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www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGY

J Support Oncol 2010;8:412 2010 Elsevier Inc. All rights reserved.
R E V I E W
Manuscript submitted September 8, 2009;
accepted January 4, 2010
Correspondence to: Jimmie C. Holland, MD, Wayne E. Chap-
man Chair in Psychiatric Oncology and Attending Psychia-
trist, Department of Psychiatry & Behavioral Sciences, Memo-
rial Sloan-Kettering Cancer Center, 641 Lexington Avenue,
7
th
Floor, New York, NY 10022; telephone: 646-888-0026; fax:
212-888-2356; e-mail: hollandj@mskcc.org
Management of Distress
in Cancer Patients
Jimmie C. Holland, MD, and Yesne Alici, MD
Abstract Psychosocial distress is highly prevalent and diverse at all
stages of cancer care. In the early 21
st
century, screening, assessment,
and management of psychological distress in cancer patients are sup-
ported by a growing body of literature. Psychosocial care of cancer pa-
tients is now considered an essential component of quality cancer care
by the Institute of Medicine. Increasing numbers of professionals from
diferent disciplines are being trained in the United States and interna-
tionally to provide consultative services in support of the psychological
care of cancer patients. This review article highlights the psychosocial
distress experienced by cancer patients, featuring an overview of the
assessment and management of psychological distress in the context
of cancer as well as the common psychiatric disorders experienced by
cancer patients at all stages of disease.
A
ll cancer patients experience some level
of distress associated with cancer and its
treatment at all stages of the disease.
1
Stud-
ies have found that 20%40% of cancer patients
experience signicant levels of distress.
2
However,
health care professionals tend to underestimate
this psychological distress.
3
Less than 10% of can-
cer patients were reported to have been identied
and referred for mental health services.
4
Under-
recognition of distress among cancer patients
leads to several problems, including difculty in
making decisions about treatment and adherence
to treatment, extra visits to medical providers, and
greater time and stress for oncology teams.
1
Screening and early identication of distress
lead to effective management of psychological
distress, which in turn facilitates medical man-
agement.
1
There is strong evidence that psycho-
social, behavioral, and pharmacologic interven-
tions to reduce distress enhance patients ability
to adhere to treatment, which improves outcomes
in cancer care. The National Comprehensive
Cancer Network (NCCN) has developed distress
management guidelines to help clinicians identify,
evaluate, and treat distress. Psychosocial care has
been considered as an important aspect of quality
cancer care since the 2007 Institute of Medicine
(IOM) report Cancer Care for the Whole Pa-
tient: Meeting Psychosocial Health Needs,
5
now
requiring integration of psychosocial care into
routine care of cancer patients.
1

This review article presents a summary of the
assessment and management of psychological dis-
tress in the context of cancer, as well as the psy-
chiatric disorders experienced by cancer patients,
including delirium, depression, anxiety, and ad-
justment disorders.
Prevalence of Distress and Psychiatric
Disorders in Cancer Patients
The prevalence of psychological distress
among cancer patients varies by the type of can-
cer and is highest among patients with advanced
disease and a poor prognosis. The prevalence
of distress among 4,496 cancer patients was re-
ported as 35.1%, varying from a prevalence of
29.6% among patients with gynecologic cancers
to 43.4% among those with lung cancer.
6
The
needs assessment surveys performed in ambula-
tory clinics using a distress thermometer show
that 20%40% of cancer patients have signi-
cant levels of distress.
1
An increase in overall
survival rates in cancer patients of all age groups
has led to several distressing symptoms, such as
fatigue, pain, anxiety, depression, and cognitive
impairment, interfering with a persons ability to
perform daily activities.
1,6,7
The prevalence of psychiatric disorders in can-
cer patients is approximately 50%.
1,8,9
More than
two-thirds of these conditions represent adjust-
ment disorders; 10%15%, major depression;
and about 10%, delirium.
8
Inpatient studies show
a higher incidence of both depression (20%45%)
Dr. Holland is the Wayne
E. Chapman chair in
psychiatric oncology
and an attending psy-
chiatrist, Department of
Psychiatry & Behavioral
Sciences, Memorial
Sloan-Kettering Cancer
Center, New York City.

Dr. Alici is an attending
psychiatrist, Geriatric
Services Unit, Central
Regional Hospital,
Butner, North Carolina.
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Holland and Alici
and delirium (rising from 15%75% with advancing disease).
9,10

Studies of psychiatric consultation data reveal that treatable syn-
dromes, such as major depression and delirium, continue to be
underdiagnosed and undertreated, despite their high prevalence
in cancer patients.
1

NCCN Guidelines for Management of Distress
Clinical practice guidelines were established in 1999 by the
NCCN to improve the psychosocial care of cancer patients. The
NCCN guidelines for distress management have served as the
basis for the IOM report Cancer Care for the Whole Patient:
Meeting Psychosocial Health Needs, which recommends
screening for distress in all cancer patients and development
of a treatment plan with referrals to psychosocial resources as
needed.
5

The term distress was chosen by the NCCN to minimize
the stigma attached to terms such as psychiatric, psycho-
logical, or emotional. According to the NCCN guidelines,
distress in cancer patients is dened as a multifactorial un-
pleasant emotional experience of a psychological, social,
and/or spiritual nature that may interfere with the ability to
cope effectively with cancer, its physical symptoms, and its
treatment.
1
Distress, as dened by the NCCN, extends along a
continuum, ranging from normal feelings of vulnerability, sad-
ness, and fears to problems that can become disabling, such as
depression, anxiety, panic, social isolation, and existential and
spiritual crises.
1
Clinicians should recognize, monitor, and treat
distress at all stages of cancer, which requires screening for dis-
tress from the initial visit through the course of the disease and
beyond (ie, through survivorship).
Screening tools have been found to be effective and feasible
in identifying psychosocial distress in cancer patients. The
distress thermometer (DT) is an initial screening tool that is
similar to the rating scale used to measure pain: 0 (no distress)
to 10 (extreme distress). The DT serves as a single-question
screen, which identies distress from any source, even unre-
lated to cancer. The DT is accompanied by a problem list. The
35-item problem list prompts patients to identify their problems
in ve different categories: practical, family, emotional, spiri-
tual/religious, and physical.
1
Scores of 4 or higher suggest a level
of distress that has clinical signicance. The DT has been vali-
dated in patients with different types of cancer and has revealed
concordance with the Hospital Anxiety and Distress Scale
(HADS).
1,1113
The DT has shown good sensitivity and speci-
city.
13
Widespread use of the DT in outpatient settings has
helped to better integrate psychosocial and psychiatric coun-
seling into the total care of cancer patients.
1
Mild distress (a DT score of less than 4) is routinely managed
by the primary oncology team and mostly includes symptoms
such as fear, worry, and uncertainty about the future; concerns
about the illness; sadness about loss of health; anger and the
feeling that life is out of control; poor sleep, appetite, and con-
centration; preoccupation with thoughts of illness and death;
treatment effects; and side effects.
1
Most patients experience
these symptoms at the time of diagnosis and during arduous
treatment cycles. They might persist long after the completion
of treatment. The quality of the physicians communication
with the patient is most important at this juncture. When com-
munication is done well at diagnosis, the stage is set for future
positive trusting encounters.
1
All cancer patients should be in-
formed of community resources, such as support groups, tele-
conferences, and helplines. The IOM report contains a list of
national organizations and their toll-free numbers.
5

If the patients distress is moderate or severe (a DT score of
4 or more), the oncology team must determine the need for re-
ferral to a mental health professional, social worker, or spiritual
counselor, depending on the problems identied in the prob-
lem list. Common symptoms, which require further evaluation,
include excessive worries and fears, excessive sadness, despair
and hopelessness, severe family problems, and spiritual crises.
1

Patients at increased risk have a history of psychiatric disorder,
substance abuse, cognitive impairment, severe comorbid ill-
nesses, social problems, or communication barriers.
1
The mental
health professional conducts an assessment of the nature of the
distress, behavior, psychological symptoms, psychiatric history,
use of medications, control of pain and other physical symptoms,
sexuality, and capacity for decision-making.
1
Social work services are recommended for patients with pri-
marily psychosocial (eg, adjustment to illness, family conicts,
social isolation, difculties in decision-making, quality-of-life
issues, advance directives, domestic abuse, neglect, and issues
pertaining to end of life and bereavement) or practical problems
(eg, housing, food, nancial assistance, help with activities of
daily living, transportation needs; employment, school, or ca-
reer concerns; cultural or language issues; and caregiver avail-
ability). Social workers intervene by using patient and family
education support groups; suggesting available local resources;
providing counseling, and psychotherapy (including sex and
grief counseling); and making advocacy, education, and protec-
tive services available, depending on the severity and the type
of problems experienced by the cancer patient.
1
Patients should be referred for pastoral counseling when
their problems are spiritual or religious or when they request
it. The NCCN guidelines have identied the spiritual and reli-
gious concerns that require pastoral counseling, and treatment
guidelines for each have been outlined.
1
Some patients may be
referred for social work or mental health services if the problems
indicate a need for more than spiritual counseling. Patients who
experience guilt or hopelessness may also have severe depres-
sive symptoms or suicidal ideation and should be evaluated by a
psychiatrist.
1

General Principles of Treatment of Distress and
Psychiatric Disorders in Cancer Patients
The hallmark of treatment in cancer patients is therapeutic
activism with the simultaneous use of several modalities in an
aggressive attempt to provide rapid relief of symptoms.
PSYCHOSOCIAL INTERVENTIONS
Psychosocial interventions, including cognitive-behavioral
therapy (CBT), crisis intervention, problem-solving techniques,
supportive psychotherapy, and group psychotherapy, have been
6
www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGY
Management of Distress in Cancer Patients
found to be effective in reducing distress and improving the over-
all quality of life among cancer patients.
5,14

CBT involves the identication and correction of dysfunc-
tional thoughts (referred to as automatic thoughts) that lead
to anxiety, depression, or other forms of distress. In addition,
CBT utilizes relaxation techniques and problem-solving skills
to reduce distress. CBT has been proven to be effective in al-
leviating distressing psychological (anxiety, depression) and
physical (pain, fatigue) symptoms in cancer patients.
1,15,16
Behavioral techniques, such as hypnosis, relaxation, de-
sensitization, and distraction, are useful in a wide range of
situations in oncology, including the relief of anxiety related
to surgical procedures; the relief or prevention of condi-
tioned symptoms such as anticipatory nausea and vomiting
(ANV) associated with chemotherapy; and, with age-appro-
priate modication, improved management of almost all pe-
diatric problems.
17

Different forms of group psychotherapy have been evalu-
ated among cancer patients. Methodologically improved re-
search on group psychotherapy interventions has shown no
evidence of increased survival rates among cancer patients,
clarifying the earlier debates on psychotherapy and can-
cer survival.
18
However, the impact of group psychotherapy
on improved quality of life, coping skills, self-esteem, pain
management, and interpersonal relations is undeniable and
well supported by several studies.
19
Supportive-expressive
group therapy has been shown to improve psychological
symptoms, pain, and overall quality of life in patients with
metastatic breast cancer.
19
Cognitive-existential group
therapy proved to reduce psychological distress among
women with early-stage breast cancer receiving adjuvant
chemotherapy.
20
Meaning-centered group psychotherapy,
designed to help patients with advanced cancer to sustain
or enhance a sense of meaning in their lives (even as they
approach the end of life), has also proved to be effective in
reducing distress among cancer patients.
21
PSYCHOPHARMACOLOGY
As there is frequently a physiologic cause or component
to psychological symptoms, clinicians should consider an
etiologic work-up and recommend medical treatments as in-
dicated, such as correction of electrolyte abnormalities and
removal of offending drugs. However, symptomatic relief must
be provided without waiting for the results. Depressed patients
may benet from a low-dose sedating antidepressant, such as
mirtazapine, amitriptyline, or trazodone. Mildly confused or
anxious patients may benet from a low dose of an antipsy-
chotic, such as olanzapine (Zyprexa), risperidone (Risperdal),
or quetiapine (Seroquel) at bedtime. Short- to medium-acting
benzodiazepines or zolpidem (Ambien) is a good hypnotic for
intermittent use in the absence of complicating factors, such as
delirium. Given the interrelatedness of physical and psycholog-
ical symptoms, clinicians should make every attempt to man-
age commonly distressing symptoms such as nausea, vomiting,
diarrhea, dry mouth, and shortness of breath while attending
to the psychological symptoms of cancer patients.
8,17
Common Psychiatric Disorders in Cancer Patients
DELIRIUM
Delirium is the most common neuropsychiatric complica-
tion of medical illness, characterized by an abrupt onset of
disturbances of consciousness, attention, cognition, and per-
ception that tend to uctuate over the course of the day, pre-
cipitated by an underlying medical condition.
22
Delirium is fre-
quently underdiagnosed and untreated in the medical setting,
which leads to increased morbidity and mortality; interference
in the management of symptoms such as pain; longer hospital-
ization; and increased health care costs, as well as distress for
patients, caregivers, and staff.
23,24

Delirium is present in 25%85% of cancer patients, depend-
ing on the stage of illness. Although prevalence rates of delirium
range from 15%30% in hospitalized cancer patients, it is highly
prevalent during the last weeks of life (40%85%).
10,23,24

A combination of factors frequently contributes to the de-
velopment of delirium. Predisposing factors such as age, de-
mentia, functional impairment, nature and severity of illness,
and malnutrition increase the risk of experiencing delirium
during hospitalization.
24,25
For patients with advanced cancer,
delirium can be due to either the direct effects of cancer on the
CNS or the indirect CNS effects of the disease or treatments
(medications, electrolyte imbalance, organ failure, infection,
vascular complications, and preexisting cognitive impairment
including dementia).
23
Chemotherapeutic agents known to
cause delirium include methotrexate, ifosfamide, uorouracil,
vincristine, vinblastine, bleomycin, carmustine (BiCNU), cis-
platinum, asparaginase (Elspar), procarbazine (Matulane), and
corticosteroids.
23
Drug withdrawal may be a common cause of
delirium, especially in postoperative patients.
Many of the clinical features and symptoms of delirium
may also be associated with other psychiatric disorders such
as depression, mania, psychosis, and dementia. Delirium, par-
ticularly the hypoactive subtype, is often initially misdiagnosed
as depression. In distinguishing delirium from depression, par-
ticularly in the context of advanced cancer, an evaluation of
the onset and temporal sequencing of depressive and cognitive
symptoms is particularly helpful.
23
A number of scales or instruments can aid clinicians in
rapidly screening for or establishing a diagnosis of delirium,
including the Delirium Rating Scale-Revised 98 (DRS-R-98),
the Confusion Assessment Method (CAM), the Abbreviated
Cognitive Test for Delirium, and the Memorial Delirium As-
sessment Scale.
23,24

The standard approach to managing delirium in cancer pa-
tients, and even in those with advanced disease, includes a
search for underlying causes, correction of reversible causes,
and management of the symptoms of delirium through non-
pharmacologic and pharmacologic approaches.
23
A complete
physical examination should assess for evidence of sepsis,
dehydration, or major organ failure. Medications that could
contribute to delirium should be reviewed. A screen of labora-
tory parameters will allow assessment of the possible role of
metabolic abnormalities. Imaging studies of the brain and as-
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Holland and Alici
sessment of the cerebrospinal uid may be appropriate in some
cases.
23,24
Delirium is irreversible 30%40% of the time, espe-
cially in terminally ill patients. In the event that the etiology
of the delirium is unidentiable or irreversible, relief from the
distressing symptoms of delirium may be provided.
Nonpharmacologic approaches include creating a calm,
comfortable, well-lit environment; using orienting objects such
as calendars and clocks; having family members around; limiting
room and staff changes; closely monitoring nutrition, uid and
electrolyte balance; and allowing patients to have uninterrupted
periods of rest at night to improve the sleep-wake cycle.
23,25

When supportive techniques alone are not effective in con-
trolling the symptoms of delirium, pharmacologic treatment
is necessary. The choice of medication in the treatment of
delirium depends on multiple factors, including the degree of
agitation, the subtype of delirium, the available route of ad-
ministration, and concurrent medical conditions.
23,24
Antipsychotics constitute the primary pharmacologic in-
tervention (Table 1).
24
Haloperidol has been effectively used
in the treatment of delirium for many years.
24
The American
Psychiatric Association (APA) guidelines for the treatment
of delirium recommend low-dose haloperidol (ie, 12 mg PO
every 4 hours as needed or 0.250.5 mg PO every 4 hours for
the elderly) as the treatment of choice in cases where medica-
tions are necessary.
24
Lorazepam (0.51.0 mg every 12 hours
PO or IV) along with haloperidol may be effective in rapidly
sedating the agitated delirious patient and may minimize the
extrapyramidal symptoms (EPS) associated with haloperidol.
However, benzodiazepine monotherapy should be avoided
unless the delirium is due to alcohol or benzodiazepine with-
drawal. Chlorpromazine may be considered as an alternative,
especially in the ICU setting, where close blood pressure
monitoring is feasible, and in terminally ill patients for severe
agitation to decrease patient, family, and staff distress.
23,24
Atypical antipsychotics, namely risperidone, olanzapine,
quetiapine, ziprasidone (Geodon), and aripiprazole (Abilify)
are also used in the treatment of delirium.
26
Risperidone may be
started at doses ranging from 0.251 mg and titrating up as nec-
essary with attention to the risk of EPS, orthostatic hypoten-
sion, and sedation at higher doses. Olanzapine can be started
between 2.5 and 5 mg nightly and titrated up, with sedation
being the major limiting factor, which may be favorable in the
treatment of hyperactive delirium. Quetiapine can be started
at a dose of 2550 mg, with a titration up to 100200 mg daily
(usually in twice-daily divided doses). Sedation and orthostatic
hypotension are the main dose-limiting factors of quetiapine.
The data on the use of ziprasidone in the treatment of delirium
are limited due to concerns of prolongation of the QT interval,
particularly in the medically ill. Case reports suggest a start-
ing dose of 1015 mg daily for aripiprazole, with a maximum
dose of 30 mg daily.
23,26
Intramuscular (IM) formulations are
available for olanzapine, aripiprazole, and ziprasidone; however,
there are no published data on the use of parenteral forms of
atypical antipsychotics in the treatment of delirium.
The FDA has released a public health advisory on increased
risk of death related to the use of antipsychotics in the treat-
ment of behavioral disturbances of patients with dementia.
27
It is unknown whether those warnings apply to short-term use
(ie, 12 weeks) of antipsychotics in a medically ill population.
A warning about the risk of prolongation of the QT interval
and torsades de pointes with the use of IV haloperidol has also
been issued by the FDA. Therefore, monitoring for prolonga-
tion of the QT interval has become the standard of practice
while treating delirium patients with intravenous haloperidol.
28
Clinicians should attempt to use low doses of antipsychotics,
especially when treating elderly patients with delirium. How-
ever, leaving delirium untreated may impose a greater risk of
morbidity and mortality.
Psychostimulants such as methylphenidate or combinations
of antipsychotics and psychostimulants have been considered
in the treatment of the hypoactive subtype of delirium.
29
How-
ever, the evidence for the use of psychostimulants in the treat-
ment of hypoactive delirium is limited. The risks of precipitat-
ing agitation and exacerbating psychotic symptoms should be
carefully evaluated when psychostimulants are considered in
the treatment of delirium among cancer patients.
ADJUSTMENT DISORDERS
Adjustment disorders with anxiety and/or depressed mood
represent the largest group of psychiatric diagnoses found in
cancer patients. The diagnosis of cancer may invoke a normal
reaction to stress, which can affedt mood. Previously used cop-
ing mechanisms usually sufce, and patients continue with their
lives without a change in their overall functioning. Adjustment
disorder resolves when the stressor is over, but it may become
chronic, requiring medications along with counseling.
17
ANXIETY DISORDERS
Anxiety is the most common response in the setting of can-
cer. It is a normal adaptive response to a threat, but it can
become maladaptive. Anxiety is manifested by a broad array of
physical signs of autonomic activation, changes in thinking (ie,
intrusive thoughts), and behavior. The most common anxiety
disorders in cancer patients are standardized in the Diagnostic
and Statistical Manual of Mental Disorders, 4
th
edition text
revision (DSM-IV-TR).
22
The prevalence of anxiety disorders in cancer patients is
Table 1
Antipsychotics Used in the Treatment of Delirium
GENERIC NAME APPROXIMATE DAILY DOSE (mg) ROUTE
Haloperidol 0.52 mg every 212 hours PO, IV, SC, IM
Chlorpromazine 12.550 mg every 412 hours PO, IV, IM
Olanzapine
a
2.510 mg every 1224 hours PO, ODT
Risperidone
a,b
0.252 mg every 1224 hours PO, ODT
Quetiapine 12.5200 mg every 1224 hours PO
Ziprasidone 1040 mg every 1224 hours PO
Aripiprazole
a,b
530 mg every 24 hours PO, ODT
PO = oral; IV = intravenous; SC = subcutaneous; IM = intramuscular
a
Available in orally disintegrating tablet (ODT) forms
b
Available in liquid formulations
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Management of Distress in Cancer Patients
generally reported to be in the range of 10%30%. However,
the prevalence data are limited due to the use of different
scales and criteria for anxiety, a lack of prospective data, and
small study sample sizes.
30
The main clinical features and assessment of the anxiety
disorders commonly encountered in cancer patients are re-
viewed here.
Acute stress disorder involves exposure to a traumatic
event. The symptoms of stress disorder include the combina-
tion of one or more dissociative and anxiety symptoms with
avoidance of reminders of the traumatic event.
22
Having can-
cer is perceived as a life-threatening event. For patients who
have signicant psychological trauma, the fear can result in
dissociative experiences, avoidance of everything related
to cancer, nightmares, irritability, hypervigilance, and poor
concentration. When acute stress disorder lasts longer than a
month, it meets the criteria for post-traumatic stress disorder
(PTSD). The literature indicates that up to 80% of patients are
likely to experience symptoms of PTSD following cancer.
8,17,31

Generalized anxiety disorder is characterized by excessive
anxiety and worry across different settings. The worrying is dif-
cult to control, evoking fatigue, irritability, muscle tension,
and sleep dysfunction. The 6-month duration of symptoms in
the cancer setting may not be a reasonable criterion for a diag-
nosis of generalized anxiety disorder. Although careful assess-
ment of a persons psychiatric history is necessary, clinicians
may also encounter cancer patients with debilitating anxiety
symptoms that developed only after a diagnosis of cancer. Pa-
tients may worry about the prognosis or the diagnostic uncer-
tainty. They may manifest a fear of recurrence, with excessive
worry about elevated cancer markers. Patients may also worry
about their treatment, role changes, loss of income, and de-
pendency on family members.
8,17
Panic attacks are discreet episodes of intense apprehension,
fear, terror, or a sense of impending doom that peak within 10
minutes; they are associated with physical symptoms such as
chest pain, shortness of breath, choking or smothering sensa-
tions, and a fear of going crazy or losing control.
22
Panic dis-
order entails recurrent unexpected panic attacks followed by
worry, concern, and behavioral changes related to the attack.
22
Panic attacks in cancer patients may reect an exacerbation
of a preexisting panic disorder. Like depression, panic disorder
is associated with an increased risk of suicide in ambulatory
cancer patients.
32
Underlying medical causes (eg, pulmonary
emboli, pancreatic cancer) and medications (eg, glucocortico-
steroids) presenting with panic attack-like symptoms should be
ruled out, particularly in hospitalized cancer patients.
8
Specic phobias are characterized by persistent and exces-
sive fear elicited by the presence or anticipation of a specic
object or situation. Phobias of blood, needles, hospitals, MRI
machines, and radiation simulators may complicate treatment
adherence. Patients undergoing chemotherapy may have nau-
sea and vomiting. Twenty-ve to 30% of these patients were
reported to develop ANV prior to development of highly ef-
fective antiemetic regimens (eg, ondansetron, granisetron).
17

Preexisting anxiety traits, younger age, susceptibility to motion
sickness, emetic chemotherapy regimens, and abnormal taste
sensations during infusions have been found to increase the
risk of developing anticipatory nausea and anxiety among can-
cer patients.
17
Anxiety disorder due to a general medical condition (Table
2) refers to anxiety symptoms that are a direct physiologic conse-
quence of medical illnesses. Anxiety in cancer can be caused by
different medical conditions, including pulmonary embolism, hy-
poxia, hypoglycemia, and cardiac disorders. Hormone-secreting
neoplasms and paraneoplastic syndromes can also cause anxi-
ety.
17
Unrelieved pain is a common cause of anxiety in cancer
patients.
Substance-induced anxiety is a common cause of anxiety
in cancer patients. Bronchodilators, corticosteroids, and an-
tipsychotics, including some of the ones used as antiemetics
(such as metoclopramide), can simulate anxiety symptoms.
Akathisia is often mistaken for anxiety by patients and staff.
Thyroxine, psychostimulants, sympathomimetic agents, sero-
tonergic agents, antihistamines, and certain antibiotics can
also produce symptoms of anxiety. It is common for delirium to
present with early symptoms of anxiety, restlessness, and irrita-
bility; thus, delirium should be ruled out as a cause of anxiety,
especially among hospitalized cancer patients.
17
Treatment of anxiety in cancer patients depends on the eti-
ology and timing of onset of symptoms. If anxiety symptoms
Table 2
Medical Conditions Associated with Anxiety
Metabolic Hyperkalemia
Hypoglycemia
Hyponatremia
Vitamin defciencies
Cancer-related Central nervous system neoplasms
Carcinoid syndrome
Lung cancer
Endocrine Adrenal abnormalities
Thyroid abnormalities
Parathyroid abnormalities
Pituitary abnormalities
Pheochromocytoma
Cardiovascular Arrhythmia
Congestive heart failure
Myocardial infarction
Coronary artery disease
Valvular disease
Pulmonary Pulmonary embolism
Asthma/chronic obstructive pulmonary disease
Pneumothorax
Pulmonary edema
Pharmacologic/ Corticosteroids
toxic conditions Antipsychotics
Thyroxine
Sympathomimetic agents
Serotonergic agents
Antihistamines
Withdrawal states (alcohol, opioid analgesics,
sedative-hypnotics, cafeine)
Antibiotics (cephalosporins, acyclovir, isoniazid)
Other Pain
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Holland and Alici
represent premorbid psychiatric disorders, treatment should
be directed to the specic disorder. In other instances, anxi-
ety may be the consequence of a medical condition or its treat-
ment, in which case the treatment should target the underlying
condition. Medications used to treat anxiety in cancer patients
are also used in primary anxiety disorders. These medications
include benzodiazepines and antidepressants. Low-dose antip-
sychotics are an option, particularly in patients with delirium
presenting with anxiety symptoms.
17,33

Nonpharmacologic treatment involves several ap-
proaches, including different modalities of psychotherapy
(ie, interpersonal psychotherapy, supportive psychothera-
py, and CBT), education, and supportive measures. Several
behavioral methods such as progressive muscle relaxation,
breathing exercises, meditation, biofeedback, and guided
imagery have been successfully used in the treatment of
anxiety disorders among cancer patients.
17,34
DEPRESSIVE DISORDERS
Depression is a common psychiatric complication of
cancer and is an important risk factor for suicide and non-
adherence to cancer treatment.
35
Cancer patients are vul-
nerable to depression at all stages of the illness, from the
appearance of the first symptoms to the time of diagnosis,
during treatment and palliative care, and even after remis-
sion or cure. Evaluating the nature and intensity of depres-
sive symptoms is important. For clinicians, the challenge
is to identify the point when normal sadness or distress
associated with cancer has become a depressive disorder.
Recognizing the risk factors for depression through careful
attention to the signs and symptoms of depression leads to
improved recognition and treatment of depressive disor-
ders, thus increasing adherence to cancer treatment, im-
proving quality of life, and reducing serious consequences
(such as desire for hastened death and suicide).
8
Many studies have documented the prevalence of depres-
sion in cancer patients. The prevalence estimates of major
depressive disorder in cancer patients have varied widely in
different studies, from a low of 1% to a high of 50%.
9
The use
of different diagnostic measures and cutoff criteria impacts
these estimates.
9

Certain cancer sites and several chemotherapy regimens
increase the risk of depression in cancer patients.
17
A higher
prevalence of depressive disorders has been found among
patients with pancreatic, head and neck, breast, and lung
cancers, with relatively lower rates observed among patients
with lymphoma, colon, and gynecologic cancers.
36
Other
risk factors for depressive disorders include advanced dis-
ease stage and physical disability, presence of other chronic
medical illnesses, a history of depression, a family history
of depression, uncontrolled pain, poor social support, so-
cial isolation, recent experience of a significant loss, and
low self-esteem. Depression may also develop secondary
to organ failure or nutritional, endocrine, and neurologic
complications of cancer.
8,17
Diagnosis of depression is challenging in cancer patients
due to the neurovegetative symptoms that mimic many symp-
toms caused by cancer and/or its treatment, such as loss of
appetite, fatigue, sleep disturbances, psychomotor retardation,
apathy, and poor concentration. The assessment of depressive
symptoms in cancer patients should focus on the presence of
dysphoria, anhedonia, hopelessness, worthlessness, excessive
or inappropriate guilt, and suicidal ideation. The presence of
these symptoms helps to distinguish depression from cancer-
related symptoms.
Although rare, delusions or hallucinations may accompany
depression. In medically ill depressed patients, the presence of
delusions or hallucinations might be reective of a diagnosis of
delirium, which should be ruled out rst. If delusions or hal-
lucinations are present, the diagnosis of delirium precludes the
diagnosis of a depressive disorder.
17
Management of depression in cancer patients requires a
comprehensive approach that addresses evaluation, treatment,
and follow-up. The APA practice guidelines for the treatment
of depressive disorders in physically healthy individuals have
been applied to the treatment of depression in cancer patients
by the NCCN.
1
There are several pharmacologic (Table 3)
and psychotherapeutic strategies available. Prior to the selec-
tion of an appropriate treatment, the site of cancer, current
cancer treatment, comorbid medical conditions, and medica-
tions should be taken into consideration, as any of them may
contribute to depressive symptoms. Reversible conditions such
as thyroid function abnormalities should be ruled out. If the
depressive disorder is believed to be caused by a medical con-
dition or a drug, clinicians should treat the underlying condi-
tion or change the drug; however, antidepressants are usually
started concurrently to relieve patients suffering as quickly as
possible.
17

The use of antidepressants in cancer patients creates unique
challenges. A rapid onset of action is preferable in cancer pa-
tients, especially in the terminally ill; however, antidepressants
may take several weeks to have a therapeutic effect due to
their delayed onset of action.
37
An appropriate antidepressant
should be selected based on its potential side effects and drug-
drug interactions, and the patients prognosis, primary symp-
toms of depression, and comorbid conditions. Antidepressants
should be started at low doses and titrated up slowly in medi-
cally frail cancer patients, especially in the elderly.
38

Selective serotonin reuptake inhibitors (SSRIs) have be-
come the first line of treatment for depressive disorders in
the medically ill. They are efficacious and generally well tol-
erated. It is important to monitor for the possibility of drug-
drug interactions with these agents. Sertraline (Zoloft), cit-
alopram (Celexa), and escitalopram (Lexapro) have a lower
risk of drug interactions with the P450 system than other
SSRIs. Many of the SSRIs are available in liquid form, mak-
ing it easier for patients who cannot swallow pills.
38
Tricyclic antidepressants are less frequently used in cancer
patients due to their anticholinergic, antiadrenergic, and an-
tihistaminergic side effects. Their role as adjunct pain medi-
cations has become their most common indication for use in
cancer patients.
38,39
10
www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGY
Management of Distress in Cancer Patients
Bupropion, an antidepressant with dopaminergic effects,
may have a mild stimulant-like effect, which can be benecial
for cancer patients with fatigue or psychomotor retardation.
Bupropion has been associated with an increased risk of sei-
zures at higher doses, however, and thus should be used with
caution in individuals with CNS tumors or seizure disorders.
Trazodone, a postsynaptic serotonin 5-HT
2
(5-hydroxytryptam-
ine) receptor blocker, is often used as a sleep aid, rather than a
primary antidepressant, because of its main side effect of sedation.
Venlafaxine (Effexor) and duloxetine (Cymbalta), reuptake
inhibitors of serotonin and norepinephrine (SNRIs), are gen-
erally well tolerated, with a benign side-effect prole similar
to that of SSRIs. Norepinephrine reuptake inhibition may re-
sult in palpitations and hypertension; therefore, blood pressure
monitoring is recommended for patients on an SNRI. Venla-
faxine and duloxetine are preferably used for patients with co-
morbid depression and neuropathic pain due to their effects as
adjunct pain medications.
Mirtazapine acts by blocking the 5-HT
2
, 5-HT
3
, and alpha
2
2-adrenergic receptor sites. Its side effects of sedation and
weight gain are benecial for many cancer patients with in-
somnia and weight loss. It also has antiemetic properties. Mir-
tazapine is available in a dissolvable tablet form, which is par-
ticularly useful for patients who cannot swallow or who have
difculty with nausea and vomiting.
38,39
Psychostimulants are helpful to treat depressed cancer pa-
tients symptoms of fatigue, psychomotor retardation, and poor
concentration. They have a major advantage over antidepres-
sants due to their rapid onset of action, their role in relieving
fatigue, and their ability to counter opioid-related sedation.
Side effects may include anorexia, anxiety, insomnia, eupho-
ria, irritability, and mood lability. However, side effects are not
common at low doses and can be avoided by slow titration.
Hypertension and cardiac complications may occur; thus, it is
advisable to monitor cardiac function.
17,38
Several different psychotherapeutic techniques, used
Table 3
Psychotropic Medications Used in Depressive Disorders
MEDICATION STARTING DOSE DOSE RANGE COMMENTS
Antidepressants
Selective serotonin reuptake Well tolerated; citalopram, escitalopram, and sertraline seem to
inhibitors (SSRIs) have the fewest drug-drug interactions
Fluoxetine
a
1020 mg/d 1060 mg/d
Paroxetine 1020 mg/d 1040 mg/d
Citalopram
a
1020 mg/d 1040 mg/d
Escitalopram
a
510 mg/d 520 mg/d
Sertraline
a
2550 mg/d 25200 mg/d
Serotonin-norepinephrine Well tolerated; monitor blood pressure, especially at higher doses
reuptake inhibitors (SNRIs)
Venlafaxine 37.575 mg/d 37.5225 mg/d
Duloxetine 2030 mg/d 2060 mg/d
Norepinephrine-dopamine Doses higher than 300 mg/d should be divided into two daily
reuptake inhibitor doses to minimize the risk of seizures
Bupropion 75 mg/d 75450 mg/d
Tricyclic antidepressants Drug-drug interactions are more common compared with SSRIs
Secondary amines
Desipramine 2550 mg/d 25200 mg/d
Nortriptyline
a
1025 mg/d 10150 mg/d
Tertiary amines
Amitriptyline 1025 mg/d 10150 mg/d
Doxepin
a
2550 mg/d 25300 mg/d
Imipramine 1025 mg/d 10200 mg/d -2 antagonist/5-HT
2
/5-HT
3
antagonist
5-HT2/5-HT3/
2
-adrenergic antagonists
Mirtazapine 7.515 mg/d 7.545 mg/d
Psychostimulants
Methylphenidate 2.55 mg once or 530 mg/d, usually Longer-acting formulations are available; capsule forms can be
twice daily divided as twice daily sprinkled on food
Dextroamphetamine 2.55 mg once or 530 mg/d, usually Longer-acting formulations are available; capsule forms can be
twice daily divided as twice daily sprinkled in food
Wakefulness-promoting agents
Modafnil 50100 mg/d 50400 mg daily or Favorable side-efect profle
divided as twice daily
5-HT = 5-hydroxytryptamine
a
Available in liquid formulations
11
VOLUME 8, NUMBER 1

JANUARY/FEBRUARY 2010 www.SupportiveOncology.net

Holland and Alici
Table 5
Suicide in Relation to Stage of Disease
Patients at all stages of cancer
Suicidal thoughts are common and serve as a means to maintain a
sense of control over the disease.
Carrying out the act is viewed as for the future when I need to do it.
Some patients maintain a means of suicide (eg, drugs) to assure
ultimate control over feared intolerable symptoms.
Patients in remission, with a good prognosis
Serious suicidal thoughts may represent underlying psychiatric
disorders.
Such patients are unlikely to appear rational and should be treated
aggressively, including with hospitalization.
Patients with a poor prognosis and poorly controlled symptoms
Thoughts of suicide often appear rational.
Patients may request advice about physician-assisted suicide.
Patients require evaluation for the presence of treatable depression.
Attention should be paid to quality-of-life issues and comfort.
Suicidal wishes usually diminish with control of distressing symptoms.
Patients in a terminal stage
Patients may request euthanasia by lethal injection from a physician.
Such a request often refects poor quality of life, hopelessness, and
depression.
Symptoms need to be controlled.
alone or in combination with a pharmacologic interven-
tion, have been successfully employed in depressed cancer
patients. The most commonly utilized forms of psychother-
apy are supportive psychotherapy and CBT. Group therapy
can be helpful to improve social networks, connecting the
patient with others who have the same diagnosis and/or
treatment and thereby decreasing the patients sense of
isolation. Supportive-expressive and cognitive-existential
group psychotherapies have also been used successfully
among cancer patients.
14,17,19,20
Assessment and Management of
Suicidal Cancer Patients
The incidence of suicide is higher in cancer patients than
in the general population. Studies suggest that although a
small number of cancer patients commit suicide, the relative
risk of suicide in this population is twice that of the general
population.
17,40
An international population-based study from
Denmark, Finland, Norway, Sweden, and the United States
has shown an increased long-term risk of suicide, even after 25
or more years after a breast cancer diagnosis.
41
Suicide is more
likely to occur in patients with advanced cancer who have es-
calating depression, hopelessness, and the presence of poorly
controlled symptoms, particularly pain. Suicidal thoughts in
patients with advanced disease, a poor prognosis, or poorly
controlled symptoms should not be viewed as rational; such
patients may have a treatable major depressive episode precipi-
tating their suicidal ideation. Clinicians should evaluate termi-
nally ill patients with a persistent desire for death or suicidal
intention for hopelessness and a diagnosis of depression.
17,40
A history of psychiatric illness, depression, or suicide at-
tempts; recent bereavement; a history of alcohol or other sub-
stance abuse or dependence; male gender; a family history of
depression or suicide and lack of family or social support; and
recent losses are common risk factors for suicide (Table 4).
8,17

Untreated delirium may lead to unpredictable suicide attempts
due to impaired judgment and impulse control. Older patients,
individuals with head and neck, lung, breast, urogenital, gas-
trointestinal cancers, and those with myeloma seem to have an
increased risk of suicide.
8,42,43
Evaluation of suicidal thoughts should take into account the
disease stage and prognosis (Table 5).
8
It is important to recog-
nize and aggressively treat high-risk patients for depression and
address suicidal risk with psychiatric hospitalization, if neces-
sary. Maintaining a supportive relationship, controlling symp-
toms (eg, pain, nausea, depression), and involving family or
friends are the initial steps in managing a suicidal patient. One
study examining the suicidal ideation and past suicidal attempts
in adult survivors of childhood cancer found a strong correla-
tion between physical health and suicidality, which underscores
the importance of symptom control in cancer patients.
44

Early psychiatric involvement with high-risk individuals can of-
ten avert suicide in cancer patients. A careful evaluation includes
an exploration of the reasons for suicidal thoughts and the serious-
ness of the risk. Clinicians should listen empathically, without ap-
pearing critical or judgmental. Allowing patients to discuss suicidal
thoughts often decreases the risk of suicide, contrary to popular
belief. Patients often reconsider and reject the idea of suicide when
physicians acknowledge the legitimacy of their option and the
need to retain a sense of control over aspects of their death. A
competent patient rarely continues to threaten suicide or to ask
for help in dying. Patients must be given intense, ongoing support,
including open discussions about treatment options. Medical staff
and family may need to be reminded of the competent patients
right to refuse all treatments, even lifesaving ones.
17
Table 4
Suicide Risk Factors in Cancer Patients
Depression
Hopelessness
Uncontrolled pain
Extreme fatigue
Anxiety
Delirium
Substance abuse or dependence
Feeling alone in the world
Objective lack of social support
Stressful family relations
Intolerance of loss of control, dependence, and loss of dignity
Severe fnancial problems
History of depression and suicide attempts
Positive family history
History of severe trauma
Presence of active statements and plans
Personality disorder
12
www.SupportiveOncology.net THE JOURNAL OF SUPPORTIVE ONCOLOGY
Management of Distress in Cancer Patients
Conclusion
Psychosocial care of cancer patients is an integral part of
quality cancer care. It is important to screen all cancer patients
for distress, identify patients at risk, and recognize and manage
psychosocial distress and common psychiatric disorders. Fur-
ther research is called for to improve assessment and treat-
ment of distress and psychiatric syndromes in the context of
cancer, especially among understudied patient populations
(eg, children, the elderly, and members of minority groups)
and to advance our ability to integrate basic science insights
into clinical practice.
Conicts of interest: None to disclose
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