Neuropsychological Outcome Following Cranio-spinal ... · Medulloblastoma is the most common...
Transcript of 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
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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.
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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
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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
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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
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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
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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
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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
Table 4. Estimated intercepts and slopes for measures of intellectual functioning
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
Table 7. Group means, overall group and mean slope differences for measures of
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
Table 9. Group means, overall group and mean slope differences for measures of
intellectual functioning in medulloblastoma patients stratified by
CSR dose……………………………………………………………………………...68
Table 10. Estimated intercepts and slopes for measures of intellectual functioning in
medulloblastoma patients stratified by CSR dose…………………...…….…………68
Table 11. Group means, overall group and mean slope differences for measures of
intellectual functioning in patients that received a PF boost stratified by
CSR dose……………………………………………………………………………...69
Table 12. Estimated intercepts and slopes for measures of intellectual functioning
in patients that received a PF boost stratified by CSR dose……………….………….69
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Table 13. Group means, overall group and mean slope differences for measures of
intellectual functioning in patients that received a TB boost stratified by
CSR dose……………………………………………………………………………...69
Table 14. Estimated intercepts and slopes for measures of intellectual functioning
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
Table 16. Group means, overall group and mean slope differences for measures of
intellectual functioning in Group 4 patients stratified by CSR dose……………....….71
Table 17. Estimated intercepts and slopes for measures of intellectual functioning
in Group 4 patients stratified by CSR dose………………………………………...…71
Table 18. Group means, overall group and mean slope differences for measures of
intellectual functioning in Group 4 patients that received a PF boost
stratified by CSR dose………………………………………………………………..71
Table 19. Estimated intercepts and slopes for measures of intellectual functioning in
Group 4 patients that received a PF boost stratified by CSR dose…………………...72
Table 20. Group means, overall group and mean slope differences for measures of
intellectual functioning in Group 4 patients that received a TB boost
stratified by CSR dose……………………………………………………………..…72
Table 21. Estimated intercepts and slopes for measures of intellectual functioning in
Group 4 patients that received a TB boost stratified by CSR dose…………………..73
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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
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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
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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
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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
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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).
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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).
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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
None of the modeled trajectories for measures of intelligence differed as a function of
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
None of the modeled trajectories for measures of intelligence differed as a function of
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
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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 -
5 Gross total Average Classic Yes CCG 9961 2340 3060 5400 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 -
15 Gross total Average Classic Yes SJMB03 2340 3240 5580 Tumor Bed -
16 Gross total Average LCA Yes Abbr. POG 9631 3600 1980 5580 Tumor Bed -
17 Gross total Average Classic Yes SJMB03 2340 3240 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 -
24 Gross total Average Classic Yes CCG 9961 2340 3060 5400 Posterior Fossa -
25 Gross total Average Classic Yes CCG 9961 2340 3060 5400 Posterior Fossa -
26 Gross total Average Classic - CCG 9961 2340 3060 5400 Posterior Fossa -
27 Gross total Average Classic - CCG 9961 2340 3060 5400 Posterior Fossa -
28 Gross total Average Classic Yes CCG 9961 2340 3060 5400 Posterior Fossa -
29 Gross total Average Classic - CCG 9961 2340 3240 5580 Posterior Fossa -
30 Gross total Average Classic - COG - ACNS 0331 1800 3600 5400 Posterior Fossa -
31 Gross total Average Classic - SJMB03 2340 5400 7740 Tumor Bed -
32 Subtotal High Classic - ICE 3600 1800 5400 Posterior Fossa -
33 Gross total Average Classic - ICE 3600 1800 5400 Posterior Fossa Yes
34 Gross total Average Classic Yes CCG 9961 2340 3240 5580 Posterior Fossa -
35 Gross total Average Classic Yes CCG 9961 2340 3060 5400 Posterior Fossa -
36 Gross total Average Classic - POG 9631 3960 1980 5940 Posterior Fossa -
37 Gross total Average Classic - CCG 9961 2340 3060 5400 Posterior Fossa -
38 Subtotal Average Classic Yes SJMB03 3960 1980 5940 Tumor Bed -
39 Gross total Average Classic Yes SJMB03 2340 3240 5580 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
Subject Extent of resection Clinical Risk Histology Hydrocephalus Chemotherapy Radiation Deceased
CSR dose Boost Total Dose Boost Site
42 Gross total Average Classic - CCG 9961 2340 3240 5580 Posterior Fossa -
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 -
46 Gross total Average Classic - SJMB03 2340 3240 5580 Tumor Bed -
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 -
50 Gross total Average Classic 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 -
55 Gross total Average Classic Yes CCG 9961 2340 3060 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
Subject Extent of resection Clinical Risk Histology Hydrocephalus Chemotherapy Radiation Deceased
CSR dose Boost Total Dose Boost Site
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 -
63 Gross total Average Classic 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 -
76 Gross total Average Classic - n/a 3600 1800 5400 Posterior Fossa -
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
Subject Extent of resection Clinical Risk Histology Hydrocephalus Chemotherapy Radiation Deceased
CSR dose Boost Total Dose Boost Site
80 Gross total Average Classic Yes SJMB03 2340 3240 5580 Tumor Bed -
81 Gross total Average Classic Yes SJMB03 2340 3240 5580 Tumor Bed -
82 Gross total Average Classic Yes SJMB03 2340 3240 5580 Tumor Bed -
83 Gross total Average Classic - SJMB03 2340 3240 5580 Tumor Bed -
84 Gross total High Classic - POG 9631 3600 1980 5580 Posterior Fossa -
85 Gross total Average Classic - CCG 9961 2340 3060 5400 Posterior Fossa -
86 Gross total Average LCA - SJMB03 3600 1980 5580 Posterior Fossa -
87 Gross total Average Classic - SJMB03 3600 1980 5580 Tumor Bed -
88 Gross total Average Classic - n/a 3600 1080 4680 Posterior Fossa -
89 Gross total Average Classic - n/a 3600 1800 5400 Posterior Fossa -
90 Gross total Average Desmoplastic - CCG 9961 3600 1800 5400 Posterior Fossa -
91 Gross total Average Classic - SJMB03 2340 3240 5580 Tumor Bed -
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).
Table 2 - Estimated intercepts and slopes for measures of intellectual functioning in
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
Mean SE Mean SE Overall Group Mean Slope
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
Table 4 - Estimated intercepts and slopes for measures of intellectual functioning in
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
Table 5 – Group means; p values for overall group and mean slope differences for measures of
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
Mean SE Mean SE Overall Group Mean Slope
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
Table 7 – Group means; p values for overall group and mean slope differences for measures of
intellectual functioning when medulloblastoma patients were stratified by clinical risk. Average
risk (n=64); high risk (n=27).
Average Risk High Risk Comparisons
Mean SE Mean SE Overall Group Mean Slope
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
Table 8 - Estimated intercepts and slopes for measures of intellectual functioning in
medulloblastoma patients stratified by clinical risk. All models presented are significant (i.e. p <
0.05). * p < 0.05
Table 9 – Group means; p values for overall group and mean slope differences for measures of
intellectual functioning when medulloblastoma patients were stratified by CSR dose. Standard
dose (n=41); reduced dose (n=48)
Standard Reduced Comparisons
Mean SE Mean SE Overall Group Mean Slope
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
Table 10 - Estimated intercepts and slopes for measures of intellectual functioning in
medulloblastoma patients stratified by CSR dose. All models presented are significant (i.e. p <
0.05). * p < 0.05
______________________________________________________________________________
Table 11 – Group means; p values for overall group and mean slope differences for measures of
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).
Table 12 - Estimated intercepts and slopes for measures of intellectual functioning in
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
Mean SE Mean SE Overall Group Mean Slope
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
Mean SE Mean SE Overall Group Mean Slope
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
Table 13 – 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=9); reduced dose – TB boost (n=23).
______________________________________________________________________________
Table 14 - Estimated intercepts and slopes for measures of intellectual functioning in
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)
______________________________________________________________________________
Table 16 – Group means; p values for overall group and mean slope differences for measures of
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
Table 18 – Group means; p values for overall group and mean slope differences for measures of
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).
______________________________________________________________________________
Table 19 - Estimated intercepts and slopes for measures of intellectual functioning in Group 4
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
Mean SE Mean SE Overall Group Mean Slope
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
Table 21 - Estimated intercepts and slopes for measures of intellectual functioning in Group 4
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 - -