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Cognitive functioning and dementia following cancer: A Swedish twin study
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Cognitive functioning and dementia following cancer: A Swedish twin study
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COGNITIVE FUNCTIONING AND DEMENTIA FOLLOWING
CANCER: A SWEDISH TWIN STUDY
Copyright 2003
by
Lara Heather Heflin
A Thesis Presented to the
FACULTY OF THE GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
MASTER OF ARTS
(PSYCHOLOGY)
December 2003
Lara Heather Heflin
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UMI Number: 1420366
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®
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UNIVERSITY OF SOUTHERN CALIFORNIA
THE'GRADUATE SCHOOL
UNIVERSITY PARK '
LOS ANGELES, CALIFORNIA 90089-1695
This thesis, written by
Lara Heather Heflin
under the direction of h e r thesis committee, and
approved by all its members, has been presented to and
accepted by the Director of Graduate and Professional
Programs, in partial fulfillment o f the requirements fo r the
degree o f
Director
Thesis Committee
7
Chair
/
/
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Table of Contents
List of Tables and Figures iii
Abstract iv
INTRODUCTION 1
Cognitive Dysfunction Following Treatment 3
Cognitive Dysfunction Resulting from Cancer 7
Cognitive-Deficits Resulting from Depression and Anxiety 7
Dementia: A Brief Overview 9
METHODS 11
Participants 11
Cognitive Functioning 11
Clinical Dementia Diagnosis 12
Procedure 13
Cognitive Functioning 13
Clinical Dementia Diagnosis 14
Cancer History 15
Materials 17
Cognitive Functioning 17
Clinical Dementia Diagnosis 18
Statistical Analysis 20
RESULTS 22
Participants 22
Cognitive Functioning 22
Clinical Dementia Diagnosis 27
DISCUSSION 30
REFERENCES 39
ii
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List of Tables and Figures
Figure 1: Participant selection for the cognitive functioning and clinical
dementia diagnosis portions of the study
Table 1: Time span (in years) between cancer diagnosis and measurement
of cognitive functioning for the 16 most common cancers in
sample
Table 2: Association of cognitive functioning scale scores with cancer
diagnosis, collapsed across cancer site, stratified by time since
cancer diagnosis
Table 3: Association of cognitive functioning scale scores with cancer
diagnosis, stratified by cancer site and by time since cancer
diagnosis
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Abstract
This study examined long-term cognitive functioning in cancer patients.
Using a co-twin control design, we compared the cognitive functioning of 800
individuals aged 65 and older who were treated for malignant cancer to that of their
cancer-free twin. Analyses indicated that, on a measure of cognitive functioning,
cancer survivors were significantly more likely than co-twin controls to demonstrate
cognitive dysfunction (p=. 02G9, OR=1.31). These effects extended beyond the 3-5
years post-treatment typically measured; individuals who survived cancer for 5 or
more years before cognitive testing remained more likely than cancer-free co-twins
to demonstrate cognitive dysfunction (p=.0174, OR=1.34). Furthermore, cancer was
found to be significantly associated with a diagnosis of dementia (ORA2.22; 95%
C.I.=[1.01, 4.88]). These results suggest that cancer patients are at increased risk for
long-term cognitive dysfunction and perhaps dementia, compared with individuals
who have never had cancer.
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Introduction
Cancer survivors frequently report memory problems or cognitive
impairments after having been diagnosed and treated for cancer. Previous studies
examining cognitive dysfunction following cancer and its treatment have found
short-term cognitive deficits in areas of memory, attention, mental flexibility, speed
of information processing, visual memory, executive functioning, reaction time, and
motor functioning (Silverfarb & Oxman, 1988; Baile, 1996; Meyers, 2000; Meyers
& Abbruzzese, 1992; Weineke & Dienst, 1995; Brezden et. ah, 2000; Schagen et. al.,
199; Troy et. al., 2000; van Dam et. al., 1998; Kaasa, Olsnes, & Masteskaasa, 1988;
Tuxen & Hansen, 1994). The nearly exclusive focus on short-term cognitive
functioning, however, has left cancer survivors who experience cognitive
dysfunction to wonder how long these problems will persist, and whether they will
worsen or improve over time.
Very few studies have examined the effects of adult cancer treatments on
cognitive function beyond 2 or 3 years of treatment cessation (Johnson et. al., 1985;
Johnson et. al., 1990). This is surprising, considering the relative 5-year survival rate
for all cancers has increased from 52% in 1983-1985 to 63% in 1992-1997
(American Cancer Society, 2002). Knowledge of the potential long-term cognitive
deficits of cancer and its treatments is increasingly important as treatments continue
to lengthen the lifespan of patients diagnosed with cancer (Ganz, 1998). This
knowledge might assist patients in understanding and coping with the cognitive
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changes they may notice years after surviving cancer, or may aid in treatment
decision-making.
Research has demonstrated that neurotoxicities are serious long-term side
effects of childhood cancer treatments (Copeland et. al., 1985; Steinherz et. al.,
1991). It is important now that we understand whether similar long-term side effects
afflict elderly survivors of adult cancer. As survivors of adult cancer age and begin
to encounter more severe cognitive difficulties, it becomes important to discern
whether the cognitive dysfunctions that can result from cancer or treatment put
survivors at increased risk for dementia or other cognitive deficits, as proposed in the
present study.
There are several mechanisms through which cancer treatments might cause
long-term cognitive deficits or dementia. Treatments that cause damage to the
cardiac, vascular, or pulmonary system, such as irradiation or treatment with
anthracyclines, might decrease cerebrovascular circulation or blood oxygenation,
increase risk of embolism, transient ischemic attacks (TIAs), or stroke, or cause
ischemic hypoxia, all of which could contribute to cerebrovascular dementia (Weller
and Preston, 2001; Marieb, 1995; Silverfarb and Oxman, 1988; Fein et. ah, 2000;
Chui, 2000). The chemicals contained in some chemotherapeutic regimens may also
increase oxidative stress, which is thought possibly to contribute to dementia risk. If
chemotherapies pass through the blood brain barrier, they could cause direct damage
to neurons, as would any direct cranial irradiation (Kroll, 1998). Furthermore,
cancer itself can cause endocrine or metabolic disturbances that disrupt cognitive
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functioning (Silverfarb, 1983). Some of the above factors may not contribute to
cognitive decline or dementia in a significant portion of cancer patients, and some
may cause impairment only when treatment received is high-dose or when a
combination of treatments compounds the neuronal insult. It is clear, however, that
there are a number of ways in which treatments or cancer can result in cognitive
deficits or dementia.
Cognitive Dysfunction Following Treatment
Cancer treatments as a whole can be divided Into two main categories:
localized or systemic. Localized treatments, which include surgery and radiation of
specific sites, affect the patient’s body only at the site of the cancer and surrounding
tissue. With the exception of cranial irradiation or surgery for brain cancers,
localized treatments are thus unlikely to affect cognitive functioning directly.
Systemic treatments affect the patient’s entire body. These treatments, which
include chemotherapy, biologic response modifiers, and tamoxifen, are more likely
to contribute to cognitive decline due to their toxic effects throughout the patient’s
body.
Many systemic cancer treatments have been found to contribute to short-term
cognitive deficits in patients (Silverfarb and Oxman, 1988; Baile, 1996; Meyers,
2000). Patients who undergo chemotherapy often report cognitive difficulty; in one
study, 31% of chemotherapy patients reported concentration problems and 21%
reported memory difficulties approximately 1.9 years after completing chemotherapy
(compared with 6% and 3%, respectively, in the control group) (Schagen et. al.
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1999). Objective measures of cognitive functioning, such as neuropsychological
tests, have also demonstrated cognitive deficits in patients treated with
chemotherapy. A study of breast cancer patients treated with chemotherapy found
that 75% scored two standard deviations below the mean on one or more
neuropsychological measures 5 to 12 months after treatment cessation (Wieneke &
Dienst, 1995). It is important to determine whether these cognitive deficits persist
throughout the long-term survival of cancer patients, as hypothesized by the present
study.
Patients treated with chemotherapy consistently demonstrate short-term
cognitive deficits in attention, mental flexibility, speed of information processing,
visual memory, motor function, and memory, and may also suffer from
leukoencephalopathy. These effects have been found spanning a time period from
prior to treatment completion to 2 years post-treatment (Brezden et. al., 2000;
Schagen et. al., 1999; Troy et. al., 2000; Silverfarb, Philibert, & Levine, 1980;
Silverfarb, 1983). The likelihood of cognitive deficits from chemotherapy appears to
be related to dose received; in a well designed, randomized study, van Dam et. al.
(1998) found that two years after treatment, 32% of patients treated with high-dose
chemotherapy exhibited cognitive deficits on neuropsychological tests, compared
with 17% of patients treated with standard-dose chemotherapy and 9% of control
patients.
The effect of cranial irradiation on cognitive function in adults is somewhat
uncertain. When compared to patients who had received chemotherapy, patients
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who had received radiation tended to show fewer deficits on some
neuropsychological tests, suggesting that irradiation may cause less severe cognitive
deficits than chemotherapy (Kaasa, Olsnes & Mastekaasa, 1988). It is unclear,
however, how radiation patients would compare with a control group who had not
received any cancer treatment. In another study, Glosser et. al. (1997) followed 16
patients for 4 years after receiving skull base irradiation, and found no indications of
cognitive deficits in the patients on a neuropsychological battery testing intelligence/
conceptual reasoning, language and visuospatial processing, verbal and nonverbal
memory, attention, motor functions, and psychiatric function. Unfortunately, the
small sample size may have prevented this study from having sufficient power to
find an effect.
It has been suggested that the combination of chemotherapy and radiation
therapy might have particularly severe neurotoxic effects (Johnson et. ah, 1985).
This speculation arises not just from the potential additive damage of the two
treatment modalities, but also from animal studies that show cranial irradiation to
weaken the blood-brain barrier, which might allow chemotherapy greater permeation
into the central nervous system (Griffin, Rasey, & Bleyer, 1977). Patients who have
been treated with chemotherapy and prophylactic cranial radiation do indeed show
decreases in performance on some neuropsychological tests immediately following
treatment, compared to their pre-treatment performance (Ahles et. al., 1998).
Furthermore, computerized cranial tomography scans of patients treated with
prophylactic cranial irradiation and chemotherapy show abnormalities such as
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progressive atrophy and ventricular dilation that worsen even 8 years after cessation
of treatment (Johnson et. al. 1985, Johnson et. al. 1990).
Treatment with biologic response modifiers, such as interferon-alpha,
interferon-gamma, tumor necrosis factor, or interleukin-2, has also been associated
with a short-term decline in cognitive functioning in cancer patients. One study
showed 53% of patients treated with biologic response modifiers and chemotherapy
to exhibit cognitive deficits in neuropsychological tests, versus 18% of patients who
received only chemotherapy (Meyers and Abbruzzese, 1992). The cognitive deficits
that may result from biologies include memory deficits, frontal lobe dysfunction,
visual-motor scanning deficits, attention deficits, simple reaction time, and choice
reaction time (Meyers and Abbruzzese, 1992; Walker et. al., 1996). Some evidence
suggests these deficits may be transient, and show indications of resolving within 10
days of ceasing therapy (Walker et. al., 1996).
Other treatments that appear to have relatively transient effects on cognitive
functioning include tamoxifen, an anti-estrogen, and opioids. Current use of
tamoxifen has been shown to have detrimental effects on the performance of several
neuropsychological tests; however, past use of tamoxifen does not appear to be
associated with any cognitive deficits five years post-treatment (Paganini-Hill &
Clark, 2000). Opioids have been linked to transient deficits in psychomotor and
cognitive functions, but there is also some evidence that pain produces more
difficulties with psychomotor and cognitive task than does the use of opioids
(Sjogren, Olsen, Thomsen, & Dalberg, 2000; Sjogren, 1997).
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Cognitive Dysfunction Resulting from Cancer
There is evidence that cancer itself can also cause cognitive deficits. Brain
tumors or brain metastasis can cause a variety of cognitive dysfunctions, depending
upon the location of the cancer (Meyers, 2000; Newton, 1999). In addition, a small
number of patients may experience paraneoplastic limbic encephalitis before
undergoing any treatment and often prior to even being diagnosed with cancer
(Gultekin et. al, 2000). A similar paraneoplastic encephalitis presents in some
cancer patients as a slowly progressing subcortical dementia (Baile, 1996). Even
without metastasis or encephalitis, infections and endocrine or metabolic
disturbances can produce cognitive deficits (Silverfarb, 1983). In one study
illustrating the cognitive effects of cancer itself, cancer patients who had recently
been admitted to an oncology unit of a hospital performed more poorly than
psychiatric patients and normal controls on the Digit Symbol Test, even when cancer
patients receiving chemotherapy or with metastases were excluded (Silverfarb,
Philibert, and Levine, 1980). However, these patients’ scores on the Zung
depression scale suggest that this effect might have been influenced by the patients’
level of fatigue and other somatic variables.
Cognitive Deficits Resulting from Depression and Anxiety
Cognitive deficits, and in particular, memory deficits, are frequently seen in
people suffering from depression or anxiety. Many early researchers studying
cognitive deficits in cancer patients thus postulated that the stresses of cancer and its
treatment cause many patients to become depressed or anxious, and that these
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emotional states resulted in the observed cognitive difficulties. However,
researchers have failed to find a relationship between the presence of depression or
anxiety and cognitive deficits in cancer patients (Silverfarb, Philibert, Levine, 1980;
Wieneke & Dienst, 1995; Brezden, Phillips, Abdolell, Bunston, and Tannock, 2000;
Abies et. al. 1996; Ahles et. al., 1998; Schagen et. al., 1999). In fact, a study by
Ahles et. al. (1996) demonstrated a decrease in cognitive functioning in patients
during a time at which their moods were improving.
One study done by van Dam et. al. (1998) did find a strong relationship
between psychological distress and self-reported cognitive problems, but failed to
demonstrate a relationship between psychological distress and cognitive deficits as
measured by neuropsychological tests. Schagen et. al. (1999) also failed to find a
relationship between reported cognitive difficulties and neuropsychological measures
of cognitive deficits. These findings suggest that although cancer patients
experiencing psychological distress may report feeling as though they exhibit
cognitive difficulties, they are probably not at an increased risk for developing long
term severe cognitive deficits. Alternatively, it is possible that these patients may be
aware of subtle problems that neuropsychological tests cannot yet detect, but which
may be detected after further decline. Research examining the long-term functioning
of cancer patients, as in the following study, may help clarify the role of
psychological distress in the cognitive deficits of cancer patients.
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Dementia: A Brief Overview
Dementia is a slow, progressive deterioration of intellectual functioning with
impairment frequently seen in cognitive, emotional, and motor domains. The
Diagnostic and Statistical Manual, 4th edition (DSM-IV) assigns the diagnosis of
dementia using the following criteria: impairment in short- and long-term memory;
impairment in abstract thinking, impaired judgement, other disturbances of higher
cortical function, or personality change; memory impairment and intellectual
impairment causing significant social and occupational impairments, which does not
occur exclusively during the course of delirium; and either evidence of an organic
factor causing this impaired memory and intellect, or impaired memory and intellect
that cannot be accounted for by any nonorganic mental disorder (APA, 1994).
There are a number of different types of dementia, the two most common
being Alzheimer’s Disease (AD) and multi-infarct vascular dementia (Cummings
and Benson, 1992). The progression of AD tends to be more gradual, with fairly
diffuse loss of functioning. Vascular dementia, by comparison, has a more sudden
onset, deterioration that occurs in a stepwise fashion, and focal loss of abilities
(Cummings and Benson, 1992). Symptoms typically seen in AD include memory
loss, aphasia, agnosia, apraxia, dyscalcula, visuospatial impairment, poor judgement,
difficulty with abstraction, and unconcerned affect. Symptoms that are frequently
present in vascular dementias are abnormal speech, forgetfulness, slowed cognition,
altered affect, stooped or extended posture, and motor impairments (Cummings and
Benson, 1992). Some of these symptoms, such as memory dysfunction, slowed
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cognition, poor judgment, difficulty with abstraction, and visuospatial im p airm en t,
are similar to the cognitive deficits seen following cancer and its treatment.
Although the true prevalence rate for dementia is unknown, it is estimated
that the rate is between 5-10 percent in people over 65 years old. This rate
approximately doubles every 5 years after age 65, increasing the risk in older adults
exponentially, with the prevalence in people aged 60-65 estimated at less than 1%
(Jorm, 1987). The number of people diagnosed with dementia will be growing
rapidly as the population, of which an increasingly large percent is over 65, ages.
This makes it progressively more important to determine the severity of any
cognitive impairment that persists long after cancer and its treatment ends, and
whether it is likely to develop into more severe cognitive dysfunction, such as
dementia.
This study examines whether cancer or cancer treatments are risk factors for
long-term cognitive deficits and dementia. This study will examine whether
survivors of adult cancer are at an increased risk for developing cognitive
impairments or dementia many years after cancer treatment is completed. The
following specific aim is addressed: To discern, using a co-twin control, whether
survivors of adult cancer over the age of 65 are at an increased risk for developing
long-term cognitive deficits or dementia compared with their co-twin who has not
been diagnosed with cancer.
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Hypothesis 1: In discordant twin pairs, individuals diagnosed with and treated
for cancer will be more likely to score worse on a cognitive impairment scale than
their co-twin controls.
Hypothesis 2: Individuals diagnosed with and treated for cancer will be more
likely to be diagnosed with dementia than their co-twin controls discordant for
cancer.
Question 3: Are specific types of cancers associated with an increased risk of
obtaining lower scores on the dementia screening and being diagnosed with
dementia?
Methods
Participants
Cognitive Functioning
The following study used participants from the Swedish Twin Registry. The
Swedish Twin Registry is a population-based registry composed of monozygotic,
dizygotic, and opposite sex twin pairs bom in Sweden. It is the largest registry in the
world and was developed in the late 1950’s as a research resource. The registry is
composed of three cohorts: the cohort bom between 1886 and 1925, called the Old
Cohort, the cohort bom between 1926 and 1958, called the Middle Cohort, and the
cohort bom between 1959 and 1990, called the Young Cohort. Between 1998 and
2001, each individual from the Swedish Twin Registry who was alive and aged 65 or
older at the time that his or her name was drawn was contacted for a telephone
screening. This screening collected data on family constellation and contact,
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illnesses, demographics, medication use, and use of caffeine, tobacco, and alcohol.
Telephone interviewers also requested permission to obtain medical records.
These twins were asked to complete a cognitive screening as part of the
telephone interview. When individuals performed poorly on the cognitive screening,
the telephone interviewers asked to speak with an informant to obtain collateral
information about individuals’ cognitive functioning. This information comprised an
ordinal cognitive functioning scale that we used as a measure of each twin’s
cognitive functioning.
Participants in the current study were drawn from twin pairs in which both
members were alive at the time of the cognitive screening. Twin pairs were only
included if: 1) one member of the pair had been diagnosed with cancer and the other
member had not been, which is referred to as discordance for cancer, 2) cancer was
diagnosed prior to obtaining cognitive functioning information for the twin who had
cancer, and 3) we had cognitive functioning scale scores for both twins, either
through completion of a telephone screening, through an informant interview, or
both.
Clinical Dementia Diagnosis
Individuals who were suspected of having dementia on the basis of their
cognitive functioning scale score were referred for a dementia work-up. All co-twins
to these individuals were also referred for the dementia work-up. This work-up
included a complete cognitive battery, interviews with informants, complete physical
and neurological examinations, a medical history review, a diagnostic assessment
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team diagnosis, and a formal diagnostic board diagnosis. Participants were eligible
for inclusion in the clinical dementia diagnosis portion of this study if: 1) the pair
was discordant for cancer, 2) the dementia status of both twins in a pairs had been
clinically determined, and 3) cancer was diagnosed in the twin who had cancer
before the clinical dementia determinations were made. These clinical
determinations rated individuals as cognitively intact, cognitively impaired not
demented, or demented.
Procedure
Cognitive Functioning
Participants were identified through their inclusion in the Old or Middle
Cohort of the Swedish Twin Registry, and were initially contacted to request
participation for the telephone screening by letters describing the study. Individuals
were then contacted by telephone between 1998 and 2000 and were administered the
standardized interview, which included the cognitive screening. Some of the
individuals contacted were unable to be interviewed; when possible, an informant
was interviewed instead to collect data on these individuals. Informant interviews
were also requested if an individual performed poorly on the cognitive screening.
Performing poorly on the cognitive screening was achieved by any one of the
following: reporting needing help with activities of daily living due to memory
problems, 2) making 3 or more errors on the Mental Status Quesionnaire, 3)
committing 2 errors on the MSQ and at least 2 errors on the word recall task, 4) 2
errors on the MSQ and inability to learn the similarities task, 5) 2 errors on the word
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recall and inability to leam the similarities task, and 6) more than 6 errors on the
entire cognitive screening.
On the basis of the cognitive screening scores and informant reports, an
algorithm was used to determine whether or not an individual was likely to have
dementia. Scores from this algorithm comprised a 4-point cognitive functioning
scale and served two purposes: they were used as a gross measure of cognitive
functioning, and identified individuals who may have dementia. Scores on this
cognitive functioning scale ranged from 0-3, and individuals who obtained a score of
3 on the cognitive functioning scale were identified as ‘suspects’ for dementia. They
and their co-twins were then referred for a complete diagnostic work-up to evaluate
for dementia.
Clinical Dementia Diagnosis
Individuals referred for the dementia evaluation were visited by a trained
assessment team including a doctor and a nurse. The nurse administered a
comprehensive cognitive battery. The doctor carried out a complete physical and
neurological examination, reviewed the individual’s medical history, and ordered the
individual’s medical chart. Informant interviews were also obtained to collect
further information about each individual’s cognitive functioning. Following this, a
diagnostic review board composed of a neurologist and a psychologist examined the
information from each individual without knowing the preliminary diagnosis, and
determined whether a diagnosis of dementia was appropriate. Diagnoses were made
using DSM-IV criteria for dementia, NINCDS/ADRDA criteria for Alzheimer’s
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disease, and NMDS-AIREN criteria for vascular dementia. If an individual was
determined to not have dementia, he or she was identified on the basis of the
diagnostic evaluation as either cognitively intact or cognitively impaired not
demented.
Cancer History
The Swedish Twin Registry obtained permission to link to other Swedish
population-based registries, including the Cancer Registry. The Cancer Registry
contains cancer-related information on all individuals diagnosed with cancer between
1958 and 1999. This study utilized the link to the Cancer Registry to obtain
information on specific cancer diagnoses, date of diagnoses with cancer, age of
diagnoses with cancer, and malignancy of cancers for individuals in the Swedish
Twin Registry. Cancers in the Cancer Registry are coded according to the
International Classification of Diseases versions 7, 9, and 10 (ICD7, 9, &10),
depending on when they were diagnosed. Since all cancers in the Registry have an
ICD7 code, these were used to determine the site of cancer for participants in this
study.
The information in the Cancer Registry was provided and updated regularly
by medical staff at Swedish hospitals. The data within this registry were cross-
referenced with the Swedish Twin Registry to discern which individuals aged 65 and
older within the Swedish Twin Registry had been diagnosed with cancer. Ail
individuals who had been diagnosed only with a benign cancer were considered to
have been cancer-free.
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From this population, long-term cancer survivors were identified as
individuals whose most recent cancer had been diagnosed 5 years or more prior to
engaging in the telephone cognitive screening. Short-term cancer survivors were
identified as individuals whose most recent cancer had been diagnosed 2-4 years
before completing the cognitive screening. Immediate survivors were identified as
individuals whose most recent cancer had been diagnosed 0-1 year before
completing the cognitive screening. The distinction between immediate and short
term cancer survivors was made in recognition of the possibility that individuals
diagnosed with cancer as recently as 1 year before the dementia screening may still
be actively undergoing cancer treatment. For individuals who had been diagnosed
with more than one cancer, the most recent cancer was used to calculate the time
span between cancer diagnosis and cognitive screening in order to provide the most
conservative estimate of length of time since cancer diagnosis.
Cancers were grouped broadly by site, which was identified by the first 3
digits of the 3 to 4 digit ICD7 code. The sixteen most common cancer sites in our
participants were identified, and separate analyses were undertaken for the 3 most
co m m o n ly diagnosed cancers in our participants.
This study utilized a co-twin design, with each co-twin who has never been
diagnosed with cancer serving as a control for his/her twin who has been diagnosed
with and treated for cancer. This provided us with a control group of genetically
similar or identical people, allowing us to make comparisons between the cognitive
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functioning of people who have and have not been diagnosed with and treated for
cancer.
Materials
Cognitive Functioning
Cognitive Screening
The cognitive screening was a cognitive functioning interview that included
10 questions from the Mental Status Questionnaire (MSQ; Kahn et al., 1961). These
questions assess level of orientation (e.g. questions about the individual’s street
address, age, and birthday) and long-term memory (e.g. naming the prime minister
and the former prime minister). The screening also included questions measuring
other aspects of cognitive functioning, including attention (serial 3’s, for which a
person must count backwards by 3’s; from the Short Portable Mental Status
Questionnaire; Pfeiffer, 1975), short-term memory (a three-item recall task; from the
Mini-Mental State Examination; Folstein et al., 1975), and abstraction (questions
about similarity between words; taken from the WAIS). Questions for the informant
interview of the cognitive screening were taken from the Blessed (Blessed et al.,
1968).
Cognitive Functioning Scale
A 4-point cognitive functioning scale was the result of an algorithm that
incorporated information from the cognitive screening and informant interview.
Scores ranged from 0 to 3, with higher levels indicative of greater cognitive
impairment. Scores of 0 or 1 are typical of cognitively intact individuals, scores of 2
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represent individuals who have some cognitive impairment, and scores of 3 are taken
as identifying individuals suspicious for dementia. A study examining this cognitive
functioning scale demonstrated that it was successfully able to discriminate between
a sample of demented and non-demented individuals who had not been previously
selected on the basis of their cognitive status (Gatz et al, 2002).
To obtain a score of 3 on the cognitive functioning scale, a twin had to
commit 3 or more errors on the MSQ portion of the cognitive screening or mention
that he or she had memory problems that necessitated assistance with daily living;
fail a third of the items on the cognitive screening or be impaired in at least two
domains of cognitive functioning, and have an informant mention dementia or report
that the twin’s functioning was significantly impaired due to cognitive dysfunction;
or fail to complete the cognitive screening and have an informant mention dementia
or report that the twin’s functioning was significantly impaired due to cognitive
dysfunction.
Clinical Dementia Diagnosis
Cognitive Battery
A neuropsychological cognitive battery was administered as part of the
dementia evaluation. It is comprised of tests assessing level of orientation, verbal
learning and recall, visual spatial and motor functioning, executive functioning, word
fluency, crystallized knowledge, and several domains of memory.
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Informant Interviews
Informant interviews were conducted as part of the dementia evaluation to
obtain further information on a twin’s cognitive functioning, and also to obtain
collateral information to determine whether a twin was answering orientation
questions correctly (e.g. place of twin’s birth). Informants were asked to give
opinions about: the twin’s cognitive functioning in various situations (e.g. ability to
remember items on a shopping list), the twin’s knowledge of his or her level of
cognitive impairment, the twin’s level of orientation, the twin’s problem solving
ability, the twin’s employment and ability to engage in activities outside of home,
and the twin’s ability to care for self and engage in previously enjoyed hobbies.
Medical Records
Medical records were obtained as part of the dementia evaluation. These
included, when available, previous neuroimaging tests and tests examining
cerebrospinal fluid. Also recorded in the medical record review was information
about cardiovascular diseases or conditions, neurological diseases or conditions,
anesthesia given for surgery, endocrine disorders, infectious diseases, respiratory
diseases, allergies, autoimmune disorders, eye diseases, psychiatric illnesses and
whether received electroconvulsive therapy, and medications.
Physical Examination
Physical exams were conducted by a physician as part of the dementia
evaluation to obtain information about previously undetected and current health
conditions and dementia-related risk factors. Physicians inquired about any current
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medical complaints (e.g. heart pains, respiratory problems, memory problems);
measured height and weight, assessed visual acuity, auditory acuity, and
communication (e.g. delirious, receptive and generative communication ability); took
blood pressure measurements and pulse; performed a thyroid examination;
performed a pulmonary examination; completed a cardiac and circulatory
examination; and performed an abdominal examination.
Neurological Examination
Neurological examinations were completed by a physician as part of the
dementia evaluation to obtain further information about neurocognitive functioning.
Physicians performed tests of twins’ gait, balance, movement (voluntary and
involuntary), muscle tone, reflexes, and cranial nerve functioning. Physicians also
tested for paresis and for symptoms of Parkinson’s disease.
Statistical Analysis
Analyses were conducted using McNemar’s chi squares and odds ratios.
Monozygotic, dizygotic, and opposite sex twin pairs were combined for the analyses.
Dependent variables included cognitive functioning scale scores and clinical
dementia diagnoses.
To examine whether there were an association between cancer and cognitive
functioning, the cognitive functioning scale was dichotomized in 3 ways to create
categorical variables for cognitive functioning, where each individual was either
relatively cognitively intact or demonstrating cognitive impairment. This allowed a
comparison of the proportions of cancer-surviving versus cancer-free twins scoring 0
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to those scoring 1, 2, or 3; proportions of twins in each group scoring 0 or 1 to those
scoring 2 or 3; and proportions of twins in each group scoring 0, 1, or 2 to those
scoring 3. Lower scores on the ordinal scale, such as 0 or 1 indicated little or no
cognitive impairment, whereas higher scores of 2 or 3 indicated moderate to
relatively severe cognitive impairment, and scores of 3 indicated relatively severe
cognitive impairment.
McNemar’s chi square analyses were first conducted using all twin pairs
discordant for cancer, regardless of site of cancer or length of time between cancer
diagnosis and completion of cognitive screening. Separate McNemar’s chi square
analyses were then conducted for twin pairs in which the cancer survivor had been
diagnosed with cancer a year or less prior to completing the cognitive screening, for
pairs in which the cancer survivor had been diagnosed with cancer between 2-4 years
prior to completing the cognitive screening, and for pairs in which it had been 5
years of longer since the cancer survivor had been diagnosed with cancer.
Analyses were then conducted separately for the three most commonly
diagnosed cancers. For these analyses, all twin pairs discordant for a given cancer
were first collapsed into one group for analysis. Pairs were then distinguished by
length of time between cancer diagnosis and completion of cognitive screening, as
described above, and separate analyses were completed for each time span grouping.
McNemar’s chi square analyses were also used to determine whether cancer
were a risk factor for dementia. The diagnostic evaluations of dementia resulted in
individuals receiving one of three designations: cognitively intact, cognitively
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impaired not-demented, or demented. Dementia diagnosis status was categorized to
compare the proportions of twins in each group who obtained a formal dementia
diagnosis versus those determined to be completely cognitively intact. To create
clear categories, individuals determined to be cognitively impaired not demented
were not included in the analyses. The proportions of cancer survivors who were
cognitively intact versus demented were compared to the proportions of their co-twin
controls who were cognitively intact versus demented.
Descriptive statistics were used to provide information about length of time
between diagnosis and completion of cognitive screening for the sixteen most
commonly diagnosed cancers in the study’s participants.
Results
Participants
Cognitive Functioning
There were 7,680 twin pairs in which both members of the pair were alive
and aged 65 or older when their names were selected between 1998 and 2000 for
participation in the telephone screening. Of these, we were able to obtain cognitive
functioning scale scores for 4,261 (55.5%) twin pairs. 752 pairs were both
discordant for cancer, and had been diagnosed with cancer prior to cognitive testing.
Figure 1 delineates participants eligible for the cognitive functioning portion of this
study. Inability to assign a cognitive functioning scale score generally resulted from
individuals failing to complete the cognitive screening. The reasons for not
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completing the cognitive screening include: refusing participation, inability to be
reached by telephone, presence of auditory impairment, and health problems.
Figure 1. Participant selection for the cognitive functioning and clinical dementia diagnosis portions
of the study
Pairs alive and
85 yr old or older
Pairs whose cancer was prior
to the cognitive screening
ndividuals scoring 1
ndividuals scoring 2
.ndividuals scoring 0
Individuals scoring 3
Pairs discordant for
cancer
Pairs where both
had cancer
Pairs where neither
had cancer
Pairs who completed
cognitive screening
Pairs whose cancer
was after the
coonifive screenina
Pairs with at least 1 twin who
did not complete screening
Note: Darkened boxes indicate participants included in the study.
The average age of participants in the cognitive functioning portion of the
study was 74 years (SD=6.35). Of the twins who had been diagnosed with cancer,
445 were long-term cancer survivors, 167 were short-term cancer survivors, and 140
were immediate cancer survivors. There were no significant differences in age
between long-term, short-term, and immediate cancer survivors (p > .10). 75
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individuals had been diagnosed with more than one cancer, or had experienced a
cancer recurrence. For those individuals diagnosed with multiple cancers,
information from the most recent cancer (e.g. site of cancer, date diagnosed) was
used for all analyses. Because the focus of this study was on long-term cognitive
functioning following cancer, this provided us with the most conservative estimate of
time span between cancer diagnosis and measurement of cognitive functioning.
The range of time between cancer survival and cognitive screening for all
twins who had been diagnosed with cancer was 0-41 years (meam=8.73, SD=8.68).
Table 1 provides a description of the time span between cancer diagnosis and
completion of cognitive screening for the sixteen most commonly diagnosed cancers
in the study’s participants. These 16 most commonly diagnosed cancers account for
95.9% of the cancers.
Table 1. Time span (in years) between cancer diagnosis and measurement o f cognitive functioning for the 16
most common cancers in sample
Cancer N Mean SD Min-Max
breast 149 8.95 8.35 0-40
prostate 126 4.23 4.4 0-24
colorectal 80 7.19 7.19 0-36
skin 49 7.65 6.89 0-24
bladder 49 7.04 7.04 0-34
corpus uteri 44 13.12 8.93 0-37
melanoma 40 12.83 10.07 1-33
endocrine gland 28 9.11 8.15 1-40
rectum 27 6.67 5.65 0-23
ovary 27 13.11 9.77 0-38
brain 20 8.42 8.45 0-29
non-Hodgkin's 20 5.63 4.7 0-15
cervical 19 20.39 14.56 0-41
lip 15 11.13 11.25 0-34
leukemia 14 7.71 6.45 1-23
thyroid 14 16.57 11.18 4-40
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Table 2 presents the results of the McNemar’s chi squares and odds ratios for
all cancers, collapsed across site. There was a significant association between cancer
and achieving a cognitive functioning scale score of 2 or 3 when including all twin
pairs, regardless of time span between cancer diagnosis and cognitive screening
completion. A significant association was also found between cancer and achieving
a cognitive functioning scale score of 3 when including ail twin pairs regardless of
time span. The association was in the expected direction, with cancer survivors
significantly more likely to achieve scores of 2 or 3, and significantly more likely to
achieve scores of 3, than their co-twins. No significant associations were found
when comparing proportions of cancer survivors who achieve a cognitive
functioning scale score of 0 to proportions of their co-twins achieving a cognitive
functioning scale score of 0.
Analyses conducted for long-term cancer survivors and their co-twins
resulted in a significant association between long-term cancer survival and achieving
a cognitive functioning score of 2 or 3, indicating moderate to severe impairment.
There was also a significant association between long-term cancer survival and
achieving a cognitive functioning score of 3, indicating relatively severe impairment.
These findings were in the expected direction, with long-term cancer survivors more
likely to obtain scores of 2 or 3, and more likely to obtain score of 3, than their
disease-free co-twins. Immediate cancer survival was significantly associated with
obtaining a cognitive functioning scale score of 3. No significant associations were
found between short-term cancer survival and cognitive functioning scale scores.
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Table 2. Association of cognitive functioning scale scores with cancer diagnosis, collapsed across cancer site, stratified by time since cancer
diagnosis
Stratification 0 vs. t.2,3_t _____________________ 0.1 vs. 2.3____________________________ 0,1.2 vs. 3 ___________
Time since N Me- p- Me- Me- p- 95%
cancer dx pair Nemar value OR 95% C.l. Nemar p-value OR 95% C.l. Nemar value OR C.l.
Ail pairs
0.0028 .0002
752 0.967 0.326 1.1 (.89, 1.41) 8.963 ** 1.5 (1.15,1.98) 14.157 *** 2.2 (1.44,3.3)
Long-term
0.0005 .0004
survivors 445 0.783 0.376 1.1 (.85, 1.52) 12.121 *** 1.9 (1.31,2.67) 12.645 *** 2.7 (1.52,4.6)
Short-term
survivors
167 0.000 >.999 1.0 (.60, 1.67) 0.000 >.999 1.0 (.56,1.78) 0.000 >.999 1.0 (.42,2.4)
Immediate
survivors
.0253
140 0.439 0.508 1.2 (.71,2.01) 0.421 0.516 1.2 (.65,2.34) 5.000 * 3.0 (1.09,8.3)
t Scores of 0 or 1 indicate that an individual is generally cognitively intact, a score of 2 indicates some cognitive dysfunction, and a score of 3
identifies individuals who are suspected of having dementia.
‘ Indicates significance at p<.05
** Indicates significance at p<.01
*** Indicates significance at p<.001
Note: 95% confidence intervals that do not contain the value of 1 are considered statistically significant.
to
Os
Table 3 presents the results of analyses stratified by site of cancer for the 3
most common cancers. When all breast cancer survivors were included in analyses
regardless of the time span between cancer diagnosis and measurement of cognitive
functioning, breast cancer was found to be significantly associated with obtaining a
cognitive functioning scale score of 2 or 3. When separate analyses were conducted
to stratify by time span, immediate cancer survival was also associated with
obtaining a cognitive functioning scale score of 2 or 3. These associations were in
the expected direction, with breast cancer survivors as a group, and also immediate
breast cancer survivors specifically, more likely than their co-twins to demonstrate
moderate to relatively severe cognitive impairment. Neither short-term nor long
term breast cancer survival was significantly associated with cognitive functioning
scale scores, although long-term breast cancer survivors showed a non-significant
trend towards obtaining cognitive functioning scale scores of 2 or 3 more frequently
than their co-twins. Neither prostate cancer nor colorectal cancer was significantly
associated with cognitive functioning scale scores, although long-term prostate
cancer survivors also showed a non-significant trend towards obtaining scores of 2 or
3 more frequently than their co-twins.
Clinical Dementia Diagnosis
718 individuals who obtained a cognitive functioning scale score of 3 had
been given the comprehensive dementia evaluation. Of these individuals, 332
(44.8%) were diagnosed with dementia, 93 (12.9%) were determined to be
cognitively impaired not demented, and 303 (42.2%) were determined to be
27
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Table 3. Association of cognitive functioning scale scores with cancer diagnosis, stratified by cancer site and by time since cancer diagnosis
0,1 vs. Z 3
Time since
Site cancer dx
N
pair
Mc-
Nemar
P-
value OR 95% C.l.
Mc-
Nemar p-value OR 95% C.l.
Mc-
Nemar
P-
value OR 95%C.I.
Breast
All pairs 149 0.065 0.800 1.1 (.65, 1.76) 5.988 0.019* 2.2 (1.1,4.16) 2.333 0.127 2.0 (.81,4.96)
Long-term 95 0.024 0.876 1.0 (.52, 1.76) 2.790 0.095 1.9 (.88,4.09) 0.692 0.405 1.6 (.52, 4.89)
Short-term 33 0.692 0.405 1.6 (.52, 4.89) 0.500 0.480 1.7 (.40,6.97) 0.200 0.655 1.5 (.25, 8.98)
Immediate 21 0.000 >.999 1.0 (.25, 4.00) 4.00 0.045* 3.000 0.083
Prostate
All pairs 126 1.089 0.297 1.4 (.76, 2.48) 1.195 0.274 1.4 (.76, 2.63) 0.474 0.491 1.4 (.55, 3.42)
Long-term 45 1.000 0.317 1.7 (.61,4.59) 2.882 0.090 2.4 (.85, 6.81) 1.000 0.317 2.0 (.50, 8.00)
Short-term 40 1.923 0.166 2.3 (.69, 7.30) 0.000 >.999 1.0 (.32,3.1) 1.000 0.317 0.3 (.03, 3.20)
Immediate 41 0.250 0.617 0.8 (.29, 2.09) 0.000 >.999 1.0 (.32, 3.1) 0.660 0.414 2.0 (.37,10.9)
Colorectal
All pairs 80 0.040
Long-term 43 0.250
Short-term 24 1.286
Immediate 13 0.000
* Indicates significance at p<.05
t A score of 0 or 1 indicates that an individual is generally cognitively intact, 2 indicates poor performance, and 3 identifies dementia suspects.
0.842 0.9 (.42, 2.02) 1.191 0.275 0.6 (.26, 1.48) 1.667 0.197 2.0 (.68, 5.85)
0.617 1.3 (.48, 3.45) 0.091 0.763 1.2 (.37, 3.93) 2.000 0.157 3.0 (.6,14.86)
0.257 0.4 (.08, 2.06) 3.571 0.059 0.2 (.02, 1.38) 0.333 0.564 2.0 (.18,22.1)
>.999 1.0 (.06,15.2) 0.333 0.564 0.5 (.05, 5.51) 0.000 >.999 1.0 (.14, 7.1)
to
o©
cognitively intact. Only three individuals who had been given a cognitive
functioning scaie score of 0 or 1 and were worked up for dementia were later
diagnosed with dementia.
There were 563 pairs of twins discordant for cancer where both members had
either undergone the comprehensive dementia evaluation, or could be assumed to be
cognitively intact due to obtaining a score of 0 or 1 on the cognitive functioning
scale. In 531 of these pairs, the twin who had survived cancer had been diagnosed
with cancer prior to completing the cognitive screening.
When collapsing across time span, cancer was found to be significantly
associated with a diagnosis of dementia (OR=2.22; 95% C.I.=[1.01, 4.88]). Twins
who had survived cancer were twice as likely as their disease-free co-twin controls to
be diagnosed with dementia. When analyses were conducted stratifying for length of
time since most recent cancer diagnosis, a similar, non-significant trend was seen for
long-term cancer survivors (OR=1.67; 95% C.l.=[.61, 4.59]). There was no
significant association between short-term cancer survivorship and diagnosis of
dementia (OR=l; 95% C.l.=[.2, 4.95]). There was, however, a significant
association between immediate cancer survivorship and diagnosis of dementia
(p=.0082; OR not able to be calculated since 1 cell contained 0 pairs). Twins who
had been diagnosed with cancer a year or less prior to completing the cognitive
screening were approximately 7 times as likely as their disease-free co-twin controls
to be diagnosed with dementia.
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Discussion
The purpose of this study was to ascertain whether cognitive deficits and
dementia are likely to be a long-term result of cancer diagnosis and treatment. We
found support for the hypothesized association between long-term cancer
survivorship and cognitive deficits. Using a heterogeneous group of long-term
cancer survivors, we found cancer to be significantly associated with cognitive
dysfunction, with cancer survivors 1.87 to 2.65 times as likely as cancer-free co
twins to demonstrate moderate or relatively severe cognitive dysfunction,
respectively. This association did not reach statistical significance when separate
analyses were conducted for the three most common cancers, although a near
significant trend in the expected direction did emerge for moderate to relatively
severe cognitive impairment in long-term breast cancer and prostate cancer
survivors.
This failure to reach statistical significance may be due to the decreased
sample size when stratifying by cancer site. It appears noteworthy that even when
analyses did not quite reach statistical significance, the odds ratios are probably
clinically significant. Long-term breast cancer survivors were nearly twice as likely,
and long-term prostate cancers more than twice as likely, as cancer-free co-twins to
show cognitive impairment on a cognitive functioning scale. These results lead us to
conclude that cancer survivors may be at increased risk for cognitive dysfunction
long after cancer treatments are completed compared to individuals who have never
had cancer.
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Interestingly, a relationship between cancer survivorship and cognitive
impairment was not demonstrated for cancer survivors who had been diagnosed with
cancer 2 to 4 years prior to completing the cognitive screening. Furthermore, in
many of the stratifications, the odds of a cancer survivor demonstrating short-term
cognitive impairment were exactly equivalent to those of their disease-free co-twins.
Only in one instance, comparing short-term survivors of colorectal cancer to their co
twins, was there even a trend towards significance, and it was in the opposite
direction expected. These findings do not support previous research that has found
short-term cognitive deficits in cancer patients (e.g. Ahles et. al, 1998; van Dam et.
al, 1998; Brezden et. al, 2000). One difference may be that many previous studies
have used other cancer patients as control groups rather than using a control group of
cancer-free individuals; this seems like an unlikely explanation, however, since
short-term cognitive deficits have been found in cancer patients using cancer-free
control groups, as well (e.g. Siddiqui et. al, 1992).
Our failure to replicate previous findings of short-term cognitive dysfunction
following cancer may be the result of many factors. It is possible that our cognitive
screening measure was less sensitive than the cognitive tests used by previous
researchers. If this were true, it would make the long-term differences in cognitive
functioning between cancer-surviving and cancer-free twins even more noteworthy.
It is furthermore possible that our inclusion of informant reports in determining
cognitive functioning has biased our results in unexpected ways. For example, it is
possible that informants may have attributed any cancer survivors’ difficulties in
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daily functioning to lasting cancer-related symptoms such as fatigue, and failed to
report it. This seems somewhat unlikely, however, since significant associations
were found between immediate cancer survivorship—a time at which cancer-related
fatigue and other symptoms would likely be most salient for informants—and
cognitive dysfunction.
Finding an association between immediate cancer survival and cognitive
dysfunction is not at all unprecedented, and has been hypothesized to be caused by
many factors, including temporary cognitive disruption due to pain medications or
tamoxifen, fatigue or anemia following chemotherapy, or rapid dementia due to
paraneoplastic encephalitis (Paganini-Hill & Clark, 2000; Walker et. al, 1996;
Gultekin et. al, 2000). A heterogeneous group of cancer survivors within a year of
diagnosis in our study were found to be three times as likely as their disease-free co
twins to demonstrate cognitive impairment that flags them as dementia suspects.
Similarly, women a year or less past diagnosis of breast cancer were at significantly
increased risk for cognitive impairment compared to their co-twins. It is unclear
which, if any, of the above factors previously found to be associated with cognitive
impairment immediately following cancer may be involved in the increased risk for
cognitive impairment we have found.
We also found support for the hypothesis that individuals who had been
diagnosed with and treated for cancer would be more likely to be diagnosed with
dementia than their cancer-free co-twins. Our heterogeneous group of cancer
survivors was more than twice as likely as their disease-free co-twins to be given a
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clinical diagnosis of dementia following a comprehensive dementia evaluation. This
suggests that cognitive impairment following cancer and its treatment is neither as
temporary nor as benign as many have previously thought. Future research is needed
to explore the ways in which cancer or treatments might cause dementia, such as
through cardiovascular damage that leads to increased risk for cerebrovascular
dementia and Alzheimer’s disease.
Cancer survivors who had been diagnosed with cancer 5 years or more prior
to completion of the cognitive screening showed a similar, non-significant trend
towards increased risk of being diagnosed with dementia compared to co-twins. It is
possible that our sample size here was insufficient to achieve statistical significance,
particularly since fewer than 20 of the 314 pairs of twins in the analysis were
discordant for both cancer and dementia. Future research will be needed to discern
with greater accuracy whether the cognitive impairment seen in many cancer
survivors is likely to develop into more serious cognitive dysfunction as survival
time increases.
Consistent with our pattern of findings on cognitive functioning, cancer
survivors 2 to 4 years past diagnosis were not found to be at increased risk for being
diagnosed with dementia compared to co-twins. This is not surprising given the
results in the first part of our study, since individuals were only referred for dementia
evaluation if they obtained a score of 3 on the cognitive functioning scale. Because
there were no differences in rates of cancer survivors versus co-twins in obtaining a
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score of 3 on the cognitive functioning scale, it is understandable that there would
not be significant differences in rates of dementia diagnosed.
Also consistent with the results of the first part of the study was the finding
that cancer survivors who had been diagnosed with cancer within a year of the
cognitive screening were at significantly increased risk for being diagnosed with
dementia, compared to disease-free co-twins. Although relatively rare, this may for
some individuals be the result of paraneoplastic encephalitis, which is thought to be
caused by cancer itself rather than treatments, and can cause dementia (Baile, 1996).
Alternatively, it is also quite possible that other risk factors, such as smoking,
alcohol use, sedentary lifestyle, or lower socioeconomic status (SES) are responsible
for the development of both cancer and dementia. Because all four of these factors
have been associated with increased risk of cancer and cognitive decline, it is thus
possible that the cognitive dysfunction we found in cancer-surviving twins could be
at least partially explained by higher rates of smoking and alcohol consumption,
more sedentary lifestyle, and lower SES, relative to cancer-free co-twins. If this
were true, the associations we have found between cancer and cognitive dysfunction
and cancer and dementia would be simply a reflection of a comorbid association
between cancer and cognitive dysfunction due to disease processes influenced by the
above confounding variables. It is thus important that future studies control for these
variables to more confidently assert that the relationship between cancer and
cognitive decline is likely to be causational.
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Although the results are not entirely consistent across stratifications, there
appears to be a tendency to see the strongest associations between cancer and
cognitive impairment both immediately following cancer diagnosis and 5 or more
years past cancer diagnosis. Our findings on dementia diagnoses showed a similar
pattern to those on cognitive impairment. This consistency suggests that the pattern
of results may not be an artifact of other factors, such as insufficient power within
certain stratifications or insufficiently sensitive cognitive measure. This pattern may
suggest a non-linear course of cognitive impairment as survival time increases, such
that cancer and treatment-related symptoms are likely to affect cognitive functioning
immediately after diagnosis, but dissipate within a few years and only after time does
subtle neurological damage worsen and begin to manifest. It is also possible,
however, that this is merely a reflection of different populations. For example, it is
possible that many individuals whose most recent cancer was diagnosed within a
year of the cognitive screening (the immediate cancer survivors) were experiencing
metastases, which can disrupt cognitive functioning if the cancer has metastasized to
the brain.
It is quite possible that cancer treatments have changed in the past few
decades such that the cancer treatments that were used in the late 1950’s through the
late 1970’s and 1980’s are more likely to result in cognitive dysfunction than more
recent treatments, and that cognitive impairment seen here within the first year of
cancer diagnosis reflects temporary treatment-related fatigue and stress. This may
reflect a growing concern for and ability to successfully circumvent treatment
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toxicities. Thus, the results obtained here that show long-term cancer survivors at
increased risk for cognitive impairment may reflect cohort differences in the type of
cancer treatment received, and future generations of cancer survivors may not show
the same pattern of cognitive impairment seen here.
Several limitations in this study should be noted that limit the confidence in
and ability to generalize our results. Since we did not have access to information on
the cancer treatments we were unable to determine the potential contributions of
different treatment modalities and treatment doses, which have previously been
found to have important implications in the severity of cognitive deficits observed
(e.g. van Dam et. al., 1998; Keime-Guibert et. al, 1998). Changes in cancer
treatments over the years may thus limit our ability to generalize these results, since
many current cancer patients may receive treatments that are less likely to result in
long-term cognitive dysfunction. This limitation also prevented us from exploring
whether different types of treatments are more likely to result in cognitive
impairment than others. Furthermore, the effects of the cancer cannot be separated
from those of the treatment received. As noted earlier, our analyses also did not
control for possible third variables that might contribute to both cancer and dementia.
Finally, the statistics used were insufficient to handle ordinal data, such as the
cognitive fimctioning scale, and in dichotomizing ordinal data as we did, information
is lost and statistical power is lessened.
This study also has several noteworthy strengths. To our knowledge, this
study is the largest to date that examines the relationship between cancer and
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cognitive functioning. With cancer survivors who are as far as 41 years past cancer
diagnosis, it also assesses the longest time span between cancer diagnosis and
cognitive functioning, allowing for a broader, more comprehensive definition of
long-term survival, for which other studies have frequently used only patients
approximately 5 years post-treatment. Since an entire cohort of twins was contacted
for participation in the cognitive screening, this study also avoids many of the
selection biases that plague similar studies when focusing only on patients in
hospitals or elderly care facilities. Similarly, since comprehensive dementia
evaluations were performed both on individuals who were suspected of having
dementia and on their co-twins, selection biases were also minimized in the clinical
dementia diagnosis portion of the study. Furthermore, the use of discordant twin
pairs allows us a control group that matches for at least 50% of genetics, and also for
many early environmental factors. We thus believe this study represents an
important step in determining whether survivors of cancer are likely to be at
increased risk for long-term cognitive dysfunction or dementia later in life.
These methodological strengths permit us greater confidence that the
association we found between long-term cancer survival and cognitive decline is a
phenomenon worthy of further investigation. Further research is stiil necessary to
identify factors that may covary with or mediate the relationship between cancer and
cognitive dysfunction. The specific domains of cognitive functioning that are likely
to show long-term impairment in cancer survivors also remains to be determined.
Perhaps most importantly, further research needs to be undertaken to ascertain
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whether specific types of treatments are more likely to be associated with long-term
cognitive dysfunction. This knowledge will help doctors and patients make
informed decisions about their treatments so that cancer survivors will have the
cognizance to live independently and enjoy their lives into older age.
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References
AMes, T.A., Silverfarb, P.M., Hemdon, I. II, Maurer, L. BL, Komblith, A.B., Aisner,
J., Perry, M.C., Eaton, W.L., Zacharski, L.L., Green, M.R., & Holland, J.C. (1998).
Psychologic and neuropsychologic functioning of patients with limited small-cell
lung cancer treated with chemotherapy and radiation therapy with or without
warfarin: A study by the cancer and leukemia group B. Journal o f Clinical
Oncology, 16 (5), 1954-1960.
AMes, T.A., Tope, D.M., Furstenberg, C., Hann, D., & Milla, L. (1996).
Psychologic and neuropsychologic impact of autologous bone marrow
transplantation. Journal o f Clinical Oncology, 14 (5), 1457-1462.
American Cancer Society (2002). Cancer Facts and Figures 2002. Atlanta:
American Cancer Society.
American Psychiatric Association (APA). (1994). Diagnostic and statistical manual
o f mental disorders (4th ed.). Washington, DC: American Psychiatric Association.
Bachman, D.L., Wolf, P.A., Linn, R., Knoefel, I.E., Cobb, J., Belanger, A.,
D ’Agostino, R.B., White, L.R. (1992). Prevalence of dementia and probable senile
dementia of the Alzheimer type in the Framingham Study. Neurology, 42 (1), 115-
119.
Bachman, D.L., Wolf, P.A., Linn, R., Knoefel, I.E., Cobb, J., Belanger, A., White,
L.R., D’Agostino, R.B. (1993). Incidence of dementia and probable Alsheimer’s
disease in a general population: the Framingham Study. Neurology, 43(3), 515-519.
Baile, Walter F. (1996). Neuropsychiatric disorders in cancer patients. Current
Opinion in Oncology, 8, 182-187.
Brezden, Christine B., Phillips, Kelly-Anne, Adolell, Mohamed, Bunston, Terry, &
Tannock, Ian F. (2000). Cognitive function in breast cancer patients receiving
adjuvant chemotherapy. Journal o f Clinical Oncology, 18 (14), 2695-2701.
Chui, Helena. (2000). Vascular dementia, a new beginning: shifting focus from
clinical phenotype to ischemic brain injury. Dementia, 18 (4), 951-977.
Copeland, Donna R., Fletcher, Jack M., Pfefferbaum-Levine, Jaffe, Norman, Ried,
Hubert, & Maor, Moshe. (1985). Neuropsychological sequelae of childhood cancer
in long-term survivors. Pediatrics, 7 (4), 745-753.
Cummings, J.L., & Benson, D.F. (1992). Dementia: A clinical approach, 2n d Edition.
Boston: Butterworth-Heinemann.
39
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Fein, G., Sclafani, V. Di, Tanabe, I., Cardenas, V., Weiner, M.W., Jagust, W.J.,
Reed, B.R., Norman, D., Schuff, N., Kusdra, L., Greenfield, T., Chui, H. (2000).
Hippocampal and cortical atrophy predict dementia in subcoitical ischemic vascular
disease. Neurology, 55, 1626-1635.
Folstein, Marshal F., Fetting, John H., Lobo, Anthony, Niaz, Unaiza, & Capozzoli,
Kathryn. (1984). Cognitive assessment of cancer patients. Cancer, 53 (10), 2250-
2257.
Folstein, M., Folstein, S., & McHugh, P. (1975). “Mini-mental state.” A practical
method for grading the cognitive state of patients for the clinician. Journal o f
Psychiatric Research, 12, 189-198.
Ganz, Patricia A. (1998). Cognitive dysfunction following adjuvant treatment of
breat cancer: a new dose-limiting toxic effect? Journal o f the National Cancer
Institute, 90 (3), 182-183.
Gatz, Margaret, Reynolds, Chandra, Nikolic, Jovanka, Lowe, Beverly, Karel,
Michele, & Pedersen, Nancy. (1995). An empirical test of telephone screening to
identify potential dementia cases. International Psychogeriatrics, 7 (3), 429-437.
Glosser, Guila, McManus, Pat, Munsenrider, John, Austin-Seymour, Mary,
Fullerton, Barbara, Adams, Judy, & Urie, Marcia M. (1997). Neuropsychological
function in adults after high dose fractionated radiation therapy of skull base tumors.
International Journal o f Radiation Oncology, Biology, and Physiology, 38 (2), 231-
239.
Griffin, T.W., Rasey, J.S., & Bleyer, W.A. (1977). The effect of photon irradiation
on blood-brain barrier permeability to methotrexate in mice. Cancer, 40, 1109-1111.
Gultekin, S. Humayun, Rosenfield, Myma R., Voltz, Raymond, Eichen, Joseph,
Posner, Jerome B., & Dalmau, Josep. (2000). Paraneoplastic limbic encephalitis:
neurological symptoms, immunological findings and tumour association in 50
patients. Brain, 123, 1481-1494.
Hachinski, Vladimir C., Iliff, Linnette D., Phil, M., Zilhka, Elias, Du Boulay, George
H., McAllister, Victor L., Marshall, John, Ross Russell, Ralph W., & Symon,
Lindsay. (1975). Cerebral blood flow in dementia. Archives o f Neurology, 32, 632-
637.
Hughes C.P., Berg, L., Danziger, W.L., Coben, L.A., Martin, R.L. (1982). A new
clinical scale for the staging of dementia. British Journal o f Psychiatry, 140, 566-
572.
40
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Johnson, Brace E., Becker, Bruce, Goff, Walter B., II, Petronas, Nicholas, Krehbiel,
Mary Ann, Makuch, Robert W., McKenna, Gilles, Glatstein, Eli, & Hide, Daniel C.
(1985). Neurologic, neuropsychologic, and computer cranial tomography scan
abnormalities in 2- to 10-year survivors of small-cell lung cancer. Journal o f Clinical
Oncology, 3 (12), 1659-1667.
Johnson, Brace E., Patronas, Nicholas, Hayes, Wendy, Grayson, Jane, Becker,
Brace, Gnepp, Diane, Rowland, Jan, Anderson, Anita, Gladstein, Eli, Hide, Daniel
C., & Frank, Joseph A. (1990). Neurologic, computed cranial tomographic, and
magnetic resonance imaging abnormalities in patients with small-cell lung cancer:
further follow-up of 6- to 13-year survivors. Journal o f Clinical Oncology, 8 (1), 48-
56.
Jonsson, C.O., & Molander, L. (1964). Manual till CVB-skalan [Manual o f the CVB
Scales]. Stockholm: Psykologi Forlaget.
Jorm, A.F., Korten, A.E., Henderson, A.S. (1987). The prevalence of dementia: a
quantitative integration of the literature. Acta Psychiatrica Scandinavica, 76 (5),
465-479.
Kaasa, S., Olsnes, B.T., and Mastekaasa, A. (1988). Neuropsychological evaluation
of patients with inoperable non-small cell lung cancer treated with combination
chemotherapy or radiotherapy. Acta Oncologica, 27, 241-246.
Kahn, R.L., Pollack, M., & Goldfarb, A.I. (1961). Factors related to individual
differences in mental status of institutionalized aged. In P. Hoch and J. Zubin (Eds.),
Psychopathology o f Aging (pp. 104-113). New York: Grune & Stratton.
Kessler, R.C., Andrews, G., Mroczek, D., Ustun, B., & Bittchen, U.L. (1998). The
World Health Organization Composite International Diagnostic Interview Short
Form (CIDI-SF). International Journal o f Methods in Psychiatric Research, 7 , 171-
185.
Kohout, Frank J., Berkman, Lisa F., Evans, Denis A., & Comoni-Huntley, Joan.
(1993). Two Shorter Forms of the CES-D Depression Symptoms Index. Journal o f
Aging and Health, 5 (2), 179-193.
Lezak. M. (1983). Neuropsychological Assessment, 2n d Edition. New York: Oxford
Press.
Marieb, Elaine N. (1995). Human anatomy and physiology, 3'd Edition. California:
The Benjamin/Cummings Publishing Company, Inc.
41
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Meyers, Christina A. (2000). Neurogocnitive dysfunction in cancer patients.
Oncology, 14 (1), 75-79.
Meyers, Christina A., & Abbruzzese, James L. (1992). Cognitive functioning in
cancer patients: effect of previous treatment. Neurology, 42, 434-436.
Morris, J.C., Heyman, A., Mohs, R.C., Hughes, J.P., van Belle, G., Fillenbaum, G.,
Mellitis, E.D., Clark, €., & the CERAD investigators. (1989). The Consortium to
Establish a Registry for Alzheimer’s Disease (CERAD). Part 1. Clinical and
neuropsychological assessment of Alzheimer’s Disease. Neurology, 48, 1508-1510.
Newton, Herbert B. (1999). Neurologic complications of systemic cancer. American
Family Physician, 59 (4), 878-886.
Oxman, Thomas E., Schnurr, Paula P., & Silverfarb, Peter M. (1986). Assessment of
cognitive function in cancer patients. Hospice Journal—Physical, Psychosocial, and
Pastoral Care o f the Dying, 2(3), 99-128.
Paganini-Hill, Annlia, & Clark, Linda J. (2000). Preliminary assessment of
cognitive function in breast cancer patients treated with tamoxifen. Breast Cancer
Research and Treatment, 64, 165-176.
Pfeiffer, E. (1975). A Short Portable Mental Status Questionnaire for the assessment
of organic brain deficits in elderly patients. Journal o f the American Geriatrics
Society, 23, 433-441.
Schagen, Sanne B., van Dam, Frits S. A.M., Muller, Martin J., Boogerd, Willem,
Lindeboom, Jaap, Bruning, Peter F. (1999). Cognitive deficits after postoperative
adjuvant chemotherapy for breast carcinoma. Cancer, 85, 640-650.
Silverfarb, Peter M. (1983). Chemotherapy and cognitive defects in cancer patients.
Annual Review o f Medicine, 34, 35-46.
Silverfarb, Peter M., & Oxman, Tomas E. (1988). The effects of cancer therapies on
the central nervous system. Advances in Psychosomatic Medicine, 18, 13-25.
Silverfarb, Peter M., Philibert, Dawn, & Levine, Peter M. (1980). Psychosocial
aspects of neoplastic disease: II. Affective and cognitive effects of chemotherapy in
cancer patients. American Journal o f Psychiatry, 137 (5), 597-601.
Sjogren, P. (1997). Psychomotor and cognitive functioning in cancer patients. Acta
Anaesthesiologica Scandanavica, 41, 159-161.
Sjogren, P., Olsen, A.K., Thomsen, A.B., & Dalberg, J. (2000). Neuropsychological
performance in cancer patients: the role of oral opioids, pain and performance status.
Pain, 86, 237-245.
42
Reproduced with permission of the copyright owner. Further reproduction prohibited without permission.
Troy, L., McFarland, K., Littman-Power, S., Kelly, B J., Walpole, E.T., Wyld, D., &
Thomson, D. (2000). Cisplatin-based therapy: a neurological and neuropsychological
review. Psycho-Oncology, 9, 29-39.
Tuxen, Malgorzata K., & Hansen, Steen Wemer. (1994). Neurotoxicity secondary to
antineoplastic drugs. Cancer Treatment Reviews, 20, 191-214.
van Dam, Frits S.A.M., Schagen, Sanne B., Muller, Martin J., Boogerd, Willem, v.d.
Wall, Elsken, Droogleever Fortuyn, Maria E., & Rodenhuis, Sjoerd. (1998).
Impairment of cognitive function in women receiving adjuvant treatment for high-
risk breast cancer: high-dose versus standard-dose chemotherapy. Journal o f the
National Cancer Institute, 90 (3), 210-218.
Walker, L.G., Wesnes, K.P., Heys, S.D., Walker, M.B., Lolley, J., & Eremin, O.
(1996). The cognitive effects of recombinant interleukin-2 (rIL-2) therapy: a
controlled clinical trial using computerized assessments. European Journal o f
Cancer, 32A (13), 2275-2283.
Weller, Roy O., & Preston, Stephen D. (2001). The spectrum of vascular disease in
dementia: from ischaemia to amyloid angiopathy. In Tolnay and Probst (Eds.),
Neuropathy and Genetics o f Dementia (pp.111-122). New York: Kluwer
Academic/Plenum Publishers.
Wieneke, Mary H., & Dienst, Evelyn R. (1995). Neuropsychological assessment of
cognitive function following chemotherapy for breast cancer. Psycho-Oncology, 4,
61-66.
43
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Heflin, Lara Heather
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Cognitive functioning and dementia following cancer: A Swedish twin study
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