Overview

This evidence report on Management of Cancer

Symptoms: Pain, Depression, and Fatigue was

produced on request from the Office of Medical

Applications of Research (OMAR) at the

National Institutes of Health (NIH) for a Stateof-the-Science Conference.

Despite dramatic advances in cancer biology

and a widening array of treatment options, cancer

continues to cause devastating suffering not only

to hundreds of thousands of patients who die of it

each year in the United States, but also to some

patients who are successfully treated and become

cancer survivors. Pain, depression, and fatigue are

prominent contributors to suffering in many of

these individuals. Clinical research on these

symptoms holds out the hope of relief for

suffering through better understanding of these

symptoms and the development of new, more

effective treatments.

Reporting the Evidence

The State-of-the-Science Conference planning

committee acknowledged that many symptoms

are relevant to the care of cancer patients, but

because the current conference can address only a

limited number of topics, pain, depression, and

fatigue were selected as the focus. The planning

committee identified prevalence, assessment, and

treatment as the key issues to be addressed for

each of the three chosen symptoms. The

following questions were formulated by the

conference planning committee:

• What is the occurrence of pain, depression,

and fatigue, alone and in combination, in

people with cancer?

• What are the methods used for clinical

assessment of these symptoms throughout

the course of cancer and what is the evidence

for their reliability and validity in cancer

patients?

• What are the treatments for cancer-related

pain, depression, and fatigue, and what is the

evidence for their effectiveness?

• What are the impediments to effective

symptom management in people diagnosed

with cancer, and what are optimal strategies

to overcome these?

• What are the directions for future research?

The symptoms and issues identified by the

planning committee create nine distinct topics,

several of which are very broad in nature and

encompass interrelated issues. Addressing each of

the nine topics fully is beyond the scope of this

evidence report. This report is structured

according to the following topics:

• Prevalence of cancer-related pain

• Prevalence of cancer-related depression

• Prevalence of cancer-related fatigue

• Assessment of cancer-related pain

• Assessment of cancer-related depression

• Assessment of cancer-related fatigue

• Treatment of cancer-related pain

• Treatment of cancer-related depression

• Treatment of cancer-related fatigue

For some of these topics, in particular the

treatment of cancer pain, there are multiple

questions. The Evidence-based Practice Center

(EPC) produced the evidence report on the

Management of Cancer Pain based on a literature

search conducted in December 1998. For the

cancer-related pain topics, the results for the key

questions addressed in the prior EPC report have

been thoroughly updated. At the request of the

conference planning committee, two new topics

were added to the treatment of cancer-related

pain: oral mucositis and post-herpetic neuralgia.

Evidence Report/Technology Assessment

Number 61

Management of Cancer Symptoms: Pain, Depression,

and Fatigue

Summary

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES • Public Health Service

Agency for Healthcare Research and Quality
The methodological approach is summarized and the new

evidence reported. Readers are referred to the earlier evidence

report for detailed information about the methodological

approach and the findings. New systematic reviews are also

included for the symptoms of cancer-related depression and

cancer-related fatigue.

Methodology

Patient Population and Settings

The EPC accepted all studies published in English of

patients with a diagnosis of cancer who suffered from pain,

depression, or fatigue due to cancer or treatment of cancer. It

placed no restrictions on the patients’ age, gender, ethnicity,

level of advancement of the primary disease (staging), or

presence of metastases. The conference planning committee

was interested in covering the full trajectory of disease,

including but not limited to, periods of active treatment and

end of life.

Literature Search

Literature searches were conducted to identify studies

published between 1966 and 2001 in MEDLINE®,

CANCERLIT®, and the Cochrane Controlled Trials Registry.

For cancer pain, the EPC applied the same search strategy

used in its previously published Management of Cancer Pain

evidence report to identify new studies published in the period

from December 1998 through June 2001. The National

Library of Medicine, as a partner in the NIH Consensus

Development Conference process, with input from the EPC

staff, performed the literature search for cancer-related

depression and cancer-related fatigue. The searches were

supplemented with reviews of bibliography of selected

references. The EPC also identified published meta-analyses

and used their data for selected topics.

Study Selection

Only studies that assessed the prevalence of the symptom as

the primary purpose of the study were used for estimating the

prevalence of cancer-related symptoms. For assessment, both

retrospective and prospective studies were used, as well as

randomized and nonrandomized trials, and cross-sectional and

longitudinal studies. Randomized controlled trials were used to

analyze efficacy of interventions.

Reporting the Results

The nine topics addressed in this evidence report are

presented in the order of prevalence, assessment, and

treatment. Each of these issues covers the symptoms of pain,

depression, and fatigue. Evidence is summarized using three

complementary approaches. Evidence tables provide detailed

information about the characteristics and outcomes of all the

studies examined. Information from the evidence tables is

synthesized into summary tables describing the findings of

each study. A narrative description of the studies along with an

evidence-grading scheme accompanies the summary tables.

Findings

Prevalence of Cancer-related Pain

Surveillance data on the incidence and prevalence of cancer

and observational and survey data on the incidence of cancerrelated pain indicate that a majority of patients experience pain

at some point during their course of treatment, and that

cancer pain impairs quality of life and functionality. This

disturbing finding reflects data from developed countries,

where patients are often in tertiary care or specialist

consultative settings. The likelihood of pain increases, as does

its severity, with advancing cancer stage. (Minorities, women,

and the elderly may be at greater risk for undertreatment of

cancer pain.) Pain is generally not eliminated, despite

analgesic therapy administered according to the World Health

Organization method for cancer pain relief, and may continue

to be a problem even after eradication of the underlying

neoplasia. Multiple processes underlie cancer-related pain, yet

survey data for the most part do not distinguish between

different etiologies and mechanisms, nor do they provide a

comprehensive picture of pain over the continuum of care, nor

of the relationship between effectiveness of pain control and

quality of life. The number of patients enrolled in

methodologically sound trials of cancer pain relief is a small

fraction of those receiving care. 

Prevalence of Cancer-related Depression

Major depression and depressive symptoms occur frequently

in patients with cancer. Despite standardized measures to

calculate incidence and prevalence, there is a wide range of

reported data. Prevalence rates varied from 10 to 25 percent

for major depressive disorders and a similar range exists for

clinically significant depressive symptoms. This range is the

probable result of several factors that include timing of the

assessment, concurrent treatment, medical morbidity, and

pain, gender, and age. Cancer patients are a heterogeneous

population with different sociodemographics, cancer types,

treatments, and responses to treatment. Given that the

estimated point prevalence of major depression in the general

population is 2.2 percent, the rates in cancer patients may be

at least four times greater.

During the time frame of the studies, reports of incidence

ranged widely from about 2 to 17 percent. However, these

studies like other prevalence studies face the same difficulties

of heterogeneous populations, and there are too few

naturalistic studies that follow patients from the point of

diagnosis and few that serially measure depression.

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Prevalence of Cancer-related Fatigue

Estimations of fatigue prevalence have been performed in

the setting of many types of cancer treatment, in the palliative

setting, and among cancer survivors, but the data is by no

means consistent or comprehensive. Many types of cancer

were not specifically addressed.

A very broad range of prevalence rates has been reported,

from 4 percent in breast cancer prior to starting chemotherapy

and 8 percent in prostate cancer prior to radiation therapy, to

91 percent in breast cancer patients after surgery and

chemotherapy and before bone marrow transplantation.

Findings of significant concern were the prevalence rates of

fatigue in cancer survivors: 26 percent in Hodgkin’s disease

survivors; 35 to 56 percent in breast cancer survivors; and 48

percent in a cohort treated for various cancers. Comparisons of

the prevalence rates in these studies are problematic, however,

since each study used different criteria for defining the

presence or absence of fatigue and its severity.

Assessment of Cancer-related Pain

Many types of instruments are applied to assess pain and

related analgesic outcomes. In 218 trials, 125 distinct tools

were employed. By far the most frequently employed were

unidimensional scales of pain intensity, followed by scales of

pain relief, then measures of peak or summed pain intensity

differences between experimental and control groups. Other

tools applied in the selected studies include global evaluations

of efficacy and the McGill-Melzack pain questionnaire. Also

applied were measures of analgesic consumption and a fourpoint side effect scale. Descriptions of the need for detailed

assessment conducted within a psychosocial framework are

presented in virtually all guidelines or monographs on cancer

pain management. A voluminous literature describes the

multidimensional, experiential nature of cancer pain and links

poor control of cancer pain to impaired quality of life,

including functionality. Current expectations for detailed,

multidimensional assessment of cancer pain, including quality

of life assessment, during cancer care contrast with the

minimalist assessments of pain intensity presented during

relatively brief observation intervals reported in nearly all of

the trials. Side effects limit analgesic dosage and hence impede

pain control in many patients, yet only one of the 16 most

widely employed outcomes measures is concerned with side

effects; that one is a coarse, four-point measure.

Assessment of Cancer-related Depression

Because depression may go undetected and thereby

untreated in oncology practice, the importance of appropriate

assessment and screening tools has been emphasized. Some

assessments, like the Structured Clinical Interview for the

Diagnostic and Statistical Manual of Mental Disorders

(SCID), may be useful in research studies, but they are too

time consuming in a clinical setting. Briefer self-report

assessments are available for clinical use. These assessments

range from questionnaires to The Distress Thermometer, a

visual analogue scale that the National Comprehensive Cancer

Network (NCCN) guidelines suggest for the screening of

psychosocial distress. 

While the standard of care for diagnosing depression is a

clinical interview, available data on the sensitivity, specificity,

predictive values, and cross-correlations of assessment

instruments are presented in the evidence-based table. 

Although these assessment tools may be valid, there is

currently no evidence on how widely they are used clinically or

whether they affect clinical care and outcomes.

Assessment of Cancer-related Fatigue

A wide array of patient self-assessment instruments has been

used to evaluate fatigue. Most studies in the last several years

have used instruments that assess multiple dimensions of

fatigue and have been tested for validity, consistency, and

reliability. Issues still remain in terms of the clinical

interpretation of the scores obtained on these instruments, and

the comparison of fatigue measurements obtained using

different instruments. Methods for evaluating fatigue in

practice settings have not been the subject of extensive

research. The NCCN has published guidelines on cancerrelated fatigue that include a general approach to assessment of

fatigue in clinical practice. This approach is based on the

experience of a panel of experts rather than on evidence from

randomized controlled trials.

Treatment of Cancer-related Pain

Direct inter-class comparisons of efficacy do not

differentiate between the relative efficacy of opioids and

NSAIDs administered through various routes to patients with

mild, moderate, or severe cancer pain. Opioid dose-sparing is

achieved by co-administration of NSAIDs but without a

consistently demonstrable reduction in side effects. The

heterogeneity of existing trials precludes meta-analyses to

address most subquestions. A difference in analgesic efficacy

between NSAIDs was only evident in a single retrieved trial.

Likewise, the efficacy of NSAIDs versus “weak” opioids could

not be discerned in the retrieved trials. However, such trials

enroll relatively small numbers of patients and follow them for

intervals of hours to days, and only occasionally as long as 2

weeks. Many examine drugs not available in the United States

or no longer in general use for cancer pain relief (e.g.,

pentazocine). Prior efforts described in the previous evidence

report to strengthen such evidence by examining

nonrandomized trials were not fruitful. One randomized

controlled trial evaluated oral transmucosal fentanyl citrate for

breakthrough pain (using a study design in which rescue doses

of morphine were available) and demonstrated its superiority

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to placebo. Another randomized study in ambulatory cancer

patients provided evidence for greater analgesia and faster

onset of relief after oral transmucosal fentanyl citrate than after

the usual rescue drugs used by these patients. The EPC found

no randomized controlled trials addressing analgesic efficacy

and safety of NSAIDs selective for the cyclooxygenase-2

isozyme in treating cancer pain. The use of bisphosphonates

and radiation therapy are both supported by the retrieved

trials. Unfortunately, studies that point to the optimal

sequence of application of the many currently available

interventions for pain control were not identified.

Treatment of Cancer-related Depression

Current evidence shows that psychosocial interventions are

beneficial for depressive symptoms in cancer patients, but the

magnitude of the effect size seems to be in the mild to

moderate range. Because there are hundreds of studies on

psychosocial interventions in cancer patients, we limited our

analysis to published meta-analyses of these studies. Here, the

contribution of preventative studies and depression treatment

studies were not defined. The effects of these interventions

may vary in these two different kinds of studies.

Although not all pharmacologic studies showed benefit for

depression in cancer patients, every study that used

antidepressants and conformed to usual practices for

antidepressant trials did. Since antidepressants typically can

take 4 to 6 weeks for their full effect, studies of antidepressants

under 6 weeks tended to show less benefit. Currently, there is

data that selective serotonin reuptake inhibitors (SSRIs) and

tricyclic antidepressants are effective. Although trazodone, an

atypical antidepressant, showed some benefit in treating

depressive symptoms, it is not commonly used as an

antidepressant because of severe sedation at therapeutic doses.

Although there have been reports describing alternative or

complementary therapy programs, there have been no

controlled trials for their efficacy for depression in people with

cancer.

Treatment of Cancer-related Fatigue

A limited number of controlled clinical trials of treatment

for cancer-related fatigue have been published. The only

treatment supported strongly by the available clinical evidence

is the use of epoetin alfa in patients with anemia due to

chemotherapy treatment. A few controlled trials evaluated

exercise programs, in some cases with promising but

preliminary results. Some positive outcomes have also been

reported with psychosocial interventions.

Treatment trials for cancer-related fatigue usually have small

sample sizes, and there is a possibility that many of these

studies were underpowered to detect the outcome of interest.

Future Research

Cancer-related Pain

Randomized controlled trials establish that many current

treatment modalities can individually reduce cancer pain. The

scientific evidence on cancer pain relief, however, compares

unfavorably with the massive amount of information known

about the efficacy and effectiveness of treatments for other

high-impact conditions, including cancer itself. Quality of life

has not been uniformly assessed in trials of analgesic drugs and

non-drug interventions for cancer pain. Limited evidence from

the retrieved trials demonstrates that optimal analgesia benefits

quality of life. Advances in quality-of-life assessment and

insights from research on chronic non-cancer pain into

relationships between pain, disability, and impairment offer

the opportunity to begin to understand these interactions in

the context of cancer pain. Carefully designed trials with

cancer pain relief as a primary outcome are required in patients

with well-defined disease and pain mechanisms. Such trials

must conform to rising expectations for clinical trials in

general. High-quality trials of cancer pain relief should enroll

greater numbers of patients for longer intervals than has

generally been true in the past; apply blinding and active

placebos when appropriate, or uniform control treatments

otherwise; employ adequate between-arm washout intervals

and consider advancing disease state in crossover trials; and

assess side effects, pain mechanisms, and rest, incident, or

breakthrough pain in a standardized, combinable fashion.

Investigations of cancer pain and its control should seek to

evaluate the influence of gender, race, age, psychosocial

context, ethnicity, and culture on the experience and report of

pain. The influence of such factors should also be examined

during studies aimed at defining the efficacy of specific

treatments and their associated side effects. Drug interactions

during long-term cancer pain treatment require clarification. It

is unclear whether a mechanism-based approach to diagnosing

and relieving each component of pain in an individual is more

effective than an empiric regimen in which each patient’s

treatment is based upon pain intensity alone. Another key

unanswered question is how to optimally combine drug with

non-drug therapies, given that the latter are safe and

inexpensive. Despite the importance of pediatric cancer pain

control, practically no analgesic drug trials focus on children. 

Data that address individual variations in preferences for,

responses to, and costs incurred by these options are a

foundation for potential evidence-based approaches to cancer

pain control, but are sparse. For example, the spinal route of

analgesia is widely employed but much remains to be learned

about optimal patient selection, the comparative efficacy of

spinal drug infusion versus systemic drug administration, and

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the selection of initial or secondary agents or combinations.

Exploring these fundamental questions will enhance the ability

of translational clinical research to clarify the clinical relevance

of an increasing number of basic insights into unique

mechanisms and mediators of cancer pain.

Cancer-related Depression

There is much variance in the literature on reports of rates

of depression in cancer patients. Even when standardized

instruments are used, wide variance is still observed. One

recommendation would be to conduct more prevalence studies

that examine the reasons for such variance and contributing

factors for differing rates. The timing of measurements of

depressive symptoms does appear to be important and may

contribute to the variance. One goal may be to develop a

statistical model that could predict the rate of depression given

the cancer and treatment demographics of the population.

Studies should always include assessment of past histories of

depression.

The existing incidence studies of depression in patients with

cancer all start at some time after the diagnosis of cancer. It is

recommended that more prospective studies start at the time

of diagnosis, or even before, in order to arrive at more accurate

estimates of the incidence of depression once people are

diagnosed with cancer. These studies should also assess past

histories of depression.

There are many instruments currently in use for assessing

depression in cancer patients. Researchers can select from a

variety of instruments based on weighing the ease of use for

their study population and the effectiveness of an individual

instrument as documented in the evidence tables. There

should be further trials to replicate the promising results of a

single-item screening, asking, “Are you depressed?”

Although some of these instruments are widely used in

clinical practice, further research on their effectiveness is

needed. The development of brief instruments that assess all

three symptoms (depression, pain, and fatigue) could be one

area of future research.

Psychopharmacologic, psychosocial, and alternative

interventions offer some benefit on treatment for depressive

symptoms with cancer patients. There are great opportunities

for research on psychopharmacologic interventions for

depression co-morbid with cancer. The newer antidepressants,

especially the atypical ones, need to be studied in this

population. Although antidepressant trials are more

complicated to conduct in cancer patients, they should still

adhere to a standard study length of 6 weeks or greater.

Common clinical practices, such as the use of

psychostimulants for depression, need to be evaluated in

controlled trials. There should also be more research on the use

of antidepressants for the prevention of depressive symptoms

in patients with cancer.

Hundreds of studies exist on psychosocial interventions for

cancer patients and depression, but a meta-analysis of

psychosocial therapies specifically for the treatment of

depression in cancer patients remains to be done. Although

many patients may be using complementary and alternative

treatments, controlled trials are required to determine their

efficacy in depression co-morbid with cancer.

Cancer-related Fatigue

Future research in cancer-related fatigue should also include

more comprehensive studies of the prevalence of fatigue in a

wider variety of diseases and settings. Longitudinal studies are

needed. Useful prevalence data can potentially be extracted

from studies of health-related quality of life, general symptom

surveys and treatment trials. However, methods to compare

results from studies that employ different assessment

instruments must be devised. Additional research is needed to

elucidate the clinical significance of the fatigue scores obtained

using these instruments.

There is sufficient preliminary evidence to support

randomized controlled trials of several interventions for

cancer-related fatigue, including exercise programs,

psychosocial interventions, and stimulant medications. Further

laboratory research and observational studies on the physiology

of cancer-related fatigue are needed in order to generate

rational hypotheses for future intervention trials. Clinical trials

for cancer-related fatigue need to utilize appropriate study

designs, including the prospective identification of outcomes

of interest and sample sizes calculated to provide a reasonable

likelihood of detecting those outcomes.

For all of the topics examined in this evidence report, there

is a paucity of studies in the pediatric population, and research

is urgently needed to address the symptoms of pain,

depression, and fatigue in children.

Availability of the Full Report

The full evidence report from which this summary was

taken was prepared for the Agency for Healthcare Research

and Quality (AHRQ) by the New England Medical Center

Evidence-based Practice Center (EPC), Boston, MA, under

contract number 290-97-0019. It is expected to be available in

summer 2002. At that time, printed copies may be obtained

free of charge from the AHRQ Publications Clearinghouse by

calling 800-358-9295. Requesters should ask for Evidence

Report/Technology Assessment No. 61, Management of Cancer

Symptoms: Pain, Depression, and Fatigue. In addition, Internet

users will be able to access the report and this summary online

through AHRQ’s Web site at www.ahrq.gov.

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AHRQ Pub. No. 02-E031

July 2002

ISSN 1530-440X