cog
ste
rat
Helena Harder , Arthur R. Van Gool , Jan J. Cornelissen , Hugo J. Duivenvoorden ,
SCT patients and 82 haematological patients completed a neuropsychological test battery and five questionnaires assessing subjec-
tive cognitive complaints, psychological functioning, health-related quality of life and fatigue. Results were compared with norma-
involve executive function, verbal memory and motor
skills [1]. Even though most of these cognitive changes
tients are exposed to a variety of profound neurotoxic
influences over a prolonged period. Firstly, most patients
have faced intensive treatment schedules, such as high-
dose systemic chemotherapy, intrathecal chemotherapy
or relapse therapies, before undergoing SCT [13,14]. This
.
*
Corresponding author. Tel.: +31 10 4391415; fax: +31 10 4391031.
E-mail address: m.vandenbent@erasmusmc.nl (M.J. van den Bent).
European Journal of Cancer 41
European
Journal of0959-8049/$ - see front matter
2005 Elsevier Ltd. All rights reservedtive data. Percentages of cognitively impaired patients were equally divided between groups. Most deficits were observed in visual
memory, visuospatial and constructional ability and psychomotor functions. The SCT group showed a higher rate of anxiety cases
and reported lower cognitive, emotional and social functioning. Results of neuropschychological testing were not associated with
outcome of the questionnaires. This study showed impaired cognitive performance prior to SCT. Haematological patients treated
with non-myeloablative cancer therapies proved to be a reliable reference group for longitudinal studies.

2005 Elsevier Ltd. All rights reserved.
Keywords: Bone marrow transplantation; Haematological malignancies; Neuropsychological evaluation; Quality of life; Psychological functioning;
Fatigue
1. Introduction
With more effective anticancer treatment, late side-
effects of treatment are an increasing source of concern.
This also holds for cognitive dysfunction. The most con-
sistent cognitive deficits in patients treated for advanced
malignancies outside the central nervous system (CNS)
are mild or subtle, they can affect many aspects of pa-
tients
lives and have serious consequences for health-
related quality of life (HRQOL), family role functions
and employment status or vocational training.
Bonemarrow or haematopoietic stem cell transplanta-
tion (SCT) in adults with haematological malignancies is
a potential cause of cognitive dysfunction [2–12]. SCT pa-Wil M.H. Eijkenboom
e
, Rene M.Y. Barge
f
, Martin J. van den Bent
a,
*
a
Department of Neuro-Oncology, Erasmus Medical Center, Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands
b
Department of Psychiatry, Erasmus Medical Center, Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands
c
Department of Haematology, Erasmus Medical Center, Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands
d
Department of Medical Psychology and Psychotherapy, Erasmus University Rotterdam, Rotterdam, The Netherlands
e
Department of Radiotherapy, Erasmus Medical Center, Daniel den Hoed Cancer Center, PO Box 5201, 3008 AE Rotterdam, The Netherlands
f
Department of Haematology, Leiden University Medical Center, Leiden, The Netherlands
Received 20 August 2004; received in revised form 5 January 2005; accepted 27 January 2005
Available online 16 March 2005
Abstract
The aim of this study was to examine cognitive performance in patients prior to bone marrow or haematopoietic stem cell trans-
plantation (SCT) and in haematological patients who received non-myeloablative cancer therapies. A consecutive sample of 101Assessment of pre-treatment
bone marrow or haematopoietic
A compa
a bdoi:10.1016/j.ejca.2005.01.015nitive performance in adult
m cell transplantation patients:
ive study
c d
www.ejconline.com
(2005) 1007–1016
Cancer

nistic infections caused by immunosuppression and they
experience acute or chronic graft versus host disease
part in the study. An appointment for assessment of the
Digit symbol [22], Finger tapping [27]; the Reaction time
rnal o(GVHD) [16]. All these factors put SCT patients at an
increased risk of CNS damage and result in possible
long-term cognitive deficits. In a retrospective study of
cognitive functioning in adult survivors of SCT, we ob-
served that a significant proportion of patients experi-
enced ongoing cognitive problems several years after
SCT treatment [11].
The curative intent of SCT underscores the impor-
tance of evaluating long-term cognitive performance in
these patients. Better insight and understanding of the
cognitive consequences of SCT can be obtained by using
a longitudinal repeated measurement design with a pre-
SCT assessment. A pre-treatment measurement is of
pivotal importance because it allows for differentiating
between observed deficits due to the SCT procedure,
the ensuing treatment and complications on the one
hand, and deficits induced by the disease itself, pre-
SCT treatment or confounding factors, such as psycho-
logical distress, on the other hand. Previous prospective
reports showed cognitive deficits prior to SCT treatment
in up to 60% of patients [4,5,12]. Although most of these
studies used measures of psychological functioning, all
failed to incorporate an appropriate reference group,
which is necessary to draw conclusions about the under-
lying causes of the observed effects. However, there are
inherent difficulties in selecting a reference group. Differ-
ences in pre-SCT treatment schedules, in particular in
the intensity of chemotherapy, may cause varying de-
grees of cognitive deficits prior to SCT. In the present
study, we therefore assessed cognitive performance, psy-
chological functioning, fatigue and HRQOL in SCT pa-
tients prior to SCT and in a group of patients with
haematological malignancies who were treated with sys-
temic chemotherapy and/or involved-field radiotherapy.
The objectives were to study pre-SCT cognitive func-
tioning in a sufficiently large sample of SCT patients
and its relation to potential confounding factors, and
to investigate whether a group of patients with haemato-
logical malignancies treated with non-myeloablative
cancer therapies can be used as a clinically relevant ref-
erence group in future longitudinal studies.
2. Patients and methods
2.1. Patient accrual and study procedure
SCT study participants and patients for the referenceis followed by the induction phase of SCT, which involves
high-dose myeloablative chemotherapy with or without
total body irradiation (TBI) [15]. Finally, post-engraft-
ment, many patients need long-term immunosuppression
with steroids or cyclosporin, they are at risk of opportu-
1008 H. Harder et al. / European Jougroup were recruited from the outpatient clinics of thetest [28]. In addition, the Dutch version of the National
Adult Reading test [29] was used to estimate pre-morbid
intelligence level. All tests were selected with regard to
available normative data and their sensitivity to measure
specific cognitive deficits. The tests were administered in
the same order to each patient and the assessment took
approximately 2 h to complete.
2.3. Assessment of subjective cognitive functioning
The Dutch version of the Cognitive Failure Question-
naire (CFQ) was administered to measure the frequency
of everyday cognitive failures in memory, attention, ac-
tion and perception [30]. It has 25 items with a 5-point
scale from 0 (never) to 4 (very often). Raw scores were
transformed and a total CFQ-score was computed by
summing the item scores. The total CFQ scores range
from 0 to 100, with higher scores indicating more cogni-
tive failures. Additionally, all patients (except for those
who reported no cognitive failures) indicated if theypatient was scheduled before starting SCT induction
regimens. The institutional ethics committee for each
participating centre approved the research protocol
and all patients provided written informed consent.
Medical data were collected from the patients
records.
Performance status was assessed using the Karnofsky
performance status scale (KPS) [17].
2.2. Assessment of cognitive performance
A comprehensive test-battery was designed to assess
four cognitive domains: Memory and learning: the
Dutch version of the California verbal learning test
[18], the Rey complex figure test and recognition trial
[19], the Benton visual retention test [20]; Attention and
executive functions: Category wordfluency [21]; Digit
span [22], the abbreviated Stroop colour-word test
[23,24], Trails A and B [25], the D2 test [26]; Visuospatial
and constructional ability: the Rey complex figure test-
copy trial [19], Block design [22]; Psychomotor functions:Departments of Haematology and Radiotherapy of
the Erasmus Medical Center, Rotterdam (n = 169) and
the Department of Haematology of Leiden University
Medical Center in The Netherlands (n = 14). Inclusion
criteria were: completion of (pre-SCT) treatment for a
haematological malignancy, age 16–65 years and fluent
in Dutch. Patients were excluded in cases of previous
or current neurological or psychiatric disorders with
known impact on cognitive and/or motor functions,
and in cases of previous or current substance abuse. Pa-
tient accrual began in June 1999 and lasted until Decem-
ber 2001. All patients were asked by their doctor to take
f Cancer 41 (2005) 1007–1016experienced an increase in cognitive failures in the last