Qual Life Res
DOI 10.1007/s11136-016-1462-8
Health-related quality of life in long-term survivors of acute
lymphoblastic leukemia in childhood and adolescence
T. Nayiager1 • L. Anderson1 • A. Cranston1 • U. Athale1,2 • R. D. Barr1,2,3
Accepted: 18 November 2016
Ó Springer International Publishing Switzerland 2016
Abstract
Purpose Children with acute lymphoblastic leukemia
(ALL), the commonest form of cancer in this age group,
suffer considerable morbidity during treatment, with the
majority returning to good health soon after therapy has
been completed, as reflected in health-related quality of life
(HRQL). However, survivors are at risk of many adverse
health outcomes later, including obesity, measured by body
mass index (BMI), that is compounded by limited physical
activity. This study examined the HRQL of long-term
survivors of ALL and its relationship to BMI and physical
activity.
Methods A cohort of 75 subjects who were more than
10 years from diagnosis was assessed for BMI (weight in
kg/height in m2) and completed two questionnaires. HRQL
was measured by the multi-attribute, preference-based
Health Utilities Index (HUI) instrument HUI23S4.15Q
designed for self-report, and physical activity was quanti-
fied by the Habitual Activity Estimation Scale.
Results The mean utility scores for overall HRQL
(HUI2 = 0.88, HUI3 = 0.83) were similar to those in the
Canadian and US general population segments of equiva-
lent age (HUI2 = 0.86, HUI3 = 0.85). However, the
minimum scores (HUI2 = 0.23, HUI3 = -0.09) revealed
a group of survivors with notable disabilities in the
& R. D. Barr
rbarr@mcmaster.ca
1
Service of Hematology-Oncology, McMaster Children’s
Hospital, Hamilton, ON, Canada
2
Division of Hematology-Oncology, Department of Pediatrics,
McMaster University, Hamilton, ON, Canada
3
Health Sciences Centre, Room 3N27, 1200 Main Street West,
Hamilton, ON L8S 4J9, Canada
attributes of hearing, emotion, cognition, and pain. There
were no statistically significant correlations between
HRQL and BMI or between HRQL and physical activity,
except for deafness and inactivity on weekdays.
Conclusions Overall, long-term survivors of ALL in
childhood enjoy good HRQL but some experience appre-
ciable disability, though this is not associated with BMI or,
in the main, with physical activity.
Keywords Quality of life
Survivors
Leukemia

Children
Introduction
Children and adolescents with acute lymphoblastic leuke-
mia (ALL, the commonest form of malignant disease in
this age group) have a high prospect of cure, now
approaching 90% [1], but experience considerable mor-
bidity during treatment that has an adverse impact on their
health-related quality of life (HRQL). This burden of
morbidity is associated with the intensity of therapy, as we
demonstrated in a cohort of patients who were treated
according to the protocols of the Dana-Farber Cancer
Institute (DFCI) Childhood ALL Consortium [2]. After
completing treatment, these patients enjoyed much
improved HRQL.
However, survivors of ALL can experience a litany of
long-term sequelae of therapy (late effects) [3], some of
which increase in prevalence and severity with increasing
time from completion of treatments, e.g., anthracycline-
induced cardiomyopathy [4], threatening HRQL and even
curtailing life expectancy [5]. Consequently, measurement
of HRQL in survivors of ALL, and other cancers in
childhood, should be performed with preference-based
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instruments that afford integration of morbidity and mor-
tality [6].
There is a particular concern about the high proportion
of survivors who are obese, risking the development of the
metabolic syndrome [7]; a combination of abdominal
obesity, atherogenic dyslipidemia, elevated blood pressure,
insulin resistance with or without glucose intolerance, a
pro-inflammatory state and a pro-thrombotic state with
attendant comorbidities [8]. These adverse outcomes may
be amplified by physical inactivity that is well described in
survivors of cancer in childhood, including ALL, and is
progressive in those who are obese [9].
As described elsewhere [10], we have established a
cohort of long-term survivors (more than 10 years from
diagnosis) of ALL in childhood and adolescence in order to
study them comprehensively. This report focuses on their
HRQL and how this is influenced by obesity and physical
inactivity, the a priori hypotheses being that these out-
comes compromise HRQL in survivors of ALL diagnosed
in early life.
Patients and methods
Details of the comprehensive study have been published
[10]. Relevant to the current report are the following. From
a cohort of patients who had been diagnosed with ALL at
least a decade previously, a study sample of 75 subjects
was assembled (Fig. 1). All had been treated according to
protocols of the DFCI Childhood ALL Consortium
(Table 1) that have followed a consistent design and ther-
apeutic strategic strategy [11]. Patients with Down
Fig. 1 Consort diagram
Exclusions (Down syndrome + relapses, n=30)
Further exclusions (Ineligible 8, missing 7, scheduling conflicts 6, declined 5: n=26)
Non-attendance at long-term follow up clinic during the study period (n=41)
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Qual Life Res
Table 1 Distribution of subjects on DFCI protocols
Protocol number Number of subjects (%)
85-001 4 (5.3)
87-001 12 (16.0)
91-001 16 (21.3)
95-001 26 (34.7)
00-001 17 (22.7)
syndrome were excluded because of preexisting con-
founding morbidities.
Health-related quality of life (HRQL) was measured by
the Health Utilities Index (HUI), a family of multi-at-
tribute, preference-based instruments developed at
McMaster University [12]. These are reliable, have been
well-validated [13], and were used first by us to measure
HRQL in survivors of ALL in childhood and adolescence
25 years ago [14]. The HUI Mark 3 (HUI3) and HUI Mark
2 (HUI2) are complementary systems. The attributes (do-
mains/dimensions) of health in HUI3 are vision, hearing,
speech, ambulation, dexterity, emotion, cognition, and
pain, with 5 or 6 levels per attribute. In HUI2 the attributes
are sensation, mobility, self-care, fertility, emotion, cog-
nition, and pain, with 3–5 levels per attribute. For the
purposes of this study fertility is assumed to be uncom-
promised (level 1). The constructs for emotion, cognition
and pain are different in HUI3 and HUI2 (Table 2). In
HUI3 there are 972,000 and in HUI2 there are 24,000
unique, identifiable health states (represented by vectors
combining the levels for each attribute). Normative data
are available for HUI3 in Canada [15] and the USA [16],
and HUI2 in the USA [16], from population surveys. The
Eligible participants (n=172)
Study subjects (n=142)
Available subjects (n=116)
Study sample (n=75)
Qual Life Res
Table 2 Basis of the attribute
Attribute HUI2
constructs
Cognition Learning and remembering
Emotion Anger and depression
Pain Use of analgesics
questionnaire HUI23S4.15Q was used in the study to allow
self-report by subjects for the preceding 4 weeks. Using
published preference functions, utility scores are deter-
mined for each level of each attribute, allowing measure-
ment of morbidity in single attributes as well as the multi-
attribute overall HRQL (comprehensive health state) for
each individual subject [17]. Single attribute score scales
range from 1.00 (no limitation) to 0.00 (lowest level of
function), while the HRQL score scale ranges from 1.00
(perfect health) through 0.00 (equivalent to being dead) to
negative scores. Negative scores are associated with states
of health considered worse than being dead [17]. Clinically
meaningful differences (CMDs) in utility scores are C0.05
for single attributes [18] and C0.03 for overall HRQL [19].
In addition, categories of disability (none, mild, moderate,
and severe), based on the HUI2 and HUI3 scores of overall
HRQL, have been validated [20]. These categories are:
HUI2 none 1.00, mild 0.91–0.99, moderate 0.80–0.90, and
severe \0.80; HUI3 none 1.00, mild 0.89–0.99, moderate
0.70–0.88, and severe \0.70. For single attribute disability
categories, levels of function were used [21].
Physical activity was assessed by self-report using the
Habitual Activity Estimation Scale (HAES), a validated
instrument, developed at McMaster University [22], that
has been used previously in survivors of ALL in childhood
and adolescence [23]. It is based on the duration and
intensity of physical activity that is categorized as inactive
(e.g., lying down), somewhat inactive (e.g., sitting),
somewhat active (e.g., walking), and very active (e.g.,
running). Each of these is reported for four intervals—
waking to breakfast, breakfast to lunch, lunch to supper,
supper to bed—and separately for weekdays (Monday to
Friday) and weekend days (Saturday and Sunday).
Overweight and obesity were determined by body mass
index (BMI- weight in kg/height in m squared). BMI was
recorded in centiles for subjects less than 18 years of age
and in absolute values for those 18 years and older. Being
overweight is defined as having a BMI between the 85th
and 95th centiles or an absolute value of 25–29, while
obesity is defined as at or above the 95th centile or an
absolute value of 30 or greater [24, 25].
Statistical Analysis
The HRQL data were analyzed descriptively by mean,
standard deviation (SD), median, and minimum, maximum
HUI3
Memory/forgetfulness and solving day-to-day problems
Happiness and unhappiness
Limitation of normal activities
and frequency distribution. Associations of single attribute
and multi-attribute utility scores with BMI, ages at diag-
nosis and time of study, and interval from diagnosis were
determined by Pearson’s correlation coefficient. The
associations with HAES scores were analyzed by Spear-
man’s rho for nonparametric data.
Results
There were 41 (54.7%) males and 34 (45.3%) females
ranging in age from 13.5 to 38 (median 21.5) years at the
time of study. The interval from diagnosis to time of study
ranged from 10 to 26 (median 15) years.
The utility scores for single attributes and overall HRQL
for HUI3 and HUI2 are displayed in Tables 3 and 4
respectively. While the mean score in HUI3 for overall
HRQL is similar to that in the Canadian and US general
populations, aged 16–37 (n = 2432) and 18–44
(n = 4048) respectively, examination of the minimum
scores (Tables 3, 4) and the distribution of categories of
disability (Table 5) indicates that the ‘tale is in the tail’.
There is one survivor whose overall HRQL is self-rated as
worse than being dead (HUI3 score -0.09).
The mean score in HUI2 for overall HRQL is similar to
that in the US general population (n = 4048). The burden of
morbidity in sensation (HUI2) resides mainly in vision and
hearing (HUI3) as shown in Fig. 2. A group of 5 subjects
reported some impairment of speech. In light of our findings
in a study of survivors of neuroblastoma in childhood, in
which there appeared to be a relationship between deafness
and speech impairment [26], we explored this possibility.
Among the small group of subjects, all were more than
15 years from diagnosis, at which time their mean age was
4.8 years, only two had received cranial irradiation, and only
one reported impairment of hearing.
There is an appreciable burden of morbidity in the
attributes of emotion and pain in both HUI2 and HUI3
(Tables 3, 4), in which the constructs for these attributes
are different, but the burden in cognition is much greater in
HUI2 than in HUI3. The construct for cognition in HUI2
focuses on learning and remembering, while in HUI3 the
emphasis is on memory/forgetfulness and solving day-to-
day problems.
There were no statistically significant differences in
overall HUI2 and HUI3 utility scores for HRQL between
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Table 3 Utility scores for

Attribute Mean (SD) Median (min, max) Canada USAa
HUI3, males and females
Mean (SD) Mean (SE)
combined
Vision 0.97 (0.12) 1.00 (0.00, 1.00) 0.97 (0.05) –
Hearing 0.97 (0.15) 1.00 (0.00, 1.00) 0.99 (0.06) –
Speech 0.98 (0.06) 1.00 (0.67, 1.00) 0.99 (0.05) –
Ambulation 0.99 (0.03) 1.00 (0.88, 1.00) 0.99 (0.05) –
Dexterity 0.996 (0.02) 1.00 (0.88, 1.00) 1.00 (0.04) –
Emotion 0.95 (0.15) 1.00 (0.00, 1.00) 0.93 (0.13) –
Cognition 0.92 (0.17) 1.00 (0.32, 1.00) 0.95 (0.13) –
Pain 0.94 (0.16) 1.00 (0.00, 1.00) 0.93 (0.11) –
Overall 0.83 (0.24) 0.93 (-0.09, 1.00) 0.85 (0.18) 0.86 (0.01)
a
Single attribute scores are not available

Table 4 Utility scores for HUI2, males and females combined

Attribute Mean (SD) Median (min, max) USAa
Mean (SE)

Sensation 0.91 (0.19) 1.00 (0.00, 1.00) –

Mobility 0.99 (0.03) 1.00 (0.86, 1.00) –
Self-care 0.997 (0.02) 1.00 (0.85, 1.00) –
Emotion 0.91 (0.19) 1.00 (0.00, 1.00) –
Cognition 0.93 (0.09) 1.00 (0.66, 1.00) –
Pain 0.96 (0.13) 1.00 (0.00, 1.00) –
Overall 0.88 (0.17) 0.95 (0.23, 1.00) 0.86 (0.01)
a
Single attribute scores are not available

Table 5 Burden of morbidity in individual attributes

None Mild Moderate Severe

Attribute HUI3
Vision 52 21 0 1
Hearing 70 0 3 1
Speech 69 3 0 0
Ambulation 71 3 0 0 Fig. 2 Graph depicting levels of function. Method: bar chart.
Dexterity 71 3 0 0 Interpretation: results in keeping with utility scores; emotion highest
Emotion 52 18 2 2 frequency with some degree of morbidity, most variability observed
in self-care, sensation and pain also demonstrate individuals with a
Cognition 45 19 6 4
degree of morbidity
Pain 51 17 2 4
Attribute HUI2
Sensation 47 18 7 2 Dividing the subjects by time from diagnosis (10–15 vs.
Mobility 70 4 0 0
[15 years) and BMI (\25 vs. 25 or greater) did not yield
Emotion 45 25 4 0
any statistically significant differences or CMDs between
overall HRQL or single attribute utility scores in HUI2 and
Cognition 70 3 0 0
HUI3.
Self-care 50 14 4 4
There were no statistically significant differences in the
Pain 49 18 0 3
mean single attribute and overall HRQL utility scores for
HUI3 between the study subjects and the Canadian popu-
males (M) and females (F). However, there were CMDs lation controls, but there was only 30% power to detect a
(mean 0.06) in HUI2 for emotion (F = 0.94, M = 0.88) difference of 0.03 (and 80% power would have been
and pain (F = 0.99, M = 0.93). There were no CMDs required to detect a difference of 0.06). Accordingly these
between males and females in HUI3 single attributes. data are subject to a Type II (beta) error. However, the

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differences in the mean overall HUI2 and HUI3 HRQL Table 7 Correlations between HRQL scores and BMI and other
utility scores between the study subjects and the US pop- variables
ulation controls were highly significant (p = 0.0001). In Variable Correlation coefficient—HUI3
these comparisons there was 99% power to detect even a
BMI at time of study 0.031
difference of 0.017, reflecting a much larger sample of
controls than was available from Canada. Age at diagnosis 0.030
The HAES scores are reported in detail elsewhere [27]. Time from diagnosis to study -0.13
Here are recorded the associations with HRQL (Table 6). Age at time of study 0.082
There were no statistically significant correlations with the Variable Correlation coefficient—HUI2
single exception of deafness and inactivity on weekdays.
BMI at time of study 0.182
There were no significant correlations between HRQL and
Age at diagnosis -0.028
BMI, ages at diagnosis and time of study, and interval from
Time from diagnosis to study -0.006
diagnosis to study (Table 7).
Age at time of study 0.043

Discussion

Life expectancy is compromised by the adverse effects of
treatment in survivors of cancer in childhood and adoles-
cence [5]. These effects are often long delayed and asso-
ciated with disabilities that compromise HRQL. Among
these late sequelae of therapy is being overweight/obese,
with its attendant health hazards, including the metabolic
syndrome [28]. Coincident loss of lean body mass (mainly
composed of skeletal muscle), resulting in the state of
sarcopenic obesity [29], especially in survivors of ALL,
contributes to the limited physical activity that is prevalent
in survivors of this disease which is the commonest form of
cancer in this age group (0–19 years) worldwide [30].
Orgel and colleagues have reported that BMI correlates
poorly in individual patients with measurements of body
fat in children with ALL during treatment, so underesti-
mating adiposity and the prevalence of sarcopenic obesity
[31].
HRQL provides an assessment of disability that can
serve as an important outcome measure in studies of
interventions to enhance physical activity [32], reduce
obesity [33], and redress sarcopenia. In this context the
study reported here examined the associations of BMI and
physical activity with HRQL. The almost complete lack of
statistically significant correlations may not be surprising,
although the sample size is small. Moreover, the non-
availability of a large proportion of survivors challenges
the representativeness of the study sample. However, the
net directionality of possible selection bias is unknown.

Table 6 Correlations of HRQL

Weekday-inactive Weekday-active Weekend-inactive Weekend-active
utility scores with physical
activity Attribute HUI3
Vision -0.194 0.159 -0.085 0.214
Hearing -0.242 (p \ 0.05) 0.166 0.154 -0.036
Speech 0.003 0.020 0.071 0.0100
Ambulation -0.134 0.116 0.061 -0.104
Dexterity 0.165 0.043 0.096 -0.108
Emotion -0.047 0.023 0.125 -0.203
Cognition 0.029 -0.006 -0.091 0.087
Pain -0.037 0.006 -0.150 0.044
Overall HRQL -0.076 0.098 -0.073 0.101
Attribute HUI2
Sensation -0.217 0.166 -0.018 0.209
Mobility -0.065 0.142 0.071 -0.060
Emotion -0.138 0.121 -0.023 -0.003
Cognition -0.002 0.016 -0.061 0.052
Self-care -0.103 0.159 -0.177 0.159
Pain -0.008 0.012 -0.120 0.055
Overall HRQL -0.161 0.124 -0.100 0.146

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Normative data for HUI are derived from populations in
North America in which overweight/obesity and physical
inactivity in young people are all too prevalent [34]. As
reflected in population means, there were no CMDs in the
HUI2 and HUI3 scores for overall HRQL between the ALL
survivors and the comparison groups from the Canadian
and US general populations. This accords with our previ-
ous report of changes in HRQL scores, addressed by HUI
instruments, across the treatment trajectory in children with
ALL on DFCI protocols, with survivors 2 years after
completion of therapy being comparable to the similar age
group in the general Canadian population [2].
However, preference-based measures of HRQL, such as
HUI2 and HUI3, are subject to ceiling effects that render
the findings susceptible to the phenomenon of range
restriction that limits the strength of correlation [35, 36]. It
is important to emphasize that all members of the general
population do not have perfect health, so there is no
expectation that young people who are cured of cancer will
be devoid of a burden of morbidity, though the components
of that burden may be different from that in their peers who
have not had cancer.
A correlation of deafness with physical inactivity on
weekdays in the present report may suggest a degree of
social isolation, but only four subjects reported morbidity
in this attribute and deafness did not appear in any of the
CMDs, so the correlation may not be clinically relevant.
The lack of clear associations between HRQL and physical
activity in the present study is consistent with the recent
report from the Cochrane Collaboration focused on chil-
dren and young adults with cancer [32]. Nevertheless, in a
large sample of the general Canadian adult population
(aged 18 years and older), it was shown that the lower the
leisure time physical activity (LTPA), the greater the
decline in HRQL (measured by HUI3) with increasing age
[37]. Moreover, a statistically significant drop in LTPA was
observed from ages 18–29 to ages 30–39.
Small numbers of survivors experience considerable
(moderate/severe) disability in the attributes of sensation,
emotion, self-care and pain (HUI2), and hearing, emotion,
cognition and pain (HUI3). Morbidity in emotion, cogni-
tion, and pain (both HUI2 and HUI3) is reported commonly
in survivors of cancer in childhood [13], including ALL
[2]. By contrast, deficits in hearing are uncommon, except
for children who received platinum-based chemotherapy
[38] (not used in the treatment of ALL), but may reflect
exposure to repeated courses of aminoglycoside antibiotics
in the management of febrile neutropenia [38]. Further-
more, in the 1994/1995 Canadian National Population
Health Survey, hearing impairment (identified by HUI3)
was associated with mortality [39]. As noted in that report,
hearing impairment may increase the risk of accident and
injury, may be a marker for neurological decline, and may
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adversely affect communication and social interaction with
resulting social isolation leading to reduction in physical
and mental health.
As advocated by Feeny [40], HRQL should be regarded
as a vital sign. Furthermore, the healthcare system pro-
duces quality-adjusted survival and the routine use of
preference-based measures of HRQL is essential for esti-
mating the output of the system at large, of course
including survivors of cancer in early life.
Acknowledgements The authors thank Dr. David Feeny for his
valuable input on this report.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest
Ethical approval This article does not contain any studies with
animals performed by any of the authors. The study was approved by
the Hamilton Integrated Research Ethics Board (Project #10-508-5)
that represents Hamilton Health Sciences, McMaster University and
St. Joseph’s Healthcare.
Informed consent Informed consent was obtained from all individ-
ual participants included in the study.
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