Critical Reviews in Oncology/Hematology 65 (2008) 143155

Depression and cancer: An unexplored and unresolved

emergent issue in elderly patients
Ilaria Spoletini a , Walter Gianni b , Lazzaro Repetto b , Pietro Bria c ,
Carlo Caltagirone a,d , Paola Boss`u a , Gianfranco Spalletta a,d,
a
IRCCS Santa Lucia Foundation, Rome, Italy
b IRCCS INRCA, Rome, Italy
c Catholic University of the Sacred Heart, Rome, Italy
d Tor Vergata University, Rome Italy

Accepted 24 October 2007

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.1. Search limits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
2.2. Selection process. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
3. Diagnosis of depressive disorders in psychiatry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 144
4. Phenomenology of depression in the elderly . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5. Mood disorders in elderly patients with cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.1. Epidemiology and risk factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 146
5.2. Phenomenology of depressive disorders in elderly patients with cancer: the problem of comorbidity and its assessment . . . 147
5.3. Suicide in elderly people with cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147
6. Common biological basis among depression, cancer and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 148
7. Treatment, cancer and depression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 150
8. Conclusions and considerations for upcoming studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 151
Reviewers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 152
Biographies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 155

Abstract
Despite the high prevalence of depressive disorders in cancer patients and elderly people, the topic of depression in elderly cancer patients
still remains unexplored. This emerges from a systematic review of the literature conducted to investigate issues of depression, diagnosis,
pathogenesis, treatment and their complex neuroimmunobiological interactions. Indeed, it becomes apparent that depression in elderly patients
with cancer may have a peculiar phenomenology. In addition, the moderate rate of major depressive disorder and the high rate of minor
depressive disorder are accompanied by subthreshold forms of depression that are at risk to be underecognized and untreated. Immune
dysfunction may represent a common pathogenic ground of depression, cancer and aging. This may have important implications for treatment.
In the near future, we need to develop validated mood disorder diagnoses and verify antidepressant treatment efficacy for elderly cancer patients
with depression in order to improve their clinical outcome and quality of life.
2007 Elsevier Ireland Ltd. All rights reserved.

Keywords: Major depression; Minor depression; Cancer; Elderly; Immunology

Corresponding author at: IRCCS Santa Lucia Foundation, Neuropsychiatry Laboratory, Via Ardeatina 306, 00179 Rome, Italy. Tel.: +39 06 51501575;

fax: +39 06 51501575.

E-mail address: g.spalletta@hsantalucia.it (G. Spalletta).

1040-8428/$ see front matter 2007 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.critrevonc.2007.10.005
144 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
1. Introduction
Cancer in the elderly has become an increasingly com-
mon problem [1]. Indeed, epidemiologic studies describe that
about 60% of all malignancies occur in people aged 65 years
or older [2], and if the current demographic trends continue,
it can be estimated that by 2020 about 70% of all cancers will
be diagnosed in those aged 65 years or older [3].
One out of two cancer patients report psychiatric disorders,
especially depression [47]. At the same time, depression
is a burdensome problem even in elderly people [8]. Thus,
depression is highly prevalent both in cancer and in the elderly
[9,10]. Consequently, depression appears to be a relevant
problem in elderly people with cancer, but the topic of mood
disorders in geriatric patients with cancer still remains unex-
plored and unresolved. In particular, we have to clarify the
biological mechanisms explaining the high comorbidity rate
between cancer and the elderly, depression and the elderly,
and consequently cancer and depression in the elderly popu-
lation. This insight may also open a new avenue for treatment.
The objective of this paper is to review the existing lit-
erature regarding the relationships between aging, cancer
and depression, in order to propose an integrated point of
view about depression and cancer in elderly patients. This
purpose was pursued with a multidisciplinary approach by
performing: (1) a critical analysis of currently used diagnos-
tic criteria for mood disorders; (2) a preliminary description
of depressive symptoms specific for the general elderly popu-
lation and in particular for the subgroup of elderly depressed
patients suffering of cancer; (3) an analysis of the current
data on epidemiology and outcome of depressive disorders;
(4) a summary of the biological mechanisms shared by cancer
and depression in aging population, with particular emphasis
on immune-mediated pathways; and finally (5) a review of
published data on depression treatment.
2. Methods
2.1. Search limits
In order to clarify the status of the art in the topic of
mood disorders in geriatric patients with cancer, we con-
ducted detailed searches of the published medical literature
with a review of the Medline (PubMed) databases.
Article inclusion criteria were as follows: (1) period of
publication between January 1980 and January 2007; (2)
subject mean age of 65 years and older; (3) articles with
a specific focus on depression in elderly people. Exclusion
criteria were: (1) articles not written in English; (2) arti-
cles with a primary focus on medical symptoms (e.g. sexual
dysfunction; anorexia or malnutrition; dysphonia or hear-
ing disorders, etc.), social factors (e.g. social support or
social stigma), or other conditions that can be secondarily
associated to depression (e.g. cognitive impairment, symp-
tom beliefs, coping resources); (3) articles with a primary
focus on outcome (quality of life or adjustment); (4) articles
with a primary focus on survivorship because of the peculiar
symptom-intense experience during terminal care.
For our purposes, we used various combinations of the fol-
lowing keywords: elderly, aging, geriatric, cancer,
depression and mood disorders.
2.2. Selection process
Search terms were used to extract records limited to the
issue of depression in elderly people. A paper was consid-
ered for inclusion if all the above-mentioned criteria were
satisfied.
An additional search was performed to identify papers
specifically focused on depression in elderly patients with
cancer. In this second stage, we chose only papers strictly
adherent to the keywords depression, elderly (or aging)
and cancer. The criterion of adherence to the keywords
of a paper was defined as the presence of all the above-
mentioned keywords in either the text or the abstract.
Eventually, we considered cross-references and review
articles reported in the different papers collected. Concep-
tually related articles were included as well. A paper was
considered as conceptually related to the issue of depres-
sion in elderly patients with cancer if it contained a source
of information (i.e. data, models or hypotheses) on a topic
that has been reported in literature to be related to the above-
mentioned keywords (e.g. immunological dysfunction).
Thus, 30.076 articles were selected by matching the key-
words depression and elderly, 6.020 by depression and
cancer, 2.098 by depression and cancer and elderly.
In particular, among these last 2098 articles picked out by
the computer, only 58 papers were initially selected by I.S.
and G.S. as possible candidates for the review because they
met the above-mentioned criteria of search limits and selec-
tion process. Only eight of the selected papers were strictly
connected with the topic of depression in elderly patients
with cancer: Bernabei et al. [11]; Charlson and Peterson
[12]; de Jonge et al. [13]; Labisi [14]; Labisi [15]; Llorente
et al. [16]; Rao and Cohen [17]; Roth and Modi [18]. All
other articles cited in the review were conceptually corre-
lated. Such discrepancy in the amount of articles selected by
the computer-search and articles considered relevant to our
aims after the complete selection process suggests that this
issue is often approached by a point of view not primarily
mood-oriented.
3. Diagnosis of depressive disorders in psychiatry
The Diagnostic and statistical manual of mental disor-
ders, 4th ed., text revised (DSM-IV-TR) [19], the most used
diagnostic manual in psychiatry, categorizes Depressive
Disorders within the wider section of Mood Disorders,
which also includes bipolar disorders. The depressive disor-
ders are distinguished from the bipolar disorders because of
 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
Table 1
Detailed list of DSM-IV-TR symptoms for depressive disorders diagnosis
Symptoms
1. Depressed mooda,b,c
2. Anhedoniaa,b
3. Appetited,b,c or weight changed,b
4. Sleep disturbanced,b,c
5. Increased or decreased psychomotor
activityd,b
6. Decreased energyd,b,c
7. Guilt or feelings of worthlessnessa,b
8. Decreased concentratione,b,c
9. Suicidal ideationa,b
10. Low of self-esteema,c
11. Hopelessnessa,c
DSM-IV-TR: Diagnostic and Statistical Manual of Mental Disorders, 4th ed., text revised.
a Psychological symptom.
b Major and minor depressive disorder symptom.
c Dysthymic disorder symptom.
d Somatic symptom.
e Cognitive symptom.
the absence in subjects history of a manic, mixed or hypo-
manic episode. In other words, unlike depressive disorders,
bipolar disorders are characterized by two poles: depressed
mood and mania (i.e. euphoria, heightened emotion and
activity). The depressive disorders include major depressive
disorder (MDD), dysthimic disorder (DD) and depressive dis-
order not otherwise specified (NOS). MDD is characterized
by one or more major depressive episodes, i.e. 2 weeks or
more of symptoms, present most of the day, nearly every
day, of depressed mood or loss of interest accompanied by
four or more additional symptoms of depression described in
Table 1, which cause significant functional impairment.
DD is characterized by a longer period (at least 2 years) in
which the depressed mood symptom is present for more days
than not, and is accompanied by two or more of the follow-
ing: poor appetite or overeating, insomnia or hypersomnia,
low energy or fatigue, low self-esteem, poor concentration or
difficulty making decisions, feeling of hopelessness. Within
the residual category of depressive disorder NOS, that is
used when depression is present and clinically relevant but
criteria for MDD or DD are not met, a category called
Minor Depressive Disorder (MIND) is included. MIND
is characterized by one or more periods in which depres-
sive features are identical to MDD in duration but which
involve fewer symptoms, at least two but less than five, of
which one is sad mood or loss of interest or pleasure in
activities.
In particular, MIND possibly includes those depressive
syndromes that do not fulfil standard diagnostic criteria for
MDD, but that appear to be of extreme relevancy in the topic
of mood disorders in elderly patients and/or in patients with
medical comorbidity. Indeed, though most elderly people do
not fulfill diagnostic criteria for MDD or DD, they mani-
fest clinically significant depressive symptoms that have been
145
Description
Significant unpleasant mood with feelings of sadness or emptiness and/or appearance of
tearfulness
Significantly reduced level of interest or pleasure in most or all activities
Substantial increase or decrease in appetite nearly every day or unintentional weight loss or
gain (e.g. 5% or more change of weight in a month when not dieting)
Difficulty falling or staying asleep (insomnia), or sleeping more than usual (hypersomnia)
Behavior that is agitated or slowed down. Others should be able to observe this
Feeling fatigued, or diminished energy
Feelings or thoughts of worthlessness or excessive guilt (not about being ill)
Diminished ability to think or concentrate, or make decisions
Frequent thoughts of death or suicide (with or without a specific plan), or attempt or suicide
Feelings of being uninteresting or incapable
Feelings of discouragement and pessimism, i.e. no hope for the future
described in literature as minor, subsyndromal or subthresh-
old depression [20].
The other two categories included in the mood disorders
section are based on their primary biological etiology, and
are: mood disorder due to a general medical condition, and
substance-induced mood disorder. In the case of a prominent
and persistent disturbance in mood, which is a direct physio-
logical consequence of a general medical condition, we can
diagnose a mood disorder due to a general medical condi-
tion. The mood disturbance must be etiologically related to
the general medical condition through a careful assessment
of several factors, such as temporal association between the
onset, the exacerbation or remission of the general medical
condition and of the mood disturbance.
There are, however, forms of depression which may be
present in patients with medical comorbidity but which
are Subsyndromal or Subthreshold. To highlight the
occurrence of these subsyndromes is very important for our
purposes because they are very often observed in cancer
patients. However, subthreshold depressions are below the
threshold of even MIND diagnosis and therefore they may
be underecognized.
In particular, subthreshold symptoms of depression have
been considered in literature in different ways: as prodromes,
because they have been found to predict the onset of an
episode of major depression [21], or as residual symptoms
after recovery from an earlier episode; finally, the subthresh-
old depression may constitute an independent condition [22].
This diagnostic construct has been well confirmed in the
elderly population [23], and there is evidence that older
patients with subsyndromal depression experience greater
severity of medical illnesses [24] and greater functional dis-
ability [25] in comparison with patients without depression.
Again, it is important to emphasize that despite the high rate
146 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
of subsyndromal depression in the general population, it is not
considered as a specific diagnostic entity in the DSM-IV-TR.
Thus, these more subtle but invalidating forms of depressive
disorders are at risk of being untreated.
A further possible limitation of the DSM-IV-TR catego-
rization in cancer patients is that it does not consider different
depressive disorders in young and in elderly people, with or
without medical comorbidity. Indeed, depression in the medi-
cal population as well as in elderly people could have specific
clinical features.
4. Phenomenology of depression in the elderly
Studies on mood disorders in aging people are focused on
unipolar depressive disorders because of the higher preva-
lence of depression versus bipolar disorder in the elderly [9].
Community studies indicate that 25% of elderly people report
having depressive symptoms, but less than 10% meet the
criteria for MDD [26]. In particular, MIND and subthresh-
old depression are highly prevalent in elderly people, may
have consequences on patients functioning, and are at risk of
being underecognized [27,28]. In fact, depressive symptoms
occurring in late-life often go underdiagnosed and untreated
[29], in part because they are erroneously assumed to be a
physiological response to aging, physical losses or other life
events which are common in elderly people [30]. In addi-
tion, depression is often difficult to identify because elderly
depressed patients may not manifest sad mood or promi-
nent anhedonia, which are the core symptoms of unipolar
mood disorders [10]. Another factor complicating diagnosis
of mood disorders in the elderly is the heterogeneity of their
clinical manifestations. Indeed, Alexopoulos and colleagues
[10,31] demonstrated that elderly people who have the onset
of the first depressive episode in late-life constitute a hetero-
geneous group of patients with higher medical burden and
neurological disorders, compared to people who suffer from
mood disorders with early-onset. In fact, in the former group,
depression appears when aging-related changes are promi-
nent, and the occurrence of brain abnormalities and cognitive
impairment may influence the development of depression
[10].
Since the prevalence of geriatric depression is much higher
in the medical setting than in the community [32], and con-
sidering that unrecognized and untreated mood disorders in
aging people may probably be the cause of disability and
suffering for patients and caregivers, these issues appear to
be of extreme relevance in the specific topic of comorbid-
ity with cancer in old age. Indeed, late-life depression often
affects individuals with other medical and/or psychosocial
problems [33]. Studies have found that depression in the
elderly is a risk factor for morbidity and poor quality of
life [8,3436], increased non-suicide mortality [37,38], and
poor recovery after a medical illness [8,39,40]. Furthermore,
depressive symptoms have been identified as predictors of
poor adjustment after a somatic event [8]. Thus, there is an
increased attention on the effect of depressive symptoms in
several somatic illnesses, and there is an agreement on the
fact that medical comorbidity is a risk factor for depression
as well as vice versa [9].
5. Mood disorders in elderly patients with cancer
5.1. Epidemiology and risk factors
Despite the growing awareness in the oncological commu-
nity about the size of the problem of depression in geriatric
patients with somatic illnesses, there are no studies specif-
ically focused on epidemiology of depressive disorders in
elderly cancer patients. However, a recent longitudinal study
by de Jonge et al. [13] analysed prevalence, persistence, and
risk factors of depression in a large sample of elderly subjects
suffering from one of the following somatic illnesses: cancer,
myocardial infarction, congestive heart failure, or fall-related
injury of the extremities. Although specific data for cancer
patients have not been reported, this study is relevant for
having investigated depressive symptoms in a large sample
of elderly patients with several somatic illnesses. Authors
found that the presence of depressive symptoms significantly
increased after the somatic illness. In particular, 38% of the
whole sample experienced significant depressive symptoms
at one of the follow-up assessments. Notably, 49% of this sub-
group with depression reported mild symptoms, 38% moder-
ate symptoms and only 13% severe symptoms. Thus, almost
all patients (about 87%) who reported mood changes suffered
from a mild or moderate symptomatology, confirming the
relevance of subsyndromal depression in elderly people with
somatic illnesses, including cancer. In addition, the majority
of patients (67%) had persistent depressive symptoms. This
study identified several independent risk factors for devel-
oping depression, i.e. age, smoking, self-reported well-being
and general health, baseline depressive symptoms, neuroti-
cism; whereas the risk factor for the persistence of depression
during time was neuroticism only. Neuroticism can be con-
sidered as a subjects tendency to emotional instability and is
a well-known risk factor of depression also in general popu-
lation [41], as well as in children and adolescents [42]. Thus,
authors conclude that the relationship between depressive
symptoms, somatic illness, and age is mediated by the pre-
morbid vulnerability to mood liability. Indeed, consistently
with the dynamic stress-vulnerability model [43], neuroti-
cism could be considered as a marker of psychobiological
vulnerability, or frailty, in elderly people. Neuroticism
could enhance the risk of onset of depression as well as
its persistence, by the amplification of stressful effects of
life events, leading to an increased and persistent depressive
reaction after a somatic illness. In our opinion, this hypothe-
sis is consistent with findings from general cancer population
studies, suggesting that one of the factors modulating the rela-
tionship between cancer and depression is the individuals
management of the distress due to the illness [4447].
 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
5.2. Phenomenology of depressive disorders in elderly
patients with cancer: the problem of comorbidity and its
assessment
The elderly patient with cancer appears as a vulnerable
or frail individual [48], burdened with additional difficulties,
for instance in carrying out daily activities such as cleaning,
cooking, shopping and self-care [18]. In addition, cogni-
tive impairment may occur concurrently with depression
in elderly cancer patients, complicating its phenomenology.
Furthermore, there is preliminary evidence in literature about
an association of depression and other psychological/somatic
symptoms, in this population. A study by Bernabei et al. [11]
investigated the relationship between depression and pain in a
large sample of elderly patients with cancer, finding that aging
patients with depression are more sensitive to pain due to
cancer. These data are consistent with studies on non-cancer
institutionalised elderly people affected by different medical
conditions [4952]. Notably, the presence of pain increases
the prevalence of depression in cancer patients [53], who
complain not only of more depressive disorders, but also of
anxious and somatic symptoms, compared to patients without
pain [54,55]. Indeed, it has been argued that anxiety disor-
ders associated with pain in elderly cancer patients decreased
after treatment with analgesics [18]. The link between pain
and depression appears to be bidirectional. On the one hand,
there is strong evidence that pain causes depression in can-
cer patients [9,53,56,57]. On the other hand, there are studies
suggesting that depression and anxiety, in particular during
the course of illness, reinforce pain by increasing its intensity
[54,58,59].
Another symptom related to both pain and depression in
cancer patients is fatigue [60], which is also reported by aging
cancer patients [17]. From studies on cancer patients, it is
well established that fatigue correlates significantly with level
of depression [6062], and that these two conditions share
several common features. In fact, some demographic vari-
ables (i.e. younger age, female gender), medical features (i.e.
prior surgery, distant metastases and cancer site), and psycho-
logical factors (i.e. increased anxiety, anger and confusion)
have been found to be related to higher levels of fatigue and
depression in cancer patients [63].
The relationship between depression, pain and fatigue
has been reviewed by Rao and Cohen [17], focusing on its
relevance for elderly patients with cancer. Although these
symptoms could be distressing for aging cancer individu-
als, little is known about possible interactions and effects.
According to the authors, diagnosis and management of
depression, pain and fatigue require further research on bio-
logical age-related changes, in order to clarify how aging
interacts with these symptoms to generate a distinctive con-
dition in elderly cancer patients. Despite the high rate of
comorbidity in elderly patients with cancer, studies on the
relationship between depression and clinical outcome often
do not take comorbidity into account, as observed by Charl-
son and Peterson in their review [12].
147
Furthermore, many somatic symptoms of depression, such
as anorexia, weight loss, low energy and sleep disturbances,
are similar to those of cancer itself [64], therefore they may
easily be misattributed to cancer and not to depression [65].
Thus, several authors have proposed to exclude these somatic
symptoms from depression diagnosis in cancer patients [66]
or to substitute them with other non-somatic symptoms [67].
In particular, four major approaches have been proposed to
assess mood symptoms in cancer patients [68]: (i) an inclu-
sive approach, in which depressive symptoms are considered,
even if they may be related to the physical illness; (ii) an eti-
ologic approach, which considers symptoms of depression
only if they are assessed by the interviewer not to be the result
of physical illness; (iii) a substitutive approach, which substi-
tutes psychological symptoms instead of somatic symptoms
of depression and (iv) an exclusive approach, which consid-
ers only those symptoms that have been demonstrated to be
more frequent in depressed than in nondepressed patients.
A study by Ciaramella and Poli [64] suggests that a com-
bination of these approaches, for instance using both the
etiologic and substitutive methods, is more accurate in identi-
fying depressed individuals with cancer. Unfortunately, such
comprehensive approach is unlikely to be used in research
studies, and, in particular, in the clinical practice because of
several practical limitations, such as time constraints [68].
Therefore, a quick but accurate approach that allows the
identification of mood disorders in cancer patients should
be employed. For this purpose, even the use of biomarkers
(i.e. the cortisol profile, indicating the presence of alterations
in the hypothalamic-pituitary-adrenal (HPA) axis) has been
suggested [69].
Thus, taking into account the described difficulties in iden-
tifying depression in the elderly patients with cancer and its
peculiar phenomenology, the assessment of depressive symp-
toms in this population requires an overall approach in order
to identify all physical, emotional, and psychological aspects
of depression, as well as a specific assessment of signs of
suicidality [14,15].
5.3. Suicide in elderly people with cancer
Chronic medical illnesses have been found to be asso-
ciated with an increased risk for suicide in elderly people
[7072,16]. There is only one study exploring the issue of
suicide in aging patients with cancer, by Llorente et al. [16].
Authors performed a population-based, retrospective study
of men aged 65 years and older, residing in South Florida
between 1983 and 1993, in order to determine the inci-
dence of suicide among prostate cancer patients. Authors
found that 20% of all the suicides were cancer-related.
Notably, prostate cancer accounted for 15% of all the cancer-
associated suicides and for 3% of all suicides in this age- and
gender-specific population. The risk of committing suicide
was four-fold higher in men with prostate cancer in this
sample. Since the prognosis for prostate cancer is generally
good, these findings appear to be surprising. However, as
148 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
argued by the authors, the treatment for this type of cancer
may involve issues about sexuality, sense of maleness, and
self-esteem, with deleterious consequences on mood [16]. In
addition, some clinical correlates of suicide were identified,
such as comorbid anxiety symptoms, depressive symptoms,
pain related to cancer and marital status. Thus, authors con-
clude that older men with prostate cancer are at increased risk
for committing suicide, especially if they manifest depres-
sion, anxiety symptoms and untreated pain. Therefore, an
increased awareness of the psychiatric effects of the cancer
diagnosis, and assessment and treatment of depression and
pain may be important preventive measures [16].
6. Common biological basis among depression,
cancer and aging
Since elderly patients with cancer are at increased risk of
depression, the study of the common molecular mechanisms
involved in the pathogenesis of both cancer and depression,
in association with the physiologic changes due to aging,
may lead to the identification of the interrelatedness of these
diseases and their causal relationships, and therefore provide
a valuable tool for new strategy of clinical intervention.
Despite aging cannot be considered directly responsible
for the neoplastic processes, the incidence of cancer gener-
ally increases with age, even though the latter may positively
or negatively influence the susceptibility to carcinogenesis
in different tissues. The cellular and molecular mechanisms
underscoring the link between cancer and aging have been
efficaciously summarized in several reviews [7375]. Inter-
estingly, besides mutation burden, telomere dysfunction,
impairment of DNA repair and alterations in proliferative
homeostasis, several disturbances in the immune system have
been consistently described in aging [76]. The immune sys-
tem is aimed to defend the host from any insult (exogenous or
endogenous) that may threat the body, by means of cellular
and humoral effectors (cytotoxic immune cells and antibod-
ies, respectively). The earlier and quickest mechanism of
the immune reaction is the triggering of the inflammatory
response and the activation of innate immunity mechanisms.
This primary, nonspecific response is directed to eliminate
the insulting agent, to initiate a more specific, long lasting
and adaptive immune activation, and to concomitantly restore
physiological homeostasis and promote tissue repair. How-
ever, in order to function properly, this network of immune
mechanisms needs a tight regulation. In fact, if inflammation
becomes unrestrained, for instance, it may eventually exert
a large range of deleterious effects in the host. The princi-
pal orchestrators of the immune response are T lymphocytes,
which differently modulate both the cellular and the humoral
responses by secreting several cytokines, the hormone-like
soluble mediators of the immune homeostasis. Distinctive
patterns of cytokines are produced by different subsets of
T helper (Th) lymphocytes with diverse functions (e.g. Th1
and Th2). Hence, Th1 are able to mainly produce interleukin
(IL)-2, interferon (IFN)-, IL-12 and IL-18 and promote cel-
lular immunity; while Th2 produce IL-4, IL-5, IL-6, IL-10,
IL-13, and transforming growth factor (TGF)- and favour
the humoral immune response. Th1 and Th2 cytokines that
are crucial in regulating the type of immune response and the
extent of inflammation, can antagonize each other, and an
imbalance in Th1/Th2 cytokines is often associated to sev-
eral common diseases. In aging, both immunosenescence,
the progressive decline in immune function resulting in an
increased susceptibility to infections and cancer [77], and
a generalized increase of immune-inflammatory response
[78] have been described. In particular, there is evidence
that immunosenescence may favour the development of
cancer in cases of lymphomas and other highly immuno-
genic tumors [79]. Overall, both cell-mediated and humoral
immune responses are affected by aging, with a downregu-
lation of specific immunity and a nonspecific activation of
pro-inflammatory pathways. In addition, a general decrease
in functioning of lymphocytes characterized by a Th1 decline
and a shift of adaptive humoral response to a nonspecific,
natural antibody-mediated immunity is observed in aged sub-
jects [80,81]. On the other hand, aging is also associated with
a low-grade chronic inflammation. In fact, elevated circulat-
ing levels of pro-inflammatory mediators, including IL-1,
tumor necrosis factor (TNF)-, IL-6 and IL-18 are suggested
to play an important role in the process of aging [8285].
Similar immune dysregulations are also observable in can-
cer, where a persistent humoral immune response exacerbates
the activation of innate immune response and inflammatory
pathways, which concur in promoting cancer development
[86,87]. Thus, since chronic inflammation and, in particu-
lar, the release of pro-inflammatory cytokines is strongly
associated with processes that contribute to the onset and
progression of cancer, the association between aging and
cancer seems to directly involve immune dysregulation and
pro-inflammatory cytokine up-regulation.
Interestingly, immune dysregulation can also be con-
sidered as one of the factors explaining the link between
depression and cancer. In fact, a predominant activation of
innate immune cells has been described also in depressive
disturbances. Indeed, two well-known physiologic correlates
of depression are decrease in cell-mediated immune function
and alterations in the activity of HPA axis, which is asso-
ciated with the levels of pro-inflammatory cytokines. From
research studies performed in the general population, we
know that these physiologic correlates of depression may
adversely affect the health status. Thus, although depres-
sion can be a secondary manifestation of cancer, it also
appears possible that, from a biological point of view, a
depressive state may favour the development of a cancer,
as reported by Reiche et al. [88], who reviewed how stress
and depression may influence the risk and the progression
of cancer trough neuroendocrine-immune-mediated mech-
anisms. In particular, depressed subjects show a reduction
of both viral and antigen specific measures of cell-mediated
immunity [8991] and a reduced ability of T cells to mount an
 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
antigen-specific response such as those necessary to combat
viruses, bacteria and tumors [9294]. Therefore, depres-
sive symptoms appear to be associated with poorer cellular
immune function across several domains [9]. These data have
been confirmed also in cancer patients. In women with cancer,
severity of depression may reduce the number of leukocytes
over short periods of time [95] and depressive symptoms are
predictors of both lower white blood cell counts and natural
killer cell number [95,96]. Similarly, cytokine dysregula-
tion has been largely associated with depression [9799] and
serum levels of pro-inflammatory cytokines including IL-1,
TNF-, IL-6 and IL-18 are all elevated in depressed patients
[100102]. Indeed, several studies investigating the inter-
actions between immunity and depressive symptoms, have
suggested that a dysfunction of the innate immune system
is a relevant contributor factor to the onset and maintenance
of depressive disorder [103,104]. The relationship appears to
be reciprocal, in the sense that immune activation may alter
mood, and a depressed state may affect immune function-
ing [105,106]. In particular, exposure to certain cytokines
such as IL-1, leads to a complex constellation of symptoms
that are similar to those of a depressive state (i.e. anhe-
donia, decreased sexual/social activity, sleep abnormalities,
decreased feeding and motor behavior, anxiety, diminished
intracranial self-stimulation) [105,107,108]. In addition,
cytokine exposure leads to neuroendocrine changes analo-
gous to those observed in individuals with depression, such
as increased corticotropin-releasing factor (CRF), adreno-
corticotropic hormone (ACTH), and corticosterone levels
[109], alterations of the monoaminergic system [105] and
decreases in brain-derived neurotrophic factor (BDNF) [110].
Another possible effect of cytokine release is the increase of
HPA activity [105], suggesting a cross-sensitization between
stress and cytokine production [106]. It has been hypothe-
sized that the inflammatory response, together with the stress
response, is involved in the survival of the organism and
the species. Therefore, immune disturbances, such as the
Fig. 1. Bidirectional mechanisms of interaction between aging, cancer and depression. Aging is associated with altered cellular (Th1) and humoral (Th2) immune
function, and pro-inflammatory cytokine up-regulation. These immune dysfunctions, mainly mediated by stress-related stimuli through neuroendocrine (HPA)
modulation, appear to be a central biological process in the interaction of aging with cancer and depression. Sympathetic/parasympathetic deregulation may
alter the homeostasis.
149
chronic inflammation state, may influence several aspects of
the individuals well being and they may be linked to the
pathogenesis of several common diseases, including cancer
and depression [111]. Cytokines are crucial in inflammatory
responses, and a disturbance at the neuroendocrine-immune
interface may imply a cytokine network imbalance, leading
to an excessive production of pro-inflammatory cytokines.
Accordingly, further evidence of the link between depres-
sion, cancer and immune dysregulation is that cytokines can
be considered reliable biomarkers for depression in cancer,
as in the case of IL-6, whose plasma concentrations are sig-
nificantly increased in depressed patients with cancer [69]
and, interestingly, pharmacological doses of cytokines in can-
cer patients have an effect on maintenance of depression
[112]. Thus, although more research is needed to clarify
the link between such measures of immunity and clinically
relevant immune function [9], there is preliminary evidence
for a directional relationship between depressive symptoms
and dysregulation of the immune system in cancer patients.
Moreover, some immunological dysfunctions have also been
described in elderly patients with depression and since both
depression and aging undoubtedly affect immunity, this link
appears to be quite meaningful. Hence, elderly depressed
patients are characterized by a history of increased expo-
sure to Cytomegalovirus, which could have resulted in a
pro-inflammatory profile [113] and these changes, in turn,
negatively affect immune response in depressed patients.
Accordingly, aged subjects are at greater risk for cytokine-
induced depressive symptoms [103,114], although it is also
possible that the action of depressive symptomatology on the
immune system causes an exacerbation of the illness.
Therefore, aging, in virtue of its ability to alter immune
competence and promote inflammation, can have an impact
on mechanisms by which both cancer and depression develop
and progress. Aging can be thus considered as a common
risk factor for both depression and cancer, as summarized in
Fig. 1.
150 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
Altogether, these observations imply that the study on
association of cancer and age involves both biological and
clinical challenges, especially taking into account the role of
depressive disorders that seem to share part of the described
pathogenic mechanisms, including immune dysregu-
lation.
7. Treatment, cancer and depression
The complexity of care in geriatric patients with cancer
makes it highly challenging to determine which treatments
are effective for depression in this population. Indeed,
because of the above-described pathogenic mechanisms,
depression in elderly patients with cancer manifests distinc-
tive characteristics from other age groups. Consequentially,
an appropriate and specific therapeutic approach in the
elderly should differ from other age groups.
In reality, in clinical practice, the procedure for the assess-
ment and the treatment of depressive symptoms in elderly
cancer patients are largely based on data obtained from the
general medical population [115]. This is because, unfortu-
nately, the treatment of depression among cancer patients has
received insufficient attention, particularly in the old age pop-
ulation but also in other age-ranges [115]. However, results
are encouraging because, despite the paucity of randomized
placebo-controlled trials, there is preliminary evidence that
depressive disorders in cancer patients can be successfully
treated with antidepressants, as summarized by Williams and
Dale [116].
The SSRI paroxetine has been found to be effective in
reducing depressive symptoms in patients with different types
of cancer [117119]. In the Roscoes double-blind random-
ized placebo-controlled trial [117], the sample consisted of 94
females with breast cancer receiving no less than four cycles
of chemotherapy and not undergoing concurrent radiation or
interferon treatments. Paroxetine 20 mg/day was found to be
more effective than placebo in improving depressive symp-
toms and reducing MDD rate during chemotherapy. In the
Morrows single-blind randomized placebo-controlled trial
[118] the sample consisted of 549 patients with a diagnosis
of breast, lung, hematological, gynecological or gastrointesti-
nal cancer, reporting fatigue at their second chemotherapy
cycle. Paroxetine 20 mg/day for 8 weeks was found to be more
effective than placebo in ameliorating depressive symptoms
during chemotherapy. In the Musselmans double-blind ran-
domized placebo-controlled trial [119], the sample consisted
of 40 patients with malignant melanoma receiving high-dose
interferon alpha therapy. Paroxetine 2040 mg/day signifi-
cantly reduced depressive symptoms and the incidence of
MDD.
The SSRI fluoxetine has been found to be effective in
reducing depressive symptoms in advanced solid tumors
[120], but not in reducing MDD rate in a trial that included
patients with various cancer sites [121]. In the Fischs double-
blind randomized placebo-controlled trial [120], the sample
consisted of 163 patients with expected survival between 3
and 24 months. Fluoxetine-treated patients 20 mg/day for 12
weeks showed significantly lower depression severity at the
end of the follow-up. In the Razavis double-blind random-
ized placebo-controlled trial [121], the sample consisted of
91 patients with MDD. Fluoxetine 20 mg/day for 5 weeks did
not show any advantage over placebo on depression improve-
ment.
A very recent double-blind randomized placebo-
controlled study [122] on 189 participants with different
cancer sites indicated that, in patients without MDD, ser-
traline 50 mg/day was not effective in reducing depression,
fatigue and anxiety symptoms and in improving survival rate.
This study suggests that antidepressant treatment should be
limited to patients with proper indication, such as major
depressive disorder.
The efficacy of the tetracyclic mianserin has been demon-
strated in improving depressive symptoms in various types of
cancer [123,124]. In the double-blind randomized placebo-
controlled trial by van Heeringen and Zivkov [123] the
sample consisted of 55 patients with breast cancer, with a
diagnosis of unipolar depression. Mianserin 60 mg/day sig-
nificantly reduced depressive symptoms at 4 and 6 weeks
of follow-up. Similarly, in the Costas randomized placebo-
controlled trial [124], mianserin significantly improved
depressive symptoms in 73 women with various cancer sites
and a MDD diagnosis.
Thus, there is evidence that antidepressants may be effec-
tive in improving depressive symptoms in adult cancer
patients with MDD. However, more data are needed in order
to clarify both antidepressant efficacy and their side effects
and tolerability in cancer patients [116]. Unfortunately, no
strong conclusion can be drawn on the effectiveness of antide-
pressants for improving depression in elderly cancer patients,
given the absence of studies in this subgroup. Additional
methodological problems linked to the difficulty in enroll-
ment and to the high rates of dropouts in elderly cancer
patients should be considered.
Another aspect to keep in mind, complicating the
treatment of depression in cancer patients, is the delete-
rious effect that certain chemotherapeutic drugs have on
mood [125127]. Thus, the presence of depressed mood
in cancer patients may be induced by treatment with
chemotherapeutic agents, such as corticosteroids, used as
premedication or for treatment of lymphomas, and vinca
alkaloids such as vinblastine and vincristine, l-asparginase,
tamoxifen, alfa-interferon, procarbazine, and cyproterone
acetate [17,112,125]. However, effects of chemotherapy,
radiotherapy and hormonal therapy on depressive symptoms
in cancer patients, especially the elderly, need to be studied
further.
Finally, there are several barriers that limit cancer treat-
ment and management in the elderly, that is polypharmacy,
difficulties in the doctorpatient relationship such as lack of
treatment adherence, patient attitudes (i.e. anxiety) hinder-
ing treatment and social stigma. All these aspects influence
 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
the compliance of the patient to the overall medical approach
[75,128]. Thus, in order to provide a comprehensive treatment
strategy, a multidimensional assessment of elderly cancer
patients, that takes into account all the physiological, med-
ical, social, emotional and cognitive changes of aging, has
been proposed [129].
Because of the interrelation between depression and
cancer, it could be hypothesized that an effective psy-
chotherapeutic treatment of depression could improve the
course of the disease. As discussed by Spiegel and Giese-
Davis [44], there is evidence of both significant reduction
in depressive symptoms and increased survival time in
cancer patients after psychotherapy. For instance, a study
found that 1 year of supportiveexpressive group psy-
chotherapy not only reduced anxiety and depression, but
also pain, and increased survival time by an average of
18 months, among breast cancer patients [130]. Neverthe-
less, other studies found no effect of psychotherapy on
survival time of cancer patients [131,132]. However, as
pointed out by Spiegel and Giese-Davis [44], variables as
intervention timing, type, and duration of psychotherapy
are crucial in modifying cancer outcome. Depression may
affect the incidence or progression of cancer in several ways.
On the one hand, it could be argued that depression may
have an effect on compliance to medical treatment [133];
thus psychotherapeutic interventions would affect survival
simply by improving treatment adherence. On the other
hand, there is evidence that dysregulation in diurnal cor-
tisol patterns, which is associated with more rapid cancer
progression, becomes normalized during psychotherapeutic
treatment [134]. Thus, as we discussed above, and in line
with other authors [13,44,135], we can conceive depres-
sion as a chronic and maladaptive stress response, affecting
HPA and immune functioning. Psychotherapy may affect
aspects of endocrine and immune function that plausibly
enhance resistance to tumor progression and survival. Unfor-
tunately, to date, this issue has never been investigated
in depressed elderly people with cancer. As discussed by
Roth and Modi [18] a useful management of depression in
elderly cancer patients is given by a combination of support-
ive psychotherapy and cognitive-behavioral techniques, with
antidepressants if necessary. An antidepressant in elderly can-
cer patients should be chosen on the basis of several factors:
the patients overall health, cognitive abilities, social and
financial resources, comorbidity with other psychiatric con-
ditions, somatic variables (such as pain, fatigue, insomnia),
and previous familiar or personal response to antidepressant
treatment [18]. In addition, it is also important to con-
sider antidepressant side effects. In fact, some side effects
may be useful, for instance a tricyclic antidepressant such
as amitriptyline has found to be effective in neuropathic
pain treatment [136]. Finally, electroconvulsive therapy may
be indicated for elderly cancer patients that are refractory
to antidepressants, that are suicidal and/or psychotic, or
when the treatment with antidepressants is contraindicated
[18].
151
8. Conclusions and considerations for upcoming
studies
From a review of the literature on the topic of mood dis-
orders in elderly patients with cancer, several considerations
and suggestions for future studies may be drawn.
Firstly, the evaluation of depressive symptoms in elderly
cancer patients may be confounded by the overlap of
symptoms of depressive disorder and symptoms of cancer.
Therefore, further studies should focus on the distinction
between symptoms which are primarily derived from mood
disorders and those that are secondarily caused by cancer
or by side effects of the cancer treatment. In particular, it
is necessary to refine specific diagnostic criteria for depres-
sion in elderly cancer patients, and to develop instruments
for the assessment of depression severity, standardized for
aging patients, that can help to distinguish the relative con-
tribution of somatic or psychological dimensions. Indeed,
it is to be considered that the currently used depression
scales may be not valid for this special population of cancer
patients.
The second problem to solve is the use of DSM-IV-
TR categorical diagnosis of depression versus subsyndromal
diagnosis. Since there is strong evidence that subclinical lev-
els of depression are commonly reported in the elderly, a
subsyndromal diagnosis, which takes into account not only
MDD, but also MIND and subthreshold forms of depression,
appears to be more appropriate for elderly patients with can-
cer. Future studies should focus on the differential effect of
clinical and subclinical depression, in order to determine their
impact on quality of life, medical use and adherence to medi-
cal regimens [68]. Additional research is needed to determine
measures that reliably and validly differentiate individuals
with subclinical versus clinical depression.
Thirdly, there is a consensus on the fact that the evaluation
of depressive symptoms in aging patients with cancer can-
not disregard the role of comorbidity with other medical and
psychiatric conditions. In fact, depressed aging patients with
cancer often suffer from pain, fatigue, and are at an increased
risk of medical comorbidity. The impact of depression and
its association with other psychological/somatic symptoms
on long-term outcomes, need to be clearly documented in
elderly cancer patients.
Fourthly, the role of immune dysfunction as common
pathophysiologic ground of depression, cancer and aging
should be considered as an emergent issue in oncological
research. The most important implication arising from the
current biological findings is that a chronic depressive state
may favour the development and exacerbation of a cancer,
especially in elderly patients that are at increased risk of
immune dysregulation. Therefore, a careful assessment of
depression could be useful for cancer management in the
elderly. However, more research on this issue is needed, in
order to clarify the link between immunological dysfunc-
tions and clinically relevant depression in elderly patients
with cancer.
152 I. Spoletini et al. / Critical Reviews in Oncology/Hematology 65 (2008) 143155
Finally, since depression and cancer share the described
biological mechanisms, it is possible to hypothesize that
antidepressant drugs have a beneficial role not only on mood
disorders but also on cancer. Thus, upcoming research should
employ clinical controlled trials in order to understand which
antidepressant drugs may be indicated in depressed elderly
patients with cancer, and to obtain information on their effi-
cacy, tolerability, and moreover on their effect on cancer
outcome and consequently on patient quality of life.
In conclusion, with these clinical and biological chal-
lenges in mind, future research should aim to provide data
about the real prevalence and severity of mood disorders in
elderly patients with cancer, to increase our knowledge of
possible effects of depression on immune functioning and
cancer progression, and to draw specific guidelines for the
treatment of depressive symptoms in this population. For all
these reasons, higher commitment and much harder work are
necessary, in order to improve the quality of life of patients
and their caregivers.
Reviewers
Friedrich Stiefel, Professor, CHUV, University Hospital
Vaud, Psychiatry Department, 44 rue du Bugnon, CH-1011
Lausanne, Switzerland.
Panteleimon Giannakopoulos, Professor, Clinique de
Psychiatrie Geriatrique, Ch. du Petit-Bel-Air 2, CH-1225
Chene-Bourg, Switzerland.
Conict of interest
The authors have no conflict of interest.
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Biographies
Ilaria Spoletini is a neuropsychologist. Her scientific
activity is dedicated to the clinical assessment of neuropsy-
155
chiatric patients at the Neuropsychiatry Laboratory of the
IRCCS Santa Lucia Foundation in Rome.
Walter Gianni is a geriatrician at the Division of Geri-
atrics at the INRCA, IRCCS, Rome, and adjunct professor of
geriatrics at the La Sapienza University of Rome.
Lazzaro Repetto is an oncologist. He is the director of
the Division of Geriatric Oncology at the Istituto Nazionale
Ricovero e Cura Anziani (INRCA), IRCCS, Rome.
Pietro Bria is a neuropsychiatrist. He is associate professor
of psychiatry at the Catholic University of the Sacred Heart
in Rome.
Carlo Caltagirone is a neurologist and psychiatrist and
full professor of neurology at the Tor Vergata University of
Rome. He is the scientific director of IRCCS Santa Lucia
Foundation, Rome.
Paola Boss`u is an immunologist. She is the head of
the Neuropsychobiology Laboratory at the IRCCS Santa
Lucia Foundation in Rome and adjunct professor of phar-
maceutical biotechnology at the La Tuscia University in
Viterbo.
Gianfranco Spalletta is a psychiatrist and the head of the
Neuropsychiatry Laboratory at the IRCCS Santa Lucia Foun-
dation in Rome. He is adjunct professor of psychiatry at the
Tor Vergata University of Rome.