis submitted in conformity with the requirements

for the degree of Master of Arts

Department of Psychology

University of Toronto

© Copyright by Iska Moxon-Emre 2013

ii

Neuropsychological Outcome Following Cranio-spinal Radiation in

Medulloblastoma Patients: a Longitudinal Analysis of Predictors

Iska Moxon-Emre

Master of Arts

Department of Psychology

University of Toronto

2013

Abstract

Medulloblastoma is the most common malignant central nervous system (CNS) tumor in

childhood. The cranio-spinal radiation (CSR) required to treat this disease results in long-term

cognitive and neurologic impairments. Medulloblastoma was recently categorized into four

genetic subgroups (WNT, SHH, Group 3, and Group 4). This study examined

neuropsychological and intellectual functioning in 91 medulloblastoma patients (41 Group 4; 20

Group 3; 18 SHH; 12 WNT) following treatment, and examined the impact of several medical,

treatment and demographic factors on functioning over time. Longitudinal growth curve analyses

revealed hydrocephalus most clearly predisposes to poor neuropsychological functioning.

Results also indicate medulloblastoma subgroups have heterogeneous intellectual outcomes

following treatment. All subgroups experience intellectual declines following treatment;

however, comparing between subgroups revealed Group 4 performs most poorly, and Group 3

has the best overall intellectual outcome. Lastly, qualitative analyses suggest treatment with a

larger CSR dose may contribute to poor intellectual functioning.

iii

Acknowledgments

The work presented in this thesis would not have been possible without the support from

several remarkable individuals. The unusual circumstances under which this thesis was written

highlighted the importance of having a supportive supervisor and colleagues, and I could not

have been luckier in this regard.

I would like to thank my supervisor, Dr. Donald Mabbott, for believing in my ability to

successfully complete a 1-year program in a single semester. Don’s flexibility and support was

truly outstanding, and I feel very fortunate to be embarking on my PhD under his supervision. I

would also like to thank my subsidiary advisor, Dr. Mary Lou Smith, for playing a key role in

permitting me to pursue this degree in a shortened time period, and for providing helpful

comments to this work. I would like to thank Dr. Michael Taylor for acting as my examiner, and

for providing useful edits to this thesis. I would also like to thank SickKids for providing me

with financial support through the Restracomp MA award.

This difficult time was made far more bearable because of all the members of lab, Nicole

Law, Nadia Scantlebury, Melanie Orfus, Frank Wang, Lily Riggs, Fang Liu, Naomi Smith and

Colleen Dockstader, who consistently showered me with encouragement and offered to help

every step along the way. I feel truly lucky to work with such a warm and supportive group of

individuals.

And last but not least, I would like to thank my family, friends and James, who provided

me with tremendous love and support through this intensely challenging time.

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Table of Contents

Acknowledgments .......................................................................................................................... iii

Table of Contents ........................................................................................................................... iv

List of Tables ................................................................................................................................ vii

List of Figures .............................................................................................................................. viii

List of Appendices ......................................................................................................................... ix

List of Supplementary Tables ......................................................................................................... x

Chapter 1 ......................................................................................................................................... 1

1 Overview .................................................................................................................................... 1

1.1 Aim 1 .................................................................................................................................. 2

1.2 Aim 2 .................................................................................................................................. 3

1.3 Aim 3 .................................................................................................................................. 4

2 Introduction ................................................................................................................................ 5

2.1 Brain Tumors ...................................................................................................................... 5

2.2 Medulloblastoma development ........................................................................................... 6

2.3 Medulloblastoma subgroups ............................................................................................... 8

2.4 Medulloblastoma treatment .............................................................................................. 10

2.5 Neuropsychological late effects of medulloblastoma treatment ....................................... 10

2.5.1 Age at diagnosis .................................................................................................... 12

2.5.2 Tumor location ...................................................................................................... 12

2.5.3 Post-Surgical/Medical Complications .................................................................. 12

2.5.4 Chemotherapy ....................................................................................................... 13

2.5.5 Cranio-spinal radiation .......................................................................................... 13

2.6 Recent advances and moving forward .............................................................................. 15

3 Patients and Methods ............................................................................................................... 17

v

3.1 Patient information ............................................................................................................ 17

3.2 Materials and Procedures .................................................................................................. 18

3.2.1 Intelligence ............................................................................................................ 18

3.2.2 Academic Performance ......................................................................................... 19

3.2.3 Receptive Vocabulary ........................................................................................... 20

3.2.4 Visual Motor Integration ....................................................................................... 20

3.2.5 Fine Motor Skills .................................................................................................. 20

3.2.6 Memory ................................................................................................................. 20

3.2.7 Attention ............................................................................................................... 20

3.3 Assessments ...................................................................................................................... 20

3.4 Medical Variables ............................................................................................................. 22

3.5 Subgrouping Medulloblastoma ......................................................................................... 24

3.6 Statistical Analysis ............................................................................................................ 26

3.6.1 Aim 1 .................................................................................................................... 27

3.6.2 Aim 2 .................................................................................................................... 28

3.6.3 Aim 3 .................................................................................................................... 28

4 Results ...................................................................................................................................... 29

4.1 Aim 1 ................................................................................................................................ 29

4.1.1 Aim 1a: Neuropsychological outcome in all medulloblastoma patients .............. 29

4.1.2 Aim 1b: Intellectual outcome as a function of demographic, medical and

treatment variables. ............................................................................................... 29

4.2 Aim 2: Intellectual Outcome as a Function of Medulloblastoma Subgroup .................... 35

4.3 Aim 3: Intellectual outcome as a function of treatment intensity in Group 4 patients ..... 40

5 Discussion ................................................................................................................................ 41

5.1 Hydrocephalus .................................................................................................................. 41

5.2 Medulloblastoma Subgroups ............................................................................................ 44

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5.2.1 WNT ..................................................................................................................... 44

5.2.2 Group 3 ................................................................................................................. 44

5.2.3 Group 4 ................................................................................................................. 45

5.2.4 SHH ....................................................................................................................... 46

5.3 Treatment Intensity (CSR dose and boost field) ............................................................... 46

5.3.1 All medulloblastoma patients ............................................................................... 47

5.3.2 Group 4 ................................................................................................................. 48

5.4 Limitations ........................................................................................................................ 48

5.5 Future directions ............................................................................................................... 49

5.5.1 All medulloblastoma patents ................................................................................. 49

5.5.2 Subgroups ............................................................................................................. 50

5.6 Conclusion ........................................................................................................................ 50

References ..................................................................................................................................... 52

Appendices .................................................................................................................................... 63

Supplementary Tables ................................................................................................................... 65

vii

List of Tables

Table 1: Clinical profiles of the most common pediatric brain tumor types……...............…….5

Table 2: Demographic profiles of medulloblastoma subgroups…………………...............……9

Table 3: Indexed scores considered equivalent across different test types and versions...….....19

Table 4: Number of observations for the different test types in each assessment year………..21

Table 5: Neuropsychological assessments…………………………………………………......22

Table 6: Therapeutic agents used in chemotherapy protocols………………………………....24

Table 7: Nanostring CodeSet…………………………………………………….....................26

Table 8: Estimated intercepts and slopes for measures of neuropsychological functioning

in all medulloblastoma patients……………………………………………………....31

Table 9: Group means, overall group and mean slope differences for neuropsychological

measures in medulloblastoma patients stratified by the presence/absence of

hydrocephalus...........................................................................................................…32

Table 10: Estimated intercepts and slopes for measures of neuropsychological

functioning in medulloblastoma patients stratified by the presence/absence

of hydrocephalus……………………………………………………………………...33

Table 11: Group means and standard error for measures of intelligence in each subgroup…….37

Table 12: Estimated intercepts and slopes for measures of intellectual functioning in

medulloblastoma patients stratified by subgroup…………….…………………….....38

viii

List of Figures

Figure 1. Patient Characteristics………………………………………………………………..17

Figure 2. Medical Variables…………………………………………………………………….25

Figure 3. Observed and estimated declines in FSIQ scores over time for patients with

and without hydrocephalus…………………………………………………………...32

Figure 4. Observed declines in PRI and WMI scores in patients that received a TB

boost treated with standard vs. reduced dose CSR…………………………...………35

Figure 5. Observed decline in FSIQ scores over time for patients within each subgroup……...36

Figure 6. Observed and estimated declines in PRI scores over time for patients in

Group 4 and SHH…………………………………………………………………….38

Figure 7. Observed and estimated declines in PSI scores over time for patients in

Group 4, Group 3 and SHH…………………………………………………………..39

Figure 8. Observed and estimated declines in WMI scores over time for patients in

Group 3 and SHH…………………………………………………………………….39

ix

List of Appendices

Appendix 1. Detailed medical information for Group 4 patients……………………………….62

Appendix 2. Detailed medical information for Group 3, SHH and WNT patients……………..63

x

List of Supplementary Tables

Table 1. Group means, overall group and mean slope differences for measures of

intellectual functioning in medulloblastoma patients stratified by age at

diagnosis…………………………...………………………………………………....65

Table 2. Estimated intercepts and slopes for measures of intellectual functioning

in medulloblastoma patients stratified by age at diagnosis……………………….…..65

Table 3. Group means, overall group and mean slope differences for

measures of intellectual functioning in medulloblastoma patients

stratified by extent of tumor resection………………………………………………..65


in medulloblastoma patients stratified by extent of tumor resection…………………66

Table 5. Group means, overall group and mean slope differences for CMS memory

measures in medulloblastoma patients stratified by the presence/absence

of hydrocephalus……………………………………………………………………...66

Table 6. Estimated intercepts and slopes for CMS memory measures in

medulloblastoma patients stratified by the presence/absence of

hydrocephalus……………………………………………………...…….…………...67


intellectual functioning in medulloblastoma patients stratified by

clinical risk……………………………………………………...………….…………67

Table 8. Estimated intercepts and slopes for measures of intellectual functioning in

medulloblastoma patients stratified by clinical risk…………………………………..68


intellectual functioning in medulloblastoma patients stratified by

CSR dose……………………………………………………………………………...68


medulloblastoma patients stratified by CSR dose…………………...…….…………68


intellectual functioning in patients that received a PF boost stratified by

CSR dose……………………………………………………………………………...69


in patients that received a PF boost stratified by CSR dose……………….………….69

xi


intellectual functioning in patients that received a TB boost stratified by

CSR dose……………………………………………………………………………...69


in patients that received a TB boost stratified by CSR dose………………………….70

Table 15. Overall group and mean slope differences for measures of intellectual

functioning in patients stratified by medulloblastoma subgroup……………………..70


intellectual functioning in Group 4 patients stratified by CSR dose……………....….71


in Group 4 patients stratified by CSR dose………………………………………...…71


intellectual functioning in Group 4 patients that received a PF boost

stratified by CSR dose………………………………………………………………..71


Group 4 patients that received a PF boost stratified by CSR dose…………………...72


intellectual functioning in Group 4 patients that received a TB boost

stratified by CSR dose……………………………………………………………..…72


Group 4 patients that received a TB boost stratified by CSR dose…………………..73

1

Chapter 1

1 Overview

Brain tumors are the most common solid tumors in childhood, and are the leading cause

of childhood cancer-related mortality and disability (Pollack and Jakacki, 2011). The treatments

required for effective tumor control often result in long-term physical, endocrine and

neuropsychological impairments that dramatically impact survivors’ quality of life.

Worldwide population-based surveys of childhood brain tumors reveal yearly incidence

rates ranging from 24-45.8 per million of the child population (Makino et al., 2010). More than

half the diagnosed central nervous system (CNS) tumors in children are located in the posterior

fossa (PF), a brain region that encompasses the cerebellum and brainstem (Poretti et al., 2012).

The most prevalent childhood brain tumor types are medulloblastoma, ependymoma and

gliomas, with medulloblastomas being the most common malignant CNS tumors in childhood

(Dubuc et al., 2010).

A recent study demonstrated only 30% of all medulloblastoma patients who survived

more than 10 years were capable of living independently as a result of physical and cognitive

morbidities (Maddrey et al., 2005). The severity and debilitating nature of these long-term

sequalae have necessitated that treatment protocols be adjusted, with the goal being to reduce

negative effects of treatment while maintaining current cure rates. In order for this to be

achieved, further characterization of medulloblastoma pathobiology is required.

Medulloblastoma was considered a single disease until recently, when RNA profiling on

expression microarrays revealed the existence of four discrete molecular variants of

medulloblastoma; WNT, SHH, Group 3 and Group 4. These four subgroups have distinct

demographics, histology, gene expression, transcriptional and clinical profiles that appear to

shape their biological behavior and response to treatment (Ellison et al., 2011, Northcott et al.,

2011, Taylor et al., 2012). The exact number of subtypes within each subgroup is still unknown,

but it is expected more than one exists for each subgroup (Taylor et al., 2012). Treatment of

medulloblastoma has remained largely homogenous for the past several decades and includes

surgery, cranial-spinal radiation (CSR), and chemotherapy. However, the recent discovery of

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medulloblastoma subgroups has led the medical community to contemplate transitioning towards

subgroup-specific treatment of this disease – where therapy would be tailored to the particular

characteristics of each subgroup (ISPNO conference, 2012). In doing so, the intent is to prevent

some of the physical, endocrine and neuropsychological impairments that result from treatment

for medulloblastoma by reducing treatment intensity for subgroups that have less aggressive

tumors and better survival profiles. In light of this pending treatment shift, it is necessary for

each subgroup to be characterized as comprehensively as possible. Tremendous work has been

done to characterize the genetic, demographic and clinical features of individual subgroups

(Taylor et al., 2012), but neuropsychological outcomes of individual subgroups have yet to be

examined. However, before outcomes are examined in a subgroup-specific manner, it is

important to clearly establish the factors that contribute to poor neuropsychological outcome in

medulloblastoma patients as a whole. To this end, this thesis seeks to characterize

neuropsychological outcome following CSR in medulloblastoma patients and is organized into 3

specific aims:

First, neuropsychological outcome will be examined in medulloblastoma patients as a

whole.

Second, potential differences in intellectual outcome between the four subgroups will be

evaluated.

Finally, differences in intellectual outcome will be examined as a function of treatment

intensity (CSR dose and boost field) in Group 4 patients only. Group 4 is the only

subgroup with which we have adequate power in our sample to address questions of

treatment intensity.

1.1 Aim 1

It is well established that treatment with CSR following the surgical resection of

medulloblastoma results in a decline in neuropsychological functioning over time (Kieffer-

Renaux et al., 2000, Ris et al., 2001, Palmer et al., 2003, Spiegler et al., 2004, Mabbott et al.,

2005, Mabbott et al., 2008). Although the overall adverse effects of CSR are well documented,

there is much less literature focused on the mediating impact of specific treatment and medical

factors on neuropsychological outcome. In Aim 1, the impact of treatment intensity (i.e. CSR

dose and field), success of surgery (i.e. extent of resection), demographics (i.e. age at diagnosis),

medical characteristics (i.e. clinical risk), and medical complications (i.e. hydrocephalus) on

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intellectual outcome will be evaluated. Standardized measures to evaluate intelligence, academic

performance, receptive vocabulary, visual motor integration, fine motor skills, memory and

attention will be used to characterize neuropsychological functioning in our entire

medulloblastoma sample longitudinally from shortly after treatment (i.e., baseline) over several

year follow-up. Intellectual outcome in our medulloblastoma sample will then be examined as a

function of the abovementioned factors to assess if any predispose to poor outcome following

treatment. Only by having a clear understanding of how our entire medulloblastoma sample

responds to treatment can we begin evaluating if, how and why the individual subgroups differ.

1.2 Aim 2

Currently it is unknown if patients in each of the four medulloblastoma subgroups

experience identical declines following treatment. Medulloblastoma subgroups have been shown

to differ considerably in their clinical and demographic profiles, factors that could contribute to

better or worse intellectual outcome. Namely, some differences that have emerged between

subgroups include age at which the tumor presents, and the proportion of patients with metastatic

disease – both factors that can affect intellectual outcome. For instance, young children are

known to be more vulnerable to the neuropsychological late effects of treatment with CSR

(Spiegler et al., 2004, Mabbott et al., 2005, Edelstein et al., 2011); thus, differences in age at

diagnosis between subgroups could translate into subgroup-specific differences in intellectual

outcome following treatment. Similarly, tumors of certain subgroups are more frequently

metastatic than others. A tumor’s metastatic status (i.e. clinical risk) plays a large role in

determining the aggressiveness of treatment received, and could therefore indirectly impact

intellectual outcome. In Aim 2 intellectual functioning following treatment will be examined as a

function of medulloblastoma subgroup. Because our medulloblastoma sample will be divided

into four for this portion of the analysis, our sample sizes will be too small to consider all

measures of neuropsychological functioning in each subgroup, therefore only measures of

intelligence will be used. If differences in intellectual functioning are observed between

subgroups, and if Aim 1 reveals any demographic, treatment or medical factors that predispose

to poor outcome following treatment (termed ‘critical factors’ for our purposes), wherever

possible, it will be examined if differences in intellectual functioning between subgroups can be

explained by the differing degree to which these ‘critical factors’ are represented in each

subgroup. In doing so, it will be evaluated, albeit indirectly, if intellectual outcome in the

4

different subgroups is dictated by something other than their demographic, treatment and

medical features (i.e. their underlying genetics).

1.3 Aim 3

There are known differences in patient survival across medulloblastoma subgroups, the

most dramatic of which are between WNT and Group 3; nearly all WNT patients survive while

Group 3 patients have very poor prognosis (Taylor et al., 2012). One of the rationales for

tailoring therapy to individual subgroups is to preserve neuropsychological functioning by

reducing treatment intensity for subgroups that have better survival outcomes. Treatment

intensity is currently decided upon by taking the tumour’s location, metastatic stage,

postoperative residual disease and patient age into consideration (Packer et al., 2003). Therapy

de-escalation should, in theory, prevent some of the intellectual morbidity associated with

aggressive treatment; however, it is important to establish a clear intellectual cost associated with

aggressive treatment in individual subgroups in order for changes in treatment to be justified on

this basis. In Aim 3, the intellectual cost associated with more aggressive treatment will be

examined by looking at Group 4 patients and by examining intellectual outcome as a function of

treatment intensity, both with respect to CSR dose and boost field. Group 4 is the most

commonly occurring subgroup, accounting for almost half the diagnosed medulloblastomas and

is the only subgroup with which we have adequate power in our sample to address questions of

treatment intensity. Evaluating the impact of treatment intensity within a single subgroup ensures

we are dealing with a clinically and demographically uniform sample, and as such, will provide

important clues about the relative importance of subgroup versus treatment factors in affecting

intellectual decline following CSR.

The information gleaned from this study will be essential for improving our

understanding of long-term neuropsychological outcome in all medulloblastoma patients and

intellectual outcome within individual subgroups. It will also provide important information

about the factors that have the greatest impact on intellectual decline in medulloblastoma

patients following treatment with CSR.

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2 Introduction

2.1 Brain Tumors

Brain tumor types differ in their developmental, biological and clinical profiles; thus,

methods to predict a tumor’s behavior is a subject of ongoing investigation. One well established

method of doing so is by assigning it a histological grade. To date, the grade a tumor receives

influences the course of treatment a patient receives, and is a key factor in determining if

radiation and chemotherapy will be used (Louis et al., 2007). Briefly, grade I tumors have low

proliferative potential, and are often cured with surgical resection alone, while Grade II lesions

generally have low proliferative activity, but are frequently infiltrative in nature and tend to recur

(Louis et al., 2007). Grade III tumors usually display evidence of malignancy, while Grade IV

tumors are malignant, mitotically active, necrosis-prone, evolve rapidly, and are often associated

with poor outcome (Louis et al., 2007). Patients with grade III and IV tumors typically receive

radiation and/or chemotherapy as an adjunct to surgery (Louis et al., 2007). While histological

classification remains routine and valuable, recent advances in genomic techniques have resulted

in the discovery of tumor-specific molecular characteristics not discernible by histology. Namely,

differences in gene mutations, copy number aberrations and deregulation of the transcriptome

that contribute to the unique biological development of these tumors are gradually being revealed

(Dubuc et al., 2010).

The differences in histological grade, tumor location, treatment protocols and prognosis

for the most common brain tumor types are described in Table 1.

Table 1

6

Table 1 - Clinical profiles of the most common pediatric brain tumor types. Data from this

table were compiled from: (Louis et al., 2007, Qaddoumi et al., 2009, Pollack and Jakacki, 2011,

Wisoff et al., 2011)

______________________________________________________________________________

Most childhood brain tumors are thought to occur sporadically, although some are known

to result from genetic cancer predisposition syndromes (Pollack and Jakacki, 2011).

Neurofibromatosis 1 (NF1), an inherited disorder characterized by the formation of nerve tissue

tumors in the skin, brain and spinal cord, is the most common genetic risk factor (Ullrich, 2008).

Other predisposition syndromes identified to date include Li-Fraumeni (LFS), a hereditary

disorder associated with a wide range of tumors that present at a young age, including sarcomas,

leukemia and breast cancer (Li et al., 1988, Ullrich, 2008). Additional risk factors include

tuberous sclerosis, Neurofibromatosis 2, Von Hippel-Lindau disease, Turcot and Gorlin

syndromes (Ullrich, 2008). Although less common than NF1, all these syndromes result from

germline mutations that increase susceptibility to tumor formation, and each are associated with

specific brain tumor types (Ullrich, 2008, Pollack and Jakacki, 2011).

Medulloblastomas are grade IV embryonal tumors and can be classified into one of five

distinct histological groups: classic, desmoplastic, anaplastic, large cell, and medulloblastoma

with extensive nodularity (Gilbertson and Ellison, 2008). Pathological classification is utilized

clinically to stratify patients into one of two risk groups, as histological groups correlate with

differing degrees of survival. Namely, large cell and anaplastic medulloblastomas have the

poorest outcome, while desmoplastic medulloblastomas have the best outcome (Bourdeaut et al.,

2011). However, subtyping medulloblastoma by histology alone is not ideal since inconsistencies

between pathologists’ interpretation and difficulties defining subtle features may be confounding

factors (Bourdeaut et al., 2011).

2.2 Medulloblastoma development

Medulloblastoma is thought to arise from disruptions in normal cerebellar development.

Neuronal progenitors with defective gene regulation or harboring abnormalities in genes and

proteins responsible for regulating normal cerebellar development are thought to underlie

medulloblastoma development (Marino, 2005).

The cerebellar cortex is comprised predominately of two neuron types; granule cells and

purkinje cells. Purkinje cells arise from the dorsomedial ventricular zone along the 4th ventricle

7

of the embryonic cerebellum, while cerebellar granule neurons are generated from the secondary

germinal zone that forms along the anterior aspect of the rhombic lip (Hatten and Roussel, 2011).

Mature cerebellar granule cells coordinate afferent input and motor output through their

excitatory connections with Purkinje cells, the main cerebellar output neuron (Ito, 2006). It is

well established that the cerebellum plays a role in sensori-motor functions, balance control, and

the vestibular ocular reflex, but several roles in motor learning, speech and spatial memory have

been documented as well (Hatten and Roussel, 2011). Furthermore, reciprocal connections

between the cerebellum and frontal lobes have been shown to play a role in higher cognitive

function (Dum and Strick, 2003).

The expression of genes and transcription factors responsible for establishing the

cerebellar territory during development are controlled in part by secreted proteins from the WNT

family (McMahon and Bradley, 1990). Medulloblastoma cells with activated WNT signalling

arise from progenitors in the embryonic dorsal brainstem and lower rhombic lip of the

cerebellum (Gibson et al., 2010, Hatten and Roussel, 2011). Interestingly, 10-15% of human

medulloblastomas have deregulated WNT signalling, where the pathway remains constitutively

activated, and transcription is increased leading to tumor development (Hatten and Roussel,

2011).

During development, the production of Sonic hedgehog (SHH) from Purkinje neurons

drives proliferation of the granule cerebellar progenitors and this process controls the number of

granule cells that enter the cerebellar circuit (Hatten, 1999). SHH binds to a transmembrane

receptor called Patched (Ptch) that is found in two forms, Ptch1 and 2 (Hatten, 1999). While

medulloblastoma can result from several disruptions along the SHH pathway, many

medulloblastomas, including those that develop in patients with Gorlin syndrome, result from

mutations in Ptch (Hatten and Roussel, 2011). Medulloblastomas arising from a constitutively

activated SHH/Ptch pathway originate from the granule cerebellar progenitors, yet it is currently

unknown if medulloblastoma resulting from different alterations along this pathway and others

also originate from granule cell precursors or from other cerebellar neurons (Gilbertson and

Ellison, 2008).

Approximately 40% of desmoplastic medulloblastomas occurring in young children have

active SHH signalling (Bourdeaut et al., 2011). Interestingly, several molecular inhibitors of the

SHH/Ptch signalling pathway have shown therapeutic promise by successfully suppressing

8

medulloblastoma formation in mouse models of medulloblastoma, and some of these compounds

have advanced to clinical trials (Hatten and Roussel, 2011). By understanding the disrupted

signalling pathways, novel animal models of human medulloblastoma can be developed, and

therapeutic molecular targets can be tested.

2.3 Medulloblastoma subgroups

The specific gene mutations and aberrations that lead to medulloblastoma development

differ considerably between subgroups and are thus characteristic of each subgroup. Notably, a

deletion of one copy of chromosome 6 is a common characteristic in WNT medulloblastomas

and the deletion of chromosome 9q, which contains the gene PTCH, is limited to SHH tumors

(Northcott et al., 2011, Taylor et al., 2012). Interestingly, some of the subgroup-specific genetic

abnormalities are related to genetic cancer predisposition syndromes. Namely, WNT tumors

occasionally harbor germline mutations in the WNT pathway inhibitor adenomatous polyposis

coli (APC), a phenomenon that predisposes to Turcot syndrome (Hamilton et al., 1995, Taylor et

al., 2012). Additionally, SHH tumors occasionally harbor germline mutations in the SHH

receptor PTCH, a feature characteristic of Gorlin syndrome (Bale et al., 1998, Taylor et al.,

2012). As previously mentioned, there are reported subgroup specific differences in the location

of tumor development, with WNT tumors developing from the dorsal brainstem and SHH tumors

developing from granule neuron precursor cells of the cerebellum (Gibson et al., 2010).

To date, most genetic alterations documented in Group 3 and Group 4 medulloblastomas

are not entirely subgroup specific. Namely, high levels of the regulator gene MYC have been

documented in Group 3 medulloblastoma, but also occur in the WNT subgroup (Hatten and

Roussel, 2011, Northcott et al., 2011). Furthermore, amplification and over expression of OTX2,

while characteristic of Group 3 medulloblastoma, is also common in Group 4 (Di et al., 2005,

Taylor et al., 2012). Group 3 tumors overexpress several genes that were initially identified

through their role in retinal development, but this relationship is not yet clearly understood (Cho

et al., 2011, Northcott et al., 2011, Kool et al., 2012).

The most common cytogenic change in Group 4, affecting 66% of patients, is found on

chromosome 17q, a phenomenon that affects 26% of Group 3 tumors as well (Taylor et al.,

2012). Several reports have documented the over-expression of genes involved in neuronal

differentiation and neuronal development in Group 3 tumors, but the importance of this is

currently unknown (Cho et al., 2011, Northcott et al., 2011, Kool et al., 2012).

9

Thus, WNT and SHH medulloblastoma are named after the signaling pathways believed

to play a role in their pathogenesis, while Group 3 and Group 4 have retained generic names

because their underlying biology have yet to be clearly established (Taylor et al., 2012).

In addition to differences in tumor biology, medulloblastoma subgroups have distinct

clinical profiles. Namely, there are considerable differences among subgroups with respect to

prevalence, male to female ratios, and age at diagnosis. These differences are summarized in

Table 2.

Table 2 – Demographic profiles of medulloblastoma subgroups. Data from this table were

compiled from: (Peris-Bonet et al., 2006, Northcott et al., 2011, Kool et al., 2012, O'Halloran et

al., 2012, Taylor et al., 2012)

There are also considerable inter-subgroup differences regarding the presence and degree

of metastasis. A tumor is defined as metastatic when it has acquired genetic alterations that allow

it to transcend physical boundaries, spread, and colonize distant tissues (Chiang and Massague,

2008). Metastasis is rare in WNT medulloblastomas, but the frequency increases progressively

for SHH, Group 4 and Group 3 medulloblastomas subgroups alike, with Group 3 tumors being

most frequently metastatic (Cho et al., 2011, Northcott et al., 2011).

10

While the overall survival rate for children with medulloblastoma has increased

considerably over the past two decades, the disparity in survival rates between subgroups is

striking. Compared with other subgroups, patients with WNT medulloblastoma have an excellent

long-term prognosis; survival rates exceed 90% (Ellison et al., 2011, Northcott et al., 2011). In

stark contrast, patients with Group 3 medulloblastoma have a poor long-term prognosis

regardless of metastatic status; a recent study by Northcott and colleagues demonstrated a

consistent decline in survival that neared zero by 8 years post-diagnosis (Northcott et al., 2011).

Patients with Group 4 and SHH medulloblastomas have similar, but intermediate survival rates

when compared with WNT and Group 3 medulloblastomas (Taylor et al., 2012).

2.4 Medulloblastoma treatment

Treatment for medulloblastoma has not changed considerably over the past 15 years, and

is determined primarily by the risk-group a patient falls into. Patients are considered either

average-risk or high-risk, and severity is determined by taking metastatic stage, postoperative

residual tumor, patient age and tumor location into consideration (Packer et al., 2003, Pollack

and Jakacki, 2011). Briefly, medulloblastomas are considered average-risk instead of high-risk

when there is a lack of neuraxis dissemination, minimal residual tumor following surgery, or if a

patient is younger than 3 years of age (Merchant et al., 2008). Typically, patients with average-

risk and high-risk medulloblastoma are treated with 2,340 and 3,600 cGy of CSR to the neuraxis

respectively and both groups receive a boost to the posterior fossa or tumor site in addition to

adjuvant chemotherapy (Pollack, 2011). With recent advances in neuroimaging, neurosurgical

technology, radiation therapy and risk-adapted chemotherapy, the 5 year-survival rate for

medulloblastoma has reached 70%, a dramatic increase from 50% only 25 years ago (Bleyer,

1999, Gatta et al., 2009).

2.5 Neuropsychological late effects of medulloblastoma treatment

All childhood cancer survivors are at risk of experiencing long term consequences from

their treatment, but brain tumor survivors are most vulnerable to the negative effects (Winick,

2011). One study reported 91.6% of 1877 CNS tumor survivors were affected by at least one

chronic medical condition (Anderson and Kunin-Batson, 2009), and others have demonstrated

40-100% of all CNS tumor survivors experience attention and concentration difficulties (Turner

et al., 2009, Winick, 2011). The location of posterior fossa tumors alone is enough to impact a

11

child’s neuropsychological functioning, with several studies having demonstrated

neuropsychological declines in patients treated with surgery alone (Levisohn et al., 2000, Ris et

al., 2008). However, patients treated with CSR, regardless of tumor location, experience a

spectrum of chronic long-term cognitive, neurologic and endocrine impairments that typically

worsen over time (Mabbott et al., 2005, Ellenberg et al., 2009, Merchant et al., 2010).

Specifically, treatment with CSR has been correlated with a decline in several

neuropsychological domains including intellectual functioning, visual-perceptual ability,

memory, learning, processing speed, attention and executive functioning (Kieffer-Renaux et al.,

2000, Spiegler et al., 2004, Mabbott et al., 2005, Mabbott et al., 2008).

To evaluate neuropsychological functioning, neuropsychologists typically administer

standardized tests that evaluate how brain functioning affects an individual’s abilities and

development. An array of measures ranging from broad indices to specific domains such as

attention and visual-motor integration are commonly used (Anderson and Kunin-Batson, 2009).

The most widely used broad measure of neuropsychological functioning is the overall

intelligence quotient (IQ), and it has been used extensively in both clinical populations and

healthy children alike. The widespread use of this broad measure has allowed for normal

development to be characterized and also for several large-scale multi-institutional studies on

neuropsychological outcome in pediatric brain tumor patients to be conducted (Levisohn et al.,

2000, Mulhern et al., 2004, Spiegler et al., 2004, Mabbott et al., 2008, Edelstein et al., 2011). In

order to arrive at an overall mean intelligence score, processing speed, working memory,

verbally expressed knowledge and visual-spatial abilities are examined (Wechsler, 2003). Taken

together, these tests estimate intellectual ability, and capture many of the core deficits

experienced by medulloblastoma patients such as poor processing speed and working memory

(Mabbott et al., 2008, Law et al., 2011).

Factors that have been shown to impact neuropsychological functioning most

dramatically following CNS tumor treatment include age at diagnosis, tumor location,

chemotherapy, the field and dose of radiation administered, and the presence of post-

surgical/medical complications (Ris et al., 2001, Mabbott et al., 2008, Turner et al., 2009). Each

contributing factor will be discussed below.

12

2.5.1 Age at diagnosis

A younger age at diagnosis has been associated with lower IQ and academic achievement

scores following CSR (Spiegler et al., 2004, Mabbott et al., 2005, Edelstein et al., 2011). The

observed neuropsychological decline following CSR is thought to result from a hindered rate of

development rather than through a loss of previously acquired skills (Ris et al., 2001, Palmer et

al., 2003, Mabbott et al., 2005). Thus, young children at early stages of brain maturation with

underdeveloped academic and intellectual skills are at greatest risk of neuropsychological

impairment following CSR. Several studies have avoided using conventional CSR to treat young

medulloblastoma patients, a strategy that has shown promise in preserving neuropsychological

outcome (Lafay-Cousin et al., 2009).

2.5.2 Tumor location

Tumors arising in the cerebral hemispheres have been suggested to pose the greatest

neuropsychological risk, as they could result in higher-order cognitive difficulties, compared

with tumors arising in the posterior fossa that are more likely to be associated with motor deficits

(Patel et al., 2011). However, several studies have demonstrated impairments in attention,

memory, academic and intellectual functioning in children with posterior fossa tumors treated

with CSR (Spiegler et al., 2004, Mabbott et al., 2005, Reeves et al., 2006). Elucidating the

discrete cerebellar regions responsible for mediating these neuropsychological deficits is an area

of ongoing investigation (O'Halloran et al., 2012). One study demonstrated that children who

underwent cerebellar tumor resection but who received neither CSR nor chemotherapy presented

with different deficits depending on the precise tumor location. Namely, left cerebellar

hemisphere tumors were related to visual-spatial deficits while tumors in the right cerebellar

hemisphere were related to language deficits (Levisohn et al., 2000). Transient impairments of

speech and communication are common following surgery for posterior fossa tumors (Ersahin et

al., 1996, Law et al., 2012). Thus, while the exact impact of tumor location on

neuropsychological outcome is still being elucidated, tumor location appears to be important.

2.5.3 Post-Surgical/Medical Complications

The presence and extent of medical complications have been shown to impact

neuropsychological functioning. Hydrocephalus, or fluid buildup in the brain, has been

correlated with lower IQs and academic skills in pediatric medulloblastoma survivors (Hardy et

13

al., 2008). Furthermore, a recent study demonstrated that patients who experienced any of the

following post-surgical complications: motor deficits, cranial nerve deficits, mutism and/or

meningitis, had greater impairments in information processing speed than patients who did not

experience postsurgical complications (Mabbott et al., 2008). While the specific contributions of

individual complications to poor neuropsychological outcome remain to be elucidated, the

presence of postsurgical complications clearly has a negative effect.

2.5.4 Chemotherapy

Although the neuropsychological late effects of chemotherapy are less dramatic than with

cranial radiation, they are not entirely insignificant (Anderson and Kunin-Batson, 2009).

Neuropsychological deficits most frequently observed in leukemia patients treated with the

chemotherapy agent methotrexate are in the domains of visual processing, visual-motor

functioning and attention (Hill et al., 1997, Buizer et al., 2005). Deficits in visual processing

negatively affect the way visual information is interpreted and understood, while visual-motor

deficits result in impaired skills such as handwriting and the ability to copy drawings. One study

demonstrated that patients treated with a combination of methotrexate, cytosine arabinoside and

hydrocortisone for leukemia had poorer attention, memory and visual processing than newly

diagnosed patients (Brown et al., 1992). It is likely that different chemotherapy agents, coupled

with intensity, timing and method of administration all result in different degrees of

neurotoxicity. For example, children who received an additional 3 weeks of chemotherapy,

regardless of the agent used, performed more poorly on visual-motor integration tasks (Kaleita et

al., 1997). In contrast, some studies did not find correlations between chemotherapy

administration and intellectual abilities (Copeland et al., 1996, von der Weid et al., 2003). Thus,

chemotherapy alone does not appear to be entirely benign, especially with respect to specific

neuropsychological domains such as attention and visual processing and visual motor

integration; however, the effects are not nearly as pronounced or consistent as they are with

CSR.

2.5.5 Cranio-spinal radiation

Neuropsychological declines in children treated with CSR do not present immediately but

have been observed within the first 12 months, and can be delayed by 1 to 2 years (Radcliffe et

14

al., 1992, Mulhern and Palmer, 2003, Palmer et al., 2010). The delayed nature of this decline

suggests CSR induces subtle, non-traumatic form of damage to the developing brain.

During CSR, no brain structures are shielded from radiation; however, not all structures

are equally susceptible to radiation-induced damage. It is plausible that structures and tracts with

long periods of development are especially vulnerable to insult during childhood. Namely, the

prefrontal cortex matures later than its caudal counterparts and its myelination continues into the

third decade of life (Sowell et al., 1999, Casey et al., 2000, Ullen, 2009, Teffer and Semendeferi,

2012). Interestingly, a study assessing white matter integrity following whole brain CSR

demonstrated frontal lobe white matter integrity was preferentially disrupted compared with

other brain regions (Qiu et al., 2007).

Increases in whole brain white matter volume occur during childhood and these increases

continue well into adolescence (Giedd et al., 1999, Paus et al., 1999, Lebel and Beaulieu, 2011).

This normal developmental structural change has been proposed to underlie the relative gains in

selective attention, working memory and problem-solving that occur with increasing age

(Anderson et al., 2001, Wolfe et al., 2012). A longitudinal neuroimaging study that compared

healthy controls with medulloblastoma patients treated with CSR and a boost to the PF

documented a relative white matter decrease of 1.1% per year, a stark contrast from the 5.4% per

year increase observed in healthy controls (Reddick et al., 2005). It is therefore not surprising

that children treated with CSR experience deficits in neuropsychological processes associated

with white matter such as processing speed and working memory (Mabbott et al., 2008, Law et

al., 2011).

The particular vulnerability of white matter to CSR induced injury may be due in part to

its unique vascular architecture. White matter contains long stretches of vessels with few

branches while gray matter contains large numbers of short branched vessels (Reinhold et al.,

1990). These structural differences result in blood flow in white matter that is 1/3 of that in gray

matter (Tuor et al., 1986). In addition to having a longer developmental period, the frontal lobe

has lower cerebral blood flow than the temporal, parietal and occipital cortices (Ito et al., 2003).

Thus, its late developmental period coupled with its decreased blood flow renders the frontal

lobe more vulnerable to CSR induced injury than other brain regions. Interestingly, decreased

15

frontal lobe white matter volume has been shown to correlate with deficits in sustained attention

following CSR (Reddick et al., 2003).

Brain regions harboring stem and progenitor cells that continue to undergo neurogenesis

are known to be particularly sensitive to radiation. In mammals, neurogenesis occurs in the

dentate gyrus of the hippocampus and in the subventricular zone of the lateral ventricles

(Blomstrand et al., 2012). Rodent studies have demonstrated the importance of neurogenesis in

hippocampal dependent memory formation (Shors et al., 2001), and it is hypothesized that

damage to the hippocampus is one of the critical determinants of poor neuropsychological

outcome following CSR (Blomstrand et al., 2012).

Radiation damages endothelial cells, one of the cell types that comprise the blood brain

barrier (BBB) (Li et al., 2003). Disruption to the BBB can lead to edema formation, or fluid

buildup in the brain, and also allows peripheral leukocytes such as macrophages and neutrophils

to infiltrate the brain (Siu et al., 2012). The infiltration of inflammatory cells can result in

secondary brain injury through the production of neurotoxic pro-inflammatory cytokines such as

tumor necrosis factor-alpha (TNF-a) and reactive oxygen species (ROS) (Siu et al., 2012). This

dynamic processes can result in tissue damage, and may underlie some of the cognitive deficits

observed in pediatric brain tumor survivors (Wong and Van der Kogel, 2004).

2.6 Recent advances and moving forward

In light of the negative sequalea discussed above, strategies for reducing CSR dose in

medulloblastoma patients has been a topic of intensive investigation, particularly for young and

average-risk patients. Average-risk patients are considered to have a more favorable outcome

than high-risk patients, thus therapy de-escalation was first attempted in the mid-1990’s for this

group (Packer et al., 1999). Reducing the dose from 3600 cGy to ~2300 in average-risk patients

was successfully accomplished with the addition of combination chemotherapy, and overall

survival rates were comparable to those receiving 3600 cGy (Packer et al., 1999, Taylor et al.,

2003, Merchant et al., 2008). To date, average-risk patients continue to be treated with ~2300

cGy. However, despite preserving overall survival rates, reducing the CSR dose has failed to

prevent the neuropsychological decline (Ris et al., 2001).

Following whole brain CSR, medulloblastoma patients have historically received a boost

of radiation to the entire PF, bringing the total PF radiation dose to a maximum of 5,000-6,000

16

cGy (Pollack and Jakacki, 2011). However, recent years have seen the emergence of

technological advances aimed at reducing complications associated with CSR. Namely, advances

in radiation oncology have led to the development of conformal techniques, allowing for three-

dimensional reconstructions of patient brains to guide treatment planning (Wolden et al., 2003).

Thus, focal conformal boosts to the tumor bed are sometimes used in place of a boost to the

entire PF, most commonly in average-risk patients. A boost to the entire PF delivers considerable

radiation to several critical brain structures located outside the targeted area, including the

cochlea, temporal lobes, parotid glands, pituitary and hypothalamus, while focal conformal

therapy to the tumor bed delivers considerably less radiation to these structures (Wolden et al.,

2003). A recent study demonstrated that treatment with focal conformal therapy to the tumor bed

resulted in disease control comparable to treatment to the PF in average-risk medulloblastoma

patients (Merchant et al., 2008). It seems plausible that focal conformal therapy would result in

fewer neuropsychological and neuroendocrine complications than a boost to the entire posterior

fossa, but this correlation has yet to be clearly established.

Recent strategies for delaying or avoiding radiotherapy in children younger than 5 that

have yielded positive results include using intraventricular chemotherapy or intensified systemic

chemotherapy and high-dose marrow-ablative chemotherapy (Rutkowski et al., 2010).

Additionally, a recent international meta-analysis on survival and prognostic factors of early

childhood medulloblastoma concluded that desmoplastic/nodular variants is a favorable

prognostic factor independent of metastatic disease in young children, and the authors suggest

de-escalation of CSR might be warranted in this population (Rutkowski et al., 2010).

In light of the recent subgrouping of medulloblastoma into four distinct subgroups, it is

becoming clear that treating medulloblastoma as a single disease may no longer make biological

sense. It has been proposed that patients with WNT medulloblastomas might benefit from

therapy de-escalation, as it is possible they are being over treated with current treatment

protocols (Taylor et al., 2012). Alternatively, it is plausible that patients with Group 3

medulloblsatomas could benefit from novel therapeutic techniques, as they consistently have

poorer outcomes than other subgroups despite receiving identical treatment. In order for

treatment protocols to become subgroup specific, a thorough understanding of

neuropsychological outcome in medulloblastoma patients as a whole and between subgroups is

necessary.

17

To this end, this thesis will aim to a) examine neuropsychological outcome in

medulloblastoma patients as a whole, b) evaluate if there are differences in intellectual outcome

between subgroups, and c) assess if treatment intensity has an impact on intellectual functioning

in Group 4 patients.

3 Patients and Methods

3.1 Patient information

Ninety-one children (28 females and 63 males) were included in this study, and all were

treated for medulloblastoma between 1995 and 2012 at the Hospital for Sick Children (Toronto,

Canada). The mean age at diagnosis for the entire medulloblastoma sample was 7.53 years

(standard deviation 3.39; range 1.09 – 14.95). Our medulloblastoma sample is comprised of 12

patients (13%) with WNT medulloblastomas, 20 patients (22%) with SHH medulloblastomas, 18

patients (20%) with Group 3 medulloblastomas, and 41 patients (45%) with group 4

medulloblastomas. Patient information for each subgroup is detailed in Figure 1.

Figure 1 – Patient Characteristics. A-D. Detailing the number of patients, the number of males

and females, and the age at diagnosis for patients in our entire medulloblsatoma sample, and for

each subgroup separately. (B-D are provided for visualization purposes).

18

3.2 Materials and Procedures

All neuropsychological assessments were conducted following treatment with CSR. Each

child underwent at least one clinical neuropsychological assessment and most underwent several,

although the number of assessments was not the same for all children. The number of patients

assessed with each measure varied across assessment points, since the original data were

collected for a variety of different clinical and research assessments, each with their own test

batteries. Our patient sample includes some individuals first diagnosed 17 years ago and several

tests and versions have changed within that time. Thus, there is considerable variability in both

the number of times, and over how many years, patients in our sample were seen. Namely, 1

patient was seen 8 times over the course of 14 years, whereas 29 patients were only seen once.

Following retrospective review, scores obtained longitudinally for neuropsychological tests were

obtained.

3.2.1 Intelligence

This study included several different test versions used to assess intelligence. Not all

versions have the same estimated and indexed scores, therefore, scaled scores obtained from the

various test types and versions were considered equivalent in the manner detailed in Table 3.

Specifically, measures to assess Full Scale IQ (FSIQ), verbal comprehension (VC), perceptional

reasoning (PR), working memory (WM) and processing speed (PS) were obtained by combining

scaled scores from the following test versions, where applicable: Wechsler Intelligence Scale for

Children – Third & Fourth Editions (WISC-III, WISC-IV), Wechsler Preschool and Primary

Scale of Intelligence – Revised and Second Edition (WPPSI-R, WPPSI-III), Wechsler

Abbreviated Scale of Intelligence (WASI) and Wechsler Adult Intelligence Scale – Third &

Fourth Editions (WAIS-III, WAIS-IV). In order to make comparison across test versions, each

child’s raw scores were converted to age-corrected scaled scores by using normative data for the

neuropsychological test provided in the manual for that particular test. The Wechsler technical

manual indicates that equivalency studies were conducted between all test versions and between

all families of Wechsler tests, and provides correlational data and details of test reliability

(Wechsler, 2003). Namely, the WISC-IV FSIQ correlates with the WISC-III, WPPSI-III and

WAIS-III FSIQ’s (r=.89), and with the WASI FSIQ (r=.86) (Wechsler, 2003). Furthermore, the

WPPSI-III FSIQ’s correlates with the WPPSI-R FSIQ (r=.86) and with the WISC-III FSIQ

19

(r=.89), and the WAIS-III FSIQ correlates with WISC-III FSIQ (r=.88) (Campbell et al., 2008).

This suggests scores obtained from all Wechsler tests and versions can be compared as long as

scaled scores are used.

Table 3 – Indexed scores considered equivalent across different test types and versions. FD:

Freedom from Distractibility; FSIQ: Full Scale Intelligence Quotient; PIQ: Performance

Intelligence Quotient; PO: Perceptual Organization; PR: Perceptual Reasoning; PS: Processing

Speed; VC: Verbal Comprehension; VIQ: Verbal Intelligence Quotient; WM: Working Memory.

WISC-III/IV: Wechsler Intelligence Scale for Children – Third & Fourth Editions; WPPSI-R/II:

Wechsler Preschool and Primary Scale of Intelligence – Revised and Second Edition; WASI:

Wechsler Abbreviated Scale of Intelligence; WAIS-III/IV: Wechsler Adult Intelligence Scale –

Third & Fourth Editions.

Assessing changes in intelligence is only one method to demonstrate and measure

neuropsychological impairment. In order to provide a more complete assessment of

neuropsychological impairment, scores obtained from standardized neuropsychological tests

designed to assess academic performance, receptive vocabulary, visual motor integration, fine

motor skills, memory and attention were also examined.

3.2.2 Academic Performance

To examine academic performance, Math, Reading and Spelling composites were created

by combining constructs from the Wide Range Achievement Test (WRAT) and Wechsler

Individual Achievement Test (WIAT) because of high correlation between them. Namely, the

WIAT-II and WRAT-3 constructs correlated with one another in the following manner: Reading,

r=.73; Math, r=.77; Spelling, r=.78 (Campbell et al., 2008). Furthermore, the WIAT-II and

WRAT-4 constructs correlated as follows: Reading, r = .78; Math, r=.92; Spelling, r=.64.

(Wilkinson, 2006). Additionally, the correlations between the constructs in WIAT-II and WIAT-

III are as follows: Reading, r=.85; Math, r=.81; Spelling, r=.86 (Breaux, 2009).

WISC-III WISC-IV WPPSI-R WPPSI-II WASI WAIS-III WAIS-IV

FSIQ FSIQ FSIQ FSIQ FSIQ FSIQ FSIQ FSIQ

VC VC VC VIQ VIQ VIQ VC VC

PR PO PR PIQ PIQ PIQ PO PO

WM FD WM - - - WM WM

PS PS PS - - - PS PS

20

3.2.3 Receptive Vocabulary

To examine receptive vocabulary, the Peabody Picture Vocabulary Test (PPVT) was

used. This test serves as a test of a child’s single-word receptive vocabulary in English and is a

screening of verbal ability.

3.2.4 Visual Motor Integration

The Beery Visual Motor Integration (VMI) test was used to determine how extensively

visual and motor abilities could be integrated. In this test, children were asked to copy geometric

forms that increased in difficulty as the test progressed.

3.2.5 Fine Motor Skills

To examine fine motor skills, the mean number of finger taps from both the dominant and

non-dominant hand were assessed by averaging over five trials, lasting 10 seconds each.

3.2.6 Memory

To evaluate memory, the Children’s Memory Scale (CMS) was used. The CMS is a

comprehensive assessment tool that assess auditory and verbal learning and memory, visual and

nonverbal learning and memory, as well as attention and concentration (Cohen, 1997).

3.2.7 Attention

The Connors’ Continuous Performance Test II was used to assess sustained attention. In

this test, children are told to press the space bar when they see any letter except X and not to

press the space bar when the see the letter X. By evaluating the child’s omissions and

commissions, this computerized test measures impulsivity and selective attention (Conners,

2000).

3.3 Assessments

Assessments were administered at different time points following diagnosis for each

patient. A summary of the number of assessments, tests, versions and the number of observations

within each, broken down by medulloblastoma subgroup, can be found in Table 4.

21

Table 4

Ass

essm

ent N

umbe

rA

sses

smen

t Num

ber

Ass

essm

ent N

umbe

rA

sses

smen

t Num

ber

Ass

essm

ent N

umbe

r

Obs

erva

tions

- to

tal

Obs

erva

tions

- W

NT

Obs

erva

tions

- S

HH

Obs

erva

tions

- G

roup

3O

bser

vatio

ns -

Gro

up 4

Mea

sure

12

34

56

71

23

41

23

45

67

12

34

51

23

45

6

WIS

CTh

ird E

ditio

n27

2514

62

--

53

--

22

21

1-

-4

42

--

1616

105

1-

Four

th E

ditio

n33

1721

127

2-

71

31

94

31

-1

-8

65

41

96

106

61

WP

PS

IR

evis

ed12

31

--

--

--

--

41

--

--

-1

--

--

72

1-

--

Sec

ond

Edi

tion

125

--

--

--

--

-3

2-

--

--

52

--

-4

1-

--

-

WA

SI

11

--

--

--

--

-1

--

--

--

--

--

--

1-

--

-

WA

ISTh

ird E

ditio

n2

--

21

--

--

-1

--

--

--

--

--

--

2-

-1

1-

Four

th E

ditio

n-

13

42

11

--

-1

--

-1

1-

1-

--

11

-1

31

-1

WR

AT

Third

Edi

tion

3628

135

31

-4

31

17

42

-1

1-

65

21

-19

168

32

-

Four

th E

ditio

n-

14

31

11

--

--

--

11

1-

1-

--

1-

-1

31

-1

WIA

TS

econ

d E

ditio

n10

919

164

21

--

22

41

22

1-

13

56

31

33

99

22

Third

Edi

tion

22

--

1-

--

--

--

2-

--

--

1-

--

-1

--

-1

-

PP

VT

Rev

ised

43

2-

1-

--

--

-1

--

--

--

--

--

-3

32

-1

-

Third

Edi

tion

4929

159

32

-4

31

29

53

12

1-

125

21

124

167

52

1

Four

th E

ditio

n3

1216

93

11

1-

21

-4

31

--

11

44

2-

14

105

11

VM

I54

4131

146

2-

53

32

109

52

21

-14

75

2-

2522

188

41

F-TA

P35

4034

2111

31

64

23

74

52

21

110

107

41

1222

2012

82

CP

TS

econ

d E

ditio

n38

3526

167

1-

85

43

73

32

--

-8

95

41

1518

147

61

CM

S45

3930

135

2-

53

31

109

51

11

-10

187

3-

2039

158

41

22

Table 4 - Number of observations for the different test types in each assessment year.

WISC: Wechsler Intelligence Scale for Children; WPPSI: Wechsler Preschool and Primary Scale

of Intelligence; WASI: Wechsler Abbreviated Scale of Intelligence; WAIS: Wechsler Adult

Intelligence Scale; WRAT: Wide Range Achievement Test; WIAT: Wechsler Individual

Achievement Test; PPVT: Peabody Picture Vocabulary Test; VMI: Visual Motor Integration; F-

TAP: Finger Tapping; CPT: Conners’ Continuous Performance Test; CMS: Children’s Memory

Scale.

______________________________________________________________________________

The median time from diagnosis to the first assessment was 0.4 years (range 0.05-8.73),

and for those who were seen more than once, the median time from diagnosis to the last

assessment was 4.76 years (range 1.29-14.16). This information, broken down by

medulloblastoma subgroup, is listed in Table 5

Table 5 – Neuropsychological assessments. Table listing the time from diagnosis to the first

neuropsychological assessment, time from diagnosis to the final neuropsychological assessment,

and the average number of assessments for the entire medulloblastoma sample and for each

subgroup.

3.4 Medical Variables

Gross total resection, where > 95% of the tumor was removed, was achieved in 74

patients (81%). 64 patients (71%) were classified as high risk, and the remainder (27 patients;

30%) were classified as average risk. 89 patients (98%) were treated with CSR; 41 patients

(45%) were treated with standard-dose (i.e 3060 to 3940 Gy), and 48 patients (53%) were treated

with reduced dose (i.e. 1800 to 2340 cGy) radiation to the whole brain. All patients treated with

CSR received an additional boost, raising the total radiation dose to a range of 4680 to 9540 cGy.

23

The type of boost a patient received differed based on the date radiotherapy was

administered. Prior to 2006 at the Hospital for Sick Children, average risk patients received a

lateral beam boost to the PF, and from 2006 onwards they received a focal conformal boost to

the tumor bed. In order to accurately elucidate the effects of cranial radiation on

neuropsychological functioning, our patient sample was divided into four categories for analysis,

as follows: 1) Patients treated with standard dose CSR and a boost to the PF (n=32; 35%), 2)

Patients treated with standard dose CSR and a focal conformal boost to the tumor bed (n=9;

11%), 3) Patients treated with reduced dose CSR and a boost to the PF (n=25; 27%), and 4)

Patients treated with reduced dose CSR and a focal conformal boost to the tumor bed (n=23;

25%). Histological classification of the tumors in our medulloblastoma sample revealed the

majority of tumors to be of the classic subtype (n=65; 71%), followed distantly by the large

cell/anaplastic (n=16; 18%), and desmoplastic (n=10; 11%) subtypes. 43 patients (47%)

presented with, and/or had treatment for hydrocephalus in the form of a shunt, external

ventricular drain, or a ventriculostomy. 11 patients (12%) in our sample died as a result of tumor

recurrence after being seen for at least 1 assessment. As previously discussed, medulloblastoma

subgroups differ in their biological and clinical features; thus, it is plausible that certain medical

characteristics may present to differing degrees in each subgroup. Medical variables for each

subgroup are summarized in Figure 2. Detailed medical information for each patient can be

found in Appendix 1 and 2.

85 patients (93%) received adjuvant chemotherapy. The chemotherapy protocols utilized

between 1995 and 2012 changed several times. Thus, patients diagnosed at different times were

treated with different agents, or with different doses and timing. Namely, 8 different

chemotherapy protocols are captured in our patient sample. The protocol names and the

therapeutic agents used in each are listed in Table 6. Although certain protocols appear identical

based on the chemotherapeutic agents used, they can differ considerably with respect to the

timing of administration and doses administered.

24

Table 6 – Therapeutic agents used in chemotherapy protocols. COG: Children’s Oncology

Group; POG: Pediatric Oncology Group; SJMB: St Jude Medulloblastoma Protocol; CCG:

Children’s Cancer Group; ICE & MOPP are abbreviations used based on the chemotherapeutic

agents administered. * Protocols typically used in children younger than 5 years of age.

3.5 Subgrouping Medulloblastoma

Medulloblastoma samples from patients whose neuropsychological data were available to

us were assigned subgroups by RNA nanostring the nanoString nCounter Analysis System at the

University Health Network Microarray Centre (Toronto, Canada) (Courtesy of Dr. Michael

Taylor’s laboratory). Nanostring is a non-enzymatic multiplexed assay that digitally measures

mRNA in a sample by using sequence specific probes (Geiss et al., 2008, Kulkarni, 2011). This

technology identifies and counts individual mRNA transcripts, a phenomenon that allows gene

transcription to be captured accurately. This technique is in contrast to technologies like

polymerase chain reaction (PCR) that rely on enzymatic amplification of RNA for signal

detection (Geiss et al., 2008). Thus, nanostring allows hundreds of unique transcripts to be

detected and counted in a single reaction.

Northcott and colleagues designed a custom CodeSet containing probes against 22

medulloblastoma subgroup-specific genes (Northcott et al., 2012b). This assay was tested

rigorously; nanostring results were compared with several samples of known subgroup, and this

CodeSet was found to be powerful enough to reliably subgroup medulloblastoma samples

(Northcott et al., 2012b). This codeset is described in Table 7.

Protocol Agents Used (in order of administration)

COG – ACNS 0331 Vincristine, Cisplatin, Lomustine (CCNU), Cyclophosphamide

Baby POG * Cyclophosphamide, Vincristine, Cisplatin, Etoposide

ICE Ifosfamide, Carboplatin, Etoposide

MOPP Mechloroethamine, Vincristine, Procarbazine, Prednisone

SJMB03 Vincristine, Cisplatin, Cyclophosphamide (amended to include Amifostine)

POG 9631 Cisplatin, Etoposide, Cyclophosphamide, Vincristine

CCG 9961 Vincristine, Lomustine (CCNU), Cisplatin

COG 99703 * Cisplatin, Vincristine, Cyclophosphamide, Etoposide

25

Figure 2

26

Figure 2 – Medical Variables. Left panels show the proportions of each medical variable for the

entire medulloblastoma sample (n=91). Right panels show the proportions of the same medical

variables for each medulloblastoma subgroup. A. The extent of tumor resection. B. Clinical Risk.

C. The dose of radiation (standard vs. reduced) and the type of boost (posterior fossa vs. tumor

bed) administered. D. The histological classification of tumors. LCA: Large Cell and Anaplastic.

E. The presence or absence of hydrocephalus.

______________________________________________________________________________

Table 7 – Nanostring CodeSet. Table listing the 22 probes against medulloblastoma subgroup-

specific genes that were used to classify medulloblastoma tissue into subgroups by Nanostring

technology. For technical details on medulloblastoma subgrouping by nanostring, please refer to

the methods section in Northcott et al.’s 2012 manuscript entitled “Rapid, reliable, and

reproducible molecular sub-grouping of clinical medulloblastoma samples”.

3.6 Statistical Analysis

To examine neuropsychological and intellectual outcome in medulloblastoma patients

following treatment, longitudinal analyses were conducted with growth curve analysis. Growth

curve analysis is a mixed model regression technique specifically designed to examine how the

shape of each individuals’ data changes over time (Singer, 2003). This analysis can handle

unbalanced and missing data, a common phenomenon in clinical samples and is thus able to

account for the different times after diagnosis that assessments were conducted in our patient

sample (Palmer and Royall, 2010). The mixed model assumes there is an underlying systematic

change in the data (Willett, 1994, Holditch-Davis et al., 1998), thus the linear model was

generated for all neuropsychological measures, and the curvilinear model (i.e. quadratic) model

was generated for all measures containing at least three data points. The model that provided the

best fit for the data was selected. When both linear and curvilinear models were generated, the

curvilinear model was reported when both were found to be significant. A significant quadratic

Subgroup Genes in codeset

WNT WIF1, TNC, GAD1, DKK2, EMX2

SHH PDLIM3, EYA1, HHIP, ATOH1, SFRP1

Group 3 KCNA1, EOMES, KHDRBS2, RBM24, UNC5D, OAS1

Group 4 KCNA1, EOMES, KHDRBS2, RBM24, UNC5D, OAS1

Housekeeping genes ACTB, GAPDH, LDHA

27

term indicates the slope of the domain being assessed curves over time because the rate of

change differs as time increases. Because the models generated are based on data from a

combination of children assessed several times, and some only assessed once, individual patient

trajectories are included to provide the reader with a visualization of the individual patient data

that resulted in the modeled change. Moreover, group means, where all points over time were

considered, were examined to establish overall group differences. This mixed model technique

was applied using the PROC MIXED procedure in the SAS software, version 9.1 (SAS institute).

Results were considered significant if P < 0.05.

3.6.1 Aim 1

To assess neuropsychological outcome following treatment in our entire

medulloblastoma sample, growth curve analysis was conducted to evaluate the change or

stability of scores for the following neuropsychological domains: intelligence, academic

performance, receptive vocabulary, visual motor integration, fine motor skills, memory and

attention. Following this neuropsychological characterization of our medulloblastoma sample,

the impact of demographic, medical and treatment factors were evaluated. The effect of these

factors on intellectual functioning was examined first, and when found to result in significantly

different intellectual outcomes, subsequent analyses were conducted to examine their impact on

additional measures of neuropsychological functioning. This approach was taken to further

characterize any differences in neuropsychological functioning observed between the groups.

Specifically, our entire medulloblastoma sample was stratified by the following factors

individually: age at diagnosis (i.e. < 7.26 years vs. > 7.26 years), clinical risk (i.e. average vs.

high), hydrocephalus (i.e. presence vs. absence), CSR dose and field (i.e. (1) standard vs.

reduced dose, (2) standard vs. reduced dose in only those patients who received a lateral beam

boost to the PF, and (3) standard vs. reduced dose in only those patients who received a focal

conformal boost to the TB), extent of tumor resection (i.e. gross total vs. subtotal), and

intellectual outcome for each condition within the factor was compared. A boost to the PF

delivers considerable radiation to several critical brain structures located outside the targeted

area, while focal conformal therapy to the TB delivers substantially less radiation to these

structures (Wolden et al., 2003). Thus, radiation field (i.e. type of boost received) should be

accounted for to accurately elucidate the effects of radiation on intellectual functioning. Prior to

2006 at the Hospital for Sick Children, average risk patients received a lateral beam boost to the

28

PF, and from 2006 onwards they received a focal conformal boost to the TB, regardless of the

CSR dose received. In order to create and compare the growth curves of patients with each

condition, the factor being assessed was specified in the CLASS statement in the SAS script.

3.6.2 Aim 2

Growth curve analysis was conducted to evaluate if intellectual functioning following

CSR differed as a function of medulloblastoma subgroup. To generate growth curves for

multiple subgroups in one model, subgroup was specified as the CLASS statement, and

comparisons between the growth curves were made using the ‘estimate’ and ‘contrast’

statements in the SAS script. Chi-square analyses were conducted to examine if the proportion of

factors shown to predispose to poor intellectual outcome in Aim 1 differed between subgroups.

3.6.3 Aim 3

To elucidate the intellectual cost associated with CSR dose and field in Group 4 patients,

growth curve analysis was conducted in an analogous manner to that in Aim 1b. Namely,

intellectual functioning in Group 4 patients was examined as a function of CSR dose and field by

stratifying Group 4 patients by 1) standard vs. reduced dose, 2) standard vs. reduced dose in only

those patients who received a lateral beam boost to the PF, and 3) standard vs. reduced dose in

only those patients who received a focal conformal boost to the TB.

29

4 Results

4.1 Aim 1

4.1.1 Aim 1a: Neuropsychological outcome in all medulloblastoma patients

Significant declines were observed in 20 out of the 24 measures of neuropsychological

functioning over the modeled time period in our entire medulloblastoma sample (F’s > 5.1 (range

5.1- 23.92), p’s < 0.05). The only non-significant declines were in fine motor skills (as measured

by the finger tapping tests) and attention (measured with the CPT-II). Intercepts represent the

modeled baseline functioning (median time from diagnosis to first assessment was 0.4 years),

and slopes represent the change in functioning over time (median time from diagnosis to final

assessment was 4.76 years and the maximum time was 14.16 years). Most declines in

neuropsychological measures fit the linear model, with the exception of PRI, the reading

composite of academic performance, and attention/concentration (measured with the CMS),

which had significant quadratic terms, indicating an attenuation of the decline. These findings

are in agreement, and replicate, what has previously been shown in the literature (Kieffer-

Renaux et al., 2000, Ris et al., 2001, Palmer et al., 2003, Spiegler et al., 2004, Mabbott et al.,

2005, Mabbott et al., 2008). Intercepts and slopes for the neuropsychological measures examined

in our entire medulloblastoma sample are provided in Table 8.

4.1.2 Aim 1b: Intellectual outcome as a function of demographic, medical and

treatment variables.

4.1.2.1 Age at diagnosis

When our medulloblastoma sample was stratified by age at diagnosis (i.e. by the median

split of 7.26 years), PSI was the only measure of intellectual functioning to differ significantly

between groups (F=5.27; p=0.008). Children younger than 7.26 years at time of diagnosis

performed more favorably than older children, a counterintuitive finding given that a younger

age has been associated with lower intelligence scores following CSR (Spiegler et al., 2004,

Maddrey et al., 2005, Edelstein et al., 2011). However, group means for all other measures of

intellectual functioning (i.e. FSIQ, PRI, VCI and WMI) were in the expected direction, with

younger children performing more poorly than older children following treatment, despite not

reaching significance. There were no significant differences in mean slope between the groups.

30

Group means, overall group differences, intercepts and slopes for measures of intellectual

functioning can be found in Supplementary Tables 1 & 2.

4.1.2.2 Extent of tumor resection

None of the modeled trajectories for measures of intellectual functioning in our

medulloblastoma sample differed as a function of extent of tumor resection. Group means,

overall group differences, intercepts and slopes for measures of intellectual functioning can be

found in Supplementary Tables 3 & 4.

4.1.2.3 Hydrocephalus

Stratifying medulloblastoma patients by the presence or absence of hydrocephalus

revealed that patients with hydrocephalus performed more poorly than patients without

hydrocephalus. The groups were found to differ significantly on all measures of intellectual

functioning, and were subsequently examined for differences in additional measures of

neuropsychological functioning, analyses that revealed significant differences in the reading and

spelling composites, receptive vocabulary, visual motor integration, and the

attention/concentration index of the CMS (F’s > 4.11, p’s < 0.05). All other memory domains

examined with the CMS were not significantly different between groups. Patients with

hydrocephalus presented with lower baseline scores for all measures of intellectual functioning.

Namely, patients with hydrocephalus presented with FSIQ, PSI and VCI scores that were

approximately 1 SD below the normative mean, a phenomenon not observed in patients without

hydrocephalus.

Mean slopes for the groups were significantly different for FSIQ, PRI, the reading

composite, and VMI (F’s > 2.14, p’s < 0.05). Patients with hydrocephalus experienced more

dramatic declines than patients without hydrocephalus, as indicated by larger negative slopes in

nearly all measures of neuropsychological functioning (Figure 3: FSIQ is shown as an example,

but similar declines were seen for nearly all other measures of neuropsychological functioning).

Group means, overall group, and mean slope differences for measures of neuropsychological

functioning showing significant differences are provided in Table 9, and intercepts and slopes are

provided Table 10. Group means, overall group differences, intercepts and slopes for memory

measures can be found in Supplementary Tables 5 & 6. Thus, having hydrocephalus appears to

31

dramatically impact neuropsychological functioning, both at baseline and over time in

medulloblastoma patients.

Table 8 - Estimated intercepts and slopes for neuropsychological measures in all

medulloblastoma patients (n=91). The following scores are standard scores (i.e. mean, 100,

standard deviation, 15): Intellectual functioning, Academic Performance, Receptive Vocabulary,

Visual Motor Integration and Memory. Fine motor skills are z scores, and Attention are T scores

(i.e. mean, 50, standard deviation 10). Higher T scores indicate poor performance. * p < 0.05

Estimated Intercepts and Slopes for Neuropsychological Measures

Domain Intercept Slope Quadratic

Estimate SE Estimate SE Estimate SE

Intellectual functioning

Full Scale IQ 91.74 1.35 -2.23 * 0.54 - -

Perceptual Reasoning Index 99.3 1.62 -4.08 * 0.97 0.22 * 0.09

Processing Speed Index 88.73 1.41 -2.36 * 0.46 - -

Verbal Comprehension Index 92.48 1.3 -1.45 * 0.5 - -

Working Memory Index 94.94 1.56 -1.8 * 0.52 - -

Academic performance

Math 93.64 1.82 -2.51 * 0.51 - -

Reading 100.96 2.09 -4.89 * 1.06 0.25 * 0.09

Spelling 94.81 1.67 -2.08 * 0.58 - -

Receptive vocabulary

PPVT 100 1.65 -1.53 * 0.48 - -

Visual motor integration

Beery - VMI 90.16 1.51 -1.72 * 0.48 - -

Memory

CMS - Visual Immediate 94.72 1.96 -1.79 * 0.65 - -

CMS - Visual Delayed 95.97 1.75 -2.01 * 0.57 - -

CMS - Verbal Immediate 93.02 1.94 -1.71 * 0.74 - -

CMS - Verbal Delayed 95.8 2.39 -2.01 * 0.78 - -

CMS - General Memory 94.26 20.8 -2.56 * 0.78 - -

CMS - Attention/Concentration 100.06 3.84 -7.19 * 2.51 0.64 * 0.29

CMS - Learning 90.67 1.98 -1.56 * 0.69 - -

CMS - Delayed Recognition 92.59 2.36 -1.96 * 0.8 - -

Fine motor skills

Dominant hand -0.17 0.21 -0.05 0.05 - -

Non-dominant hand -1.3 0.24 0.24 * 0.12 -0.03 * 0.01

Attention

CPT-II-Omissions 57.03 2.27 -0.42 0.52 - -

CPT-II-Commissions 45.07 1.22 1.51 * 0.37 - -

CPT-II-Hit Reaction Time 55.15 1.63 -0.12 0.53 - -

CPT-II-Hit Reaction Time - SE 54.79 1.32 -0.14 0.36 - -

32

Figure 3 – A. Observed declines in FSIQ scores over time for patients with and without

hydrocephalus (n=43/n=48). B. Estimated declines in FSIQ in patients with and without

hydrocephalus in a model that includes linear and quadratic terms. Overall group difference, * p

< 0.0001.

Table 9 – Group means; p values for overall group and mean slope differences for

neuropsychological measures when medulloblastoma patients were stratified by the

presence/absence of hydrocephalus. Presence of hydrocephalus (n=43); absence of

hydrocephalus (n=48).

B A

33

Table 10 - Estimated intercepts and slopes for measures of neuropsychological functioning in

medulloblastoma patients stratified by the presence/absence of hydrocephalus. All models

presented are significant (i.e. p < 0.05) * p < 0.05

4.1.2.4 Clinical Risk

None of the modeled trajectories for measures of intelligence differed as a function of

clinical risk in our medulloblastoma sample. Group means, overall group differences, intercepts

and slopes for measures of intellectual functioning can be found in Supplementary Tables 7 & 8.

4.1.2.5 Radiation Dose

To elucidate the effect of standard vs. reduced dose CSR on intellectual functioning, our

34

medulloblastoma sample was stratified by the following: 1) CSR dose alone, 2) CSR dose in

only those patients who received a PF boost, 3) CSR dose in only those patients who received a

TB boost.

4.1.2.5.1 Standard vs. Reduced dose


radiation dose. Group means, overall group differences, intercepts and slopes for measures of

intellectual functioning can be found in Supplementary Tables 9 & 10.

4.1.2.5.2 Standard dose – PF boost vs. Reduced dose – PF boost


radiation dose when only those patients who received a lateral beam boost to the PF were

included in the analysis. Group means, overall group differences, intercepts and slopes for

measures of intellectual functioning can be found in Supplementary Tables 11 & 12.

4.1.2.5.3 Standard dose – TB boost vs. Reduced dose – TB boost

A boost to the TB does not deliver widespread radiation to multiple brain structures, thus

examining standard vs. reduced dose in this group should have provided the most accurate

information regarding the impact of CSR dose on intellectual functioning. None of the modeled

trajectories for measures of intelligence differed as a function of radiation dose when only those

patients who received a boost to the TB were included in the analysis; however, some qualitative

observations can be made. Most notably, patients who received reduced dose CSR displayed

stable functioning over time, and sometimes displayed increases, in measures of PRI and WMI

(Shown in Figure 4 – blue lines). No qualitative observations can be made about patients who

received standard dose because longitudinal data were only available for two patients. The lack

of significance in the growth curve models likely resulted from the unequal and small sample

sizes (n=9/n=23), and from the shortage of longitudinal data in this comparison group. Group

differences, intercepts and slopes for measures of intellectual functioning are provided in

Supplementary tables 13 & 14.

35

Figure 4 – Observed declines in PRI and WMI scores in patients who received a boost to the

TB, treated with either standard (n=9) or reduced dose (n=23) CSR.

Results from Aim 1 indicate that hydrocephalus clearly predisposes to poor

neuropsychological outcome in medulloblastoma patients, both at baseline, and over time.

Results from Aim 1 also suggest, albeit qualitatively, that treatment with reduced dose CSR and

a TB boost might mitigate declines in certain measures of intellectual functioning.

4.2 Aim 2: Intellectual Outcome as a Function of Medulloblastoma

Subgroup

Plotting FSIQ scores for patients within each subgroup visibly demonstrated that all

subgroups declined following treatment with CSR. The observed FSIQ scores over time for

patients within each subgroup are shown in Figure 5. This figure demonstrates that Group 4,

Group 3 and SHH, but not WNT, have considerable longitudinal data. Overall group means for

measures of intellectual functioning in each subgroup are provided in Table 11. These means

suggest WNT did not differ considerably from the other subgroups, but had greater variability

across all measures examined. In light of the scarce longitudinal data in the WNT group, highly

variable scores and similar trajectory to other subgroups, the WNT subgroup was removed from

all subsequent analyses. This was done to prevent the generation of unstable longitudinal models.

Standard Reduced

Standard Reduced

36

Figure 5 – Observed decline in FSIQ over time for all patients within each subgroup.

Stratifying medulloblastoma patients by subgroup (i.e. by Group 4, Group 3 and SHH)

revealed subgroups differ in their intellectual functioning following treatment. Significant overall

group differences between subgroups were observed in PRI, PSI and WMI. Specifically, when

all scores across time were considered, SHH patients performed more favorably than Group 4

patients in PRI (F=3.89; p=0.0259); Group 3 patients performed more favorably than both SHH

and Group 4 patients in PSI (F’s > 3.7; p’s < 0.05); and Group 3 patients performed more

favorably than SHH patients in WMI (F=4.06; p=0.0235). Overall group means for measures of

intellectual functioning in each subgroup can be found in Table 11, and the significant overall

group differences are highlighted. To arrive at an overall group difference, both the mean values

over time and slopes are considered. A summary of overall group differences between subgroups

for all measures of intellectual functioning can be found in Supplementary Table 15.

37

Table 11 – Group means and standard error for measures of intelligence in each subgroup. *

Significant overall group difference between SHH and Group 4; ** Significant overall group

difference between SHH and Group 3; *** Significant overall group difference between Group 3

and Group 4. p < 0.05 for all significant comparisons. Because WNT was removed from the

longitudinal analyses, no overall group comparisons were made with WNT.

The subgroups did not differ significantly in how their scores changed over time (i.e. in

mean slope) (See supplemental Table 15). However, qualitatively, it appears that despite

performing more favorably than Group 4 and SHH patients on several measures of intellectual

functioning at baseline, Group 3 patients decline more dramatically than SHH on all measures of

intellectual functioning, and more dramatically than Group 4 patients on some measures over

time. This can be gleaned from Table 12, where intercepts and slopes for all measures of

intellectual functioning in Group 4, Group 3 and SHH are provided. Moreover, it appears that

while SHH patients presented with similar, and sometimes lower, baseline scores than Group 3

and Group 4, SHH patients experienced less dramatic declines over time. Observed and modeled

38

declines in PRI scores for Group 4 and SHH are shown in Figure 6, observed and modeled

declines in PSI scores for Group 4, Group 3 and SHH are shown in Figure 7, and observed and

modeled declines in WMI scores for Group 3 and SHH are shown in Figure 8.

Table 12 - Estimated intercepts and slopes for measures of intellectual functioning in

medulloblastoma patients stratified by medulloblastoma subgroup. All models presented are

significant (i.e. p < 0.05) * p < 0.05.

Figure 6 – A. Observed declines in PRI scores over time for patients in Group 4 (n=41) and

SHH (n=20). B. Estimated declines in PRI scores in a model that has linear and quadratic terms.

A B

39

Figure 7 – A. Observed declines in PSI scores over time for patients in Group 4 (n=41), Group 3

(n=18), SHH (n=20). B. Estimated declines in PSI scores in a model that has linear terms.

Figure 8 – A. Observed declines in WMI scores over time for patients in Group 3 (n=18) and

SHH (n=20). B. Estimated declines in WMI scores in a model that has linear and quadratic

terms.

Results from Aim 1b-i suggested an older age at diagnosis might predispose to poor PSI,

a phenomenon that could explain the differences in PSI observed between some subgroups.

However, patient age was not statistically different between subgroups included in the growth

curve analysis (i.e. Group 4, Group 3 and SHH): χ² (2, N=78) = 0.0648, p = 0.9681, and

therefore cannot account for this finding.

Results from Aim 1b-iii demonstrated hydrocephalus predisposes to poor

neuropsychological outcome in medulloblastoma patients following treatment. The incidence of

hydrocephalus was not significantly different between subgroups included in the growth curve

A B

A B

40

analysis (i.e. Group 4, Group 3 and SHH): χ² (2, N=78) = 1.5121, p = 0.4695. Thus,

hydrocephalus cannot explain the differences observed in certain measures of intellectual

functioning between subgroups.

Results from Aim 2 indicate patients in Group 4 have the poorest intellectual outcome

and patients in Group 3 have the most favorable outcome following treatment. Qualitatively, it

appears SHH patients have the most stable intellectual functioning over time following

treatment. Taken together, these results demonstrate medulloblastoma subgroups have

heterogeneous intellectual outcomes following treatment.

4.3 Aim 3: Intellectual outcome as a function of treatment intensity in

Group 4 patients

No differences in intellectual functioning were observed when Group 4 patients were

stratified by the following: 1) CSR dose alone, 2) CSR dose in only those Group 4 patients who

received a PF boost, 3) CSR dose in only those Group 4 patients who received a TB boost.

Group means and overall group differences for measures of intellectual functioning in Group 4

patients stratified by all three above mentioned conditions can be found in Supplementary Tables

16, 18 & 20, and intercepts and slopes for measures of intellectual functioning can be found in

Supplementary Tables 17, 19 & 21.

Despite the generation of non-significant longitudinal models, qualitatively, group means

suggest Group 4 patients treated with reduced dose CSR and a TB boost (n=7) performed more

favorably than patients treated with standard dose CSR and a TB boost (n=6), on all measures of

intellectual functioning, except processing speed. FSIQ: 91.95 vs. 87.40, PRI: 98.20 vs. 74.24,

VCI: 98.77 vs. 83.60, WMI: 98.63 vs. 88.11. Notably, patients treated with reduced dose CSR

were 1 standard deviation (1 SD = 15) below patients treated with standard dose CSR in PRI.

The lack of significant difference between these group means is likely due to the small sample

sizes.

Results from Aim 3 suggest that treatment with reduced dose CSR and a TB boost may

mitigate some of the intellectual declines observed following treatment in Group 4 patients.

41

5 Discussion

In this thesis, neuropsychological and intellectual functioning were examined in

medulloblastoma patients following treatment. Our medulloblastoma sample was stratified by

several demographic, medical and treatment factors to evaluate their impact on functioning.

Differences were examined by comparing overall means (i.e. including all time points in a

group) and by examining changes over time (i.e. up to 14 years post-diagnosis) both within and

between groups. The novel findings from this thesis are as follows:

1. Among the demographic, treatment and medical factors examined, hydrocephalus most

clearly predisposes to poor neuropsychological functioning in medulloblastoma patients.

2. Medulloblastoma subgroups have heterogeneous intellectual outcomes following

treatment. All subgroups experience intellectual declines following treatment. When

comparing the subgroups, Group 4 performs most poorly, and Group 3 has the best

overall outcome following treatment.

5.1 Hydrocephalus

Results from Aim 1 demonstrate that the presence of hydrocephalus clearly predisposes

to greater declines in neuropsychological functioning following treatment with CSR.

Hydrocephalus is defined as the excessive accumulation of cerebrospinal fluid (CSF) in the CNS

ventricular system and results in increased intracranial pressure (ICP) (Erickson et al., 2001).

Hydrocephalus has been correlated with lower intellectual functioning and academic skills in

pediatric medulloblastoma survivors (Hardy et al., 2008) and ependymoma survivors alike

(Merchant et al., 2004); however, no equivalent longitudinal study has been conducted to my

knowledge. As such, this thesis makes an important contribution to the pediatric

medulloblastoma field regarding predictors of neuropsychological outcomes.

It is well documented that children with hydrocephalus, regardless of the underlying

cause, perform more poorly on measures of intellectual functioning than healthy developing

children, and also as compared to children with the same underlying etiology who do not develop

hydrocephalus (Erickson et al., 2001). For example, only 54% of patients with spina bifida who

developed hydrocephalus had intelligence scores within the normal range, while 76% of patients

42

with spina bifida who didn’t develop hydrocephalus had intelligence scores in the normal range

(Mirzai et al., 1998). In our medulloblastoma sample, patients with hydrocephalus had

significantly lower baseline scores (i.e. shortly after treatment) on several measures of

neuropsychological functioning than patients without hydrocephalus. One study demonstrated

that pediatric brain tumor patients with hydrocephalus performed more poorly than patients

without hydrocephalus on measures of intelligence, executive functioning, visual-motor, and

fine-motor functioning, prior to treatment (Brookshire et al., 1990). Brookshire’s findings raise

the possibility that patients in our sample who presented with hydrocephalus at diagnosis would

have performed more poorly than patients without hydrocephalus, but this information cannot be

gleaned from the present study. In light of the considerable emphasis placed on delineating the

neuropsychological late effects of treatment for medulloblastoma, it will be important to tease

out the contribution of presenting with hydrocephalus. This is especially important if patients’

neuropsychological ‘baseline’ functioning are routinely examined following treatment, as was

the case in the present study. The present study demonstrates that in addition to presenting with

lower baseline neuropsychological scores, patients with hydrocephalus continue to decline more

dramatically on measures of neuropsychological functioning following treatment than patients

without hydrocephalus.

Hydrocephalus in medulloblastoma patients is most commonly due to blockage of CSF

within the ventricular system as a result of the tumor mass. Tumors located in the posterior fossa

frequently compress the 4th

ventricle, a phenomenon that contributes to the development of

hydrocephalus (Crawford et al., 2007). The accumulation of CSF in the ventricular system

increases ICP, a phenomenon that may exert negative effects on neuropsychological functioning

by way of direct structural damage to the developing brain. Raised ICP has been shown to

produce mechanical stress that decreases cerebral blood flow, thereby reducing the availability of

neurotransmitters, damaging axons and myelin, and resulting in neuronal dysfunction (Del Bigio,

1993, Mataro et al., 2001). A position emission tomography (PET) study in infants with

hydrocephalus demonstrated considerable hypoperfusion in brain regions surrounding the dilated

lateral ventricles, including the frontal, parietal and visual association cortices (Shirane et al.,

1992). Intellectual functioning is negatively affected by several factors that result directly from

hydrocephalus, most notably the size of the ventricles, displacement of brain structures, and the

degree of myelination (Fletcher et al., 1992, Mataro et al., 2001). Treatment with CSR has been

43

correlated with decreased white matter integrity and deficits in neuropsychological processes

associated with white matter such as processing speed and working memory (Mabbott et al.,

2008, Law et al., 2011). Thus, patients with hydrocephalus may receive several independent, yet

cumulative, insults to white matter, a unique situation that may render them particularly

vulnerable to neuropsychological deficits following treatment. It is therefore not surprising that

patients with hydrocephalus in our medulloblastoma sample had lower baseline scores and larger

declines on measures of neuropsychological functioning than patients without hydrocephalus.

Prior to the development of valve shunting systems, it was not uncommon for children to

die from untreated hydrocephalus (Hirsch, 1992). Shunting procedures significantly improved

survival rates, and while shunting is clearly preferable to untreated hydrocephalus, shunt

placement increases the risk of post-operative complications (Mataro et al., 2001). Specifically,

shunts have been associated with infection, seizures, migration of the catheter, shunt malfunction

and shunt obstruction (Gopalakrishnan et al., 2012). The presence of additional complications

following treatment increases the risk of cognitive impairment in patients with hydrocephalus,

regardless of etiology, and in medulloblastoma patients (Mataro et al., 2001, Mabbott et al.,

2008). Taken together, medulloblastoma patients appear to be uniquely disadvantaged with

respect to their risk of developing and suffering from the negative effects of having

hydrocephalus, a fragile situation that is compounded further by aggressive treatment with CSR.

In light of the increased risk of poor neuropsychological functioning as a result of

hydrocephalus, medulloblastoma patients who develop hydrocephalus at any point stand to

benefit from increased neuropsychological monitoring. Our results suggest these assessments

need not be exhaustive, as measures of intellectual functioning, academic achievement and visual

motor functioning appear to be highly sensitive to decreases in functioning. Thus, in theory,

routine testing could be easily implemented into a child’s academic experience upon returning to

school. While extra monitoring cannot preserve or help to regain any previously lost functioning,

it can attempt to mitigate further declines by alerting patients and their caregivers to newly

developing areas of difficulty, and by providing individualized coaching and directed academic

support in response.

44

5.2 Medulloblastoma Subgroups

Medulloblastoma subgroups have heterogeneous intellectual outcomes following

treatment. This finding has different implications for each subgroup, owing most heavily to their

varied survival profiles following treatment.

5.2.1 WNT

Results from Aim 2 highlight that no subgroup is spared intellectual decline following

treatment. This finding is particularly relevant for patients with WNT tumors given their

favorable survival outcome. Hydrocephalus cannot account for the observed declines, as only 3

of the 12 WNT patients had hydrocephalus, indicating other treatment factors (i.e. surgery or

CSR) could be responsible. In light of the >90% survival rate patients for with WNT

medulloblastomas, recent clinical studies have recommended WNT patients be treated with

lower doses of CSR, or that it be used at all (Taylor et al., 2012, ISPNO 2012). If CSR is

principally responsible for the intellectual decline observed in WNT patients, they stand to

benefit intellectually from therapy de-escalation. Despite the absence of a significant relationship

between CSR dose and intellectual functioning in this study, results from Aim 1 and Aim 3

suggest treatment with a reduced dose and a TB boost may mitigate some of the intellectual

declines.

5.2.2 Group 3

Group 3 had the most favorable intellectual outcome following treatment, performing

better than Group 4 and SHH on several measures of intellectual functioning despite still

experiencing declines. This optimistic finding about Group 3 comes in stark contrast to their

poor long-term prognosis (Northcott et al., 2011, Taylor et al., 2012). Northcott and colleagues

recently demonstrated that survival in Group 3 patients neared zero by 8 years post-diagnosis

(Northcott et al., 2011). We did not have exhaustive longitudinal data in the order of 8 years

post-diagnosis for our Group 3 patients, and the current status of patients in this group is

unknown. However, only three Group 3 patients in our sample are known to have died. The

intellectual functioning of Group 3 patients is encouraging, in particular their performance at

early time points following treatment, which we can interpret with greatest certainty owing to the

increased stability of the longitudinal model at early time points. Since survival is dismal for

45

Group 3 patients treated with current protocols, perhaps Group 3 patients would benefit from

novel experimental therapies, aimed primarily at promoting survival, but with the added benefit

of preserving their favorable intellectual functioning should the experimental treatment prove to

be effective.

5.2.3 Group 4

Recent research has placed considerable emphasis on elucidating the genetic variations

that contribute to individual differences in toxicity due to radiotherapy. Radiation results in DNA

damage and alters the microenvironment by way of inflammatory cytokines, cell-cell

interactions, infiltration of inflammatory cells, and through the induction of restorative processes

(Barnett et al., 2009, West and Barnett, 2011, Haston, 2012). Thus, it is plausible genes

responsible for DNA damage recognition, apoptosis and inflammation could differ between the

subgroups and consequently impact a subgroup’s response to radiation. Of the three subgroups

(Group 4, Group 3 and SHH) included in the longitudinal growth curve modeling, Group 4 had

the poorest intellectual outcome following CSR. The heterogeneity of neuropsychological

functioning observed in Group 4, Group 3 and SHH patients cannot be attributed to differences

in medical or treatment factors, and suggest there may be something inherent to the subgroups

that predispose to better or worse outcome following treatment. Perhaps Group 4 patients harbor

germline mutations, single-nucleotide polymorphisms (SNPs), copy number variations (CNVs)

or other genetic characteristics that render them more susceptible to radiation-induced damage.

Despite being the most prevalent medulloblastoma subgroup, Group 4 remains the most

poorly understood (Northcott et al., 2012a). Attempting to explain the genetic characteristics of

Group 4 medulloblastoma that could account for its poor outcome is beyond the scope of this

thesis. However, an idea is proposed. Nuclear factor-kB (NF-kB) signaling is related to the

transcription of pro-inflammatory cytokines and its activity is regulated by NF-kB inhibitor alpha

(NFKBIA) (Tak and Firestein, 2001, Zhang et al., 2011). Intriguingly, NF-kB has recently been

implicated in Group 4 medulloblastomas in that deletions affecting several regulators of the NF-

kB pathway, including NFKBIA, have been identified (Northcott et al., 2012a). Importantly,

treatment with radiation activates NF-kB in both tumor and non-tumor cells (Hei et al., 2011).

Thus, in theory, a comparatively heightened inflammatory response could ensue following CSR

in Group 4 patients as a result of their compromised NF-kB regulatory system. Pro-inflammatory

46

cytokines and the subsequent generation of reactive oxygen species (ROS) are be directly

neurotoxic and could exert negative effects on brain integrity and subsequent developing

cognitive processes (Wong and Van der Kogel, 2004, Siu et al., 2012). Although speculative, this

model serves to highlight how differences in genetic characteristics between medulloblastoma

subgroups could translate into heterogeneous intellectual outcomes following treatment.

A recent study by Northcott and colleagues demonstrated the overall survival probability

for Group 4 (formerly Group D) patients was identical when patients were treated with standard

and reduced dose CSR (Northcott et al., 2011). Group 4’s poor intellectual functioning following

treatment and lack of increased survival with standard dose CSR treatment suggest patients in

Group 4 stand to benefit intellectually from therapy de-escalation without an associated survival

cost. The potential mitigation of intellectual decline following less aggressive treatment in Group

4 will be discussed in section 5.3.2.

5.2.4 SHH

Qualitatively, it appears SHH patients have the most stable intellectual functioning

following treatment, declining less than both Group 4 and Group 3 on several measures. It is

plausible SHH medulloblastomas may harbor genetic characteristics that render them less

susceptible to radiation-induced damage. In contrast to Group 4, a clear increase in survival was

demonstrated for SHH patients treated with standard vs. reduced dose CSR (Northcott et al.,

2011). In light of their comparatively stable intellectual functioning and increased survival

associated with more aggressive treatment (Taylor et al., 2012), considerable modification to

current SHH treatment protocols may not be warranted.

5.3 Treatment Intensity (CSR dose and boost field)

While it is logical to assume that treatment with reduced dose CSR would be less

damaging and translate into better intellectual functioning, several studies have failed to

demonstrate this outcome (Ris et al., 2001, Mabbott et al., 2008). However, findings in these

studies may have been confounded by boost field heterogeneity. Interestingly, a study that

successfully demonstrated a preservation of intellectual functioning with reduced dose CSR

treatment only included patients treated with focal conformal boosts (Mulhern et al., 2005).

Analyses conducted in Aim 1 and Aim 3 on CSR dose and boost field yielded interesting

47

qualitative results worthy of discussion. Qualitative analysis suggests treatment with a higher

CSR dose may contribute to poor intellectual functioning. Furthermore, receiving a lateral beam

boost to the entire PF following reduced dose CSR may negate any preservation of intellectual

functioning yielded by receiving a reduced dose.

5.3.1 All medulloblastoma patients

Treatment intensity (i.e. CSR dose and boost field) did not significantly predict

intellectual functioning in our entire medulloblastoma sample. Treatment with a reduced dose +

TB boost appears to be associated with a more favorable intellectual functioning, but this finding

is qualitative and as such interpretation remains speculative. The standard dose TB boost

comparison group contained the least number of patients (n=9/23), and also had minimal

longitudinal data, owing to the treatment shift occurring within the past 6 years. In contrast,

sample sizes for the other two groups: 1) standard vs. reduced dose (n=41/48) and 2) standard

dose + PF vs. reduced dose + PF (n=32/25) should have been large enough to detect significant

differences had clear associations been present. Rather, these results suggest treatment with a

reduced dose + PF boost doesn’t yield considerably different effects on intellectual functioning

than treatment with standard dose, yet it remains possible that treatment with a reduced dose +

TB boost does.

A potential example of the effect of treatment with reduced dose CSR and a boost to the

TB in mitigating declines is the stable trajectories observed in WMI. The concept behind

working memory (WM) suggests an underlying system is responsible for maintaining,

manipulating and storing information in the absence of external availability (Baddeley, 2003).

Namely, tests that assess WM examine the amount of information an individual can keep in mind

over a short period of time (Baddeley, 2003). Neuropsychological, neuroimaging and

electrophysiological studies have provided considerable evidence for the involvement of white

matter, in addition to neocortical and hippocampal regions in WM (Mabbott et al., 2008, Law et

al., 2011, Poch and Campo, 2012). A TB boost delivers considerably less radiation to the

temporal lobes than a PF boost (Wolden et al., 2003), a phenomenon that could underlie the

observed difference in WM by way of decreased radiation-induced damage to the hippocampus.

48

5.3.2 Group 4

We capitalized on the recent discovery of medulloblastoma subgroups to be the first to

examine the effect of treatment intensity on intellectual functioning in a homogenous subsample

of medulloblastoma. Previous studies may have missed the contribution of CSR dose on

intellectual functioning as a result of medulloblastoma subgroup heterogeneity. Examining the

effect of treatment intensity both within a single subgroup and within the entire medulloblastoma

sample seemed to be the most comprehensive manner to elucidate the impact of CSR dose on

intellectual functioning. Namely, if clear trends were to emerge in a single subgroup but not for

the entire medulloblastoma sample, one could argue that future studies should examine the

impact of treatment on intellectual functioning in a subgroup-specific manner to prevent

significant findings from being overshadowed.

Unfortunately, we were left with small sample sizes when our Group 4 sample was

subdivided into the four different CSR dose and boost conditions. Specifically, of the Group 4

patient treated with a TB boost, we only had an n=6 for standard dose and an n=7 for reduced

dose. Despite these small sample sizes, trends emerged that approached significance.

Furthermore, the effect observed in Group 4 was far more pronounced than when the entire

medulloblastoma sample was examined. This finding lends support to the notion that intellectual

functioning might be best examined in a subgroup-specific manner to prevent inter-subgroup

variability from obscuring the results.

While speculative, our results suggest that treatment with reduced dose CSR and a TB

boost may mitigate some of the intellectual decline observed following treatment. This finding is

encouraging, and provides impetus for future studies on treatment intensity to be conducted

using larger sample sizes, and in a subgroup-specific manner.

5.4 Limitations

A few limitations to the current study should be noted. Firstly, despite having a large

sample size (n=91), we became limited by small sample sizes when our sample was stratified by

the demographic, medical and treatment factors. These small sample sizes precluded analysis in

Group 3, SHH and WNT, but also reduced power in Group 4 and within our entire sample,

particularly when subdivisions were made based on treatment intensity.

49

Secondly, baseline assessments were only conducted following treatment. This is

particularly important considering the emphasis placed on elucidating the impact of treatment on

neuropsychological functioning. Neuropsychological declines in children treated with CSR have

been observed within the first 12 months, but can be delayed by 1 to 2 years (Radcliffe et al.,

1992, Mulhern and Palmer, 2003, Palmer et al., 2010). Our results suggest patients with

hydrocephalus would have demonstrated lower neuropsychological functioning had they been

assessed prior to treatment. Patients will likely continue to be evaluated for the first time

following treatment, thus future studies seeking to elucidate the effect of treatment on

neuropsychological functioning could benefit from controlling for patients who presented with

hydrocephalus.

Thirdly, the current study could have benefited from the inclusion of controls (i.e.

surgery-only patients). Several studies have demonstrated neuropsychological declines in

patients treated with surgery alone (Levisohn et al., 2000, Ris et al., 2008), and controlling for

surgery could have provided a clearer picture concerning the impact of medical and treatment

factors examined. However, a control group would only have been relevant for Aim1, as almost

all medulloblastoma patients are treated with CSR, and it would have been impossible to include

surgery-only controls in the subgroup-specific analyses.

Finally, the current study was limited by the use of several different tests and test

versions to examine neuropsychological and intellectual functioning. Using a variety of tests was

unavoidable because of the longitudinal nature of this study, but it is not ideal. While

equivalency studies have been conducted between all test versions and between all families of

tests, the different tests and versions have different normative means, and direct comparisons

between the tests and versions should be made with caution. However, results from Aim 1

paralleled what others have shown in the literature and suggests our results can be interpreted

with a good degree of certainty.

5.5 Future directions

5.5.1 All medulloblastoma patents

Based on the findings in this study, it would be interesting to examine the effects of CSR

dose and boost field in patients without hydrocephalus. Hydrocephalus has a dramatic impact on

50

neuropsychological functioning, and a clearer picture regarding the neuropsychological impact

of CSR dose and boost field would likely emerge if patients predisposed to poor

neuropsychological functioning for other reasons were excluded from the analysis.

5.5.2 Subgroups

In order to expand upon the subgroup specific findings in this study, it will be crucial to

conduct subsequent studies with larger sample sizes. However, because medulloblastoma

subgroups present to differing degrees in the population, it might only be possible to conduct

such large scale studies in a collaborative manner, as is currently being done with the MAGIC

(Medulloblastoma Advanced Genomics International Consortium). With larger sample sizes, it

would be ideal to examine neuropsychological functioning in addition to simply intelligence in

all subgroups. Intelligence measures are clearly sensitive to declines in functioning, and

examining intelligence was a logical starting point for subgroup characterization. However,

subgroup analyses would benefit from a more comprehensive assessment of brain function,

which could be gleaned by using an array of neuropsychological tests.

In light of the subgroup differences in intellectual functioning that emerged in this study,

it would be interesting to examine genetic variations known to predispose to toxicity following

radiotherapy and to examine their prevalence in the subgroups. It would also be interesting to

revisit the tumor genetics of Group 4 patients in our sample to determine if NFKBIA deletions

predict poor intellectual functioning. If a correlation was established, theoretically, Group 4

patients could be screened for this deletion prior to the commencement of treatment, a process

that could serve to inform patients about their relative risk of intellectual morbidity following

treatment.

5.6 Conclusion

This thesis provides an in-depth assessment of neuropsychological and intellectual

functioning in medulloblastoma patients, and assesses the contribution of several demographic,

medical and treatment factors. The results from this thesis recapitulate what has been shown in

the literature, and also presents several novel findings.

The negative impact of hydrocephalus on neuropsychological functioning, both at

baseline and over a prolonged period of time, was clearly documented in medulloblastoma

51

patients for the first time. The predisposition to poor neuropsychological functioning suggests

patients with hydrocephalus could benefit from increased neuropsychological monitoring and

individualized support. Medulloblastoma patients suffer tremendously from neuropsychological

morbidity, a phenomenon that is visibly worsened by the presence of hydrocephalus. The

implementation of strategies to prevent further declines in this particularly vulnerable population

clearly warrants further examination.

Moreover, establishing that patients with hydrocephalus perform more poorly than

patients without hydrocephalus has direct implications for future studies aimed at elucidating the

effects of treatment on neuropsychological functioning in medulloblastoma patients. Controlling

for the presence of hydrocephalus might lend itself to the generation of a clearer picture

regarding the direct impact of treatment intensity on neuropsychological functioning.

This thesis also provides the first evidence that medulloblastoma subgroups differ in their

intellectual functioning following treatment. This important finding comes at an appropriate time

given the pending shift towards subgroup-specific therapy in the medical community. Findings

in this thesis suggest subgroup-specific treatment protocols may be a suitable way to achieve

optimal intellectual functioning in each subgroup without compromising survival.

52

References

Anderson FS, Kunin-Batson AS (2009) Neurocognitive late effects of chemotherapy in children:

the past 10 years of research on brain structure and function. Pediatric blood & cancer

52:159-164.

Anderson VA, Anderson P, Northam E, Jacobs R, Catroppa C (2001) Development of executive

functions through late childhood and adolescence in an Australian sample.

Developmental neuropsychology 20:385-406.

Baddeley A (2003) Working memory: looking back and looking forward. Nature reviews

Neuroscience 4:829-839.

Bale SJ, Falk RT, Rogers GR (1998) Patching together the genetics of Gorlin syndrome. Journal

of cutaneous medicine and surgery 3:31-34.

Barnett GC, West CM, Dunning AM, Elliott RM, Coles CE, Pharoah PD, Burnet NG (2009)

Normal tissue reactions to radiotherapy: towards tailoring treatment dose by genotype.

Nature reviews Cancer 9:134-142.

Bleyer WA (1999) Epidemiologic impact of children with brain tumors. Child's nervous system :

ChNS : official journal of the International Society for Pediatric Neurosurgery 15:758-

763.

Blomstrand M, Brodin NP, Munck Af Rosenschold P, Vogelius IR, Sanchez Merino G, Kiil-

Berthlesen A, Blomgren K, Lannering B, Bentzen SM, Bjork-Eriksson T (2012)

Estimated clinical benefit of protecting neurogenesis in the developing brain during

radiation therapy for pediatric medulloblastoma. Neuro-oncology 14:882-889.

Bourdeaut F, Miquel C, Alapetite C, Roujeau T, Doz F (2011) Medulloblastomas: update on a

heterogeneous disease. Current opinion in oncology 23:630-637.

Breaux KC (2009) Technical Manual. Wechsler Individual Achievement Test-Third Edition: San

Antonio, TX: NCS Pearson, Inc.

Brookshire B, Copeland DR, Moore BD, Ater J (1990) Pretreatment neuropsychological status

and associated factors in children with primary brain tumors. Neurosurgery 27:887-891.

Brown RT, Madan-Swain A, Pais R, Lambert RG, Sexson S, Ragab A (1992) Chemotherapy for

acute lymphocytic leukemia: cognitive and academic sequelae. The Journal of pediatrics

121:885-889.

Buizer AI, De Sonneville LM, van den Heuvel-Eibrink MM, Njiokiktjien C, Veerman AJ (2005)

Visuomotor control in survivors of childhood acute lymphoblastic leukemia treated with

chemotherapy only. Journal of the International Neuropsychological Society : JINS

11:554-565.

53

Campbell JM, Brown RT, Cavanagh SE, Vess SF, Segall MJ (2008) Evidence-based assessment

of cognitive functioning in pediatric psychology. Journal of pediatric psychology 33:999-

1014; discussion 1015-1020.

Casey BJ, Giedd JN, Thomas KM (2000) Structural and functional brain development and its

relation to cognitive development. Biological psychology 54:241-257.

Chiang AC, Massague J (2008) Molecular basis of metastasis. The New England journal of

medicine 359:2814-2823.

Cho YJ, Tsherniak A, Tamayo P, Santagata S, Ligon A, Greulich H, Berhoukim R, Amani V,

Goumnerova L, Eberhart CG, Lau CC, Olson JM, Gilbertson RJ, Gajjar A, Delattre O,

Kool M, Ligon K, Meyerson M, Mesirov JP, Pomeroy SL (2011) Integrative genomic

analysis of medulloblastoma identifies a molecular subgroup that drives poor clinical

outcome. Journal of clinical oncology : official journal of the American Society of

Clinical Oncology 29:1424-1430.

Cohen MJ (1997) Children's Memory Scale: San Antonio, TX: The Psychological Corporation.

Conners CK (2000) Conners’ Continuous Performance Test II: Computer Program for Windows

Technical Guide and Software Manual: North Tonwanda, NY: Mutli-Health Systems.

Copeland DR, Moore BD, 3rd, Francis DJ, Jaffe N, Culbert SJ (1996) Neuropsychologic effects

of chemotherapy on children with cancer: a longitudinal study. Journal of clinical

oncology : official journal of the American Society of Clinical Oncology 14:2826-2835.

Crawford JR, MacDonald TJ, Packer RJ (2007) Medulloblastoma in childhood: new biological

advances. Lancet neurology 6:1073-1085.

Del Bigio MR (1993) Neuropathological changes caused by hydrocephalus. Acta

neuropathologica 85:573-585.

Di C, Liao S, Adamson DC, Parrett TJ, Broderick DK, Shi Q, Lengauer C, Cummins JM,

Velculescu VE, Fults DW, McLendon RE, Bigner DD, Yan H (2005) Identification of

OTX2 as a medulloblastoma oncogene whose product can be targeted by all-trans

retinoic acid. Cancer research 65:919-924.

Dubuc AM, Northcott PA, Mack S, Witt H, Pfister S, Taylor MD (2010) The genetics of

pediatric brain tumors. Current neurology and neuroscience reports 10:215-223.

Dum RP, Strick PL (2003) An unfolded map of the cerebellar dentate nucleus and its projections

to the cerebral cortex. Journal of neurophysiology 89:634-639.

Edelstein K, Spiegler BJ, Fung S, Panzarella T, Mabbott DJ, Jewitt N, D'Agostino NM, Mason

WP, Bouffet E, Tabori U, Laperriere N, Hodgson DC (2011) Early aging in adult

survivors of childhood medulloblastoma: long-term neurocognitive, functional, and

physical outcomes. Neuro-oncology 13:536-545.

54

Ellenberg L, Liu Q, Gioia G, Yasui Y, Packer RJ, Mertens A, Donaldson SS, Stovall M, Kadan-

Lottick N, Armstrong G, Robison LL, Zeltzer LK (2009) Neurocognitive status in long-

term survivors of childhood CNS malignancies: a report from the Childhood Cancer

Survivor Study. Neuropsychology 23:705-717.

Ellison DW, Dalton J, Kocak M, Nicholson SL, Fraga C, Neale G, Kenney AM, Brat DJ, Perry

A, Yong WH, Taylor RE, Bailey S, Clifford SC, Gilbertson RJ (2011) Medulloblastoma:

clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups.

Acta neuropathologica 121:381-396.

Erickson K, Baron IS, Fantie BD (2001) Neuropsychological functioning in early hydrocephalus:

review from a developmental perspective. Child neuropsychology : a journal on normal

and abnormal development in childhood and adolescence 7:199-229.

Ersahin Y, Mutluer S, Cagli S, Duman Y (1996) Cerebellar mutism: report of seven cases and

review of the literature. Neurosurgery 38:60-65;discussion 66.

Fletcher JM, Bohan TP, Brandt ME, Brookshire BL, Beaver SR, Francis DJ, Davidson KC,

Thompson NM, Miner ME (1992) Cerebral white matter and cognition in hydrocephalic

children. Archives of neurology 49:818-824.

Gatta G, Zigon G, Capocaccia R, Coebergh JW, Desandes E, Kaatsch P, Pastore G, Peris-Bonet

R, Stiller CA (2009) Survival of European children and young adults with cancer

diagnosed 1995-2002. Eur J Cancer 45:992-1005.

Geiss GK, Bumgarner RE, Birditt B, Dahl T, Dowidar N, Dunaway DL, Fell HP, Ferree S,

George RD, Grogan T, James JJ, Maysuria M, Mitton JD, Oliveri P, Osborn JL, Peng T,

Ratcliffe AL, Webster PJ, Davidson EH, Hood L, Dimitrov K (2008) Direct multiplexed

measurement of gene expression with color-coded probe pairs. Nature biotechnology

26:317-325.

Gibson P, Tong Y, Robinson G, Thompson MC, Currle DS, Eden C, Kranenburg TA, Hogg T,

Poppleton H, Martin J, Finkelstein D, Pounds S, Weiss A, Patay Z, Scoggins M, Ogg R,

Pei Y, Yang ZJ, Brun S, Lee Y, Zindy F, Lindsey JC, Taketo MM, Boop FA, Sanford

RA, Gajjar A, Clifford SC, Roussel MF, McKinnon PJ, Gutmann DH, Ellison DW,

Wechsler-Reya R, Gilbertson RJ (2010) Subtypes of medulloblastoma have distinct

developmental origins. Nature 468:1095-1099.

Giedd JN, Blumenthal J, Jeffries NO, Rajapakse JC, Vaituzis AC, Liu H, Berry YC, Tobin M,

Nelson J, Castellanos FX (1999) Development of the human corpus callosum during

childhood and adolescence: a longitudinal MRI study. Progress in neuro-

psychopharmacology & biological psychiatry 23:571-588.

Gilbertson RJ, Ellison DW (2008) The origins of medulloblastoma subtypes. Annual review of

pathology 3:341-365.

Gopalakrishnan CV, Dhakoji A, Menon G, Nair S (2012) Factors Predicting the Need for

Cerebrospinal Fluid Diversion following Posterior Fossa Tumor Surgery in Children.

Pediatric neurosurgery.

55

Hamilton SR, Liu B, Parsons RE, Papadopoulos N, Jen J, Powell SM, Krush AJ, Berk T, Cohen

Z, Tetu B, et al. (1995) The molecular basis of Turcot's syndrome. The New England

journal of medicine 332:839-847.

Hardy KK, Bonner MJ, Willard VW, Watral MA, Gururangan S (2008) Hydrocephalus as a

possible additional contributor to cognitive outcome in survivors of pediatric

medulloblastoma. Psycho-oncology 17:1157-1161.

Haston CK (2012) Mouse genetic approaches applied to the normal tissue radiation response.

Frontiers in oncology 2:94.

Hatten ME (1999) Expansion of CNS precursor pools: a new role for Sonic Hedgehog. Neuron

22:2-3.

Hatten ME, Roussel MF (2011) Development and cancer of the cerebellum. Trends in

neurosciences 34:134-142.

Hei TK, Zhou H, Chai Y, Ponnaiya B, Ivanov VN (2011) Radiation induced non-targeted

response: mechanism and potential clinical implications. Current molecular

pharmacology 4:96-105.

Hill DE, Ciesielski KT, Sethre-Hofstad L, Duncan MH, Lorenzi M (1997) Visual and verbal

short-term memory deficits in childhood leukemia survivors after intrathecal

chemotherapy. Journal of pediatric psychology 22:861-870.

Hirsch JF (1992) Surgery of hydrocephalus: past, present and future. Acta neurochirurgica

116:155-160.

Holditch-Davis D, Edwards LJ, Helms RW (1998) Modeling development of sleep-wake

behaviors: I. Using the mixed general linear model. Physiology & behavior 63:311-318.

Ito H, Kanno I, Takahashi K, Ibaraki M, Miura S (2003) Regional distribution of human cerebral

vascular mean transit time measured by positron emission tomography. NeuroImage

19:1163-1169.

Ito M (2006) Cerebellar circuitry as a neuronal machine. Progress in neurobiology 78:272-303.

Kaleita TA, Tubergen DG, Sthbens JA (1997) Longitudinal study of cognitive, motor, and

behavioral functioning in children diagnosed with acute lymphoblastic leukemia: A

report of early findings from the Childrens Cancer Group. Berlin Heidelberg: Springer-

Verlag Acute leukmias VI: Prognostic factors and treatment strategies:660–673.

Kieffer-Renaux V, Bulteau C, Grill J, Kalifa C, Viguier D, Jambaque I (2000) Patterns of

neuropsychological deficits in children with medulloblastoma according to craniospatial

irradiation doses. Developmental medicine and child neurology 42:741-745.

Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J,

Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO,

Rutkowski S, McCabe M, Collins VP, Backlund ML, Haberler C, Bourdeaut F, Delattre

56

O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM

(2012) Molecular subgroups of medulloblastoma: an international meta-analysis of

transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group

4 medulloblastomas. Acta neuropathologica 123:473-484.

Kulkarni MM (2011) Digital multiplexed gene expression analysis using the NanoString

nCounter system. Current protocols in molecular biology / edited by Frederick M

Ausubel [et al] Chapter 25:Unit25B 10.

Lafay-Cousin L, Bouffet E, Hawkins C, Amid A, Huang A, Mabbott DJ (2009) Impact of

radiation avoidance on survival and neurocognitive outcome in infant medulloblastoma.

Curr Oncol 16:21-28.

Law N, Bouffet E, Laughlin S, Laperriere N, Briere ME, Strother D, McConnell D, Hukin J,

Fryer C, Rockel C, Dickson J, Mabbott D (2011) Cerebello-thalamo-cerebral connections

in pediatric brain tumor patients: impact on working memory. NeuroImage 56:2238-

2248.

Law N, Greenberg M, Bouffet E, Taylor MD, Laughlin S, Strother D, Fryer C, McConnell D,

Hukin J, Kaise C, Wang F, Mabbott DJ (2012) Clinical and neuroanatomical predictors

of cerebellar mutism syndrome. Neuro-oncology.

Lebel C, Beaulieu C (2011) Longitudinal development of human brain wiring continues from

childhood into adulthood. The Journal of neuroscience : the official journal of the Society

for Neuroscience 31:10937-10947.

Levisohn L, Cronin-Golomb A, Schmahmann JD (2000) Neuropsychological consequences of

cerebellar tumour resection in children: cerebellar cognitive affective syndrome in a

paediatric population. Brain : a journal of neurology 123 ( Pt 5):1041-1050.

Li FP, Fraumeni JF, Jr., Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW (1988)

A cancer family syndrome in twenty-four kindreds. Cancer research 48:5358-5362.

Li YQ, Chen P, Haimovitz-Friedman A, Reilly RM, Wong CS (2003) Endothelial apoptosis

initiates acute blood-brain barrier disruption after ionizing radiation. Cancer research

63:5950-5956.

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW,

Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous

system. Acta neuropathologica 114:97-109.

Mabbott DJ, Penkman L, Witol A, Strother D, Bouffet E (2008) Core neurocognitive functions

in children treated for posterior fossa tumors. Neuropsychology 22:159-168.

Mabbott DJ, Spiegler BJ, Greenberg ML, Rutka JT, Hyder DJ, Bouffet E (2005) Serial

evaluation of academic and behavioral outcome after treatment with cranial radiation in

childhood. Journal of clinical oncology : official journal of the American Society of

Clinical Oncology 23:2256-2263.

57

Maddrey AM, Bergeron JA, Lombardo ER, McDonald NK, Mulne AF, Barenberg PD, Bowers

DC (2005) Neuropsychological performance and quality of life of 10 year survivors of

childhood medulloblastoma. Journal of neuro-oncology 72:245-253.

Makino K, Nakamura H, Yano S, Kuratsu J (2010) Population-based epidemiological study of

primary intracranial tumors in childhood. Child's nervous system : ChNS : official journal

of the International Society for Pediatric Neurosurgery 26:1029-1034.

Marino S (2005) Medulloblastoma: developmental mechanisms out of control. Trends in

molecular medicine 11:17-22.

Mataro M, Junque C, Poca MA, Sahuquillo J (2001) Neuropsychological findings in congenital

and acquired childhood hydrocephalus. Neuropsychology review 11:169-178.

McMahon AP, Bradley A (1990) The Wnt-1 (int-1) proto-oncogene is required for development

of a large region of the mouse brain. Cell 62:1073-1085.

Merchant TE, Kun LE, Krasin MJ, Wallace D, Chintagumpala MM, Woo SY, Ashley DM,

Sexton M, Kellie SJ, Ahern V, Gajjar A (2008) Multi-institution prospective trial of

reduced-dose craniospinal irradiation (23.4 Gy) followed by conformal posterior fossa

(36 Gy) and primary site irradiation (55.8 Gy) and dose-intensive chemotherapy for

average-risk medulloblastoma. International journal of radiation oncology, biology,

physics 70:782-787.

Merchant TE, Lee H, Zhu J, Xiong X, Wheeler G, Phipps S, Boop FA, Sanford RA (2004) The

effects of hydrocephalus on intelligence quotient in children with localized infratentorial

ependymoma before and after focal radiation therapy. Journal of neurosurgery 101:159-

168.

Merchant TE, Pollack IF, Loeffler JS (2010) Brain tumors across the age spectrum: biology,

therapy, and late effects. Seminars in radiation oncology 20:58-66.

Mirzai H, Ersahin Y, Mutluer S, Kayahan A (1998) Outcome of patients with

meningomyelocele: the Ege University experience. Child's nervous system : ChNS :

official journal of the International Society for Pediatric Neurosurgery 14:120-123.

Mulhern RK, Merchant TE, Gajjar A, Reddick WE, Kun LE (2004) Late neurocognitive

sequelae in survivors of brain tumours in childhood. The lancet oncology 5:399-408.

Mulhern RK, Palmer SL (2003) Neurocognitive late effects in pediatric cancer. Current problems

in cancer 27:177-197.

Mulhern RK, Palmer SL, Merchant TE, Wallace D, Kocak M, Brouwers P, Krull K,

Chintagumpala M, Stargatt R, Ashley DM, Tyc VL, Kun L, Boyett J, Gajjar A (2005)

Neurocognitive consequences of risk-adapted therapy for childhood medulloblastoma.

Journal of clinical oncology : official journal of the American Society of Clinical

Oncology 23:5511-5519.

58

Northcott PA, Korshunov A, Witt H, Hielscher T, Eberhart CG, Mack S, Bouffet E, Clifford SC,

Hawkins CE, French P, Rutka JT, Pfister S, Taylor MD (2011) Medulloblastoma

comprises four distinct molecular variants. Journal of clinical oncology : official journal

of the American Society of Clinical Oncology 29:1408-1414.

Northcott PA, Shih DJ, Peacock J, Garzia L, Morrissy AS, Zichner T, Stutz AM, Korshunov A,

Reimand J, Schumacher SE, Beroukhim R, Ellison DW, Marshall CR, Lionel AC, Mack

S, Dubuc A, Yao Y, Ramaswamy V, Luu B, Rolider A, Cavalli FM, Wang X, Remke M,

Wu X, Chiu RY, Chu A, Chuah E, Corbett RD, Hoad GR, Jackman SD, Li Y, Lo A,

Mungall KL, Nip KM, Qian JQ, Raymond AG, Thiessen NT, Varhol RJ, Birol I, Moore

RA, Mungall AJ, Holt R, Kawauchi D, Roussel MF, Kool M, Jones DT, Witt H,

Fernandez LA, Kenney AM, Wechsler-Reya RJ, Dirks P, Aviv T, Grajkowska WA,

Perek-Polnik M, Haberler CC, Delattre O, Reynaud SS, Doz FF, Pernet-Fattet SS, Cho

BK, Kim SK, Wang KC, Scheurlen W, Eberhart CG, Fevre-Montange M, Jouvet A,

Pollack IF, Fan X, Muraszko KM, Gillespie GY, Di Rocco C, Massimi L, Michiels EM,

Kloosterhof NK, French PJ, Kros JM, Olson JM, Ellenbogen RG, Zitterbart K, Kren L,

Thompson RC, Cooper MK, Lach B, McLendon RE, Bigner DD, Fontebasso A, Albrecht

S, Jabado N, Lindsey JC, Bailey S, Gupta N, Weiss WA, Bognar L, Klekner A, Van

Meter TE, Kumabe T, Tominaga T, Elbabaa SK, Leonard JR, Rubin JB, Liau LM, Van

Meir EG, Fouladi M, Nakamura H, Cinalli G, Garami M, Hauser P, Saad AG, Iolascon

A, Jung S, Carlotti CG, Vibhakar R, Ra YS, Robinson S, Zollo M, Faria CC, Chan JA,

Levy ML, Sorensen PH, Meyerson M, Pomeroy SL, Cho YJ, Bader GD, Tabori U,

Hawkins CE, Bouffet E, Scherer SW, Rutka JT, Malkin D, Clifford SC, Jones SJ, Korbel

JO, Pfister SM, Marra MA, Taylor MD (2012a) Subgroup-specific structural variation

across 1,000 medulloblastoma genomes. Nature 488:49-56.

Northcott PA, Shih DJ, Remke M, Cho YJ, Kool M, Hawkins C, Eberhart CG, Dubuc A,

Guettouche T, Cardentey Y, Bouffet E, Pomeroy SL, Marra M, Malkin D, Rutka JT,

Korshunov A, Pfister S, Taylor MD (2012b) Rapid, reliable, and reproducible molecular

sub-grouping of clinical medulloblastoma samples. Acta neuropathologica 123:615-626.

O'Halloran CJ, Kinsella GJ, Storey E (2012) The cerebellum and neuropsychological

functioning: a critical review. Journal of clinical and experimental neuropsychology

34:35-56.

Packer RJ, Goldwein J, Nicholson HS, Vezina LG, Allen JC, Ris MD, Muraszko K, Rorke LB,

Wara WM, Cohen BH, Boyett JM (1999) Treatment of children with medulloblastomas

with reduced-dose craniospinal radiation therapy and adjuvant chemotherapy: A

Children's Cancer Group Study. Journal of clinical oncology : official journal of the

American Society of Clinical Oncology 17:2127-2136.

Packer RJ, Rood BR, MacDonald TJ (2003) Medulloblastoma: present concepts of stratification

into risk groups. Pediatric neurosurgery 39:60-67.

Palmer RF, Royall DR (2010) Missing data? Plan on it! Journal of the American Geriatrics

Society 58 Suppl 2:S343-348.

59

Palmer SL, Gajjar A, Reddick WE, Glass JO, Kun LE, Wu S, Xiong X, Mulhern RK (2003)

Predicting intellectual outcome among children treated with 35-40 Gy craniospinal

irradiation for medulloblastoma. Neuropsychology 17:548-555.

Palmer SL, Hassall T, Evankovich K, Mabbott DJ, Bonner M, Deluca C, Cohn R, Fisher MJ,

Morris EB, Broniscer A, Gajjar A (2010) Neurocognitive outcome 12 months following

cerebellar mutism syndrome in pediatric patients with medulloblastoma. Neuro-oncology

12:1311-1317.

Patel SK, Mullins WA, O'Neil SH, Wilson K (2011) Neuropsychological differences between

survivors of supratentorial and infratentorial brain tumours. Journal of intellectual

disability research : JIDR 55:30-40.

Paus T, Zijdenbos A, Worsley K, Collins DL, Blumenthal J, Giedd JN, Rapoport JL, Evans AC

(1999) Structural maturation of neural pathways in children and adolescents: in vivo

study. Science 283:1908-1911.

Peris-Bonet R, Martinez-Garcia C, Lacour B, Petrovich S, Giner-Ripoll B, Navajas A,

Steliarova-Foucher E (2006) Childhood central nervous system tumours--incidence and

survival in Europe (1978-1997): report from Automated Childhood Cancer Information

System project. Eur J Cancer 42:2064-2080.

Poch C, Campo P (2012) Neocortical-hippocampal dynamics of working memory in healthy and

diseased brain states based on functional connectivity. Frontiers in human neuroscience

6:36.

Pollack IF (2011) Multidisciplinary management of childhood brain tumors: a review of

outcomes, recent advances, and challenges. Journal of neurosurgery Pediatrics 8:135-148.

Pollack IF, Jakacki RI (2011) Childhood brain tumors: epidemiology, current management and

future directions. Nature reviews Neurology 7:495-506.

Poretti A, Meoded A, Huisman TA (2012) Neuroimaging of pediatric posterior fossa tumors

including review of the literature. Journal of magnetic resonance imaging : JMRI 35:32-

47.

Qaddoumi I, Sultan I, Gajjar A (2009) Outcome and prognostic features in pediatric gliomas: a

review of 6212 cases from the Surveillance, Epidemiology, and End Results database.

Cancer 115:5761-5770.

Qiu D, Kwong DL, Chan GC, Leung LH, Khong PL (2007) Diffusion tensor magnetic resonance

imaging finding of discrepant fractional anisotropy between the frontal and parietal lobes

after whole-brain irradiation in childhood medulloblastoma survivors: reflection of

regional white matter radiosensitivity? International journal of radiation oncology,

biology, physics 69:846-851.

Radcliffe J, Packer RJ, Atkins TE, Bunin GR, Schut L, Goldwein JW, Sutton LN (1992) Three-

and four-year cognitive outcome in children with noncortical brain tumors treated with

whole-brain radiotherapy. Annals of neurology 32:551-554.

60

Reddick WE, Glass JO, Palmer SL, Wu S, Gajjar A, Langston JW, Kun LE, Xiong X, Mulhern

RK (2005) Atypical white matter volume development in children following craniospinal

irradiation. Neuro-oncology 7:12-19.

Reddick WE, White HA, Glass JO, Wheeler GC, Thompson SJ, Gajjar A, Leigh L, Mulhern RK

(2003) Developmental model relating white matter volume to neurocognitive deficits in

pediatric brain tumor survivors. Cancer 97:2512-2519.

Reeves CB, Palmer SL, Reddick WE, Merchant TE, Buchanan GM, Gajjar A, Mulhern RK

(2006) Attention and memory functioning among pediatric patients with

medulloblastoma. Journal of pediatric psychology 31:272-280.

Reinhold HS, Calvo W, Hopewell JW, van der Berg AP (1990) Development of blood vessel-

related radiation damage in the fimbria of the central nervous system. International

journal of radiation oncology, biology, physics 18:37-42.

Ris MD, Beebe DW, Armstrong FD, Fontanesi J, Holmes E, Sanford RA, Wisoff JH (2008)

Cognitive and adaptive outcome in extracerebellar low-grade brain tumors in children: a

report from the Children's Oncology Group. Journal of clinical oncology : official journal

of the American Society of Clinical Oncology 26:4765-4770.

Ris MD, Packer R, Goldwein J, Jones-Wallace D, Boyett JM (2001) Intellectual outcome after

reduced-dose radiation therapy plus adjuvant chemotherapy for medulloblastoma: a

Children's Cancer Group study. Journal of clinical oncology : official journal of the

American Society of Clinical Oncology 19:3470-3476.

Rutkowski S, von Hoff K, Emser A, Zwiener I, Pietsch T, Figarella-Branger D, Giangaspero F,

Ellison DW, Garre ML, Biassoni V, Grundy RG, Finlay JL, Dhall G, Raquin MA, Grill J

(2010) Survival and prognostic factors of early childhood medulloblastoma: an

international meta-analysis. Journal of clinical oncology : official journal of the American

Society of Clinical Oncology 28:4961-4968.

Shirane R, Sato S, Sato K, Kameyama M, Ogawa A, Yoshimoto T, Hatazawa J, Ito M (1992)

Cerebral blood flow and oxygen metabolism in infants with hydrocephalus. Child's

nervous system : ChNS : official journal of the International Society for Pediatric

Neurosurgery 8:118-123.

Shors TJ, Miesegaes G, Beylin A, Zhao M, Rydel T, Gould E (2001) Neurogenesis in the adult is

involved in the formation of trace memories. Nature 410:372-376.

Singer JD, & Willett, J. B. (2003) Applied longitudinal data analysis: Modeling change and

event occurrence: New York: Oxford University Press.

Siu A, Wind JJ, Iorgulescu JB, Chan TA, Yamada Y, Sherman JH (2012) Radiation necrosis

following treatment of high grade glioma--a review of the literature and current

understanding. Acta neurochirurgica 154:191-201; discussion 201.

61

Sowell ER, Thompson PM, Holmes CJ, Jernigan TL, Toga AW (1999) In vivo evidence for

post-adolescent brain maturation in frontal and striatal regions. Nature neuroscience

2:859-861.

Spiegler BJ, Bouffet E, Greenberg ML, Rutka JT, Mabbott DJ (2004) Change in neurocognitive

functioning after treatment with cranial radiation in childhood. Journal of clinical

oncology : official journal of the American Society of Clinical Oncology 22:706-713.

Tak PP, Firestein GS (2001) NF-kappaB: a key role in inflammatory diseases. The Journal of

clinical investigation 107:7-11.

Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons

DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool

M, Pfister SM (2012) Molecular subgroups of medulloblastoma: the current consensus.

Acta neuropathologica 123:465-472.

Taylor RE, Bailey CC, Robinson K, Weston CL, Ellison D, Ironside J, Lucraft H, Gilbertson R,

Tait DM, Walker DA, Pizer BL, Imeson J, Lashford LS (2003) Results of a randomized

study of preradiation chemotherapy versus radiotherapy alone for nonmetastatic

medulloblastoma: The International Society of Paediatric Oncology/United Kingdom

Children's Cancer Study Group PNET-3 Study. Journal of clinical oncology : official

journal of the American Society of Clinical Oncology 21:1581-1591.

Teffer K, Semendeferi K (2012) Human prefrontal cortex: evolution, development, and

pathology. Progress in brain research 195:191-218.

Tuor UI, Fitch W, Graham DI, Mendelow AD (1986) Comparison of quantitative

autoradiographic and xenon-133 clearance methods: correlation of gray and white matter

cerebral blood flow with compartmental blood flow indices. Journal of cerebral blood

flow and metabolism : official journal of the International Society of Cerebral Blood

Flow and Metabolism 6:481-485.

Turner CD, Rey-Casserly C, Liptak CC, Chordas C (2009) Late effects of therapy for pediatric

brain tumor survivors. Journal of child neurology 24:1455-1463.

Ullen F (2009) Is activity regulation of late myelination a plastic mechanism in the human

nervous system? Neuron glia biology 5:29-34.

Ullrich NJ (2008) Inherited disorders as a risk factor and predictor of neurodevelopmental

outcome in pediatric cancer. Developmental disabilities research reviews 14:229-237.

von der Weid N, Mosimann I, Hirt A, Wacker P, Nenadov Beck M, Imbach P, Caflisch U, Niggli

F, Feldges A, Wagner HP (2003) Intellectual outcome in children and adolescents with

acute lymphoblastic leukaemia treated with chemotherapy alone: age- and sex-related

differences. Eur J Cancer 39:359-365.

Wechsler D (2003) Wechsler Intelligence Scale for Children Fourth Edition (WISC-IV). The

Psychological Corporation San Antonio, TX.

62

West CM, Barnett GC (2011) Genetics and genomics of radiotherapy toxicity: towards

prediction. Genome medicine 3:52.

Wilkinson GS, & Robertson, G. J. (2006) Wide Range Achievement Test—Fourth Edition: Lutz,

FL: Psychological Assessment Resources.

Willett J (1994) Measuring change more effectively by modeling individual growth over time:

Oxford (UK): Pergamon.

Winick N (2011) Neurocognitive outcome in survivors of pediatric cancer. Curr Opin Pediatr

23:27-33.

Wisoff JH, Sanford RA, Heier LA, Sposto R, Burger PC, Yates AJ, Holmes EJ, Kun LE (2011)

Primary neurosurgery for pediatric low-grade gliomas: a prospective multi-institutional

study from the Children's Oncology Group. Neurosurgery 68:1548-1554; discussion

1554-1545.

Wolden SL, Dunkel IJ, Souweidane MM, Happersett L, Khakoo Y, Schupak K, Lyden D, Leibel

SA (2003) Patterns of failure using a conformal radiation therapy tumor bed boost for

medulloblastoma. Journal of clinical oncology : official journal of the American Society

of Clinical Oncology 21:3079-3083.

Wolfe KR, Madan-Swain A, Kana RK (2012) Executive dysfunction in pediatric posterior fossa

tumor survivors: a systematic literature review of neurocognitive deficits and

interventions. Developmental neuropsychology 37:153-175.

Wong CS, Van der Kogel AJ (2004) Mechanisms of radiation injury to the central nervous

system: implications for neuroprotection. Molecular interventions 4:273-284.

Zhang GL, Zou YF, Feng XL, Shi HJ, Du XF, Shao MH, Gu Y, Zhou Q (2011) Association of

the NFKBIA gene polymorphisms with susceptibility to autoimmune and inflammatory

diseases: a meta-analysis. Inflammation research : official journal of the European

Histamine Research Society [et al] 60:11-18.

63

Appendices

Appendix 1 – Detailed medical information for Group 4 patients

Group 4

Subject Extent of resection Clinical Risk Histology Hydrocephalus Chemotherapy Radiation Deceased

CSR dose Boost Total Dose Boost Site

1 Gross total Average Classic - Baby POG 3400 1800 5200 Posterior Fossa -

2 Subtotal Average Classic Yes ICE 3600 1620 5220 Posterior Fossa -

3 Subtotal High Classic - ICE 3600 1800 5400 Posterior Fossa -

4 Gross total Average Classic Yes CCG 9961 2340 3240 5580 Posterior Fossa -


6 Subtotal High Classic Yes POG 9631 3600 1980 5580 Posterior Fossa -

7 Gross total High Classic - CCG 9961 3600 5940 9540 Posterior Fossa -

8 Gross total High Classic - SJMB03 3600 1980 5580 Tumor Bed -

9 Gross total Average Classic Yes SJMB03 2340 3240 5580 Tumor Bed -

10 Gross total High Classic Yes SJMB03 3600 1980 5580 Tumor Bed Yes

11 Gross total Average Classic - SJMB03 2340 3240 5580 Tumor Bed -

12 Gross total High LCA Yes SJMB03 3600 1980 5580 Tumor Bed -

13 Gross total High Classic Yes SJMB03 3600 1800 5400 Tumor Bed -

14 Gross total Average LCA - SJMB03 2340 3240 5580 Tumor Bed -


16 Gross total Average LCA Yes Abbr. POG 9631 3600 1980 5580 Tumor Bed -


18 Gross total High Desmoplastic - CCG 9961 3600 1980 5580 Posterior Fossa -

19 Gross total Average Desmoplastic Yes POG 9631 3600 1800 5400 Posterior Fossa -

20 Gross total Average Classic - CCG 9961 2340 3060 5400 Posterior Fossa -

21 Subtotal Average Classic - CCG 9961 2340 3240 5580 Posterior Fossa Yes

22 Subtotal High Classic - POG 9631 3960 1620 5580 Posterior Fossa -

23 Gross total High Classic Yes POG 9631 3600 1800 5400 Posterior Fossa -







30 Gross total Average Classic - COG - ACNS 0331 1800 3600 5400 Posterior Fossa -


32 Subtotal High Classic - ICE 3600 1800 5400 Posterior Fossa -

33 Gross total Average Classic - ICE 3600 1800 5400 Posterior Fossa Yes



36 Gross total Average Classic - POG 9631 3960 1980 5940 Posterior Fossa -


38 Subtotal Average Classic Yes SJMB03 3960 1980 5940 Tumor Bed -


40 Subtotal High LCA - ICE 3600 1800 5400 Posterior Fossa -

41 Gross total Average Classic - ICE 3600 1800 5400 Posterior Fossa -

64

Appendix 2 – Detailed medical information for Group 3, SHH and WNT patients.

Group 3




43 Gross total Average LCA - POG 9631 3600 1800 5400 Posterior Fossa Yes

44 Gross total High Desmoplastic Yes COG 99703 2160 2880 5040 Posterior Fossa -

45 Gross total High Classic - POG 9631 3060 2340 5400 Posterior Fossa -


47 Subtotal Average LCA - SJMB03 2340 3240 5580 Tumor Bed -

48 Subtotal High Classic Yes SJMB03 3600 1800 5400 Tumor Bed -

49 Subtotal Average LCA Yes SJMB03 2340 3240 5580 Tumor Bed -


51 Gross total Average Classic - COG - ACNS 0331 2340 3060 5400 Posterior Fossa Yes

52 Gross total Average Classic Yes COG 99703 1800 3780 5580 Tumor Bed -

53 Gross total High Classic Yes CCG 9961 2340 3060 5400 Posterior Fossa -

54 Gross total Average LCA - POG 9631 3600 1800 5400 Posterior Fossa -


56 Gross total High LCA - POG 9631 3600 1800 5400 Posterior Fossa -

57 Gross total High Classic - ICE 3600 1800 5400 Posterior Fossa -

58 Subtotal High Classic - Baby POG 1800 3600 5400 Posterior Fossa Yes

59 Gross total Average Classic Yes CCG 9961 2340 3060 5400 Posterior Fossa Yes

SHH



60 Gross total Average Desmoplastic Yes CCG 9961 2340 3060 5400 Posterior Fossa -

61 Gross total High Desmoplastic Yes POG 9631 3600 1800 5400 Posterior Fossa -

62 Gross total Average Desmoplastic Yes SJMB03 2340 3240 5580 Tumor Bed -


64 Subtotal High Classic Yes POG 9631 3596 1800 5396 Posterior Fossa Yes

65 Gross total Average LCA - SJMB03 3600 1980 5580 Tumor Bed Yes

66 Gross total Average Desmoplastic Yes MOPP n/a n/a n/a n/a -

67 Subtotal High Classic - POG 9631 2340 3240 5580 Posterior Fossa -

68 Subtotal High Classic - CCG 9961 2340 5580 7920 Posterior Fossa -

69 Gross total High Classic Yes COG 99703 n/a n/a n/a n/a -

70 Gross total Average Classic - n/a 3600 1800 5400 Posterior Fossa -

71 Gross total Average Desmoplastic - n/a 3600 1800 5400 Posterior Fossa -

72 Gross total Average LCA Yes POG 9631 3600 1800 5400 Posterior Fossa Yes

73 Subtotal High Classic Yes POG 9631 3940 1640 5580 Posterior Fossa -

74 Gross total High LCA - COG 99703 n/a 5400 5400 Tumor Bed -

75 Gross total Average LCA Yes SJMB03 2340 3240 5580 Tumor Bed -


77 Gross total Average LCA Yes SJMB03 2340 3240 5580 Tumor Bed Yes

78 Subtotal Average Classic Yes SJMB03 2340 3240 5580 Tumor Bed -

79 Gross total Average Desmoplastic - n/a 3600 1800 5400 Posterior Fossa -

WNT







84 Gross total High Classic - POG 9631 3600 1980 5580 Posterior Fossa -


86 Gross total Average LCA - SJMB03 3600 1980 5580 Posterior Fossa -




90 Gross total Average Desmoplastic - CCG 9961 3600 1800 5400 Posterior Fossa -


65

Supplementary Tables

Table 1 – Group means; p values for overall group and mean slope differences for measures of

intellectual functioning when medulloblastoma patients were stratified by age at diagnosis. <

7.26 years (n=44); > 7.26 years (n=47).


medulloblastoma patients stratified by age at diagnosis. All models presented are significant (i.e.

p < 0.05). * p < 0.05

Table 3 – Group means; p values for overall group and mean slope differences in measures of

intellectual functioning when medulloblastoma patients were stratified by extent of tumor

resection. Subtotal (n=17); gross total (n =74).

< 7.26 years > 7.26 years Comparisons

Mean SE Mean SE Overall Group Mean Slope

FSIQ 83.50 2.36 85.27 2.97 0.7575 0.4654

PRI 86.18 2.64 87.89 3.22 0.9192 0.7581

PSI 83.19 1.95 78.94 2.52 0.008* 0.3353

VCI 85.72 2.06 90.64 2.56 0.319 0.2105

WMI 86.22 2.30 90.63 2.81 0.4469 0.6096

Gross total Subtotal Comparisons


FSIQ 83.01 2.05 87.82 3.96 0.3388 0.5413

PRI 86.32 2.30 88.44 4.49 0.1127 0.1394

PSI 80.37 1.73 79.57 3.29 0.6557 0.7563

VCI 86.00 1.75 93.75 3.42 0.6653 0.0732

WMI 87.22 1.95 91.58 3.76 0.6391 0.2051

66


medulloblastoma patients stratified by extent of tumor resection. All models presented, with the

exception of PR, are significant (i.e. p < 0.05) * p < 0.05


memory when medulloblastoma patients were stratified by the presence/absence of

hydrocephalus. Presence of hydrocephalus (n =43); absence of hydrocephalus (n=48).

Hydrocephalus No Hydrocephalus Comparisons


Visual Immediate 86.62 2.91 90.20 2.29 0.2374 0.0928

Visual Delayed 87.30 2.50 90.77 1.96 0.3969 0.2147

Verbal Immediate 86.57 3.38 90.93 2.73 0.2359 0.5171

Verbal Delayed 83.15 3.40 90.42 2.77 0.609 0.6277

General Memory 79.90 3.42 89.85 2.62 0.0802 0.0832

Attention/Concentration 83.59 3.93 91.45 3.11 0.0339* 0.5481

Learning 82.20 3.14 87.60 2.47 0.4119 0.4254

Delayed Recognition 82.04 3.57 88.67 2.89 0.3149 0.2097

67

Table 6 - Estimated intercepts and slopes for CMS memory measures in medulloblastoma

patients stratified by the presence/absence of hydrocephalus. All models presented are significant

(i.e. p < 0.05) * p < 0.05


intellectual functioning when medulloblastoma patients were stratified by clinical risk. Average

risk (n=64); high risk (n=27).

Average Risk High Risk Comparisons


FSIQ 84.41 2.30 83.15 3.07 0.8503 0.924

PRI 87.48 2.53 84.94 3.38 0.2181 0.5082

PSI 80.76 1.87 79.08 2.56 0.8048 0.9775

VCI 87.23 2.03 88.18 2.74 0.9585 0.9062

WMI 88.14 2.18 88.41 3.06 0.9157 0.7808

68


medulloblastoma patients stratified by clinical risk. All models presented are significant (i.e. p <

0.05). * p < 0.05


intellectual functioning when medulloblastoma patients were stratified by CSR dose. Standard

dose (n=41); reduced dose (n=48)

Standard Reduced Comparisons


FSIQ 85.05 2.77 83.21 2.67 0.6694 0.8905

PRI 87.54 3.00 86.52 2.94 0.8115 0.8449

PSI 80.53 2.19 79.08 2.20 0.6104 0.3296

VCI 87.30 2.44 87.39 2.35 0.7747 0.6322

WMI 89.38 2.57 86.81 2.57 0.7732 0.5772

69


medulloblastoma patients stratified by CSR dose. All models presented are significant (i.e. p <

0.05). * p < 0.05

______________________________________________________________________________


intellectual functioning when patients that received a boost to the entire PF were stratified by

CSR dose. Standard dose – PF boost (n=32); reduced dose – PF boost (n=25).


medulloblastoma patients stratified by radiation dose, when field was kept consistent (i.e. PF

boost). All models presented are significant (i.e. p < 0.05). * p < 0.05

Standard - PF boost Reduced - PF boost Comparisons


FSIQ 83.89 3.08 82.99 3.37 0.168 0.0634

PRI 89.06 3.22 85.47 3.58 0.1775 0.111

PSI 78.24 2.33 76.91 2.62 0.1856 0.0965

VCI 87.56 2.67 85.92 2.89 0.5526 0.3096

WMI 87.79 2.84 84.67 3.12 0.3458 0.1534

Standard - TB boost Reduced - TB boost Comparisons


FSIQ 89.79 6.20 85.33 3.54 0.2469 0.532

PRI 79.95 7.00 90.84 4.56 0.113 0.052

PSI 89.37 6.76 82.21 3.63 0.5747 0.7707

VCI 87.48 5.36 89.44 3.25 0.9455 0.8819

WMI 95.39 5.64 91.47 3.38 0.055 0.0846

70


intellectual functioning when patients that received a boost to the TB were stratified by CSR

dose. Standard dose –TB boost (n=9); reduced dose – TB boost (n=23).

______________________________________________________________________________


medulloblastoma patients stratified by radiation dose, when field was kept consistent (i.e. TB

boost). The models presented are not significant (i.e. p > 0.05).

71

Table 15 - p values for overall group and mean slope differences for measures of intellectual

functioning when patients were stratified by medulloblastoma subgroup. Group 4 (n=41); Group

3 (n=18); SHH (n=20)

______________________________________________________________________________


intellectual functioning when Group 4 patients were stratified by CSR dose. Standard dose

(n=20); reduced dose (n=21).

Table 17 - Estimated intercepts and slopes for measures of intellectual functioning in Group 4

patients stratified by radiation dose. All models presented, except VCI and WMI, are significant

(i.e. p < 0.05). * p < 0.05

72


intellectual functioning when Group 4 patients were stratified by CSR dose in only those patients

who received a lateral beam boost to the PF. Standard dose (n=14); reduced dose (n=14).

______________________________________________________________________________


patients stratified by radiation dose, when field was kept consistent (i.e. PF boost). All models

presented, except VCI, are significant (i.e. p < 0.05). * p < 0.05

Table 20 – Group 4 - Group means; p values for overall group and mean slope differences for

measures of intellectual functioning when patients that received a boost to the TB were stratified

by CSR dose. Standard dose –TB boost (n=6); reduced dose – TB boost (n=7). Despite the

appearance of significant overall group differences (i.e. p < 0.05), the growth curve models

generated were not significant, and means generated from this model cannot be interpreted.

Standard - TB boost Reduced - TB boost Comparisons


FSIQ 87.40 5.31 91.95 4.89 0.3104 0.1733

PRI 74.24 9.97 98.20 11.48 0.1633 0.0749

PSI 89.61 8.35 81.46 6.64 0.4214 0.8306

VCI 83.60 2.35 98.77 2.00 0.0201 0.0835

WMI 88.11 5.89 97.63 5.01 0.1476 0.0767

73


patients stratified by CSR dose in only those patients who received a TB boost. None of the

models presented are significant (i.e. p > 0.05)

Intercept Slope Quadratic

INTELLIGENCE Estimate SE Estimate SE Estimate SE

Standard Dose - TB boost

FSIQ 97.78 4.28 -6.55 2.99 - -

PRI 101.36 7.78 -16.95 6.55 - -

PSI 100.91 5.40 -7.22 4.27 - -

VCI 94.25 4.52 -6.71 2.97 - -

WMI 102.43 5.18 -8.65 3.60 - -

Reduced Dose - TB boost

FSIQ 91.75 5.53 0.12 4.03 - -

PRI 91.38 10.03 4.26 8.86 - -

PSI 90.79 6.91 -5.96 5.50 - -

VCI 94.65 5.55 2.60 4.05 - -

WMI 93.20 5.85 2.67 4.27 - -

Neuropsychological Outcome Following Cranio-spinal ... · Medulloblastoma is the most common...

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Transcript of Neuropsychological Outcome Following Cranio-spinal ... · Medulloblastoma is the most common...