Study of the Cognitive Effects of Chemotherapy : How Choice of Control Group Affects Outcome

The Effect of Control Group in the Study
of the Cognitive Effects of Chemotherapy
Barbara Collins
Collins, The Ottawa
Hospital, Canada
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Control Groups
p
Many breast cancer patients report cognitive
disturbances during and after their
chemotherapy
Neuropsychological studies yield inconsistent
results
Cognitive effects, when found, are subtle
Detection susceptible to methodological
differences among studies
 Prospective versus retrospective study design
 Number and nature of cognitive tests used
 Manner in which impairment is defined
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Control Groups
General consensus that, in most instances,
prospective
ti llongitudinal
it di l study
t d with
ith pre- and
d postt
treatment testing is the preferred study design
In prospective designs, subjects serve as their
own controls
However, repeat testing associated with practice
effects
Practice effects may actually be larger than
treatment effects themselves
Thus, still need to include a control group to
account for practice
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Control Groups
Options:
Disease-specific control group
Disease-nonspecific
Disease
nonspecific control group
Healthy control group
Hi t i l controls/Published
Historical
t l /P bli h d norms
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Disease-Specific Control Group
Advantages
 Controls
C t l +/
+/- for
f effects
ff t off disease
di
itself
it lf and
dh
hostt
factors that may predispose to disease and cognitive
dysfunction
y
 Controls for stress and distress associated with the
diagnosis
Disadvantages
 Patients not receiving treatment of interest (e.g.,
chemotherapy)
h
th
) may b
be receiving
i i alternate
lt
t ttreatments
t
t
that affect cognition (e.g., anti-estrogen therapy in the
case of BC))
 Treatment prescribed according to disease
characteristics, so treatment confounded with disease
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Healthy Control Group
Advantages
Availability
May allow better matching on key
demographic variables
Disadvantages
Fails to account for possible confounding
factors, such as constitutional risk factors,
psychological distress, and disease-related
cognitive changes
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Published Norms
Advantages
 Convenience, economy
 May have access to larger samples (with more reliable
estimate
ti t off PE)
Disadvantages
 May be no published test-retest data
 Difficulty achieving good match on relevant
demographic variables and testing intervals
 May be regional differences in test performance
 Testing conditions such as environment, examiner
less consistent between groups
 Limited
Li it d tto published
bli h d measures
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Objective of Current Study
To determine if results and conclusions
drawn from a prospective, longitudinal
y of cognitive
g
function in BC p
patients
study
would differ according to control group
used
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Methods: Participants
 3 groups post-menopausal women between the ages of 50 and 65
 28 BC patients who received adjuvant chemotherapy (Chemo Group)
 28 BC patients who received hormonal therapy but no chemotherapy (Hormonal
Group)
 28 healthy volunteers (Healthy Group)
 Chemo and hormonal groups were selected from larger samples to most
yp
participants
p
on age
g and education
closelyy match the 28 healthy
 Previous history of cancer or chemotherapy, unstable psychiatric,
neurological, or substance use disorders that might affect cognition were
grounds for exclusion
Group
Chemo
p
Hormonal
Healthy
Age – Mean (SD)
Range
59.07 (3.39)
52-66
58.64 (4.23) 59.32 (4.23) 0.81
51-65
51-66
Education – Mean (SD)
Range
15.96 (2.69)
12-22
15.86 (2.86) 15.93 (2.54) 0.99
12-23
12-21
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Methods: Assessment Schedule
T1 (baseline) conducted prior to initiation
of chemotherapy
T2 conducted ~ 1 month following last
chemotherapy treatment in chemo group
H
Hormonal
l and
dh
healthy
lth groups assessed
d att
equivalent intervals
Average T1-T2 interval of 5-6 months
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Methods: Assessment Battery (Source for Norms)
Executive Function
Verbal Memory
 Trails B (Levine et al
al., 2004)
 WCST (Tate et al., 1998)
 CVLT-II
CVLT II (Total T1
T1-T5,
T5 Delayed
Recall) (Delis et al., 2000)
 Logical Memory II (WMS-III
Manual)
Language
 Boston Naming Test (Flanagan
& Jackson, 1997)
 COWA (Levine et al., 2004)
Processing Speed
 Digit-Symbol Coding (WAIS-III
Manual)
 Symbol Search (WAIS-III
(WAIS III
Manual)
 Trails A (Levine et al., 2004)
Visual Memory
 Family Pictures II (WMS-III
Manual)
Visuospatial Function
 Block Design (WAIS-III
Manual)
Working Memory
 Arithmetic (WAIS-III Manual)
 Digit Span (WAIS-III Manual)
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Methods: Analysis
Reliable Change Index (RCI) plus practice effects model
Calculated standardized change scores for each subject
on each neuropsychological measure according to the
following formula:
[T2 score – (T1 + PE)] / Sdiff
 Where PE (practice effect) = mean difference between test and
retest scores in the control group
 Sdiff (standard error of the difference) = √2(SE)2 ; SE = S1√1-r
 r = correlation between test-retest scores in control group
RCI calculated 3 times using scores from hormonal
group healthy group,
group,
group and published norms
norms, respectively
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Methods: Analysis
RCI of –2.0 or lower criterion for decline on a given
measure
RCIs of -2.0 or lower on ≥ 2 measures criterion for
reliable cognitive decline for a given subject
Reliable cognitive improvement = RCI score greater than
or equal to +2.0 on ≥ 2 measures
Chi
Chi-square
used
d tto compare frequency
f
off reliable
li bl
cognitive decline and improvement across groups
When using published norms
norms, frequency of cognitive
decline in chemo group was compared to the expected
frequency of this occurrence in a normal sample (i.e., the
bi
binomial
i l probability
b bilit off obtaining
bt i i ttwo or more
standardized change scores of ≤ -2.0 by chance)
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Frequency of Decline by Control Group
Group
Basis for RCI
Chemo
Control
Χ2
P
Hormonal Group
29%
7%
4.38
0.04
Healthy Group
21%
0%
6.72
0.01
Norms
21%
4%
4.08
0.04
No difference in frequency of decline in chemo group across control
conditions: Χ2 = 0.53, p = 0.77
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Conclusions
Significantly higher rate of cognitive decline in
chemo group vs controls regardless of control
method used
Suggests
gg
that “chemo fog”
g q
quite robust p
provided
that measured adequately and that practice
effects, base rates and relevant demographic
factors accounted for
At present, may be a challenge to find suitable
published test-retest
test retest norms for all tests so may
require local controls
Byy p
pooling
g control data from harmonised studies,,
will establish an appropriate normative database
which can be used for future studies
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE
Thank You!
Participants!
The Ontario Chapter of the Canadian
Breast Cancer Foundation and their
pp
supporters
St d Coordinator
Study
C
di t
Joyce MacKenzie, M Ps
ICCTF International Cognition and Cancer Task Force Conference
March 15
15--17
th
2012 – PARIS - FRANCE